TW202220970A - Compounds and methods of use - Google Patents

Compounds and methods of use Download PDF

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TW202220970A
TW202220970A TW110128222A TW110128222A TW202220970A TW 202220970 A TW202220970 A TW 202220970A TW 110128222 A TW110128222 A TW 110128222A TW 110128222 A TW110128222 A TW 110128222A TW 202220970 A TW202220970 A TW 202220970A
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heterocyclyl
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凱文 Ｍ 可特瑞爾
強恩 Ｐ 麥斯威爾
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美商譚格醫療公司
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Abstract

Compounds are provided according to Formula (I):
Figure 110128222-A0202-11-0001-1097
 and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1 , R2 , R3 , R4 , R6 , R7 , R8 and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

Description

化合物及使用方法Compounds and methods of use

癌症治療劑可以廣泛分成兩個類別，細胞毒性療法及靶向療法。儘管細胞毒性療法與廣泛毒性相關，而靶向療法具有依賴於其受質活性而選擇性靶向腫瘤細胞之優點。已分別以BCR/ABL及EGFR治療劑治療CML及非小細胞肺癌證實了靶向療法之臨床功效。這些計劃之成功促進了特異性靶向經擴增或突變活化之致癌基因之其他療法的開發。更大的挑戰為開發出靶向具有功能喪失型突變或腫瘤抑制基因缺失之腫瘤的選擇性療法，該等基因之損失排除了分子靶向治療劑之傳統策略。Cancer therapeutics can be broadly divided into two categories, cytotoxic and targeted therapies. While cytotoxic therapies are associated with a wide range of toxicities, targeted therapies have the advantage of selectively targeting tumor cells depending on their receptor activity. The clinical efficacy of targeted therapy has been demonstrated in the treatment of CML and non-small cell lung cancer with BCR/ABL and EGFR therapeutics, respectively. The success of these programs has led to the development of other therapies that specifically target amplified or mutationally activated oncogenes. A greater challenge is to develop selective therapies that target tumors with loss-of-function mutations or deletions of tumor suppressor genes that preclude traditional strategies of molecularly targeted therapeutics.

由如癌症基因體圖譜(Cancer Genome Atlas，TCGA)之組引導之表徵癌症基因體的工作在藉由引起腫瘤抑制基因之損失來闡明促進腫瘤生長的缺失事件之大小及頻率方面取得了極大進步。然而，這些事件通常為區域性的且引起其預期靶標附近基因之共同缺失。儘管不知道這些意外事件(passenger event)是否引起適應優勢，但其可引起附帶缺陷，該等附帶缺陷可經治療性加槓桿。一個實例為藉由甲硫腺苷磷酸化酶(MTAP)之損失賦予之PRMT5抑制的附帶缺陷，該酶頻繁與經充分描述之腫瘤抑制基因CDKN2A 共同缺失(Kruykov等人，2016；Marjon等人，2016及Markarov等人，2016)。Efforts to characterize cancer genomes, led by groups such as the Cancer Genome Atlas (TCGA), have made great strides in elucidating the magnitude and frequency of deletion events that promote tumor growth by causing loss of tumor suppressor genes. However, these events are often regional and cause co-deletion of genes near their intended targets. Although it is not known whether these passenger events give rise to adaptive advantages, they can give rise to collateral deficits that can be leveraged therapeutically. An example is the collateral defect in PRMT5 inhibition conferred by loss of methylthioadenosine phosphorylase (MTAP), which is frequently co-deleted with the well-described tumor suppressor gene CDKN2A (Kruykov et al., 2016; Marjon et al., 2016 and Markarov et al., 2016).

在所有人類癌症中約10-15%發生CDKN2A 之損失，且在組織學中十分頻繁，諸如惡性周邊神經鞘瘤、神經膠質母細胞瘤、間皮瘤、膀胱尿路上皮癌、食道鱗狀細胞癌、胰臟腺癌、黑素瘤、非小細胞肺癌、頭頸癌及膽管癌(cholangiosarcoma)(Gao等人Sci.Signal. 2013；Cerami等人Cancer Discov. 2012； 及Marjon等人Cell Reports 2016)。由於與染色體9p21上的CDKN2A 相鄰，所以MTAP 頻繁包括在缺失中。MTAP為甲硫胺酸再利用路徑之關鍵酶，甲硫胺酸再利用路徑為從多胺合成產物甲基硫腺苷(MTA)再循環甲硫胺酸的六步過程。MTAP之損失引起其受質MTA累積，該受質已由多個組證實了起SAM競爭性PRMT5抑制劑的作用(Kruykov等人，2016；Marjon等人，2016；及Markarov等人，2016)。Loss of CDKN2A occurs in approximately 10-15% of all human cancers and is very frequent in histology such as malignant peripheral schwannoma, glioblastoma, mesothelioma, bladder urothelial carcinoma, esophageal squamous cell carcinoma, pancreatic adenocarcinoma, melanoma, non-small cell lung cancer, head and neck cancer, and cholangiosarcoma (Gao et al . Sci. Signal. 2013; Cerami et al. Cancer Discov. 2012; and Marjon et al. Cell Reports 2016) . MTAP is frequently included in deletions due to its proximity to CDKN2A on chromosome 9p21. MTAP is a key enzyme in the methionine reuse pathway, which is a six-step process of recycling methionine from polyamine synthesis product methylthioadenosine (MTA). Loss of MTAP leads to accumulation of its substrate MTA, which has been shown by multiple groups to function as a SAM-competitive PRMT5 inhibitor (Kruykov et al., 2016; Marjon et al., 2016; and Markarov et al., 2016).

PRMT5為藉由使參與轉錄及傳訊之蛋白質對稱二甲基化來調控必需細胞功能的II型精胺酸甲基轉移酶，該等功能包括調控細胞週期進展、細胞凋亡及DNA損害反應(Koh,Bezzi及GuccioneCurr Mol Bio Rep 2015以及Wu等人Nat Rev Drug Discovery 2021)。然而，使用shRNA自全基因體基因攝動篩選得到之資料揭示了在MTAP 缺失癌細胞株中對PRMT5活性之選擇性要求(Kruykov等人，2016；Marjon等人，2016；及Markarov等人，2016)。在這些細胞株中由MTAP 缺失引起之MTA累積部分抑制PRMT5，從而使那些細胞對額外PRMT5抑制選擇性敏感。PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions including regulation of cell cycle progression, apoptosis, and DNA damage responses by symmetrically dimethylating proteins involved in transcription and signaling (Koh , Bezzi and Guccione Curr Mol Bio Rep 2015 and Wu et al Nat Rev Drug Discovery 2021). However, data from genome-wide gene perturbation screening using shRNA revealed a selective requirement for PRMT5 activity in MTAP- deficient cancer cell lines (Kruykov et al., 2016; Marjon et al., 2016; and Markarov et al., 2016 ). MTA accumulation caused by MTAP deletion in these cell lines partially inhibited PRMT5, thereby selectively sensitizing those cells to additional PRMT5 inhibition.

已開發了PRMT5抑制劑，但它們並未證實對MTAP缺失癌細胞株之選擇性。此選擇性缺乏可藉由抑制劑之作用機制來解釋，因為它們為SAM無競爭性或SAM競爭性抑制劑，且因此為MTAP不可知的(MTAP-agnostic)(Kruykov等人，2016；Marjon等人，2016及Markarov等人，2016)。然而，若開發了藉由以MTA無競爭性、非競爭性或混合模式方式藉或以MTA協作結合方式進行結合來對MTA累積加槓桿的PRMT5抑制劑，則其可證實對MTAP缺失腫瘤細胞之選擇性。PRMT5 inhibitors have been developed, but they have not demonstrated selectivity for MTAP-deficient cancer cell lines. This lack of selectivity can be explained by the mechanism of action of the inhibitors, as they are either SAM-uncompetitive or SAM-competitive inhibitors and therefore MTAP-agnostic (Kruykov et al., 2016; Marjon et al. Man, 2016 and Markarov et al., 2016). However, if a PRMT5 inhibitor were developed that leveraged MTA accumulation by binding in an MTA-uncompetitive, non-competitive, or mixed-mode manner, or in an MTA-cooperative binding manner, it would demonstrate the ability to inhibit MTAP-deficient tumor cells. Optional.

在本發明之一個態樣中，提供了一種式(I)化合物或其醫藥學上可接受之鹽； 其中：In one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof; in:

Figure 110128222-A0202-12-0003-1100
各R1 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa1 、-N(Ra1 )2 、-C(=O)Ra1 、-C(=O)ORa1 、-NRa1 C(=O)Ra1 、-NRa1 C(=O)ORa1 、-C(=O)N(Ra1 )2 、-OC(=O)N(Ra1 )2 、-S(=O)Ra1 、-S(=O)2 Ra1 、-SRa1 、-S(=O)(=NRa1 )Ra1 、-NRa1 S(=O)2 Ra1 及-S(=O)2 N(Ra1 )2 ；各R2 獨立地選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)ORa2 、-NRa2 C(=O)Ra2 、-NRa2 C(=O)ORa2 、-C(=O)N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )、-OC(=O)N(Ra2 )2 、-S(=O)Ra2 、-S(=O)2 Ra2 、-SRa2 、-S(=O)(=NRa2 )Ra2 、-NRa2 S(=O)2 Ra2 及-S(=O)2 N(Ra2 )2 ；各R3 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa3 、-N(Ra3 )2 、-C(=O)Ra3 、-C(=O)ORa3 、-NRa3 C(=O)Ra3 、-NRa3 C(=O)ORa3 、-C(=O)N(Ra3 )2 、-OC(=O)N(Ra3 )2 、-S(=O)Ra3 、-S(=O)2 Ra3 、-SRa3 、-S(=O)(=NRa3 )Ra3 、-NRa3 S(=O)2 Ra3 及-S(=O)2 N(Ra3 )2 ；各R4 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa4 、-N(Ra4 )2 、-C(=O)Ra4 、-C(=O)ORa4 、-NRa4 C(=O)Ra4 、-NRa4 C(=O)ORa4 、-C(=O)N(Ra4 )2 、-OC(=O)N(Ra4 )2 、-S(=O)Ra4 、-S(=O)2 Ra4 、-SRa4 、-S(=O)(=NRa4 )Ra4 、-NRa4 S(=O)2 Ra4 及-S(=O)2 N(Ra4 )2 ； 各R6 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代；各R7 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 羥基烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、5-6員單環雜芳基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa7 、-N(Ra7 )2 、-C(=O)Ra7 、-C(=O)ORa7 、-NRa7 C(=O)Ra7 、-Na7 C(=O)ORa7 、-C(=O)N(Ra7 )2 、-OC(=O)N(Ra7 )2 、-S(=O)Ra7 、-S(=O)2 Ra7 、-SRa7 、-S(=O)(=NRa7 )Ra7 、-NRa7 S(=O)2 Ra7 及-S(=O)2 N(Ra7 )2 ；各R8 獨立地選自H、-D、=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa8 、-N(Ra8 )2 、-C(=O)Ra8 、-C(=O)ORa8 、-NRa8 C(=O)Ra8 、-NRa8 C(=O)ORa8 、-CH2 C(=O)N(Ra8 )2 、-C(=O)N(Ra8 )2 、-OC(=O)N(Ra8 )2 、-CH2 C(=O)N(Ra8 )2 、-S(=O)Ra8 、-S(=O)2 Ra8 、-SRa8 、-S(=O)(=NRa8 )Ra8 、-NRa8 S(=O)2 Ra8 及-S(=O)2 N(Ra8 )2 ，其中R8 之兩個實例連同其所連接之一或多個原子可一起形成3-10員環烷基或雜環基環(例如，連同結構I之哌啶環可以形成橋聯、稠合或螺雙環雜環的環)各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地選自H、C1 -C6 烷基、-C1 -C6 雜烷基、C3 -C9 環烷基、3-7員雜環基、環烷基烷基、雜環基烷基、芳基、5-6員雜芳基、芳基烷基及雜芳基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代(例 如， 經R9 之0、1、2或3個實例取代，其中各R9 獨立地選自=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、-ORb 、-N(Rb )2 、-C(=O)Rb 、-C(=O)ORb 、-NRb C(=O)Rb 、-NRb C(=O)ORb 、-C(=O)N(Rb )2 、-OC(=O)N(Rb )2 、-S(=O)Rb 、-S(=O)2 Rb 、-SRb 、-S(=O)(=NRb )Rb 、-NRb S(=O)2 Rb 及-S(=O)2 N(Rb )2 ，其中各Rb 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)；且n為0、1、2或3前提條件為：(i)當R1 為H時，R2 不為鹵基、-OPr、-N(CH3 )2 或-CF3 ；(ii)當R1 為ORa1 時，R2 不為-ORa2 ；(iii)當R1 為H且R2 為-CH3 時，R8 基團不可一起形成環且R6 並非不存在或為H，且不為噻唑基、呋喃基或吡咯基；(iv)當R2 為Me時，R1 不為視情況經取代之哌啶(v)該化合物不為：(A)5-(2-(5-甲基-2-(對甲苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺或其任何鏡像異構物或非鏡像異構物；(B)2-(2-(4-(2H-四唑-5-基)苯基)-5-甲基哌啶-1-基)-N-(5,6-二甲基吡啶-3-基)-2-側氧基乙醯胺或其任何鏡像異構物或非鏡像異構物；(C)2-氰基-5-(2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺或其任何鏡像異構物或非鏡像異構物。
Figure 110128222-A0202-12-0003-1100
 Each R 1 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)(=NR a1 ) R a1 , -NR a1 S(=O) 2 R a1 and -S(=O) 2 N(R a1 ) 2 ; each R 2 is independently selected from halo, -CN, -C 1 -C 6 alkyl , -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, Heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O) OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )( R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 ) R a2 , -NR a2 S(=O) 2 R a2 and -S(=O) 2 N(R a2 ) 2 ; each R 3 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclyl alkyl , heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(= O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 and -S(=O ) 2 N(R a3 ) 2 ; each R 4 is independent Stereally selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 ring Alkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(= O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , - OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , - NR a4 S(=O) 2 R a4 and -S(=O) 2 N(R a4 ) 2 ; each R 6 is independently absent or selected from H, -D, halo, -CN, -C 1 - C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 -aryl, 5-10-membered heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O) R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC( =O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl , heteroaryl, arylalkyl, and heteroarylalkyl are optionally substituted at any available position; each R7 is independently absent or selected from H, -D, halo, -CN, -C1 -C 6 alkyl, -C 1 -C 6 hydroxyalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclic group, 5-6 membered monocyclic heteroaryl group, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a7 , -N(R a7 ) 2 , -C(=O)R a7 , -C(= O)OR a7 , -NR a7 C(=O)R a7 , -N a7 C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -OC(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , -SR a7 , -S(=O) (=NR a7 )R a7 , -NR a7 S(=O) 2 R a7 and -S(=O) 2 N(R a7 ) 2 ; each R 8 is independently selected from H, -D, =O, halogen base, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocycle group, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(= O)OR a8 , -NR a8 C(=O)R a8 , -NR a8 C(=O)OR a8 , -CH 2 C(=O)N(R a8 ) 2 , -C(=O)N( R a8 ) 2 , -OC(=O)N(R a8 ) 2 , -CH 2 C(=O)N(R a8 ) 2 , -S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S(=O)(=NR a8 )R a8 , -NR a8 S(=O) 2 R a8 and -S(=O) 2 N(R a8 ) 2 , wherein R 8 Both instances together with one or more of the atoms to which they are attached can form a 3-10 membered cycloalkyl or heterocyclyl ring (e.g., together with the piperidine ring of structure I can form a bridged, fused or spirobicyclic heterocycle) ring) each R a1 , R a2 , R a3 , R a4 , R a6 , R a7 and R a8 are independently selected from H, C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, C 3 -C 9 cycloalkyl, 3-7 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl, wherein Each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted at any available position ( For example , substituted with 0, 1, 2 or 3 instances of R 9 , wherein each R 9 is independently selected from =O, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkane Alkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , - S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b and -S(=O) 2 N(R b ) 2 , wherein each R b is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr) , -nBu, -tBu , -sec -Bu, -iso -Bu) and C3 - C9cycloalkyl ( eg, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl); and n is 0, 1, 2 or 3 The preconditions are: (i) when R 1 is H, R 2 is not halo, -OPr, -N(CH 3 ) 2 or -CF 3 ; (ii) when R 1 is When OR a1 , R 2 is not -OR a2 ; (iii) when R 1 is H and R 2 is -CH 3 , R 8 groups cannot form a ring together and R 6 is not absent or H, and not thiazolyl, furanyl or pyrrolyl; (iv) when R2 is Me, R1 is not optionally substituted piperidine (v) the compound is not: ( A ) 5-( 2- (5-methyl) (B) 2- (2-(4-(2H-Tetrazol-5-yl)phenyl)-5-methylpiperidin-1-yl)-N-(5,6-lutidine-3-yl)-2 - Pendant oxyacetamide or any of its enantiomers or diastereomers; (C) 2-cyano-5-(2-(5-methyl-2-phenylpiperidin-1-yl) )-2-Pendant oxyacetamido)nicotinamide or any of its enantiomers or diastereomers.

在某些實施例中，R6 及R7 不為H且呈反式相對組態。在一些實施例中，R6 及R7 不為H且呈順式相對組態。In certain embodiments, R 6 and R 7 are not H and are in a trans relative configuration. In some embodiments, R 6 and R 7 are not H and are in a cis-relative configuration.

在式(I)之一些實施例中，表示為

Figure 110128222-A0202-12-0006-1106
之部分選自：In some embodiments of formula (I), expressed as
Figure 110128222-A0202-12-0006-1106
part from:

Figure 110128222-A0202-12-0006-1103
Figure 110128222-A0202-12-0006-1103

在式(I)之一些實施例中，表示為

Figure 110128222-A0202-12-0006-1107
之部分選自：In some embodiments of formula (I), expressed as
Figure 110128222-A0202-12-0006-1107
part from:

Figure 110128222-A0202-12-0006-1104
Figure 110128222-A0202-12-0006-1104

在式(I)之其他實施例中，表示為

Figure 110128222-A0202-12-0006-1108
之部分選自：In other embodiments of formula (I), expressed as
Figure 110128222-A0202-12-0006-1108
part from:

Figure 110128222-A0202-12-0006-1105
Figure 110128222-A0202-12-0006-1105

在一些實施例中，化合物為式(Ia)化合物In some embodiments, the compound is a compound of formula (Ia)

Figure 110128222-A0202-12-0006-1101
Figure 110128222-A0202-12-0006-1101

在其他實施例中，化合物為式(Ib)化合物In other embodiments, the compound is a compound of formula (Ib)

Figure 110128222-A0202-12-0006-1102
Figure 110128222-A0202-12-0006-1102

在一些實施例中，化合物為式(Ic)化合物In some embodiments, the compound is a compound of formula (Ic)

Figure 110128222-A0202-12-0007-1109
Figure 110128222-A0202-12-0007-1109

在其他實施例中，化合物為式(Id)化合物In other embodiments, the compound is a compound of formula (Id)

Figure 110128222-A0202-12-0007-1110
Figure 110128222-A0202-12-0007-1110

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R8 獨立地選自H、-D、=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa8 、-N(Ra8 )2 、-C(=O)Ra8 、-C(=O)ORa8 、-NRa8 C(=O)Ra8 、-NRa8 C(=O)ORa8 、-CH2 C(=O)N(Ra8 )2 -C(=O)N(Ra8 )2 、-OC(=O)N(Ra8 )2 、-CH2 C(=O)N(Ra8 )2 、-S(=O)Ra8 、-S(=O)2 Ra8 、-SRa8 、-S(=O)(=NRa8 )Ra8 、-NRa8 S(=O)2 Ra8 及-S(=O)2 N(Ra8 )2 。 In some embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), each R is independently selected from H, -D, =O, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclyl alkyl , heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O)OR a8 , -NR a8 C(=O)R a8 , -NR a8 C(=O)OR a8 , -CH 2 C(=O)N(R a8 ) 2 -C(=O)N(R a8 ) 2 , -OC( =O)N(R a8 ) 2 , -CH 2 C(=O)N(R a8 ) 2 , -S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S (=O)(=NR a8 )R a8 , -NR a8 S(=O) 2 R a8 and -S(=O) 2 N(R a8 ) 2 .

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，R1 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa1 、-N(Ra1 )2 、-C(=O)Ra1 、-C(=O)ORa1 、-NRa1 C(=O)Ra1 、-NRa1 C(=O)ORa1 、-C(=O)N(Ra1 )2 及-OC(=O)N(Ra1 )2 。在一些實施例中，R1 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基、-ORa1 及-N(Ra1 )2 。在一些實施例中，R1 選自H、-C1 -C6 烷基、-C1 -C6 鹵烷基、-ORa1 及-N(Ra1 )2 。在其他實施例中，各Ra1 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及-C1 -C6 鹵烷基(例如， -CHF2 、-CF3 )。In some embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), R 1 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a1 , -N(R a1 ) 2 , -C (=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 and -OC(=O)N(R a1 ) 2 . In some embodiments, R 1 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -OR a1 , and -N(R a1 ) 2 . In some embodiments, R 1 is selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -OR a1 , and -N(R a1 ) 2 . In other embodiments, each R a1 is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec- Bu, -iso -Bu) and -C1 - C6 haloalkyl ( eg, -CHF2, -CF3 ).

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之某些實施例中，R1 選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-C1 -C6 烷基(例如， -CF3 、-CHF2 )、-OH、-O-(C1 -C6 烷基)(例如， -OMe、-OEt)、-O-(C1 -C6 鹵烷基)(例如， -OCF3 、-OCHF2 )、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。在一些實施例中，R1 選自H、-Me、-Et、-CHF2 、-OMe、-OEt、-OCHF2 、-OCF3 、-OH及-NH2 。在其他實施例中，R1 選自H、-Et、-OMe、-OEt、-OCHF2 、-OCF3 及-OH。在某些實施例中，R1 選自H及-OMe。在一些實施例中，R1 為H。在其他實施例中，R1 為-OMe。In certain embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), R 1 is selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec - Bu, -iso-Bu), -C 1 -C 6 alkyl ( eg, -CF 3 , -CHF 2 ), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe, -OEt), -O-(C 1 -C 6 haloalkyl) ( eg, -OCF 3 , -OCHF 2 ), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg, -NHMe), and -N-(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). In some embodiments, R1 is selected from H, -Me, -Et, -CHF2, -OMe, -OEt , -OCHF2, -OCF3 , -OH , and -NH2 . In other embodiments, R1 is selected from H, -Et , -OMe, -OEt , -OCHF2, -OCF3 , and -OH. In certain embodiments, R1 is selected from H and -OMe. In some embodiments, R 1 is H. In other embodiments, R 1 is -OMe.

在某些實施例中，R1 選自H、-Me、-CHF2 及-NH2 。在其他實施例中，R1 選自-Me及-NH2 。在某些實施例中，R1 為-Me。在其他實施例中，R1 為-NH2 。In certain embodiments, R 1 is selected from H, -Me, -CHF 2 and -NH 2 . In other embodiments, R1 is selected from -Me and -NH2 . In certain embodiments, R 1 is -Me. In other embodiments, R 1 is -NH 2 .

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，R2 選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-10員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)ORa2 、-NRa2 C(=O)Ra2 、-NRa2 C(=O)ORa2 、-C(=O)N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )及-OC(=O)N(Ra2 )2 。在其他實施例中，R2 選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )、-C(=O)Ra2 及-C(=O)N(Ra2 )2 。在某些實施例中，R2 選自鹵基、-C1 -C6 烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-C(=O)Ra2 及-C(=O)N(Ra2 )2 。在一些實施例中，R2 選自鹵基、-C1 -C6 烷基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-ORa2 及-C(=O)N(Ra2 )2 。在其他實施例中，各Ra2 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在某些實施例中，R2 選自鹵基(例如， -Cl)、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-C1 -C6 鹵烷基(例如， -CF3 、CHF2 )、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-C1 -C6 鹵烷氧基(例如， -OCF3 、-OCHF2 )、-OMe、-C(=O)H、-C(=O)NHOH及-C(=O)NH2 。在其他實施例中，R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、CHF2 、-OCHF2 、-OCF3 、環丙基、 -C(=O)NHOH、-C(=O)H及-C(=O)NH2 。在某些實施例中，R2 選自-C(=O)NH2 及-C(=O)H。在一些實施例中，R2 為-C(=O)NH2 。在某些實施例中，R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、-CHF2 、-OCHF2 、-OCF3 、氧呾-3-基、四氫呋喃-3-基及環丙基。在其他實施例中，R2 選自環丙基、-Me及-Et。In some embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), R 2 is selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-10 membered heterocycle radicals ( eg, oxo group, tetrahydrofuranyl), -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O) R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ) and -OC(=O)N (R a2 ) 2 . In other embodiments, R 2 is selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 - C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxo, tetrahydrofuranyl), -OR a2 , -N(R a2 ) 2 , -C(=O)N (OR a2 )(R a2 ), -C(=O)R a2 and -C(=O)N(R a2 ) 2 . In certain embodiments, R 2 is selected from halo, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 Cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxanyl, tetrahydrofuranyl), -OR a2 , -C(=O)R a2 and -C(=O)N ( R a2 ) 2 . In some embodiments, R 2 is selected from halo, -C 1 -C 6 alkyl, -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxygen tetrahydrofuranyl), -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -OR a2 and -C(=O)N(R a2 ) 2 . In other embodiments, each R a2 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec- Bu, -iso -Bu). In certain embodiments, R 2 is selected from halo ( eg, -Cl), -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -i Pr, -nBu, -t Bu, -sec -Bu, -iso -Bu), -C 1 -C 6 haloalkyl ( eg, -CF 3 , CHF 2 ), -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxoyl, tetrahydrofuranyl), -C 1 -C 6 haloalkoxy ( eg, -OCF 3 , -OCHF 2 ), -OMe, -C(=O)H , -C(=O)NHOH and -C(=O) NH2 . In other embodiments, R 2 is selected from -Cl, -Me, -Et, -i Pr, -CF 3 , CHF 2 , -OCHF 2 , -OCF 3 , cyclopropyl, -C(=O)NHOH, -C(=O)H and -C(=O) NH2 . In certain embodiments, R 2 is selected from -C(=O)NH 2 and -C(=O)H. In some embodiments, R 2 is -C(=O)NH 2 . In certain embodiments, R2 is selected from -Cl, -Me, -Et , -iPr , -CF3 , -CHF2, -OCHF2, -OCF3 , oxo - 3 -yl, tetrahydrofuran-3 - base and cyclopropyl. In other embodiments, R 2 is selected from cyclopropyl, -Me and -Et.

在一些實施例中，R1 選自H、-OMe、-OEt、-OCF3 、-OCHF2 、-CHF2 、-Me、-Et、-OH及-NH2 ，且R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、-CHF2 、-OCHF2 、-OCF3 、環丙基、-C(=O)NH2 及-C(=O)H，前提條件為當R2 為-Me時，R1 為NH2 。在一些實施例中，R1 選自H、-CHF2 、-Me及-NH2 ，且R2 選自-Cl、-Me、-Et、-CF3 、-CHF2 、-OCHF2 及環丙基，前提條件為當R2 為-Me時，R1 為NH2 。在某些實施例中，R1 選自-NH2 及-Me，且R2 選自-Me及-Et。在其他實施例中，R1 為-NH2 ，且R2 選自環丙基、-Me及-Et。In some embodiments, R 1 is selected from H, -OMe, -OEt, -OCF 3 , -OCHF 2 , -CHF 2 , -Me, -Et, -OH, and -NH 2 , and R 2 is selected from -Cl , -Me, -Et , -iPr , -CF3 , -CHF2, -OCHF2, -OCF3 , cyclopropyl, -C(=O) NH2 and -C (=O)H, prerequisites is that when R 2 is -Me, R 1 is NH 2 . In some embodiments, R 1 is selected from H, -CHF 2 , -Me, and -NH 2 , and R 2 is selected from -Cl, -Me, -Et, -CF 3 , -CHF 2 , -OCHF 2 , and cyclic propyl , with the proviso that when R2 is -Me , R1 is NH2 . In certain embodiments, R1 is selected from -NH2 and -Me, and R2 is selected from -Me and -Et . In other embodiments, R 1 is -NH 2 and R 2 is selected from cyclopropyl, -Me, and -Et.

在一些實施例中，R1 選自H、-OMe、-OEt、-OCF3 、-OCHF2 、-Et及-OH，且R2 選自-C(=O)NH2 及-C(=O)H。在其他實施例中，R1 選自H及-OMe且R2 為-C(=O)NH2 。In some embodiments, R 1 is selected from H, -OMe, -OEt, -OCF 3 , -OCHF 2 , -Et, and -OH, and R 2 is selected from -C(=O)NH 2 and -C(= O)H. In other embodiments, R1 is selected from H and -OMe and R2 is -C (=O) NH2 .

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，R3 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa3 、-N(Ra3 )2 、-C(=O)Ra3 、-C(=O)ORa3 、-NRa3 C(=O)Ra3 、-NRa3 C(=O)ORa3 、-C(=O)N(Ra3 )2 及-OC(=O)N(Ra3 )2 。在一些實施例中，R3 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基及-N(Ra3 )2 。在其他實施例中，Ra3 選自H及C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在某些實施例中，R3 選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-OH、-O-(C1 -C6 烷基)(例如， -OMe)、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。在其他實施例中，R3 選自H、-Me及-NH2 。在某些實施例中，R3 選自H及-Me。在其他實施例中，R3 為-Me。In some embodiments of formulae (I), (Ia), (Ib), (Ic), and (Id), R 3 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a3 , -N(R a3 ) 2 , -C (=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 and -OC(=O)N(R a3 ) 2 . In some embodiments, R 3 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, and -N(R a3 ) 2 . In other embodiments, R a3 is selected from H and C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr , -iPr , -nBu, -tBu, -sec -Bu, -iso -Bu). In certain embodiments, R3 is selected from -C1 - C6 alkyl ( eg, -Me, -Et , -Pr , -iPr , -nBu, -tBu, -sec -Bu, -iso -Bu), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg, -NHMe) and - N-(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). In other embodiments, R3 is selected from H, -Me and -NH2 . In certain embodiments, R3 is selected from H and -Me. In other embodiments, R3 is -Me.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，R4 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa4 、-N(Ra4 )2 、-C(=O)Ra4 、-C(=O)ORa4 、-NRa4 C(=O)Ra4 、-NRa4 C(=O)ORa4 、-C(=O)N(Ra4 )2 及-OC(=O)N(Ra4 )2 。在一些實施例中，R4 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基及-N(Ra4 )2 。在其他實施例中，各Ra4 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在某些實施例中，R4 選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-nBu、-t Bu、-sec -Bu、-iso -Bu)、-OH、-O-(C1 -C6 烷基)(例如， -OMe)、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。在其他實施例中，R4 為H。In some embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), R 4 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a4 , -N(R a4 ) 2 , -C (=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 and -OC(=O)N(R a4 ) 2 . In some embodiments, R 4 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, and -N(R a4 ) 2 . In other embodiments, each R is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu , -sec- Bu, -iso -Bu). In certain embodiments, R 4 is selected from -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu, -tBu, -sec -Bu, -iso- Bu), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg, -NHMe) and -N -(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). In other embodiments, R4 is H.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R6 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、-S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、雜環基烷 氧基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-OH、C(=O)Me、-C(=O)NHMe、-NH2 、-NHC(=O)Me或其組合之0、1、2或3個實例取代)；各Rb10 獨立地為H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；或經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。In some embodiments of Formulas (I), (Ia), (Ib), (Ic), and (Id ), each R is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(= O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SRa 6 , -S(=O)(=NR a6 )R a6 , -NR a6 S (=O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycle Alkylalkyl, arylalkyl and heteroarylalkyl are substituted at any available position with 0 , 1, 2 or 3 instances of R10, wherein: each R10 is independently selected from -D, =O, -CN , halogen, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl , C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkoxy, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O)R b10 , -NR b10 C(=O)OR b10 , - C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , -S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S(=O) 2 N(R b10 ) 2 , where R 10 each of alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, heterocyclylalkoxy, arylalkyl and heteroaryl Alkyl is optionally substituted ( eg, 0, 1 with -Me, -OH, C(=O)Me, -C(=O)NHMe, -NH2 , -NHC(=O)Me, or combinations thereof , 2 or 3 instances substituted); each R b10 is independently H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl ; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 -C 9 cycloalkyl; or 3 substituted with 0 or 1 instance of =0, -Me, or a combination thereof -10-membered heterocyclyl.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R6 獨立地選自-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、-S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、雜環基烷氧基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-OH、C(=O)Me、-C(=O)NHMe、-NH2 、-NHC(=O)Me或其組合之0、1、2或3個實例取代)；各Rb10 獨立地為H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；或經=O、-Me或其組合之0或1個實例取代之3-10員雜 環基。In some embodiments of Formulas (I), (Ia), (Ib), (Ic), and (Id ), each R is independently selected from -D, halo, -CN, -C 1 -C alkane base, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 -aryl, 5-10-membered heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O) N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(= O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkane aryl, arylalkyl and heteroarylalkyl are substituted at any available position with 0 , 1, 2 or 3 instances of R10, wherein: each R10 is independently selected from -D, =O, -CN, halo base, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkoxy, -OR b10 , - N(R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O)R b10 , -NR b10 C(=O)OR b10 , -C( =O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , -S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S(=O) 2 N(R b10 ) 2 , wherein each of R 10 Alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, heterocyclylalkoxy, arylalkyl and heteroarylalkane Base is optionally substituted ( eg, 0, 1, 2 with -Me, -OH, C(=O)Me, -C(=O)NHMe, -NH2 , -NHC(=O)Me, or combinations thereof or 3 examples substituted); each R b10 is independently H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 -C 9 cycloalkyl; or 3-10 substituted with 0 or 1 instance of =0, -Me or a combination thereof Member heterocyclyl.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R6 獨立地選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、-S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、雜環基烷氧基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-OH、C(=O)Me、-C(=O)NHMe、-NH2 、-NHC(=O)Me或其組合之0、1、2或3個實例取代)；各Rb10 獨立地為H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；或經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。In some embodiments of formulae (I), (Ia), (Ib), (Ic) and (Id), each R 6 is independently selected from H, halo, -CN, -C 1 -C 6 alkyl , -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , - C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N (R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O ) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl , arylalkyl, and heteroarylalkyl are substituted at any available position with 0 , 1, 2, or 3 instances of R10, wherein: each R10 is independently selected from -D, =O, -CN, halo , -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkoxy, -OR b10 , -N (R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O)R b10 , -NR b10 C(=O)OR b10 , -C(= O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , -S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S(=O) 2 N(R b10 ) 2 , wherein each alkane of R 10 radical, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, heterocyclylalkoxy, arylalkyl and heteroarylalkyl Optionally substituted ( eg, with -Me, -OH, C(=O)Me, -C(=O)NHMe, -NH2 , -NHC(=O)Me, or 0, 1, 2, or 3 examples substituted); each R b10 is independently H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of O; C 3 -C 9 cycloalkyl; or 3-10 members substituted with 0 or 1 instance of =0, -Me or a combination thereof Heterocyclyl.

在一些實施例中，各Ra6 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。In some embodiments, each R is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu , -sec- Bu, -iso -Bu).

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R6 獨立地選自H、 -C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置視情況經取代。In some embodiments of Formulas (I), (Ia), (Ib), (Ic), and (Id), each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 Member heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, Heteroaryl, arylalkyl, and heteroarylalkyl are optionally substituted at any available position.

在一些實施例中，各R6 獨立地選自-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置視情況經取代。In some embodiments, each R 6 is independently selected from -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocycle group, 3-10 membered heterocyclyl, heterocyclylalkyl, C6 - C10 -membered aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein Each of the alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups is optionally substituted at any available position.

在一些實施例中，各R6 獨立地選自H、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、雜環基烷基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、-S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、 -N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)；且各Rb10 獨立地選自H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；及經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。In some embodiments, each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 Carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, C6 - C10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl , wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is at any available position via R 10 0, 1, 2 or 3 instances of substitution, wherein: each R 10 is independently selected from -D, =O, -CN, halo, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkane base, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkylalkane group, arylalkyl, heteroarylalkyl, heterocyclylalkoxy, heterocyclylalkyl, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C( =O)OR b10 , -NR b10 C(=O)R b10 , -NR b10 C(=O)OR b10 , -C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , -S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S(=O) 2 N(R b10 ) 2 , wherein each of R 10 's alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, hetero Aryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl are optionally substituted ( eg, with -Me, -Et, -iPr , cyclopropyl, oxo and - 3 -yl, -OH , =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C ( = O)Me, -N(Me) 2 , -CH2N( CH3 ) 2 , -CH2N ( CH3 ) CH2CH3 , -N( iPr )(Et ) , -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or 0, 1, 2, 3, 4, or 5 instances of a combination thereof substituted); and each R b10 is independently selected from H; - C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 -C 9 cycloalkyl; and 3-10 membered heterocyclyl substituted by 0 or 1 instance of =O, -Me or a combination thereof.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R6 獨立地選自H、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置視情況經取代。在某些實施例中，各R6 獨立地選自H、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、雜環基烷基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、-S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、 -N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)；且各Rb10 獨立地選自H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；及經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。In some embodiments of formula (I), (Ia), (Ib), (Ic), and (Id), each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 Member heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, Heteroaryl, arylalkyl, and heteroarylalkyl are optionally substituted at any available position. In certain embodiments, each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 -carbocyclyl, 3-10-membered heterocyclyl, heterocyclylalkyl, C6 - C10 -aryl, 5-10-membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkane wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl is modified by R at any available position 0 , 1, 2 or 3 instances of 10 are substituted, wherein: each R 10 is independently selected from -D, =O, -CN, halo, -C 1 -C 6 alkyl, -C 1 -C 6 hetero Alkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkyl Alkyl, arylalkyl, heteroarylalkyl, heterocyclylalkoxy, heterocyclylalkyl, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C (=O)OR b10 , -NR b10 C(=O)R b10 , -NR b10 C(=O)OR b10 , -C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , -S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S(=O) 2 N(R b10 ) 2 , wherein each of the alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, Heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl are optionally substituted ( eg, with -Me, -Et, -iPr , cyclopropyl, oxo and -3-yl, -OH, =O, -F, -OMe, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C(=O)Me, -N(Me ) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr)(Et), -N( i Pr)(Me), -N(Et ) 2 , -N( CH3 )(Et), -NHC(=O)Me, or 0, 1, 2, 3, 4, or 5 instances of a combination thereof substituted); and each R b10 is independently selected from H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 -C 9 cycloalkyl; and 3-10 membered heterocyclyl substituted with 0 or 1 instance of =0, -Me or a combination thereof.

在一些實施例中，各R6 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- i Bu、sec -Bu、- t Bu)、-C3 -C10 單環或雙環碳環基(例如， 環丙基、環丁基、環戊基、環己基、環庚基、雙環[1.1.1]戊-基、4,5,6,7-四氫-1H-吲唑基、螺[3.3]庚基)、3-10員單環或雙環雜環基(例如， 氧呾基、氮雜環庚烷基(azepanyl)、哌啶基、吡咯啶基、四氫呋喃基、四氫哌喃基、1,2-二氫吡啶基、嗎啉基、異吲哚啉基)、C6 -C10 單環或雙環芳基(例如， 苯基、萘基、1,2,3,4-四氫萘基、2,3-二氫-1H-茚基、1,2,3,4-四氫喹啉基、1,2-二氫喹啉基、1,2-二氫異喹啉基、1,2,3,4-四氫異喹啉基、色原烷基、吲哚啉基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、2,3-二氫苯并呋喃基、苯并[d ][1,3]二氧雜環戊烯基、2,3-二氫-1H-苯并[d]咪唑基)、5-6員單環雜芳基(例如， 噻吩基、噻唑基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基)、8-10員雙環雜芳基(例如， 苯并[d]異噻唑基、吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b]噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、咪唑并[1,5-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基)，其中各烷基、碳環基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。在一些實施例中，各R6 獨立地選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- i Bu、sec -Bu、- t Bu)、-C3 -C10 單環或雙環碳環基(例如， 環丙基、環丁基、環戊基、環己基、環庚基、雙環[1.1.1]戊基、4,5,6,7-四氫-1H-吲唑基、螺[3.3]庚基)、3-10員單環或雙環雜環 基(例如， 氧呾基、氮雜環庚烷基、哌啶基、吡咯啶基、四氫呋喃基、四氫哌喃基、1,2-二氫吡啶基、嗎啉基、異吲哚啉基)、C6 -C10 單環或雙環芳基(例如， 苯基、萘基、1,2,3,4-四氫萘基、2,3-二氫-1H-茚基、1,2,3,4-四氫喹啉基、1,2-二氫喹啉基、1,2-二氫異喹啉基、1,2,3,4-四氫異喹啉基、色原烷基、吲哚啉基、異吲哚啉基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、2,3-二氫苯并呋喃基、苯并[d ][1,3]二氧雜環戊烯基(dioxolyl)、2,3-二氫-1H-苯并[d]咪唑基)、5-6員單環雜芳基(例如， 噻吩基、噻唑基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基)、8-10員雙環雜芳基(例如， 苯并[d]異噻唑基、吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b]噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、咪唑并[1,5-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基)，其中各烷基、碳環基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。In some embodiments, each R6 is independently selected from H, -C1 -C6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -iBu , sec -Bu, -tBu ), -C 3 -C 10 monocyclic or bicyclic carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pent-yl, 4,5 , 6,7-tetrahydro-1H-indazolyl, spiro[3.3]heptyl), 3-10 membered monocyclic or bicyclic heterocyclyl ( eg, oxanyl, azepanyl, azepanyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2-dihydropyridyl, morpholinyl, isoindolinyl), C6 - C10 monocyclic or bicyclic aryl ( eg , phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2- Dihydroquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, chromogenyl, indolinyl, 3,4-dihydro-2H -benzo[b][1,4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[ d ][1,3]dioxolyl, 2,3-dihydro -1H-benzo[d]imidazolyl), 5-6 membered monocyclic heteroaryl ( eg, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl), 8- 10-membered bicyclic heteroaryl ( eg, benzo[d]isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl, quinolinyl , 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl, benzo [ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1,2- a ]pyridyl, imidazo[1,5- a ]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl, 1H- thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridyl), wherein each alkyl, carbocyclyl, Heterocyclyl, aryl, and heteroaryl are optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10). In some embodiments, each R 6 is independently selected from -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -iBu , sec -Bu, -tBu), -C 3 -C 10 monocyclic or bicyclic carbocyclyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, 4,5,6, 7-tetrahydro-1H-indazolyl, spiro[3.3]heptyl), 3-10 membered monocyclic or bicyclic heterocyclyl ( eg, oxanyl, azepanyl, piperidinyl, pyrrolidine yl, tetrahydrofuranyl, tetrahydropyranyl, 1,2-dihydropyridyl, morpholinyl, isoindolinyl), C6 - C10 monocyclic or bicyclic aryl ( eg, phenyl, naphthyl , 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, chromogen alkyl, indolinyl, isoindolinyl, 3,4-dihydro-2H -benzo[b][1,4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[ d ][1,3]dioxolyl, 2,3 -Dihydro-1H-benzo[d]imidazolyl), 5-6 membered monocyclic heteroaryl ( eg, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl) , 8-10 membered bicyclic heteroaryl ( e.g., benzo[d]isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl, Quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl , benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1 ,2- a ]pyridyl, imidazo[1,5- a ]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl , 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridyl), wherein each alkyl, carbon Cyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10).

在某些實施例中，各R6 為8-10員雙環雜芳基(例如， 吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b]噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、咪唑并[1,2-a]吡啶基、咪唑并[1,5-a]吡啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d]異噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基、1,2,3,4-四氫-1,8-萘啶基)，其中雙環雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。在一些實施例中，各R6 獨立地選自H、-Me、- i Pr、- i Bu、sec -Bu、環丁基、環戊基、環己基、雙環[1.1.1]戊烷-1-基、螺[3.3]庚-2-基、4,5,6,7-四氫-1H-吲唑-6-基、哌啶-4-基、哌啶-3-基、吡咯啶-3-基、1,2- 二氫吡啶-4-基、苯基、萘-2-基、1,2,3,4-四氫喹啉-6-基、1,2,3,4-四氫萘-6-基、色原烷-6-基、1,5-萘啶-6-基、1,2,3,4-四氫-1,8-萘啶-6-基、2,3-二氫-1H-茚-5-基、吲哚啉-5-基、吲哚啉-4-基、2,3-二氫-1H-苯并[d]咪唑-5-基、2,3-二氫苯并呋喃-5-基、2,3-二氫苯并呋喃-6-基、苯并[d ][1,3]二氧雜環戊烯-5-基]、異吲哚啉-5-基、異吲哚啉-6-基、3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基、1,2-二氫喹啉-6-基、1,2-二氫異喹啉-7-基、噻吩-2-基、噻吩-3-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、吡唑-1-基、吡唑-5-基、吡唑-3-基、吡唑-4-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基、吲哚-4-基、吲哚-5-基、苯并呋喃-5-基、苯并呋喃-6-基、1H 吲唑-5-基、1H 吲唑-4-基、2H-吲唑-6-基、2H-吲唑-5-基、苯并[b ]噻吩-3-基、苯并[b ]噻吩-5-基、喹啉-6-基、喹啉-3-基、異喹啉-6-基、苯并[d ]咪唑并-5-基、1H-苯并[d]咪唑-4-基、苯并[d ]噻唑-5-基、苯并[d]噻唑-6-基、苯并[d]噻唑-4-基、苯并[d]異噻唑-5-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、[1,2,4]三唑并[4,3-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-6-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,5-a]吡啶-6-基、吡唑并[4,3-b ]吡啶-6-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-6-基、1H-噻吩并[2,3-c]吡唑-5-基、1H-噻吩并[3,2-c]吡唑-5-基、噻唑并[5,4-b]吡啶-6-基)，其各自視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。 In certain embodiments, each R6 is an 8-10 membered bicyclic heteroaryl ( eg, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl) , quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[ 1,2-a]pyridyl, imidazo[1,5-a]pyridyl, isoquinolinyl, benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[d]isothiazolyl , benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1,2- a ]pyridyl, 1H-pyrazolo[4, 3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyridyl oxazolyl, thiazolo[5,4-b]pyridyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), wherein bicyclic heteroaryl is optionally substituted ( eg, via R 10 0, 1, 2 or 3 instances of substituted). In some embodiments, each R is independently selected from H, -Me, -i Pr, -i Bu, sec -Bu, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane- 1-yl, spiro[3.3]hept-2-yl, 4,5,6,7-tetrahydro-1H-indazol-6-yl, piperidin-4-yl, piperidin-3-yl, pyrrolidine -3-yl, 1,2-dihydropyridin-4-yl, phenyl, naphth-2-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 1,2,3,4 -Tetrahydronaphthalene-6-yl, chroman-6-yl, 1,5-naphthyridin-6-yl, 1,2,3,4-tetrahydro-1,8-naphthyridin-6-yl, 2,3-Dihydro-1H-inden-5-yl, indolin-5-yl, indolin-4-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-yl , 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[ d ][1,3]dioxol-5-yl] , isoindolin-5-yl, isoindolin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1,2-dihydro- Hydroquinolin-6-yl, 1,2-dihydroisoquinolin-7-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5- base, pyrazol-1-yl, pyrazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidine- 5-yl, indol-4-yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1Hindazol -5-yl, 1Hindazol -4- base, 2H-indazol-6-yl, 2H-indazol-5-yl, benzo[ b ]thien-3-yl, benzo[ b ]thien-5-yl, quinolin-6-yl, quinoline Lin-3-yl, isoquinolin-6-yl, benzo[ d ]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[ d ]thiazol-5-yl, Benzo[d]thiazol-6-yl, benzo[d]thiazol-4-yl, benzo[d]isothiazol-5-yl, benzo[ d ]oxazol-4-yl, benzo[ d ] ]oxazol-5-yl, [1,2,4]triazolo[4,3- a ]pyridin-6-yl, imidazo[1,2- a ]pyridin-6-yl, imidazo[1 ,2-a]pyridin-7-yl, imidazo[1,5-a]pyridin-6-yl, pyrazolo[4,3- b ]pyridin-6-yl, 1H-pyrazolo[3, 4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazole [4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c]pyrazol-5-yl, thiazolo[5,4-b]pyridin-6-yl), each of which is optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10).

在一些實施例中，各R6 獨立地選自-Me、- i Pr、- i Bu、sec -Bu、環丁基、環戊基、環己基、雙環[1.1.1]戊烷-1-基、螺[3.3]庚-2-基、4,5,6,7-四氫-1H-吲唑-6-基、哌啶-4-基、哌啶-3-基、吡咯啶-3-基、1,2-二氫吡啶-4-基、苯基、萘-2-基、1,2,3,4-四氫喹啉-6-基、1,2,3,4-四氫萘-6-基、色原烷-6-基、1,5-萘啶-6-基、1,2,3,4-四氫-1,8-萘啶-6-基、2,3-二氫-1H-茚-5-基、吲哚啉-5-基、吲哚啉-4-基、2,3-二氫-1H-苯并[d]咪唑-5-基、2,3-二氫苯并呋喃-5-基、2,3-二氫苯并呋喃-6-基、苯并[d ][1,3]二氧雜環戊烯-5-基]、異吲哚啉-5-基、異吲哚啉-6-基、3,4-二氫-2H-苯并 [b][1,4]噁嗪-7-基、1,2-二氫喹啉-6-基、1,2-二氫異喹啉-7-基、噻吩-2-基、噻吩-3-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、吡唑-1-基、吡唑-5-基、吡唑-3-基、吡唑-4-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基、吲哚-4-基、吲哚-5-基、苯并呋喃-5-基、苯并呋喃-6-基、1H 吲唑-5-基、1H -吲唑-4-基、2H-吲唑-6-基、2H-吲唑-5-基、苯并[b ]噻吩-3-基、苯并[b ]噻吩-5-基、喹啉-6-基、喹啉-3-基、異喹啉-6-基、苯并[d ]咪唑并-5-基、1H-苯并[d]咪唑-4-基、苯并[d ]噻唑-5-基、苯并[d]噻唑-6-基、苯并[d ]噻唑-4-基、苯并[d ]異噻唑-5-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、[1,2,4]三唑并[4,3-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-7-基、咪唑并[1,5-a]吡啶-6-基、吡唑并[4,3-b ]吡啶-6-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-6-基、1H-噻吩并[2,3-c]吡唑-5-基、1H-噻吩并[3,2-c]吡唑-5-基、噻唑并[5,4-b]吡啶-6-基)，其各自視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。In some embodiments, each R is independently selected from -Me, -iPr , -iBu , sec -Bu, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane-1- base, spiro[3.3]hept-2-yl, 4,5,6,7-tetrahydro-1H-indazol-6-yl, piperidin-4-yl, piperidin-3-yl, pyrrolidine-3 -yl, 1,2-dihydropyridin-4-yl, phenyl, naphth-2-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 1,2,3,4-tetra Hydronaphthalen-6-yl, chromogen-6-yl, 1,5-naphthyridin-6-yl, 1,2,3,4-tetrahydro-1,8-naphthyridin-6-yl, 2, 3-Dihydro-1H-inden-5-yl, indolin-5-yl, indolin-4-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-yl, 2 ,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[ d ][1,3]dioxol-5-yl], iso Indolin-5-yl, isoindolin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1,2-dihydroquinoline olin-6-yl, 1,2-dihydroisoquinolin-7-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, Pyrazol-1-yl, Pyrazol-5-yl, Pyrazol-3-yl, Pyrazol-4-yl, Pyridin-2-yl, Pyridin-3-yl, Pyridin-4-yl, Pyrimidine-5- yl, indol-4-yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1 H -indazol-5-yl, 1 H -indazol-4-yl , 2H-indazol-6-yl, 2H-indazol-5-yl, benzo[ b ]thien-3-yl, benzo[ b ]thien-5-yl, quinolin-6-yl, quinoline -3-yl, isoquinolin-6-yl, benzo[ d ]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[ d ]thiazol-5-yl, benzene zo[d]thiazol-6-yl, benzo[ d ]thiazol-4-yl, benzo[ d ]isothiazol-5-yl, benzo[ d ]oxazol-4-yl, benzo[ d ] Oxazol-5-yl, [1,2,4]triazolo[4,3- a ]pyridin-6-yl, imidazo[1,2- a ]pyridin-6-yl, imidazo[1, 2- a ]pyridin-7-yl, imidazo[1,5-a]pyridin-6-yl, pyrazolo[4,3- b ]pyridin-6-yl, 1H-pyrazolo[3,4 -b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo [4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c]pyrazol-5-yl, thiazole and [5,4-b]pyridin-6-yl), each of which is optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10) ).

在一些實施例中，R6 選自視情況經取代之苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基及嘧啶-5-基(例如， 經R10 之0、1、2或3個實例取代)。在一些實施例中，R6 選自苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基及經R10 之一個實例取代之苯基。In some embodiments, R 6 is selected from optionally substituted phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyrimidin-5-yl ( eg, through R 0 , 1, 2 or 3 instances instead). In some embodiments, R 6 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, and phenyl substituted with an instance of R 10 .

在一些實施例中，R6 選自：

Figure 110128222-A0202-12-0018-1111
。在其他實施例中，R6 為
Figure 110128222-A0202-12-0018-1113
。In some embodiments, R 6 is selected from:
Figure 110128222-A0202-12-0018-1111
. In other embodiments, R 6 is
Figure 110128222-A0202-12-0018-1113
.

在一些實施例中，R6 為視情況經取代之苯基(例如， 經R10 之0、1、2 或3個實例取代)。在某些實施例中，R6 為

Figure 110128222-A0202-12-0018-1112
。In some embodiments, R 6 is optionally substituted phenyl ( eg, substituted with 0, 1, 2, or 3 instances of R 10 ). In certain embodiments, R 6 is
Figure 110128222-A0202-12-0018-1112
.

在一些實施例中，R6 選自視情況經取代之雙環雜芳基(例如， 經R10 之0、1、2或3個實例取代)。在其他實施例中，R6 選自視情況經取代之1H -吲唑-5-基、2H -吲唑-5-基、苯并[d]異噻唑-5-基、苯并[d]噻唑-5-基、苯并[b]噻吩-5-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、喹啉-7-基、1H-噻吩并[2,3-c]吡唑-5-基、咪唑并[1,2-a]吡啶-7-基及咪唑并[1,5-a]吡啶-6-基(例如， 經R10 之0、1、2或3個實例取代)。In some embodiments, R 6 is selected from optionally substituted bicyclic heteroaryl ( eg, substituted with 0, 1, 2, or 3 instances of R 10 ). In other embodiments, R 6 is selected from optionally substituted 1 H -indazol-5-yl, 2 H -indazol-5-yl, benzo[d]isothiazol-5-yl, benzo[ d]thiazol-5-yl, benzo[b]thien-5-yl, benzo[ d ]oxazol-4-yl, benzo[ d ]oxazol-5-yl, quinolin-7-yl, 1H-thieno[2,3-c]pyrazol-5-yl, imidazo[1,2-a]pyridin-7-yl and imidazo[1,5-a]pyridin-6-yl ( eg, Substituted with 0 , 1, 2 or 3 instances of R10).

在一些實施例中，R6 為

Figure 110128222-A0202-12-0019-1114
、
Figure 110128222-A0202-12-0019-1115
或
Figure 110128222-A0202-12-0019-1117
。在其他實施例中，
Figure 110128222-A0202-12-0019-1116
。In some embodiments, R 6 is
Figure 110128222-A0202-12-0019-1114
,
Figure 110128222-A0202-12-0019-1115
or
Figure 110128222-A0202-12-0019-1117
. In other embodiments,
Figure 110128222-A0202-12-0019-1116
.

在本發明之某些實施例中，R10 獨立地選自-D、=O、鹵基(例如，F、Cl、Br)、-CN、-C1-C6烷基(例如，-Me、-Et、-Pr、-iPr、-sec-Bu、-tBu、CH2(CH3)(iPr))、-C1-C6雜烷基(例如，-CH(CH3)(NMe2)、-CH2CH2N(Me)(氧呾-3-基))、-CH2CH(CH3)(NMe2)、-CH2OH、-CH(OH)(CH3)、-C(OH)(CH3)2、-CH2NH2)、-C1-C6鹵烷基(例如，-CHF2、-CH2CF3、-CF3)、-C3-C9環烷基(例如，環丙基、環丁基、環戊基、環己基)、3-10員雜環基(例如，四氫呋喃基、四氫哌喃基、氧呾基、嗎啉基、吡咯啶基、哌啶基、哌啶-2-酮基、哌嗪基、哌嗪-2-酮基、吖呾基、十氫-1,6-萘啶基、2-氮雜螺[3.3]庚基、5-氧雜-2,8-二氮雜螺[3.5]壬基、8-氮雜雙環[3.2.1]辛基、2-氮雜雙環[2.2.2]辛基、3-氮雜雙環[3.2.0]庚基、3-氮雜雙環[3.1.1]庚基、3-氮雜雙環[3.1.0]己基、2-氮雜雙環[2.1.1]己基、1-氮雜雙環[2.2.1]庚基、3-氮雜雙環[3.2.0]庚基、2,9-二氮雜螺[5.5]十一烷基、雙環[1.1.1]戊基、八氫環戊[c]吡咯基、十氫-1,6-萘啶基、八氫-1H-吡咯并[3,4-c]吡啶基、十氫-2,7-萘啶基、2,9-二氮雜螺[5.5]十一烷基)、5-10員雜芳基(例如，吡啶基、咪唑并[1,2-a]吡啶基、咪唑基、吡唑基、噻唑基、噻吩基)、環烷基烷基(例如-CH2-環丙基)、雜環基烷基(例如，-CH2-嗎啉基、-(CH2)2-吡咯啶基、-(Ch2)2-吡咯啶 基、-CH2-咪唑基、-CH2-吡唑基、-CH2-1,2,4-三唑基、-CH2-嗎啉基、-(CH2)2-嗎啉基)、雜環基烷氧基(例如，-O-(CH2)2-吡咯啶基、-O-CH2-哌啶基、-O-CH2-氧呾基、-O-CH2-四氫呋喃基、-O-CH2-四氫哌喃基)、雜芳基烷基(例如，-CH2-三唑基、-CH2-咪唑基、-CH2-吡唑基)、-ORb10(例如，-OH、-OMe、OEt、-O-四氫呋喃基、-O-四氫哌喃-4-基、-OCF3、-OCHF2)、-N(Rb10)2、(例如，-NH2、-NHRb10、-NHMe、-NMe2、-NHCH2CF3、-NH-氧呾-3-基、-NH-(N-Me-2-側氧基-吡咯啶-3-基)、-NRb10C(=O)Rb10(例如，-NHC(=O)Me)、-C(=O)N(Rb10)2、(例如，-C(=O)NH2、C(=O)NHMe)、-OC(=O)Rb10(例如，-OC(=O)Me)、-S(=O)Rb10(例如，-SO2Me)、-NRb10S(=O)2Rb10(例如，NHSO2Me)及-S(=O)2N(Rb10)2(例如，SO2NH2、SO2NHMe)，其中各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基視情況經取代(例如，經-Me、-Et、-iPr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2CH2F、-CH2CHF2、-CH2CH2CF3、-C(=O)Me、-N(Me)2、-CH2N(CH3)2、-CH2N(CH3)CH2CH3、-N(iPr)(Et)、-N(iPr)(Me)、-N(Et)2、-N(CH3)(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)；且其中：各Rb10 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、-C1 -C6 鹵烷基(例如， -CF3 、-CHF2 、-CH2 CF3 )、經=O之0或1個實例取代之-C1 -C6 雜烷基(例如， -CH2 CH2 NMe2 、-CH2 C(=O)NMe2 、-CH(CH3 )CH2 NMe2 、-CH(CH3 )C(=O)NMe2 )、C3 -C9 環烷基及經=O、-Me或其組合之0或1個實例取代之3-10員雜環基(例如 四氫呋喃-3-基、四氫哌喃-4-基、氧呾-3-基、N-Me-2-側氧基-吡咯啶-3-基、哌啶-4-基)。In certain embodiments of the invention, R 10 is independently selected from -D, =O, halo (eg, F, Cl, Br), -CN, -C1-C6 alkyl (eg, -Me, - Et, -Pr, -iPr, -sec-Bu, -tBu, CH2(CH3)(iPr)), -C1-C6 heteroalkyl (eg, -CH(CH3)(NMe2), -CH2CH2N(Me)( Oxygen-3-yl)), -CH2CH(CH3)(NMe2), -CH2OH, -CH(OH)(CH3), -C(OH)(CH3)2, -CH2NH2), -C1-C6 haloalkanes base (eg, -CHF2, -CH2CF3, -CF3), -C3-C9 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-10 membered heterocyclyl (eg, tetrahydrofuranyl, tetrahydropyranyl, oxanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperidin-2-one, piperazinyl, piperazin-2-one, acridine, deca Hydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptyl, 5-oxa-2,8-diazaspiro[3.5]nonyl, 8-azabicyclo[3.2.1] Octyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.0]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1. 0] Hexyl, 2-azabicyclo[2.1.1]hexyl, 1-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.0]heptyl, 2,9-diazaspiro [5.5]Undecyl, bicyclo[1.1.1]pentyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4- c]pyridyl, decahydro-2,7-naphthyridinyl, 2,9-diazaspiro[5.5]undecyl), 5-10 membered heteroaryl (eg, pyridyl, imidazo[1] ,2-a]pyridyl, imidazolyl, pyrazolyl, thiazolyl, thienyl), cycloalkylalkyl (eg -CH2-cyclopropyl), heterocyclylalkyl (eg, -CH2-morpholine Base, -(CH2)2-pyrrolidinyl, -(Ch2)2-pyrrolidinyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-1,2,4-triazolyl, -CH2 -morpholinyl, -(CH2)2-morpholinyl), heterocyclylalkoxy (eg, -O-(CH2)2-pyrrolidinyl, -O-CH2-piperidinyl, -O-CH2 -Oxygenyl, -O-CH2-tetrahydrofuranyl, -O-CH2-tetrahydropyranyl), heteroarylalkyl (eg, -CH2-triazolyl, -CH2-imidazolyl, -CH2-pyridyl) azolyl), -ORb10 (for example, -OH, -OMe, OEt, -O-tetrahydrofuranyl, -O-tetrahydropyran-4-yl, -OCF3, -OCHF2), -N(Rb10)2, ( For example, -NH2, -NHRb10, -NHMe, -NMe2, -NHCH2CF3, -N H-oxo-3-yl, -NH-(N-Me-2-oxo-pyrrolidin-3-yl), -NRb10C(=O)Rb10 (eg, -NHC(=O)Me), -C(=O)N(Rb10)2, (eg, -C(=O)NH2, C(=O)NHMe), -OC(=O)Rb10 (eg, -OC(=O)Me), -S(=O)Rb10 (eg, -SO2Me), -NRb10S(=O)2Rb10 (eg, NHSO2Me), and -S(=O)2N(Rb10)2 (eg, SO2NH2, SO2NHMe), where each alkyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl are optionally substituted (eg, with -Me, - Et, -iPr, cyclopropyl, oxo-3-yl, -OH, =O, -F, -OMe, -CH2CH2F, -CH2CHF2, -CH2CH2CF3, -C(=O)Me, -N(Me) 2. -CH2N(CH3)2, -CH2N(CH3)CH2CH3, -N(iPr)(Et), -N(iPr)(Me), -N(Et)2, -N(CH3)(Et), -NHC(=0)Me or 0, 1, 2, 3, 4, or 5 instances of a combination thereof substituted); and wherein: each R b10 is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -sec -Bu, -tBu), -C 1 -C 6 haloalkyl ( eg, -CF 3 , -CHF 2 , -CH 2 CF 3 ), -C1 - C6 heteroalkyl substituted with 0 or 1 instance of =0 ( eg, -CH2CH2NMe2 , -CH2C (=O) NMe2 , -CH ( CH3 ) CH2 NMe 2 , -CH(CH 3 )C(=O)NMe 2 ), C 3 -C 9 cycloalkyl and 3-10 membered heterocycles substituted with 0 or 1 instance of =0, -Me or combinations thereof radicals ( eg tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxo-3-yl, N-Me-2-oxy-pyrrolidin-3-yl, piperidin-4-yl).

在某些實施例中，各Rb10 獨立地選自H、-Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、-CF3 、-CHF2 、-CH2 CF3 、-CH2 CH2 NMe2 、-CH2 C(=O)NMe2 、-CH(CH3 )CH2 NMe2 、-CH(CH3 )C(=O)NMe2 )、四氫呋喃-3-基、四氫哌喃-4-基、 氧呾-4-基及N-Me-2-側氧基-吡咯啶-3-基。In certain embodiments, each R b10 is independently selected from H, -Me, -Et , -Pr, -iPr , -sec - Bu, -tBu, -CF3 , -CHF2 , -CH2CF 3 , -CH 2 CH 2 NMe 2 , -CH 2 C(=O)NMe 2 , -CH(CH 3 )CH 2 NMe 2 , -CH(CH 3 )C(=O) NMe 2 ), tetrahydrofuran-3 -yl, tetrahydropyran-4-yl, oxo-4-yl and N-Me-2-side oxy-pyrrolidin-3-yl.

在一些實施例中，各R10 獨立地選自由以下組成之群：-D、=O、-OH、-F、-Cl、-Br、-CN、-Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、-OMe、-OEt、-CHF2 、-CH2 CF3 、-CF3 、-OCF3 、-OCHF2 、-CH2 OH、-CH(OH)(CH3 )、-CH2 OMe、-C(OH)(CH3 )2 、-CH2 NH2 、-CH(CH3 )(NMe2 )、-CH2 CH(CH3 )(NMe2 )、-CH2 (CH3 )( i Pr)、-NH2 、-NHMe、-NHCH2 CF3 、-NMe2 、環丙基、環丁基、環戊基、環己基、噻唑-2-基、噻唑-5-基、噻吩-2-基、四氫呋喃-3-基、四氫哌喃-4-基、氧呾-3-基、嗎啉-2-基、-CH2 -嗎啉-4-基、-(CH2 )2 -嗎啉-4-基、咪唑-2-基、1H-吡唑-5-基、1H-咪唑-4-基、咪唑并[1,2-a]吡啶-7-基、吡咯啶-1-基、吡咯啶-3-基、哌啶-4-基、哌啶-3-基、哌啶-2-酮-4-基、哌嗪-4-基、哌嗪-4-基、哌嗪-2-酮-5-基、吡啶-4-基、吡啶-3-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、1H-吡唑-5-基、吖呾-3-基、-(CH2 )2 -吡咯啶-1-基、-(CH2 )2 -吡咯啶-2-基、-CH2 -咪唑-1-基、-CH2 -吡唑-1-基、-CH2 -1,2,4-三唑-1-基、-CH2 -環丙基、-O(CH2 )2 NMe2 、-O-四氫呋喃-3-基、-O-四氫哌喃-4-基、-O-(N-Me-2-側氧基-吡咯啶-3-基)、-O-(CH2 )2 -吡咯啶-2-基、-O-CH2 -哌啶-4-基、-O-CH2 -氧呾-3-基、-NCH3 -哌啶-4-基、-NH-氧呾-3-基、-NH-(N-Me-2-側氧基-吡咯啶-3-基)、十氫-1,6-萘啶-6-基、2-氮雜螺[3.3]庚-6-基、5-氧雜-2,8-二氮雜螺[3.5]壬-8-基、8-氮雜雙環[3.2.1]辛-3-基、2-氮雜雙環[2.2.2]辛-4-基、3-氮雜雙環[3.2.0]庚-6-基、3-氮雜雙環[3.1.1]庚-1-基、3-氮雜雙環[3.1.0]己-6-基、1-氮雜雙環[2.2.1]庚-4-基、3-氮雜雙環[3.2.0]庚-6-基、2-氮雜雙環[2.1.1]己-4-基、2,9-二氮雜螺[5.5]十一烷-9-基、雙環[1.1.1]戊烷-2-基、八氫環戊[c]吡咯-5-基、十氫-1,6-萘啶-6-基、八氫-1H-吡咯并[3,4-c]吡啶-5-基、十氫-2,7-萘啶-2-基、2,9-二氮雜螺[5.5]十一烷-2-基、-NHC(=O)Me、-NHCH2 C(=O)NMe2 、-NHCH(CH3 )C(=O)NMe2 、-C(=O)NH2 、C(=O)NHMe、-OC(=O)Me、-SO2 Me、-NHSO2 Me、-SO2 NH2 及-SO2 NHMe，其中各-OMe、-OEt、 -Me、-Et、-Pr、- i Pr、環丙基、環丁基、環戊基、環己基、四氫呋喃-3-基、氧呾-3-基、吡咯啶-1-基、吡咯啶-3-基、哌啶-4-基、哌啶-3-基、哌啶-2-酮-4-基、哌嗪-4-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、噻唑-2-基、噻吩-2-基、-CH2 -環丙基、-CH2 -嗎啉-4-基、-(CH2 )2 -嗎啉-4-基、-嗎啉-2-基、-(CH2 )2 -吡咯啶-1-基、-CH2 -1,2,4-三唑-1-基、-CH2 -咪唑-1-基、咪唑-2-基、-CH2 -吡唑-1-基、-OCH2 -哌啶-4-基、吖呾-3-基、2-氮雜螺[3.3]庚-6-基、2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基、8-氮雜雙環[3.2.1]辛-3-基及十氫-1,6-萘啶-6-基；且其中各R10 可獨立地經以下之0、1、2、3、4或5個實例取代：-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合。In some embodiments, each R 10 is independently selected from the group consisting of -D, =O, -OH, -F, -Cl, -Br, -CN, -Me, -Et, -Pr, -i Pr, -sec -Bu, -tBu , -OMe, -OEt , -CHF2, -CH2CF3 , -CF3 , -OCF3 , -OCHF2 , -CH2OH , -CH ( OH)( CH 3 ), -CH 2 OMe, -C(OH)(CH 3 ) 2 , -CH 2 NH 2 , -CH(CH 3 )(NMe 2 ), -CH 2 CH(CH 3 )(NMe 2 ), -CH2 ( CH3 )( iPr ), -NH2 , -NHMe, -NHCH2CF3 , -NMe2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazol- 2 -yl, Thiazol-5-yl, thiophen-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxo-3-yl, morpholin-2-yl, -CH 2 -morpholin-4- base, -( CH2 ) 2 -morpholin-4-yl, imidazol-2-yl, 1H-pyrazol-5-yl, 1H-imidazol-4-yl, imidazo[1,2-a]pyridine- 7-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-on-4-yl, piperazin-4-yl, Piperazin-4-yl, piperazin-2-on-5-yl, pyridin-4-yl, pyridin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl , pyrazol-5-yl, 1H-pyrazol-5-yl, acridine-3-yl, -(CH 2 ) 2 -pyrrolidin-1-yl, -(CH 2 ) 2 -pyrrolidin-2- base, -CH 2 -imidazol-1-yl, -CH 2 -pyrazol-1-yl, -CH 2 -1,2,4-triazol-1-yl, -CH 2 -cyclopropyl, -O (CH 2 ) 2 NMe 2 , -O-tetrahydrofuran-3-yl, -O-tetrahydropyran-4-yl, -O-(N-Me-2-oxo-pyrrolidin-3-yl) , -O-(CH 2 ) 2 -pyrrolidin-2-yl, -O-CH 2 -piperidin-4-yl, -O-CH 2 -oxygen-3-yl, -NCH 3 -piperidine- 4-yl, -NH-oxo-3-yl, -NH-(N-Me-2-oxo-pyrrolidin-3-yl), decahydro-1,6-naphthyridin-6-yl, 2-Azaspiro[3.3]hept-6-yl, 5-oxa-2,8-diazaspiro[3.5]nonan-8-yl, 8-azabicyclo[3.2.1]octane-3- base, 2-azabicyclo[2.2.2]oct-4-yl, 3-azabicyclo[3.2.0]hept-6-yl, 3-azabicyclo[3.1.1]hept-1-yl, 3-azabicyclo[3.1.0]hex-6-yl, 1-azabicyclo [2.2.1]Hept-4-yl, 3-azabicyclo[3.2.0]hept-6-yl, 2-azabicyclo[2.1.1]hex-4-yl, 2,9-diaza Spiro[5.5]undecan-9-yl, bicyclo[1.1.1]pentan-2-yl, octahydrocyclopenta[c]pyrrol-5-yl, decahydro-1,6-naphthyridine-6- base, octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl, decahydro-2,7-naphthyridin-2-yl, 2,9-diazaspiro[5.5]undecane -2-yl, -NHC(=O)Me, -NHCH 2 C(=O)NMe 2 , -NHCH(CH 3 )C(=O)NMe 2 , -C(=O)NH 2 , C(= O)NHMe, -OC(=O)Me, -SO 2 Me, -NHSO 2 Me, -SO 2 NH 2 and -SO 2 NHMe, wherein each of -OMe, -OEt, -Me, -Et, -Pr, - i Pr, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, oxo-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidine-4 -yl, piperidin-3-yl, piperidin-2-on-4-yl, piperazin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazole oxazol-5-yl, thiazol-2-yl, thien-2-yl, -CH2 -cyclopropyl, -CH2 -morpholin-4-yl, -( CH2 ) 2 -morpholin-4-yl , -morpholin-2-yl, -(CH 2 ) 2 -pyrrolidin-1-yl, -CH 2 -1,2,4-triazol-1-yl, -CH 2 -imidazol-1-yl, Imidazol-2-yl, -CH 2 -pyrazol-1-yl, -OCH 2 -piperidin-4-yl, acridine-3-yl, 2-azaspiro[3.3]hept-6-yl, 2 -Methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl, 8-azabicyclo[3.2.1]oct-3-yl and decahydro-1,6-naphthalene and wherein each R 10 may be independently substituted with 0, 1, 2, 3, 4 or 5 of the following instances: -Me, -Et, -iPr , cyclopropyl, oxo-3 -Base, -OH , =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C ( = O)Me, -N(Me ) 2 , -CH2N( CH3 ) 2 , -CH2N ( CH3 ) CH2CH3 , -N( iPr )(Et ) , -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or a combination thereof.

在一些實施例中，R10 為視情況經取代之3-6員單環雜環基或視情況經取代之6-10員雙環雜環基。在其他實施例中，R10 為-D、-Cl、-F、-Me、-CH2 -OH、

Figure 110128222-A0202-12-0022-1118
In some embodiments, R 10 is an optionally substituted 3-6 membered monocyclic heterocyclyl or an optionally substituted 6-10 membered bicyclic heterocyclyl. In other embodiments, R 10 is -D, -Cl, -F, -Me, -CH 2 -OH,
Figure 110128222-A0202-12-0022-1118

Figure 110128222-A0202-12-0023-1119
Figure 110128222-A0202-12-0023-1119

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R7 獨立地選自H、鹵基(例如， F、Cl)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、5員雜芳基(例如， 吡唑基)、-C1 -C6 鹵烷基(例如，-CF3 、-CHF2 、-CH2 CF3 )、-C1 -C6 羥基烷基(例如， -CH2 OH)、-C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)、-ORa7 (例如， -OH、-OMe、-OCHF2 )、-N(Ra7 )2 及-C(=O)N(Ra7 )2 (例如， -C(=O)NH2 、-C(=O)NHMe)。在其他實施例中，各Ra7 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在一些實施例中，各R7 獨立地選自H及甲基。在某些實施例中，各R7 為H。在其他實施例中，各R7 為甲基。In some embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), each R is independently selected from H, halo ( eg, F, Cl), -CN, - C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -i Pr, -sec-Bu, -t Bu), 5-membered heteroaryl ( eg, pyrazolyl), -C 1 - C 6 haloalkyl (eg, -CF 3 , -CHF 2 , -CH 2 CF 3 ), -C 1 -C 6 hydroxyalkyl ( eg, -CH 2 OH), -C 3 -C 9 cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), -OR a7 ( eg, -OH, -OMe, -OCHF 2 ), -N(R a7 ) 2 and -C(=O) N(R a7 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHMe). In other embodiments, each R a7 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec- Bu, -iso -Bu). In some embodiments, each R7 is independently selected from H and methyl. In certain embodiments, each R7 is H. In other embodiments, each R7 is methyl.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，各R8 獨立地選自H、-D、鹵基(例如， -F、-Cl)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、芳基烷基(例如， 苯甲基)、-C(=O)Ra8 (例如， -C(=O)Me、-C(=O)Et、-C(=O)Pr、-C(=O) i Pr)、-N(Ra8 )2 (例如， -NHMe、NH2 、NMe2 )、-NRa8 C(=O)Ra8 (例如， -NHC(=O)Me)、-CH2 C(=O)N(Ra8 )2 (例如， -CH2 C(=O)NH2 )及-ORa8 (例如， -OH、-OMe、-O i Pr、-OCF3 )。在其他實施例中，各Ra8 獨立地選自H、-CF3 及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在一些實施例中，各R8 獨立地選自H、-D、-F、-Me、-Et、-CN、-OMe、-O i Pr、-OFC3 、苯甲基、-NHC(=O)Me、-NMe2 、-CH2 C(=O)NH2 、-C(=O) i Pr及-OH。在某些實施例中，各R8 獨立地選自H、-D、-F、-Me、-Et及-CN。在其他實施例中，各R8 獨立地選自H、-D、-F及-Me。 In some embodiments of Formulas (I), (Ia), (Ib), (Ic), and (Id), each R is independently selected from H, -D, halo ( eg, -F, -Cl) , -CN, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -i Pr, -sec-Bu, -t Bu), arylalkyl ( eg, benzyl), -C(=O)R a8 ( for example, -C(=O)Me, -C(=O)Et, -C(=O)Pr, -C(=O) i Pr), -N(R a8 ) 2 ( eg, -NHMe, NH 2 , NMe 2 ), -NR a8 C(=O)R a8 ( eg, -NHC(=O)Me), -CH 2 C(=O)N(R a8 ) 2 ( eg, -CH 2 C(=O)NH 2 ) and -OR a8 ( eg, -OH, -OMe, -O i Pr, -OCF 3 ). In other embodiments, each R a8 is independently selected from H, -CF 3 and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu , -sec -Bu, -iso -Bu). In some embodiments, each R is independently selected from H, -D, -F, -Me, -Et, -CN, -OMe, -OiPr , -OFC3 , benzyl, -NHC (= O)Me, -NMe2, -CH2C (=O) NH2 , -C (=O) iPr and -OH. In certain embodiments, each R8 is independently selected from H, -D, -F, -Me, -Et, and -CN. In other embodiments, each R8 is independently selected from H, -D, -F, and -Me.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，n為0。在其他實施例中，n為1。在某些實施例中，n為2。在其他實施例中，n為3。In some embodiments of Formulas (I), (Ia), (Ib), (Ic), and (Id), n is zero. In other embodiments, n is one. In certain embodiments, n is 2. In other embodiments, n is three.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，表示為

Figure 110128222-A0202-12-0024-1120
之 部分選自：In some embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), represented as
Figure 110128222-A0202-12-0024-1120
part from:

Figure 110128222-A0202-12-0025-1122
Figure 110128222-A0202-12-0025-1122

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，表示為

Figure 110128222-A0202-12-0025-1123
之 部分選自：In some embodiments of formula (I), (Ia), (Ib), (Ic) and (Id), represented as
Figure 110128222-A0202-12-0025-1123
part from:

Figure 110128222-A0202-12-0025-1121
Figure 110128222-A0202-12-0025-1121

Figure 110128222-A0202-12-0026-1124
Figure 110128222-A0202-12-0026-1124

在以上實施例中之一些中，其中哌啶為大環之一部分，n為2。在一些實施例中，各R6 及R7 獨立地選自H及-CH3 。在其他實施例中，R6 為H。在其他實施例中，R6 為-CH3 。在某些實施例中，R7 為H。在某些實施例中，R7 為-CH3 。In some of the above embodiments, wherein piperidine is part of a macrocycle, n is 2. In some embodiments, each of R 6 and R 7 is independently selected from H and -CH 3 . In other embodiments, R6 is H. In other embodiments, R 6 is -CH 3 . In certain embodiments, R7 is H. In certain embodiments, R 7 is -CH 3 .

在一些實施例中，式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物選自表1。In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), and (Id) are selected from Table 1.

在一個態樣中，提供了一種醫藥組成物，其包含如本文所定義之式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物及醫藥學上可接受之載劑。在一些實施例中，醫藥組成物進一步包含第二治療劑。In one aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic) and (Id) as defined herein and a pharmaceutically acceptable carrier . In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent.

在一個態樣中，提供了一種治療有需要之個體之MTAP缺乏及/或MTA累積疾病的方法，其藉由向該個體投與治療有效量之c或其醫藥學上可接受之組成物來進行。在一些實施例中，化合物或組成物與第二治療劑組合投與。In one aspect, there is provided a method of treating a disease of MTAP deficiency and/or MTA accumulation in an individual in need thereof by administering to the individual a therapeutically effective amount of c or a pharmaceutically acceptable composition thereof conduct. In some embodiments, the compound or composition is administered in combination with a second therapeutic agent.

在一些實施例中，疾病為增殖性疾病。在一個實施例中，疾病為MTAP缺乏及/或MTA累積癌症。在某些實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例 如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如， 肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤(undifferentiated pleiomorphic sarcoma)、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In some embodiments, the disease is a proliferative disease. In one embodiment, the disease is MTAP deficiency and/or MTA accumulating cancer. In certain embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg , bladder urothelial carcinoma) carcinoma), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg, lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphism Sarcoma (undifferentiated pleiomorphic sarcoma), diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, stomach cancer, kidney cancer, breast cancer, endometrial cancer, urine Road cancer, liver cancer, soft tissue cancer, pleural or colorectal cancer or sarcoma.

在一個態樣中，提供了一種治療有需要之個體之癌症的方法，其包含以下步驟：In one aspect, there is provided a method of treating cancer in an individual in need thereof, comprising the steps of:

a)評定自該個體獲得之測試樣品中MTAP及/或MTA之水準，其中該MTA水準可直接(例如， 藉由ELISA或LC-MS/MS)或間接(例如， 藉由SDMA修飾之蛋白質ELISA或IHC或藉由RNA剪接)評定；a) Assessing the level of MTAP and/or MTA in a test sample obtained from the individual, wherein the MTA level can be directly ( eg, by ELISA or LC-MS/MS) or indirectly ( eg, by SDMA-modified protein ELISA) or IHC or by RNA splicing) assessment;

b)將測試樣品與參考物相比較，其中該測試樣品中與參考物相比之MTAP缺乏及/或MTA累積表明該個體之癌症將對以PRMT5抑制劑之治療性治療有反應；及b) comparing a test sample to a reference, wherein a lack of MTAP and/or accumulation of MTA in the test sample compared to the reference indicates that the individual's cancer will respond to therapeutic treatment with a PRMT5 inhibitor; and

c)向步驟b)中鑑定之個體投與療有效量之如本文所定義之式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或其醫藥組成物。c) administering to the individual identified in step b) a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic) and (Id) as defined herein, or a pharmaceutical composition thereof.

圖1.根據癌症基因體圖譜(TCGA)在表示示範性癌症之細胞株中MTAP同型合子缺失之頻率。Figure 1. Frequency of MTAP homozygous deletions in cell lines representing exemplary cancers according to The Cancer Genome Atlas (TCGA).

圖2.在MTAP-無效Sw1573癌細胞株中之7日活力檢定中MAT2A抑制劑AG-270與範例MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強。Figure 2. The combination of the MAT2A inhibitor AG-270 with the exemplary MTAP- null selective PRMT5 inhibitor demonstrates the lack of enhanced cell viability in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line.

圖3.根據HSA模型，MAT2A抑制劑AG-270之組合的作用為協同的，其中協同得分定量了過量最高單一化合物反應。Figure 3. The effect of the combination of the MAT2A inhibitor AG-270 is synergistic according to the HSA model, with the synergy score quantifying the highest excess single compound response.

圖4.在MTAP-無效Sw1573癌細胞株中之7日活力檢定中KRASG12C抑制劑 AMG-510與範例MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強。Figure 4. The combination of the KRASG12C inhibitor AMG-510 with the exemplary MTAP- null selective PRMT5 inhibitor demonstrates the lack of enhanced cell viability in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line.

圖5.在MTAP-無效Sw1573癌細胞株中之在7日活力檢定中MAPK1/MAPK3抑制劑(由烏裡替尼(ulixertinib)及SCH772984例示)與示範性MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強。Figure 5. Demonstration of the combination of a MAPK1/MAPK3 inhibitor (exemplified by ulixertinib and SCH772984) with an exemplary MTAP- null selective PRMT5 inhibitor in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line Lack of enhancement of cell viability.

圖6.在MTAP-無效Sw1573癌細胞株中之7日活力檢定中MEK抑制劑(由曲美替尼(trametinib)例示)與示範性MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強。Figure 6. The combination of a MEK inhibitor (exemplified by trametinib) with an exemplary MTAP- null selective PRMT5 inhibitor demonstrates the lack of enhanced cell viability in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line.

圖7.在MTAP-無效A101D癌細胞株中之7日活力檢定中CDK4/6抑制劑(由帕博西尼(palbociclib)及玻瑪西尼(abemaciclib)例示)與示範性MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強。Figure 7. CDK4/6 inhibitors (exemplified by palbociclib and abemaciclib) and an exemplary MTAP- null selective PRMT5 in a 7-day viability assay in the MTAP-null A101D cancer cell line The combination of inhibitors demonstrated a lack of enhancement of cell viability.

定義definition

MTAPMTAP

如本文所用之「MTAP」係指甲基硫腺苷酸磷酸化酶，其為甲硫胺酸再利用路徑中之酶，亦稱為S-甲基-5'-硫腺苷磷酸化酶；亦稱為BDMF、DMSFH、DMSMFH、LGMBF、MSAP及c86fus。外部ID：OMIM：156540MGI：1914152HomoloGene：1838 chEMBL：4941 GeneCards：MTAP基因；Entrez 4507；RefSeq(mRNA)：NM__002451；位置：Chr 9：21.8-21.93 Mb。「野生型」MTAP意謂其由NM_002451編碼或具有相同胺基酸序列(NP_002442)。(Schmid等人Oncogene 2000,19，第5747-54頁)。"MTAP" as used herein refers to methylthioadenosine phosphorylase, an enzyme in the methionine reuse pathway, also known as S-methyl-5'-thioadenosine phosphorylase; Also known as BDMF, DMSFH, DMSMFH, LGMBF, MSAP, and c86fus. External ID: OMIM: 156540 MGI: 1914152 HomoloGene: 1838 chEMBL: 4941 GeneCards: MTAP gene; Entrez 4507; RefSeq(mRNA): NM__002451; Location: Chr 9: 21.8-21.93 Mb. "Wild type" MTAP means that it is encoded by NM_002451 or has the same amino acid sequence (NP_002442). (Schmid et al. Oncogene 2000, 19, pp. 5747-54).

如本文所用，術語「MTAP缺乏」、「MTAP缺乏症」、「MTAP無效」及其類似者係指其MTAP之轉譯後修飾、產生、表現、水準、穩定性及/或活性相對於對照(例如，參考或正常或非癌細胞)中顯著減少的細胞(包括但不限於癌細胞、細胞株、組織、組織類型、腫瘤等)。減少可為至少約20%、30%、 40%、50%、60%、70%、80%或90%。在一些實施例中，減少為至少20%。在一些實施例中，減少為至少50%。關於一或多個細胞等的術語「MTAP缺乏及/或MTA累積(MTAP-deficient and/or MTA accumulating，MTAP-deficient and/or MTA-accumulating」、「MTAP缺乏及/或MTA上調」及其類似者指示細胞等缺乏MTAP且/或過度產生或累積MTA。MTAP缺乏細胞包括其中MTAP基因已突變、缺失或轉錄沉默的細胞。作為非限制性實例，MTAP缺乏細胞可具有同型合子缺失。MTAP減弱並不致命。在一些實施例中，MTAP缺乏細胞亦為CDKN2A缺乏。MTAP缺乏症可使用此項技術中已知的任何試劑或技術進行偵測，例如：利用針對MTAP的抗體的免疫組織化學；及/或基因體定序；及/或核酸雜交；及/或利用至少一種包含MTAP序列之至少12個連續核苷酸(nt)之序列的探針或引子之擴增，其中引子不長於約30 nt。As used herein, the terms "MTAP deficiency", "MTAP deficiency", "MTAP null" and the like refer to their post-translational modification, production, expression, level, stability and/or activity of MTAP relative to a control (e.g. , reference or normal or non-cancer cells) significantly reduced cells (including but not limited to cancer cells, cell lines, tissues, tissue types, tumors, etc.). The reduction may be at least about 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the reduction is at least 20%. In some embodiments, the reduction is at least 50%. The terms "MTAP-deficient and/or MTA-accumulating, MTAP-deficient and/or MTA-accumulating", "MTAP-deficient and/or MTA-up-regulated" and the like in relation to one or more cells, etc. Those indicate cells, etc. that lack MTAP and/or overproduce or accumulate MTA. MTAP-deficient cells include cells in which the MTAP gene has been mutated, deleted, or transcriptionally silenced. As a non-limiting example, MTAP-deficient cells may have a homozygous deletion. MTAP is attenuated and Not lethal. In some embodiments, the MTAP deficient cells are also CDKN2A deficient. MTAP deficiency can be detected using any reagent or technique known in the art, for example: immunohistochemistry using antibodies against MTAP; and and/or nucleic acid hybridization; and/or amplification using at least one probe or primer comprising a sequence of at least 12 contiguous nucleotides (nt) of the MTAP sequence, wherein the primer is no longer than about 30 nt.

「MTAP缺乏症相關」或「MTAP缺乏症」或「MTAP缺乏」疾病(例如，增殖性疾病，例如 癌症)、或「與MTAP缺乏症相關之」疾病(例如，增殖性疾病，例如 癌症)、或「特徵在於MTAP缺乏症」之疾病(例如，增殖性疾病，例如 癌症)及其類似者係指其中大量細胞為MTAP缺乏的輕症(例如，增殖性疾病，例如 癌症)。例如，在MTAP缺乏症相關疾病中，一或多個患病細胞之MTAP之轉譯後修飾、產生、表現、水準、穩定性及/或活性可顯著減少。MTAP缺乏症相關疾病之實例包括但不限於癌症，包括但不限於：神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤(參見圖1)。在罹患MTAP缺乏症相關疾病之患者中，有可能一些患病 細胞(例如， 癌細胞)可為MTAP缺乏，而其他細胞則不是。類似地，一些患病細胞可為MTA累積，而其他細胞則不是。"MTAP-deficiency-related" or "MTAP-deficiency" or "MTAP-deficiency" diseases (e.g., proliferative diseases, such as cancer), or "MTAP-deficiency-related" diseases (e.g., proliferative diseases, such as cancer), Or diseases "characterized by MTAP deficiency" (e.g., proliferative diseases such as cancer) and the like refer to mild diseases (e.g., proliferative diseases such as cancer) in which a large number of cells are MTAP deficient. For example, in a disease associated with MTAP deficiency, the post-translational modification, production, expression, level, stability and/or activity of MTAP in one or more diseased cells can be significantly reduced. Examples of diseases associated with MTAP deficiency include, but are not limited to, cancer, including but not limited to: glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder Carcinoma ( eg, bladder urothelial carcinoma), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), star cell tumor, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural or colorectal cancer or sarcoma (see Figure 1). In a patient suffering from a disease associated with MTAP deficiency, it is possible that some diseased cells ( eg, cancer cells) may be MTAP deficient, while others are not. Similarly, some diseased cells can accumulate MTA, while others do not.

因此，本揭露涵蓋涉及這些組織或任何其他組織之疾病的治療方法，其中MTAP缺乏及/或MTA累積細胞之增殖可藉由投與PRMT5抑制劑來抑制。Accordingly, the present disclosure encompasses methods of treatment of diseases involving these tissues or any other tissue in which the proliferation of MTAP deficient and/or MTA accumulating cells can be inhibited by administration of a PRMT5 inhibitor.

一些MTAP缺乏的癌細胞亦缺乏CDKN2A；CDKN2A或其產物之轉譯後修飾、產生、表現、水準、穩定性及/或活性在這些細胞中降低。MTAP及CDKN2A之基因在染色體9p21上相鄰；MTAP位於CDKN2A之端粒端約100kb處。許多癌細胞類型具有CDKN2A/MTAP損失(兩種基因之損失)。因此，在一些實施例中，MTAP缺乏細胞亦缺乏CDKN2A。Some MTAP-deficient cancer cells also lack CDKN2A; post-translational modification, production, expression, levels, stability, and/or activity of CDKN2A or its products are reduced in these cells. The genes for MTAP and CDKN2A are adjacent on chromosome 9p21; MTAP is located about 100 kb from the telomeric end of CDKN2A. Many cancer cell types have CDKN2A/MTAP loss (loss of both genes). Thus, in some embodiments, the MTAP-deficient cells are also CDKN2A-deficient.

MTA及MTA累積MTA and MTA accumulation

「MTA」意謂PRMT5抑制劑，亦稱為甲基-硫腺苷、S-甲基-5'-硫腺苷、[5'去氧-5'-(甲基硫)-fl-D-呋喃核糖基]腺嘌呤、5'-甲基-硫腺苷、5'-去氧,5'-甲基硫腺苷及其類似者。MTA選擇性抑制PRMT5甲基轉移酶活性。MTA為MTAP之唯一已知異化代謝受質。術語「MTA累積」、「MTA過度產生」、「MTA上調」及其類似者係指其MTA之產生、水準及/或穩定性顯著增加的細胞(包括但不限於癌細胞、細胞株、組織、組織類型、腫瘤等)。MTA累積細胞包括以下細胞，其中細胞包含與在正常或非癌細胞中相比高至少約20%、30%、40%、50%、60%、70%、80%、90%、100%或大於100%的MTA之產生、水準及/或穩定性。在一些實施例中，MTA累積細胞包括以下細胞，其中細胞包含與在正常或非癌細胞中相比高至少20%的MTA之產生、水準及/或穩定性。在一些實施例中，MTA累積細胞包括以下細胞，其中細胞包含與在正常或非癌細胞中相比高至少50%的MTA之產生、水準及/或穩定性。測試樣品(例如， 正測試MTA累積的細胞，諸如癌細胞)及參考樣品及其他細胞、組織、樣品等中MTA累積之確定可使用此項技術中已知之任何方法來進行。此類用於偵測MTA的方法包括(作為非限制性實例) 液相層析-電噴霧電離-串聯式質譜法(LC-ESI-MS/MS)，如Stevens等人J.Chromatogr.A. 2010,1217，第3282-3288頁；及Kirovski等人Am.J.Pathol. 2011,178，第1145-1152頁及本文引用之參考文獻中所述。MTAP損失與MTA累積相關(Williams-Ashman等人Biochem.Pharm. 1982,31，第277-288頁；及Limm等人Eur.J.Cancer. 2013,49，第6期。"MTA" means PRMT5 inhibitor, also known as methyl-thioadenosine, S-methyl-5'-thioadenosine, [5'deoxy-5'-(methylthio)-fl-D- Ribofuranosyl] adenine, 5'-methyl-thioadenosine, 5'-deoxy, 5'-methylthioadenosine and the like. MTA selectively inhibits PRMT5 methyltransferase activity. MTA is the only known dissimilatory metabolic substrate for MTAP. The terms "MTA accumulation", "MTA overproduction", "MTA upregulation" and the like refer to cells (including but not limited to cancer cells, cell lines, tissues, tissue type, tumor, etc.). MTA accumulating cells include cells wherein the cells comprise at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% higher than in normal or non-cancerous cells, or The production, level and/or stability of MTA greater than 100%. In some embodiments, MTA accumulating cells include cells comprising at least 20% higher production, levels and/or stability of MTA compared to normal or non-cancerous cells. In some embodiments, MTA accumulating cells include cells comprising at least 50% higher production, levels and/or stability of MTA compared to normal or non-cancerous cells. Determination of MTA accumulation in test samples ( eg, cells being tested for MTA accumulation, such as cancer cells) and reference samples and other cells, tissues, samples, etc., can be performed using any method known in the art. Such methods for detecting MTA include, by way of non-limiting example, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), as described in Stevens et al . J. Chromatogr. A. 2010, 1217, pp. 3282-3288; and Kirovski et al . Am. J. Pathol. 2011, 178, pp. 1145-1152 and references cited herein. MTAP loss correlates with MTA accumulation (Williams-Ashman et al . Biochem. Pharm. 1982, 31, pp. 277-288; and Limm et al. Eur. J. Cancer. 2013, 49, no. 6.

「MTA累積相關」、「MTA累積(MTA-accumulation，MTA-accumulating)」、「MTA過度產生」、「MTA上調」疾病(例如，增殖性疾病，例如癌症)、或「與MTA累積相關」疾病(例如，增殖性疾病，例如癌症)、或「特徵在於MTA累積」之疾病(例如，增殖性疾病，例如癌症)及其類似者係指其中大量細胞為MTA累積的輕症(例如，增殖性疾病，例如癌症)。MTA累積相關疾病之實例包括但不限於癌症，包括但不限於：神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤(參見圖1)。在罹患MTAP缺乏症相關疾病之患者中，有可能一些患病細胞(例如， 癌細胞)可為MTAP缺乏，而其他細胞則不是。在患有或已診斷為患有MTA累積疾病之患者中，一些細胞可為MTA累積，而其他細胞不是。"MTA-accumulation-related", "MTA-accumulation (MTA-accumulating)", "MTA overproduction", "MTA-up-regulated" diseases (eg, proliferative diseases such as cancer), or "MTA-accumulation-related" diseases (e.g., proliferative diseases such as cancer), or diseases "characterized by MTA accumulation" (e.g., proliferative diseases such as cancer), and the like, refer to mild conditions in which a large number of cells accumulate MTA (e.g., proliferative disease, such as cancer). Examples of diseases associated with MTA accumulation include, but are not limited to, cancer, including but not limited to: glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytes tumor, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer , urinary tract cancer, liver cancer, soft tissue cancer, pleural or colorectal cancer or sarcoma (see Figure 1). In a patient suffering from a disease associated with MTAP deficiency, it is possible that some diseased cells ( eg, cancer cells) may be MTAP deficient, while others are not. In a patient with or diagnosed with an MTA accumulation disease, some cells may accumulate MTA while others are not.

正常細胞與MTAP缺失/MTA累積細胞之間的治療窗口之增加可藉由使用以與MTA無競爭地結合PRMT5之抑制劑來達成。如本文所用，「無競爭性結合」、及「無競爭性抑制」、及「協同結合」、及「協同抑制」(例如， MTA無競爭性結合、MTA無競爭性抑制、MTA協同結合、MTA協同抑制)係指抑制劑 與蛋白質(例如， PRMT5)之結合在存在輔助因子(例如， MTA)之情況下相對於同一抑制劑在不存在輔助因子之情況下之結合有所增加。此項技術中已知之PRMT5抑制劑通常為SAM(S-腺苷甲硫胺酸)無競爭的或SAM競爭的。由於在野生型及MTAP無效細胞中之SAM濃度類似，所以這些抑制劑預期以類似效力結合至兩種細胞類型。相比之下，MTA協同(及SAM競爭性或顯示出相對於SAM而與MTA之協同增強的)抑制劑將在存在高濃度MTA之情況下以明顯更大的效力結合，且因此將導致在MTA累積細胞中的PRMT5抑制相對於正常細胞優先。An increase in the therapeutic window between normal cells and MTAP deficient/MTA accumulating cells can be achieved by the use of inhibitors that bind PRMT5 without competition with MTA. As used herein, "uncompetitive binding", and "uncompetitive inhibition", and "cooperative binding", and "synergistic inhibition" ( eg, MTA uncompetitive binding, MTA uncompetitive inhibition, MTA synergistic binding, MTA Synergistic inhibition) refers to increased binding of an inhibitor to a protein ( eg, PRMT5) in the presence of a cofactor ( eg, MTA) relative to the binding of the same inhibitor in the absence of the cofactor. PRMT5 inhibitors known in the art are generally SAM (S-adenosylmethionine) uncompeted or SAM competitive. Since SAM concentrations were similar in wild-type and MTAP null cells, these inhibitors are expected to bind to both cell types with similar potency. In contrast, MTA synergistic (and SAM-competitive or exhibiting enhanced synergy with MTA relative to SAM) inhibitors will bind with significantly greater potency in the presence of high concentrations of MTA and will therefore result in PRMT5 inhibition in MTA accumulating cells is preferential over normal cells.

如本文進一步描述，癌細胞、癌類型或患有癌症之個體為「PRMT5抑制劑敏感」，「對使用PRMT5抑制劑之治療敏感」，「對PRMT5治療性抑制敏感」或若其易於用PRMT5抑制劑治療(例如， 由於其MTAP缺乏症及/或MTA累積特性)則以類似術語描述。As further described herein, cancer cells, cancer types, or individuals with cancer are "sensitive to PRMT5 inhibitors,""sensitive to treatment with PRMT5 inhibitors,""sensitive to therapeutic inhibition of PRMT5," or if they are susceptible to PRMT5 inhibition Agent therapy ( eg, due to its MTAP deficiency and/or MTA accumulation properties) is described in similar terms.

PRMT5PRMT5

如本文所用之「PRMT5」為基因或蛋白質蛋白精胺酸甲基轉移酶5，亦稱為HRMT1L5、IBP72、JBP1、SKB1或SKB1H。外部ID：OMIM：604045，MGI：1351645，HomoloGene：4454，ChEMBL：1795116，GeneCards：PRMT5 Gene；EC編號2.1.1.125.Ensembl ENSG00000100462；UniProt O14744；Entrez Gene ID：10419；RefSeq(mRNA)：NM_001039619。小鼠同源物為NM_013768。甲基轉移酶諸如PRMT5催化一至三個甲基自輔助因子S-腺苷甲硫胺酸(亦稱為SAM或AdoMet)向組蛋白之離胺酸或精胺酸的轉移。精胺酸甲基化藉由人類之9種不同的蛋白質精胺酸甲基轉移酶(PRMT)來進行。存在三種類型之甲基精胺酸物質：(1)單甲基精胺酸(MMA)；(2)不對稱二甲基精胺酸(ADMA)，其藉由I型甲基轉移酶(PRMT1、PRMT2、PRMT3、CARM1、PRMT6及PRMT8)產生；及(3)對稱二甲基精胺酸(SDMA)，其藉由II型甲基轉移酶(PRMT5及PRMT7)產生。PRMT1及PRMT5分別為主要的不對稱及對稱精胺酸甲基轉移酶。PRMT5 促進在組蛋白之H3R8及H4R3處之對稱二甲基化(H4R3me2)。H4R3之對稱甲基化與轉錄抑制相關且可用作DNMT3A之結合位點。PRMT5損失導致DNMT3A結合及基因活化減少。腫瘤抑制基因ST7及趨化介素RNATES、IP10、CXCL11經PRMT5靶向並沉默。WO 2011/079236。"PRMT5" as used herein is the gene or protein protein arginine methyltransferase 5, also known as HRMT1L5, IBP72, JBP1, SKB1 or SKB1H. External ID: OMIM: 604045, MGI: 1351645, HomoloGene: 4454, ChEMBL: 1795116, GeneCards: PRMT5 Gene; EC number 2.1.1.125. Ensembl ENSG00000100462; UniProt O14744; Entrez Gene ID: 10419; The mouse homologue is NM_013768. Methyltransferases such as PRMT5 catalyze the transfer of one to three methyl groups from the cofactor S-adenosylmethionine (also known as SAM or AdoMet) to histone lysine or arginine. Arginine methylation is carried out by 9 different protein arginine methyltransferases (PRMTs) in humans. There are three types of methylarginine species: (1) monomethylarginine (MMA); (2) asymmetric dimethylarginine (ADMA), which is produced by a type I methyltransferase ( PRMT1, PRMT2, PRMT3, CARM1, PRMT6 and PRMT8); and (3) symmetric dimethylarginine (SDMA), which is produced by type II methyltransferases (PRMT5 and PRMT7). PRMT1 and PRMT5 are the major asymmetric and symmetric arginine methyltransferases, respectively. PRMT5 Promotes symmetric dimethylation (H4R3me2) at H3R8 and H4R3 of histones. Symmetrical methylation of H4R3 is associated with transcriptional repression and serves as a binding site for DNMT3A. Loss of PRMT5 results in reduced DNMT3A binding and gene activation. The tumor suppressor gene ST7 and the chemokines RNATES, IP10, and CXCL11 were targeted and silenced by PRMT5. WO 2011/079236.

額外受質包括E2F1、p53、EGFR及CRAF。PRMT5在G1/S轉換期間為包含共調節因子WDR77(亦稱為MEP50，為CDK4受質)之多蛋白複合物。磷酸化增加PRMT5/WDR77活性。WDR77為複合物之非催化組分且介導與結合配偶體(partner)及受質之相互作用。PRMT5亦可以相互排斥的方式與pICIn或RioK1轉接蛋白相互作用以調節複合物組成及受質特異性。Additional substrates include E2F1, p53, EGFR and CRAF. PRMT5 is a multiprotein complex containing the coregulator WDR77 (also known as MEP50, a substrate for CDK4) during the G1/S transition. Phosphorylation increases PRMT5/WDR77 activity. WDR77 is the non-catalytic component of the complex and mediates interactions with binding partners and substrates. PRMT5 can also interact with pICIn or RioK1 adaptor proteins in a mutually exclusive manner to modulate complex composition and substrate specificity.

PRMT5當與許多複合物相互作用時藉由精胺酸甲基化而對其受質具有陽性或陰性作用且參與多種細胞過程，包括RNA加工、訊息轉導、轉錄調節及生殖細胞發育。PRMT5為調節eIF4E表現及p53轉譯的主要促存活因子。PRMT5誘發p53依賴性細胞凋亡且使各種癌細胞對腫瘤壞死因子(TNF)相關細胞凋亡誘導性配體(TRAIL)敏感而不影響非轉型細胞中之TRAIL抗性。PRMT5 has positive or negative effects on its substrates through arginine methylation when interacting with a number of complexes and is involved in a variety of cellular processes, including RNA processing, signal transduction, transcriptional regulation, and germ cell development. PRMT5 is a major pro-survival factor regulating eIF4E expression and p53 translation. PRMT5 induces p53-dependent apoptosis and sensitizes various cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) without affecting TRAIL resistance in non-transformed cells.

術語「PRMT5抑制劑」係指能夠抑制PRMT5之產生、水準、活性、表現或存在的任何化合物。這些包括(作為非限制性實例)抑制基因之轉錄、RNA之成熟、mRNA之轉譯、蛋白質之轉譯後修飾、蛋白質之酶促活性、其與受質之相互作用等的任何化合物。該術語亦指代藉由活性位點之ATP競爭性抑制、蛋白質結構之異位調節、蛋白質-蛋白質相互作用之破壞或藉由抑制PRMT5蛋白之轉錄、轉譯、轉譯後修飾或穩定性來抑制PRMT5蛋白之細胞功能的任何劑。The term "PRMT5 inhibitor" refers to any compound capable of inhibiting the production, level, activity, expression or presence of PRMT5. These include, by way of non-limiting example, any compound that inhibits transcription of a gene, maturation of RNA, translation of mRNA, post-translational modification of a protein, enzymatic activity of a protein, its interaction with a substrate, and the like. The term also refers to inhibition of PRMT5 by ATP-competitive inhibition of the active site, ectopic regulation of protein structure, disruption of protein-protein interactions, or by inhibition of transcription, translation, post-translational modification, or stability of the PRMT5 protein Any agent of the cellular function of a protein.

在一些實施例中，PRMT5抑制劑與同PRMT5相互作用的另一種化合物、蛋白質或其他分子競爭且為PRMT5功能所必需的。作為非限制性實例，PRMT5抑制劑可與輔助因子S-腺苷甲硫胺酸(亦稱為SAM或AdoMet)競爭。In some embodiments, the PRMT5 inhibitor competes with another compound, protein or other molecule that interacts with PRMT5 and is required for PRMT5 function. As a non-limiting example, PRMT5 inhibitors can compete with the cofactor S-adenosylmethionine (also known as SAM or AdoMet).

在一些實施例中，PRMT5抑制劑與MTA無競爭。在其他實施例中，PRMT5抑制劑與MTA無競爭且與SAM有競爭。In some embodiments, the PRMT5 inhibitor does not compete with MTA. In other embodiments, the PRMT5 inhibitor does not compete with MTA and competes with SAM.

在一些實施例中，PRMT5抑制劑與MTA無競爭且與SAM無競爭，但對於MTA複合物以相對於SAM複合物更高的效力程度結合。In some embodiments, the PRMT5 inhibitor does not compete with MTA and does not compete with SAM, but binds to the MTA complex with a higher degree of potency relative to the SAM complex.

化學定義chemical definition

特定官能團及化學術語之定義在下文中更詳細地描述。化學元素根據元素週期表，CAS版，Handbook of Chemistry and Physics ，第75版，內封面來鑑定，且特定官能團通常如本文所描述地定義。另外，有機化學之一般理論以及特定官能部分及反應性描述於Thomas Sorrell,Organic Chemistry ,University Science Books,Sausalito,1999；Smith及March,March's Advanced Organic Chemistry ，第5版，John Wiley & Sons,Inc.,New York,2001；Larock,Comprehensive Organic Transformations ,VCH Publishers,Inc.,New York,1989；及Carruthers,Some Modern Methods of Organic Synthesis ，第3版，Cambridge University Press,Cambridge,1987中。Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics , 75th Edition, inside cover, and specific functional groups are generally defined as described herein. Additionally, general theory of organic chemistry as well as specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry , University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry , 5th Edition, John Wiley & Sons, Inc. , New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , 3rd Edition, Cambridge University Press, Cambridge, 1987.

本文所述之化合物可包含一或多個不對稱中心，且因此可以各種異構形式存在，例如 鏡像異構物及/或非鏡像異構物。例如，本文所述之化合物可以呈個別鏡像異構物、非鏡像異構物或幾何異構物之形式，或可呈立體異構物之混合物之形式，包括外消旋混合物及富含一或多種立體異構物的混合物。異構物可藉由熟習此項技術者已知之方法自混合物分離，該等方法包括高壓液相層析(HPLC)及掌性鹽之形成及結晶；或較佳異構物可藉由不對稱合成來製備。參見例如Jacques等人，Enantiomers,Racemates and Resolutions (Wiley Interscience,New York,1981)；Wilen等人，Tetrahedron 33：2725(1977)；Eliel,Stereochemistry of Carbon Compounds (McGraw-Hill,NY,1962)；及Wilen,Tables of Resolving Agents and Optical Resolutions 第268頁(E.L.Eliel編，Univ.of Notre Dame Press,Notre Dame,IN 1972)。本發明另外涵蓋在本文中描述為實質上不含其他異構物的個別異構物及替代地描述為各種異構物之混合物的化合物。The compounds described herein may contain one or more asymmetric centers, and thus may exist in various isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and enriched in one or Mixtures of various stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferably isomers can be separated by asymmetric synthetically prepared. See, eg, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions , p. 268 (ed. ELEliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses individual isomers described herein as being substantially free of other isomers and compounds described alternatively as mixtures of the various isomers.

如本文所用之組成物之「鏡像異構物超越量」(「e.e.」)或「%鏡像異構物超越量」(「%e.e.」)係指存在於組成物中之一種鏡像異構物相對於另一種鏡像異構物之超越量。例如，組成物可含有90%之一種鏡像異構物(例如， S鏡像異構物)及10%之另一種鏡像異構物(亦即，R鏡像異構物)。As used herein, "enantiomer excess"("ee") or "% enantiomer excess"("%ee") of a composition refers to the relative amount of one enantiomer present in the composition The transcendent amount of another mirror isomer. For example, a composition may contain 90% of one enantiomer ( eg, S enantiomer) and 10% of the other enantiomer (ie, R enantiomer).

e.e.=(90-10)/100=80%。e.e.=(90-10)/100=80%.

因此，含有90%之一種鏡像異構物及10%之另一種鏡像異構物之組成物被稱為鏡像異構物超越量為80%。Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is referred to as an excess of 80% enantiomer.

如本文所用之組成物之「非鏡像異構物超越量」(「d.e.」)或「%非鏡像異構物超越量」(「%d.e.」)係指存在於組成物中之一種非鏡像異構物相對於一或多種不同的非鏡像異構物之超越量。例如，組成物可含有90%之一種非鏡像異構物及10%之一或多種不同的非鏡像異構物。As used herein, "aspiroisomer excess" ("d.e.") or "% non-spideromer excess" ("% d.e.") of a composition refers to a non-spideromer present in the composition The excess amount of a construct relative to one or more different diastereoisomers. For example, a composition may contain 90% of one diastereomer and 10% of one or more different diastereomers.

d.e.=(90-10)/100=80%。d.e.=(90-10)/100=80%.

因此，含有90%之一種非鏡像異構物及10%之一或多種不同的非鏡像異構物之組成物被稱為非鏡像異構物超越量為80%。Thus, a composition containing 90% of one diastereomer and 10% of one or more of the different diastereomers is referred to as the 80% excess of the diastereomer.

在一個替代性實施例中，本文所述之化合物亦可包含一或多個同位素取代。例如，氫可為2 H(D或氘)或3 H(T或氚)；碳可為例如13 C或14 C；氧可為例如18 O；氮可為例如15 N及其類似者。在其他實施例中，特定同位素(例如， 3 H、13 C、14 C、18 O或15 N)可表示佔據化合物之特定位點之元素的總同位素豐度之至少1%、至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少99%或至少99.9%。In an alternative embodiment, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen can be2H (D or deuterium) or3H (T or tritium); carbon can be, for example, 13C or14C ; oxygen can be, for example, 18O ; nitrogen can be, for example, 15N and the like. In other embodiments, a particular isotope ( eg, 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75% %, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%.

在一式中，

Figure 110128222-A0202-12-0035-677
為單鍵，其中與之直接連接的部分之立體化學未經指 定。In one formula,
Figure 110128222-A0202-12-0035-677
is a single bond in which the stereochemistry of the moiety to which it is directly attached is unspecified.

當列出值之範圍時，意欲涵蓋該範圍之各值及子範圍。例如，「C1-6 烷基」意欲涵蓋C1 、C2 、C3 、C4 、C5 、C6 、C1-6 、C1-5 、C1-4 、C1-3 、C1-2 、C2-6 、C2-5 、C2-4 、C2-3 、C3-6 、C3-5 、C3-4 、C4-6 、C4-5 及C5-6 烷基。When a range of values is listed, it is intended to encompass each value and sub-range of that range. For example, "C 1-6 alkyl" is intended to encompass C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

以下術語意欲具有下文中與之一起呈現的含義且可用於理解本發明之描述及預期範圍。當描述可包括化合物、含有此類化合物之醫藥組成物及使用此類化合物及組成物之方法的發明時，除非另外指示，否則以下術語(若存在的話)具有以下含義。亦應理解，當在本文中描述時，下文所定義之部分中任一者均可經多個取代基取代且相應定義意欲在其如下文所列出之範圍內包括此類經取代之部分。除非另外說明，否則術語「經取代」如下文所列出地定義。應進一步理解，術語「基(group)」及「基團(radical)」當在本文中使用時可被認為可互換的。冠詞「一個/種(a/an)」可在本文中用於指代冠詞之一個或多於一個(亦即，至少一個)語法對象。舉例而言，「一類似物」意謂一種類似物或多於一種類似物。The following terms are intended to have the meanings presented together with them hereinafter and can be used to understand the description and intended scope of the invention. When describing inventions that may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, if present, have the following meanings, unless otherwise indicated. It is also to be understood that, when described herein, any of the moieties defined below may be substituted with multiple substituents and the corresponding definitions are intended to include such substituted moieties within their scope as set forth below. Unless otherwise stated, the term "substituted" is defined as set forth below. It will be further understood that the terms "group" and "radical" may be considered interchangeable when used herein. The article "a/an" may be used herein to refer to one or more than one (ie, at least one) grammatical object of the article. For example, "an analog" means one analog or more than one analog.

術語「不飽和鍵」係指雙鍵或參鍵。The term "unsaturated bond" refers to a double bond or a double bond.

術語「不飽和」或「部分不飽和」係指包括至少一個雙鍵或參鍵的部分。The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or double bond.

術語「飽和」係指不含有雙鍵或參鍵的部分，亦即部分僅含有單鍵。將後綴「-伸(-ene)」附接至基團指示基團為二價部分，例如， 伸烷基為烷基之二價部分，伸烯基為烯基之二價部分，伸炔基為炔基之二價部分，伸雜烷基為雜烷基之二價部分，伸雜烯基為雜烯基之二價部分，伸雜炔基為雜炔基之二價部分，伸碳環基為碳環基之二價部分，伸雜環基為雜環基之二價部分，伸芳基為芳基之二價部分，且伸雜芳基為雜芳基之二價部分。The term "saturated" refers to a moiety that does not contain double bonds or double bonds, ie the moiety contains only single bonds. Attaching the suffix "-ene" to a group indicates that the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkenylene It is the divalent part of the alkynyl group, the heteroalkylene group is the divalent part of the heteroalkyl group, the heteroalkenyl group is the divalent part of the heteroalkenyl group, the heteroalkynyl group is the divalent part of the heteroalkynyl group, and the carbocyclic extension Radix is the divalent moiety of a carbocyclyl, heterocyclylene is the divalent moiety of a heterocyclyl, arylextended is the divalent moiety of an aryl, and heteroarylextended is the divalent moiety of a heteroaryl.

術語「疊氮基」係指基團-N3 。The term "azido" refers to the group -N3 .

「脂族」係指如本文所定義之烷基、烯基、炔基或碳環基。"Aliphatic" refers to an alkyl, alkenyl, alkynyl or carbocyclyl group as defined herein.

「環烷基烷基」係指以下烷基基團，其中烷基經環烷基取代。典型環烷基烷基包括但不限於環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基、環辛基甲基、環丙基乙基、環丁基乙基、環戊基乙基、環己基乙基、環庚基乙基及環辛基乙基及其類似者。"Cycloalkylalkyl" refers to an alkyl group wherein the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclo Butylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl and cyclooctylethyl and the like.

「雜環基烷基」係指以下烷基基團，其中烷基經雜環基取代。典型雜環基烷基包括但不限於吡咯啶基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、吡咯啶基乙基、哌啶基乙基、哌嗪基乙基、嗎啉基乙基及其類似者。「芳烷基」或「芳基烷基」為如本文所定義之烷基及芳基之子集，且係指藉由視情況經取代之芳基取代的視情況經取代之烷基。"Heterocyclylalkyl" refers to an alkyl group wherein the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl group, morpholinoethyl and the like. "Aralkyl" or "arylalkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl substituted with an optionally substituted aryl.

「烷基」係指具有1至20個碳原子之直鏈或分枝飽和烴基(「C1-20 烷基」)。在一些實施例中，烷基具有1至12個碳原子(「C1-12 烷基」)。在一些實施例中，烷基具有1至10個碳原子(「C1-10 烷基」)。在一些實施例中，烷基具有1至9個碳原子(「C1-9 烷基」)。在一些實施例中，烷基具有1至8個碳原子(「C1-8 烷基」)。在一些實施例中，烷基具有1至7個碳原子(「C1-7 烷基」)。在一些實施例中，烷基具有1至6個碳原子(「C1-6 烷基」，在本文中亦稱為「低級烷基」)。在一些實施例中，烷基具有1至5個碳原子(「C1-5 烷基」)。在一些實施例中，烷基具有1至4個碳原子(「C1-4 烷基」)。在一些實施例中，烷基具有1至3個碳原子(「C1-3 烷基」)。在一些實施例中，烷基具有1至2個碳原子(「C1-2 烷基」)。在一些實施例中，烷基具有1個碳原子(「C1 烷基」)。在一些實施例中，烷基具有2至6個碳原子(「C2-6 烷基」)。C1-6 烷基之實例包括甲基(C1 )、乙基(C2 )、正丙基(C3 )、異丙基(C3 )、正丁基(C4 )、第三丁基(C4 )、第二丁基(C4 )、異丁基(C4 )、正戊基(C5 )、3-戊基(C5 )、戊基(C5 )、新戊基(C5 )、3-甲基-2-丁基(C5 )、第三戊基(C5 )及正己基(C6 )。烷基之額外實例包括正庚基(C7 )、正辛基(C8 )等。除非另外指定，否則烷基之各 實例獨立地視情況經取代，亦即未經取代(「未經取代之烷基」)或經一或多個取代基(例如， 1至5個取代基、1至3個取代基或1個取代基)取代(「經取代之烷基」)。在某些實施例中，烷基為未經取代之C1-10 烷基(例如， -CH3 )。在某些實施例中，烷基為經取代之C1-10 烷基。常見烷基縮寫包括Me(-CH3 )、Et(-CH2 CH3 )、 i Pr(-CH(CH3 )2 )、 n Pr(-CH2 CH2 CH3 )、 n Bu(-CH2 CH2 CH2CH3 )或 i Bu(-CH2 CH(CH3 )2 )。"Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms (" C1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl"). Examples of C 1-6 alkyl include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tertiary pentyl (C 5 ) and n-hexyl (C 6 ). Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, that is, unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ( eg, 1 to 5 substituents, 1 to 3 substituents or 1 substituent) substituted ("substituted alkyl"). In certain embodiments, the alkyl group is an unsubstituted C 1-10 alkyl group ( eg, -CH 3 ). In certain embodiments, the alkyl group is a substituted C 1-10 alkyl group. Common alkyl abbreviations include Me(-CH 3 ), Et(-CH 2 CH 3 ), i Pr(-CH(CH 3 ) 2 ), n Pr(-CH 2 CH 2 CH 3 ), n Bu(-CH 2CH2CH2CH3 ) or iBu (-CH2CH ( CH3 ) 2 ) .

「伸烷基」係指其中兩個氫經移除以提供二價基團且其可經取代或未經取代的烷基。未經取代之伸烷基包括但不限於亞甲基(-CH2 -)、伸乙基(-CH2 CH2 -)、伸丙基(-CH2 CH2 CH2 -)、伸丁基(-CH2 CH2 CH2 CH2 -)、伸戊基(-CH2 CH2 CH2 CH2 CH2 -)、伸己基(-CH2 CH2 CH2 CH2 CH2 CH2 -)等。示範性經取代之伸烷基(例如， 經一或多個烷基(甲基)取代)包括但不限於經取代之亞甲基(-CH(CH3 )-、(-C(CH3 )2 -)、經取代之伸乙基(-CH(CH3 )CH2 -、-CH2 CH(CH3 )-、-C(CH3 )2 CH2 -、-CH2 C(CH3 )2 -)、經取代之伸丙基(-CH(CH3 )CH2 CH2 -、-CH2 CH(CH3 )CH2 -、-CH2 CH2 CH(CH3 )-、-C(CH3 )2 CH2 CH2 -、-CH2 C(CH3 )2 CH2 -、-CH2 CH2 C(CH3 )2 -)等。當提供特定伸烷基之碳之範圍或數目時，應理解該範圍或數目係指線性碳二價鏈中碳之範圍或數目。伸烷基可經一或多個如本文所述之取代基取代或未經取代。"Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent group, which may be substituted or unsubstituted. Unsubstituted alkylene groups include but are not limited to methylene ( -CH2- ), ethylidene ( -CH2CH2- ) , propylidene ( -CH2CH2CH2- ) , butylene (-CH 2 CH 2 CH 2 CH 2 -), Pentyl (-CH 2 CH 2 CH 2 CH 2 CH 2 -), Hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), etc. . Exemplary substituted alkylene groups ( eg, substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted methylene groups (-CH( CH3 )-, (-C( CH3 ) 2 -), substituted ethylidene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -), substituted propylidene (-CH( CH3 )CH2CH2-, -CH2CH( CH3 )CH2-, -CH2CH2CH ( CH3 ) - , -C ( CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), etc. When providing the range or number of carbons for a particular alkylene It should be understood that the range or number refers to the range or number of carbons in the linear carbon bivalent chain. The alkylene group may be substituted or unsubstituted with one or more substituents as described herein.

「烯基」係指具有2至20個碳原子、一或多個碳-碳雙鍵(例如， 1、2、3或4個碳-碳雙鍵)及視情況一或多個碳-碳參鍵(例如， 1、2、3或4個碳-碳參鍵)(「C2-20 烯基」)之直鏈或分枝烴基。在某些實施例中，烯基不含有任何參鍵。在一些實施例中，烯基具有2至10個碳原子(「C2-10 烯基」)。在一些實施例中，烯基具有2至9個碳原子(「C2-9 烯基」)。在一些實施例中，烯基具有2至8個碳原子(「C2-8 烯基」)。在一些實施例中，烯基具有2至7個碳原子(「C2-7 烯基」)。在一些實施例中，烯基具有2至6個碳原子(「C2-6 烯基」)。在一些實施例中，烯基具有2至5個碳原子(「C2-5 烯基」)。在一些實施例中，烯基具有2至4個碳原子(「C2-4 烯基」)。在一些實施例中，烯基具有2至3個碳原子(「C2-3 烯基」)。在一些實施例中，烯基具有2個碳原子(「C2 烯基」)。一或多個碳-碳雙鍵可在內部(諸如在2-丁烯基中)或末端(諸如在1-丁烯基中)。C2-4 烯基之實例包括乙烯基(C2 )、1-丙烯基(C3 )、2-丙烯基(C3 )、1-丁烯基(C4 )、2-丁烯基(C4 )、丁二烯基(C4 )及其類似者。C2-6 烯基之實例包括前述C2-4 烯基以及戊烯基(C5 )、戊二烯基(C5 )、己烯基(C6 )及其類似者。烯基之額外實例包括庚烯基(C7 )、辛烯基(C8 )、辛三烯基(C8 )及其類似者。除非另外指定，否則烯基之各實例獨立地視情況經取代，亦即未經取代(「未經取代之烯基」)或經一或多個取代基(例如， 1至5個取代基、1至3個取代基或1個取代基)取代(「經取代之烯基」)。在某些實施例中，烯基為未經取代之C2-10 烯基。在某些實施例中，烯基為經取代之C2-10 烯基。"Alkenyl" means having 2 to 20 carbon atoms, one or more carbon-carbon double bonds ( eg, 1, 2, 3 or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon bonds A linear or branched hydrocarbon group with a double bond ( eg, 1, 2, 3, or 4 carbon-carbon bonds) (" C2-20 alkenyl"). In certain embodiments, the alkenyl group does not contain any double bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C 2-4 alkenyl groups include vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl ( C 4 ), butadienyl (C 4 ) and the like. Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl groups include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of alkenyl is independently optionally substituted, that is, unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ( eg, 1 to 5 substituents, 1 to 3 substituents or 1 substituent) substituted ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl group. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl group.

「炔基」係指具有2至20個碳原子、一或多個碳-碳參鍵(例如， 1、2、3或4個碳-碳參鍵)及視情況一或多個碳-碳雙鍵(例如， 1、2、3或4個碳-碳雙鍵)(「C2-20 炔基」)之直鏈或分枝烴基。在某些實施例中，炔基不含有任何雙鍵。在一些實施例中，炔基具有2至10個碳原子(「C2-10 炔基」)。在一些實施例中，炔基具有2至9個碳原子(「C2-9 炔基」)。在一些實施例中，炔基具有2至8個碳原子(「C2-8 炔基」)。在一些實施例中，炔基具有2至7個碳原子(「C2-7 炔基」)。在一些實施例中，炔基具有2至6個碳原子(「C2-6 炔基」)。在一些實施例中，炔基具有2至5個碳原子(「C2-5 炔基」)。在一些實施例中，炔基具有2至4個碳原子(「C2-4 炔基」)。在一些實施例中，炔基具有2至3個碳原子(「C2-3 炔基」)。在一些實施例中，炔基具有2個碳原子(「C2 炔基」)。一或多個碳-碳參鍵可在內部(諸如在2-丁炔基中)或末端(諸如在1-丁炔基中)。C2-4 炔基之實例包括但不限於乙炔基(C2 )、1-丙炔基(C3 )、2-丙炔基(C3 )、1-丁炔基(C4 )、2-丁炔基(C4 )及其類似者。C2-6 烯基之實例包括前述C2-4 炔基以及戊炔基(C5 )、己炔基(C6 )及其類似者。炔基之額外實例包括庚炔基(C7 )、辛炔基(C8 )及其類似者。除非另外指定，否則炔基之各 實例獨立地視情況經取代，亦即未經取代(「未經取代之炔基」)或經一或多個取代基(例如， 1至5個取代基、1至3個取代基或1個取代基)取代(「經取代之炔基」)。在某些實施例中，炔基為未經取代之C2-10 炔基。在某些實施例中，炔基為經取代之C2-10 炔基。"Alkynyl" means having 2 to 20 carbon atoms, one or more carbon-carbon bonds ( eg, 1, 2, 3 or 4 carbon-carbon bonds), and optionally one or more carbon-carbon bonds Linear or branched hydrocarbon groups of double bonds ( eg, 1, 2, 3 or 4 carbon-carbon double bonds) (" C2-20 alkynyl"). In certain embodiments, the alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (" C2-4alkynyl "). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C 2-4 alkynyl groups include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2 -butynyl (C 4 ) and the like. Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl groups include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of alkynyl is independently optionally substituted, that is, unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ( eg, 1 to 5 substituents, 1 to 3 substituents or 1 substituent) substituted ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl group. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl group.

如本文所用，術語「雜烷基」係指如本文所定義之烷基，其進一步在母體鏈內包含1或多個(例如， 1、2、3或4個)雜原子(例如， 氧、硫、氮、硼、矽、磷)，其中該一或多個雜原子插入在母體碳鏈內之相鄰碳原子之間，且/或一或多個雜原子插入在碳原子與母體分子之間，亦即連接點之間。在某些實施例中，雜烷基係指具有1至10個碳原子及1、2、3或4個雜原子之飽和基團(「雜C1-10 烷基」)。在一些實施例中，雜烷基為具有1至9個碳原子及1、2、3或4個雜原子之飽和基團(「雜C1-9 烷基」)。在一些實施例中，雜烷基為具有1至8個碳原子及1、2、3或4個雜原子之飽和基團(「雜C1-8 烷基」)。在一些實施例中，雜烷基為具有1至7個碳原子及1、2、3或4個雜原子之飽和基團(「雜C1-7 烷基」)。在一些實施例中，雜烷基為具有1至6個碳原子及1、2或3個雜原子之基團(「雜C1-6 烷基」)。在一些實施例中，雜烷基為具有1至5個碳原子及1或2個雜原子之飽和基團(「雜C1-5 烷基」)。在一些實施例中，雜烷基為具有1至4個碳原子及1或2個雜原子之飽和基團(「雜C1-4 烷基」)。在一些實施例中，雜烷基為具有1至3個碳原子及1個雜原子之飽和基團(「雜C1-3 烷基」)。在一些實施例中，雜烷基為具有1至2個碳原子及1個雜原子之飽和基團(「雜C1-2 烷基」)。在一些實施例中，雜烷基為具有1個碳原子及1個雜原子之飽和基團(「雜C1 烷基」)。在一些實施例中，雜烷基為具有2至6個碳原子及1或2個雜原子之飽和基團(「雜C2-6 烷基」)。除非另外指定，否則雜烷基之各實例獨立地未經取代(「未經取代之雜烷基」)或經一或多個取代基取代(「經取代之雜烷基」)。在某些實施例中，雜烷基為未經取代之雜C1-10 烷基。在某些實施例中，雜烷基為經取代之雜C1-10 烷基。示範性雜烷基包括： -CH2 OH、-CH2 OCH3 、-CH2 NH2 、-CH2 NH(CH3 )、-CH2 N(CH3 )2 、-CH2 CH2 OH、-CH2 CH2 OCH3 、-CH2 CH2 NH2 、-CH2 CH2 NH(CH3 )、-CH2 CH2 N(CH3 )2 。As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, that further comprises 1 or more ( eg, 1, 2, 3, or 4) heteroatoms ( eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain, and/or one or more heteroatoms are inserted between the carbon atom and the parent molecule between the connection points. In certain embodiments, heteroalkyl refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (" heteroC1-10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi- 9alkyl "). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (" heteroCi_8alkyl "). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi- 7alkyl "). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (" heteroCi_6alkyl "). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroCi_4alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (" heteroC2-6alkyl "). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, heteroalkyl is unsubstituted heteroC 1-10 alkyl. In certain embodiments, heteroalkyl is substituted heteroC 1-10 alkyl. Exemplary heteroalkyl groups include: -CH2OH , -CH2OCH3 , -CH2NH2 , -CH2NH ( CH3 ) , -CH2N ( CH3 ) 2 , -CH2CH2OH , -CH2CH2OCH3 , -CH2CH2NH2 , -CH2CH2NH ( CH3 ) , -CH2CH2N ( CH3 ) 2 .

「芳基」係指具有在芳族環體系中提供之6-14個環碳原子及零個雜原子的單環或多環(例如， 雙環或三環)4n+2芳族環體系(例如， 具有在環狀陣列中共享之6、10或14個π電子)(「C6-14 芳基」)。在一些實施例中，芳基具有六個環碳原子(「C6 芳基」；例如， 苯基)。在一些實施例中，芳基具有十個環碳原子(「C10 芳基」；例如， 萘基，諸如1-萘基及2-萘基)。在一些實施例中，芳基具有十四個環碳原子(「C14 芳基」；例如， 蒽基)。「芳基」亦包括以下環體系，其中如上文所定義之芳基環與一或多個碳環基或雜環基稠合，其中連接基團或連接點係在芳基環上，且在此類情況下，碳原子之數目繼續指示芳基環體系中碳原子之數目。具體而言，芳基包括苯基、萘基、茚基及四氫萘基。除非另外指定，否則芳基之各實例獨立地視情況經取代，亦即未經取代(「未經取代之芳基」)或經一或多個取代基取代(「經取代之芳基」)。在某些實施例中，芳基為未經取代之C6-14 芳基。在某些實施例中，芳基為經取代之C6-14 芳基。"Aryl" refers to a monocyclic or polycyclic ( eg, bicyclic or tricyclic) 4n+2 aromatic ring system ( eg , bicyclic or tricyclic) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system , with 6, 10 or 14 pi electrons shared in a ring array) ("C 6-14 aryl"). In some embodiments, an aryl group has six ring carbon atoms (" C6 aryl"; eg, phenyl). In some embodiments, aryl groups have ten ring carbon atoms (" C10 aryl"; eg, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (" C14 aryl"; eg, anthracenyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, wherein the group or point of attachment is on the aryl ring and in In such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Specifically, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of aryl is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl") . In certain embodiments, aryl is unsubstituted C6-14 aryl. In certain embodiments, aryl is substituted C 6-14 aryl.

在某些實施例中，芳基經一或多個選自以下之基團取代：鹵基、C1 -C8 烷基、C1 -C8 鹵烷基、氰基、羥基、C1 -C8 烷氧基及胺基。In certain embodiments, the aryl group is substituted with one or more groups selected from the group consisting of: halo, C1 - C8 alkyl, C1 - C8 haloalkyl, cyano, hydroxy, C1- C 8 alkoxy and amine groups.

代表性經取代之芳基之實例包括以下Examples of representative substituted aryl groups include the following

Figure 110128222-A0202-12-0041-1125
其中R56 及R57 中之一者可為氫，且R56 及R57 中之至少一者各自獨立地選自C1 -C8 烷基、C1 -C8 鹵烷基、4-10員雜環基、烷醯基、C1 -C8 烷氧基、雜芳基氧基、烷胺基、芳胺基、雜芳胺基、NR58 COR59 、NR58 SOR59 NR58 SO2 R59 、COO烷基、COO芳基、CONR58 R59 、CONR58 OR59 、NR58 R59 、SO2 NR58 R59 、S-烷基、SO烷基、SO2 烷基、S芳基、SO芳基、SO2 芳基；或R56 及R57 可連接以形成5至8個原子之視情況含有一或多個選自組N、O或S之雜原子之環狀環(飽和或不飽和)。R60 及R61 獨立地為氫、C1 -C8 烷基、C1 -C4 鹵烷基、C3 -C10 環烷基、4-10員雜環基、C6 -C10 芳基、經取代之C6 -C10 芳基、5-10員雜芳基或經取代之5-10員雜芳基。
Figure 110128222-A0202-12-0041-1125
 wherein one of R 56 and R 57 can be hydrogen, and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 Member Heterocyclyl, Alkyl, C1 - C8alkoxy , Heteroaryloxy, Alkylamino, Arylamino, Heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COO alkyl, COO aryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SO alkyl, SO 2 alkyl, S aryl , SO aryl, SO 2 aryl; or R 56 and R 57 may be linked to form a cyclic ring of 5 to 8 atoms optionally containing one or more heteroatoms selected from the group N, O or S (saturated or unsaturated). R 60 and R 61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl group, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl.

「稠合芳基」係指以下芳基，其與第二芳基或雜芳基環或與碳環基或雜環基環共同具有兩個環碳。"Fused aryl" refers to an aryl group having two ring carbons in common with the second aryl or heteroaryl ring or with the carbocyclyl or heterocyclyl ring.

「雜芳基」係指具有在芳族環體系中提供之環碳原子及1-4個環雜原子的5-10員單環或雙環4n+2芳族環體系(例如， 具有在環陣列中共享之6或10個π電子)，其中各雜原子獨立地選自氮、氧及硫(「5-10員雜芳基」)。在含有一或多個氮原子之雜芳基中，當化合價允許時，連接點可為碳或氮原子。雜芳基雙環環體系可在一個或兩個環中包括一或多個雜原子。「雜芳基」包括以下環體系，其中如上文所定義之雜芳基環與一或多個碳環基或雜環基稠合，其中連接點係在雜芳基環上，且在此類情況下，環成員之數目繼續指示雜芳基環體系中環成員之數目。「雜芳基」亦包括以下環體系，其中如上文所定義之雜芳基環與一或多個芳基稠合，其中連接點係在芳基或雜芳基環上，且在此類情況下，環成員之數目指示稠合(芳基/雜芳基)環體系中環成員之數目。雙環雜芳基，其中一個環不含有雜原子(例如， 吲哚基、喹啉基、咔唑基及其類似者)，連接點可在任一環上，亦即攜帶雜原子之環(例如， 2-吲哚基)或不含有雜原子之環(例如， 5-吲哚基)。"Heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in an aromatic ring system ( eg, having a ring array 6 or 10 π electrons shared in ), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in which In this case, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases Below, the number of ring members indicates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom ( eg, indolyl, quinolinyl, carbazolyl, and the like), and the point of attachment may be on either ring, ie, the ring bearing the heteroatom ( eg, 2 -indolyl) or a ring containing no heteroatoms ( eg, 5-indolyl).

在一些實施例中，雜芳基為具有芳族環體系中提供之環碳原子及1-4個環雜原子的5-10員芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「5-10員雜芳基」)。在一些實施例中，雜芳基為具有芳族環體系中提供之環碳原子及1-4個環雜原子的5-8員芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「5-8員雜芳基」)。在一些實施例中，雜芳基為具有芳族環體系中提供之環碳原子及 1-4個環雜原子的5-6員芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「5-6員雜芳基」)。在一些實施例中，5-6員雜芳基具有1-3個選自氮、氧及硫之環雜原子。在一些實施例中，5-6員雜芳基具有1-2個選自氮、氧及硫之環雜原子。在一些實施例中，5-6員雜芳基具有1個選自氮、氧及硫之環雜原子。除非另外指定，否則雜芳基之各實例獨立地視情況經取代，亦即未經取代(「未經取代之雜芳基」)或經一或多個取代基取代(「經取代之雜芳基」)。在某些實施例中，雜芳基為未經取代之5-14員雜芳基。在某些實施例中，雜芳基為經取代之5-14員雜芳基。在一些實施例中，雜芳基為具有芳族環體系中提供之環碳原子及1-6個環雜原子的8-12員雙環芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「8-12員雙環雜芳基」)。在一些實施例中，雜芳基為具有芳族環體系中提供之環碳原子及1-6個環雜原子的8-10員雙環芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「8-10員雙環雜芳基」)。在一些實施例中，雜芳基為具有芳族環體系中提供之環碳原子及1-6個環雜原子的9-10員雙環芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「9-10員雙環雜芳基」)。除非另外指定，否則雜芳基之各實例獨立地未經取代(「未經取代之雜芳基」)或經一或多個取代基取代(「經取代之雜芳基」)。在某些實施例中，雜芳基為未經取代之5-14員雜芳基。在某些實施例中，雜芳基為經取代之5-14員雜芳基。In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group has ring carbon atoms provided in an aromatic ring system and A 5-6 membered aromatic ring system of 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl groups have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of heteroaryl is independently optionally substituted, that is, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl") base"). In certain embodiments, heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, heteroaryl is a substituted 5-14 membered heteroaryl. In some embodiments, a heteroaryl group is an 8-12 membered bicyclic aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1-6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, Oxygen and sulfur ("8-12 membered bicyclic heteroaryl"). In some embodiments, heteroaryl is an 8-10 membered bicyclic aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1-6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, Oxygen and sulfur ("8-10 membered bicyclic heteroaryl"). In some embodiments, a heteroaryl group is a 9-10 membered bicyclic aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1-6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, Oxygen and sulfur ("9-10 membered bicyclic heteroaryl"). Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, heteroaryl is a substituted 5-14 membered heteroaryl.

含有一個雜原子之示範性5員雜芳基包括但不限於吡咯基、呋喃基及噻吩基。含有兩個雜原子之示範性5員雜芳基包括但不限於咪唑基、吡唑基、噁唑基、異噁唑基、噻唑基及異噻唑基。含有三個雜原子之示範性5員雜芳基包括但不限於三唑基、噁二唑基及噻二唑基。含有四個雜原子之示範性5員雜芳基包括但不限於四唑基。含有一個雜原子之示範性6員雜芳基包括但不限於吡啶基。含有兩個雜原子之示範性6員雜芳基包括但不限於噠嗪基、嘧啶基及吡嗪基。含有三個或四個雜原子之示範性6員雜芳基分別包括但不限於三嗪基及四嗪基。含 有一個雜原子之示範性7員雜芳基包括但不限於氮呯基、噁呯基及噻呯基。示範性5,6-雙環雜芳基包括但不限於吲哚基、異吲哚基、吲唑基、苯并三唑基、苯并噻吩基、異苯并噻吩基、苯并呋喃基、苯并異呋喃基、苯并咪唑基、苯并噁唑基、苯并異噁唑基、苯并噁二唑基、苯并噻唑基、苯并異噻唑基、苯并噻二唑基、吲哚嗪基及嘌呤基。示範性6,6-雙環雜芳基包括但不限於萘啶基、喋啶基、喹啉基、異喹啉基、噌啉基、喹噁啉基、酞嗪基及喹唑啉基。Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. contains Exemplary 7-membered heteroaryl groups having one heteroatom include, but are not limited to, azathiol, oxazolyl, and thiadiyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzene isofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benziisothiazolyl, benzothiadiazolyl, indole oxazinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl.

代表性雜芳基之實例包括以下：Examples of representative heteroaryl groups include the following:

Figure 110128222-A0202-12-0044-1126
其中各Z選自羰基、N、NR65 、O及S；且R65 獨立地為氫、C1 -C8 烷基、C3 -C10 環烷基、4-10員雜環基、C6 -C10 芳基及5-10員雜芳基。
Figure 110128222-A0202-12-0044-1126
 wherein each Z is selected from carbonyl, N, NR 65 , O and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl.

在本文所述之結構中，以跨越兩個或更多個環之鍵連接至多環(例如， 雙環或三環)環烷基、雜環基、芳基或雜芳基之取代基應理解為意謂取代基可連接於各環中之任一位置。In the structures described herein, a substituent attached to a polycyclic ( eg, bicyclic or tricyclic) cycloalkyl, heterocyclyl, aryl, or heteroaryl group with a bond spanning two or more rings is understood to be It is meant that the substituent may be attached at any position in each ring.

「雜芳烷基」或「雜芳基烷基」為「烷基」之子集且係指經雜芳基取代之烷基，其中連接點在烷基部分上。"Heteroaralkyl" or "heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl substituted with a heteroaryl, wherein the point of attachment is on the alkyl moiety.

術語「碳環基」或「碳環」係指在非芳族環體系中具有3至14個環碳原子(「C3-14 碳環基」)及零個雜原子之非芳族單環、雙環或三環或多環烴環體系之基團。碳環基包括完全飽和之環體系(例如， 環烷基)及部分飽和之環體系。在 一些實施例中，碳環基具有3至10個環碳原子(「C3-10 碳環基」)。在一些實施例中，碳環基具有3至8個環碳原子(「C3-8 碳環基」)。在一些實施例中，碳環基具有3至7個環碳原子(「C3-7 碳環基」)。在一些實施例中，碳環基具有3至6個環碳原子(「C3-6 碳環基」)。在一些實施例中，碳環基具有4至6個環碳原子(「C4-6 碳環基」)。在一些實施例中，碳環基具有5至6個環碳原子(「C5-6 碳環基」)。在一些實施例中，碳環基具有5至10個環碳原子(「C5-10 碳環基」)。示範性C3-6 碳環基包括但不限於環丙基(C3 )、環丙烯基(C3 )、環丁基(C4 )、環丁烯基(C4 )、環戊基(C5 )、環戊烯基(C5 )、環己基(C6 )、環己烯基(C6 )、環己二烯基(C6 )及其類似者。示範性C3-8 碳環基包括但不限於前述C3-6 碳環基以及環庚基(C7 )、環庚烯基(C7 )、環庚二烯基(C7 )、環庚四烯基(C7 )、環辛基(C8 )、環辛烯基(C8 )、雙環[2.2.1]庚基(C7 )、雙環[2.2.2]辛基(C8 )及其類似者。示範性C3-10 碳環基包括但不限於前述C3-8 碳環基以及環壬基(C9 )、環壬烯基(C9 )、環癸基(C10 )、環癸烯(C10 )、八氫-1H-茚基(C9 )、十氫萘基(C10 )、螺[4.5]癸基(C10 )及其類似者。The term "carbocyclyl" or "carbocycle" refers to a non-aromatic monocyclic ring having 3 to 14 ring carbon atoms (" C3-14 carbocyclyl") and zero heteroatoms in a non-aromatic ring system , bicyclic or tricyclic or polycyclic hydrocarbon ring system. Carbocyclyl groups include fully saturated ring systems ( eg, cycloalkyl) as well as partially saturated ring systems. In some embodiments, carbocyclyl groups have 3 to 10 ring carbon atoms ("C 3-10 carbocyclyl"). In some embodiments, carbocyclyl groups have 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl"). In some embodiments, carbocyclyl groups have 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl"). In some embodiments, carbocyclyl groups have 3 to 6 ring carbon atoms ("C 3-6 carbocyclyl"). In some embodiments, carbocyclyl groups have 4 to 6 ring carbon atoms ("C 4-6 carbocyclyl"). In some embodiments, carbocyclyl groups have 5 to 6 ring carbon atoms ("C 5-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl"). Exemplary C3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3 ) , cyclopropenyl (C3 ) , cyclobutyl ( C4 ), cyclobutenyl ( C4 ), cyclopentyl ( C5 ), cyclopentenyl ( C5 ), cyclohexyl ( C6 ), cyclohexenyl ( C6 ), cyclohexadienyl ( C6 ) and the like. Exemplary C3-8 carbocyclyl groups include, but are not limited to, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl ( C7 ), cycloheptenyl ( C7 ), cycloheptadienyl ( C7 ), cycloheptyl (C7) Heptatetraenyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptyl (C 7 ), bicyclo[2.2.2]octyl (C 8 ) and the like. Exemplary C3-10 carbocyclyl groups include, but are not limited to, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl ( C9 ), cyclononenyl ( C9 ), cyclodecyl ( C10 ), cyclodecene (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like.

如前述實例所說明，在某些實施例中，碳環基為單環(「單環碳環基」)或多環(例如， 含有稠合、橋聯或螺環體系，諸如雙環體系(「雙環碳環基」)或三環體系(「三環碳環基」))且可為飽和的或可含有一或多個碳-碳雙鍵或參鍵。「碳環基」亦包括以下環體系，其中如上文所定義之碳環基環與一或多個芳基或雜芳基稠合，其中連接點在碳環基環上，且在此類情況下，碳之數目繼續指示碳環環體系中碳之數目。除非另外指定，否則碳環基之各實例獨立地未經取代(「未經取代之碳環基」)或經一或多個取代基取代(「經取代之碳環基」)。在某些實施例中，碳環基為未經取代之C3-14 碳環基。在某些實施例中，碳環基為經取代之C3-14 碳環基。As the preceding examples illustrate, in certain embodiments, carbocyclyl groups are monocyclic ("monocyclic carbocyclyl") or polycyclic ( eg, containing fused, bridged, or spiro ring systems, such as bicyclic ring systems ("monocyclic carbocyclyl") Bicyclic carbocyclyl") or tricyclic ring system ("tricyclic carbocyclyl")) and may be saturated or may contain one or more carbon-carbon double bonds or double bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases Below, the number of carbons continues to indicate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl group. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl group.

如本文所用之術語「環烷基」包括具有3至14個碳且含有指定數目之環及碳原子之飽和環狀、雙環、三環或多環烴基(例如C3 -C14 單環、C4 -C14 雙環、 C5 -C14 三環或C6 -C14 多環環烷基)。在一些實施例中，「環烷基」為單環環烷基。在一些實施例中，單環環烷基具有3-14個環碳原子(「C3-14 單環環烷基」)。在一些實施例中，單環環烷基具有3至10個環碳原子(「C3-10 單環環烷基」)。在一些實施例中，單環環烷基具有3至8個環碳原子(「C3-8 單環環烷基」)。在一些實施例中，單環環烷基具有3至6個環碳原子(「C3-6 單環環烷基」)。在一些實施例中，單環環烷基具有4至6個環碳原子(「C4-6 單環環烷基」)。在一些實施例中，單環環烷基具有5至6個環碳原子(「C5-6 單環環烷基」)。在一些實施例中，單環環烷基具有5至10個環碳原子(「C5-10 單環環烷基」)。單環C5-6 環烷基之實例包括環戊基(C5 )及環己基(C5 )。C3-6 環烷基之實例包括前述C5-6 環烷基以及環丙基(C3 )及環丁基(C4 )。C3-8 環烷基之實例包括前述C3-6 環烷基以及環庚基(C7 )及環辛基(C8 )。The term "cycloalkyl" as used herein includes saturated cyclic, bicyclic, tricyclic or polycyclic hydrocarbon groups having 3 to 14 carbons and containing the specified number of rings and carbon atoms (eg C3 - C14 monocyclic, C 4 -C 14 bicyclic, C 5 -C 14 tricyclic or C 6 -C 14 polycyclic cycloalkyl). In some embodiments, "cycloalkyl" is a monocyclic cycloalkyl. In some embodiments, the monocyclic cycloalkyl has 3-14 ring carbon atoms ("C 3-14 monocyclic cycloalkyl"). In some embodiments, the monocyclic cycloalkyl has 3 to 10 ring carbon atoms ("C 3-10 monocyclic cycloalkyl"). In some embodiments, a monocyclic cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 monocyclic cycloalkyl"). In some embodiments, the monocyclic cycloalkyl has 3 to 6 ring carbon atoms ("C 3-6 monocyclic cycloalkyl"). In some embodiments, the monocyclic cycloalkyl has 4 to 6 ring carbon atoms ("C 4-6 monocyclic cycloalkyl"). In some embodiments, a monocyclic cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 monocyclic cycloalkyl"). In some embodiments, a monocyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 monocyclic cycloalkyl"). Examples of monocyclic C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-6 cycloalkyl include the aforementioned C 5-6 cycloalkyl as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ). Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).

在一些實施例中，「環烷基」為雙環環烷基。在一些實施例中，雙環環烷基具有4-14個環碳原子(「C4-14 雙環環烷基」)。在一些實施例中，雙環環烷基具有4至12個環碳原子(「C4-12 雙環環烷基」)。在一些實施例中，雙環環烷基具有4至10個環碳原子(「C4-10 雙環環烷基」)。在一些實施例中，雙環環烷基具有5至10個環碳原子(「C5-10 雙環環烷基」)。在一些實施例中，雙環環烷基具有6至10個環碳原子(「C6-10 雙環環烷基」)。在一些實施例中，雙環環烷基具有8至10個環碳原子(「C8-10 雙環環烷基」)。在一些實施例中，雙環環烷基具有7至9個環碳原子(「C7-9 雙環環烷基」)。雙環環烷基之實例包括雙環[1.1.0]丁烷(C4 )、雙環[1.1.1]戊烷(C5 )、螺[2.2]戊烷(C5 )、雙環[2.1.0]戊烷(C5 )、雙環[2.1.1]己烷(C6 )、雙環[3.1.0]己烷(C6 )、螺[2.3]己烷(C6 )、雙環[2.2.1]庚烷(降莰烷)(C7 )、雙環[3.2.0]庚烷(C7 )、雙環[3.1.1]庚烷(C7 )、雙環[3.1.1]庚烷(C7 )、雙環[4.1.0]庚烷(C7 )、螺[2.4]庚烷(C7 )、螺[3.3]庚烷(C7 )、雙環[2.2.2]辛烷(C8 )、雙環[4.1.1]辛烷(C8 )、八氫戊搭烯(C8 )、雙環[3.2.1]辛烷(C8 )、雙環[4.2.0]辛烷(C8 )、螺[2.5]辛烷(C8 )、螺[3.4]辛烷(C8 )、雙環[3.3.1]壬烷(C9 )、八氫-1H-茚(C9 )、雙環[4.2.1]壬烷(C9 )、螺[3.5]壬烷(C9 )、 螺[4.4]壬烷(C9 )、雙環[3.3.2]癸烷(C10 )、雙環[4.3.1]癸烷(C10 )、螺[4.5]癸烷(C10 )、雙環[3.3.3]十一烷(C11 )、十氫萘(C10 )、雙環[4.3.2]十一烷(C11 )、螺[5.5]十一烷(C11 )及雙環[4.3.3]十二烷(C12 )。In some embodiments, "cycloalkyl" is a bicyclic cycloalkyl. In some embodiments, the bicyclic cycloalkyl group has 4-14 ring carbon atoms ("C 4-14 bicyclic cycloalkyl"). In some embodiments, a bicyclic cycloalkyl group has 4 to 12 ring carbon atoms ("C 4-12 bicyclic cycloalkyl"). In some embodiments, the bicyclic cycloalkyl group has 4 to 10 ring carbon atoms ("C 4-10 bicyclic cycloalkyl"). In some embodiments, bicyclic cycloalkyl groups have 5 to 10 ring carbon atoms ("C 5-10 bicyclic cycloalkyl"). In some embodiments, bicyclic cycloalkyl groups have 6 to 10 ring carbon atoms ("C 6-10 bicyclic cycloalkyl"). In some embodiments, bicyclic cycloalkyl groups have 8 to 10 ring carbon atoms ("C 8-10 bicyclic cycloalkyl"). In some embodiments, a bicyclic cycloalkyl group has 7 to 9 ring carbon atoms ("C 7-9 bicyclic cycloalkyl"). Examples of bicyclic cycloalkyl groups include bicyclo[1.1.0]butane ( C4 ), bicyclo[1.1.1]pentane ( C5 ), spiro[2.2]pentane ( C5 ), bicyclo[2.1.0] Pentane ( C5 ), Bicyclo[2.1.1]hexane ( C6 ), Bicyclo[3.1.0]hexane ( C6 ), Spiro[2.3]hexane ( C6 ), Bicyclo[2.2.1] Heptane (norbornane) ( C7 ), bicyclo[3.2.0]heptane ( C7 ), bicyclo[3.1.1]heptane ( C7 ), bicyclo[3.1.1]heptane ( C7 ) , bicyclo[4.1.0]heptane ( C7 ), spiro[2.4]heptane ( C7 ), spiro[3.3]heptane ( C7 ), bicyclo[2.2.2]octane ( C8 ), bicyclo [4.1.1]Octane (C8), Octahydropentalyne (C8), Bicyclo [3.2.1]octane (C8), Bicyclo [4.2.0]octane ( C8 ), Spiro[ 2.5] Octane (C 8 ), spiro[3.4] octane (C 8 ), bicyclo[3.3.1]nonane (C 9 ), octahydro-1H-indene (C 9 ), bicyclo[4.2.1] Nonane ( C9 ), Spiro[3.5]nonane ( C9 ), Spiro[4.4]nonane ( C9 ), Bicyclo[3.3.2]decane ( C10 ), Bicyclo[4.3.1]decane (C 10 ), spiro[4.5]decane (C 10 ), bicyclo[3.3.3]undecane (C 11 ), decalin (C 10 ), bicyclo[4.3.2]undecane (C 11 ) ), spiro[5.5]undecane (C 11 ) and bicyclo[4.3.3]dodecane (C 12 ).

在一些實施例中，「環烷基」為三環環烷基。在一些實施例中，三環環烷基具有6-14個環碳原子(「C6-14 三環環烷基」)。在一些實施例中，三環環烷基具有8至12個環碳原子(「C8-12 三環環烷基」)。在一些實施例中，三環環烷基具有10至12個環碳原子(「C10-12 三環環烷基」)。三環環烷基之實例包括金剛硼(C12 )。In some embodiments, "cycloalkyl" is a tricyclic cycloalkyl. In some embodiments, a tricyclic cycloalkyl group has 6-14 ring carbon atoms ("C 6-14 tricyclic cycloalkyl"). In some embodiments, a tricyclic cycloalkyl group has 8 to 12 ring carbon atoms ("C 8-12 tricyclic cycloalkyl"). In some embodiments, a tricyclic cycloalkyl group has 10 to 12 ring carbon atoms ("C 10-12 tricyclic cycloalkyl"). Examples of tricyclic cycloalkyl groups include adamantine (C 12 ).

除非另外指定，否則環烷基之各實例獨立地未經取代(「未經取代之環烷基」)或經一或多個取代基取代(「經取代之環烷基」)。在某些實施例中，環烷基為未經取代之C3-14 環烷基。在某些實施例中，環烷基為經取代之C3-14 環烷基。Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3-14 cycloalkyl group.

「雜環基」或「雜環」係指具有環碳原子及1至4個環雜原子之3至10員非芳族環體系之基團，其中各雜原子獨立地選自氮、氧、硫、硼、磷及矽(「3-10員雜環基」)。在含有一或多個氮原子之雜環基中，當化合價允許時，連接點可為碳或氮原子。雜環基可為單環(「單環雜環基」)或稠合、橋聯或螺環體系，諸如雙環體系(「雙環雜環基」)，且可為飽和的或可為部分飽和的。雜環基雙環環體系可包括一個或兩個環中之一或多個雜原子。「雜環基」亦包括：其中如上文所定義之雜環基環與一或多個碳環基稠合的環體系，其中連接點在碳環基或雜環基環上；或其中如上文所定義之雜環基環與一或多個芳基或雜芳基稠合的環體系，其中連接點在雜環基環上，且在此類情況下，環成員之數目繼續指示雜環基環體系中環成員之數目。除非另外指定，否則雜環基之各實例獨立地視情況經取代，亦即未經取代(「未經取代之雜環基」)或經一或多個取代基取代(「經取代之雜環基」)。在某些實施例中，雜環基為未經取代之3-10員雜環基。在某 些實施例中，雜環基為經取代之3-10員雜環基。"Heterocyclyl" or "heterocycle" refers to a group of 3 to 10 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence permits. Heterocyclyl may be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially saturated . Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes: a ring system in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or wherein a heterocyclyl ring, as defined above, is fused A heterocyclyl ring as defined is a ring system fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members continues to indicate the heterocyclyl group The number of ring members in a ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl") base"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl group. in a In some embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl group.

在一些實施例中，雜環基為具有環碳原子及1-4個環雜原子之5-10員非芳族環體系，其中各雜原子獨立地選自氮、氧、硫、硼、磷及矽(「5-10員雜環基」)。在一些實施例中，雜環基為具有環碳原子及1-4個環雜原子之5-8員非芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「5-8員雜環基」)。在一些實施例中，雜環基為具有環碳原子及1-4個環雜原子之5-6員非芳族環體系，其中各雜原子獨立地選自氮、氧及硫(「5-6員雜環基」)。在一些實施例中，5-6員雜環基具有1-3個選自氮、氧及硫之環雜原子。在一些實施例中，5-6員雜環基具有1-2個選自氮、氧及硫之環雜原子。在一些實施例中，5-6員雜環基具有一個選自氮、氧及硫之環雜原子。In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 8-membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 6-membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

含有一個雜原子之示範性3員雜環基包括但不限於氮丙啶基、環氧乙烷基、硫嗯基(thiorenyl)。含有一個雜原子之示範性4員雜環基包括但不限於吖呾基、氧呾基及硫呾基。含有一個雜原子之示範性5員雜環基包括但不限於四氫呋喃基、二氫呋喃基、四氫噻吩基、二氫噻吩基、吡咯啶基、二氫吡咯基及吡咯基-2,5-二酮。含有兩個雜原子之示範性5員雜環基包括但不限於二氧環戊烷基、氧雜硫烷基(oxasulfuranyl)、二硫烷基及噁唑啶-2-酮。含有三個雜原子之示範性5員雜環基包括但不限於三唑啉基、噁二唑啉基及噻二唑啉基。含有一個雜原子之示範性6員雜環基包括但不限於哌啶基、四氫哌喃基、二氫吡啶基及噻烷基(thianyl)。含有兩個雜原子之示範性6員雜環基包括但不限於哌嗪基、嗎啉基、二噻烷基、二噁烷基。含有兩個雜原子之示範性6員雜環基包括但不限於三嗪烷基(triazinanyl)。含有一個雜原子之示範性7員雜環基包括但不限於氮雜環庚烷基、氧雜環庚烷基(oxepanyl)及硫雜環庚烷基(thiepanyl)。含有一個雜原子之示範性8員雜環基包括但不限於氮雜環辛烷基(azocanyl)、氧雜環辛烷基(oxecanyl)及硫雜環辛烷基(thiocanyl)。與C6 芳基環稠合之示範性5員雜環基(在本文中亦稱為 5,6-雙環雜環)包括但不限於吲哚啉基、異吲哚啉基、二氫苯并呋喃基、二氫苯并噻吩基、苯并噁唑啉酮基及其類似者。示範性雙環雜環基包括但不限於吲哚啉基、異吲哚啉基、二氫苯并呋喃基、二氫苯并噻吩基、四氫苯并噻吩基、四氫苯并呋喃基、四氫吲哚基、四氫喹啉基、四氫異喹啉基、十氫喹啉基、十氫異喹啉基、八氫色原烯基、八氫異色原烯基、十氫萘啶基、十氫-1,8-萘啶基、八氫吡咯并[3,2-b]吡咯、吲哚啉基、酞醯亞胺基、萘二甲醯亞胺基、色原烷基、色原烯基、1H-苯并[e][1,4]二氮呯基、1,4,5,7-四氫哌喃并[3,4-b]吡咯基、5,6-二氫-4H-呋喃并[3,2-b]吡咯基、6,7-二氫-5H-呋喃并[3,2-b]哌喃基、5,7-二氫-4H-噻吩并[2,3-c]哌喃基、2,3-二氫-1H-吡咯并[2,3-b]吡啶基、2,3-二氫呋喃并[2,3-b]吡啶基、4,5,6,7-四氫-1H-吡咯并[2,3-b]吡啶基、4,5,6,7-四氫呋喃并[3,2-c]吡啶基、4,5,6,7-四氫噻吩并[3,2-b]吡啶基、1,2,3,4-四氫-1,6-萘啶基及其類似者。與芳基環稠合之示範性6員雜環基(在本文中亦稱為6,6-雙環雜環)包括但不限於四氫喹啉基、四氫異喹啉基及其類似者。Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, acryl, oxanyl, and thiazide. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5- diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6 -bicyclic heterocycles) fused to a C aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzyl Furanyl, dihydrobenzothienyl, benzoxazolinone and the like. Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydrobenzofuranyl Indolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl , decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimide, naphthalimide, chromogen alkyl, chromogen Orthoalkenyl, 1H-benzo[e][1,4]diazoyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro -4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2 ,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydrofuro[2,3-b]pyridyl, 4, 5,6,7-Tetrahydro-1H-pyrrolo[2,3-b]pyridyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridyl, 4,5,6,7 - Tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

「含氮雜環基」意謂含有至少一個氮原子之4至7員非芳族環狀基團，例如但不限於嗎啉、哌啶(例如， 2-哌啶基、3-哌啶基及4-哌啶基)、吡咯啶(例如， 2-吡咯啶基及3-吡咯啶基)、吖呾、吡咯啶酮、咪唑啉、咪唑啶酮、2-吡唑啉、吡唑啶、哌嗪及N-烷基哌嗪諸如N-甲基哌嗪。特定實例包括吖呾、哌啶酮及哌嗪酮。"Nitrogen-containing heterocyclyl" means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine ( eg, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine ( eg, 2-pyrrolidinyl and 3-pyrrolidinyl), acridine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, Piperazine and N-alkylpiperazine such as N-methylpiperazine. Specific examples include acridine, piperidinone, and piperazinone.

「雜」當用於描述化合物或呈現於化合物上之基團時意謂化合物或基團中之一或多個碳原子已由氮、氧或硫雜原子置換。雜可適用於上文所述之具有1至5個及特別地1至3個雜原子之任一烴基，諸如烷基(例如 雜烷基)、環烷基(例如 雜環基)、芳基(例如 雜芳基)、環烯基(例如 環雜烯基)及其類似者。"Hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group has been replaced with a nitrogen, oxygen or sulfur heteroatom. Hetero can be applied to any of the hydrocarbyl groups described above having 1 to 5 and particularly 1 to 3 heteroatoms, such as alkyl ( e.g. heteroalkyl), cycloalkyl ( e.g. heterocyclyl), aryl ( e.g. heteroaryl), cycloalkenyl ( e.g. cycloheteroalkenyl) and the like.

「醯基」係指基團-C(=O)R20 ，其中R20 為氫、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代 之碳環基、經取代或未經取代之雜環基、經取代或未經取代之芳基或經取代或未經取代之雜芳基，如本文所定義。「烷醯基」為以下醯基，其中R20 為除氫以外之基團。代表性醯基包括但不限於甲醯基(-CHO)、乙醯基(-C(=O)CH3 )、環己基羰基、環己基甲基羰基、苯甲醯基(-C(=O)Ph)、苯甲基羰基(-C(=O)CH2 Ph)、-C(=O)-C1 -C8 烷基、-C(=O)-(CH2 )t (C6 -C10 芳基)、-C(=O)-(CH2 )t (5-10員雜芳基)、-C(=O)-(CH2 )t (C3 -C10 環烷基)及-C(=O)-(CH2 )t (4-10員雜環基)，其中t為0至4之整數。在某些實施例中，R21 為C1 -C8 烷基，其經鹵基或羥基取代；或C3 -C10 環烷基、4-10員雜環基、C6 -C10 芳基、芳基烷基、5-10員雜芳基或雜芳基烷基，其各自經未經取代之C1 -C4 烷基、鹵基、未經取代之C1 -C4 烷氧基、未經取代之C1 -C4 鹵烷基、未經取代之C1 -C4 羥基烷基或未經取代之C1 -C4 鹵烷氧基或羥基取代。"Acyl" refers to the group -C(=O) R20 , wherein R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein . "Alkyl group" is the following alkyl group, wherein R 20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O) CH3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzyl (-C(=O) )Ph), benzylcarbonyl (-C(=O)CH 2 Ph), -C(=O)-C 1 -C 8 alkyl, -C(=O)-(CH 2 ) t (C 6 -C 10 aryl), -C(=O)-(CH 2 ) t (5-10 membered heteroaryl), -C(=O)-(CH 2 ) t (C 3 -C 10 cycloalkyl) ) and -C(=O)-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R 21 is C 1 -C 8 alkyl substituted with halo or hydroxy; or C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl group, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted by unsubstituted C1 - C4 alkyl, halo, unsubstituted C1 - C4 alkoxy group, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl or unsubstituted C 1 -C 4 haloalkoxy or hydroxy substituted.

術語胺基烷基係指以下經取代之烷基，其中氫原子中之一或多者獨立地經-NH2 基團置換。The term aminoalkyl refers to the following substituted alkyl groups in which one or more of the hydrogen atoms are independently replaced with a -NH2 group.

術語羥基烷基係指以下經取代之烷基，其中氫原子中之一或多者獨立地經-OH基團置換。The term hydroxyalkyl refers to the following substituted alkyl groups wherein one or more of the hydrogen atoms are independently replaced by -OH groups.

術語「烷胺基」及「二烷胺基」分別係指-NH(烷基)及-N(烷基)2 基團。在一些實施例中，烷胺基為-NH(C1 -C4 烷基)。在一些實施例中，烷胺基為甲胺基、乙胺基、丙胺基、異丙胺基、正丁胺基、異丁胺基、第二丁胺基或第三丁胺基。在一些實施例中，二烷胺基為-N(C1 -C6 烷基)2 。在一些實施例中，二烷胺基為二甲胺基、甲基乙胺基、二乙胺基、甲基丙胺基、甲基異丙胺基、甲基丁胺基、甲基異丁胺基或甲基第三丁胺基。The terms "alkylamino" and "dialkylamino" refer to -NH(alkyl) and -N(alkyl) 2 groups, respectively. In some embodiments, the alkylamino group is -NH(C 1 -C 4 alkyl). In some embodiments, the alkylamino group is methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, second-butylamine, or third-butylamine. In some embodiments, the dialkylamino group is -N(C 1 -C 6 alkyl) 2 . In some embodiments, the dialkylamine group is dimethylamine, methylethylamine, diethylamine, methylpropylamine, methylisopropylamine, methylbutylamine, methylisobutylamine or methyl tertiary butylamine.

術語「芳基氧基」係指-O-芳基。在一些實施例中，芳基氧基為苯氧基。The term "aryloxy" refers to -O-aryl. In some embodiments, the aryloxy group is phenoxy.

術語「鹵烷氧基」係指經一或多個鹵基或其組合取代之烷氧基結構。例如，術語「氟烷氧基」包括鹵基為氟的鹵烷氧基。在一些實施例中，鹵烷氧 基為二氟甲氧基及三氟甲氧基。The term "haloalkoxy" refers to an alkoxy structure substituted with one or more halo groups or a combination thereof. For example, the term "fluoroalkoxy" includes haloalkoxy groups wherein the halo group is fluorine. In some embodiments, haloalkoxy The groups are difluoromethoxy and trifluoromethoxy.

「烷氧基」係指基團-OR29 ，其中R29 為經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之碳環基、經取代或未經取代之雜環基、經取代或未經取代之芳基或經取代或未經取代之雜芳基。特定烷氧基為甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第三丁氧基、第二丁氧基、正戊氧基、正己氧基及1,2-二甲基丁氧基。特定烷氧基為低級烷氧基，亦即具有1至6個碳原子。另外的特定烷氧基具有1至4個碳原子。"Alkoxy" refers to the group -OR 29 , wherein R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, 2nd-butoxy, n-pentoxy, n-hexyloxy and 1 , 2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy groups, ie having 1 to 6 carbon atoms. Additional specific alkoxy groups have 1 to 4 carbon atoms.

在某些實施例中，R29 為具有1或多個取代基，例如1至5個取代基且特別地1至3個取代基，具體地1個取代基之基團，取代基選自由以下組成之群：胺基、經取代之胺基、C6 -C10 芳基、芳基氧基、羰基、氰基、C3 -C10 環烷基、4-10員雜環基、鹵素、5-10員雜芳基、羥基、硝基、硫代烷氧基、硫代芳基氧基、硫醇、烷基-S(O)-、芳基-S(O)-、烷基-S(O)2 -及芳基-S(O)2 -。示範性『經取代之烷氧基』基團包括但不限於-O-(CH2 )t (C6 -C10 芳基)、-O-(CH2 )t (5-10員雜芳基)、-O-(CH2 )t (C3 -C10 環烷基)及-O-(CH2 )t (4-10員雜環基)，其中t為0至4之整數且存在的任何芳基、雜芳基、環烷基或雜環基本身可經未經取代之C1 -C4 烷基、鹵基、未經取代之C1 -C4 烷氧基、未經取代之C1 -C4 鹵烷基、未經取代之C1 -C4 羥基烷基或未經取代之C1 -C4 鹵烷氧基或羥基取代。具體示範性『經取代之烷氧基』基團為-OCF3 、-OCH2 CF3 、-OCH2 Ph、-OCH2 -環丙基、-OCH2 CH2 OH及-OCH2 CH2 NMe2 。In certain embodiments, R 29 is a group having 1 or more substituents, such as 1 to 5 substituents and specifically 1 to 3 substituents, specifically 1 substituent, the substituents being selected from the following The group consists of: amine group, substituted amine group, C 6 -C 10 aryl group, aryloxy group, carbonyl group, cyano group, C 3 -C 10 cycloalkyl group, 4-10 membered heterocyclic group, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl- S(O) 2 - and aryl-S(O) 2 -. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH 2 ) t (C 6 -C 10 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl) ), -O-(CH 2 ) t (C 3 -C 10 cycloalkyl) and -O-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and is present Any aryl, heteroaryl, cycloalkyl or heterocyclic group may itself be substituted with unsubstituted C1 - C4 alkyl, halo, unsubstituted C1 - C4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl or unsubstituted C 1 -C 4 haloalkoxy or hydroxy substituted. Specific exemplary "substituted alkoxy " groups are -OCF3 , -OCH2CF3 , -OCH2Ph , -OCH2 - cyclopropyl , -OCH2CH2OH , and -OCH2CH2NMe 2 .

「胺基」係指基團-NH2 。"Amino" refers to the group -NH2 .

「側氧基」係指-C(=O)-。"Pendant oxy" refers to -C(=O)-.

「經取代之胺基」係指具有式-N(R38 )2 之胺基，其中R38 為氫、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之碳環基、經取代或未經取代之雜環基、經取代或未經取代之 芳基、經取代或未經取代之雜芳基或胺基保護基，其中R38 中之至少一者不為氫。在某些實施例中，各R38 獨立地選自氫、C1 -C8 烷基、C3 -C8 烯基、C3 -C8 炔基、C6 -C10 芳基、5-10員雜芳基、4-10員雜環基或C3 -C10 環烷基；或C1 -C8 烷基，其經鹵基或羥基取代；C3 -C8 烯基，其經鹵基或羥基取代；C3 -C8 炔基，其經鹵基或羥基取代；或-(CH2 )t (C6 -C10 芳基)、-(CH2 )t (5-10員雜芳基)、-(CH2 )t (C3 -C10 環烷基)或-(CH2 )t (4-10員雜環基)，其中t為0至8之整數，其各自經未經取代之C1 -C4 烷基、鹵基、未經取代之C1 -C4 烷氧基、未經取代之C1 -C4 鹵烷基、未經取代之C1 -C4 羥基烷基或未經取代之C1 -C4 鹵烷氧基或羥基取代；或兩個R38 基團連接在一起形成伸烷基。"Substituted amine group" refers to an amine group having the formula -N( R38 ) 2 , wherein R38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amine protecting group, wherein at least one of R 38 is not hydrogen. In certain embodiments, each R 38 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 6 -C 10 aryl, 5- 10-membered heteroaryl, 4-10-membered heterocyclyl, or C 3 -C 10 cycloalkyl; or C 1 -C 8 alkyl, which is substituted by halo or hydroxy; C 3 -C 8 alkenyl, which is substituted by Halo or hydroxy substituted; C 3 -C 8 alkynyl, which is substituted with halo or hydroxy; or -(CH 2 ) t (C 6 -C 10 aryl), -(CH 2 ) t (5-10 members heteroaryl), -(CH 2 ) t (C 3 -C 10 cycloalkyl) or -(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 8, each of which is Unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 haloalkoxy or hydroxy substituted; or two R 38 groups joined together to form an alkylene group.

示範性「經取代之胺基」包括但不限於-NR39 -C1 -C8 烷基、-NR39 -(CH2 )t (C6 -C10 芳基)、-NR39 -(CH2 )t (5-10員雜芳基)、-NR39 -(CH2 )t (C3 -C10 環烷基)及-NR39 -(CH2 )t (4-10員雜環基)，其中t為0至4之整數，例如1或2，各R39 獨立地表示H或C1 -C8 烷基；且存在的任何烷基本身可經鹵基、經取代或未經取代之胺基或羥基取代；且存在的任何芳基、雜芳基、環烷基或雜環基本身可經未經取代之C1 -C4 烷基、鹵基、未經取代之C1 -C4 烷氧基、未經取代之C1 -C4 鹵烷基、未經取代之C1 -C4 羥基烷基或未經取代之C1 -C4 鹵烷氧基或羥基取代。為了避免存疑，術語『經取代之胺基』包括如下文所定義之烷胺基、經取代之烷胺基、烷基芳胺基、經取代之烷基芳胺基、芳胺基、經取代之芳胺基、二烷胺基及經取代之二烷胺基。經取代之胺基涵蓋經單取代之胺基及經二取代之胺基。Exemplary "substituted amine groups" include, but are not limited to, -NR39 - C1 -C8 alkyl, -NR39- ( CH2 ) t ( C6 - C10 aryl), -NR39- ( CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C 3 -C 10 cycloalkyl) and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl) ), where t is an integer from 0 to 4, such as 1 or 2 , each R39 independently represents H or C1 -C8 alkyl; and any alkyl groups present may themselves be halo, substituted or unsubstituted and any aryl, heteroaryl, cycloalkyl or heterocyclic groups present may themselves be substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 - C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl or unsubstituted C 1 -C 4 haloalkoxy or hydroxy substituted. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted alkylamino, arylamine group, dialkylamine group and substituted dialkylamine group. Substituted amine groups encompass mono-substituted amine groups and di-substituted amine groups.

在某些實施例中，存在於氮原子上之取代基為氮保護基(在本文中亦稱為「胺基保護基」)。氮保護基包括但不限於-OH、-ORaa 、-N(Rcc )2 、-C(=O)Raa 、-C(=O)N(Rcc )2 、-CO2 Raa 、-SO2 Raa 、-C(=NRcc )Raa 、-C(=NRcc )ORaa 、-C(=NRcc )N(Rcc )2 、-SO2 N(Rcc )2 、-SO2 Rcc 、-SO2 ORcc 、-SORaa 、-C(=S)N(Rcc )2 、-C(=O)SRcc 、-C(=S)SRcc 、-C1-10 烷基(例如， 芳烷基、雜芳烷基)、-C2-10 烯基、-C2-10 炔基、雜C1-10 烷基、雜C2-10 烯基、雜C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，其中各烷基、烯基、炔基、雜烷基、雜烯基、雜炔基、碳環基、雜環基、芳烷基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代，且其中Raa 、Rbb 、Rcc 及Rdd 如本文所定義。氮保護基為此項技術中熟知的且包括Protecting Groups in Organic Synthesis,T.W.Greene及P.G.M.Wuts，第3版，John Wiley & Sons,1999中詳述者，該文獻以引用之方式併入本文。Raa 之各實例獨立地選自-C1-10 烷基、-C1-10 全鹵基烷基、-C2-10 烯基、-C2-10 炔基、雜C1-10 烷基、雜C2-10 烯基、雜C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，或兩個Raa 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、雜烷基、雜烯基、雜炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代；Rbb 之各實例獨立地選自氫、-OH、-ORaa 、-N(Rcc )2 、-CN、-C(=O)Raa 、-C(=O)N(Rcc )2 、-CO2 Raa 、-SO2 Raa 、-C(=NRcc )ORaa 、-C(=NRcc )N(Rcc )2 、-SO2 N(Rcc )2 、-SO2 Rcc 、-SO2 ORcc 、-SORaa 、-C(=S)N(Rcc )2 、-C(=O)SRcc 、-C(=S)SRcc 、-P(=O)(Raa )2 、-P(=O)(ORcc )2 、-P(=O)(N(Rcc )2 )2 、-C1-10 烷基、-C1-10 全鹵基烷基、-C2-10 烯基、-C2-10 炔基、雜C1-10 烷基、雜C2-10 烯基、雜C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，或兩個Rbb 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、雜烷基、雜烯基、雜炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 取代；其中X- 為相對離子。In certain embodiments, substituents present on nitrogen atoms are nitrogen protecting groups (also referred to herein as "amine protecting groups"). Nitrogen protecting groups include but are not limited to -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -C 1 -10 alkyl ( eg, aralkyl, heteroaralkyl), -C 2-10 alkenyl, -C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 membered aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heterocyclic Alkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as defined herein. Nitrogen protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Each instance of R aa is independently selected from -C 1-10 alkyl, -C 1-10 perhaloalkyl, -C 2-10 alkenyl, -C 2-10 alkynyl, -C 1-10 alkynyl group, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 membered aryl and 5-14 membered heteroaryl, or Two R aa groups are joined together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R bb is independently selected from hydrogen, -OH, - OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C (=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C (=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O)(N(R cc ) 2 ) 2 , -C 1-10 alkyl, -C 1-10 perhaloalkyl, -C 2-10 alkenyl, -C 2- 10 alkynyl, heteroC 1-10 alkyl, hetero C 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14-membered heteroaryl, or two R bb groups are joined together to form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkane wherein X- is the opposite ion .

Rcc 之各實例獨立地選自氫、-C1-10 烷基、-C1-10 全鹵基烷基、-C2-10 烯基、-C2-10 炔基、雜C1-10 烷基、雜C2-10 烯基、雜C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，或兩個Rcc 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、雜烷基、雜烯基、雜炔基、碳環基、雜 環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代；Rdd 之各實例獨立地選自鹵素、-CN、-NO2 、-N3 、-SO2 H、-SO3 H、-OH、-ORee 、-ON(Rff )2 、-N(Rff )2 、-N(Rff )3 + X- 、-N(ORee )Rff 、-SH、-SRee 、-SSRee 、-C(=O)Ree 、-CO2 H、-CO2 Ree 、-OC(=O)Ree 、-OCO2 Ree 、-C(=O)N(Rff )2 、-OC(=O)N(Rff )2 、-NRff C(=O)Ree 、-NRff CO2 Ree 、-NRff C(=O)N(Rff )2 、-C(=NRff )ORee 、-OC(=NRff )Ree 、-OC(=NRff )ORee 、-C(=NRff )N(Rff )2 、-OC(=NRff )N(Rff )2 、-NRff C(=NRff )N(Rff )2 、-NRff SO2 Ree 、-SO2 N(Rff )2 、-SO2 Ree 、-SO2 ORee 、-OSO2 Ree 、-S(=O)Ree 、-Si(Ree )3 、-OSi(Ree )3 、-C(=S)N(Rff )2 、-C(=O)SRee 、-C(=S)SRee 、-SC(=S)SRee 、-P(=O)(ORee )2 、-P(=O)(Ree )2 、-OP(=O)(Ree )2 、-OP(=O)(ORee )2 、-C1-6 烷基、-C1-6 全鹵基烷基、-C2-6 烯基、-C2-6 炔基、雜C1-6 烷基、雜C2-6 烯基、雜C2-6 炔基、C3-10 碳環基、3-10員雜環基、C6-10 芳基、5-10員雜芳基，其中各烷基、烯基、炔基、雜烷基、雜烯基、雜炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rgg 基團取代，或兩個偕Rdd 取代基可連接在一起形成=O或=S；其中X- 為相對離子；Ree 之各實例獨立地選自-C1-6 烷基、-C1-6 全鹵基烷基、-C2-6 烯基、-C2-6 炔基、雜C1-6 烷基、雜C2-6 烯基、雜C2-6 炔基、C3-10 碳環基、C6-10 芳基、3-10員雜環基及3-10員雜芳基，其中各烷基、烯基、炔基、雜烷基、雜烯基、雜炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rgg 基團取代；Rff 之各實例獨立地選自氫、-C1-6 烷基、-C1-6 全鹵基烷基、-C2-6 烯基、-C2-6 炔基、雜C1-6 烷基、雜C2-6 烯基、雜C2-6 炔基、C3-10 碳環基、3-10員雜環基、C6-10 芳基及5-10員雜芳基，或兩個Rff 基團連接在一起形成3-10員雜環基或5-10員雜芳基環，其中各烷基、烯基、炔基、雜烷基、雜烯基、雜炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rgg 基團取代；且Rgg 之各實例獨立地為鹵素、-CN、-NO2 、-N3 、-SO2 H、-SO3 H、-OH、-OC1-6 烷 基、-ON(C1-6 烷基)2 、-N(C1-6 烷基)2 、-N(C1-6 烷基)3 + X- 、-NH(C1-6 烷基)2 + X- 、-NH2 (C1-6 烷基)+ X- 、-NH3 + X- 、-N(OC1-6 烷基)(C1-6 烷基)、-N(OH)(C1-6 烷基)、-NH(OH)、-SH、-SC1-6 烷基、-SS(C1-6 烷基)、-C(=O)(C1-6 烷基)、-CO2 H、-CO2 (C1-6 烷基)、-OC(=O)(C1-6 烷基)、-OCO2 (C1-6 烷基)、-C(=O)NH2 、-C(=O)N(C1-6 烷基)2 、-OC(=O)NH(C1-6 烷基)、-NHC(=O)(C1-6 烷基)、-N(C1-6 烷基)C(=O)(C1-6 烷基)、-NHCO2 (C1-6 烷基)、-NHC(=O)N(C1-6 烷基)2 、-NHC(=O)NH(C1-6 烷基)、-NHC(=O)NH2 、-C(=NH)O(C1-6 烷基)、-OC(=NH)(C1-6 烷基)、-OC(=NH)OC1-6 烷基、-C(=NH)N(C1-6 烷基)2 、-C(=NH)NH(C1-6 烷基)、-C(=NH)NH2 、-OC(=NH)N(C1-6 烷基)2 、-OC(NH)NH(C1-6 烷基)、-OC(NH)NH2 、-NHC(NH)N(C1-6 烷基)2 、-NHC(=NH)NH2 、-NHSO2 (C1-6 烷基)、-SO2 N(C1-6 烷基)2 、-SO2 NH(C1-6 烷基)、-SO2 NH2 、-SO2 C1-6 烷基、-SO2 OC1-6 烷基、-OSO2 C1-6 烷基、-SOC1-6 烷基、-Si(C1-6 烷基)3 、-OSi(C1-6 烷基)3 、-C(=S)N(C1-6 烷基)2 、-C(=S)NH(C1-6 烷基)、-C(=S)NH2 、-C(=O)S(C1-6 烷基)、-C(=S)SC1-6 烷基、-SC(=S)SC1-6 烷基、-P(=O)(OC1-6 烷基)2 、-P(=O)(C1-6 烷基)2 、-OP(=O)(C1-6 烷基)2 、-OP(=O)(OC1-6 烷基)2 、-C1-6 烷基、-C1-6 全鹵基烷基、-C2-6 烯基、-C2-6 炔基、雜C1-6 烷基、雜C2-6 烯基、雜C2-6 炔基、C3-10 碳環基、C6-10 芳基、3-10員雜環基、5-10員雜芳基；或兩個偕Rgg 取代基可以連接在一起形成=O或=S；其中X- 為相對離子。Each instance of R cc is independently selected from hydrogen, -C 1-10 alkyl, -C 1-10 perhaloalkyl, -C 2-10 alkenyl, -C 2-10 alkynyl, heteroC 1- 10 alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 membered aryl and 5-14 membered heteroaryl , or two R cc groups are joined together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkyne , carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R dd is independently selected from halogen, -CN , -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N(R ff ) 2 , -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO 2 H , -CO 2 Re ee , -OC(=O)R ee , -OCO 2 Ree , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O) Ree , -NR ff CO 2 Ree , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff ) Ree , -OC(=NR ff )OR ee , -C (=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 Ree , -SO 2 N(R ff ) 2 , -SO 2 Ree , -SO 2 OR ee , -OSO 2 Ree , -S(=O) Ree , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)( OR ee ) 2 , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 , -C 1-6 alkyl, - C 1-6 perhaloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, heteroC 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently represented by 0, 1, 2, 3, 4 Or 5 R gg groups are substituted, or two gem R dd substituents can be joined together to form =O or =S; wherein X- is the opposite ion; each instance of Re is independently selected from -C 1-6 alkanes base, -C 1-6 perhaloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, heteroC 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 Alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, hetero Alkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is independently selected From hydrogen, -C 1-6 alkyl, -C 1-6 perhaloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2- 6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 membered aryl and 5-10 membered heteroaryl, or two Rff groups linked together to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocycle , aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and each instance of Rgg is independently halogen, -CN, -NO2 , -N3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 + X - , -NH(C 1-6 alkyl) 2 + X - , -NH 2 (C 1-6 alkyl) + X - , -NH 3 + X - , -N (OC 1-6 alkyl) (C 1-6 alkyl), -N(OH) (C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS (C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1 -6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O) NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl) C(=O)(C 1-6 alkyl), - NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O) NH 2 , -C(=NH)O(C 1-6 alkyl ), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C( =NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), - SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkane base, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 , -C(=S) N(C 1-6 alkyl) 2 , -C(=S)NH(C 1-6 alkyl), -C(=S)NH 2 , -C(=O)S(C 1-6 alkyl) ), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O)(OC 1-6 alkyl) 2 , -P(=O) (C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , -C 1-6 alkyl, -C 1-6 perhaloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, heteroC 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl , C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two gem R gg substituents can be linked together to form =O or =S ; where X - is the relative ion.

例如，氮保護基諸如醯胺基團(例如， -C(=O)Raa )包括但不限於甲醯胺、乙醯胺、氯乙醯胺、三氯乙醯胺、三氟乙醯胺、苯基乙醯胺、3-苯基丙醯胺、吡啶醯胺、3-吡啶基甲醯胺、N-苯甲醯基苯基丙胺醯基衍生物、苯甲醯胺、對苯基苯甲醯胺、鄰硝基苯基乙醯胺、鄰硝基苯氧基乙醯胺、乙醯乙醯胺、(N'-二硫苯甲基氧基醯基胺基)乙醯胺、3-(對羥基苯基)丙醯胺、3-(鄰硝基苯基)丙醯胺、2-甲基-2-(鄰硝基苯氧基)丙醯胺、2-甲基-2-(鄰苯基氮雜苯氧基)丙醯胺、4-氯丁醯胺、3-甲基-3-硝基丁醯胺、鄰硝基桂皮醯胺、N-乙醯基甲硫胺酸衍生物、鄰 硝基苯甲醯胺及鄰(苯甲醯基氧基甲基)苯甲醯胺。For example, nitrogen protecting groups such as amide groups ( eg, -C(=O)R aa ) include, but are not limited to, carboxamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide , Phenylacetamide, 3-Phenylpropionamide, Pyridinamide, 3-Pyridylcarboxamide, N-benzyl phenylpropanamide derivatives, benzyl amide, p-phenylbenzene Formamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetamide, (N'-dithiobenzyloxyacetamide) acetamide, 3 -(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2- (o-Phenylazepineoxy) Propionamide, 4-Chlorobutanamide, 3-Methyl-3-Nitrobutanamide, o-Nitrocinnamamide, N-Acetyl Methionine Derivatives, o-nitrobenzamide and o-(benzyloxymethyl)benzamide.

氮保護基諸如胺甲酸酯基團(例如， -C(=O)ORaa )包括但不限於胺甲酸甲酯、胺甲酸乙酯、9-茀基甲基胺甲酸酯(Fmoc)、9-(2-磺酸基)茀基甲基胺甲酸酯、9-(2,7-二溴)茀基甲基胺甲酸酯、2,7-二-第三丁基-[9-(10,10-二側氧基-10,10,10,10-四氫硫雜蒽基)]甲基胺甲酸酯(DBD-Tmoc)、4-甲氧基苯醯基胺甲酸酯(Phenoc)、2,2,2-三氯乙基胺甲酸酯(Troc)、2-三甲基矽基乙基胺甲酸酯(Teoc)、2-苯基乙基胺甲酸酯(hZ)、1-(1-金剛烷基)-1-甲基乙基胺甲酸酯(Adpoc)、1,1-二甲基-2-鹵基乙基胺甲酸酯、1,1-二甲基-2,2-二溴乙基胺甲酸酯(DB-t -BOC)、1,1-二甲基-2,2,2-三氯乙基胺甲酸酯(TCBOC)、1-甲基-1-(4-聯苯基)乙基胺甲酸酯(Bpoc)、1-(3,5-二-第三丁基苯基)-1-甲基乙基胺甲酸酯(t -Bumeoc)、2-(2'-及4'-吡啶基)乙基胺甲酸酯(Pyoc)、2-(N,N-二環己基甲醯胺基)乙基胺甲酸酯、第三丁基 胺甲酸酯(BOC或Boc)、1-金剛烷基胺甲酸酯(Adoc)、乙烯基胺甲酸酯(Voc)、烯丙基胺甲酸酯(Alloc)、1-異丙基烯丙基胺甲酸酯(Ipaoc)、桂醯基胺甲酸酯(Coc)、4-硝基桂醯基胺甲酸酯(Noc)、8-喹啉基胺甲酸酯、N-羥基哌啶基胺甲酸酯、烷基二硫基胺甲酸酯、苯甲基胺甲酸酯(Cbz)、對甲氧基苯甲基胺甲酸酯(Moz)、對硝基苯甲基胺甲酸酯、對溴苯甲基胺甲酸酯、對氯苯甲基胺甲酸酯、2,4-二氯苯甲基胺甲酸酯、4-甲基亞磺醯基苯甲基胺甲酸酯(Msz)、9-蒽基甲基胺甲酸酯、聯苯基甲基胺甲酸酯、2-甲基硫乙基胺甲酸酯、2-甲基磺醯基乙基胺甲酸酯、2-(對甲苯磺醯基)乙基胺甲酸酯、[2-(1,3-二噻烷基)]甲基胺甲酸酯(Dmoc)、4-甲基噻吩基胺甲酸酯(Mtpc)、2,4-二甲基噻吩基胺甲酸酯(Bmpc)、2-膦基乙基胺甲酸酯(Peoc)、2-三苯基膦基異丙基胺甲酸酯(Ppoc)、1,1-二甲基-2-氰基乙基胺甲酸酯、間氯對醯氧基苯甲基胺甲酸酯、對(二羥基氧硼基)苯甲基胺甲酸酯、5-苯并異噁唑基甲基胺甲酸酯、2-(三氟甲基)-6-色原酮基甲基胺甲酸酯(Tcroc)、間硝基苯基胺甲酸酯、3,5-二甲氧基苯甲基胺甲酸酯、鄰硝基苯甲基胺甲酸酯、3,4-二甲氧 基-6-硝基苯甲基胺甲酸酯、苯基(鄰硝基苯基)甲基胺甲酸酯、第三戊基胺甲酸酯、S-苯甲基硫代胺甲酸酯、對氰基苯甲基胺甲酸酯、環丁基胺甲酸酯、環己基胺甲酸酯、環戊基胺甲酸酯、環丙基甲基胺甲酸酯、對癸基氧基苯甲基胺甲酸酯、2,2-二甲氧基醯基乙烯基胺甲酸酯、鄰 (N,N-二甲基甲醯胺基)苯甲基胺甲酸酯、1,1-二甲基-3-(N,N-二甲基甲醯胺基)丙基胺甲酸酯、1,1-二甲基丙炔基胺甲酸酯、二(2-吡啶基)甲基胺甲酸酯、2-呋喃基甲基胺甲酸酯、2-碘乙基胺甲酸酯、異冰片基胺甲酸酯、異丁基胺甲酸酯、異菸基胺甲酸酯、對(對'甲氧基苯基氮雜)苯甲基胺甲酸酯、1-甲基環丁基胺甲酸酯、1-甲基環己基胺甲酸酯、1-甲基-1-環丙基甲基胺甲酸酯、1-甲基-1-(3,5-二甲氧基苯基)乙基胺甲酸酯、1-甲基-1-(對苯基氮雜苯基)乙基胺甲酸酯、1-甲基-1-苯基乙基胺甲酸酯、1-甲基-1-(4-吡啶基)乙基胺甲酸酯、苯基胺甲酸酯、對(苯基氮雜)苯甲基胺甲酸酯、2,4,6-三-第三丁基 苯基胺甲酸酯、4-(三甲基銨)苯甲基胺甲酸酯及2,4,6-三甲基苯甲基胺甲酸酯。Nitrogen protecting groups such as carbamate groups ( eg, -C(=O)OR aa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-inylmethyl carbamate (Fmoc), 9-(2-Sulfonyl)phenylmethylcarbamate, 9-(2,7-dibromo)phenylmethylcarbamate, 2,7-di-tert-butyl-[9 -(10,10-Di-oxy-10,10,10,10-tetrahydrothanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxybenzylcarbamate Esters (Phenoc), 2,2,2-Trichloroethylcarbamate (Troc), 2-Trimethylsilylethylcarbamate (Teoc), 2-Phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1 - Dimethyl-2,2-dibromoethylcarbamate (DB- t -BOC), 1,1-Dimethyl-2,2,2-trichloroethylcarbamate (TCBOC) , 1-methyl-1-(4-biphenyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethylcarbamate Acetate ( t -Bumeoc), 2-(2'- and 4'-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-dicyclohexylcarbamido)ethylcarbamate Acid esters, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc) , 1-isopropylallylcarbamate (Ipaoc), cinnamylcarbamate (Coc), 4-nitrocinnamylcarbamate (Noc), 8-quinolinylcarbamate acid esters, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylidene Sulfonylbenzylcarbamate (Msz), 9-Anthracenylmethylcarbamate, Biphenylmethylcarbamate, 2-Methylthioethylcarbamate, 2-Methylcarbamate Sulfonylethylcarbamate, 2-(p-Toluenesulfonyl)ethylcarbamate, [2-(1,3-Dithianyl)]methylcarbamate (Dmoc) , 4-methylthienylcarbamate (Mtpc), 2,4-dimethylthienylcarbamate (Bmpc), 2-phosphinoethylcarbamate (Peoc), 2-triphenyl Phosphinoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-oxobenzylcarbamate, p-(dimethy) ( Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, tertiary Amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate acid ester, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacrylovinyl carbamate, o- (N,N-di Methylformamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propylcarbamate, 1,1-dimethycarbamate Methylpropynylcarbamate, bis(2-pyridyl)methylcarbamate, 2-furylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate acid ester, isobutyl carbamate, isonicotinyl carbamate, p-(p'methoxyphenylazepine)benzyl carbamate, 1-methylcyclobutyl carbamate , 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl Carbamate, 1-Methyl-1-(p-phenylazaphenyl)ethylcarbamate, 1-Methyl-1-phenylethylcarbamate, 1-Methyl-1 -(4-Pyridyl)ethylcarbamate, Phenylcarbamate, p-(Phenylazepine)benzylcarbamate, 2,4,6-Tri- tert- butylphenyl Carbamate, 4-(trimethylammonium)benzylcarbamate and 2,4,6-trimethylbenzylcarbamate.

氮保護基諸如磺醯胺基團(例如， -S(=O)2 Raa )包括但不限於對甲苯磺醯胺(Ts)、苯磺醯胺、2,3,6-三甲基-4-甲氧基苯磺醯胺(Mtr)、2,4,6-三甲氧基苯磺醯胺(Mtb)、2,6-二甲基-4-甲氧基苯磺醯胺(Pme)、2,3,5,6-四甲基-4-甲氧基苯磺醯胺(Mte)、4-甲氧基苯磺醯胺(Mbs)、2,4,6-三甲基苯磺醯胺(Mts)、2,6-二甲氧基-4-甲基苯磺醯胺(iMds)、2,2,5,7,8-五甲基色原烷-6-磺醯胺(Pmc)、甲磺醯胺(Ms)、β-三甲基矽基乙磺醯胺(SES)、9-蒽磺醯胺、4-(4',8'-二甲氧基萘基甲基)苯磺醯胺(DNMBS)、苯甲基磺醯胺、三氟甲基磺醯胺及苯醯基磺醯胺。Nitrogen protecting groups such as sulfonamides ( eg, -S(=O) 2 R aa ) include, but are not limited to, p-toluenesulfonamides (Ts), benzenesulfonamides, 2,3,6-trimethyl- 4-Methoxybenzenesulfonamide (Mtr), 2,4,6-Trimethoxybenzenesulfonamide (Mtb), 2,6-Dimethyl-4-methoxybenzenesulfonamide (Pme) , 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonic acid Amide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide ( Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl) ) benzenesulfonamides (DNMBS), benzylsulfonamides, trifluoromethylsulfonamides and benzylsulfonamides.

其他氮保護基包括但不限於啡噻嗪基-(10)-醯基衍生物、N'-對甲苯磺醯基胺基醯基衍生物、N'-苯基胺基硫醯基衍生物、N-苯甲醯基苯基丙胺醯基衍生物、N-乙醯基甲硫胺酸衍生物、4,5-聯苯基-3-噁唑啉-2-酮、N-酞醯亞胺、N-二硫雜琥珀醯亞胺(Dts)、N-2,3-聯苯基順丁烯二醯亞胺、N-2,5-二甲基吡咯、N-1,1,4,4-四甲基二矽基氮雜環戊烷加合物(STABASE)、5-取代之1,3-二甲基 -1,3,5-三氮雜環己-2-酮、5-取代之1,3-二苯甲基-1,3,5-三氮雜環己-2-酮、1-取代之3,5-二硝基-4-吡啶酮、N-甲胺、N-烯丙胺、N-[2-(三甲基矽基)乙氧基]甲胺(SEM)、N-3-乙醯氧基丙胺、N-(1-異丙基-4-硝基-2-側氧基-3-吡咯啉-3-基)胺、第四銨鹽、N-苯甲胺、N-二(4-甲氧基苯基)甲胺、N-5-二苯并環庚胺、N-三苯基甲胺(Tr)、N-[(4-甲氧基苯基)聯苯基甲基]胺(MMTr)、N-9-苯基茀胺(PhF)、N-2,7-二氯-9-茀基亞甲胺、N-二茂鐵基甲胺基(Fcm)、N-2-甲基吡啶胺基N'-氧化物、N-1,1-二甲基硫亞甲胺、N-亞苯甲胺、N-對甲氧基亞苯甲胺、N-聯苯基亞甲胺、N-[(2-吡啶基)2,4,6-三甲苯基]亞甲胺、N-(N',N'-二甲基胺基亞甲基)胺、N,N'-亞異丙二胺、N-對硝基亞苯甲胺、N-亞柳基胺、N-5-氯亞柳基胺、N-(5-氯-2-羥基苯基)苯基亞甲胺、N-亞環己胺、N-(5,5-二甲基-3-側氧基-1-環己烯基)胺、N-硼烷衍生物、N-聯苯基硼酸衍生物、N-[苯基(五醯基鉻或鎢)醯基]胺、N-銅螯合物、N-鋅螯合物、N-硝胺、N-亞硝胺、胺N-氧化物、聯苯基膦醯胺(Dpp)、二甲基硫代膦醯胺(Mpt)、聯苯基硫膦醯胺(Ppt)、二烷基胺基磷酸酯、二苯甲基胺基磷酸酯、聯苯基胺基磷酸酯、苯次磺醯胺、鄰 硝基苯次磺醯胺(Nps)、2,4-二硝基苯次磺醯胺、五氯苯次磺醯胺、2-硝基-4-甲氧基苯次磺醯胺、三苯基甲基次磺醯胺及3-硝基吡啶次磺醯胺(Npys)。Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-yl derivatives, N'-p-toluenesulfonamidoyl derivatives, N'-phenylaminosulfonamido derivatives, N-benzylphenylpropylamine derivatives, N-acetylmethionine derivatives, 4,5-biphenyl-3-oxazolin-2-one, N-phthalimide , N-dithiasuccinimide (Dts), N-2,3-biphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4, 4-Tetramethyldisilazane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5- Substituted 1,3-Diphenylmethyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N -Allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro- 2-oxy-3-pyrrolin-3-yl)amine, fourth ammonium salt, N-benzylamine, N-bis(4-methoxyphenyl)methanamine, N-5-dibenzo Cycloheptylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)biphenylmethyl]amine (MMTr), N-9-phenylindeneamine (PhF), N-2,7-Dichloro-9-phenylmethyleneamine, N-ferrocenylmethylamine (Fcm), N-2-picoline N'-oxide, N-1,1 -Dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-biphenylmethyleneamine, N-[(2-pyridyl)2,4,6 -Trimethylyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylenediamine, N-p-nitrobenzidineamine, N-salylideneamine, N-5-chlorosalylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyleneamine, N-(5,5- Dimethyl-3-side oxy-1-cyclohexenyl)amine, N-borane derivatives, N-biphenylboronic acid derivatives, N-[phenyl(pentaylchromium or tungsten)yl ] Amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, biphenylphosphinoamide (Dpp), dimethyl thiophosphine Amide (Mpt), Biphenylphosphinoamide (Ppt), Dialkyl Amino Phosphate, Diphenylmethyl Amino Phosphate, Biphenyl Amino Phosphate, Benzsulfenamide, O -Nitro Benzyl sulfenamide (Nps), 2,4-dinitrobenzene sulfenamide, pentachlorobenzene sulfenamide, 2-nitro-4-methoxybenzene sulfenamide, triphenyl Methylsulfenamide and 3-nitropyridinesulfenamide (Npys).

在某些實施例中，存在於氧原子上之取代基為氧保護基(在本文中亦稱為「羥基保護基」)。氧保護基包括但不限於-Raa 、-N(Rbb )2 、-C(=O)SRaa 、-C(=O)Raa 、-CO2 Raa 、-C(=O)N(Rbb )2 、-C(=NRbb )Raa 、-C(=NRbb )ORaa 、-C(=NRbb )N(Rbb )2 、-S(=O)Raa 、-SO2 Raa 、-Si(Raa )3 、-P(Rcc )2 、-P(Rcc )3 + X- 、-P(ORcc )2 、-P(ORcc )3 + X- 、-P(=O)(Raa )2 、-P(=O)(ORcc )2 及-P(=O)(N(Rbb )2 )2 ，其中Raa 、Rbb 及Rcc 如本文所定義。氧保護基為此項技術中熟知的且包括Protecting Groups in Organic Synthesis,T.W.Greene及P.G.M.Wuts，第3版，John Wiley & Sons,1999中詳述者，該文獻以引用之方式併入本文。In certain embodiments, a substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxy protecting group"). Oxygen protecting groups include but are not limited to -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N (R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , - SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 + X - , -P(OR cc ) 2 , -P(OR cc ) 3 + X - , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 and -P(=O)(N(R bb ) 2 ) 2 , where R aa , R bb and R cc as defined herein. Oxygen protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

示範性氧保護基包括但不限於甲基、甲氧基甲基(MOM)、甲基硫甲基(MTM)、第三丁基硫 甲基、(苯基二甲基矽基)甲氧基甲基(SMOM)、苯甲基氧基甲基(BOM)、對甲氧基苯甲基氧基甲基(PMBM)、(4-甲氧基苯氧基)甲基(p-AOM)、癒創木酚甲基(GUM)、第三丁氧基甲基、4-戊烯基氧基甲基(POM)、矽氧基甲基、2-甲氧基乙氧基甲基(MEM)、2,2,2-三氯乙氧基甲基、雙(2-氯乙氧基)甲基、2-(三甲基矽基)乙氧基甲基(SEMOR)、四氫哌喃基(THP)、3-溴四氫哌喃基、四氫硫哌喃基、1-甲氧基環己基、4-甲氧基四氫哌喃基(MTHP)、4-甲氧基四氫硫哌喃基、4-甲氧基四氫硫哌喃基S,S-二氧化物、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基(CTMP)、1,4-二噁烷-2-基、四氫呋喃基、四氫硫呋喃基、2,3,3a,4,5,6,7,7a-八氫-7,8,8-三甲基-4,7-甲橋苯并呋喃-2-基、1-乙氧基乙基、1-(2-氯乙氧基)乙基、1-甲基-1-甲氧基乙基、1-甲基-1-苯甲基氧基乙基、1-甲基-1-苯甲基氧基-2-氟乙基、2,2,2-三氯乙基、2-三甲基矽基乙基、2-(苯基氧硒基)乙基、第三丁基 、烯丙基、對氯苯基、對甲氧基苯基、2,4-二硝基苯基、苯甲基(Bn)、對甲氧基苯甲基、3,4-二甲氧基苯甲基、鄰 硝基苯甲基、對硝基苯甲基、對鹵基苯甲基、2,6-二氯苯甲基、對氰基苯甲基、對苯基苯甲基、2-甲基吡啶、4-甲基吡啶、3-甲基-2-甲基吡啶N-氧化物、聯苯基甲基、對,對'-二硝基二苯甲基、5-二苯并環庚基、三苯基甲基、α-萘基聯苯基甲基、對甲氧基苯基聯苯基甲基、二(對甲氧基苯基)苯基甲基、三(對甲氧基苯基)甲基、4-(4'-溴苯醯基氧基苯基)聯苯基甲基、4,4',4"-參(4,5-二氯酞醯亞胺基苯基)甲基、4,4',4"-參(左戊醯基氧基苯基)甲基、4,4',4"-參(苯甲醯基氧基苯基)甲基、3-(咪唑-1-基)雙(4',4"-二甲氧基苯基)甲基、1,1-雙(4-甲氧基苯基)-1'-芘基甲基、9-蒽基、9-(9-苯基)氧雜蒽基、9-(9-苯基-10-側氧基)蒽基、1,3-苯并二硫戊環-2-基、苯并異噻唑基S,S-二氧化物、三甲基矽基(TMS)、三乙基矽基(TES)、三異丙基矽基(TIPS)、二甲基異丙基矽基(IPDMS)、二乙基異丙基矽基(DEIPS)、二甲基新己基矽基(dimethylthexylsilyl)、第三丁基 二甲基矽基(TBDMS)、第三丁基 聯苯基矽基(TBDPS)、三苯甲基矽基、三-對二甲苯基矽基、三苯基矽基、聯苯基甲基矽基(DPMS)、第三丁基 甲氧基苯基矽基(TBMPS)、甲酸酯、苯甲醯基甲酸酯、乙酸酯、氯乙酸酯、二氯乙酸酯、三氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、苯氧基乙酸酯、對氯苯氧基乙酸酯、3-苯基丙酸酯、4-側氧基戊酸酯(乙醯丙酸酯)、4,4-(亞乙基二硫)戊酸酯(乙醯丙醯基二硫縮醛)、新戊酸酯(pivaloate)、金剛烷酸酯、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、對苯基苯甲酸酯、2,4,6-三甲基苯甲酸酯(萊酸酯(mesitoate))、碳酸甲酯、9-茀基甲基碳酸酯(Fmoc)、碳酸乙酯、2,2,2-三氯乙基碳酸酯(Troc)、2-(三甲基矽基)乙基碳酸酯(TMSEC)、2-(苯基磺醯基)乙基碳酸酯(Psec)、2-(三苯基膦基)乙基碳酸酯(Peoc)、碳酸異丁酯、碳酸乙烯酯、碳酸烯丙酯、碳酸第三丁 酯(BOC或Boc)、碳酸對硝基苯酯、碳酸苯甲酯、碳酸對甲氧基苯甲酯、碳酸3,4-二甲氧基苯甲酯、碳酸鄰 硝基苯甲酯、碳酸對硝基苯甲酯、硫碳酸S-苯甲酯、碳酸4-乙氧基-1-萘酯、二硫碳酸甲酯、2-碘苯甲酸酯、4-疊氮基丁酸酯、4-硝基-4-甲基戊酸酯、鄰 (二溴甲基)苯甲酸酯、2-甲醯基苯磺酸酯、2-(甲基硫代甲氧基)乙基、4-(甲基硫甲氧基)丁酸酯、2-(甲基硫甲氧基甲基)苯甲酸酯、2,6-二氯-4-甲基苯氧基乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯、2,4-雙(1,1-二甲基丙基)苯氧基乙酸酯、氯聯苯基乙酸酯、異丁酸酯、單琥珀酸酯、(E)-2-甲基-2-丁酸酯、鄰 (甲氧基醯基)苯甲酸酯、α-萘酸酯、硝酸酯、N,N,N',N'-四甲基磷酸二醯胺烷基酯、N-苯基胺甲酸烷基酯、硼酸酯、二甲基硫膦基、2,4-二硝基苯基次磺酸烷基酯、硫酸酯、甲磺酸酯(methanesulfonate/mesylate)、磺酸苯甲酯及甲苯磺酸酯(Ts)。Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl , (phenyldimethylsilyl)methoxy methyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM) , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl Piperanyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidine-4- (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8 -Trimethyl-4,7-methylbenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxy Ethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2- Trimethylsilylethyl, 2-(phenyloxyseleno)ethyl, tert-butyl , allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl , Benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o -nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2 ,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-methylpyridine, 4-methylpyridine, 3-methyl-2-methylpyridine N-oxide, Biphenylmethyl, p,p'-dinitrobenzyl, 5-dibenzocycloheptyl, triphenylmethyl, α-naphthylbiphenylmethyl, p-methoxyphenyl Biphenylmethyl, bis(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromobenzyloxyphenyl)biphenyl Methyl, 4,4',4"-para(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-para(levamyloxyphenyl)methyl base, 4,4',4"-para(benzyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl , 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthrenyl, 9-(9-phenyl- 10-oxy) anthracenyl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl base (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropyl Silicon (DEIPS), dimethylthexylsilyl (dimethylthexylsilyl), tertiary butyl dimethylsilyl (TBDMS), tertiary butyl biphenylsilyl (TBDPS), tritylsilyl, Tri-p-xylylsilyl, triphenylsilyl, biphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzylmethyl Acetate, Acetate, Chloroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxy Acetate, p-Chlorophenoxyacetate, 3-Phenylpropionate, 4-Pendoxoxyvalerate (Acetylpropionate), 4,4-(Ethylenedithio)valeric Acid Esters (acetylpropionyl dithioacetal), pivaloate, adamantanoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoic acid Esters, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-phenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2- Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenyl) phosphino) ethyl carbonate (Peoc), isobutyl carbonate, ethylene carbonate, allyl carbonate, tert- butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, paracarbonate Methoxybenzyl, 3,4-dimethoxybenzyl carbonate, o -nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxycarbonate -1-naphthyl ester, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o- (dibromomethyl)benzene Formate, 2-Methylaminobenzenesulfonate, 2-(Methylthiomethoxy)ethyl, 4-(Methylthiomethoxy)butyrate, 2-(Methylthiomethoxy) ylmethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl) ) phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorobiphenyl acetate, isobutyrate, monosuccinate, ( E)-2-methyl-2-butyrate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, N,N,N',N'-tetramethylphosphoric acid Diamide alkyl ester, N-phenylcarbamate alkyl ester, borate ester, dimethyl phosphinothioate, 2,4-dinitrophenyl sulfenic acid alkyl ester, sulfate ester, methanesulfonic acid Esters (methanesulfonate/mesylate), benzyl sulfonate and tosylate (Ts).

在某些實施例中，存在於硫原子上之取代基為硫保護基(在本文中亦稱為「硫醇保護基」)。硫保護基包括但不限於-Raa 、-N(Rbb )2 、-C(=O)SRaa 、-C(=O)Raa 、-CO2 Raa 、-C(=O)N(Rbb )2 、-C(=NRbb )Raa 、-C(=NRbb )ORaa 、 -C(=NRbb )N(Rbb )2 、-S(=O)Raa 、-SO2 Raa 、-Si(Raa )3 、-P(Rcc )2 、-P(Rcc )3 + X- 、-P(ORcc )2 、-P(ORcc )3 + X- 、-P(=O)(Raa )2 、-P(=O)(ORcc )2 及-P(=O)(N(Rbb )2 )2 ，其中Raa 、Rbb 及Rcc 如本文所定義。硫保護基為此項技術中熟知的且包括Protecting Groups in Organic Synthesis,T.W.Greene及P.G.M.Wuts，第3版，John Wiley & Sons,1999中詳述者，該文獻以引用之方式併入本文。In certain embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also referred to herein as "thiol protecting groups"). Sulfur protecting groups include but are not limited to -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N (R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , - SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 + X - , -P(OR cc ) 2 , -P(OR cc ) 3 + X - , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 and -P(=O)(N(R bb ) 2 ) 2 , where R aa , R bb and R cc as defined herein. Sulfur protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

術語「脫離基」在合成有機化學技術中給予其普通含義且係指能夠經親核劑置換之原子或基團。合適的脫離基之實例包括但不限於鹵素(諸如F、Cl、Br、或I(碘))、烷氧基羰基氧基、芳基氧基羰基氧基、烷磺醯基氧基、芳磺醯基氧基、烷基-羰基氧基(例如， 乙醯氧基)、芳基羰基氧基、芳基氧基、甲氧基、N ,O -二甲基羥基胺基、咕噸基(pixyl)及鹵基甲酸酯。在某些實施例中，脫離基為鹵素、烷磺醯基氧基、芳磺醯基氧基、重氮、烷基二氮烯、芳基二氮烯、烷基三氮烯、芳基三氮烯、硝基、硝酸烷基酯、硝酸芳基酯、磷酸烷基酯、磷酸芳基酯、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基氨、烷基胺、芳基胺、羥基、烷基氧基或芳基氧基。在一些情況下，脫離基為磺酸酯，諸如甲苯磺酸酯(甲苯磺酸酯(tosylate)，-OT)、甲磺酸酯(甲磺酸酯(mesylate)，-OM)、對溴苯磺醯基氧基(對溴苯磺酸酯(brosylate)，-OB)、-OS(=O)2 (CF2 )3 CF3 (全氟丁磺酸酯(nonaflate)，-ONf)或三氟甲磺酸酯(三氟甲磺酸酯(triflate)，-OTf)。在一些情況下，脫離基為對溴苯磺酸酯，諸如對溴苯磺醯基氧基。在一些情況下，脫離基為全氟丁磺酸酯，諸如2-硝基苯磺醯基氧基。在一些實施例中，脫離基為含有磺酸酯之基團。在一些實施例中，脫離基為甲苯磺酸酯基。脫離基亦可為氧化膦(例如， 在光延反應(Mitsunobu reaction)期間形成)或內部脫離基諸如環氧化物或環狀硫酸酯。脫離基之其他非限制性實例為水、氨、醇、醚部分、硫醚部分、鋅鹵化物、鎂部分、重氮鹽及銅部分。The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or group capable of displacement by a nucleophile. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alksulfonyloxy, arylsulfonic acid Acyloxy, alkyl-carbonyloxy ( eg, acetyloxy), arylcarbonyloxy, aryloxy, methoxy, N , O -dimethylhydroxylamino, xanthyl ( pixyl) and haloformates. In certain embodiments, the leaving group is halogen, alksulfonyloxy, arylsulfonyloxy, diazo, alkyldiazene, aryldiazene, alkyltriazene, aryltriazene Nitrene, nitro, alkyl nitrate, aryl nitrate, alkyl phosphate, aryl phosphate, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy amino, alkylamine, arylamine, hydroxyl, alkyloxy or aryloxy. In some cases, the leaving group is a sulfonate, such as tosylate (tosylate, -OT), mesylate (mesylate, -OM), p-bromobenzene Sulfonyloxy (brosylate, -OB), -OS(=O) 2 (CF 2 ) 3 CF 3 (nonaflate, -ONf) or tris Fluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is p-bromobenzenesulfonate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a perfluorobutanesulfonate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. Leaving groups may also be phosphine oxides ( eg, formed during the Mitsunobu reaction) or internal leaving groups such as epoxides or cyclic sulfates. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

「羧基」係指基團-C(=O)OH。"Carboxyl" refers to the group -C(=O)OH.

「氰基」係指基團-CN。"Cyano" refers to the group -CN.

「鹵基」或「鹵素」係指氟(F)、氯(Cl)、溴(Br)及碘(I)。在某些實施例中，鹵基為氟或氯。"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In certain embodiments, the halo group is fluoro or chloro.

「鹵烷基」係指以下烷基基團，其中烷基經一或多個鹵素取代。典型鹵烷基包括但不限於三氟甲基(-CF3 )、二氟甲基(-CHF2 )、氟甲基(-CH2 F)、氯甲基(-CH2 Cl)、二氯甲基(-CHCl2 )、三溴甲基(-CH2 Br)及其類似者。"Haloalkyl" refers to an alkyl group wherein the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl ( -CF3 ), difluoromethyl (-CHF2), fluoromethyl ( -CH2F ), chloromethyl ( -CH2Cl ), dichloromethyl Methyl ( -CHCl2 ), tribromomethyl ( -CH2Br) and the like.

「羥基」係指基團-OH。"Hydroxy" refers to the group -OH.

「硝基」係指基團-NO2 。"Nitro" refers to the group -NO2 .

「硫酮基」係指基團=S。"Thione" refers to the group =S.

如本文所定義之烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基視情況經取代(例如， 「經取代」或「未經取代」之烷基、「經取代」或「未經取代」之烯基、「經取代」或「未經取代」之炔基、「經取代」或「未經取代」之碳環基、「經取代」或「未經取代」之雜環基、「經取代」或「未經取代」之芳基或「經取代」或「未經取代」之雜芳基)。一般而言，術語「經取代」，無論前面是否有術語「視情況」，均意謂存在於基團(例如， 碳或氮原子)上之至少一個氫經可允許取代基置換，例如 ，在取代之後產生穩定化合物(例如 ，不自發經歷轉化(諸如藉由重排、環化、消除或其他反應)之化合物)之取代基。除非另外指示，否則「經取代」之基團在該基團之一或多個可取代位置處具有取代基，且當任何給定結構中之多於一個位置經取代時，各位置處之取代基為相同或不同的。預期術語「經取代」包括經有機化合物之所有可允許取代基、導致形成穩定化合物之任一本文所述之取代基進行取代。本發明涵蓋達成穩定化合物的任何及所有此類組合。出於本發明之目的，諸如氮之雜原子可具有如本文所述之氫取代基及/或任何合適的取代基，其滿足雜原子之化合價且導致形成穩定部分。Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted ( eg, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted"substituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl). In general, the term "substituted", whether preceded by the term "optional" or not, means that at least one hydrogen present on a group ( eg, a carbon or nitrogen atom) is replaced with a permissible substituent, eg , at Substituents that yield stable compounds ( eg , compounds that do not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reactions) following substitution. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substitution at each position The bases are the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds that result in the formation of stable compounds with any of the substituents described herein. The present invention contemplates any and all such combinations that achieve stable compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent as described herein and/or any suitable substituent that satisfies the valence of the heteroatom and results in the formation of a stabilizing moiety.

示範性碳原子取代基包括但不限於鹵素、-CN、-NO2 、-N3 、-SO2 H、-SO3 H、-OH、-ORaa 、-ON(Rbb )2 、-N(Rbb )2 、-N(Rbb )3 + X- 、-N(ORcc )Rbb 、-SH、-SRaa 、-SSRcc 、-C(=O)Raa 、-CO2 H、-CHO、-C(ORcc )2 、-CO2 Raa 、-OC(=O)Raa 、-OCO2 Raa 、-C(=O)N(Rbb )2 、-OC(=O)N(Rbb )2 、-NRbb C(=O)Raa 、-NRbb CO2 Raa 、-NRbb C(=O)N(Rbb )2 、-C(=NRbb )Raa 、-C(=NRbb )ORaa 、-OC(=NRbb )Raa 、-OC(=NRbb )ORaa 、-C(=NRbb )N(Rbb )2 、-OC(=NRbb )N(Rbb )2 、-NRbb C(=NRbb )N(Rbb )2 、-C(=O)NRbb SO2 Raa 、-NRbb SO2 Raa 、-SO2 N(Rbb )2 、-SO2 Raa 、-SO2 ORaa 、-OSO2 Raa 、-S(=O)Raa 、-S(=O)(=NRbb )Raa 、-OS(=O)Raa 、-Si(Raa )3 、-OSi(Raa )3 -C(=S)N(Rbb )2 、-C(=O)SRaa 、-C(=S)SRaa 、-SC(=S)SRaa 、-SC(=O)SRaa 、-OC(=O)SRaa 、-SC(=O)ORaa 、-SC(=O)Raa 、-P(=O)2 Raa 、-OP(=O)2 Raa 、-P(=O)(Raa )2 、-OP(=O)(Raa )2 、-OP(=O)(ORcc )2 、-P(=O)2 N(Rbb )2 、-OP(=O)2 N(Rbb )2 、-P(=O)(NRbb )2 、-OP(=O)(NRbb )2 、-NRbb P(=O)(ORcc )2 、-NRbb P(=O)(NRbb )2 、-P(Rcc )2 、-P(Rcc )3 、-OP(Rcc )2 、-OP(Rcc )3 、-B(Raa )2 、-B(ORcc )2 、-BRaa (ORcc )、C1-10 烷基、C1-10 鹵烷基、C2-10 烯基、C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代；或碳原子上之兩個偕氫經基團=O、=S、=NN(Rbb )2 、=NNRbb C(=O)Raa 、=NNRbb C(=O)ORaa 、=NNRbb S(=O)2 Raa 、=NRbb 或=NORcc 置換；Raa 之各實例獨立地選自C1-10 烷基、C1-10 鹵烷基、C2-10 烯基、C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，或兩個Raa 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代；Rbb 之各實例獨立地選自氫、-OH、-ORaa 、-N(Rcc )2 、-CN、-C(=O)Raa 、-C(=O)N(Rcc )2 、-CO2 Raa 、-SO2 Raa 、-C(=NRcc )ORaa 、-C(=NRcc )N(Rcc )2 、-SO2 N(Rcc )2 、-SO2 Rcc 、-SO2 ORcc 、-SORaa 、-C(=S)N(Rcc )2 、-C(=O)SRcc 、-C(=S)SRcc 、-P(=O)2 Raa 、 -P(=O)(Raa )2、-P(=O)2 N(Rcc )2 、-P(=O)(NRcc )2 、C1-10 烷基、C1-10 鹵烷基、C2-10 烯基、C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，或兩個Rbb 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代；Rcc 之各實例獨立地選自氫、C1-10 烷基、C1-10 鹵烷基、C2-10 烯基、C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，或兩個Rcc 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代；Rdd 之各實例獨立地選自鹵素、-CN、-NO2 、-N3 、-SO2 H、-SO3 H、-OH、-ORee 、-ON(Rff )2 、-N(Rff )2 、-N(Rff )3 + X- 、-N(ORee )Rff 、-SH、-SRee 、-SSRee 、-C(=O)Ree 、-CO2 H、-CO2 Ree 、-OC(=O)Ree 、-OCO2 Ree 、-C(=O)N(Rff )2 、-OC(=O)N(Rff )2 、-NRff C(=O)Ree 、-NRff CO2 Ree 、-NRff C(=O)N(Rff )2 、-C(=NRff )ORee 、-OC(=NRff )Ree 、-OC(=NRff )ORee 、-C(=NRff )N(Rff )2 、-OC(=NRff )N(Rff )2 、-NRff C(=NRff )N(Rff )2 、-NRff SO2 Ree 、-SO2 N(Rff )2 、-SO2 Ree 、-SO2 ORee 、-OSO2 Ree 、-S(=O)Ree 、-Si(Ree )3 、-OSi(Ree )3 、-C(=S)N(Rff )2 、-C(=O)SRee 、-C(=S)SRee 、-SC(=S)SRee 、-P(=O)2 Ree 、-P(=O)(Ree )2 、-OP(=O)(Ree )2 、-OP(=O)(ORee )2 、C1-6 烷基、C1-6 鹵烷基、C2-6 烯基、C2-6 炔基、C3-10 碳環基、3-10員雜環基、C6-10 芳基、5-10員雜芳基，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rgg 基團取代，或兩個偕Rdd 取代基可連接在一起形成=O或=S；Ree 之各實例獨立地選自C1-6 烷基、C1-6 鹵烷基、C2-6 烯基、C2-6 炔基、C3-10 碳環基、C6-10 芳基、3-10員雜環基及3-10員雜芳基，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rgg 基團取代；Rff 之各實例獨立地選自氫、C1-6 烷基、C1-6 鹵烷基、C2-6 烯基、C2-6 炔基、C3-10 碳環基、3-10員雜環基、C6-10 芳基及5-10員雜芳基，或兩個Rff 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rgg 基團取代；且Rgg 之各實例獨立地為鹵素、-CN、-NO2 、-N3 、-SO2 H、-SO3 H、-OH、-OC1-6 烷基、-ON(C1-6 烷基)2 、-N(C1-6 烷基)2 、-N(C1-6 烷基)3 + X- 、-NH(C1-6 烷基)2 + X- 、-NH2 (C1-6 烷基)+ X- 、-NH3 + X- 、-N(OC1-6 烷基)(C1-6 烷基)、-N(OH)(C1-6 烷基)、-NH(OH)、-SH、-SC1-6 烷基、-SS(C1-6 烷基)、-C(=O)(C1-6 烷基)、-CO2 H、-CO2 (C1-6 烷基)、-OC(=O)(C1-6 烷基)、-OCO2 (C1-6 烷基)、-C(=O)NH2 、-C(=O)N(C1-6 烷基)2 、-OC(=O)NH(C1-6 烷基)、-NHC(=O)(C1-6 烷基)、-N(C1-6 烷基)C(=O)(C1-6 烷基)、-NHCO2 (C1-6 烷基)、-NHC(=O)N(C1-6 烷基)2 、-NHC(=O)NH(C1-6 烷基)、-NHC(=O)NH2 、-C(=NH)O(C1-6 烷基)、-OC(=NH)(C1-6 烷基)、-OC(=NH)OC1-6 烷基、-C(=NH)N(C1-6 烷基)2 、-C(=NH)NH(C1-6 烷基)、-C(=NH)NH2 、-OC(=NH)N(C1-6 烷基)2 、-OC(NH)NH(C1-6 烷基)、-OC(NH)NH2 、-NHC(NH)N(C1-6 烷基)2 、-NHC(=NH)NH2 、-NHSO2 (C1-6 烷基)、-SO2 N(C1-6 烷基)2 、-SO2 NH(C1-6 烷基)、-SO2 NH2 、-SO2 C1-6 烷基、-SO2 OC1-6 烷基、-OSO2 C1-6 烷基、-SOC1-6 烷基、-Si(C1-6 烷基)3 、-OSi(C1-6 烷基)3 -C(=S)N(C1-6 烷基)2 、C(=S)NH(C1-6 烷基)、C(=S)NH2 、-C(=O)S(C1-6 烷基)、-C(=S)SC1-6 烷基、-SC(=S)SC1-6 烷基、-P(=O)2 (C1-6 烷基)、-P(=O)(C1-6 烷基)2 、-OP(=O)(C1-6 烷基)2 、-OP(=O)(OC1-6 烷基)2 、C1-6 烷基、C1-6 鹵烷基、C2-6 烯基、C2-6 炔基、C3-10 碳環基、C6-10 芳基、3-10員雜環基、5-10員雜芳基；或兩個偕Rgg 取代基可連接在一起形成=O或=S；其中X- 為相對離子。Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2 , -N3 , -SO2H, -SO3H , -OH, -ORaa , -ON( Rbb )2 , -N (R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO 2 H , -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(= O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -C(=NR bb ) R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2 , -OC( =NR bb )N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb SO 2 R aa , -NR bb SO 2 R aa , -SO 2 N(R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R aa , -S(=O)R aa , -S(=O)(=NR bb )R aa , - OS(=O)R aa , -Si(R aa ) 3 , -OSi(R aa ) 3 -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S )SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , - P(=O) 2 R aa , -OP(=O) 2 R aa , -P(=O)(R aa ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)( OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , -OP(=O) 2 N(R bb ) 2 , -P(=O)(NR bb ) 2 , -OP(=O )(NR bb ) 2 , -NR bb P(=O)(OR cc ) 2 , -NR bb P(=O)(NR bb ) 2 , -P(R cc ) 2 , -P(R cc ) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 membered aryl and 5-14 membered heteroaryl, wherein each alkyl, Alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; or two geminal hydrogens on a carbon atom Via the groups =O, =S, =NN( Rbb ) 2 , = NNRbbC (=O) Raa , = NNRbbC (=O) ORaa , = NNRbbS (=O ) 2Raa , =NR bb or =NOR cc substitution; each instance of R aa is independently selected from C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 membered aryl and 5-14 membered heteroaryl, or two R aa groups joined together to form a 3-14 membered heterocyclyl or 5- 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups group substitution; each instance of R bb is independently selected from hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P( =O) 2 R aa , -P(=O)(R aa )2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , C 1-10 alkane group, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 Member heteroaryl, or two R bb groups joined together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle , aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R cc is independently selected from hydrogen, C 1-10 alkyl, C 1- 10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3- 14-membered heterocyclyl, C 6-14 -membered aryl and 5-14-membered heteroaryl, or two R cc groups joined together to form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring, wherein Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; examples of R dd independently selected from halogen, -CN, -NO2 , -N3 , -SO2H, -SO3H , -OH, -ORee , -ON( Rff ) 2 , -N( Rff )2 , -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO 2 H , -CO 2 R ee , -OC(=O) Ree , -OCO 2 Ree , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O) Ree , -NR ff CO 2 Ree , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff ) Ree , -OC (= NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 Ree , -SO 2 N(R ff ) 2 , -SO 2 Ree , -SO 2 OR ee , -OSO 2 Ree , -S(=O) Ree , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 Re , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)( OR ee ) 2 , C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5 -10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently via 0, 1, 2, 3, 4, or 5 R gg groups group substitution, or two gem R dd substituents may be joined together to form =O or =S; each instance of R ee is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 member heterocycle Cyclic and 3-10 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently 0, 1, 2, 3, 4, or 5 R gg groups are substituted; each instance of R ff is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 -carbocyclyl, 3-10-membered heterocyclyl, C6-10 -membered aryl and 5-10-membered heteroaryl, or two Rff groups linked together to form 3-14-membered heterocyclyl or 5-14 membered heterocyclyl A membered heteroaryl ring in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups and each instance of Rgg is independently halogen, -CN, -NO2 , -N3 , -SO2H , -SO3H , -OH, -OC1-6alkyl , -ON( C1 -6 alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 + X - , -NH(C 1-6 alkyl) 2 + X - , - NH 2 (C 1-6 alkyl) + X - , -NH 3 + X - , -N(OC 1-6 alkyl) (C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N (C 1-6 alkyl) C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkane base), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) ) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkane base, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl base) 3 -C(=S)N(C 1-6 alkyl) 2 , C(=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S (C 1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S) SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl) , -P(=O)(C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl , 5-10 membered heteroaryl; or two gem R gg substituents can be linked together to form =O or =S; wherein X - is the opposite ion.

「相對離子」或「陰離子相對離子」為與陽離子四級胺基締合以便保持電荷中性之帶負電荷基團。示範性相對離子包括鹵化物離子(例如， F- 、Cl- 、Br- 、I- )、NO3 - 、ClO4 - 、OH- 、H2 PO4 - 、HSO4 - 、SO4 -2 磺酸根離子(例如， 甲磺酸根、三氟甲磺酸根、對甲苯磺酸根、苯磺酸根、10-樟腦磺酸根、萘-2-磺酸根、萘-1- 磺酸-5-磺酸根、乙-1-磺酸-2-磺酸根及其類似者)及羧酸根離子(例如， 乙酸根(acetate)、乙酸根(ethanoate)、丙酸根、苯甲酸根、甘油酸根、乳酸根、酒石酸根、甘醇酸根等)。A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amine group in order to maintain charge neutrality. Exemplary counter ions include halide ions ( eg, F − , Cl − , Br − , I − ), NO 3 − , ClO 4 − , OH − , H 2 PO 4 − , HSO 4 − , SO 4 -2 sulfonic acid Acid ions ( eg, mesylate, triflate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethanesulfonate -1-sulfo-2-sulfonate and the like) and carboxylate ions ( eg acetate, ethanoate, propionate, benzoate, glycerate, lactate, tartrate, Glycolate, etc.).

氮原子可經取代或未經取代，只要化合價允許，且包括一級、二級、三級或四級氮原子。示範性氮原子取代基包括但不限於氫、-OH、-ORaa 、-N(Rcc )2 、-CN、-C(=O)Raa 、-C(=O)N(Rcc )2 、-CO2 Raa 、-SO2 Raa 、-C(=NRbb )Raa 、-C(=NRcc )ORaa 、-C(=NRcc )N(Rcc )2 、-SO2 N(Rcc )2 、-SO2 Rcc 、-SO2 ORcc 、-SORaa 、-C(=S)N(Rcc )2 、-C(=O)SRcc 、-C(=S)SRcc 、-P(=O)2 Raa 、-P(=O)(Raa )2 、-P(=O)2 N(Rcc )2 、-P(=O)(NRcc )2 、C1-10 烷基、C1-10 鹵烷基、C2-10 烯基、C2-10 炔基、C3-10 碳環基、3-14員雜環基、C6-14 芳基及5-14員雜芳基，或連接至氮原子之兩個Rcc 基團連接在一起形成3-14員雜環基或5-14員雜芳基環，其中各烷基、烯基、炔基、碳環基、雜環基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd 基團取代，且其中Raa 、Rbb 、Rcc 及Rdd 如上文所定義。Nitrogen atoms may be substituted or unsubstituted, as valence allows, and include primary, secondary, tertiary, or quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(= S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -14 -membered aryl and 5-14-membered heteroaryl, or two R cc groups attached to a nitrogen atom are joined together to form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring, wherein each alkyl , alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , Rcc and Rdd are as defined above.

這些及其他示範性取代基更詳細描述於[實施方式]、[實例]及[發明申請專利範圍]。本發明不意欲以任何方式藉由取代基之以上示範性清單來進行限制。These and other exemplary substituents are described in more detail in [Embodiments], [Examples], and [Inventive Claims]. The invention is not intended to be limited in any way by the above exemplary list of substituents.

其他定義Other Definitions

如本文所用，術語「鹽」係指任何及所有鹽且涵蓋醫藥學上可接受之鹽。As used herein, the term "salt" refers to any and all salts and encompasses pharmaceutically acceptable salts.

術語「醫藥學上可接受之鹽」係指以下那些鹽，在合理醫學判斷之範圍內，其適用於與人類及低級動物之組織接觸，而無異常毒性、刺激性、過敏反應及其類似者，且與合理的效益/風險比率相稱。醫藥學上可接受之鹽為此項技術中熟知的。例如，Berge等人在J.Pharmaceutical Sciences (1977)66：1-19中詳細描述了醫藥學上可接受之鹽。本發明之化合物的醫藥學上可接受之鹽包括 衍生自合適無機及有機酸及鹼之鹽。醫藥學上可接受之無毒酸加成鹽之實例為胺基與無機酸或有機酸形成之鹽或藉由使用此項技術中所用之其他方法諸如離子交換形成之鹽，無機酸諸如鹽酸、氫溴酸、磷酸、硫酸及過氯酸，有機酸諸如乙酸、草酸、順丁烯二酸、酒石酸、檸檬酸、琥珀酸或丙二酸。其他醫藥學上可接受之鹽包括己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡萄糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡萄糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘酸鹽、2-羥基-乙磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽(pamoate)、果膠酸鹽(pectinate)、過硫酸鹽、3-苯基丙酸酯、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一烷酸鹽、戊酸鹽及其類似者。衍生自適當鹼之醫藥學上可接受之鹽包括鹼金屬鹽、鹼土金屬鹽、銨鹽及N+ (C1-4 烷基)4 鹽。代表性鹼金屬鹽或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽及其類似者。其他醫藥學上可接受之鹽在適當時包括使用相對離子形成之無毒銨、三級銨及胺陽離子，相對離子諸如鹵素離子、氫氧根、羧酸根、硫酸根、磷酸根、硝酸根、低級烷基磺酸根及芳基磺酸根。The term "pharmaceutically acceptable salts" means those salts which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without abnormal toxicity, irritation, allergic reactions and the like , and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amine groups formed with inorganic or organic acids or by using other methods used in the art such as ion exchange, inorganic acids such as hydrochloric acid, hydrogen Bromic acid, phosphoric acid, sulfuric acid and perchloric acid, organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonic acid Salt, Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate salt, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, Pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, Succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + ( C1-4alkyl ) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, tertiary ammonium and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower Alkyl sulfonate and aryl sulfonate.

考慮投與之「個體」包括但不限於人類(亦即，任何年齡組之男性或女性，例如， 小兒個體(例如， 嬰兒、兒童、青少年)或成人個體(例如， 年輕成人、中年成人或老年成人))及/或非人類動物，例如， 哺乳動物，諸如靈長類動物(例如， 石蟹獼猴、恆河猴)、牛、豬、馬、綿羊、山羊、嚙齒動物、貓及/或狗。在某些實施例中，個體為人類。在某些實施例中，個體為非人類動物。術語「人類」、「患者」及「個體」在本文中可互換使用。"Individuals" include, but are not limited to, humans (i.e., male or female of any age group, eg, pediatric subjects ( eg, infants, children, adolescents) or adult subjects ( eg, young adults, middle-aged adults or elderly adults)) and/or non-human animals, eg, mammals, such as primates ( eg, stone crab macaques, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats and/or dogs . In certain embodiments, the individual is a human. In certain embodiments, the individual is a non-human animal. The terms "human", "patient" and "individual" are used interchangeably herein.

疾病、病症及疾患在本文中可互換使用。Disease, disorder and disorder are used interchangeably herein.

如本文所用且除非另外指定，否則術語「治療(treat/treating/treatment)」涵蓋在個體罹患指定疾病、病症或疾患時進行的動作，其降低疾病、病症或疾患之嚴重性，或延緩或延遲疾病、病症或疾患之進展(「治療性治療」)；且亦涵蓋在個體開始罹患指定疾病、病症或疾患之前進行的動作(「預防性治療」)。As used herein and unless otherwise specified, the terms "treat/treating/treatment" encompass actions performed while an individual suffers from a specified disease, disorder or condition that reduces the severity, or delays or delays the disease, disorder or condition progression of a disease, disorder, or disorder ("therapeutic treatment"); and also encompass actions taken before an individual begins to suffer from a specified disease, disorder, or disorder ("prophylactic treatment").

一般而言，化合物之「有效量」係指足以引發所要生物反應之量。如熟習此項技術者將瞭解的，本發明之化合物之有效量可根據諸如以下之因素而改變：所要生物端點、化合物之藥物動力學、欲治療之疾病、投與模式以及個體年齡、健康及狀況。有效量涵蓋治療性及預防性治療。In general, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of the compounds of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health, and health of the individual. and status. An effective amount encompasses both therapeutic and prophylactic treatment.

如本文所用且除非另外指定，否則化合物之「治療有效量」為足以提供治療疾病、病症或疾患之治療益處或延遲或最小化與疾病、病症或疾患相關之一或多種症狀的量。化合物之治療有效量意謂單獨或與其他療法組合之治療劑提供治療疾病、病症或疾患之治療益處的量。術語「治療有效量」可涵蓋改進總體療法、減少或避免疾病或疾患之症狀或原因或者增強另一種治療劑之治療功效的量。As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder or disorder or to delay or minimize one or more symptoms associated with the disease, disorder or disorder. A therapeutically effective amount of a compound means that amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

如本文所用且除非另外指定，否則化合物之「預防有效量」為足以預防疾病、病症或疾患或與疾病、病症或疾患相關之一或多種症狀或預防其復發的量。化合物之預防有效量意謂單獨或與其他劑組合之治療劑提供預防疾病、病症或疾患之預防益處的量。術語「預防有效量」可涵蓋改進總體預防或增強另一種預防劑之預防功效的量。As used herein and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder or disorder or one or more symptoms associated with a disease, disorder or disorder. A prophylactically effective amount of a compound means that amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit of preventing a disease, disorder, or disorder. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

本發明之某些實施例之詳細描述Detailed Description of Certain Embodiments of the Invention

如本文大體上所述，本發明提供化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)，其為可用於治療與MTA 缺乏症及/或MTA累積相關之增殖性病症(例如， 癌症)之MTA無競爭性PRMT5抑制劑。As generally described herein, the present invention provides compounds ( eg, compounds of formula (I), (Ia), (Ib), (Ic), and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) , which is an MTA-uncompetitive PRMT5 inhibitor useful in the treatment of proliferative disorders ( eg, cancer) associated with MTA deficiency and/or MTA accumulation.

在一些實施例中，本發明提供化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)，其為可用於治療與MTA缺乏症及/或MTA累積相關之增殖性病症(例如， 癌症)之MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑。In some embodiments, the present invention provides compounds ( eg, compounds of formula (I), (Ia), (Ib), (Ic), and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof), It is an MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitor or MTA synergistic binder useful in the treatment of proliferative disorders ( eg, cancer) associated with MTA deficiency and/or MTA accumulation.

化合物compound

在一個態樣中，本文提供了根據式(I)之化合物或其醫藥學上可接受之鹽，其中：In one aspect, provided herein is a compound according to formula (I), or a pharmaceutically acceptable salt thereof, wherein:

Figure 110128222-A0202-12-0069-1127
各R1 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa1 、-N(Ra1 )2 、-C(=O)Ra1 、-C(=O)ORa1 、-NRa1 C(=O)Ra1 、-NRa1 C(=O)ORa1 、-C(=O)N(Ra1 )2 、-OC(=O)N(Ra1 )2 、-S(=O)Ra1 、-S(=O)2 Ra1 、-SRa1 、-S(=O)(=NRa1 )Ra1 、-NRa1 S(=O)2 Ra1 及-S(=O)2 N(Ra1 )2 ；各R2 獨立地選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)ORa2 、-NRa2 C(=O)Ra2 、-NRa2 C(=O)ORa2 、-C(=O)N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )、-OC(=O)N(Ra2 )2 、-S(=O)Ra2 、-S(=O)2 Ra2 、-SRa2 、-S=O)(=NRa2 )Ra2 、-NRa2 S(=O)2 Ra2 及-S(=O)2 N(Ra2 )2 ；各R3 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷 基烷基、-ORa3 、-N(Ra3 )2 、-C(=O)Ra3 、-C(=O)ORa3 、-NRa3 C(=O)Ra3 、-NRa3 C(=O)ORa3 、-C(=O)N(Ra3 )2 、-OC(=O)N(Ra3 )2 、-S(=O)Ra3 、-S(=O)2 Ra3 、-SRa3 、-S(=O)(=NRa3 )Ra3 、-NRa3 S(=O)2 Ra3 及-S(=O)2 N(Ra3 )2 ；各R4 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa4 、-N(Ra4 )2 、-C(=O)Ra4 、-C(=O)ORa4 、-NRa4 C(=O)Ra4 、-NRa4 C(=O)ORa4 、-C(=O)N(Ra4 )2 、-OC(=O)N(Ra4 )2 、-S(=O)Ra4 、-S(=O)2 Ra4 、-SRa4 、-S(=O)(=NRa4 )Ra4 、-NRa4 S(=O)2 Ra4 及-S(=O)2 N(Ra4 )2 ；各R6 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代；各R7 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 羥基烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、5-6員單環雜芳基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa7 、-N(Ra7 )2 、-C(=O)Ra7 、-C(=O)ORa7 、-NRa7 C(=O)Ra7 、-NRa7 C(=O)ORa7 、-C(=O)N(Ra7 )2 、-OC(=O)N(Ra7 )2 、-S(=O)Ra7 、-S(=O)2 Ra7 、-SRa7 、-S(=O)(=NRa7 )Ra7 、-NRa7 S(=O)2 Ra7 及-S(=O)2 N(Ra7 )2 ；各R8 獨立地選自H、-D、=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa8 、-N(Ra8 )2 、-C(=O)Ra8 、-C(=O)ORa8 、-NRa8 C(=O)Ra8 、-NRa8 C(=O)ORa8 、-CH2 C(=O)N(Ra8 )2 、-C(=O)N(Ra8 )2 、-OC(=O)N(Ra8 )2 、 -CH2 C(=O)N(Ra8 )2 、-S(=O)Ra8 、-S(=O)2 Ra8 、-SRa8 、-S(=O)(=NRa8 )Ra8 、-NRa8 S(=O)2 Ra8 及-S(=O)2 N(Ra8 )2 ，其中R8 之兩個實例連同其所連接之一或多個原子可一起形成3-10員環烷基或雜環基環(例如，連同結構I之哌啶環可以形成橋聯、稠合或螺雙環雜環的環)各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地選自H、C1 -C6 烷基、-C1 -C6 雜烷基、C3 -C9 環烷基、3-7員雜環基、環烷基烷基、雜環基烷基、芳基、5-6員雜芳基、芳基烷基及雜芳基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代(例如， 經R9 之0、1、2或3個實例取代，其中各R9 獨立地選自=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、-ORb 、-N(Rb )2 、-C(=O)Rb 、-C(=O)ORb 、-NRb C(=O)Rb 、-NRb C(=O)ORb 、-C(=O)N(Rb )2 、-OC(=O)N(Rb )2 、-S(=O)Rb 、-S(=O)2 Rb 、-SRb 、-S(=O)(=NRb )Rb 、-NRb S(=O)2 Rb 及-S(=O)2 N(Rb )2 ，其中各Rb 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)；且n為0、1、2或3前提條件為：當R1 為H時，R2 不為鹵基、-OPr、-N(CH3 )2 或-CF3 ；當R1 為ORa1 時，R2 不為-ORa2 ；當R1 為H且R2 為-CH3 時，R8 基團不可一起形成環且R6 並非不存在或為H，且不為噻唑基、呋喃基或吡咯基；當R2 為Me時，R1 不為視情況經取代之哌啶該化合物不為： 5-(2-(5-甲基-2-(對甲苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺或其任何鏡像異構物或非鏡像異構物2-(2-(4-(2H-四唑-5-基)苯基)-5-甲基哌啶-1-基)-N-(5,6-二甲基吡啶-3-基)-2-側氧基乙醯胺2-氰基-5-(2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺。
Figure 110128222-A0202-12-0069-1127
 Each R 1 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)(=NR a1 ) R a1 , -NR a1 S(=O) 2 R a1 and -S(=O) 2 N(R a1 ) 2 ; each R 2 is independently selected from halo, -CN, -C 1 -C 6 alkyl , -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, Heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O) OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )( R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S(=O) 2 R a2 , -SR a2 , -S=O)(=NR a2 ) R a2 , -NR a2 S(=O) 2 R a2 and -S(=O) 2 N(R a2 ) 2 ; each R 3 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, Heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O )R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 and -S(=O) 2 N(R a3 ) 2 ; each R 4 is independent is selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 ring Alkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(= O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , - OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 )R a4 , - NR a4 S(=O) 2 R a4 and -S(=O) 2 N(R a4 ) 2 ; each R 6 is independently absent or selected from H, -D, halo, -CN, -C 1 - C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 -aryl, 5-10-membered heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O) R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC( =O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl , heteroaryl, arylalkyl, and heteroarylalkyl are optionally substituted at any available position; each R7 is independently absent or selected from H, -D, halo, -CN, -C1 -C 6 alkyl, -C 1 -C 6 hydroxyalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclic group, 5-6 membered monocyclic heteroaryl group, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a7 , -N(R a7 ) 2 , -C(=O)R a7 , -C(= O)OR a7 , -NR a7 C(=O)R a7 , -NR a7 C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -OC(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , -SR a7 , -S(=O)( =NR a7 )R a7 , -NR a7 S(=O) 2 R a7 and -S(=O) 2 N(R a7 ) 2 ; each R 8 is independently selected from H, -D, =O, halo , -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl , heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O )OR a8 , -NR a8 C(=O)R a8 , -NR a8 C(=O)OR a8 , -CH 2 C(=O)N(R a8 ) 2 , -C(=O)N(R a8 ) 2 , -OC(=O)N(R a8 ) 2 , -CH 2 C(=O)N(R a8 ) 2 , -S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S(=O)(=NR a8 )R a8 , -NR a8 S(=O) 2 R a8 and -S(=O) 2 N(R a8 ) 2 , wherein two of R 8 This example, taken together with one or more of the atoms to which it is attached, can form a 3-10 membered cycloalkyl or heterocyclyl ring (eg, taken together with the piperidine ring of structure I can form a bridged, fused, or spirobicyclic heterocyclic ring) ring) each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 and R a8 is independently selected from H, C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, C 3 - C 9 cycloalkyl, 3-7 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl, each of which Alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl are optionally substituted at any available position ( eg, , substituted with 0, 1, 2 or 3 instances of R 9 , wherein each R 9 is independently selected from =O, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkane base, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkylalkane group, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , - NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S( =O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b and -S(=O) 2 N(R b ) 2 , wherein each R b is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr) , -nBu, -tBu , -sec -Bu, -iso -Bu) and C3 - C9cycloalkyl ( eg, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl); and n is 0, 1, 2 or 3 The prerequisites are: when R 1 is H, R 2 is not halogen, -OPr, -N(CH 3 ) 2 or -CF 3 ; when R 1 is OR a1 , R 2 not -OR a2 ; when R1 is H and R2 is -CH3 , the R8 groups may not form a ring together and R6 is not absent or H, and not thiazolyl, furanyl or pyrrolyl ; When R2 is Me, R1 is not optionally substituted piperidine The compound is not: 5-( 2- (5-methyl-2-(p-tolyl)piperidin-1-yl)-2 - Pendant oxyacetamido)nicotinamide or any of its enantiomers or diastereomers 2-(2-(4-(2H-tetrazol-5-yl)phenyl)-5- Methylpiperidin-1-yl)-N-(5,6-lutidine-3-yl)-2-oxyacetamide 2-cyano-5-(2-(5-methyl) -2-Phenylpiperidin-1-yl)-2-oxoacetamido)nicotinamide.

在一些實施例中，R6 不存在(例如， 若藉由兩個R8 基團形成之螺環連接至另外攜帶R6 之原子)。In some embodiments, R 6 is absent ( eg, if attached to an atom that otherwise carries R 6 by a spiro ring formed by two R 8 groups).

在一些實施例中，R7 不存在(例如， 若藉由兩個R8 基團形成之螺環連接至另外攜帶R7 之原子)。In some embodiments, R7 is absent ( eg, if attached to an atom that otherwise carries R7 by a spiro ring formed by two R8 groups).

在某些實施例中，R6 及R7 不為H且呈反式相對組態。在其他實施例中，R6 及R7 不為H且呈順式相對組態。In certain embodiments, R 6 and R 7 are not H and are in a trans relative configuration. In other embodiments, R 6 and R 7 are not H and are in a cis-relative configuration.

在一些實施例中，表示為式(I)中之

Figure 110128222-A0202-12-0072-1133
的部分選自：
Figure 110128222-A0202-12-0072-1129
、
Figure 110128222-A0202-12-0072-1130
、
Figure 110128222-A0202-12-0072-1131
、
Figure 110128222-A0202-12-0072-1132
，其中R6 、R7 、R8 及n 如本文所述。In some embodiments, represented as in formula (I)
Figure 110128222-A0202-12-0072-1133
part is selected from:
Figure 110128222-A0202-12-0072-1129
,
Figure 110128222-A0202-12-0072-1130
,
Figure 110128222-A0202-12-0072-1131
,
Figure 110128222-A0202-12-0072-1132
, wherein R 6 , R 7 , R 8 and n are as described herein.

在某些實施例中，表示為

Figure 110128222-A0202-12-0072-1134
的部分選自：In some embodiments, expressed as
Figure 110128222-A0202-12-0072-1134
part is selected from:

Figure 110128222-A0202-12-0072-1128
Figure 110128222-A0202-12-0072-1128

在其他實施例中，表示為

Figure 110128222-A0202-12-0073-1140
的部分選自：In other embodiments, expressed as
Figure 110128222-A0202-12-0073-1140
part is selected from:

Figure 110128222-A0202-12-0073-1139
Figure 110128222-A0202-12-0073-1139

在本發明之一些實施例中，式(I)化合物為式(Ia)化合物In some embodiments of the present invention, the compound of formula (I) is a compound of formula (Ia)

Figure 110128222-A0202-12-0073-1135
其中R1 、R2 、R3 、R4 、R6 、R7 、R8 及n如本文所述。
Figure 110128222-A0202-12-0073-1135
 wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and n are as described herein.

在本發明之一些實施例中，式(I)化合物為式(Ib)化合物In some embodiments of the present invention, the compound of formula (I) is the compound of formula (Ib)

Figure 110128222-A0202-12-0073-1136
其中R1 、R2 、R3 、R4 、R6 、R7 、R8 及n如本文所述。
Figure 110128222-A0202-12-0073-1136
 wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and n are as described herein.

在本發明之一些實施例中，式(I)化合物為式(Ic)化合物In some embodiments of the present invention, the compound of formula (I) is the compound of formula (Ic)

Figure 110128222-A0202-12-0073-1137
其中R1 、R2 、R3 、R4 、R6 、R7 、R8 及n如本文所述。
Figure 110128222-A0202-12-0073-1137
 wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and n are as described herein.

在本發明之一些實施例中，式(I)化合物為式(Id)化合物In some embodiments of the present invention, the compound of formula (I) is the compound of formula (Id)

Figure 110128222-A0202-12-0073-1138
其中R1 、R2 、R3 、R4 、R6 、R7 、R8 及n如本文所述。
Figure 110128222-A0202-12-0073-1138
 wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and n are as described herein.

在式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例中，當R2 為Me時，R1 不為H。In some embodiments of Formulas (I), (Ia), (Ib), (Ic), and (Id), when R 2 is Me, R 1 is not H.

如本文大體上所定義，各R1 獨立地選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa1 、-N(Ra1 )2 、-C(=O)Ra1 、-C(=O)ORa1 、-NRa1 C(=O)Ra1 、-NRa1 C(=O)ORa1 、-C(=O)N(Ra1 )2 、-OC(=O)N(Ra1 )2 、-S(=O)Ra1 、-S(=O)2 Ra1 、-SRa1 、-S(=O)(=NRa1 )Ra1 、-NRa1 S(=O)2 Ra1 及-S(=O)2 N(Ra1 )2 ，其中Ra1 如本文所定義。As generally defined herein, each R 1 is independently selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl , -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O) N(R a1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)( =NR a1 )R a1 , -NR a1 S(=O) 2 R a1 and -S(=O) 2 N(R a1 ) 2 , where R a1 is as defined herein.

在一些實施例中，R1 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa1 、-N(Ra1 )2 、-C(=O)Ra1 、-C(=O)ORa1 、-NRa1 C(=O)Ra1 、-NRa1 C(=O)ORa1 、-C(=O)N(Ra1 )2 及-OC(=O)N(Ra1 )2 。在其他實施例中，R1 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基、-ORa1 及-N(Ra1 )2 。In some embodiments, R 1 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C( =O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 and -OC(=O)N(R a1 ) 2 . In other embodiments, R 1 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -OR a1 and -N(R a1 ) 2 .

在某些實施例中，R1 選自H、-C1 -C6 烷基、-C1 -C6 鹵烷基、-ORa1 及-N(Ra1 )2 ，其中Ra1 如本文所定義。在其他實施例中，各Ra1 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及-C1 -C6 鹵烷基(例如， -CHF2 、-CF3 )。In certain embodiments, R 1 is selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -OR a1 and -N(R a1 ) 2 , wherein R a1 is as described herein definition. In other embodiments, each R a1 is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec- Bu, -iso -Bu) and -C1 - C6 haloalkyl ( eg, -CHF2, -CF3 ).

在一些實施例中，R1 選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-C1 -C6 鹵烷基(例如， -CF3 、-CHF2 )、-OH、-O-(C1 -C6 烷基)(例如， -OMe、-OEt)、-O-(C1 -C6 鹵烷基)(例如， -OCF3 、-OCHF2 )、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。在某些實施例中，R1 選自H、-Me、-Et、-CHF2 、-OMe、-OEt、-OCHF2 、-OCF3 、-OH及-NH2 。在其他實施例中，R1 選自H、-Et、-OMe、-OEt、-OCHF2 、-OCF3 及-OH。In some embodiments, R 1 is selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr , -iPr , -nBu, -tBu, -sec -Bu, - iso -Bu), -C 1 -C 6 haloalkyl ( eg, -CF 3 , -CHF 2 ), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe, -OEt) , -O-(C 1 -C 6 haloalkyl) ( eg, -OCF 3 , -OCHF 2 ), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg, -NHMe) and - N-(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). In certain embodiments, R1 is selected from H, -Me, -Et, -CHF2, -OMe, -OEt , -OCHF2, -OCF3 , -OH , and -NH2 . In other embodiments, R1 is selected from H, -Et , -OMe, -OEt , -OCHF2, -OCF3 , and -OH.

在一些實施例中，R1 選自H及-OMe。In some embodiments, R 1 is selected from H and -OMe.

在其他實施例中，R1 選自H、-Me、-CHF2 及-NH2 。在其他實施例中，R1 選自-Me及-NH2 。In other embodiments, R 1 is selected from H, -Me, -CHF 2 and -NH 2 . In other embodiments, R1 is selected from -Me and -NH2 .

在一些實施例中，R1 為H。在一些實施例中，R1 為-D。In some embodiments, R 1 is H. In some embodiments, R 1 is -D.

在某些實施例中，R1 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R1 為-Cl。在一些實施例中，R1 為-F。在一些實施例中，R1 為-Br。在一些實施例中，R1 為-I。 In certain embodiments, R1 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R 1 is -Cl. In some embodiments, R 1 is -F. In some embodiments, R 1 is -Br. In some embodiments, R 1 is -I.

在一些實施例中，R1 為-CN。In some embodiments, R 1 is -CN.

在某些實施例中，R1 為-C1 -C6 烷基。在其他實施例中，R1 為-Me。在一些實施例中，R1 為-Et。在一些實施例中，R1 為-Pr或-iPr。In certain embodiments, R 1 is -C 1 -C 6 alkyl. In other embodiments, R 1 is -Me. In some embodiments, R 1 is -Et. In some embodiments, R 1 is -Pr or -iPr.

在一些實施例中，R1 為-C1 -C6 雜烷基。在其他實施例中，R1 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R1 為羥基甲基(-CH2 OH)。在一些實施例中，R1 為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 N(CH3 )2 。In some embodiments, R 1 is -C 1 -C 6 heteroalkyl. In other embodiments, R 1 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 1 is hydroxymethyl (-CH 2 OH). In some embodiments, R 1 is aminomethyl ( eg, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 .

在一些實施例中，R1 為-C1 -C6 鹵烷基。在其他實施例中，R1 為三氟甲基(-CF3 )。在其他實施例中，R1 為二氟甲基(-CHF2 )。In some embodiments, R 1 is -C 1 -C 6 haloalkyl. In other embodiments, R 1 is trifluoromethyl (-CF 3 ). In other embodiments, R 1 is difluoromethyl (-CHF 2 ).

在一些實施例中，R1 為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R1 為環丙基。在一些實施例中，R1 為環丁基。在一些實施例中，R1 為環戊基。在一些實施例中，R1 為環己基。In some embodiments, R 1 is -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is cyclohexyl.

在一些實施例中，R1 為3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)。在一些實施例中，R1 為氧呾基。在一些實施例中，R1 為四氫哌喃基。在一些實施例中，R1 為四氫呋喃基。在一些實施例中，R1 為吖呾基。在一些實施例中，R1 為吡咯啶基。在一些實施例中，R1 為哌啶基。在一些實施例中，R1 為哌嗪基。在一些實施例中，R1 為嗎啉基。在一些實施例中，R1 為氮雜環庚烷基。In some embodiments, R 1 is a 3-10 membered heterocyclyl group ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholine group, azepanyl group). In some embodiments, R 1 is oxo. In some embodiments, R 1 is tetrahydropyranyl. In some embodiments, R 1 is tetrahydrofuranyl. In some embodiments, R 1 is an acridine. In some embodiments, R 1 is pyrrolidinyl. In some embodiments, R 1 is piperidinyl. In some embodiments, R 1 is piperazinyl. In some embodiments, R 1 is morpholinyl. In some embodiments, R 1 is azepanyl.

在一些實施例中，R1 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、 環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R1 為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。In some embodiments, R 1 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 1 is heterocyclylalkyl ( eg, oxanylmethyl, aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidine) pyridylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

在一些實施例中，R1 為芳基烷基。在一些實施例中，R1 為苯甲基。在一些實施例中，R1 為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)。In some embodiments, R 1 is arylalkyl. In some embodiments, R 1 is benzyl. In some embodiments, R 1 is heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

在一些實施例中，R1 為-ORa1 (例如， 羥基(-OH)、甲氧基、二氟甲氧基(-OCHF2 )、三氟甲氧基(-OCF3 )、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R1 為羥基。在一些實施例中，R1 為甲氧基。在一些實施例中，R1 為乙氧基。在一些實施例中，R1 為丙氧基。在一些實施例中，R1 為異丙氧基。在一些實施例中，R1 為二氟甲氧基(-OCHF2 )。在一些實施例中，R1 為三氟甲氧基(-OCF3 )。In some embodiments, R 1 is -OR a1 ( eg, hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy , propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 1 is hydroxyl. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is ethoxy. In some embodiments, R 1 is propoxy. In some embodiments, R 1 is isopropoxy. In some embodiments, R 1 is difluoromethoxy (-OCHF 2 ). In some embodiments, R 1 is trifluoromethoxy (-OCF 3 ).

在一些實施例中，R1 為-N(Ra1 )2 (例如， -NH2 、-NHRa1 、-N(CH3 )Ra1 )。在一些實施例中，R1 為-NH2 。在一些實施例中，R1 為-NHRa1 (例如， -NHMe、-NHEt、-NHPr、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R1 為-N(CH3 )Ra1 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。In some embodiments, R 1 is -N(R a1 ) 2 ( eg, -NH 2 , -NHR a1 , -N(CH 3 )R a1 ). In some embodiments, R 1 is -NH 2 . In some embodiments, R 1 is -NHR al ( eg, -NHMe, -NHEt, -NHPr, -NHiPr , -NHcyclopropyl, -NHcyclobutyl). In some embodiments, R1 is -N( CH3 )R a1 ( eg, -NMe2, -N( CH3 )Et, -N( CH3 )Pr, -N( CH3 ) iPr , - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl).

在一些實施例中，R1 為-C(=O)Ra1 或-C(=O)ORa1 。在一些實施例中，R1 為-C(=O)Ra1 ，其中Ra1 如本文所述。在一些實施例中，R1 為-C(=O)烷基。在一些實施例中，R1 為-C(O)CH3 、-C(O)環丙基、-C(O)環丁基、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu或-C(=O)OMe。在一些實施例中，R1 為乙醯基(-C(=O)Me)。在一些實施例中，R1 為-C(=O)ORa1 。在一些實施例中，R1 為-COOH。在一些實施例中，R1 為COOMe。In some embodiments, R 1 is -C(=O)R a1 or -C(=O)OR a1 . In some embodiments, R 1 is -C(=O)R a1 , wherein R a1 is as described herein. In some embodiments, R 1 is -C(=O)alkyl. In some embodiments, R1 is -C(O) CH3 , -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) tBu , -C(O) iPr , -C(O)Pr, -C(O) iBu or -C(=O)OMe. In some embodiments, R 1 is acetyl (-C(=O)Me). In some embodiments, R 1 is -C(=0)OR a1 . In some embodiments, R 1 is -COOH. In some embodiments, R 1 is COOMe.

在一些實施例中，R1 為-NRa1 C(=O)Ra1 。在某些實施例中，R1 為 -NHC(=O)Ra1 (例如， NHC(=O)Me、NHC(=O)Et、NHC(=O)Pr、NHC(=O)i Pr、NHC(=O)Bu、NHC(=O)t Bu、NHC(=O)環丙基、NHC(=O)環丁基)。在一些實施例中，R1 為-N(CH3 )C(=O)Ra1 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 1 is -NR a1 C(=O)R a1 . In certain embodiments, R 1 is -NHC(=O)R a1 ( eg, NHC(=O)Me, NHC(=O)Et, NHC(=O)Pr, NHC(=O) iPr , NHC(=O)Bu, NHC(=O) tBu , NHC(=O)cyclopropyl, NHC(=O)cyclobutyl). In some embodiments, R 1 is -N(CH 3 )C(=O)R a1 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R1 為-NRa1 C(=O)ORa1 。在某些實施例中，R1 為-NHC(=O)ORa1 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R1 為-N(CH3 )C(=O)ORa1 (例如， N(CH3 )C(=O)OMe、N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 1 is -NR a1 C(=O)OR a1 . In certain embodiments, R 1 is -NHC(=O)OR a1 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 1 is -N(CH 3 )C(=O)OR a1 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R1 為-C(=O)N(Ra1 )2 (例如， -C(=O)NH2 、-C(=O)NHRa1 、-C(=O)N(CH3 )Ra1 )。在一些實施例中，R1 為-C(=O)NH2 。在某些實施例中，R1 為-C(=O)NHRa1 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在某些實施例中，R1 為-C(=O)N(CH3 )Ra1 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 1 is -C(=O)N(R a1 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR a1 , -C(=O)N( CH 3 )R a1 ). In some embodiments, R 1 is -C(=O)NH 2 . In certain embodiments, R 1 is -C(=O)NHR a1 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O) ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In certain embodiments, R 1 is -C(=O)N(CH 3 )R a1 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R1 為-OC(=O)N(Ra1 )2 。在某些實施例中，R1 為-OC(=O)NHRa1 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R1 為-OC(=O)N(CH3 )Ra1 (例如， -OC(=O)NMe2 、-OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 1 is -OC(=O)N(R a1 ) 2 . In certain embodiments, R 1 is -OC(=O)NHR a1 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O) ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 1 is -OC(=O)N(CH 3 )R a1 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R1 為-S(=O)Ra1 。在某些實施例中，R1 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在某些實施例中，R1 為-S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 1 is -S(=0)R a1 . In certain embodiments, R 1 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In certain embodiments, R 1 is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R1 為-S(=O)2 Ra1 。在某些實施例中，R1 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在某些實施例中，R1 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R1 為S(=O)2 芳基(例如， S(=O)2 苯基)。In some embodiments, R 1 is -S(=0) 2 R a1 . In certain embodiments, R 1 is -S(=O) 2 alkyl ( eg, -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, - S(=O) 2 i Pr). In certain embodiments, R 1 is -S(=O) 2cycloalkyl ( eg, -S(=O) 2cyclopropyl , -S(=O) 2cyclobutyl , -S(=O ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 1 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl).

在一些實施例中，R1 為-SRa1 。在某些實施例中，R1 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R1 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R1 為-S芳基(例如， S苯基)。In some embodiments, R 1 is -SR a1 . In certain embodiments, R1 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R 1 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 1 is -S aryl ( eg, S phenyl).

在一些實施例中，R1 為-S(=O)(=NRa1 )Ra1 。在某些實施例中，R1 為-S(=O)(=NH)Ra1 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R1 為-S(=O)(=NCH3 )Ra1 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 1 is -S(=O)(=NR a1 )R a1 . In certain embodiments, R 1 is -S(=O)(=NH)R a1 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 1 is -S(=O)(=NCH 3 )R a1 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R1 為-NRa1 S(=O)2 Ra1 。在某些實施例中，R1 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R1 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R1 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、-N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R1 為-N(CH3 )S(=O)2 環 烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 1 is -NR a1 S(=0) 2 R a1 . In certain embodiments, R 1 is -NHS(=O) 2 alkyl ( eg, -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 Pr, -NHS(=O) 2 Me NHS(=O) 2 i Pr). In certain embodiments, R 1 is -NHS(=0) 2 cycloalkyl ( eg, -NHS(=0) 2 cyclopropyl, -NHS(=0) 2 cyclobutyl, -NHS(=0) ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 1 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R1 is -N( CH3 )S( = O) 2cycloalkyl ( eg, -N( CH3 )S(=O) 2cyclopropyl , -N( CH3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R1 為-S(=O)2 N(Ra1 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRa1 、-S(=O)2 N(CH3 )Ra1 )。在一些實施例中，R1 為-S(=O)2 NH2 。在一些實施例中，R1 為-S(=O)2 NHRa1 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、-S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R1 為-S(=O)2 N(CH3 )Ra1 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 1 is -S(=O) 2 N(R a1 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR a1 , -S(=O ) 2 N(CH 3 )R a1 ). In some embodiments, R 1 is -S(=O) 2 NH 2 . In some embodiments, R 1 is -S(=O) 2 NHR a1 ( eg, -S(=O) 2 NHMe, -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 1 is -S(=O) 2 N(CH 3 )R a1 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

如本文大體上所定義，各R2 獨立地選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基、3-6員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)ORa2 、-NRa2 C(=O)Ra2 、-NRa2 C(=O)ORa2 、-C(=O)N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )、-OC(=O)N(Ra2 )2 、-S(=O)Ra2 、-S(=O)2 Ra2 、-SRa2 、-S(=O)(=NRa2 )Ra2 、-NRa2 S(=O)2 Ra2 及-S(=O)2 N(Ra2 )2 ，其中Ra2 如本文所定義。As generally defined herein, each R 2 is independently selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, - C 1 -C 6 haloalkoxy, -C 3 -C 9 cycloalkyl, 3-6 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl , -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O) OR a2 , -C(=O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O )R a2 , -S(=O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 and -S(=O) 2 N(R a2 ) 2 , wherein R a2 is as defined herein.

在一些實施例中，R2 選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)ORa2 、-NRa2 C(=O)Ra2 、-NRa2 C(=O)ORa2 、-C(=O)N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )、-OC(=O)N(Ra2 )2 。In some embodiments, R 2 is selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 -haloalkoxy, -C 3 -C 9 cycloalkyl ( for example, cyclopropyl), 3-6 membered heterocyclyl ( for example, oxo group, tetrahydrofuranyl), -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N (R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 .

在某些實施例中，R2 選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )、-C(=O)Ra2 及-C(=O)N(Ra2 )2 。In certain embodiments, R 2 is selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxo group, tetrahydrofuranyl), -OR a2 , -N(R a2 ) 2 , -C(=O) N(OR a2 )(R a2 ), -C(=O)R a2 and -C(=O)N(R a2 ) 2 .

在一些實施例中，R2 選自鹵基、-C1 -C6 烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋 喃基)、-ORa2 、-C(=O)Ra2 及-C(=O)N(Ra2 )2 。In some embodiments, R 2 is selected from halo, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 ring Alkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxo group, tetrahydrofuranyl), -OR a2 , -C(=O)R a2 and -C(=O)N(R a2 ) 2 .

在一些實施例中，R2 選自鹵基、-C1 -C6 烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 及-C(=O)N(Ra2 )2 ，其中各Ra2 如本文所述。在其他實施例中，各Ra2 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。In some embodiments, R 2 is selected from halo, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 ring Alkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxo group, tetrahydrofuranyl), -OR a2 and -C(=O)N(R a2 ) 2 , wherein each R a2 is as described in this article. In other embodiments, each R a2 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec- Bu, -iso -Bu).

在某些實施例中，R2 選自鹵基(例如， -Cl)、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-C1 -C6 鹵烷基(例如， -CF3 、CHF2 )、-C1 -C6 鹵烷氧基(例如， -OCF3 、-OCHF2 )、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 (例如， -OMe)、-C(=O)NHOH、-C(=O)H及-C(=O)NH2 。在其他實施例中，R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、-CHF2 、-OCHF2 、-OCF3 、環丙基、-OMe、氧呾-3-基、四氫呋喃-3-基、-C(=O)NHOH、-C(=O)H及-C(=O)NH2 。In certain embodiments, R 2 is selected from halo ( eg, -Cl), -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -i Pr, -nBu, -t Bu, -sec -Bu, -iso -Bu), -C 1 -C 6 haloalkyl ( eg, -CF 3 , CHF 2 ), -C 1 -C 6 haloalkoxy ( eg, -OCF 3 , -OCHF 2 ), -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxo group, tetrahydrofuranyl), -OR a2 ( eg, -OMe), -C(=O)NHOH, -C(=O)H and -C(=O) NH2 . In other embodiments, R2 is selected from -Cl, -Me, -Et , -iPr , -CF3 , -CHF2, -OCHF2, -OCF3 , cyclopropyl, -OMe, oxo - 3 -yl, tetrahydrofuran-3-yl, -C(=O)NHOH, -C(=O)H and -C(=O)NH 2 .

在一些實施例中，R2 選自-C(=O)NH2 及-C(=O)H。In some embodiments, R 2 is selected from -C(=O)NH 2 and -C(=O)H.

在一些實施例中，R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、CHF2 、-OCHF2 、-OCF3 及環丙基。在其他實施例中，R2 選自環丙基、-Me及-Et。In some embodiments, R2 is selected from -Cl, -Me, -Et , -iPr , -CF3 , CHF2 , -OCHF2 , -OCF3 , and cyclopropyl. In other embodiments, R 2 is selected from cyclopropyl, -Me and -Et.

在某些實施例中，R2 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R2 為-Cl。在一些實施例中，R2 為-F。在一些實施例中，R2 為-Br。在一些實施例中，R2 為-I。In certain embodiments, R 2 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R 2 is -Cl. In some embodiments, R 2 is -F. In some embodiments, R 2 is -Br. In some embodiments, R 2 is -I.

在一些實施例中，R2 為-CN。In some embodiments, R 2 is -CN.

在某些實施例中，R2 為-C1 -C6 烷基。在其他實施例中，R2 為-Me。在一些實施例中，R2 為-Et。在一些實施例中，R2 為-Pr或-iPr。In certain embodiments, R 2 is -C 1 -C 6 alkyl. In other embodiments, R 2 is -Me. In some embodiments, R 2 is -Et. In some embodiments, R 2 is -Pr or -iPr.

在一些實施例中，R2 為-C1 -C6 雜烷基。在其他實施例中，R2 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R2 為羥基甲基(-CH2 OH)。在一些實施例中，R2 為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 N(CH3 )2 。In some embodiments, R 2 is -C 1 -C 6 heteroalkyl. In other embodiments, R 2 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 2 is hydroxymethyl (-CH 2 OH). In some embodiments, R 2 is aminomethyl ( eg, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 .

在一些實施例中，R2 為-C1 -C6 鹵烷基。在其他實施例中，R2 為三氟甲基(-CF3 )。在其他實施例中，R2 為二氟甲基(-CHF2 )。In some embodiments, R 2 is -C 1 -C 6 haloalkyl. In other embodiments, R 2 is trifluoromethyl (-CF 3 ). In other embodiments, R 2 is difluoromethyl (-CHF 2 ).

在一些實施例中，R2 為-C1 -C6 鹵烷氧基。在其他實施例中，R2 為三氟甲氧基(-OCF3 )。在其他實施例中，R2 為二氟甲氧基(-OCHF2 )。In some embodiments, R 2 is -C 1 -C 6 haloalkoxy. In other embodiments, R 2 is trifluoromethoxy (-OCF 3 ). In other embodiments, R 2 is difluoromethoxy (-OCHF 2 ).

在一些實施例中，R2 為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R2 為環丙基。在一些實施例中，R2 為環丁基。在一些實施例中，R2 為環戊基。在一些實施例中，R2 為環己基。In some embodiments, R 2 is -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl.

在一些實施例中，R2 為3-6員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)。在一些實施例中，R2 為氧呾基。在一些實施例中，R2 為四氫哌喃基。在一些實施例中，R2 為四氫呋喃基。在一些實施例中，R2 為吖呾基。在一些實施例中，R2 為吡咯啶基。在一些實施例中，R2 為哌啶基。在一些實施例中，R2 為哌嗪基。在一些實施例中，R2 為嗎啉基。在一些實施例中，R2 為氮雜環庚烷基。In some embodiments, R 2 is a 3-6 membered heterocyclyl group ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acridyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholine group, azepanyl group). In some embodiments, R 2 is oxo group. In some embodiments, R 2 is tetrahydropyranyl. In some embodiments, R 2 is tetrahydrofuranyl. In some embodiments, R 2 is an acridine. In some embodiments, R 2 is pyrrolidinyl. In some embodiments, R 2 is piperidinyl. In some embodiments, R 2 is piperazinyl. In some embodiments, R 2 is morpholinyl. In some embodiments, R 2 is azepanyl.

在一些實施例中，R2 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R2 為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。In some embodiments, R 2 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 2 is heterocyclylalkyl ( eg, oxanylmethyl, aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidine) pyridylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

在一些實施例中，R2 為芳基烷基。在一些實施例中，R2 為苯甲基。In some embodiments, R 2 is arylalkyl. In some embodiments, R 2 is benzyl.

在一些實施例中，R2 為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)。In some embodiments, R 2 is heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

在一些實施例中，R2 為-ORa2 (例如， 羥基(-OH)、甲氧基、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R2 為羥基。在一些實施例中，R2 為甲氧基。在一些實施例中，R2 為乙氧基。在一些實施例中，R2 為丙氧基。在一些實施例中，R2 為異丙氧基。In some embodiments, R 2 is -OR a2 ( eg, hydroxy (-OH), methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy) . In some embodiments, R 2 is hydroxyl. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is ethoxy. In some embodiments, R 2 is propoxy. In some embodiments, R 2 is isopropoxy.

在一些實施例中，R2 為-N(Ra2 )2 (例如， -NH2 、-NHRa2 、-N(CH3 )Ra2 )。在一些實施例中，R2 為-NH2 。在一些實施例中，R2 為-NHRa2 (例如， -NHMe、-NHEt、-NHPr、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R2 為-N(CH3 )Ra2 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。In some embodiments, R 2 is -N(R a2 ) 2 ( eg, -NH 2 , -NHR a2 , -N(CH 3 )R a2 ). In some embodiments, R 2 is -NH 2 . In some embodiments, R 2 is -NHR a2 ( eg, -NHMe, -NHEt, -NHPr, -NHiPr , -NHcyclopropyl, -NHcyclobutyl). In some embodiments, R 2 is -N(CH 3 )R a2 ( eg, -NMe 2 , -N(CH 3 )Et, -N(CH 3 )Pr, -N(CH 3 ) i Pr, - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl).

在一些實施例中，R2 為-C(=O)Ra2 或-C(=O)ORa2 。在一些實施例中，R2 為-C(=O)Ra2 ，其中Ra2 如本文所述。在一些實施例中，R2 為-C(=O)烷基。在一些實施例中，R2 為-C(O)CH3 、-C(O)環丙基、-C(O)環丁基、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu或-C(=O)OMe。在一些實施例中，R2 為乙醯基(-C(=O)Me)。在一些實施例中，R2 為-C(=O)ORa2 。在一些實施例中，R2 為-COOH。在一些實施例中，R2 為COOMe。In some embodiments, R 2 is -C(=O)R a2 or -C(=O)OR a2 . In some embodiments, R 2 is -C(=O)R a2 , wherein R a2 is as described herein. In some embodiments, R 2 is -C(=O)alkyl. In some embodiments, R 2 is -C(O)CH 3 , -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) tBu , -C(O) iPr , -C(O)Pr, -C(O) iBu or -C(=O)OMe. In some embodiments, R 2 is acetyl (-C(=O)Me). In some embodiments, R 2 is -C(=0)OR a2 . In some embodiments, R 2 is -COOH. In some embodiments, R 2 is COOMe.

在一些實施例中，R2 為-NRa2 C(=O)Ra2 。在某些實施例中，R2 為-NHC(=O)Ra2 (例如， NHC(=O)Me、NHC(=O)Et、NHC(=O)Pr、NHC(=O)i Pr、NHC(=O)Bu、NHC(=O)t Bu、NHC(=O)環丙基、NHC(=O)環丁基)。在一些實施例中，R2 為-N(CH3 )C(=O)Ra2 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 2 is -NR a2 C(=O)R a2 . In certain embodiments, R 2 is -NHC(=O)R a2 ( eg, NHC(=O)Me, NHC(=O)Et, NHC(=O)Pr, NHC(=O) iPr , NHC(=O)Bu, NHC(=O) tBu , NHC(=O)cyclopropyl, NHC(=O)cyclobutyl). In some embodiments, R 2 is -N(CH 3 )C(=O)R a2 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R2 為-NRa2 C(=O)ORa2 。在某些實施例中，R2 為-NHC(=O)ORa2 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R2 為-N(CH3 )C(=O)ORa2 (例如， N(CH3 )C(=O)OMe、N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 2 is -NR a2 C(=0)OR a2 . In certain embodiments, R 2 is -NHC(=O)OR a2 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 2 is -N(CH 3 )C(=O)OR a2 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R2 為-C(=O)N(Ra2 )2 (例如， -C(=O)NH2 、 -C(=O)NHRa2 、-C(=O)N(CH3 )Ra2 )。在一些實施例中，R2 為-C(=O)NH2 。在某些實施例中，R2 為-C(=O)NHRa2 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在某些實施例中，R2 為-C(=O)N(CH3 )Ra2 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 2 is -C(=O)N(R a2 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR a2 , -C(=O)N ( CH 3 )R a2 ). In some embodiments, R 2 is -C(=O)NH 2 . In certain embodiments, R is -C (=O)NHR a2 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In certain embodiments, R 2 is -C(=O)N(CH 3 )R a2 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R2 為-C(=O)N(ORa2 )(Ra2 )。在某些實施例中，R2 為-C(=O)NH(ORa2 )(例如， -C(=O)NHOH、-C(=O)NHOMe)。在一些實施例中，R2 為-C(=O)NHOH。In some embodiments, R 2 is -C(=O)N(OR a2 )(R a2 ). In certain embodiments, R 2 is -C(=O)NH(OR a2 ) ( eg, -C(=O)NHOH, -C(=O)NHOMe). In some embodiments, R 2 is -C(=O)NHOH.

在一些實施例中，R2 為-OC(=O)N(Ra2 )2 。在某些實施例中，R2 為-OC(=O)NHRa2 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R2 為-OC(=O)N(CH3 )Ra2 (例如， -OC(=O)NMe2 、-OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 2 is -OC(=O)N(R a2 ) 2 . In certain embodiments, R 2 is -OC(=O)NHR a2 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 2 is -OC(=O)N(CH 3 )R a2 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R2 為-S(=O)Ra2 。在某些實施例中，R2 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在某些實施例中，R2 為-S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 2 is -S(=0)R a2 . In certain embodiments, R 2 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In certain embodiments, R 2 is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R2 為-S(=O)2 Ra2 。在某些實施例中，R2 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在某些實施例中，R2 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R2 為S(=O)2 芳基(例如， S(=O)2 苯基)。In some embodiments, R 2 is -S(=0) 2 R a2 . In certain embodiments, R 2 is -S(=O) 2 alkyl ( eg, -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, - S(=O) 2 i Pr). In certain embodiments, R 2 is -S(=0) 2 cycloalkyl ( eg, -S(=0) 2 cyclopropyl, -S(=0) 2 cyclobutyl, -S(=0 ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 2 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl).

在一些實施例中，R2 為-SRa2 。在某些實施例中，R2 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R2 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R2 為-S芳基(例如， S苯基)。在一些實施例中，R2 為-S(=O)(=NRa2 )Ra2 。在某些實施例中，R2 為-S(=O)(=NH)Ra2 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R2 為-S(=O)(=NCH3 )Ra2 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 2 is -SR a2 . In certain embodiments, R 2 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R 2 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 2 is -S aryl ( eg, S phenyl). In some embodiments, R 2 is -S(=O)(=NR a2 )R a2 . In certain embodiments, R 2 is -S(=O)(=NH)R a2 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 2 is -S(=O)(=NCH 3 )R a2 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R2 為-NRa2 S(=O)2 Ra2 。在某些實施例中，R2 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R2 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R2 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、-N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R2 為-N(CH3 )S(=O)2 環烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 2 is -NR a2 S(=0) 2 R a2 . In certain embodiments, R 2 is -NHS(=O) 2 alkyl ( eg, -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 Pr, -NHS(=O) 2 Me NHS(=O) 2 i Pr). In certain embodiments, R 2 is -NHS(=O) 2 cycloalkyl ( eg, -NHS(=O) 2 cyclopropyl, -NHS(=O) 2 cyclobutyl, -NHS(=O) 2 cyclobutyl ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 2 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R 2 is -N(CH 3 )S(=O) 2cycloalkyl ( eg, -N(CH 3 )S(=O) 2cyclopropyl , -N(CH 3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R2 為-S(=O)2 N(Ra2 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRa2 、-S(=O)2 N(CH3 )Ra2 )。在一些實施例中，R2 為-S(=O)2 NH2 。在一些實施例中，R2 為-S(=O)2 NHRa2 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、-S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R2 為-S(=O)2 N(CH3 )Ra2 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 2 is -S(=O) 2 N(R a2 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR a2 , -S(=O ) 2 N(CH 3 )R a2 ). In some embodiments, R 2 is -S(=O) 2 NH 2 . In some embodiments, R 2 is -S(=O) 2 NHR a2 ( eg, -S(=O) 2 NHMe, -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 2 is -S(=O) 2 N(CH 3 )R a2 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

式(I)、(Ia)、(Ib)、(Ic)及(Id)之一些實施例以R1 及R2 之某些組合為特徵。在一個實施例中，R1 選自H、-OMe、-OEt、-OCF3 、-OCHF2 、-CHF2 、-Me、 -Et、-OH及-NH2 ，且R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、-CHF2 、-OCHF2 、環丙基、-C(=O)NH2 及-C(=O)H，前提條件為當R2 為-Me時，R1 為NH2 。在一個實施例中，R1 選自H、-CHF2 、-Me及-NH2 ，且R2 選自-Cl、-Me、-Et、-CF3 、-CHF2 、-OCHF2 及環丙基，前提條件為當R2 為-Me時，R1 為NH2 。在另一個實施例中，R1 選自-NH2 及-Me，且R2 選自-Me及-Et。在一個實施例中，R1 為-NH2 ，且R2 選自-Me或-Et。在另一個實施例中，R1 選自H、-OMe、-OEt、-OCF3 、-OCHF2 、-Et及-OH，且R2 選自-C(=O)NH2 及-C(=O)H。在另一個實施例中，R1 選自H及-OMe，且R2 為-C(=O)NH2 。Some embodiments of formulae (I), (Ia), (Ib), (Ic), and (Id) feature certain combinations of R 1 and R 2 . In one embodiment, R 1 is selected from H, -OMe, -OEt, -OCF 3 , -OCHF 2 , -CHF 2 , -Me, -Et, -OH, and -NH 2 , and R 2 is selected from -Cl , -Me, -Et, -i Pr, -CF 3 , -CHF 2 , -OCHF 2 , cyclopropyl, -C(=O)NH 2 and -C(=O)H, provided that when R 2 When -Me, R 1 is NH 2 . In one embodiment, R1 is selected from H, -CHF2, -Me, and -NH2 , and R2 is selected from -Cl, -Me, -Et , -CF3 , -CHF2 , -OCHF2 , and cyclic propyl , with the proviso that when R2 is -Me , R1 is NH2 . In another embodiment, R1 is selected from -NH2 and -Me, and R2 is selected from -Me and -Et . In one embodiment, R 1 is -NH 2 and R 2 is selected from -Me or -Et. In another embodiment, R 1 is selected from H, -OMe, -OEt, -OCF 3 , -OCHF 2 , -Et and -OH, and R 2 is selected from -C(=O)NH 2 and -C( =O)H. In another embodiment, R1 is selected from H and -OMe, and R2 is -C (=O) NH2 .

如本文大體上所述，各R3 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa3 、-N(Ra3 )2 、-C(=O)Ra3 、-C(=O)ORa3 、-NRa3 C(=O)Ra3 、-NRa3 C(=O)ORa3 、-C(=O)N(Ra3 )2 、-OC(=O)N(Ra3 )2 、-S(=O)Ra3 、-S(=O)2 Ra3 、-SRa3 、-S(=O)(=NRa3 )Ra3 、-NRa3 S(=O)2 Ra3 及-S(=O)2 N(Ra3 )2 ，其中Ra3 如本文所述。As generally described herein, each R 3 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , - N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C( =O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(= O)(=NR a3 )R a3 , -NR a3 S(=O) 2 R a3 and -S(=O) 2 N(R a3 ) 2 , where R a3 is as described herein.

在一些實施例中，R3 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa3 、-N(Ra3 )2 、-C(=O)Ra3 、-C(=O)ORa3 、-NRa3 C(=O)Ra3 、-NRa3 C(=O)ORa3 、-C(=O)N(Ra3 )2 及-OC(=O)N(Ra3 )2 。In some embodiments, R 3 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C( =O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 and -OC(=O)N(R a3 ) 2 .

在某些實施例中，R3 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基及-N(Ra3 )2 ，其中Ra3 如本文所述。在其他實施例中，Ra3 選自H及C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在一些實施例中，R3 選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-OH、-O-(C1 -C6 烷基)(例如， -OMe)、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。在其他實施例中，R3 選自H、-Me及-NH2 。在某些實施例中，R3 選自H及-Me。In certain embodiments, R 3 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, and -N(R a3 ) 2 , wherein R a3 is as described in this article. In other embodiments, R a3 is selected from H and C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr , -iPr , -nBu, -tBu, -sec -Bu, -iso -Bu). In some embodiments, R3 is selected from -C1 - C6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec -Bu, -iso- Bu), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg, -NHMe) and -N -(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). In other embodiments, R3 is selected from H, -Me and -NH2 . In certain embodiments, R3 is selected from H and -Me.

在一些實施例中，R3 為H。在一些實施例中，R3 為-D。In some embodiments, R 3 is H. In some embodiments, R 3 is -D.

在某些實施例中，R3 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R3 為-Cl。在一些實施例中，R3 為-F。在一些實施例中，R3 為-Br。在一些實施例中，R3 為-I。In certain embodiments, R3 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R3 is -Cl. In some embodiments, R 3 is -F. In some embodiments, R 3 is -Br. In some embodiments, R 3 is -I.

在一些實施例中，R3 為-CN。In some embodiments, R 3 is -CN.

在某些實施例中，R3 為-C1 -C6 烷基。在其他實施例中，R3 為-Me。在一些實施例中，R3 為-Et。在一些實施例中，R3 為-Pr或-iPr。In certain embodiments, R 3 is -C 1 -C 6 alkyl. In other embodiments, R3 is -Me. In some embodiments, R 3 is -Et. In some embodiments, R 3 is -Pr or -iPr.

在一些實施例中，R3 為-C1 -C6 雜烷基。在其他實施例中，R3 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R3 為羥基甲基(-CH2 OH)。在一些實施例中，R3 為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 N(CH3 )2 。In some embodiments, R 3 is -C 1 -C 6 heteroalkyl. In other embodiments, R 3 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 3 is hydroxymethyl (-CH 2 OH). In some embodiments, R 3 is aminomethyl ( eg, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 .

在一些實施例中，R3 為-C1 -C6 鹵烷基。在其他實施例中，R3 為三氟甲基(-CF3 )。在其他實施例中，R3 為二氟甲基(-CHF2 )。In some embodiments, R 3 is -C 1 -C 6 haloalkyl. In other embodiments, R 3 is trifluoromethyl (-CF 3 ). In other embodiments, R 3 is difluoromethyl (-CHF 2 ).

在一些實施例中，R3 為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R3 為環丙基。在一些實施例中，R3 為環丁基。在一些實施例中，R3 為環戊基。在一些實施例中，R3 為環己基。In some embodiments, R 3 is -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is cyclohexyl.

在一些實施例中，R3 為3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)。在一些實施例中，R3 為氧呾基。在一些實施例中，R3 為四氫哌喃基。在一些實施例中，R3 為四氫呋喃基。在一些實施例中，R3 為吖呾基。在一些實施例中，R3 為吡咯啶基。在一些實施例中，R3 為哌啶基。在一些實施例中，R3 為哌嗪基。在一些實施例中，R3 為嗎啉基。在一些實施例中，R3 為氮雜環庚烷基。In some embodiments, R 3 is a 3-10 membered heterocyclyl group ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholine group, azepanyl group). In some embodiments, R 3 is oxo group. In some embodiments, R 3 is tetrahydropyranyl. In some embodiments, R 3 is tetrahydrofuranyl. In some embodiments, R 3 is an acridine. In some embodiments, R 3 is pyrrolidinyl. In some embodiments, R 3 is piperidinyl. In some embodiments, R 3 is piperazinyl. In some embodiments, R 3 is morpholinyl. In some embodiments, R 3 is azepanyl.

在一些實施例中，R3 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R3 為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃 基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。In some embodiments, R 3 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 3 is heterocyclylalkyl ( eg, oxanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidine) pyridylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

在一些實施例中，R3 為芳基烷基。在一些實施例中，R3 為苯甲基。在一些實施例中，R3 為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)。In some embodiments, R 3 is arylalkyl. In some embodiments, R 3 is benzyl. In some embodiments, R 3 is heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

在一些實施例中，R3 為-ORa3 (例如， 羥基(-OH)、甲氧基、二氟甲氧基(-OCHF2 )、三氟甲氧基(-OCF3 )、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R3 為羥基。在一些實施例中，R3 為甲氧基。在一些實施例中，R3 為乙氧基。在一些實施例中，R3 為丙氧基。在一些實施例中，R3 為異丙氧基。在一些實施例中，R3 為二氟甲氧基(-OCHF2 )。在一些實施例中，R3 為三氟甲氧基(-OCF3 )。In some embodiments, R 3 is -OR a3 ( eg, hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy , propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 3 is hydroxy. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is isopropoxy. In some embodiments, R 3 is difluoromethoxy (-OCHF 2 ). In some embodiments, R 3 is trifluoromethoxy (-OCF 3 ).

在一些實施例中，R3 為-N(Ra3 )2 (例如， -NH2 、-NHRa3 、-N(CH3 )Ra3 )。在一些實施例中，R3 為-NH2 。在一些實施例中，R3 為-NHRa3 (例如， -NHMe、-NHEt、-NHPr、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R3 為-N(CH3 )Ra3 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。In some embodiments, R 3 is -N(R a3 ) 2 ( eg, -NH 2 , -NHR a3 , -N(CH 3 )R a3 ). In some embodiments, R 3 is -NH 2 . In some embodiments, R3 is -NHRa3 ( eg, -NHMe, -NHEt, -NHPr, -NHiPr , -NHcyclopropyl, -NHcyclobutyl). In some embodiments, R 3 is -N(CH 3 )R a3 ( eg, -NMe 2 , -N(CH 3 )Et, -N(CH 3 )Pr, -N(CH 3 ) i Pr, - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl).

在一些實施例中，R3 為-C(=O)Ra3 或-C(=O)ORa3 。在一些實施例中，R3 為-C(=O)Ra3 ，其中Ra3 如本文所述。在一些實施例中，R3 為-C(=O)烷基。在一些實施例中，R3 為-C(O)CH3 、-C(O)環丙基、-C(O)環丁基、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu或-C(=O)OMe。在一些實施例中，R3 為乙醯基(-C(=O)Me)。在一些實施例中，R3 為-C(=O)ORa3 。在一些實施例中，R3 為-COOH。在一些實施例中，R3 為COOMe。In some embodiments, R 3 is -C(=O)R a3 or -C(=O)OR a3 . In some embodiments, R 3 is -C(=O)R a3 , wherein R a3 is as described herein. In some embodiments, R 3 is -C(=O)alkyl. In some embodiments, R 3 is -C(O)CH 3 , -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) tBu , -C(O) iPr , -C(O)Pr, -C(O) iBu or -C(=O)OMe. In some embodiments, R 3 is acetyl (-C(=O)Me). In some embodiments, R 3 is -C(=0)OR a3 . In some embodiments, R 3 is -COOH. In some embodiments, R 3 is COOMe.

在一些實施例中，R3 為-NRa3 C(=O)Ra3 。在某些實施例中，R3 為-NHC(=O)Ra3 (例如， NHC(=O)Me、NHC(=O)Et、NHC(=O)Pr、NHC(=O)i Pr、NHC(=O)Bu、NHC(=O)t Bu、NHC(=O)環丙基、NHC(=O)環丁基)。在一些實施 例中，R3 為-N(CH3 )C(=O)Ra3 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 3 is -NR a3 C(=O)R a3 . In certain embodiments, R is -NHC(=O)R a3 ( eg, NHC(=O)Me, NHC(=O)Et, NHC(=O)Pr, NHC(=O) iPr , NHC(=O)Bu, NHC(=O) tBu , NHC(=O)cyclopropyl, NHC(=O)cyclobutyl). In some embodiments, R 3 is -N(CH 3 )C(=O)R a3 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R3 為-NRa3 C(=O)ORa3 。在某些實施例中，R3 為-NHC(=O)ORa3 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R3 為-N(CH3 )C(=O)ORa3 (例如， N(CH3 )C(=O)OMe、N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 3 is -NR a3 C(=0)OR a3 . In certain embodiments, R 3 is -NHC(=O)OR a3 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 3 is -N(CH 3 )C(=O)OR a3 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R3 為-C(=O)N(Ra3 )2 (例如， -C(=O)NH2 、-C(=O)NHRa3 、-C(=O)N(CH3 )Ra3 )。在一些實施例中，R3 為-C(=O)NH2 。在某些實施例中，R3 為-C(=O)NHRa3 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在某些實施例中，R3 為-C(=O)N(CH3 )Ra3 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 3 is -C(=O)N(R a3 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR a3 , -C(=O)N ( CH 3 )R a3 ). In some embodiments, R 3 is -C(=O)NH 2 . In certain embodiments, R is -C(=O)NHR a3 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In certain embodiments, R 3 is -C(=O)N(CH 3 )R a3 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R3 為-OC(=O)N(Ra3 )2 。在某些實施例中，R3 為-OC(=O)NHRa3 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R3 為-OC(=O)N(CH3 )Ra3 (例如， -OC(=O)NMe2 、-OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 3 is -OC(=O)N(R a3 ) 2 . In certain embodiments, R is -OC(=O)NHR a3 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 3 is -OC(=O)N(CH 3 )R a3 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R3 為-S(=O)Ra3 。在某些實施例中，R3 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在某些實施例中，R3 為 -S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 3 is -S(=0)R a3 . In certain embodiments, R 3 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In certain embodiments, R 3 is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R3 為-S(=O)2 Ra3 。在某些實施例中，R3 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在某些實施例中，R3 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R3 為S(=O)2 芳基(例如， S(=O)2 苯基)。In some embodiments, R 3 is -S(=0) 2 R a3 . In certain embodiments, R 3 is -S(=O) 2 alkyl ( eg, -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, - S(=O) 2 i Pr). In certain embodiments, R 3 is -S(=0) 2 cycloalkyl ( eg, -S(=0) 2 cyclopropyl, -S(=0) 2 cyclobutyl, -S(=0 ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 3 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl).

在一些實施例中，R3 為-SRa3 。在某些實施例中，R3 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R3 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R3 為-S芳基(例如， S苯基)。In some embodiments, R 3 is -SR a3 . In certain embodiments, R3 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R 3 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 3 is -S aryl ( eg, S phenyl).

在一些實施例中，R3 為-S(=O)(=NRa3 )Ra3 。在某些實施例中，R3 為-S(=O)(=NH)Ra3 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R3 為-S(=O)(=NCH3 )Ra3 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 3 is -S(=O)(=NR a3 )R a3 . In certain embodiments, R is -S(=O)(=NH)R a3 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 3 is -S(=O)(=NCH 3 )R a3 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R3 為-NRa3 S(=O)2 Ra3 。在某些實施例中，R3 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R3 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R3 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、-N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R3 為-N(CH3 )S(=O)2 環烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 3 is -NR a3 S(=0) 2 R a3 . In certain embodiments, R 3 is -NHS(=O) 2 alkyl ( eg, -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 Pr, -NHS(=O) 2 Me NHS(=O) 2 i Pr). In certain embodiments, R 3 is -NHS(=0) 2cycloalkyl ( eg, -NHS(=0) 2cyclopropyl , -NHS(=0) 2cyclobutyl , -NHS(=0 ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 3 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R3 is -N( CH3 )S(=O) 2cycloalkyl ( eg, -N( CH3 )S(=O) 2cyclopropyl , -N( CH3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R3 為-S(=O)2 N(Ra3 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRa3 、-S(=O)2 N(CH3 )Ra3 )。在一些實施例中，R3 為-S(=O)2 NH2 。在一些實施例中，R3 為-S(=O)2 NHRa3 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、-S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R3 為-S(=O)2 N(CH3 )Ra3 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 3 is -S(=O) 2 N(R a3 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR a3 , -S(=O ) 2 N(CH 3 )R a3 ). In some embodiments, R 3 is -S(=O) 2 NH 2 . In some embodiments, R 3 is -S(=O) 2 NHR a3 ( eg, -S(=O) 2 NHMe, -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 3 is -S(=O) 2 N(CH 3 )R a3 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

如本文大體上所述，各R4 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa4 、-N(Ra4 )2 、-C(=O)Ra4 、-C(=O)ORa4 、-NRa4 C(=O)Ra4 、-NRa4 C(=O)ORa4 、-C(=O)N(Ra4 )2 、-OC(=O)N(Ra4 )2 、-S(=O)Ra4 、-S(=O)2 Ra4 、-SRa4 、-S(=O)(=NRa4 )Ra4 、-NRa4 S(=O)2 Ra4 及-S(=O)2 N(Ra4 )2 ，其中各Ra4 如本文所述。As generally described herein, each R4 is independently selected from H, -D, halo, -CN, -C1 - C6 alkyl, -C1 - C6 heteroalkyl, -C1 - C6 Haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , - N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C( =O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(= O)(=NR a4 )R a4 , -NR a4 S(=O) 2 R a4 and -S(=O) 2 N(R a4 ) 2 , wherein each R a4 is as described herein.

在某些實施例中，R4 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa4 、-N(Ra4 )2 、-C(=O)Ra4 、-C(=O)ORa4 、-NRa4 C(=O)Ra4 、-NRa4 C(=O)ORa4 、-C(=O)N(Ra4 )2 及-OC(=O)N(Ra4 )2 。In certain embodiments, R 4 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C (=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 and -OC(=O)N(R a4 ) 2 .

在一些實施例中，R4 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基及-N(Ra4 )2 ，其中各Ra4 如本文所述。在其他實施例中，各Ra4 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在一些實施例中，R4 選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-nBu、- t Bu、-sec -Bu、-iso -Bu)、-OH、-O-(C1 -C6 烷基)(例如， -OMe)、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。In some embodiments, R 4 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, and -N(R a4 ) 2 , wherein each R a4 is as described in this article. In other embodiments, each R is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu , -sec- Bu, -iso -Bu). In some embodiments, R4 is selected from -C1 - C6 alkyl ( eg, -Me, -Et , -Pr , -iPr , -nBu , -tBu, -sec-Bu, -iso-Bu ), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg, -NHMe) and -N- (C 1 -C 6 alkyl) 2 ( eg, NMe 2 ).

在一些實施例中，R4 為H。在一些實施例中，R4 為-D。In some embodiments, R 4 is H. In some embodiments, R 4 is -D.

在某些實施例中，R4 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R4 為-Cl。在一些實施例中，R4 為-F。在一些實施例中，R4 為-Br。在一些實 施例中，R4 為-I。 In certain embodiments, R4 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R4 is -Cl. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Br. In some embodiments, R 4 is -I.

在一些實施例中，R4 為-CN。在某些實施例中，R4 為-C1 -C6 烷基。在其他實施例中，R4 為-Me。在一些實施例中，R4 為-Et。在一些實施例中，R4 為-Pr或-iPr。In some embodiments, R 4 is -CN. In certain embodiments, R 4 is -C 1 -C 6 alkyl. In other embodiments, R4 is -Me. In some embodiments, R 4 is -Et. In some embodiments, R 4 is -Pr or -iPr.

在一些實施例中，R4 為-C1 -C6 雜烷基。在其他實施例中，R4 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R4 為羥基甲基(-CH2 OH)。在一些實施例中，R4為胺基甲基(例如， -CH2 NH2 、-CH2NHCH3 、-CH2 N(CH3 )2 。In some embodiments, R 4 is -C 1 -C 6 heteroalkyl. In other embodiments, R 4 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 4 is hydroxymethyl (-CH 2 OH). In some embodiments, R4 is aminomethyl ( eg, -CH2NH2 , -CH2NHCH3, -CH2N ( CH3 ) 2 .

在一些實施例中，R4 為-C1 -C6 鹵烷基。在其他實施例中，R4 為三氟甲基(-CF3 )。在其他實施例中，R4 為二氟甲基(-CHF2 )。In some embodiments, R 4 is -C 1 -C 6 haloalkyl. In other embodiments, R 4 is trifluoromethyl (-CF 3 ). In other embodiments, R 4 is difluoromethyl (-CHF 2 ).

在一些實施例中，R4 為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R4 為環丙基。在一些實施例中，R4 為環丁基。在一些實施例中，R4 為環戊基。在一些實施例中，R4 為環己基。In some embodiments, R 4 is -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 is cyclopentyl. In some embodiments, R 4 is cyclohexyl.

在一些實施例中，R4 為3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)。在一些實施例中，R4 為氧呾基。在一些實施例中，R4 為四氫哌喃基。在一些實施例中，R4 為四氫呋喃基。在一些實施例中，R4 為吖呾基。在一些實施例中，R4 為吡咯啶基。在一些實施例中，R4 為哌啶基。在一些實施例中，R4 為哌嗪基。在一些實施例中，R4 為嗎啉基。在一些實施例中，R4 為氮雜環庚烷基。In some embodiments, R 4 is a 3-10 membered heterocyclyl group ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholine group, azepanyl group). In some embodiments, R 4 is oxo. In some embodiments, R 4 is tetrahydropyranyl. In some embodiments, R 4 is tetrahydrofuranyl. In some embodiments, R 4 is an acridine. In some embodiments, R 4 is pyrrolidinyl. In some embodiments, R 4 is piperidinyl. In some embodiments, R 4 is piperazinyl. In some embodiments, R 4 is morpholinyl. In some embodiments, R 4 is azepanyl.

在一些實施例中，R4 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R4 為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。In some embodiments, R 4 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R is heterocyclylalkyl ( eg, oxanylmethyl , aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidine) pyridylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

在一些實施例中，R4 為芳基烷基。在一些實施例中，R4 為苯甲基。In some embodiments, R 4 is arylalkyl. In some embodiments, R 4 is benzyl.

在一些實施例中，R4 為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、 三唑基甲基、吡唑基甲基)。In some embodiments, R 4 is heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

在一些實施例中，R4 為-ORa4 (例如， 羥基(-OH)、甲氧基、二氟甲氧基(-OCHF2 )、三氟甲氧基(-OCF3 )、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R4 為羥基。在一些實施例中，R4 為甲氧基。在一些實施例中，R4 為乙氧基。在一些實施例中，R4 為丙氧基。在一些實施例中，R4 為異丙氧基。在一些實施例中，R4 為二氟甲氧基(-OCHF2 )。在一些實施例中，R4 為三氟甲氧基(-OCF3 )。In some embodiments, R 4 is -OR a4 ( eg, hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy , propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 4 is hydroxyl. In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is propoxy. In some embodiments, R 4 is isopropoxy. In some embodiments, R 4 is difluoromethoxy (-OCHF 2 ). In some embodiments, R 4 is trifluoromethoxy (-OCF 3 ).

在一些實施例中，R4 為-N(Ra4 )2 (例如， -NH2 、-NHRa4 、-N(CH3 )Ra4 )。在一些實施例中，R4 為-NH2 。在一些實施例中，R4 為-NHRa4 (例如， -NHMe、-NHEt、-NHPr、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R4 為-N(CH3 )Ra4 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。In some embodiments, R 4 is -N(R a4 ) 2 ( eg, -NH 2 , -NHR a4 , -N(CH 3 )R a4 ). In some embodiments, R 4 is -NH 2 . In some embodiments, R4 is -NHRa4 ( eg, -NHMe, -NHEt , -NHPr, -NHiPr , -NHcyclopropyl, -NHcyclobutyl). In some embodiments, R 4 is -N(CH 3 )R a4 ( eg, -NMe 2 , -N(CH 3 )Et, -N(CH 3 )Pr, -N(CH 3 ) i Pr, - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl).

在一些實施例中，R4 為-C(=O)Ra4 或-C(=O)ORa4 。在一些實施例中，R4 為-C(=O)Ra4 ，其中Ra4 如本文所述。在一些實施例中，R4 為-C(=O)烷基。在一些實施例中，R4 為-C(O)CH3 、-C(O)環丙基、-C(O)環丁基、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu或-C(=O)OMe。在一些實施例中，R4 為乙醯基(-C(=O)Me)。在一些實施例中，R4 為-C(=O)ORa4 。在一些實施例中，R4 為-COOH。在一些實施例中，R4 為COOMe。In some embodiments, R 4 is -C(=O)R a4 or -C(=O)OR a4 . In some embodiments, R 4 is -C(=O)R a4 , wherein R a4 is as described herein. In some embodiments, R 4 is -C(=O)alkyl. In some embodiments, R 4 is -C(O)CH 3 , -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) tBu , -C(O) iPr , -C(O)Pr, -C(O) iBu or -C(=O)OMe. In some embodiments, R 4 is acetyl (-C(=O)Me). In some embodiments, R 4 is -C(=0)OR a4 . In some embodiments, R 4 is -COOH. In some embodiments, R 4 is COOMe.

在一些實施例中，R4 為-NRa4 C(=O)Ra4 。在某些實施例中，R4 為-NHC(=O)Ra4 (例如NHC(=O)Me、NHC(=O)Et、NHC(=O)Pr、NHC(=O)i Pr、NHC(=O)Bu、NHC(=O)t Bu、NHC(=O)環丙基、NHC(=O)環丁基)。在一些實施例中，R4 為-N(CH3 )C(=O)Ra4 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 4 is -NR a4 C(=O)R a4 . In certain embodiments, R 4 is -NHC(=O)R a4 (eg, NHC(=O)Me, NHC(=O)Et, NHC(=O)Pr, NHC(=O) iPr , NHC (=O)Bu, NHC(=O) tBu , NHC(=O)cyclopropyl, NHC(=O)cyclobutyl). In some embodiments, R 4 is -N(CH 3 )C(=O)R a4 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R4 為-NRa4 C(=O)ORa4 。在某些實施例中，R4 為-NHC(=O)ORa4 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R4 為-N(CH3 )C(=O)ORa4 (例如， N(CH3 )C(=O)OMe、N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 4 is -NR a4 C(=0)OR a4 . In certain embodiments, R 4 is -NHC(=O)OR a4 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 4 is -N(CH 3 )C(=O)OR a4 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R4 為-C(=O)N(Ra4 )2 (例如， -C(=O)NH2 、-C(=O)NHRa4 、-C(=O)N(CH3 )Ra4 )。在一些實施例中，R4 為-C(=O)NH2 。在某些實施例中，R4 為-C(=O)NHRa4 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在某些實施例中，R4 為-C(=O)N(CH3 )Ra4 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 4 is -C(=O)N(R a4 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR a4 , -C(=O)N( CH 3 )R a4 ). In some embodiments, R 4 is -C(=O)NH 2 . In certain embodiments, R is -C(=O)NHR a4 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In certain embodiments, R 4 is -C(=O)N(CH 3 )R a4 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R4 為-OC(=O)N(Ra4 )2 。在某些實施例中，R4 為-OC(=O)NHRa4 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R4 為-OC(=O)N(CH3 )Ra4 (例如， -OC(=O)NMe2 、-OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 4 is -OC(=O)N(R a4 ) 2 . In certain embodiments, R is -OC(=O)NHR a4 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 4 is -OC(=O)N(CH 3 )R a4 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R4 為-S(=O)Ra4 。在某些實施例中，R4 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在某些實施例中，R4 為-S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 4 is -S(=0)R a4 . In certain embodiments, R 4 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In certain embodiments, R 4 is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R4 為-S(=O)2 Ra4 。在某些實施例中，R4 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在某些實施例中，R4 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R4 為S(=O)2 芳基(例如， S(=O)2 苯基)。In some embodiments, R 4 is -S(=0) 2 R a4 . In certain embodiments, R 4 is -S(=O) 2 alkyl ( eg, -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, - S(=O) 2 i Pr). In certain embodiments, R 4 is -S(=0) 2cycloalkyl ( eg, -S(=0) 2cyclopropyl , -S(=0) 2cyclobutyl , -S(=0 ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 4 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl).

在一些實施例中，R4 為-SRa4 。在某些實施例中，R4 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R4 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R4 為-S芳基(例如， S苯基)。In some embodiments, R 4 is -SR a4 . In certain embodiments, R4 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R 4 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 4 is -S aryl ( eg, S phenyl).

在一些實施例中，R4 為-S(=O)(=NRa4 )Ra4 。在某些實施例中，R4 為-S(=O)(=NH)Ra4 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R4 為-S(=O)(=NCH3 )Ra4 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 4 is -S(=O)(=NR a4 )R a4 . In certain embodiments, R 4 is -S(=O)(=NH)R a4 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 4 is -S(=O)(=NCH 3 )R a4 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R4 為-NRa4 S(=O)2 Ra4 。在某些實施例中，R4 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R4 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R4 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、-N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R4 為-N(CH3 )S(=O)2 環烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 4 is -NR a4 S(=0) 2 R a4 . In certain embodiments, R 4 is -NHS(=O) 2 alkyl ( eg, -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 Pr, -NHS(=O) 2 Me NHS(=O) 2 i Pr). In certain embodiments, R 4 is -NHS(=0) 2 cycloalkyl ( eg, -NHS(=0) 2 cyclopropyl, -NHS(=0) 2 cyclobutyl, -NHS(=0) ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 4 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R4 is -N( CH3 )S(=O) 2cycloalkyl ( eg, -N( CH3 )S(=O) 2cyclopropyl , -N( CH3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R4 為-S(=O)2 N(Ra4 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRa4 、-S(=O)2 N(CH3 )Ra4 )。在一些實施例中，R4 為-S(=O)2 NH2 。在一些實施例中，R4 為-S(=O)2 NHRa4 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、 -S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R4 為-S(=O)2 N(CH3 )Ra4 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 4 is -S(=O) 2 N(R a4 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR a4 , -S(=O ) 2 N(CH 3 )R a4 ). In some embodiments, R 4 is -S(=O) 2 NH 2 . In some embodiments, R 4 is -S(=O) 2 NHR a4 ( eg, -S(=O) 2 NHMe, -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 4 is -S(=O) 2 N(CH 3 )R a4 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

如本文大體上所述，各R6 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代，其中各Ra6 如本文所述。在一些實施例中，各R6獨立地選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代，其中各Ra6 如本文所述。在一些實施例中，各Ra6 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。As generally described herein, each R is independently absent or selected from H, -D, halo, -CN, -C1 - C6alkyl , -C1 - C6heteroalkyl, -C1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroaryl Alkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(= O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N( R a6 ) 2 , wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally One available position is substituted, wherein each R a6 is as described herein. In some embodiments, each R6 is independently selected from halo, -CN, -C1 - C6 alkyl, -C1 - C6 heteroalkyl, -C1 - C6 haloalkyl, -C3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, C 6 -C 10 membered aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl, cycloalkane Alkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C( =O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each alkyl group, Carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted at any available position, wherein each R a6 as described herein. In some embodiments, each R is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu , -sec- Bu, -iso -Bu).

在一些實施例中，R6 之各烷基、碳環基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中各R10 如本文所述。In some embodiments, each alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl of R 6 Substituted at any available position with 0 , 1, 2 or 3 instances of R10, wherein each R10 is as described herein.

在一些實施例中，各R6 獨立地選自H、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10 員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代(例如， 在任一可用位置經R10 之0、1、2或3個實例取代，其中各R10 如本文所述)。在一些實施例中，各R6 獨立地選自-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代(例如， 在任一可用位置經R10 之0、1、2或3個實例取代，其中各R10 如本文所述)。In some embodiments, each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 Carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, C6 - C10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl , where each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally Substituted ( eg, with 0 , 1 , 2, or 3 instances of R10 at any available position, where each R10 is as described herein). In some embodiments, each R 6 is independently selected from -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocycle group, 3-10 membered heterocyclyl, heterocyclylalkyl, C6 - C10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein Each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted at any available position ( For example, substituted at any available position with 0 , 1, 2 or 3 instances of R10, wherein each R10 is as described herein).

在一些實施例中，R6 獨立地選自H、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中R10 如本文所述。在一些實施例中，R6 獨立地選自-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中R10 如本文所述。在一些實施例中，各R6 未經取代。在一些實施例中，各R6 經R10 之1個實例取代。在一些實施例中，各R6 經R10 之2個實例取代。在一些實施例中，各R6 經R10 之3個實例取代。In some embodiments, R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbon Cyclyl, 3-10-membered heterocyclyl, heterocyclylalkyl, C6 - C10 -aryl, 5-10-membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is separated by R at any available position 0, 1, 2 or 3 instance substitutions, wherein R 10 is as described herein. In some embodiments, R 6 is independently selected from -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl , 3-10 membered heterocyclyl, heterocyclylalkyl, C6 - C10 -membered aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein each Alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl at any available position via R 10 of 0, 1, 2 or 3 instance substitutions, wherein R 10 is as described herein. In some embodiments, each R 6 is unsubstituted. In some embodiments, each R6 is substituted with 1 instance of R10. In some embodiments, each R6 is substituted with 2 instances of R10. In some embodiments, each R6 is substituted with 3 instances of R10.

在一些實施例中，R6 獨立地選自H、-C1 -C6 烷基、-C3 -C10 單環或雙環碳環基(例如， -C3 -C10 單環或雙環環烷基、部分不飽和之-C3 -C10 單環或雙環碳環基、與苯基稠合之-C3 -C7 單環碳環基或含有1-3個獨立地選自N、O、S或其氧化 形式之原子的5-6員雜環基或雜芳基環)、3-10員單環或雙環雜環基(例如， 含有1-3個選自N、O及S或其氧化形式之雜原子之3-8員單環雜環基、含有1-3個獨立地選自N、O及S或其氧化形式之雜原子之4-10員雙環雜環基)、-C6 -C10 單環或雙環芳基(例如， 苯基、完全芳族9-10員雙環芳基、含有與C5 -C6 碳環稠合之苯環之雙環芳基、含有與含有1-3個獨立地選自N、O及S或其氧化形式之雜原子的5-6員雜環稠合之苯環之雙環芳基)、5-6員單環雜芳基(例如， 含有1-4個獨立地選自N、O及S之雜原子)、8-10員雙環雜芳基(例如， 含有1-4個獨立地選自N、O及S之雜原子)，其中各烷基、碳環基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代，其中R10 如本文所述)。在一些實施例中，R6 獨立地選自-C1 -C6 烷基、-C3 -C10 單環或雙環碳環基(例如， -C3 -C10 單環或雙環環烷基、部分不飽和之-C3 -C10 單環或雙環碳環基、與苯基稠合之-C3 -C7 單環碳環基或含有1-3個獨立地選自N、O、S或其氧化形式之原子的5-6員雜環基或雜芳基環)、3-10員單環或雙環雜環基(例如， 含有1-3個選自N、O及S或其氧化形式之雜原子之3-8員單環雜環基、含有1-3個獨立地選自N、O及S或其氧化形式之雜原子之4-10員雙環雜環基)、-C6 -C10 單環或雙環芳基(例如， 苯基、完全芳族9-10員雙環芳基、含有與C5 -C6 碳環稠合之苯環之雙環芳基、含有與含有1-3個獨立地選自N、O及S或其氧化形式之雜原子的5-6員雜環稠合之苯環之雙環芳基)、5-6員單環雜芳基(例如， 含有1-4個獨立地選自N、O及S之雜原子)、8-10員雙環雜芳基(例如， 含有1-4個獨立地選自N、O及S之雜原子)，其中各烷基、碳環基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代，其中R10 如本文所述)。In some embodiments, R 6 is independently selected from H, -C 1 -C 6 alkyl, - C 3 -C 10 monocyclic or bicyclic carbocyclyl ( eg, -C 3 -C 10 monocyclic or bicyclic ring Alkyl, partially unsaturated -C 3 -C 10 monocyclic or bicyclic carbocyclic group, -C 3 -C 7 monocyclic carbocyclic group fused with phenyl or containing 1-3 independently selected from N, 5-6 membered heterocyclyl or heteroaryl ring of atoms of O, S or their oxidized forms), 3-10 membered monocyclic or bicyclic heterocyclyl ( eg, containing 1-3 members selected from N, O and S 3-8 membered monocyclic heterocyclyl of heteroatoms in its oxidized form, 4-10 membered bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S or its oxidized form), -C 6 -C 10 monocyclic or bicyclic aryl ( eg, phenyl, fully aromatic 9-10 membered bicyclic aryl, bicyclic aryl containing a benzene ring fused to a C 5 -C 6 carbocycle, containing and A 5-6 membered heterocyclic fused benzene ring containing 1-3 heteroatoms independently selected from N, O and S or their oxidized forms, a bicyclic aryl group), a 5-6 membered monocyclic heteroaryl group ( such as , containing 1-4 heteroatoms independently selected from N, O and S), 8-10 membered bicyclic heteroaryl ( for example, containing 1-4 heteroatoms independently selected from N, O and S), wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10, where R10 is as described herein). In some embodiments, R 6 is independently selected from -C 1 -C 6 alkyl, -C 3 -C 10 monocyclic or bicyclic carbocyclyl ( eg, -C 3 -C 10 monocyclic or bicyclic cycloalkyl) , Partially unsaturated -C 3 -C 10 monocyclic or bicyclic carbocyclic group, -C 3 -C 7 monocyclic carbocyclic group fused with phenyl or containing 1-3 independently selected from N, O, 5-6 membered heterocyclyl or heteroaryl ring of atoms of S or its oxidized form), 3-10 membered monocyclic or bicyclic heterocyclyl ( eg, containing 1-3 members selected from N, O and S or its 3-8 membered monocyclic heterocyclyl of heteroatoms in oxidized form, 4-10 membered bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S or their oxidized forms), -C 6 - C10 monocyclic or bicyclic aryl ( for example, phenyl, fully aromatic 9-10 membered bicyclic aryl, bicyclic aryl containing a benzene ring fused with a C5 - C6 carbocyclic ring, containing and containing 1 -3 bicyclic aryl groups of 5-6 membered heterocyclic fused benzene rings independently selected from the heteroatoms of N, O and S or their oxidized forms), 5-6 membered monocyclic heteroaryl groups ( for example, containing 1-4 heteroatoms independently selected from N, O and S), 8-10 membered bicyclic heteroaryl ( for example, containing 1-4 heteroatoms independently selected from N, O and S), wherein each Alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10, where R10 is as described herein).

在一些實施例中，各R6 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- i Bu、sec -Bu、- t Bu)、-C3 -C10 單環或雙環碳環基(例如， 環丙基、環丁基、環戊基、環己基、環庚基、雙環[1.1.1]戊基、4,5,6,7-四氫-1H-吲唑基、螺[3.3]庚基)、3-10員單環或雙環雜環基(例如， 氧呾基、氮雜環庚烷基、哌啶基、吡咯 啶基、四氫呋喃基、四氫哌喃基、1,2-二氫吡啶基、嗎啉基)、C6 -C10 單環或雙環芳基(例如， 苯基、萘基、1,2,3,4-四氫萘基、2,3-二氫-1H-茚基、1,2,3,4-四氫喹啉基、1,2-二氫喹啉基、1,2-二氫異喹啉基、1,2,3,4-四氫異喹啉基、色原烷基、吲哚啉基、異吲哚啉基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、2,3-二氫苯并呋喃基、苯并[d ][1,3]二氧雜環戊烯基、2,3-二氫-1H-苯并[d]咪唑基)、5-6員單環雜芳基(例如， 噻吩基、噻唑基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基)、8-10員雙環雜芳基(例如， 苯并[d]異噻唑基、吲哚基、苯并呋喃基、1H-吲唑基、2-H-吲唑基、苯并[b]噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、咪唑并[1,5-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基)，其中各烷基、環烷基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代，其中R10 如本文所述)。在一些實施例中，各R6 獨立地選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- i Bu、sec -Bu、- t Bu)、-C3 -C10 單環或雙環碳環基(例如， 環丙基、環丁基、環戊基、環己基、環庚基、雙環[1.1.1]戊基、4,5,6,7-四氫-1H-吲唑基、螺[3.3]庚基)、3-10員單環或雙環雜環基(例如， 氧呾基、氮雜環庚烷基、哌啶基、吡咯啶基、四氫呋喃基、四氫哌喃基、1,2-二氫吡啶基、嗎啉基)、C6 -C10 單環或雙環芳基(例如， 苯基、萘基、1,2,3,4-四氫萘基、2,3-二氫-1H-茚基、1,2,3,4-四氫喹啉基、1,2-二氫喹啉基、1,2-二氫異喹啉基、1,2,3,4-四氫異喹啉基、色原烷基、吲哚啉基、異吲哚啉基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、2,3-二氫苯并呋喃基、苯并[d ][1,3]二氧雜環戊烯基、2,3-二氫-1H-苯并[d]咪唑基)、5-6員單環雜芳基(例如， 噻吩基、噻唑基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基)、8-10員雙環雜芳基(例如， 苯并[d]異噻唑基、吲哚基、苯并呋喃基、1H-吲唑基、2-H-吲唑基、苯并[b]噻吩 基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a]吡啶基、咪唑并[1,2-a ]吡啶基、咪唑并[1,5-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基)，其中各烷基、環烷基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代，其中R10 如本文所述)。In some embodiments, each R6 is independently selected from H, -C1 -C6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -iBu , sec -Bu, -tBu ), -C 3 -C 10 monocyclic or bicyclic carbocyclyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, 4,5, 6,7-Tetrahydro-1H-indazolyl, spiro[3.3]heptyl), 3-10 membered monocyclic or bicyclic heterocyclyl ( e.g., oxanyl, azepanyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2-dihydropyridyl, morpholinyl), C6 - C10 monocyclic or bicyclic aryl ( eg, phenyl, naphthyl, 1,2 ,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2-dihydroquinolinyl, 1,2- Dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, chromogen alkyl, indolinyl, isoindolinyl, 3,4-dihydro-2H-benzo[ b][1,4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[ d ][1,3]dioxolyl, 2,3-dihydro-1H-benzene [d]imidazolyl), 5-6 membered monocyclic heteroaryl ( eg, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl), 8-10 membered bicyclic heteroaryl Aryl ( eg, benzo[d]isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2-H-indazolyl, benzo[b]thienyl, quinolinyl, 1 ,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl, benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1,2- a ] pyridyl, imidazo[1,5- a ]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl, 1H-thieno [2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridyl), wherein each alkyl, cycloalkyl, heterocycle Radyl, aryl, and heteroaryl are optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10, where R10 is as described herein). In some embodiments, each R 6 is independently selected from -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -iBu , sec -Bu, -tBu), -C 3 -C 10 monocyclic or bicyclic carbocyclyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, 4,5,6, 7-tetrahydro-1H-indazolyl, spiro[3.3]heptyl), 3-10 membered monocyclic or bicyclic heterocyclyl ( eg, oxanyl, azepanyl, piperidinyl, pyrrolidine group, tetrahydrofuranyl, tetrahydropyranyl, 1,2-dihydropyridyl, morpholinyl), C6 - C10 monocyclic or bicyclic aryl ( eg, phenyl, naphthyl, 1,2,3 ,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2-dihydroquinolinyl, 1,2-dihydro isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, chromogen alkyl, indolinyl, isoindolinyl, 3,4-dihydro-2H-benzo[b] [1,4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[ d ][1,3]dioxolyl, 2,3-dihydro-1H-benzo[ d] imidazolyl), 5-6 membered monocyclic heteroaryl ( eg, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl), 8-10 membered bicyclic heteroaryl ( For example, benzo[d]isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2-H-indazolyl, benzo[b]thienyl, quinolinyl, 1,5 -Naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl, benzo[ d ]imidazole base, benzo[ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3-a]pyridyl, imidazo[1,2- a ]pyridyl , imidazo[1,5- a ]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl, 1H-thieno[2 ,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridyl), wherein each alkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10, where R10 is as described herein).

在一些實施例中，各R6 獨立地選自H、-Me、- i Pr、- i Bu、sec -Bu、環丁基、環戊基、環己基、雙環[1.1.1]戊烷-1-基、螺[3.3]庚-2-基、4,5,6,7-四氫-1H-吲唑-6-基、哌啶-4-基、哌啶-3-基、吡咯啶-3-基、1,2-二氫吡啶-4-基、苯基、萘-2-基、1,2,3,4-四氫喹啉-6-基、1,2,3,4-四氫萘-6-基、色原烷-6-基、1,5-萘啶-6-基、1,2,3,4-四氫-1,8-萘啶-6-基、2,3-二氫-1H-茚-5-基、吲哚啉-5-基、吲哚啉-4-基、2,3-二氫-1H-苯并[d]咪唑-5-基、2,3-二氫苯并呋喃-5-基、2,3-二氫苯并呋喃-6-基、苯并[d ][1,3]二氧雜環戊烯-5-基]、異吲哚啉-5-基、3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基、1,2-二氫喹啉-6-基、1,2-二氫異喹啉-7-基、噻吩-2-基、噻吩-3-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、吡唑-1-基、吡唑-5-基、吡唑-3-基、吡唑-4-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基、吲哚-4-基、吲哚-5-基、苯并呋喃-5-基、苯并呋喃-6-基、1H -吲唑-5-基、1H -吲唑-4-基、2H-吲唑-6-基、2H-吲唑-5-基、異吲哚啉-6-基、苯并[d]異噻唑-5-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,5-a]吡啶-6-基、苯并[b ]噻吩-3-基、苯并[b ]噻吩-5-基、喹啉-6-基、喹啉-3-基、異喹啉-6-基、苯并[d ]咪唑并-5-基、1H-苯并[d]咪唑-4-基、苯并[d ]噻唑-5-基、苯并[d]噻唑-6-基、苯并[d]噻唑-4-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、[1,2,4]三唑并[4,3-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-6-基、吡唑并[4,3-b ]吡啶-6-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-6-基、1H-噻吩并[2,3-c]吡唑-5-基、1H-噻吩并[3,2-c]吡唑-5- 基、噻唑并[5,4-b]吡啶-6-基)，其各自視情況經取代(例如， 經R10 之0、1、2或3個實例取代，其中R10 如本文所述)。在一些實施例中，各R6 獨立地選自-Me、- i Pr、- i Bu、sec -Bu、環丁基、環戊基、環己基、雙環[1.1.1]戊烷-1-基、螺[3.3]庚-2-基、4,5,6,7-四氫-1H-吲唑-6-基、哌啶-4-基、哌啶-3-基、吡咯啶-3-基、1,2-二氫吡啶-4-基、苯基、萘-2-基、1,2,3,4-四氫喹啉-6-基、1,2,3,4-四氫萘-6-基、色原烷-6-基、1,5-萘啶-6-基、1,2,3,4-四氫-1,8-萘啶-6-基、2,3-二氫-1H-茚-5-基、吲哚啉-5-基、吲哚啉-4-基、2,3-二氫-1H-苯并[d]咪唑-5-基、2,3-二氫苯并呋喃-5-基、2,3-二氫苯并呋喃-6-基、苯并[d ][1,3]二氧雜環戊烯-5-基]、異吲哚啉-5-基、3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基、1,2-二氫喹啉-6-基、1,2-二氫異喹啉-7-基、噻吩-2-基、噻吩-3-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、吡唑-1-基、吡唑-5-基、吡唑-3-基、吡唑-4-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基、吲哚-4-基、吲哚-5-基、苯并呋喃-5-基、苯并呋喃-6-基、1H -吲唑-5-基、1H -吲唑-4-基、2H-吲唑-6-基、2H-吲唑-5-基、異吲哚啉-6-基、苯并[d]異噻唑-5-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,5-a]吡啶-6-基、苯并[b ]噻吩-3-基、苯并[b ]噻吩-5-基、喹啉-6-基、喹啉-3-基、異喹啉-6-基、苯并[d ]咪唑并-5-基、1H-苯并[d]咪唑-4-基、苯并[d ]噻唑-5-基、苯并[d]噻唑-6-基、苯并[d]噻唑-4-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、[1,2,4]三唑并[4,3-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-6-基、吡唑并[4,3-b ]吡啶-6-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-6-基、1H-噻吩并[2,3-c]吡唑-5-基、1H-噻吩并[3,2-c]吡唑-5-基、噻唑并[5,4-b]吡啶-6-基)，其各自視情況經取代(例如， 經R10 之0、1、2或3個實例取代，其中R10 如本文所述)。 In some embodiments, each R is independently selected from H, -Me, -i Pr, -i Bu, sec -Bu, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane- 1-yl, spiro[3.3]hept-2-yl, 4,5,6,7-tetrahydro-1H-indazol-6-yl, piperidin-4-yl, piperidin-3-yl, pyrrolidine -3-yl, 1,2-dihydropyridin-4-yl, phenyl, naphth-2-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 1,2,3,4 -Tetrahydronaphthalene-6-yl, chroman-6-yl, 1,5-naphthyridin-6-yl, 1,2,3,4-tetrahydro-1,8-naphthyridin-6-yl, 2,3-Dihydro-1H-inden-5-yl, indolin-5-yl, indolin-4-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-yl , 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[ d ][1,3]dioxol-5-yl] , isoindolin-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1,2-dihydroquinolin-6-yl, 1 , 2-dihydroisoquinolin-7-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl, Pyrazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, indole-4- yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1 H -indazol-5-yl, 1 H -indazol-4-yl, 2H-indazol- 6-yl, 2H-indazol-5-yl, isoindolin-6-yl, benzo[d]isothiazol-5-yl, imidazo[1,2-a]pyridin-7-yl, imidazole zo[1,5-a]pyridin-6-yl, benzo[ b ]thien-3-yl, benzo[ b ]thien-5-yl, quinolin-6-yl, quinolin-3-yl, Isoquinolin-6-yl, benzo[ d ]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[ d ]thiazol-5-yl, benzo[d]thiazole -6-yl, benzo[d]thiazol-4-yl, benzo[ d ]oxazol-4-yl, benzo[ d ]oxazol-5-yl, [1,2,4]triazolo [4,3- a ]pyridin-6-yl, imidazo[1,2- a ]pyridin-6-yl, pyrazolo[4,3- b ]pyridin-6-yl, 1H-pyrazolo[ 3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H- Pyrazolo[4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c]pyrazol-5- yl, thiazolo[5,4-b]pyridin-6-yl), each of which is optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10, wherein R 10 is as described herein). In some embodiments, each R is independently selected from -Me, -iPr , -iBu , sec -Bu, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane-1- base, spiro[3.3]hept-2-yl, 4,5,6,7-tetrahydro-1H-indazol-6-yl, piperidin-4-yl, piperidin-3-yl, pyrrolidine-3 -yl, 1,2-dihydropyridin-4-yl, phenyl, naphth-2-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 1,2,3,4-tetra Hydronaphthalen-6-yl, chromogen-6-yl, 1,5-naphthyridin-6-yl, 1,2,3,4-tetrahydro-1,8-naphthyridin-6-yl, 2, 3-Dihydro-1H-inden-5-yl, indolin-5-yl, indolin-4-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-yl, 2 ,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[ d ][1,3]dioxol-5-yl], iso Indolin-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1,2-dihydroquinolin-6-yl, 1,2 - Dihydroisoquinolin-7-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl, pyrazole -5-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, indol-4-yl, Indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1 H -indazol-5-yl, 1 H -indazol-4-yl, 2H-indazol-6-yl yl, 2H-indazol-5-yl, isoindolin-6-yl, benzo[d]isothiazol-5-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[ 1,5-a]pyridin-6-yl, benzo[ b ]thien-3-yl, benzo[ b ]thien-5-yl, quinolin-6-yl, quinolin-3-yl, isoquinoline Linn-6-yl, benzo[ d ]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[ d ]thiazol-5-yl, benzo[d]thiazol-6 -yl, benzo[d]thiazol-4-yl, benzo[ d ]oxazol-4-yl, benzo[ d ]oxazol-5-yl, [1,2,4]triazolo[4 ,3- a ]pyridin-6-yl, imidazo[1,2- a ]pyridin-6-yl, pyrazolo[4,3- b ]pyridin-6-yl, 1H-pyrazolo[3, 4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazole [4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c]pyrazol-5-yl, thiazolo[5,4-b]pyridin-6-yl), each of which is optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10, wherein R 10 as described herein).

在一些實施例中，R6 為H。在一些實施例中，R6 為-D。In some embodiments, R 6 is H. In some embodiments, R 6 is -D.

在某些實施例中，R6 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R6 為-Cl。在一些實施例中，R6 為-F。在一些實施例中，R6 為-Br。在一些實 施例中，R6 為-I。In certain embodiments, R 6 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R 6 is -Cl. In some embodiments, R 6 is -F. In some embodiments, R 6 is -Br. In some embodiments, R 6 is -I.

在一些實施例中，R6 為-CN。In some embodiments, R 6 is -CN.

在某些實施例中，R6 為-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- i Bu、sec -Bu、- t Bu)。在其他實施例中，R6 為-Me。在一些實施例中，R6 為-Et。在一些實施例中，R6 為丙基。在一些實施例中，R6 為異丙基。在一些實施例中，R6 為sec -Bu。在一些實施例中，R6 為- t Bu。In certain embodiments, R 6 is -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -iBu , sec -Bu, -tBu). In other embodiments, R 6 is -Me. In some embodiments, R 6 is -Et. In some embodiments, R 6 is propyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is sec -Bu. In some embodiments, R 6 is -t Bu.

在一些實施例中，R6 為-C1 -C6 雜烷基。在其他實施例中，R6 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R6 為羥基甲基(-CH2 OH)。在一些實施例中，R6 為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 N(CH3 )2 。In some embodiments, R 6 is -C 1 -C 6 heteroalkyl. In other embodiments, R 6 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 6 is hydroxymethyl (-CH 2 OH). In some embodiments, R 6 is aminomethyl ( eg, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 .

在一些實施例中，R6 為-C1 -C6 鹵烷基。在其他實施例中，R6 為三氟甲基(-CF3 )。在其他實施例中，R6 為二氟甲基(-CHF2 )。In some embodiments, R 6 is -C 1 -C 6 haloalkyl. In other embodiments, R 6 is trifluoromethyl (-CF 3 ). In other embodiments, R 6 is difluoromethyl (-CHF 2 ).

在一些實施例中，R6 為-C3 -C10 碳環基。在一些實施例中，碳環基未經進一步取代。在一些實施例中，碳環基經R10 之0、1、2或3個實例取代，其中R10 如本文所述。在一些實施例中，碳環基經鹵基之1或2個實例(例如， -F、-Cl)、-Me、-Et、-iPr、-OH、=O或-CN取代。在其他實施例中，碳環基為-C3 -C10 單環或雙環環烷基(例如， 單環環烷基、稠合雙環環烷基、螺環烷基或橋聯環烷基)。在一些實施例中，碳環基為-C3 -C7 單環環烷基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R6 為環丙基。在一些實施例中，R6 為環丁基。在一些實施例中，R6 為環戊基。在一些實施例中，R6 為環己基。在一些實施例中，碳環基為-C4 -C10 雙環環烷基。在一些實施例中，R6 為-C4 -C10 稠合環烷基(例如， 十氫萘基、八氫茚基)。在一些實施例中，R6 為-C4 -C10 螺環烷基(例如， 螺[4.5]癸基、螺[4.4]壬基、螺[3.3]庚基、螺[3.4]辛基)。在其他實施例中，R6 為螺[3.3]庚基。在一些實施例中，R6 為橋聯雙環環烷基(例如， 雙環[1.1.1]戊基、雙環[2.2.1]庚基、雙環[3.3.1]庚基、雙環[2.1.1]己基、雙環[3.2.1]辛基、雙環[3.3.1]壬基。在 一些實施例中，R6 為雙環[1.1.1]戊基。In some embodiments, R 6 is -C 3 -C 10 carbocyclyl. In some embodiments, the carbocyclyl group is not further substituted. In some embodiments, the carbocyclyl group is substituted with 0 , 1, 2, or 3 instances of R10, wherein R10 is as described herein. In some embodiments, the carbocyclyl is substituted with 1 or 2 instances of halo ( eg, -F, -Cl), -Me, -Et, -iPr, -OH, =O, or -CN. In other embodiments, the carbocyclyl group is -C3 - C10 monocyclic or bicyclic cycloalkyl ( eg, monocyclic cycloalkyl, fused bicyclic cycloalkyl, spirocycloalkyl, or bridged cycloalkyl) . In some embodiments, the carbocyclyl group is a -C3 - C7 monocyclic cycloalkyl group ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is cyclopentyl. In some embodiments, R 6 is cyclohexyl. In some embodiments, the carbocyclyl group is -C 4 -C 10 bicyclic cycloalkyl. In some embodiments, R 6 is -C 4 -C 10 fused cycloalkyl ( eg, decalinyl, octahydroindenyl). In some embodiments, R 6 is -C 4 -C 10 spirocycloalkyl ( eg, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl) . In other embodiments, R 6 is spiro[3.3]heptyl. In some embodiments, R is bridged bicyclic cycloalkyl ( eg, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]heptyl, bicyclo[2.1.1 ]hexyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl. In some embodiments, R 6 is bicyclo[1.1.1]pentyl.

在一些實施例中，碳環基為與苯基稠合的-C3 -C7 單環碳環基(例如， 1,2,3,4-四氫萘基、2,3-二氫-1H-茚基，其中連接點在飽和環上)。在一些實施例中，R6 為與含有1-3個獨立地選自N、O、S或其氧化形式之原子之5-6員雜環基環稠合的-C3 -C7 單環碳環基(例如， 八氫色原烯基、十氫異喹啉基、十氫喹啉基、八氫吲哚基、八氫異吲哚基六氫色原烷、六氫異喹啉、六氫喹啉、八氫苯并呋喃，其中連接點在碳環上)。在一些實施例中，R6 為與含有1-3個獨立地選自N、O、S或其氧化形式之原子之5-6員雜芳基環稠合的-C3 -C7 單環碳環基(例如， 4,5,6,7-四氫-1H-吲唑基)。在一個實施例中，R6 為4,5,6,7-四氫-1H-吲唑-6-基。In some embodiments, the carbocyclyl group is a -C3 - C7 monocyclic carbocyclyl group ( eg, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro- 1H-indenyl where the point of attachment is on the saturated ring). In some embodiments, R 6 is -C 3 -C 7 monocyclic ring fused to a 5-6 membered heterocyclyl ring containing 1-3 atoms independently selected from N, O, S or oxidized forms thereof Carbocyclyl ( e.g., octahydrochromogenyl, decahydroisoquinolyl, decahydroquinolyl, octahydroindolyl, octahydroisoindolylhexahydrochromane, hexahydroisoquinoline, Hexahydroquinoline, octahydrobenzofuran, where the point of attachment is on the carbocyclic ring). In some embodiments, R6 is a -C3 - C7 monocyclic ring fused to a 5-6 membered heteroaryl ring containing 1-3 atoms independently selected from N, O, S or oxidized forms thereof Carbocyclyl ( eg, 4,5,6,7-tetrahydro-1H-indazolyl). In one embodiment, R 6 is 4,5,6,7-tetrahydro-lH-indazol-6-yl.

在某些實施例中，R6 選自：In certain embodiments, R 6 is selected from:

Figure 110128222-A0202-12-0102-1141
Figure 110128222-A0202-12-0102-1141

在一些實施例中，R6 為3-10員單環或雙環雜環基。在一些實施例中，R6 為含有1-3個選自N、O及S或其氧化形式之雜原子之3-8員單環雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基、四氫吡啶基)。在一些實施例中，R6 為氧呾基。在一些實施例中，R6 為四氫哌喃基。在一些實施例中，R6 為四氫呋喃基。在一些實施例中，R6 為吖呾基。在一些實施例中，R6 為吡咯啶基。在一些實施例中，R6 為哌啶基。在一些實施例中，R6 為哌嗪基。在一些實施例中，R6 為嗎啉基。在一些實施例中，R6 為氮雜環庚烷基。在一些實施例中，R6 為四氫吡啶基。在一些實施例中，R6 為含有1-3個獨立地選自N、O及S或其氧化形式之雜原子之4-10員雙環雜環基。在一些實施例中，單環或雙環雜環基未經進一步取代。在一些實施例中，雜環基經鹵基之1或2個實例(例如， -F、-Cl)、-Me、-Et、-iPr、-OH、=O或-CN取代。在一些情況下，雜環基經=O取代(例如， 2-側氧基-1,2-二氫吡啶-4- 基)。In some embodiments, R 6 is a 3-10 membered monocyclic or bicyclic heterocyclyl. In some embodiments, R 6 is a 3-8 membered monocyclic heterocyclyl ( eg, oxanyl, tetrahydropyranyl) containing 1-3 heteroatoms selected from N, O, and S or their oxidized forms. , tetrahydrofuranyl, acridine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydropyridyl). In some embodiments, R 6 is oxo. In some embodiments, R 6 is tetrahydropyranyl. In some embodiments, R 6 is tetrahydrofuranyl. In some embodiments, R 6 is an acridine. In some embodiments, R 6 is pyrrolidinyl. In some embodiments, R 6 is piperidinyl. In some embodiments, R 6 is piperazinyl. In some embodiments, R 6 is morpholinyl. In some embodiments, R 6 is azepanyl. In some embodiments, R 6 is tetrahydropyridyl. In some embodiments, R 6 is a 4-10 membered bicyclic heterocyclyl group containing 1-3 heteroatoms independently selected from N, O, and S or oxidized forms thereof. In some embodiments, the monocyclic or bicyclic heterocyclyl is not further substituted. In some embodiments, the heterocyclyl group is substituted with 1 or 2 instances of halo ( eg, -F, -Cl), -Me, -Et, -iPr, -OH, =O, or -CN. In some cases, the heterocyclyl group is substituted with =0 ( eg, 2-pendantoxy-1,2-dihydropyridin-4-yl).

在一些實施例中，R6 為視情況經取代之6-10員單環或雙環芳基。在一些實施例中，R6 經R10 之0、1、2或3個實例取代，其中R10 如本文所述。In some embodiments, R 6 is optionally substituted 6-10 membered monocyclic or bicyclic aryl. In some embodiments, R 6 is substituted with 0, 1, 2, or 3 instances of R 10 , wherein R 10 is as described herein.

在一些實施例中，R6 為視情況經取代之苯基。在一些實施例中，R6 為經R10 之0、1、2或3個實例取代之苯基，其中各R10 獨立地如本文所述。在一些實施例中，苯基未經取代。在一些實施例中，苯基經R10 之一個實例取代。在一些實施例中，苯基在與哌啶之連接點之對位經R10 之1個實例取代。In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is phenyl substituted with 0, 1, 2, or 3 instances of R 10 , wherein each R 10 is independently as described herein. In some embodiments, the phenyl group is unsubstituted. In some embodiments, phenyl is substituted with one instance of R 10 . In some embodiments, the phenyl group is substituted with 1 instance of R 10 at the para position to the point of attachment to the piperidine.

在一些實施例中，R6 為

Figure 110128222-A0202-12-0103-1142
。在一些實施例中，苯基經R10 之2個實 例取代。在一些實施例中，苯基經R10 之3個實例取代。在一些實施例中，R6 為經鹵基(例如， 氟、氯、溴)取代之苯基。In some embodiments, R 6 is
Figure 110128222-A0202-12-0103-1142
. In some embodiments, phenyl is substituted with 2 instances of R 10 . In some embodiments, phenyl is substituted with 3 instances of R 10 . In some embodiments, R 6 is phenyl substituted with halo ( eg, fluoro, chloro, bromo).

在一些實施例中，R6 為視情況經取代之9-10員雙環芳基(例如， 萘基)。在一些實施例中，R6 為含有與C5 -C6 碳環稠合之苯環的視情況經取代之雙環芳基(例如， 四氫萘基、二氫茚基)。在一些實施例中，R6 為1,2,3,4-四氫萘基。在一些實施例中，R6 為2,3-二氫-1H-茚基。在一些實施例中，R6 為含有與含有1-3個獨立地選自N、O及S或其氧化形式之雜原子之5-6員雜環稠合的苯基之視情況經取代之雙環芳基(例如， 四氫萘基、二氫茚基、1,2,3,4四氫喹啉基、1,2二氫喹啉基、1,2-二氫異喹啉基、四氫異喹啉基、色原烷基、吲哚啉基、異吲哚啉基、二氫苯并噁嗪、二氫苯并呋喃基、苯并二氧雜環戊烯基、二氫苯并咪唑基。在一些實施例中，R6 為1,2,3,4-四氫喹啉基。在一些實施例中，R6 為1,2-二氫喹啉基。在一些實施例中，R6 為1,2-二氫異喹啉基。在一些實施例中，R6 為1,2,3,4-四氫異喹啉基。在一些實施例中，R6 為色原烷基。在一些實施例中，R6 為吲哚啉基。在一些實施例中，R6 為異吲哚啉基。在一些實施例中，R6 為3,4-二氫-2H-苯并 [b][1,4]噁嗪基。在一些實施例中，R6 為2,3-二氫苯并呋喃基。在一些實施例中，R6 為苯并[d ][1,3]二氧雜環戊烯基。在一些實施例中，R6 為2,3-二氫-1H-苯并[d]咪唑基。在一些實施例中，R6 選自：In some embodiments, R 6 is an optionally substituted 9-10 membered bicyclic aryl ( eg, naphthyl). In some embodiments, R 6 is an optionally substituted bicyclic aryl group ( eg, tetrahydronaphthyl, indenyl) containing a benzene ring fused to a C 5 -C 6 carbocyclic ring. In some embodiments, R 6 is 1,2,3,4-tetrahydronaphthyl. In some embodiments, R 6 is 2,3-dihydro-lH-indenyl. In some embodiments, R is optionally substituted containing phenyl fused to a 5-6 membered heterocycle containing 1-3 heteroatoms independently selected from N, O, and S or their oxidized forms. Bicyclic aryl groups ( eg, tetrahydronaphthyl, indenyl, 1,2,3,4 tetrahydroquinolinyl, 1,2 dihydroquinolinyl, 1,2-dihydroisoquinolinyl, tetrahydroquinolinyl Hydroisoquinolyl, chromogen alkyl, indolinyl, isoindolinyl, dihydrobenzoxazine, dihydrobenzofuranyl, benzodioxolyl, dihydrobenzoyl Imidazolyl. In some embodiments, R is 1,2,3,4 - tetrahydroquinolinyl. In some embodiments, R is 1,2 - dihydroquinolinyl. In some embodiments , R 6 is 1,2-dihydroisoquinolinyl. In some embodiments, R 6 is 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, R 6 is chromogen Alkyl. In some embodiments, R is indolinyl. In some embodiments, R is isoindolinyl. In some embodiments, R is 3,4 - dihydro-2H- Benzo[b][1,4]oxazinyl. In some embodiments, R6 is 2,3 - dihydrobenzofuranyl. In some embodiments, R6 is benzo[ d ][1 ,3] dioxolyl. In some embodiments, R 6 is 2,3-dihydro-1H-benzo[d]imidazolyl. In some embodiments, R 6 is selected from:

Figure 110128222-A0202-12-0104-1144
Figure 110128222-A0202-12-0104-1144

在一些實施例中，雙環芳基未經取代。在一些實施例中，雙環芳基經R10 之0、1、2或3個實例取代，其中各R10 如本文所述。在一些實施例中，雙環芳基經R10 之1個實例取代。在其他實施例中，雙環芳基經R10 之一個實例取代，其中R10 選自鹵基(例如， F、Cl、Br)、-Me、=O。在一些實施例中，R10 為=O且R6 選自：In some embodiments, the bicyclic aryl group is unsubstituted. In some embodiments, the bicyclic aryl group is substituted with 0, 1, 2, or 3 instances of R 10 , wherein each R 10 is as described herein. In some embodiments, the bicyclic aryl group is substituted with 1 instance of R 10 . In other embodiments, the bicyclic aryl group is substituted with one instance of R 10 , wherein R 10 is selected from halo ( eg, F, Cl, Br), -Me, =O. In some embodiments, R 10 is =0 and R 6 is selected from:

Figure 110128222-A0202-12-0104-1143
Figure 110128222-A0202-12-0104-1143

在一些實施例中，R6 為視情況經取代之5-6員單環雜芳基(例如， 含有 1-3個獨立地選自O、N及S之雜原子之5員單環雜芳基；含有1-3個N雜原子之6員單環雜芳基)。In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ( eg, a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S) 6-membered monocyclic heteroaryl group containing 1-3 N heteroatoms).

在一些實施例中，5-6員單環雜芳基未經取代。在一些實施例中，5-6員單環雜芳基經R10 之0、1、2或3個實例取代，其中各R10 如本文所述。在一些實施例中，5-6員單環雜芳基經R10 之1個實例取代。在一些實施例中，5-6員單環雜芳基經R10 之2個實例取代。在一些實施例中，5-6員單環雜芳基經R10 之2個實例取代。在一些實施例中，5-6員單環雜芳基經R10 之3個實例取代。在一些實施例中，R6 為5員單環雜芳基(例如， 吡唑基、吡咯基、噻吩基、呋喃基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、三唑基、噻二唑基、噁二唑基)。在一些實施例中，R6 為噻吩基(例如， 噻吩-2-基、噻吩-3-基)。在一些實施例中，R6 為吡唑基(例如吡唑-1-基、吡唑-3-基、吡唑-5-基)。在一些實施例中，R6 為噻唑基(例如， 噻唑-2-基、噻唑-4-基、噻唑-5-基)。在一些實施例中，R6 選自：In some embodiments, the 5-6 membered monocyclic heteroaryl is unsubstituted. In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with 0, 1, 2, or 3 instances of R 10 , wherein each R 10 is as described herein. In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with 1 instance of R10. In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with 2 instances of R 10 . In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with 2 instances of R 10 . In some embodiments, the 5-6 membered monocyclic heteroaryl is substituted with 3 instances of R 10 . In some embodiments, R is a 5 -membered monocyclic heteroaryl ( eg, pyrazolyl, pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl , triazolyl, thiadiazolyl, oxadiazolyl). In some embodiments, R 6 is thienyl ( eg, thien-2-yl, thien-3-yl). In some embodiments, R 6 is pyrazolyl (eg, pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, R 6 is thiazolyl ( eg, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R is selected from:

Figure 110128222-A0202-12-0105-1145
Figure 110128222-A0202-12-0105-1145

在一些實施例中，R6 為6員單環雜芳基(例如， 吡啶基、嘧啶基、三嗪基、吡嗪基、噠嗪基)。在一些實施例中，6員單環雜芳基未經取代。在一些實施例中，6員單環雜芳基經R10 之0、1、2或3個實例取代。在一些實施例中，6員單環雜芳基經R10 之1個實例取代。在一些實施例中，6員單環雜芳基在與哌啶之連接點之對位經R10 之1個實例取代。在一些實施例中，6員單環雜芳基經R10 之2個實例取代。在一些實施例中，6員單環雜芳基經R10 之3個實例取代。在一些實施例中，R6 為吡啶基(例如， 吡啶-2-基、吡啶-3-基、吡啶-4-基)。在一些實施例中，R6 為嘧啶基(例如， 嘧啶-2-基、嘧啶-4-基、嘧啶-5-基)。在一些實施例中， R6 選自：

Figure 110128222-A0202-12-0106-1146
In some embodiments, R 6 is a 6-membered monocyclic heteroaryl ( eg, pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, the 6-membered monocyclic heteroaryl is unsubstituted. In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 0 , 1, 2, or 3 instances of R10. In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 1 instance of R 10 . In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 1 instance of R 10 at the para position to the point of attachment to the piperidine. In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 2 instances of R 10 . In some embodiments, the 6-membered monocyclic heteroaryl is substituted with 3 instances of R 10 . In some embodiments, R 6 is pyridinyl ( eg, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, R 6 is pyrimidinyl ( eg, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl). In some embodiments, R is selected from:
Figure 110128222-A0202-12-0106-1146

在一些實施例中，R6 選自：

Figure 110128222-A0202-12-0106-1147
。在其他實施例中，R6 為
Figure 110128222-A0202-12-0106-1148
In some embodiments, R is selected from:
Figure 110128222-A0202-12-0106-1147
. In other embodiments, R 6 is
Figure 110128222-A0202-12-0106-1148

在一些實施例中，R6 為8-10員雙環雜芳基(例如， 5,5-雙環雜芳基(例如 1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基)、5,6-雙環雜芳基(例如， 吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b]噻吩基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、苯并[d]異噻唑基、咪唑并[1,2-a]吡啶基、咪唑并[1,2-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、噻唑并[5,4-b]吡啶基)或6,6雙環雜芳基(例如， 喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基)，其中各雙環雜芳基含有1-3個獨立地選自O、N及S之雜原子)。In some embodiments, R 6 is 8-10 membered bicyclic heteroaryl ( eg, 5,5-bicyclic heteroaryl ( eg 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[ 3,2-c]pyrazolyl), 5,6-bicyclic heteroaryl ( eg, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl , benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, benzo[d]oxazolyl ]isothiazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2- a ]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo [3,4-b]pyridyl, thiazolo[5,4-b]pyridyl) or 6,6 bicyclic heteroaryl ( eg, quinolinyl, 1,5-naphthyridinyl, 1,2-dicyclic Hydrogen-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl), wherein each bicyclic heteroaryl group contains 1-3 independently selected from heteroatoms of O, N and S).

在一些實施例中，R6 選自吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b]噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、苯并[d]異噻唑基、咪唑并[1,2-a]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基、1,2,3,4-四氫-1,8-萘啶基)，其中雙環雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。 In some embodiments, R is selected from indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl, quinolinyl, 1,5-naphthyridinyl , 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl, benzo[ d ]imidazolyl, benzo [ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1,2- a ]pyridyl, benzo[ d]isothiazolyl, imidazo[1,2-a]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl, 1H - Thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridyl, 1,2,3,4-tetrakis hydrogen-1,8-naphthyridinyl), wherein bicyclic heteroaryl is optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10).

在一些實施例中，R6 為選自以下之8-10員雙環雜芳基：In some embodiments, R 6 is an 8-10 membered bicyclic heteroaryl selected from the group consisting of:

Figure 110128222-A0202-12-0107-1149
Figure 110128222-A0202-12-0107-1149

在一些實施例中，8-10員雙環雜芳基未經取代。在一些實施例中，8-10員雙環雜芳基經R10 之0、1、2或3個實例取代，其中各R10 如本文所述。在一些實施例中，8-10員雙環雜芳基經R10 之1個實例取代。在其他實施例中，8-10員雙環雜芳基經R10 之一個實例取代，其中R10 選自鹵基(例如， F、Cl、Br)、-Me、=O。在一些實施例中，R10 為=O且R6 選自：In some embodiments, the 8-10 membered bicyclic heteroaryl is unsubstituted. In some embodiments, the 8-10 membered bicyclic heteroaryl is substituted with 0, 1, 2, or 3 instances of R 10 , wherein each R 10 is as described herein. In some embodiments, the 8-10 membered bicyclic heteroaryl is substituted with 1 instance of R10. In other embodiments, the 8-10 membered bicyclic heteroaryl is substituted with one instance of R 10 , wherein R 10 is selected from halo ( eg, F, Cl, Br), -Me, =O. In some embodiments, R 10 is =0 and R 6 is selected from:

Figure 110128222-A0202-12-0107-1150
Figure 110128222-A0202-12-0107-1150

在一些實施例中，R6 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R6 為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。In some embodiments, R 6 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R is heterocyclylalkyl ( eg, oxanylmethyl , aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidine) pyridylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

在一些實施例中，R6 為芳基烷基。在一些實施例中，R6 為苯甲基。In some embodiments, R 6 is arylalkyl. In some embodiments, R 6 is benzyl.

在一些實施例中，R6 為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)。In some embodiments, R 6 is heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

在一些實施例中，R6 為-ORa6 (例如， 羥基(-OH)、甲氧基、二氟甲氧基(-OCHF2 )、三氟甲氧基(-OCF3 )、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R6 為羥基。在一些實施例中，R6 為甲氧基。在一些實施例中，R6 為乙氧基。在一些實施例中，R6 為丙氧基。在一些實施例中，R6 為異丙氧基。在一些實施例中，R6 為二氟甲氧基(-OCHF2 )。在一些實施例中，R6 為三氟甲氧基(-OCF3 )。In some embodiments, R 6 is -OR a6 ( eg, hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy , propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 6 is hydroxy. In some embodiments, R 6 is methoxy. In some embodiments, R 6 is ethoxy. In some embodiments, R 6 is propoxy. In some embodiments, R 6 is isopropoxy. In some embodiments, R 6 is difluoromethoxy (-OCHF 2 ). In some embodiments, R 6 is trifluoromethoxy (-OCF 3 ).

在一些實施例中，R6 為-N(Ra6 )2 (例如， -NH2 、-NHRa6 、-N(CH3 )Ra6 )。在一些實施例中，R6 為-NH2 。在一些實施例中，R6 為-NHRa6 (例如， -NHMe、-NHEt、-NHPr、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R6 為-N(CH3 )Ra6 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。In some embodiments, R 6 is -N(R a6 ) 2 ( eg, -NH 2 , -NHR a6 , -N(CH 3 )R a6 ). In some embodiments, R 6 is -NH 2 . In some embodiments, R6 is -NHRa6 ( eg, -NHMe, -NHEt , -NHPr, -NHiPr , -NHcyclopropyl, -NHcyclobutyl). In some embodiments, R6 is -N( CH3 ) Ra6 ( eg, -NMe2 , -N( CH3 )Et, -N( CH3 )Pr, -N( CH3 ) iPr , - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl).

在一些實施例中，R6 為-C(=O)Ra6 或-C(=O)ORa6 。在一些實施例中，R6 為-C(=O)Ra6 ，其中Ra6 如本文所述。在一些實施例中，R6 為-C(=O)烷基。在一些實施例中，R6 為-C(O)CH3 、-C(O)環丙基、-C(O)環丁基、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu或-C(=O)OMe。在一些實施例中，R6 為乙醯基(-C(=O)Me)。在一些實施例中，R6 為-C(=O)ORa6 。在一些實施例中，R6 為-COOH。在一些實施例中，R6 為COOMe。In some embodiments, R 6 is -C(=O)R a6 or -C(=O)OR a6 . In some embodiments, R 6 is -C(=O)R a6 , wherein R a6 is as described herein. In some embodiments, R 6 is -C(=O)alkyl. In some embodiments, R 6 is -C(O)CH 3 , -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) tBu , -C(O) iPr , -C(O)Pr, -C(O) iBu or -C(=O)OMe. In some embodiments, R 6 is acetyl (-C(=O)Me). In some embodiments, R 6 is -C(=0)OR a6 . In some embodiments, R 6 is -COOH. In some embodiments, R 6 is COOMe.

在一些實施例中，R6 為-NRa6 C(=O)Ra6 。在某些實施例中，R6 為-NHC(=O)Ra6 (例如， NHC(=O)Me、NHC(=O)Et、NHC(=O)Pr、NHC(=O)i Pr、NHC(=O)Bu、NHC(=O)t Bu、NHC(=O)環丙基、NHC(=O)環丁基)。在一些實施例中，R6 為-N(CH3 )C(=O)Ra6 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、 N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 6 is -NR a6 C(=O)R a6 . In certain embodiments, R is -NHC(=O)R a6 ( eg, NHC(=O)Me, NHC(=O)Et, NHC(=O)Pr, NHC(=O) iPr , NHC(=O)Bu, NHC(=O) tBu , NHC(=O)cyclopropyl, NHC(=O)cyclobutyl). In some embodiments, R 6 is -N(CH 3 )C(=O)R a6 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R6 為-NRa6 C(=O)ORa6 。在某些實施例中，R6 為-NHC(=O)ORa6 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R6 為-N(CH3 )C(=O)ORa6 (例如， N(CH3 )C(=O)OMe、N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 6 is -NR a6 C(=0)OR a6 . In certain embodiments, R 6 is -NHC(=O)OR a6 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 6 is -N(CH 3 )C(=O)OR a6 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R6 為-C(=O)N(Ra6 )2 (例如， -C(=O)NH2 、-C(=O)NHRa6 、-C(=O)N(CH3 )Ra6 )。在一些實施例中，R6 為-C(=O)NH2 。在某些實施例中，R6 為-C(=O)NHRa6 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在某些實施例中，R6 為-C(=O)N(CH3 )Ra6 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 6 is -C(=O)N(R a6 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR a6 , -C(=O)N ( CH 3 )R a6 ). In some embodiments, R 6 is -C(=O)NH 2 . In certain embodiments, R is -C(=O)NHR a6 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In certain embodiments, R 6 is -C(=O)N(CH 3 )R a6 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R6 為-OC(=O)N(Ra6 )2 。在某些實施例中，R6 為-OC(=O)NHRa6 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R6 為-OC(=O)N(CH3 )Ra6 (例如， -OC(=O)NMe2 、-OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 6 is -OC(=O)N(R a6 ) 2 . In certain embodiments, R is -OC(=O)NHR a6 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 6 is -OC(=O)N(CH 3 )R a6 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R6 為-S(=O)Ra6 。在某些實施例中，R6 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在某些實施例中，R6 為-S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 6 is -S(=O)R a6 . In certain embodiments, R 6 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In certain embodiments, R 6 is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R6 為-S(=O)2 Ra6 。在某些實施例中，R6 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在某些實施例中，R6 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R6 為S(=O)2 芳基(例如， S(=O)2 苯基)。In some embodiments, R 6 is -S(=0) 2 R a6 . In certain embodiments, R 6 is -S(=O) 2 alkyl ( eg, -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, - S(=O) 2 i Pr). In certain embodiments, R 6 is -S(=0) 2cycloalkyl ( eg, -S(=0) 2cyclopropyl , -S(=0) 2cyclobutyl , -S(=0 ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 6 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl).

在一些實施例中，R6 為-SRa6 。在某些實施例中，R6 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R6 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R6 為-S芳基(例如， S苯基)。In some embodiments, R 6 is -SR a6 . In certain embodiments, R 6 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R 6 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 6 is -S aryl ( eg, S phenyl).

在一些實施例中，R6 為-S(=O)(=NRa6 )Ra6 。在某些實施例中，R6 為-S(=O)(=NH)Ra6 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R6 為-S(=O)(=NCH3 )Ra6 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 6 is -S(=O)(=NR a6 )R a6 . In certain embodiments, R is -S(=O)(=NH)R a6 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 6 is -S(=O)(=NCH 3 )R a6 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R6 為-NRa6 S(=O)2 Ra6 。在某些實施例中，R6 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R6 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R6 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、-N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R6 為-N(CH3 )S(=O)2 環烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 6 is -NR a6 S(=0) 2 R a6 . In certain embodiments, R 6 is -NHS(=O) 2 alkyl ( eg, -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 Pr, -NHS(=O) 2 Me NHS(=O) 2 i Pr). In certain embodiments, R 6 is -NHS(=O) 2cycloalkyl ( eg, -NHS(= 0 ) 2cyclopropyl , -NHS(=0)2cyclobutyl, -NHS(=0 ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 6 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R 6 is -N(CH 3 )S(=O) 2cycloalkyl ( eg, -N(CH 3 )S(=O) 2cyclopropyl , -N(CH 3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R6 為-S(=O)2 N(Ra6 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRa6 、-S(=O)2 N(CH3 )Ra6 )。在一些實施例中，R6 為-S(=O)2 NH2 。在一些 實施例中，R6 為-S(=O)2 NHRa6 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、-S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R6 為-S(=O)2 N(CH3 )Ra6 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 6 is -S(=O) 2 N(R a6 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR a6 , -S(=O ) 2 N(CH 3 )R a6 ). In some embodiments, R 6 is -S(=O) 2 NH 2 . In some embodiments, R 6 is -S(=O) 2 NHR a6 ( eg, -S(=O) 2 NHMe, -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 6 is -S(=O) 2 N(CH 3 )R a6 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

如本文通常所定義，各R7 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 羥基烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、5-6員單環雜芳基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa7 、-N(Ra7 )2 、-C(=O)Ra7 、-C(=O)ORa7 、-NRa7 C(=O)Ra7 、-NRa7 C(=O)ORa7 、-C(=O)N(Ra7 )2 、-OC(=O)N(Ra7 )2 ,-S(=O)Ra7 、-S(=O)2 Ra7 、-SRa7 、-S(=O)(=NRa7 )Ra7 、-NRa7 S(=O)2 Ra7 及-S(=O)2 N(Ra7 )2 ，其中Ra7 如本文所定義。As generally defined herein, each R7 is independently absent or selected from H, -D, halo, -CN, -C1 - C6 alkyl, -C1 - C6 hydroxyalkyl, -C1- C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, 5-6 membered monocyclic heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl , cycloalkylalkyl, -OR a7 , -N(R a7 ) 2 , -C(=O)R a7 , -C(=O)OR a7 , -NR a7 C(=O)R a7 , -NR a7 C(=O)OR a7 , -C(=O)N(R a7 ) 2 , -OC(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , -SR a7 , -S(=O)(=NR a7 )R a7 , -NR a7 S(=O) 2 R a7 and -S(=O) 2 N(R a7 ) 2 , wherein R a7 is as defined herein.

在一些實施例中，各R7 獨立地選自H、鹵基(例如， F、Cl)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、5員雜芳基(例如， 吡唑基)、-C1 -C6 鹵烷基(例如， -CF3 、-CHF2 、-CH2 CF3 )、-C1 -C6 羥基烷基(例如， -CH2 OH)、-C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)、-ORa7 (例如， -OH、-OMe、-OCHF2 )、-N(Ra7 )2 及-C(=O)N(Ra7 )2 (例如， -C(=O)NH2 、-C(=O)NHMe)，其中各Ra7 如本文所定義。在其他實施例中，各Ra7 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。In some embodiments, each R7 is independently selected from H, halo ( eg, F, Cl), -CN, -C1 - C6 alkyl ( eg, -Me, -Et, -Pr, -i Pr, -sec -Bu, -tBu ), 5-membered heteroaryl ( eg, pyrazolyl), -C1 - C6 haloalkyl ( eg, -CF3 , -CHF2 , -CH2CF3 ), -C 1 -C 6 hydroxyalkyl ( eg, -CH 2 OH), -C 3 -C 9 cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), -OR a7 ( eg, -OH, -OMe, -OCHF 2 ), -N(R a7 ) 2 and -C(=O)N(R a7 ) 2 ( eg, -C(=O)NH 2 , -C( =O)NHMe), wherein each R a7 is as defined herein. In other embodiments, each R a7 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec- Bu, -iso -Bu).

在某些實施例中，各R7 獨立地選自H及甲基。In certain embodiments, each R7 is independently selected from H and methyl.

在一些實施例中，R7 為H。在一些實施例中，R7 為-D。In some embodiments, R7 is H. In some embodiments, R7 is -D.

在某些實施例中，R7 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R7 為-Cl。在一些實施例中，R7 為-F。在一些實施例中，R7 為-Br。在一些實施例中，R7 為-I。In certain embodiments, R7 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R7 is -Cl. In some embodiments, R7 is -F. In some embodiments, R7 is -Br. In some embodiments, R 7 is -I.

在一些實施例中，R7 為-CN。In some embodiments, R 7 is -CN.

在某些實施例中，R7 為-C1 -C6 烷基。在其他實施例中，R7 為-Me。在 一些實施例中，R7 為-Et。在一些實施例中，R7 為-Pr或-iPr。In certain embodiments, R 7 is -C 1 -C 6 alkyl. In other embodiments, R7 is -Me. In some embodiments, R7 is -Et. In some embodiments, R7 is -Pr or -iPr.

在一些實施例中，R7 為-C1 -C6 雜烷基。在其他實施例中，R7 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R7 為羥基甲基(-CH2 OH)。在一些實施例中，R7 為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 N(CH3 )2 。In some embodiments, R 7 is -C 1 -C 6 heteroalkyl. In other embodiments, R 7 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 7 is hydroxymethyl (-CH 2 OH). In some embodiments, R 7 is aminomethyl ( eg, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 .

在一些實施例中，R7 為-C1 -C6 鹵烷基。在其他實施例中，R7 為三氟甲基(-CF3 )。在其他實施例中，R7 為二氟甲基(-CHF2 )。In some embodiments, R 7 is -C 1 -C 6 haloalkyl. In other embodiments, R 7 is trifluoromethyl (-CF 3 ). In other embodiments, R 7 is difluoromethyl (-CHF 2 ).

在一些實施例中，R7 為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R7 為環丙基。在一些實施例中，R7 為環丁基。在一些實施例中，R7 為環戊基。在一些實施例中，R7 為環己基。In some embodiments, R 7 is -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 7 is cyclopropyl. In some embodiments, R 7 is cyclobutyl. In some embodiments, R 7 is cyclopentyl. In some embodiments, R 7 is cyclohexyl.

在一些實施例中，R7 為3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)。在一些實施例中，R7 為氧呾基。在一些實施例中，R7 為四氫哌喃基。在一些實施例中，R7 為四氫呋喃基。在一些實施例中，R7 為吖呾基。在一些實施例中，R7 為吡咯啶基。在一些實施例中，R7 為哌啶基。在一些實施例中，R7 為哌嗪基。在一些實施例中，R7 為嗎啉基。在一些實施例中，R7 為氮雜環庚烷基。In some embodiments, R 7 is a 3-10 membered heterocyclyl group ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholine group, azepanyl group). In some embodiments, R 7 is oxo. In some embodiments, R 7 is tetrahydropyranyl. In some embodiments, R 7 is tetrahydrofuranyl. In some embodiments, R 7 is an acridine. In some embodiments, R 7 is pyrrolidinyl. In some embodiments, R 7 is piperidinyl. In some embodiments, R 7 is piperazinyl. In some embodiments, R 7 is morpholinyl. In some embodiments, R 7 is azepanyl.

在一些實施例中，R7 為5-6員單環雜芳基(例如， 含有1-3個獨立地選自O、N及S之雜原子之5員單環雜芳基；含有1-3個N雜原子之6員單環雜芳基)。在一些實施例中，R7 為5員單環雜芳基(例如， 吡唑基、吡咯基、噻吩基、呋喃基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、三唑基、噻二唑基、噁二唑基)。在一些實施例中，R7 為噻吩基(例如， 噻吩-2-基、噻吩-3-基)。在一些實施例中，R7 為吡唑基(例如 吡唑-1-基、吡唑-3-基、吡唑-5-基)。在一些實施例中，R7 為噻唑基(例如， 噻唑-2-基、噻唑-4-基、噻唑-5-基)。在一些實施例中，R7 為6員單環雜芳基(例如， 吡啶基、嘧啶基、三嗪基、吡嗪基、噠嗪基)。在一些實施例中，R7 為吡啶基(例如， 吡啶-2-基、吡啶-3-基、吡啶-4-基)。在一些實施例中， R7 為嘧啶基(例如， 嘧啶-2-基、嘧啶-4-基、嘧啶-5-基)。在一些實施例中，R7 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R7 為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。In some embodiments, R 7 is a 5-6 membered monocyclic heteroaryl ( eg, a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S; containing 1- 6-membered monocyclic heteroaryl with 3 N heteroatoms). In some embodiments, R 7 is a 5-membered monocyclic heteroaryl group ( eg, pyrazolyl, pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl , triazolyl, thiadiazolyl, oxadiazolyl). In some embodiments, R 7 is thienyl ( eg, thien-2-yl, thien-3-yl). In some embodiments, R 7 is pyrazolyl ( e.g. , pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, R 7 is thiazolyl ( eg, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R 7 is a 6-membered monocyclic heteroaryl ( eg, pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, R 7 is pyridinyl ( eg, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, R7 is pyrimidinyl ( eg, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl). In some embodiments, R 7 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 7 is heterocyclylalkyl ( eg, oxanylmethyl, aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidine) pyridylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

在一些實施例中，R7 為芳基烷基。在一些實施例中，R7 為苯甲基。In some embodiments, R 7 is arylalkyl. In some embodiments, R 7 is benzyl.

在一些實施例中，R7 為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)。In some embodiments, R 7 is heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

在一些實施例中，R7 為-ORa7 (例如， 羥基(-OH)、甲氧基、二氟甲氧基(-OCHF2 )、三氟甲氧基(-OCF3 )、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R7 為羥基。在一些實施例中，R7 為甲氧基。在一些實施例中，R7 為乙氧基。在一些實施例中，R7 為丙氧基。在一些實施例中，R7 為異丙氧基。在一些實施例中，R7 為二氟甲氧基(-OCHF2 )。在一些實施例中，R7 為三氟甲氧基(-OCF3 )。In some embodiments, R 7 is -OR a7 ( eg, hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy , propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 7 is hydroxy. In some embodiments, R 7 is methoxy. In some embodiments, R 7 is ethoxy. In some embodiments, R 7 is propoxy. In some embodiments, R 7 is isopropoxy. In some embodiments, R 7 is difluoromethoxy (-OCHF 2 ). In some embodiments, R 7 is trifluoromethoxy (-OCF 3 ).

在一些實施例中，R7 為-N(Ra7 )2 (例如， -NH2 、-NHRa7 、-N(CH3 )Ra7 )。在一些實施例中，R7 為-NH2 。在一些實施例中，R7 為-NHRa7 (例如， -NHMe、-NHEt、-NHPr、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R7 為-N(CH3 )Ra7 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。在一些實施例中，R7 為-C(=O)Ra7 或-C(=O)ORa7 。在一些實施例中，R7 為-C(=O)Ra7 ，其中Ra7 如本文所述。在一些實施例中，R7 為-C(=O)烷基。在一些實施例中，R7 為-C(O)CH3 、-C(O)環丙基、-C(O)環丁基、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu或-C(=O)OMe。在一些實施例中，R7 為乙醯基(-C(=O)Me)。在一些實施例中，R7 為-C(=O)ORa7 。在一些實施例中，R7 為-COOH。在一些實 施例中，R7 為COOMe。In some embodiments, R 7 is -N(R a7 ) 2 ( eg, -NH 2 , -NHR a7 , -N(CH 3 )R a7 ). In some embodiments, R 7 is -NH 2 . In some embodiments, R7 is -NHRa7 ( eg, -NHMe, -NHEt, -NHPr, -NHiPr , -NHcyclopropyl, -NHcyclobutyl). In some embodiments, R7 is -N( CH3 ) Ra7 ( eg, -NMe2, -N( CH3 )Et, -N( CH3 )Pr, -N( CH3 ) iPr , - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl). In some embodiments, R 7 is -C(=O)R a7 or -C(=O)OR a7 . In some embodiments, R 7 is -C(=O)R a7 , wherein R a7 is as described herein. In some embodiments, R 7 is -C(=O)alkyl. In some embodiments, R7 is -C(O) CH3 , -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) tBu , -C(O) iPr , -C(O)Pr, -C(O) iBu or -C(=O)OMe. In some embodiments, R 7 is acetyl (-C(=O)Me). In some embodiments, R 7 is -C(=0)OR a7 . In some embodiments, R 7 is -COOH. In some embodiments, R 7 is COOMe.

在一些實施例中，R7 為-NRa7 C(=O)Ra7 。在某些實施例中，R7 為-NHC(=O)Ra7 (例如， NHC(=O)Me、NHC(=O)Et、NHC(=O)Pr、NHC(=O)i Pr、NHC(=O)Bu、NHC(=O)t Bu、NHC(=O)環丙基、NHC(=O)環丁基)。在一些實施例中，R7 為-N(CH3 )C(=O)Ra7 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 7 is -NR a7 C(=O)R a7 . In certain embodiments, R 7 is -NHC(=O)R a7 ( eg, NHC(=O)Me, NHC(=O)Et, NHC(=O)Pr, NHC(=O) iPr , NHC(=O)Bu, NHC(=O) tBu , NHC(=O)cyclopropyl, NHC(=O)cyclobutyl). In some embodiments, R 7 is -N(CH 3 )C(=O)R a7 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R7 為-NRa7 C(=O)ORa7 。在某些實施例中，R7 為-NHC(=O)ORa7 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R7 為-N(CH3 )C(=O)ORa7 (例如， N(CH3 )C(=O)OMe、N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 7 is -NR a7 C(=0)OR a7 . In certain embodiments, R 7 is -NHC(=O)OR a7 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 7 is -N(CH 3 )C(=O)OR a7 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R7 為-C(=O)N(Ra7 )2 (例如， -C(=O)NH2 、-C(=O)NHRa7 、-C(=O)N(CH3 )Ra7 )。在一些實施例中，R7 為-C(=O)NH2 。在某些實施例中，R7 為-C(=O)NHRa7 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在某些實施例中，R7 為-C(=O)N(CH3 )Ra7 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 7 is -C(=O)N(R a7 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR a7 , -C(=O)N ( CH 3 )R a7 ). In some embodiments, R 7 is -C(=O)NH 2 . In certain embodiments, R 7 is -C(=O)NHR a7 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O) ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In certain embodiments, R 7 is -C(=O)N(CH 3 )R a7 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R7 為-OC(=O)N(Ra7 )2 。在某些實施例中，R7 為-OC(=O)NHRa7 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R7 為-OC(=O)N(CH3 )Ra7 (例如， -OC(=O)NMe2 、 -OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 7 is -OC(=O)N(R a7 ) 2 . In certain embodiments, R 7 is -OC(=O)NHR a7 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O) ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 7 is -OC(=O)N(CH 3 )R a7 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R7 為-S(=O)Ra7 。在某些實施例中，R7 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在某些實施例中，R7 為-S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 7 is -S(=0)R a7 . In certain embodiments, R 7 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In certain embodiments, R 7 is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R7 為-S(=O)2 Ra7 。在某些實施例中，R7 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在某些實施例中，R7 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R7 為S(=O)2 芳基(例如， S(=O)2 苯基)。在一些實施例中，R7 為-SRa7 。在某些實施例中，R7 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R7 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R7 為-S芳基(例如， S苯基)。在一些實施例中，R7 為-S(=O)(=NRa7 )Ra7 。在某些實施例中，R7 為-S(=O)(=NH)Ra7 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R7 為-S(=O)(=NCH3 )Ra7 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 7 is -S(=0) 2 R a7 . In certain embodiments, R 7 is -S(=O) 2 alkyl ( eg, -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, - S(=O) 2 i Pr). In certain embodiments, R 7 is -S(=0) 2cycloalkyl ( eg, -S(=0) 2cyclopropyl , -S(=0) 2cyclobutyl , -S(=0 ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 7 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl). In some embodiments, R 7 is -SR a7 . In certain embodiments, R7 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R7 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 7 is -S aryl ( eg, S phenyl). In some embodiments, R 7 is -S(=O)(=NR a7 )R a7 . In certain embodiments, R7 is -S(=O)(=NH) Ra7 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 7 is -S(=O)(=NCH 3 )R a7 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R7 為-NRa7 S(=O)2 Ra7 。在某些實施例中，R7 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R7 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R7 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、 -N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R7 為-N(CH3 )S(=O)2 環烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 7 is -NR a7 S(=0) 2 R a7 . In certain embodiments, R 7 is -NHS(=O) 2 alkyl ( eg, -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 Pr, -NHS(=O) 2 Me NHS(=O) 2 i Pr). In certain embodiments, R 7 is -NHS(=0) 2 cycloalkyl ( eg, -NHS(=0) 2 cyclopropyl, -NHS(=0) 2 cyclobutyl, -NHS(=0) ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 7 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R7 is -N( CH3 )S(=O) 2cycloalkyl ( eg, -N( CH3 )S(=O) 2cyclopropyl , -N( CH3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R7 為-S(=O)2 N(Ra7 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRa7 、-S(=O)2 N(CH3 )Ra7 )。在一些實施例中，R7 為-S(=O)2 NH2 。在一些實施例中，R7 為-S(=O)2 NHRa7 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、-S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R7 為-S(=O)2 N(CH3 )Ra7 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 7 is -S(=O) 2 N(R a7 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR a7 , -S(=O ) 2 N(CH 3 )R a7 ). In some embodiments, R 7 is -S(=O) 2 NH 2 . In some embodiments, R 7 is -S(=O) 2 NHR a7 ( eg, -S(=O) 2 NHMe, -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 7 is -S(=O) 2 N(CH 3 )R a7 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

如本文通常所定義，各R8 獨立地選自H、-D、=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa8 、-N(Ra8 )2 、-C(=O)Ra8 、-C(=O)ORa8 、-NRa8 C(=O)Ra8 、-NRa8 C(=O)ORa8 、-CH2 C(=O)N(Ra8 )2 、-C(=O)N(Ra8 )2 、-OC(=O)N(Ra8 )2 、-CH2 C(=O)N(Ra8 )2 、-S(=O)Ra8 、-S(=O)2 Ra8 、-SRa8 、-S(=O)(=NRa8 )Ra8 、-NRa8 S(=O)2 Ra8 及-S(=O)2 N(Ra8 )2 ，其中R8 之兩個實例連同其所連接之一或多個原子可一起形成3-10員碳環基(例如， 環烷基)或雜環基環(例如，連同結構I之哌啶環可以形成橋聯、稠合或螺雙環雜環之環)，其中Ra8 如本文所定義。As generally defined herein, each R 8 is independently selected from H, -D, =O, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 - C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O)OR a8 , -NR a8 C(=O)R a8 , -NR a8 C(=O)OR a8 , - CH 2 C(=O)N(R a8 ) 2 , -C(=O)N(R a8 ) 2 , -OC(=O)N(R a8 ) 2 , -CH 2 C(=O)N( R a8 ) 2 , -S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S(=O)(=NR a8 )R a8 , -NR a8 S(=O) 2 R a8 and -S(=O) 2 N(R a8 ) 2 , wherein two instances of R 8 together with one or more atoms to which they are attached can form a 3-10 membered carbocyclyl group ( eg, cycloalkane) group) or a heterocyclyl ring (eg, together with the piperidine ring of structure I can form a bridged, fused or spirobicyclic heterocycle ring), wherein R a8 is as defined herein.

在式(I)之一些實施例中，兩個R8 基團連同其所連接之原子一起形成3-10員螺環烷基(例如， 環丙基、環丁基、環戊基、環己基、環庚基)或螺雜環基環(例如， 氧呾基、四氫呋喃基、四氫哌喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基、四氫硫哌喃基、硫嗎啉基)。 In some embodiments of formula (I), the two R groups together with the atom to which they are attached form a 3-10 membered spirocycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl) or spiroheterocyclyl rings ( e.g., oxanyl, tetrahydrofuranyl, tetrahydropyranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azacyclic heptyl, tetrahydrothiopyranyl, thiomorpholinyl).

在式(I)之一些實施例中，兩個R8 基團連同其所連接之相鄰原子一起形成3-10員稠合環烷基(例如， 環丙基、環丁基、環戊基、環己基、環庚基)或稠 合雜環基環(例如， 氧呾基、四氫呋喃基、四氫哌喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基、四氫硫哌喃基、硫嗎啉基)。 In some embodiments of formula (I), the two R groups together with the adjacent atoms to which they are attached form a 3-10 membered fused cycloalkyl group ( eg, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl) or fused heterocyclyl rings ( e.g., oxanyl, tetrahydrofuranyl, tetrahydropyranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl , azepanyl, tetrahydrothiopyranyl, thiomorpholinyl).

在一些實施例中，兩個R8 基團連同其所連接之原子一起形成含有橋聯哌啶之碳環基或雜環基環(例如， 2-氮雜雙環[2.2.1]庚烷、2-氮雜雙環[2.2.2]辛烷、3-氮雜雙環[3.2.1]辛烷)。 In some embodiments, the two R groups together with the atom to which they are attached form a carbocyclyl or heterocyclyl ring containing a bridged piperidine ( eg, 2-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane).

在某些實施例中，表示為式(I)中之

Figure 110128222-A0202-12-0117-1151
的部分選自：In certain embodiments, represented by formula (I)
Figure 110128222-A0202-12-0117-1151
part is selected from:

Figure 110128222-A0202-12-0117-1155
及
Figure 110128222-A0202-12-0117-1152
，其中R6 、R7 、R8 及n如本文所定義。
Figure 110128222-A0202-12-0117-1155
 and
Figure 110128222-A0202-12-0117-1152
, wherein R 6 , R 7 , R 8 and n are as defined herein.

在其他實施例中，表示為式(I)中之

Figure 110128222-A0202-12-0117-1153
的部分選自：In other embodiments, expressed as in formula (I)
Figure 110128222-A0202-12-0117-1153
part is selected from:

Figure 110128222-A0202-12-0117-1154
Figure 110128222-A0202-12-0117-1154

Figure 110128222-A0202-12-0118-1156
Figure 110128222-A0202-12-0118-1157
，其中R6 、R7 、R8 及n如本文所定義。
Figure 110128222-A0202-12-0118-1156
Figure 110128222-A0202-12-0118-1157
, wherein R 6 , R 7 , R 8 and n are as defined herein.

在上文所述之雙環及多環部分之某些實施例中，n為2(亦即，該等環不攜帶任何R8 取代基)。在上文所述之雙環及多環部分之一些實施例中，各R6 及R7 獨立地選自H及-CH3 。在一些實施例中，R6 為H。在一些實施例中，R6 為-CH3 在某些實施例中，R7 為H。在其他實施例中，R7 為-CH3 。在某些實施例中，R6 及R7 均為H。In certain embodiments of the bicyclic and polycyclic moieties described above, n is 2 (ie, the rings do not carry any R8 substituents). In some embodiments of the bicyclic and polycyclic moieties described above, each R6 and R7 is independently selected from H and -CH3 . In some embodiments, R 6 is H. In some embodiments, R 6 is -CH 3 In certain embodiments, R 7 is H. In other embodiments, R 7 is -CH 3 . In certain embodiments, both R 6 and R 7 are H.

在其他實施例中，R8 基團不在一起形成環烷基或雜環基環(亦即， 各R8 獨立地選自H、-D、=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷 基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa8 、-N(Ra8 )2 、-C(=O)Ra8 、-C(=O)ORa8 、-NRa8 C(=O)Ra8 、-NRa8 C(=O)ORa8 、-CH2 C(=O)N(Ra8 )2 、-C(=O)N(Ra8 )2 、-OC(=O)N(Ra8 )2 、-CH2 C(=O)N(Ra8 )2 、-S(=O)Ra8 、-S(=O)2 Ra8 、-SRa8 、-S(=O)(=NRa8 )Ra8 、-NRa8 S(=O)2 Ra8 及-S(=O)2 N(Ra8 )2 )，其中Ra8 如本文所定義。 In other embodiments, the R groups are not taken together to form a cycloalkyl or heterocyclyl ring ( ie, each R is independently selected from H, -D, = O, halo, -CN, -C1- C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heterocyclyl Arylalkyl, arylalkyl, cycloalkylalkyl, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O)OR a8 , -NR a8 C (=O)R a8 , -NR a8 C(=O)OR a8 , -CH 2 C(=O)N(R a8 ) 2 , -C(=O)N(R a8 ) 2 , -OC(= O)N(R a8 ) 2 , -CH 2 C(=O)N(R a8 ) 2 , -S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S( =O)(=NR a8 )R a8 , -NR a8 S(=O) 2 R a8 and -S(=O) 2 N(R a8 ) 2 ), where R a8 is as defined herein.

在一些實施例中，各R8 獨立地選自H、-D、鹵基(例如， -F、-Cl)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、芳基烷基(例如， 苯甲基)、-C(=O)Ra8 (例如， -C(=O)Me、-C(=O)Et、-C(=O)Pr、-C(=O) i Pr)、-N(Ra8 )2 (例如， -NHMe、NH2 、NMe2 )、-NRa8 C(=O)Ra8 (例如， -NHC(=O)Me)、-CH2 C(=O)N(Ra8 )2 (例如， -CH2 C(=O)NH2 )及-ORa8 (例如， -OH、-OMe、-Oi Pr、-OCF3 )，其中各Ra8 如本文所定義。在其他實施例中，各Ra8 獨立地選自H、-CF3 及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。In some embodiments, each R8 is independently selected from H, -D, halo ( eg, -F, -Cl), -CN, -C1 - C6 alkyl ( eg, -Me, -Et, -Pr, -iPr , -sec -Bu , -tBu), arylalkyl ( eg, benzyl), -C(=O)R a8 ( eg, -C(=O)Me, -C (=O)Et, -C(=O)Pr, -C(=O) i Pr), -N(R a8 ) 2 ( eg, -NHMe, NH 2 , NMe 2 ), -NR a8 C(= O)R a8 ( eg, -NHC(=O)Me), -CH 2 C(=O)N(R a8 ) 2 ( eg, -CH 2 C(=O)NH 2 ), and -OR a8 ( eg , -OH, -OMe, -OiPr , -OCF3 ), wherein each R a8 is as defined herein. In other embodiments, each R a8 is independently selected from H, -CF 3 and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu , -sec -Bu, -iso -Bu).

在一些實施例中，各R8 獨立地選自H、-D、-F、-Me、-Et、-CN、苯甲基、-OMe、-O i Pr、-OCF3 、-NHC(=O)Me、-NMe2 、-CH2 C(=O)NH2 、-C(=O) i Pr及-OH。在一些實施例中，R8 選自H、-D、-F、-Me、-Et及-CN。在一些實施例中，R8 選自H、-D、-F及-Me。 In some embodiments, each R is independently selected from H, -D, -F, -Me, -Et, -CN, benzyl, -OMe, -OiPr , -OCF3 , -NHC (= O)Me, -NMe2, -CH2C (=O) NH2 , -C (=O) iPr and -OH. In some embodiments, R8 is selected from H, -D, -F, -Me, -Et, and -CN. In some embodiments, R8 is selected from H, -D, -F and -Me.

在一些實施例中，R8 為H。In some embodiments, R8 is H.

在一些實施例中，R8 為-D。In some embodiments, R 8 is -D.

在某些實施例中，R8 為=O。In certain embodiments, R 8 is =0.

在某些實施例中，R8 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R8 為-Cl。在一些實施例中，R8 為-F。在一些實施例中，R8 為-Br。在一些實施例中，R8 為-I。In certain embodiments, R8 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R8 is -Cl. In some embodiments, R8 is -F. In some embodiments, R 8 is -Br. In some embodiments, R 8 is -I.

在一些實施例中，R8 為-CN。In some embodiments, R 8 is -CN.

在某些實施例中，R8 為-C1 -C6 烷基。在其他實施例中，R8 為-Me。在 一些實施例中，R8 為-Et。在一些實施例中，R8 為-Pr或-iPr。In certain embodiments, R 8 is -C 1 -C 6 alkyl. In other embodiments, R8 is -Me. In some embodiments, R 8 is -Et. In some embodiments, R8 is -Pr or -iPr.

在一些實施例中，R8 為-C1 -C6 雜烷基。在其他實施例中，R8 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R8 為羥甲基(-CH2 OH)。在一些實施例中，R8 為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 N(CH3 )2 。在一些實施例中，R8 為-C1 -C6 鹵烷基。在其他實施例中，R8 為三氟甲基(-CF3 )。In some embodiments, R 8 is -C 1 -C 6 heteroalkyl. In other embodiments, R 8 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 8 is hydroxymethyl (-CH 2 OH). In some embodiments, R8 is aminomethyl ( eg, -CH2NH2 , -CH2NHCH3 , -CH2N (CH3)2 . In some embodiments, R8 is -C1 -C6 haloalkyl. In other embodiments, R8 is trifluoromethyl ( -CF3 ).

在一些實施例中，R8 為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R8 為環丙基。在一些實施例中，R8 為環丁基。在一些實施例中，R8 為環戊基。在一些實施例中，R8 為環己基。In some embodiments, R 8 is -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 8 is cyclopropyl. In some embodiments, R 8 is cyclobutyl. In some embodiments, R 8 is cyclopentyl. In some embodiments, R 8 is cyclohexyl.

在一些實施例中，R8 為3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)。在一些實施例中，R8 為氧呾基。在一些實施例中，R8 為四氫哌喃基。在一些實施例中，R8 為四氫呋喃基。在一些實施例中，R8 為吖呾基。在一些實施例中，R8 為吡咯啶基。在一些實施例中，R8 為哌啶基。在一些實施例中，R8 為哌嗪基。在一些實施例中，R8 為嗎啉基。在一些實施例中，R8 為氮雜環庚烷基。In some embodiments, R 8 is a 3-10 membered heterocyclyl group ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholine group, azepanyl group). In some embodiments, R 8 is oxo. In some embodiments, R 8 is tetrahydropyranyl. In some embodiments, R 8 is tetrahydrofuranyl. In some embodiments, R 8 is an acridine. In some embodiments, R 8 is pyrrolidinyl. In some embodiments, R 8 is piperidinyl. In some embodiments, R 8 is piperazinyl. In some embodiments, R 8 is morpholinyl. In some embodiments, R 8 is azepanyl.

在一些實施例中，R8 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R8 為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。在一些實施例中，R8 為芳基烷基(例如 苯甲基)。在一些實施例中，R8 為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)。In some embodiments, R 8 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 8 is heterocyclylalkyl ( eg, oxanylmethyl, aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidine) pyridylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl). In some embodiments, R 8 is arylalkyl ( e.g., benzyl). In some embodiments, R 8 is heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

在一些實施例中，R8 為-CH2 C(=O)N(Ra8 )2 (例如， -CH2 C(=O)N(Ra8 )2 )。In some embodiments, R 8 is -CH 2 C(=O)N(R a8 ) 2 ( eg, -CH 2 C(=O)N(R a8 ) 2 ).

在一些實施例中，R8 為-ORa8 (例如， -OH、甲氧基、異丙氧基、二氟甲氧基(-OCHF2 )、三氟甲氧基(-OCF3 )、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R8 為-OH。在一些實施例中，R8 為甲氧基。 在一些實施例中，R8 為乙氧基。在一些實施例中，R8 為丙氧基。在一些實施例中，R8 為異丙氧基。在一些實施例中，R8 為二氟甲氧基(-OCHF2 )。在一些實施例中，R8 為三氟甲氧基(-OCF3 )。In some embodiments, R 8 is -OR a8 ( eg, -OH, methoxy, isopropoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethyl oxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 8 is -OH. In some embodiments, R 8 is methoxy. In some embodiments, R 8 is ethoxy. In some embodiments, R 8 is propoxy. In some embodiments, R 8 is isopropoxy. In some embodiments, R 8 is difluoromethoxy (-OCHF 2 ). In some embodiments, R 8 is trifluoromethoxy (-OCF 3 ).

在一些實施例中，R8 為-N(Ra8 )2 (例如， -NH2 、-NHRa8 、-N(CH3 )Ra8 )。在一些實施例中，R8 為-NH2 。在一些實施例中，R8 為-NHRa8 (例如， -NHMe、-NHEt、-NHPr、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R8 為-N(CH3 )Ra8 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。In some embodiments, R 8 is -N(R a8 ) 2 ( eg, -NH 2 , -NHR a8 , -N(CH 3 )R a8 ). In some embodiments, R 8 is -NH 2 . In some embodiments, R8 is -NHRa8 ( eg, -NHMe, -NHEt, -NHPr, -NHiPr , -NHcyclopropyl, -NHcyclobutyl). In some embodiments, R8 is -N( CH3 )Ra8 ( eg, -NMe2 , -N( CH3 )Et, -N( CH3 )Pr, -N( CH3 ) iPr , - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl).

在一些實施例中，R8 為-C(=O)Ra8 ，其中Ra8 如本文所述。在一些實施例中，R8 為-C(=O)Ra8 ，其中Ra8 為C1 -C6 烷基、C3 -C9 碳環基或3-10員雜環基(例如 -C(=O)Me、-C(=O)Et、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu、-C(=O)環丙基、-C(=O)環丁基、-C(=O)氧呾基、-C(=O)四氫哌喃基)。在一些實施例中，R8 為-C(=O)Me、-C(=O)Et、-C(O) t Bu、-C(O) i Pr、-C(O)Pr或-C(O) i Bu。在一些實施例中，R8 為-C(=O) i Pr。In some embodiments, R 8 is -C(=O)R a8 , wherein R a8 is as described herein. In some embodiments, R 8 is -C(=O)R a8 , wherein R a8 is C 1 -C 6 alkyl, C 3 -C 9 carbocyclyl, or 3-10 membered heterocyclyl ( eg -C (=O)Me, -C(=O)Et, -C(O) t Bu, -C(O) i Pr, -C(O)Pr, -C(O) i Bu, -C(=O ) cyclopropyl, -C(=O) cyclobutyl, -C(=O) oxyalkyl, -C(=O) tetrahydropyranyl). In some embodiments, R 8 is -C(=O)Me, -C(=O)Et, -C(O) tBu , -C(O) iPr , -C(O)Pr, or -C (O) i Bu. In some embodiments, R 8 is -C(=0) iPr .

在一些實施例中，R8 為-NRa8 C(=O)Ra8 。在某些實施例中，R8 為-NHC(=O)Ra8 (例如， NHC(=O)Me、NHC(=O)Et、NHC(=O)Pr、NHC(=O)i Pr、NHC(=O)Bu、NHC(=O)t Bu、NHC(=O)環丙基、NHC(=O)環丁基)。在某些實施例中，R8 為NHC(=O)Me。在一些實施例中，R8 為-N(CH3 )C(=O)Ra8 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 8 is -NR a8 C(=O)R a8 . In certain embodiments, R 8 is -NHC(=O)R a8 ( eg, NHC(=O)Me, NHC(=O)Et, NHC(=O)Pr, NHC(=O) iPr , NHC(=O)Bu, NHC(=O) tBu , NHC(=O)cyclopropyl, NHC(=O)cyclobutyl). In certain embodiments, R 8 is NHC(=O)Me. In some embodiments, R 8 is -N(CH 3 )C(=O)R a8 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R8 為-NRa8 C(=O)ORa8 。在某些實施例中，R8 為-NHC(=O)ORa8 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R8 為-N(CH3 )C(=O)ORa8 (例如， N(CH3 )C(=O)OMe、 N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 8 is -NR a8 C(=0)OR a8 . In certain embodiments, R 8 is -NHC(=O)OR a8 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 8 is -N(CH 3 )C(=O)OR a8 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R8 為-C(=O)N(Ra8 )2 (例如， -C(=O)NH2 、-C(=O)NHRa8 、-C(=O)N(CH3 )Ra8 )。在一些實施例中，R8 為-C(=O)NH2 。在某些實施例中，R8 為-C(=O)NHRa8 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在某些實施例中，R8 為-C(=O)N(CH3 )Ra8 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 8 is -C(=O)N(R a8 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR a8 , -C(=O)N ( CH 3 )R a8 ). In some embodiments, R 8 is -C(=O)NH 2 . In certain embodiments, R is -C(=O)NHR a8 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In certain embodiments, R 8 is -C(=O)N(CH 3 )R a8 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R8 為-OC(=O)N(Ra8 )2 。在某些實施例中，R8 為-OC(=O)NHRa8 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R8 為-OC(=O)N(CH3 )Ra8 (例如， -OC(=O)NMe2 、-OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 8 is -OC(=O)N(R a8 ) 2 . In certain embodiments, R is -OC(=O)NHR a8 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 8 is -OC(=O)N(CH 3 )R a8 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R8 為-S(=O)Ra8 。在某些實施例中，R8 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在某些實施例中，R8 為-S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 8 is -S(=0)R a8 . In certain embodiments, R 8 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In certain embodiments, R is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R8 為-S(=O)2 Ra8 。在某些實施例中，R8 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在某些實施例中，R8 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R8 為S(=O)2 芳基(例如， S(=O)2 苯基)。In some embodiments, R 8 is -S(=0) 2 R a8 . In certain embodiments, R 8 is -S(=O) 2 alkyl ( eg, -S(=O) 2 Me, -S(=O) 2 Et, -S(=O) 2 Pr, - S(=O) 2 i Pr). In certain embodiments, R 8 is -S(=0) 2cycloalkyl ( eg, -S(=0) 2cyclopropyl , -S(=0) 2cyclobutyl , -S(=0 ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 8 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl).

在一些實施例中，R8 為-SRa8 。在某些實施例中，R8 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R8 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R8 為-S芳基(例如， S苯基)。在一些實施例中，R8 為-S(=O)(=NRa8 )Ra8 。在某些實施例中，R8 為-S(=O)(=NH)Ra8 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R8 為-S(=O)(=NCH3 )Ra8 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 8 is -SR a8 . In certain embodiments, R8 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R 8 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 8 is -S aryl ( eg, S phenyl). In some embodiments, R 8 is -S(=O)(=NR a8 )R a8 . In certain embodiments, R is -S(=O)(=NH)R a8 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 8 is -S(=O)(=NCH 3 )R a8 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R8 為-NRa8 S(=O)2 Ra8 。在某些實施例中，R8 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R8 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R8 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、-N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R8 為-N(CH3 )S(=O)2 環烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 8 is -NR a8 S(=0) 2 R a8 . In certain embodiments, R 8 is -NHS(=O) 2 alkyl ( eg, -NHS(=O) 2 Me, -NHS(=O) 2 Et, -NHS(=O) 2 Pr, -NHS(=O) 2 Pr, -NHS(=O) 2 Me NHS(=O) 2 i Pr). In certain embodiments, R 8 is -NHS(=0) 2cycloalkyl ( eg, -NHS(=0) 2cyclopropyl , -NHS(=0) 2cyclobutyl , -NHS(=0 ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 8 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R8 is -N( CH3 )S(=O) 2cycloalkyl ( eg, -N( CH3 )S(=O) 2cyclopropyl , -N( CH3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R8 為-S(=O)2 N(Ra8 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRa8 、-S(=O)2 N(CH3 )Ra8 )。在一些實施例中，R8 為-S(=O)2 NH2 。在一些實施例中，R8 為-S(=O)2 NHRa8 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、-S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R8 為-S(=O)2 N(CH3 )Ra8 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 8 is -S(=O) 2 N(R a8 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR a8 , -S(=O ) 2 N(CH 3 )R a8 ). In some embodiments, R 8 is -S(=O) 2 NH 2 . In some embodiments, R 8 is -S(=O) 2 NHR a8 ( eg, -S(=O) 2 NHMe, -S(=O) 2 NHEt, -S(=O) 2 NHPr, -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 8 is -S(=O) 2 N(CH 3 )R a8 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

如本文通常所述，各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、 5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、-S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、雜環基烷氧基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)。As generally described herein, each R 10 is independently selected from -D, =O, -CN, halo, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 Haloalkyl, -C 3 -C 9 cycloalkyl, 3-10-membered heterocyclyl, C 6 -C 10 -membered aryl, 5-10-membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, Arylalkyl, heteroarylalkyl, heterocyclylalkoxy, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O)R b10 , -NR b10 C(=O)OR b10 , -C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N( R b10 ) 2 , -S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S(=O) 2 N(R b10 ) 2 , wherein each of R 10 is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl , heterocyclylalkyl, heterocyclylalkoxy, arylalkyl, and heteroarylalkyl are optionally substituted ( eg, with -Me, -Et, -iPr , cyclopropyl, oxo and -3 -Base, -OH , =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C ( = O)Me, -N(Me ) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr)(Et), -N( i Pr)(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or 0, 1, 2, 3, 4, or 5 instances of a combination thereof substituted).

在一些實施例中，R10 之各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基未經取代。在一些實施例中，R10 之各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基獨立地經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之1個實例取代。在一些實施例中，R10 之各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基獨立地經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之2個實例取代。在一些實施例中，R10 之各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基獨立地經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、 -CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之3個實例取代。在一些實施例中，R10 之各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基獨立地經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之4個實例取代。In some embodiments, each of R 10 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl Not substituted. In some embodiments, each of R 10 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently via -Me, -Et, -iPr , cyclopropyl, oxo- 3 -yl, -OH, =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , - CH 2 CH 2 CF 3 , -C(=O)Me, -N(Me) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr 1 example substitution of )(Et), -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or a combination thereof. In some embodiments, each of R 10 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently via -Me, -Et, -iPr , cyclopropyl, oxo- 3 -yl, -OH, =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , - CH 2 CH 2 CF 3 , -C(=O)Me, -N(Me) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr 2 instance substitutions of )(Et), -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or a combination thereof. In some embodiments, each of R 10 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently via -Me, -Et, -iPr , cyclopropyl, oxo- 3 -yl, -OH, =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , - CH 2 CH 2 CF 3 , -C(=O)Me, -N(Me) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr 3 example substitutions of )(Et), -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or combinations thereof. In some embodiments, each of R 10 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently via -Me, -Et, -iPr , cyclopropyl, oxo- 3 -yl, -OH, =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , - CH 2 CH 2 CF 3 , -C(=O)Me, -N(Me) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr 4 example substitutions of )(Et), -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or combinations thereof.

在一些實施例中，R10 之各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基獨立地經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之5個實例取代。In some embodiments, each of R 10 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl independently via -Me, -Et, -iPr , cyclopropyl, oxo- 3 -yl, -OH, =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , - CH 2 CH 2 CF 3 , -C(=O)Me, -N(Me) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr 5 example substitutions of )(Et), -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or combinations thereof.

在一些實施例中，各R10 獨立地選自-D、=O、鹵基(例如， F、Cl、Br)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、CH2 (CH3 )( i Pr))、-C1 -C6 雜烷基(例如， -CH(CH3 )(NMe2 )、-CH2 CH2 N(Me)(氧呾-3-基))、-CH2 CH(CH3 )(NMe2 )、-CH2 OH、-CH(OH)(CH3 )、-C(OH)(CH3 )2 、-CH2 NH2 )、-C1 -C6 鹵烷基(例如， -CHF2 、-CH2 CF3 、-CF3 )、-C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)、3-10員雜環基(例如， 四氫呋喃基、四氫哌喃基、氧呾基、嗎啉基、吡咯啶基、哌啶基、哌啶-2-酮基、哌嗪基、哌嗪-2-酮基、吖呾基、十氫-1,6-萘啶基、2-氮雜螺[3.3]庚基、5-氧雜-2,8-二氮雜螺[3.5]壬基、8-氮雜雙環[3.2.1]辛基、2-氮雜雙環[2.2.2]辛基、3-氮雜雙環[3.2.0]庚基、3-氮雜雙環[3.1.1]庚基、3-氮雜雙環[3.1.0]己基、2-氮雜雙環[2.1.1]己基、1-氮雜雙環[2.2.1]庚基、3-氮雜雙環[3.2.0]庚基、2,9-二氮雜螺[5.5]十一烷基、雙環[1.1.1]戊基、八氫環戊[c]吡咯基、十氫-1,6-萘啶基、八氫-1H-吡咯并[3,4-c]吡啶基、十氫-2,7-萘啶基、2,9- 二氮雜螺[5.5]十一烷基)、5-10員雜芳基(例如， 吡啶基、咪唑并[1,2-a]吡啶基、咪唑基、吡唑基、噻唑基、噻吩基)、環烷基烷基(例如 -CH2 -環丙基)、雜環基烷基(例如， -CH2 -嗎啉基、-(CH2 )2 -吡咯啶基-(CH2 )2 -吡咯啶基-CH2 -咪唑基、-CH2 -吡唑基、-CH2 -1,2,4-三唑基、-CH2 -嗎啉基、-(CH2 )2 -嗎啉基)、雜環基烷氧基(例如，-O-(CH2 )2 -吡咯啶基、-O-CH2 -哌啶基、-O-CH2 -氧呾基、-O-CH2 -四氫呋喃基、-O-CH2 -四氫哌喃基)、雜芳基烷基(例如， -CH2 -三唑基、-CH2 -咪唑基、-CH2 -吡唑基)、-ORb10 (例如， -OH、-OMe、OEt、-O-四氫呋喃基、-O-四氫哌喃-4-基、-OCF3 、-OCHF2 )、-N(Rb10 )2 、(例如， -NH2 、-NHRb10 、-NHMe、-NMe2 、-NHCH2 CF3 、-NH-氧呾-3-基、-NH-(N-Me-2-側氧基-吡咯啶-3-基)、-NRb10 C(=O)Rb10 (例如， -NHC(=O)Me)、-C(=O)N(Rb10 )2 、(例如， -C(=O)NH2 、C(=O)NHMe)、-OC(=O)Rb10 (例如， -OC(=O)Me)、-S(=O)Rb10 (例如， -SO2 Me)、-NRb10 S(=O)2 Rb10 (例如， NHSO2 Me)及-S(=O)2 N(Rb10 )2 (例如， SO2 NH2 、SO2 NHMe)，其中各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)，且其中：各Rb10 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、-C1 -C6 鹵烷基(例如， -CF3 、-CHF2 、-CH2 CF3 )、經=O之0或1個實例取代之-C1 -C6 雜烷基(例如， -CH2 CH2 NMe2 、-CH2 C(=O)NMe2 、-CH(CH3 )CH2 NMe2 、-CH(CH3 )C(=O)NMe2 )、C3 -C9 環烷基及經=O、-Me或其組合之0或1個實例取代之3-10員雜環基(例如 四氫呋喃-3-基、四氫哌喃-4-基、氧呾-3-基、N-Me-2-側氧基-吡咯啶-3-基、哌啶-4-基)。In some embodiments, each R 10 is independently selected from -D, =O, halo ( eg, F, Cl, Br), -CN, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -i Pr, -sec -Bu, -t Bu, CH 2 (CH 3 )( i Pr)), -C 1 -C 6 heteroalkyl ( eg, -CH(CH 3 )(NMe 2 ), -CH2CH2N (Me) (oxygen- 3 -yl)), -CH2CH( CH3 ) ( NMe2 ), -CH2OH , -CH(OH)( CH3 ), - C(OH)( CH3 ) 2 , -CH2NH2 ), -C1 - C6 haloalkyl ( eg, -CHF2, -CH2CF3 , -CF3 ) , -C3 - C9 Cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-10 membered heterocyclyl ( eg, tetrahydrofuranyl, tetrahydropyranyl, oxanyl, morpholinyl, pyrrole Peridyl, piperidinyl, piperidin-2-one, piperazinyl, piperazin-2-one, acryl, decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3] Heptyl, 5-oxa-2,8-diazaspiro[3.5]nonyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.0]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 1- Azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.0]heptyl, 2,9-diazaspiro[5.5]undecyl, bicyclo[1.1.1]pentyl, octa Hydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, decahydro-2,7-naphthyridinyl, 2, 9-diazaspiro[5.5]undecyl), 5-10 membered heteroaryl ( eg, pyridyl, imidazo[1,2-a]pyridyl, imidazolyl, pyrazolyl, thiazolyl, thienyl), cycloalkylalkyl ( eg -CH2 -cyclopropyl), heterocyclylalkyl ( eg, -CH2 -morpholinyl, -( CH2 ) 2 -pyrrolidinyl-(CH2 ) ) 2 -pyrrolidinyl-CH 2 -imidazolyl, -CH 2 -pyrazolyl, -CH 2 -1,2,4-triazolyl, -CH 2 -morpholinyl, -(CH 2 ) 2 - morpholinyl), heterocyclylalkoxy (eg, -O-( CH2 ) 2 -pyrrolidinyl, -O- CH2 -piperidinyl, -O- CH2 -oxocyclyl, -O- CH2 -tetrahydrofuranyl, -O- CH2 -tetrahydropyranyl), heteroarylalkyl ( eg, -CH2 -triazolyl, -CH2 -imidazolyl, -CH2 -pyrazolyl) , -OR b10 ( eg, -OH, -OMe, OEt, -O-tetrahydrofuranyl, -O-tetrahydropyran-4-yl, -OCF 3 , -OCHF 2 ), -N(R b10 ) 2 , ( eg, - NH 2 , -NHR b10 , -NHMe, -NMe 2 , -NHCH 2 CF 3 , -NH-oxon-3-yl, -NH-(N-Me-2-oxy-pyrrolidin-3-yl ), -NR b10 C(=O)R b10 ( eg, -NHC(=O)Me), -C(=O)N(R b10 ) 2 , ( eg, -C(=O)NH 2 , C (=O)NHMe), -OC(=O)R b10 ( eg, -OC(=O)Me), -S(=O)R b10 ( eg, -SO 2 Me), -NR b10 S(= O) 2 R b10 ( eg, NHSO 2 Me) and -S(=O) 2 N(R b10 ) 2 ( eg, SO 2 NH 2 , SO 2 NHMe), where each alkyl, cycloalkyl, heterocycle aryl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl are optionally substituted ( eg, via -Me, -Et, -iPr , ring Propyl, oxo- 3 -yl, -OH , =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C ( = O)Me , -N(Me) 2 , -CH2N ( CH3 ) 2 , -CH2N ( CH3 ) CH2CH3 , -N( iPr )(Et ) , -N( iPr )(Me) , -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or 0, 1, 2, 3, 4, or 5 instances of a combination thereof substituted), and wherein: each R b10 is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -i Pr, -sec -Bu, -t Bu), -C 1 -C 6 haloalkyl ( eg, -CF3 , -CHF2, -CH2CF3 ), -C1 - C6 heteroalkyl substituted with 0 or 1 instance of = 0 ( eg, -CH2CH2NMe2 , - CH 2 C(=O)NMe 2 , -CH(CH 3 )CH 2 NMe 2 , -CH(CH 3 )C(=O)NMe 2 ), C 3 -C 9 cycloalkyl and via =O, - 3-10 membered heterocyclyl substituted with 0 or 1 instance of Me or a combination thereof ( eg tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxo-3-yl, N-Me-2-side oxy-pyrrolidin-3-yl, piperidin-4-yl).

如本文通常所定義，各Rb10 獨立地為H；-C1 -C6 烷基；-C1 -C6 鹵烷基； 經=O之0或1個實例取代之-C1 -C6 雜烷基(例如， 未經取代或經=O之一個實例取代)；C3 -C9 環烷基；或經=O、-Me或其組合之0或1個實例取代之3-10員雜環基(例如， 未經取代、經=O之一個實例取代、經-Me之一個實例取代或經=O之一個實例及-Me之一個實例取代)。在R10 之某些實施例中，各Rb10 獨立地選自H、-Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、-CF3 、-CHF2 、-CH2 CF3 、-CH2 CH2 NMe2 、-CH2 C(=O)NMe2 、-CH(CH3 )CH2 NMe2 、-CH(CH3 )C(=O)NMe2 )、四氫呋喃-3-基、四氫哌喃-4-基、氧呾-4-基及N-Me-2-側氧基-吡咯啶-3-基。As generally defined herein, each R b10 is independently H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 substituted with 0 or 1 instance of =0 Heteroalkyl ( eg, unsubstituted or substituted with one instance of =O); C3 - C9cycloalkyl ; or 3-10 members substituted with 0 or 1 instance of =0, -Me, or a combination thereof Heterocyclyl ( eg, unsubstituted, substituted with one instance of =0, substituted with one instance of -Me, or substituted with one instance of =0 and one instance of -Me). In certain embodiments of R10, each Rb10 is independently selected from H, -Me, -Et , -Pr, -iPr , -sec - Bu, -tBu, -CF3 , -CHF2, - CH 2 CF 3 , -CH 2 CH 2 NMe 2 , -CH 2 C(=O)NMe 2 , -CH(CH 3 )CH 2 NMe 2 , -CH(CH 3 )C(=O)NMe 2 ), Tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxypyran-4-yl and N-Me-2-oxo-pyrrolidin-3-yl.

在一些實施例中，R10 獨立地選自-D、=O、-OH、-F、-Cl、-Br、-CN、-Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、-OMe、-OEt、-CHF2 、-CH2 CF3 、-CF3 、-OCF3 、-OCHF2 、-CH2 OH、-CH(OH)(CH3 )、-CH2 OMe、-C(OH)(CH3 )2 、-CH2 NH2 、-CH(CH3 )(NMe2 )、-CH2 CH(CH3 )(NMe2 )、-CH2 (CH3 )( i Pr)、-NH2 、-NHMe、-NHCH2 CF3 、-NMe2 、環丙基、環丁基、環戊基、環己基、噻唑-2-基、噻唑-5-基、噻吩-2-基、四氫呋喃-3-基、四氫哌喃-4-基、氧呾-3-基、嗎啉-2-基、-CH2 -嗎啉-4-基、-(CH2 )2 -嗎啉-4-基、咪唑-2-基、1H-吡唑-5-基、1H-咪唑-4-基、咪唑并[1,2-a]吡啶-7-基、吡咯啶-1-基、吡咯啶-3-基、哌啶-4-基、哌啶-3-基、哌啶-2-酮-4-基、哌嗪-4-基、哌嗪-4-基、哌嗪-2-酮-5-基、吡啶-4-基、吡啶-3-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、1H-吡唑-5-基、吖呾-3-基、-(CH2 )2 -吡咯啶-1-基、-(CH2 )2 -吡咯啶-2-基、-CH2 -咪唑-1-基、-CH2 -吡唑-1-基、-CH2 -1,2,4-三唑-1-基、-CH2 -環丙基、-O(CH2 )2 NMe2 、-O-四氫呋喃-3-基、-O-四氫哌喃-4-基、-O-(N-Me-2-側氧基-吡咯啶-3-基)、-O-(CH2 )2 -吡咯啶-2-基、-O-CH2 -哌啶-4-基、-O-CH2 -氧呾-3-基、-NCH3 -哌啶-4-基、-NH-氧呾-3-基、-NH-(N-Me-2-側氧基-吡咯啶-3-基)、十氫-1,6-萘啶-6-基、2-氮雜螺[3.3]庚-6-基、5-氧雜-2,8-二氮雜螺[3.5]壬-8-基、8-氮雜雙環[3.2.1]辛-3-基、2-氮雜雙環[2.2.2]辛-4-基、3-氮雜雙環[3.2.0]庚-6-基、3-氮雜雙環[3.1.1]庚-1-基、3-氮雜雙環[3.1.0]己-6-基、1-氮雜 雙環[2.2.1]庚-4-基、3-氮雜雙環[3.2.0]庚-6-基、2-氮雜雙環[2.1.1]己-4-基、2,9-二氮雜螺[5.5]十一烷-9-基、雙環[1.1.1]戊烷-2-基、八氫環戊[c]吡咯-5-基、十氫-1,6-萘啶-6-基、八氫-1H-吡咯并[3,4-c]吡啶-5-基、十氫-2,7-萘啶-2-基、2,9-二氮雜螺[5.5]十一烷-2-基、-NHC(=O)Me、-NHCH2 C(=O)NMe2 、-NHCH(CH3 )C(=O)NMe2 、-C(=O)NH2 、C(=O)NHMe、-OC(=O)Me、-SO2 Me、-NHSO2 Me、-SO2 NH2 及-SO2 NHMe，其中各-OMe、-OEt、-Me、-Et、-Pr、- i Pr、環丙基、環丁基、環戊基、環己基、四氫呋喃-3-基、氧呾-3-基、吡咯啶-1-基、吡咯啶-3-基、哌啶-4-基、哌啶-3-基、哌啶-2-酮-4-基、哌嗪-4-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、噻唑-2-基、噻吩-2-基、-CH2 -環丙基、-CH2 -嗎啉-4-基、-(CH2 )2 -嗎啉-4-基、-嗎啉-2-基、-(CH2 )2 -吡咯啶-1-基、-CH2 -1,2,4-三唑-1-基、-CH2 -咪唑-1-基、咪唑-2-基、-CH2 -吡唑-1-基、-OCH2 -哌啶-4-基、吖呾-3-基、2-氮雜螺[3.3]庚-6-基、2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基、8-氮雜雙環[3.2.1]辛-3-基及十氫-1,6-萘啶-6-基，其中各R10 可獨立地經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代。In some embodiments, R 10 is independently selected from -D, =O, -OH, -F, -Cl, -Br, -CN, -Me, -Et , -Pr, -iPr , -sec-Bu , -tBu , -OMe, -OEt , -CHF2, -CH2CF3 , -CF3 , -OCF3 , -OCHF2, -CH2OH , -CH ( OH)( CH3 ) , -CH 2OMe , -C(OH)( CH3 ) 2 , -CH2NH2 , -CH( CH3 )( NMe2 ), -CH2CH( CH3 )( NMe2 ) , -CH2 ( CH3 ) )( iPr ), -NH2 , -NHMe, -NHCH2CF3 , -NMe2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazol- 2 -yl, thiazol-5-yl, Thiophen-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxo-3-yl, morpholin-2-yl, -CH 2 -morpholin-4-yl, -(CH 2 ) 2 -morpholin-4-yl, imidazol-2-yl, 1H-pyrazol-5-yl, 1H-imidazol-4-yl, imidazo[1,2-a]pyridin-7-yl, pyrrolidine -1-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-on-4-yl, piperazin-4-yl, piperazin-4-yl , piperazin-2-on-5-yl, pyridin-4-yl, pyridin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl base, 1H-pyrazol-5-yl, acridine-3-yl, -(CH 2 ) 2 -pyrrolidin-1-yl, -(CH 2 ) 2 -pyrrolidin-2-yl, -CH 2 - Imidazol-1-yl, -CH 2 -pyrazol-1-yl, -CH 2 -1,2,4-triazol-1-yl, -CH 2 -cyclopropyl, -O(CH 2 ) 2 NMe 2 , -O-tetrahydrofuran-3-yl, -O-tetrahydropyran-4-yl, -O-(N-Me-2-oxygen-pyrrolidin-3-yl), -O-(CH 2 ) 2 -pyrrolidin-2-yl, -O-CH 2 -piperidin-4-yl, -O-CH 2 -oxo-3-yl, -NCH 3 -piperidin-4-yl, -NH -Oxygen-3-yl, -NH-(N-Me-2-oxo-pyrrolidin-3-yl), decahydro-1,6-naphthyridin-6-yl, 2-azaspiro[ 3.3] Hept-6-yl, 5-oxa-2,8-diazaspiro[3.5]nonan-8-yl, 8-azabicyclo[3.2.1]oct-3-yl, 2-aza Bicyclo[2.2.2]oct-4-yl, 3-azabicyclo[3.2.0]heptan-6-yl, 3-azabicyclo[3.1.1]heptan-1-yl, 3-azabicyclo[ 3.1.0] Hex-6-yl, 1-azabicyclo[2.2.1]heptane- 4-yl, 3-azabicyclo[3.2.0]hept-6-yl, 2-azabicyclo[2.1.1]hex-4-yl, 2,9-diazaspiro[5.5]undecane -9-yl, bicyclo[1.1.1]pentan-2-yl, octahydrocyclopenta[c]pyrrol-5-yl, decahydro-1,6-naphthyridin-6-yl, octahydro-1H- Pyrrolo[3,4-c]pyridin-5-yl, decahydro-2,7-naphthyridin-2-yl, 2,9-diazaspiro[5.5]undecan-2-yl, -NHC (=O)Me, -NHCH 2 C(=O)NMe 2 , -NHCH(CH 3 )C(=O)NMe 2 , -C(=O)NH 2 , C(=O)NHMe, -OC( =O)Me, -SO2Me , -NHSO2Me , -SO2NH2 and -SO2NHMe , wherein each -OMe, -OEt , -Me, -Et , -Pr, -iPr, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, oxo-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3 -yl, piperidin-2-on-4-yl, piperazin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazole -2-yl, thiophen-2-yl, -CH2 -cyclopropyl, -CH2 -morpholin-4-yl, -( CH2 ) 2 -morpholin-4-yl, -morpholin-2- base, -(CH 2 ) 2 -pyrrolidin-1-yl, -CH 2 -1,2,4-triazol-1-yl, -CH 2 -imidazol-1-yl, imidazol-2-yl, - CH 2 -pyrazol-1-yl, -OCH 2 -piperidin-4-yl, acridine-3-yl, 2-azaspiro[3.3]hept-6-yl, 2-methyl-5-oxo Hetero-2,8-diazaspiro[3.5]nonan-8-yl, 8-azabicyclo[3.2.1]oct-3-yl and decahydro-1,6-naphthyridin-6-yl, wherein Each R 10 can be independently via -Me, -Et, -iPr , cyclopropyl, oxo- 3 -yl, -OH, =O, -F, -OMe, -CH2CH2F , -CH2 CHF 2 , -CH 2 CH 2 CF 3 , -C(=O)Me, -N(Me) 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , - 0, 1 of N( iPr )(Et), -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me or a combination thereof , 2, 3, 4 or 5 instance substitutions.

在一些實施例中，R10 為H。在一些實施例中，R10 為-D。In some embodiments, R 10 is H. In some embodiments, R 10 is -D.

在某些實施例中，R10 為鹵基(例如， 氟、氯、溴、碘)。在其他實施例中，R10 為-Cl。在一些實施例中，R10 為-F。在一些實施例中，R10 為-Br。在一些實施例中，R10 為-I。In certain embodiments, R 10 is halo ( eg, fluoro, chloro, bromo, iodo). In other embodiments, R 10 is -Cl. In some embodiments, R 10 is -F. In some embodiments, R 10 is -Br. In some embodiments, R 10 is -I.

在一些實施例中，R10 為-CN。In some embodiments, R 10 is -CN.

在某些實施例中，R10 為-C1 -C6 烷基。在其他實施例中，R10 為-Me。在一些實施例中，R10 為-Et。在一些實施例中，R10 為-Pr或- i Pr。在一些實施例中，R10 為- t Bu或-sec -Bu。在一些實施例中，R10 為-CH2 (CH3 )( i Pr)。In certain embodiments, R 10 is -C 1 -C 6 alkyl. In other embodiments, R 10 is -Me. In some embodiments, R 10 is -Et. In some embodiments, R 10 is -Pr or -i Pr. In some embodiments, R10 is -tBu or -sec -Bu. In some embodiments, R 10 is -CH 2 (CH 3 )( i Pr).

在一些實施例中，R10 為-C1 -C6 雜烷基。在其他實施例中，R10 為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，R10 為羥基甲基(-CH2 OH)。在一些實施例中，R10 為-CH(OH)CH3 、C(OH)(CH3)2 。在一些實施例中，R10 為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 NHCH2 CH3 、-CH2 N(CH3 )2 、-CH(CH3 )(NMe2 )、-CH2 CH2 N(Me)(氧呾-3-基)、-CH2 CH(CH3 )(NMe2 )。在一些實施例中，雜烷基進一步經=O取代(例如， -CH2 NHC(=O)CH3 )。在一些實施例中，R10 為-C1 -C6 鹵烷基。在其他實施例中，R10 為三氟甲基(-CF3 )。在其他實施例中，R10 為二氟甲基(-CHF2 )。在一些實施例中，R10 為三氟乙基(-CH2 CF3 )In some embodiments, R 10 is -C 1 -C 6 heteroalkyl. In other embodiments, R 10 is methoxymethyl (-CH 2 OCH 3 ). In some embodiments, R 10 is hydroxymethyl (-CH 2 OH). In some embodiments, R10 is -CH(OH) CH3 , C(OH)(CH3) 2 . In some embodiments, R 10 is aminomethyl ( eg, -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 NHCH 2 CH 3 , -CH 2 N(CH 3 ) 2 , -CH(CH 3 ) (NMe 2 ), -CH 2 CH 2 N(Me)(oxygen-3-yl), -CH 2 CH(CH 3 )(NMe 2 ). In some embodiments, the heteroalkyl group is further modified by = O-substituted ( eg, -CH2NHC(=O) CH3 ) . In some embodiments, R10 is -C1 - C6 haloalkyl. In other embodiments, R10 is trifluoromethyl ( -CF3 ). In other embodiments, R10 is difluoromethyl (-CHF2). In some embodiments, R10 is trifluoroethyl ( -CH2CF3 ) .

在一些實施例中，R10 為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，R10 為環丙基。在一些實施例中，R10 為環丁基。在一些實施例中，R10 為環戊基。在一些實施例中，R10 為環己基。在一些實施例中，碳環基經-OH取代(例如， 羥基環丁基)。In some embodiments, R 10 is -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 10 is cyclopropyl. In some embodiments, R 10 is cyclobutyl. In some embodiments, R 10 is cyclopentyl. In some embodiments, R 10 is cyclohexyl. In some embodiments, the carbocyclyl group is substituted with -OH ( eg, hydroxycyclobutyl).

在一些實施例中，R10 為3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基、哌啶-2-酮基、哌嗪-2-酮基、十氫-1,6-萘啶基、2-氮雜螺[3.3]庚基、5-氧雜-2,8-二氮雜螺[3.5]壬基、8-氮雜雙環[3.2.1]辛基、2-氮雜雙環[2.2.2]辛基、3-氮雜雙環[3.2.0]庚基、3-氮雜雙環[3.1.1]庚基、3-氮雜雙環[3.1.0]己基、2-氮雜雙環[2.1.1]己基、1-氮雜雙環[2.2.1]庚基、3-氮雜雙環[3.2.0]庚基、2,9-二氮雜螺[5.5]十一烷基、雙環[1.1.1]戊基、八氫環戊[c]吡咯基、十氫-1,6-萘啶基、八氫-1H-吡咯并[3,4-c]吡啶基、十氫-2,7-萘啶基、2,9-二氮雜螺[5.5]十一烷基)。In some embodiments, R 10 is a 3-10 membered heterocyclyl group ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholine base, azepanyl, piperidin-2-one, piperazin-2-one, decahydro-1,6-naphthyridinyl, 2-azaspiro[3.3]heptyl, 5-oxo Hetero-2,8-diazaspiro[3.5]nonyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2. 0]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 1-azabicyclo[2.2. 1]Heptyl, 3-azabicyclo[3.2.0]heptyl, 2,9-diazaspiro[5.5]undecyl, bicyclo[1.1.1]pentyl, octahydrocyclopenta[c] Pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, decahydro-2,7-naphthyridinyl, 2,9-diazaspiro [5.5]Undecyl).

在一些實施例中，R10 為氧呾基。在一些實施例中，R10 為四氫哌喃基。在一些實施例中，R10 為四氫呋喃基。在一些實施例中，R10 為吖呾基。在一些實施例中，R10 為吡咯啶基。在一些實施例中，R10 為哌啶基。在一些實施例中，R10 為哌嗪基。在一些實施例中，R10 為嗎啉基。在一些實施例中，R10 為氮雜環庚烷 基。在一些實施例中，R10 為哌啶酮基。In some embodiments, R 10 is oxo. In some embodiments, R 10 is tetrahydropyranyl. In some embodiments, R 10 is tetrahydrofuranyl. In some embodiments, R 10 is an acridine. In some embodiments, R 10 is pyrrolidinyl. In some embodiments, R 10 is piperidinyl. In some embodiments, R 10 is piperazinyl. In some embodiments, R 10 is morpholinyl. In some embodiments, R 10 is azepanyl. In some embodiments, R 10 is piperidonyl.

在一些實施例中，R10 為哌啶-2-酮基。在一些實施例中，R10 為哌嗪-2-酮基。在一些實施例中，R10 為十氫-1,6-萘啶基。在一些實施例中，R10 為2-氮雜螺[3.3]庚基。在一些實施例中，R10 為5-氧雜-2,8-二氮雜螺[3.5]壬基。在一些實施例中，R10 為8-氮雜雙環[3.2.1]辛基。在一些實施例中，R10 為2-氮雜雙環[2.2.2]辛基。在一些實施例中，R10 為3-氮雜雙環[3.2.0]庚基。在一些實施例中，R10 為3-氮雜雙環[3.1.1]庚基。在一些實施例中，R10 為3-氮雜雙環[3.1.0]己基。在一些實施例中，R10 為2-氮雜雙環[2.1.1]己基。在一些實施例中，R10 為1-氮雜雙環[2.2.1]庚基。在一些實施例中，R10 為3-氮雜雙環[3.2.0]庚基。在一些實施例中，R10 為2,9-二氮雜螺[5.5]十一烷基。在一些實施例中，R10 為雙環[1.1.1]戊基。在一些實施例中，R10 為八氫環戊[c]吡咯基。在一些實施例中，R10 為十氫-1,6-萘啶基。在一些實施例中，R10 為八氫-1H-吡咯并[3,4-c]吡啶基。在一些實施例中，R10 為十氫-2,7-萘啶基。在一些實施例中，R10 為2,9-二氮雜螺[5.5]十一烷基)。在一些實施例中，雜環基經-D、=O、-Me、-C(=O)Me或-C(=O)NHCH3 之0、1、2或3個實例取代。In some embodiments, R 10 is piperidin-2-one. In some embodiments, R 10 is piperazin-2-one. In some embodiments, R 10 is decahydro-1,6-naphthyridinyl. In some embodiments, R 10 is 2-azaspiro[3.3]heptyl. In some embodiments, R 10 is 5-oxa-2,8-diazaspiro[3.5]nonyl. In some embodiments, R 10 is 8-azabicyclo[3.2.1]octyl. In some embodiments, R 10 is 2-azabicyclo[2.2.2]octyl. In some embodiments, R 10 is 3-azabicyclo[3.2.0]heptyl. In some embodiments, R 10 is 3-azabicyclo[3.1.1]heptyl. In some embodiments, R 10 is 3-azabicyclo[3.1.0]hexyl. In some embodiments, R 10 is 2-azabicyclo[2.1.1]hexyl. In some embodiments, R 10 is 1-azabicyclo[2.2.1]heptyl. In some embodiments, R 10 is 3-azabicyclo[3.2.0]heptyl. In some embodiments, R 10 is 2,9-diazaspiro[5.5]undecyl. In some embodiments, R 10 is bicyclo[1.1.1]pentyl. In some embodiments, R 10 is octahydrocyclopenta[c]pyrrolyl. In some embodiments, R 10 is decahydro-1,6-naphthyridinyl. In some embodiments, R 10 is octahydro-lH-pyrrolo[3,4-c]pyridyl. In some embodiments, R 10 is decahydro-2,7-naphthyridinyl. In some embodiments, R 10 is 2,9-diazaspiro[5.5]undecyl). In some embodiments, heterocyclyl is substituted with 0, 1, 2, or 3 instances of -D, =O, -Me, -C(=O)Me, or -C(=O) NHCH3 .

在一些實施例中，R10 為5-10員雜芳基(例如， 含有1-3個獨立地選自N、O及S之雜原子之5-6員單環雜芳基或8-10員雙環雜芳基)。In some embodiments, R 10 is a 5-10 membered heteroaryl ( eg, a 5-6 membered monocyclic heteroaryl or 8-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S) membered bicyclic heteroaryl).

在一些實施例中，R10 為5-6員單環雜芳基(例如， 含有1-3個獨立地選自O、N及S之雜原子之5員單環雜芳基；含有1-3個N雜原子之6員單環雜芳基)。In some embodiments, R 10 is a 5-6 membered monocyclic heteroaryl ( eg, a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S; containing 1- 6-membered monocyclic heteroaryl with 3 N heteroatoms).

在一些實施例中，R10 為5員單環雜芳基(例如， 吡唑基、吡咯基、噻吩基、呋喃基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、三唑基、噻二唑基、噁二唑基)。In some embodiments, R 10 is a 5-membered monocyclic heteroaryl group ( eg, pyrazolyl, pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl , triazolyl, thiadiazolyl, oxadiazolyl).

在一些實施例中，R10 為噻吩基(例如， 噻吩-2-基、噻吩-3-基)。在一些實施例中，R10 為吡唑基(例如 吡唑-1-基、吡唑-3-基、吡唑-5-基)。在一些實施 例中，R10 為噻唑基(例如， 噻唑-2-基、噻唑-4-基、噻唑-5-基)。在一些實施例中，R10 為6員單環雜芳基(例如， 吡啶基、嘧啶基、三嗪基、吡嗪基、噠嗪基)。In some embodiments, R 10 is thienyl ( eg, thiophen-2-yl, thiophen-3-yl). In some embodiments, R 10 is pyrazolyl ( e.g. , pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, R 10 is thiazolyl ( eg, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, R 10 is a 6-membered monocyclic heteroaryl ( eg, pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl).

在一些實施例中，R10 為吡啶基(例如， 吡啶-2-基、吡啶-3-基、吡啶-4-基)。在一些實施例中，R10 為嘧啶基(例如， 嘧啶-2-基、嘧啶-4-基、嘧啶-5-基)。在一些實施例中，雜芳基經-Me之0、1或2個實例取代。In some embodiments, R 10 is pyridinyl ( eg, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, R 10 is pyrimidinyl ( eg, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl). In some embodiments, the heteroaryl group is substituted with 0, 1, or 2 instances of -Me.

在一些實施例中，R10 為單環雜環基。在一些實施例中，R10 為單環雜芳基。在一些實施例中，R10 為四氫呋喃-3-基。在一些實施例中，R10 為四氫哌喃-4-基。在一些實施例中，R10 為氧呾-3-基。在一些實施例中，R10 為嗎啉-2-基。在一些實施例中，R10 為-咪唑-2-基。在一些實施例中，R10 為1H-吡唑-5-基。在一些實施例中，R10 為1H-咪唑-4-基。在一些實施例中，R10 為咪唑并[1,2-a]吡啶-7-基。在一些實施例中，R10 為吡咯啶-1-基。在一些實施例中，R10 為吡咯啶-3-基。在一些實施例中，R10 為哌啶-4-基。在一些實施例中，R10 為哌啶-3-基。在一些實施例中，R10 為哌啶-2-酮-4-基。在一些實施例中，R10 為哌嗪-4-基。在一些實施例中，R10 為哌嗪-4-基。在一些實施例中，R10 為哌嗪-2-酮-5-基。在一些實施例中，R10 為吡啶-4-基。在一些實施例中，R10 為吡啶-3-基。在一些實施例中，R10 為吡唑-1-基。在一些實施例中，R10 為吡唑-3-基。在一些實施例中，R10 為吡唑-4-基。在一些實施例中，R10 為吡唑-5-基。在一些實施例中，R10 為1H-吡唑-5-基。在一些實施例中，R10 為吖呾-3-基。In some embodiments, R 10 is monocyclic heterocyclyl. In some embodiments, R 10 is monocyclic heteroaryl. In some embodiments, R 10 is tetrahydrofuran-3-yl. In some embodiments, R 10 is tetrahydropyran-4-yl. In some embodiments, R 10 is oxo-3-yl. In some embodiments, R 10 is morpholin-2-yl. In some embodiments, R 10 is -imidazol-2-yl. In some embodiments, R 10 is 1H-pyrazol-5-yl. In some embodiments, R 10 is 1H-imidazol-4-yl. In some embodiments, R 10 is imidazo[1,2-a]pyridin-7-yl. In some embodiments, R 10 is pyrrolidin-1-yl. In some embodiments, R 10 is pyrrolidin-3-yl. In some embodiments, R 10 is piperidin-4-yl. In some embodiments, R 10 is piperidin-3-yl. In some embodiments, R 10 is piperidin-2-on-4-yl. In some embodiments, R 10 is piperazin-4-yl. In some embodiments, R 10 is piperazin-4-yl. In some embodiments, R 10 is piperazin-2-on-5-yl. In some embodiments, R 10 is pyridin-4-yl. In some embodiments, R 10 is pyridin-3-yl. In some embodiments, R 10 is pyrazol-1-yl. In some embodiments, R 10 is pyrazol-3-yl. In some embodiments, R 10 is pyrazol-4-yl. In some embodiments, R 10 is pyrazol-5-yl. In some embodiments, R 10 is 1H-pyrazol-5-yl. In some embodiments, R 10 is acridine-3-yl.

在一些實施例中，R10 為雜環基烷氧基。在一些實施例中，R10 為-O(CH2 )2 NMe2 。在一些實施例中，R10 為-O-四氫呋喃-3-基。在一些實施例中，R10 為-O-四氫哌喃-4-基。在一些實施例中，R10 為-O-(N-Me-2-側氧基-吡咯啶-3-基)。在一些實施例中，R10 為-O-(CH2 )2 -吡咯啶-2-基。在一些實施例中，R10 為-O-CH2 -哌啶-4-基。在一些實施例中，R10 為-O-CH2 -氧呾-3-基。In some embodiments, R 10 is heterocyclylalkoxy. In some embodiments, R 10 is -O(CH 2 ) 2 NMe 2 . In some embodiments, R 10 is -O-tetrahydrofuran-3-yl. In some embodiments, R 10 is -O-tetrahydropyran-4-yl. In some embodiments, R 10 is -O-(N-Me-2-oxy-pyrrolidin-3-yl). In some embodiments, R 10 is -O-(CH 2 ) 2 -pyrrolidin-2-yl. In some embodiments, R 10 is -O-CH 2 -piperidin-4-yl. In some embodiments, R 10 is -O-CH 2 -oxo-3-yl.

在一些實施例中，R10 為單環雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。在一些實施例中，R10 為-CH2 -嗎啉-4-基。在一些實施例中，R10 為-(CH2 )2 -嗎啉-4-基。在一些實施例中，R10 為-(CH2 )2 -吡咯啶-1-基。在一些實施例中，R10 為-(CH2 )2 -吡咯啶-2-基。In some embodiments, R 10 is a monocyclic heterocyclylalkyl ( eg, oxanylmethyl, aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl) , piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl). In some embodiments, R 10 is -CH 2 -morpholin-4-yl. In some embodiments, R 10 is -(CH 2 ) 2 -morpholin-4-yl. In some embodiments, R 10 is -(CH 2 ) 2 -pyrrolidin-1-yl. In some embodiments, R 10 is -(CH 2 ) 2 -pyrrolidin-2-yl.

在一些實施例中，R10 為雙環3-10員雜環基。在一些實施例中，R10 為十氫-1,6-萘啶-6-基。在一些實施例中，R10 為2-氮雜螺[3.3]庚-6-基。在一些實施例中，R10 為5-氧雜-2,8-二氮雜螺[3.5]壬-8-基。在一些實施例中，R10 為8-氮雜雙環[3.2.1]辛-3-基。在一些實施例中，R10 為2-氮雜雙環[2.2.2]辛-4-基。在一些實施例中，R10 為3-氮雜雙環[3.2.0]庚-6-基。在一些實施例中，R10 為3-氮雜雙環[3.1.1]庚-1-基。在一些實施例中，R10 為3-氮雜雙環[3.1.0]己-6-基。在一些實施例中，R10 為1-氮雜雙環[2.2.1]庚-4-基。在一些實施例中，R10 為3-氮雜雙環[3.2.0]庚-6-基。在一些實施例中，R10 為2-氮雜雙環[2.1.1]己-4-基。在一些實施例中，R10 為2,9-二氮雜螺[5.5]十一烷-9-基。在一些實施例中，R10 為雙環[1.1.1]戊烷-2-基。在一些實施例中，R10 為八氫環戊[c]吡咯-5-基。在一些實施例中，R10 為十氫-1,6-萘啶-6-基。在一些實施例中，R10 為八氫-1H-吡咯并[3,4-c]吡啶-5-基。在一些實施例中，R10 為十氫-2,7-萘啶-2-基、2,9-二氮雜螺[5.5]十一烷-2-基。在一些實施例中，R10 為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，R10 為環丙基甲基。In some embodiments, R 10 is bicyclic 3-10 membered heterocyclyl. In some embodiments, R 10 is decahydro-1,6-naphthyridin-6-yl. In some embodiments, R 10 is 2-azaspiro[3.3]hept-6-yl. In some embodiments, R 10 is 5-oxa-2,8-diazaspiro[3.5]non-8-yl. In some embodiments, R 10 is 8-azabicyclo[3.2.1]oct-3-yl. In some embodiments, R 10 is 2-azabicyclo[2.2.2]oct-4-yl. In some embodiments, R 10 is 3-azabicyclo[3.2.0]heptan-6-yl. In some embodiments, R 10 is 3-azabicyclo[3.1.1]heptan-1-yl. In some embodiments, R 10 is 3-azabicyclo[3.1.0]hex-6-yl. In some embodiments, R 10 is 1-azabicyclo[2.2.1]heptan-4-yl. In some embodiments, R 10 is 3-azabicyclo[3.2.0]heptan-6-yl. In some embodiments, R 10 is 2-azabicyclo[2.1.1]hex-4-yl. In some embodiments, R 10 is 2,9-diazaspiro[5.5]undecan-9-yl. In some embodiments, R 10 is bicyclo[1.1.1]pentan-2-yl. In some embodiments, R 10 is octahydrocyclopenta[c]pyrrol-5-yl. In some embodiments, R 10 is decahydro-1,6-naphthyridin-6-yl. In some embodiments, R 10 is octahydro-lH-pyrrolo[3,4-c]pyridin-5-yl. In some embodiments, R 10 is decahydro-2,7-naphthyridin-2-yl, 2,9-diazaspiro[5.5]undecan-2-yl. In some embodiments, R 10 is cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, R 10 is cyclopropylmethyl.

在一些實施例中，R10 為芳基烷基。在一些實施例中，R10 為苯甲基。在一些實施例中，R10 為雜芳基烷基(例如， -CH2 -咪唑、-CH2 -吡唑、-CH2 -吡啶基)。在一些實施例中，R10 為吡啶基甲基(例如， 吡啶基-4-甲基)。在一些實施例中，R10 為-CH2 -1,2,4-三唑-1-基。在一些實施例中，R10 為-CH2 -咪唑-1-基。在一些實施例中，R10 為-CH2 -吡唑-1-基。In some embodiments, R 10 is arylalkyl. In some embodiments, R 10 is benzyl. In some embodiments, R10 is heteroarylalkyl ( eg, -CH2 -imidazole, -CH2 -pyrazole, -CH2 -pyridyl). In some embodiments, R 10 is pyridylmethyl ( eg, pyridyl-4-methyl). In some embodiments, R 10 is -CH 2 -1,2,4-triazol-1-yl. In some embodiments, R 10 is -CH 2 -imidazol-1-yl. In some embodiments, R 10 is -CH 2 -pyrazol-1-yl.

在一些實施例中，R10 為-ORb10 (例如， 羥基(-OH)、甲氧基、二氟甲氧基(-OCHF2 )、三氟甲氧基(-OCF3 )、乙氧基、丙氧基、異丙氧基、環丙基氧基、環丁基氧基)。在一些實施例中，R10 為羥基。在一些實施例中，R10 為甲氧基。在一些實施例中，R10 為乙氧基。在一些實施例中，R10 為丙氧基。在一些實施例中，R10 為異丙氧基。在一些實施例中，R10 為二氟甲氧基(-OCHF2 )。在一些實施例中，R10 為三氟甲氧基(-OCF3 )。In some embodiments, R 10 is -OR b10 ( eg, hydroxy (-OH), methoxy, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy , propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, R 10 is hydroxyl. In some embodiments, R 10 is methoxy. In some embodiments, R 10 is ethoxy. In some embodiments, R 10 is propoxy. In some embodiments, R 10 is isopropoxy. In some embodiments, R 10 is difluoromethoxy (-OCHF 2 ). In some embodiments, R 10 is trifluoromethoxy (-OCF 3 ).

在一些實施例中，R10 為-N(Rb10 )2 (例如， -NH2 、-NHRb10 、-N(CH3 )Rb10 )。在一些實施例中，R10 為-NH2 。在一些實施例中，R10 為-NHRb10 (例如， -NHMe、-NHEt、-NHPr、-NHCH2 CF3 、-NH i Pr、-NH環丙基、-NH環丁基)。在一些實施例中，R10 為NHCH2 CF3 。在一些實施例中，R10 為-N(CH3 )Rb10 (例如， -NMe2 、-N(CH3 )Et、-N(CH3 )Pr、-N(CH3 ) i Pr、-N(CH3 )環丙基、-N(CH3 )環丁基)。在一些實施例中，R10 為-C(=O)Rb10 或-C(=O)ORb10 。在一些實施例中，R10 為-C(=O)Rb10 ，其中Rb10 如本文所述。在一些實施例中，R10 為-C(=O)烷基。在一些實施例中，R10 為-C(O)CH3 、-C(O)環丙基、-C(O)環丁基、-C(O) t Bu、-C(O) i Pr、-C(O)Pr、-C(O) i Bu或-C(=O)OMe。在一些實施例中，R10 為乙醯基(-C(=O)Me)。在一些實施例中，R10 為-C(=O)ORb10 。在一些實施例中，R10 為-COOH。在一些實施例中，R10 為COOMe。In some embodiments, R 10 is -N(R b10 ) 2 ( eg, -NH 2 , -NHR b10 , -N(CH 3 )R b10 ). In some embodiments, R 10 is -NH 2 . In some embodiments, R10 is -NHRb10 ( eg, -NHMe, -NHEt , -NHPr, -NHCH2CF3 , -NHiPr , -NHcyclopropyl , -NHcyclobutyl). In some embodiments, R 10 is NHCH 2 CF 3 . In some embodiments, R10 is -N( CH3 ) Rb10 ( eg, -NMe2 , -N( CH3 )Et, -N( CH3 )Pr, -N( CH3 ) iPr , - N( CH3 )cyclopropyl, -N( CH3 )cyclobutyl). In some embodiments, R 10 is -C(=O)R b10 or -C(=O)OR b10 . In some embodiments, R 10 is -C(=O)R b10 , wherein R b10 is as described herein. In some embodiments, R 10 is -C(=O)alkyl. In some embodiments, R10 is -C(O) CH3 , -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O) tBu , -C(O) iPr , -C(O)Pr, -C(O) iBu or -C(=O)OMe. In some embodiments, R 10 is acetyl (-C(=O)Me). In some embodiments, R 10 is -C(=0)OR b10 . In some embodiments, R 10 is -COOH. In some embodiments, R 10 is COOMe.

在一些實施例中，R10 為-NRb10 C(=O)Rb10 。在某些實施例中，R10 為-NHC(=O)Rb10 (例如， -NHC(=O)Me、-NHC(=O)Et、-NHC(=O)Pr、-NHC(=O)i Pr、-NHC(=O)Bu、-NHC(=O)t Bu、-NHC(=O)環丙基、-NHC(=O)環丁基)。在一些實施例中，R10 為-NHC(=O)Me。在一些實施例中，R10 為-N(CH3 )C(=O)Rb10 (例如， N(CH3 )C(=O)Me、N(CH3 )C(=O)Et、N(CH3 )C(=O)Pr、N(CH3 )C(=O)i Pr、N(CH3 )C(=O)Bu、N(CH3 )C(=O)t Bu、N(CH3 )C(=O)環丙基、N(CH3 )C(=O)環丁基)。In some embodiments, R 10 is -NR b10 C(=0)R b10 . In certain embodiments, R 10 is -NHC(=O)R b10 ( eg, -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Pr, -NHC(=O) ) i Pr, -NHC(=O)Bu, -NHC(=O) tBu , -NHC(=O)cyclopropyl, -NHC(=O)cyclobutyl). In some embodiments, R 10 is -NHC(=O)Me. In some embodiments, R 10 is -N(CH 3 )C(=O)R b10 ( eg, N(CH 3 )C(=O)Me, N(CH 3 )C(=O)Et, N (CH 3 )C(=O)Pr, N(CH 3 )C(=O) i Pr, N(CH 3 )C(=O)Bu, N(CH 3 )C(=O) t Bu, N ( CH3 )C(=O)cyclopropyl, N( CH3 )C(=O)cyclobutyl).

在一些實施例中，R10 為-NRb10 C(=O)ORb10 。在某些實施例中，R10 為 -NHC(=O)ORb10 (例如， NHC(=O)OMe、NHC(=O)OEt、NHC(=O)OPr、NHC(=O)Oi Pr、NHC(=O)OBu、NHC(=O)Ot Bu、NHC(=O)O環丙基、NHC(=O)O環丁基)。在一些實施例中，R10 為-N(CH3 )C(=O)ORb10 (例如， N(CH3 )C(=O)OMe、N(CH3 )C(=O)OEt、N(CH3 )C(=O)OPr、N(CH3 )C(=O)Oi Pr、N(CH3 )C(=O)OBu、N(CH3 )C(=O)Ot Bu、N(CH3 )C(=O)O環丙基、N(CH3 )C(=O)O環丁基)。In some embodiments, R 10 is -NR b10 C(=0)OR b10 . In certain embodiments, R 10 is -NHC(=O)OR b10 ( eg, NHC(=O)OMe, NHC(=O)OEt, NHC(=O)OPr, NHC(=O)O i Pr , NHC(=O)OBu, NHC(=O)O t Bu, NHC(=O)O cyclopropyl, NHC(=O)O cyclobutyl). In some embodiments, R 10 is -N(CH 3 )C(=O)OR b10 ( eg, N(CH 3 )C(=O)OMe, N(CH 3 )C(=O)OEt, N (CH 3 )C(=O)OPr, N(CH 3 )C(=O)O i Pr, N(CH 3 )C(=O)OBu, N(CH 3 )C(=O)O t Bu , N(CH 3 )C(=O)O cyclopropyl, N(CH 3 )C(=O)O cyclobutyl).

在一些實施例中，R10 為-C(=O)N(Rb10 )2 (例如， -C(=O)NH2 、-C(=O)NHRb10 、-C(=O)N(CH3 )Rb10 )。在一些實施例中，R10 為-C(=O)NH2 。在某些實施例中，R10 為-C(=O)NHRb10 (例如， -C(=O)NHMe、-C(=O)NHEt、-C(=O)NHPr、-C(=O)NH i Pr、-C(=O)NHBu、-C(=O)NH t Bu、-C(=O)NH環丙基、-C(=O)NH環丁基)。在一些實施例中，R10 為-C(=O)NHMe。在某些實施例中，R10 為-C(=O)N(CH3 )Rb10 (例如， -C(=O)NMe2 、-C(=O)N(CH3 )Et、-C(=O)N(CH3 )Pr、-C(=O)N(CH3 ) i Pr、-C(=O)N(CH3 )Bu、-C(=O)N(CH3 ) t Bu、-C(=O)N(CH3 )環丙基、-C(=O)N(CH3 )環丁基)。In some embodiments, R 10 is -C(=O)N(R b10 ) 2 ( eg, -C(=O)NH 2 , -C(=O)NHR b10 , -C(=O)N( CH 3 )R b10 ). In some embodiments, R 10 is -C(=O)NH 2 . In certain embodiments, R 10 is -C(=O)NHR b10 ( eg, -C(=O)NHMe, -C(=O)NHEt, -C(=O)NHPr, -C(=O ) NHiPr , -C(=O)NHBu, -C(=O) NHtBu , -C(=O)NH cyclopropyl, -C(=O)NH cyclobutyl). In some embodiments, R 10 is -C(=0)NHMe. In certain embodiments, R 10 is -C(=O)N(CH 3 )R b10 ( eg, -C(=O)NMe 2 , -C(=O)N(CH 3 )Et, -C (=O)N(CH 3 )Pr, -C(=O)N(CH 3 ) i Pr, -C(=O)N(CH 3 )Bu, -C(=O)N(CH 3 ) t Bu, -C(=O)N( CH3 )cyclopropyl, -C(=O)N( CH3 )cyclobutyl).

在一些實施例中，R10 為-OC(=O)N(Rb10 )2 。在某些實施例中，R10 為-OC(=O)NHRb10 (例如， -OC(=O)NHMe、-OC(=O)NHEt、-OC(=O)NHPr、-OC(=O)NH i Pr、-OC(=O)NHBu、-OC(=O)NH t Bu、-OC(=O)NH環丙基、-OC(=O)NH環丁基)。在某些實施例中，R10 為-OC(=O)N(CH3 )Rb10 (例如， -OC(=O)NMe2 、-OC(=O)N(CH3 )Et、-OC(=O)N(CH3 )Pr、-OC(=O)N(CH3 ) i Pr、-OC(=O)N(CH3 )Bu、-OC(=O)N(CH3 ) t Bu、-OC(=O)N(CH3 )環丙基、-OC(=O)N(CH3 )環丁基)。In some embodiments, R 10 is -OC(=O)N(R b10 ) 2 . In certain embodiments, R 10 is -OC(=O)NHR b10 ( eg, -OC(=O)NHMe, -OC(=O)NHEt, -OC(=O)NHPr, -OC(=O ) NHiPr , -OC(=O)NHBu, -OC(=O) NHtBu , -OC(=O)NH cyclopropyl, -OC(=O)NH cyclobutyl). In certain embodiments, R 10 is -OC(=O)N(CH 3 )R b10 ( eg, -OC(=O)NMe 2 , -OC(=O)N(CH 3 )Et, -OC (=O)N(CH 3 )Pr, -OC(=O)N(CH 3 ) i Pr, -OC(=O)N(CH 3 )Bu, -OC(=O)N(CH 3 ) t Bu, -OC(=O)N( CH3 )cyclopropyl, -OC(=O)N( CH3 )cyclobutyl).

在一些實施例中，R10 為-OC(=O)Rb10 (例如， -OC(=O)Me、-OC(=O)Et、-OC(=O)Pr、-OC(=O)Pr、-OC(=O)Bu、-OC(=O)Bu、-OC(=O)環丙基、-OC(=O)環丁基)。在一些實施例中，R10 為-OC(=O)Me。In some embodiments, R 10 is -OC(=O)R b10 ( eg, -OC(=O)Me, -OC(=O)Et, -OC(=O)Pr, -OC(=O) Pr, -OC(=O)Bu, -OC(=O)Bu, -OC(=O)cyclopropyl, -OC(=O)cyclobutyl). In some embodiments, R 10 is -OC(=O)Me.

在一些實施例中，R10 為-S(=O)Rb10 。在某些實施例中，R10 為-S(=O)烷基(例如， -S(=O)Me、-S(=O)Et、-S(=O)Pr、-S(=O) i Pr)。在一些實施例中，R10 為-S(=O)Me。在某些實施例中，R10 為-S(=O)環烷基(例如， -S(=O)環丙基、-S(=O)環丁基、-S(=O)環戊基、-S(=O)環己基)。In some embodiments, R 10 is -S(=0)R b10 . In certain embodiments, R 10 is -S(=O)alkyl ( eg, -S(=O)Me, -S(=O)Et, -S(=O)Pr, -S(=O) ) i Pr). In some embodiments, R 10 is -S(=O)Me. In certain embodiments, R 10 is -S(=O)cycloalkyl ( eg, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentan base, -S (=O) cyclohexyl).

在一些實施例中，R10 為-S(=O)2 Rb10 。在某些實施例中，R10 為-S(=O)2 烷基(例如， -S(=O)2 Me、-S(=O)2 Et、-S(=O)2 Pr、-S(=O)2 i Pr)。在一些實施例中，R10 為-S(=O)2 Me。在某些實施例中，R10 為-S(=O)2 環烷基(例如， -S(=O)2 環丙基、-S(=O)2 環丁基、-S(=O)2 環戊基、-S(=O)2 環己基)。在一些實施例中，R10 為S(=O)2 芳基(例如， S(=O)2 苯基)。In some embodiments, R 10 is -S(=0) 2 R b10 . In certain embodiments, R 10 is -S(=O ) 2alkyl ( eg, -S(=O)2Me, -S(=O) 2Et , -S(=O) 2Pr , - S(=O) 2 i Pr). In some embodiments, R 10 is -S(=0) 2 Me. In certain embodiments, R 10 is -S(=0) 2cycloalkyl ( eg, -S(=0) 2cyclopropyl , -S(=0) 2cyclobutyl , -S(=0 ) 2 cyclopentyl, -S(=O) 2 cyclohexyl). In some embodiments, R 10 is S(=O) 2 aryl ( eg, S(=O) 2 phenyl).

在一些實施例中，R10 為-SRb10 。在某些實施例中，R10 為-S烷基(例如， -SMe、-SEt、-SPr、-S i Pr)。在某些實施例中，R10 為-S環烷基(例如， -S環丙基、-S環丁基、-S環戊基、-S環己基)。在某些實施例中，R10 為-S芳基(例如， S苯基)。In some embodiments, R 10 is -SR b10 . In certain embodiments, R 10 is -S alkyl ( eg, -SMe, -SEt, -SPr , -SiPr). In certain embodiments, R 10 is -S cycloalkyl ( eg, -S cyclopropyl, -S cyclobutyl, -S cyclopentyl, -S cyclohexyl). In certain embodiments, R 10 is -S aryl ( eg, S phenyl).

在一些實施例中，R10 為-S(=O)(=NRb10 )Rb10 。在某些實施例中，R10 為-S(=O)(=NH)Rb10 (例如， -S(=O)(=NH)Me、-S(=O)(=NH)Et、-S(=O)(=NH)Pr、-S(=O)(=NH)i Pr、-S(=O)(=NH)Bu、-S(=O)(=NH)t Bu、-S(=O)(=NH)環丙基、-S(=O)(=NH)環丁基)。在一些實施例中，R10 為-S(=O)(=NCH3 )Rb10 (例如， -S(=O)(=NCH3 )Me、-S(=O)(=NCH3 )Et、-S(=O)(=NCH3 )Pr、-S(=O)(=NCH3 )i Pr、-S(=O)(=NCH3 )Bu、-S(=O)(=NCH3 )t Bu、-S(=O)(=NCH3 )環丙基、-S(=O)(=NCH3 )環丁基)。In some embodiments, R 10 is -S(=0)(=NR b10 )R b10 . In certain embodiments, R 10 is -S(=O)(=NH)R b10 ( eg, -S(=O)(=NH)Me, -S(=O)(=NH)Et, - S(=O)(=NH)Pr, -S(=O)(=NH) i Pr, -S(=O)(=NH)Bu, -S(=O)(=NH) t Bu, - S(=O)(=NH) cyclopropyl, -S(=O)(=NH) cyclobutyl). In some embodiments, R 10 is -S(=O)(=NCH 3 )R b10 ( eg, -S(=O)(=NCH 3 )Me, -S(=O)(=NCH 3 )Et , -S(=O)(=NCH 3 )Pr, -S(=O)(=NCH 3 ) i Pr, -S(=O)(=NCH 3 )Bu, -S(=O)(=NCH 3 ) tBu , -S(=O)(= NCH3 )cyclopropyl, -S(=O)(= NCH3 )cyclobutyl).

在一些實施例中，R10 為-NRb10 S(=O)2 Rb10 。在某些實施例中，R10 為-NHS(=O)2 烷基(例如， -NHS(=O)2 Me、-NHS(=O)2 Et、-NHS(=O)2 Pr、-NHS(=O)2 i Pr)。在某些實施例中，R10 為-NHS(=O)2 環烷基(例如， -NHS(=O)2 環丙基、-NHS(=O)2 環丁基、-NHS(=O)2 環戊基、-NHS(=O)2 環己基)。在某些實施例中，R10 為-N(CH3 )S(=O)2 烷基(例如， -N(CH3 )S(=O)2 Me、-N(CH3 )S(=O)2 Et、-N(CH3 )S(=O)2 Pr、-N(CH3 )S(=O)2 i Pr)。在某些實施例中，R10 為-N(CH3 )S(=O)2 環烷基(例如， -N(CH3 )S(=O)2 環丙基、-N(CH3 )S(=O)2 環丁基、-N(CH3 )S(=O)2 環戊 基、-N(CH3 )S(=O)2 環己基)。In some embodiments, R 10 is -NR b10 S(=0) 2 R b10 . In certain embodiments, R 10 is -NHS(=0) 2 alkyl ( eg, -NHS(=0)2Me, -NHS(= 0 ) 2Et , -NHS(=0)2Pr, -NHS(=0) 2 NHS(=O) 2 i Pr). In certain embodiments, R 10 is -NHS(=0) 2cycloalkyl ( eg, -NHS(=0) 2cyclopropyl , -NHS(=0) 2cyclobutyl , -NHS(=0)2cyclobutyl ) 2 cyclopentyl, -NHS(=O) 2 cyclohexyl). In certain embodiments, R 10 is -N(CH 3 )S(=O) 2 alkyl ( eg, -N(CH 3 )S(=O) 2 Me, -N(CH 3 )S(= O) 2 Et, -N(CH 3 )S(=O) 2 Pr, -N(CH 3 )S(=O) 2 i Pr). In certain embodiments, R10 is -N( CH3 )S(=O) 2cycloalkyl ( eg, -N( CH3 )S(=O) 2cyclopropyl , -N( CH3 ) S(=O) 2 cyclobutyl, -N(CH 3 )S(=O) 2 cyclopentyl, -N(CH 3 )S(=O) 2 cyclohexyl).

在一些實施例中，R10 為-S(=O)2 N(Rb10 )2 (例如， -S(=O)2 NH2 、-S(=O)2 NHRb10 、-S(=O)2 N(CH3 )Rb10 )。在一些實施例中，R10 為-S(=O)2 NH2 。在一些實施例中，R10 為-S(=O)2 NHRb10 (例如， -S(=O)2 NHMe、-S(=O)2 NHEt、-S(=O)2 NHPr、-S(=O)2 NH i Pr、-S(=O)2 NH環丙基、-S(=O)2 NH環丁基)。在一些實施例中，R10 為-S(=O)2 N(CH3 )Rb10 (例如， -S(=O)2 NMe2 、-S(=O)2 N(CH3 )Et、-S(=O)2 N(CH3 )Pr、-S(=O)2 N(CH3 ) i Pr、-S(=O)2 N(CH3 )環丙基、-S(=O)2 N(CH3 )環丁基)。In some embodiments, R 10 is -S(=O) 2 N(R b10 ) 2 ( eg, -S(=O) 2 NH 2 , -S(=O) 2 NHR b10 , -S(=O ) 2 N(CH 3 )R b10 ). In some embodiments, R 10 is -S(=O) 2 NH 2 . In some embodiments, R10 is -S(=0) 2NHR b10 ( eg, -S(= 0 ) 2NHMe , -S(=0) 2NHEt , -S(=0) 2NHPr , -S (=O) 2 NH i Pr, -S(=O) 2 NH cyclopropyl, -S(=O) 2 NH cyclobutyl). In some embodiments, R 10 is -S(=O) 2 N(CH 3 )R b10 ( eg, -S(=O) 2 NMe 2 , -S(=O) 2 N(CH 3 )Et, -S(=O) 2 N(CH 3 )Pr, -S(=O) 2 N(CH 3 ) i Pr, -S(=O) 2 N(CH 3 )cyclopropyl, -S(=O ) 2 N(CH 3 )cyclobutyl).

如本文通常所定義，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地選自H、C1 -C6 烷基、-C1 -C6 雜烷基、C3 -C9 環烷基、3-7員雜環基、環烷基烷基、雜環基烷基、芳基、5-6員雜芳基、芳基烷基及雜芳基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代(例如， 經R9 之0、1、2或3個實例取代，其中各R9 獨立地選自=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、-ORb 、-N(Rb )2 、-C(=O)Rb 、-C(=O)ORb 、-NRb C(=O)Rb 、-NRb C(=O)ORb 、-C(=O)N(Rb )2 、-OC(=O)N(Rb )2 、-S(=O)Rb 、-S(=O)2 Rb 、-SRb 、-S(=O)(=NRb )Rb 、-NRb S(=O)2 Rb 及-S(=O)2 N(Rb )2 ，其中各Rb 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)。As generally defined herein, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 and R a8 is independently selected from H, C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl , C 3 -C 9 cycloalkyl, 3-7 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkane wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally in any of the available positions Substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R, wherein each R is independently selected from =O, halo, -CN, -Ci - C6alkyl , -Ci- C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, Cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O) OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b and -S(=O)2N( Rb )2 , wherein each Rb is independently selected from H, -C1 - C6 alkyl ( eg, -Me, -Et , -Pr, -iPr, -n Bu, -tBu , -sec -Bu, -iso -Bu) and C3 - C9 cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地未經取代。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地經R9 之1個實例取代。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地經R9 之2個實例取代。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地 經R9 之3個實例取代。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently unsubstituted. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently substituted with 1 instance of R 9 . In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently substituted with 2 instances of R 9 . In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently substituted with 3 instances of R 9 .

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及-C1 -C6 鹵烷基(例如， -CHF2 、-CF3 )。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr , -iPr , -nBu , -tBu, -sec - Bu, -iso-Bu) and -C1 - C6 haloalkyl ( eg, -CHF2, -CF3 ). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr, -i Pr, -n Bu, -t Bu, -sec -Bu, -iso -Bu).

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為H。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為-Me。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為-Et。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為-Pr或- i Pr。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently H. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr, -i Pr, -n Bu, -t Bu, -sec -Bu, -iso -Bu). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently -Me. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently -Et. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently -Pr or -iPr .

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為-C1 -C6 雜烷基。在其他實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為甲氧基甲基(-CH2 OCH3 )。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為羥基甲基(-CH2 OH)。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為胺基甲基(例如， -CH2 NH2 、-CH2 NHCH3 、-CH2 N(CH3 )2 )。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently -C 1 -C 6 heteroalkyl. In other embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 and R a8 is independently methoxymethyl (-CH 2 OCH 3 ). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently hydroxymethyl (-CH 2 OH). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently aminomethyl ( eg, -CH 2 NH 2 , -CH 2 NHCH 3 , - CH 2 N(CH 3 ) 2 ).

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為-C1 -C6 鹵烷基。在其他實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為三氟甲基(-CF3 )。在其他實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為二氟甲基(-CHF2 )。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently -C 1 -C 6 haloalkyl. In other embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 and R a8 is independently trifluoromethyl (-CF 3 ). In other embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently difluoromethyl (-CHF 2 ).

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為-C3 -C9 碳環基(例如， 環丙基、環丁基、環戊基、環己基)。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為環丙基。在一些實施例中，各Ra1 、Ra2 、 Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為環丁基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為環戊基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為環己基。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently a -C 3 -C 9 carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently cyclopropyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently cyclobutyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently cyclopentyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently cyclohexyl.

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為氧呾基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為四氫哌喃基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為四氫呋喃基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為吖呾基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為吡咯啶基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為哌啶基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為哌嗪基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為嗎啉基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為氮雜環庚烷基。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently a 3-10 membered heterocyclyl ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acridine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently an oxo group. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently tetrahydropyranyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently tetrahydrofuranyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently an acridine. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently pyrrolidinyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently piperidinyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently piperazinyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently morpholinyl. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently an azepanyl group.

在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為雜芳基。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為5-10員雜芳基(例如， 含有1-3個獨立地選自N、O及S之雜原子之5-6員單環雜芳基或8-10員雙環雜芳基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為5-6員單環雜芳基(例如， 含有1-3個獨立地選自O、N及S之雜原子之5員單環雜芳基；含有1-3個N雜原子之6員單環雜芳基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為5員單環雜芳基(例如， 吡唑基、吡咯基、噻吩基、呋喃基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、三唑基、噻二唑基、噁二唑基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為噻吩基(例如， 噻 吩-2-基、噻吩-3-基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為吡唑基(例如 吡唑-1-基、吡唑-3-基、吡唑-5-基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為噻唑基(例如， 噻唑-2-基、噻唑-4-基、噻唑-5-基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為6員單環雜芳基(例如， 吡啶基、嘧啶基、三嗪基、吡嗪基、噠嗪基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為吡啶基(例如， 吡啶-2-基、吡啶-3-基、吡啶-4-基)。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為嘧啶基(例如， 嘧啶-2-基、嘧啶-4-基、嘧啶-5-基)。In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently heteroaryl. In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently 5-10 membered heteroaryl groups ( eg, contain 1-3 members independently selected from N, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl of the heteroatoms of O and S). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently 5-6 membered monocyclic heteroaryl groups ( eg, containing 1-3 groups independently selected from 5-membered monocyclic heteroaryl with heteroatoms of O, N and S; 6-membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently 5-membered monocyclic heteroaryl ( eg, pyrazolyl, pyrrolyl, thienyl, furan base, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently thienyl ( eg, thien-2-yl, thien-3-yl). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently pyrazolyl ( eg , pyrazol-1-yl, pyrazol-3-yl, pyrazole -5-base). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently thiazolyl ( eg, thiazol-2-yl, thiazol-4-yl, thiazol-5- base). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently 6-membered monocyclic heteroaryl ( eg, pyridyl, pyrimidinyl, triazinyl, pyridine azinyl, pyridazinyl). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently pyridyl ( eg, pyridin-2-yl, pyridin-3-yl, pyridin-4- base). In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently pyrimidinyl ( eg, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidine-5- base).

在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為芳基。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為6-10員單環或雙環芳基。在一些實施例中，Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為苯基。在一些實施例中，苯基經如本文所定義之R9 之0、1、2或3個實例取代。In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently aryl. In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently 6-10 membered monocyclic or bicyclic aryl groups. In some embodiments, R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 are independently phenyl. In some embodiments, phenyl is substituted with 0, 1, 2, or 3 instances of R 9 as defined herein.

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為芳基烷基。在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為苯甲基。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl) cyclohexylmethyl, cyclohexylmethyl, cycloheptylmethyl). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently heterocyclylalkyl ( eg, oxanylmethyl, aziridinylmethyl) , tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl). In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently an arylalkyl group. In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently benzyl.

在一些實施例中，各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地為雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)。In some embodiments, each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 , and R a8 is independently heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazole ylmethyl, pyrazolylmethyl).

如本文通常所定義，各R9 獨立地選自=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、-ORb 、-N(Rb )2 、 -C(=O)Rb 、-C(=O)ORb 、-NRb C(=O)Rb 、-NRb C(=O)ORb 、-C(=O)N(Rb )2 、-OC(=O)N(Rb )2 、-S(=O)Rb 、-S(=O)2 Rb 、-SRb 、-S(=O)(=NRb )Rb 、-NRb S(=O)2 Rb 及-S(=O)2 N(Rb )2 ，其中各Rb 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr 、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)。As generally defined herein, each R 9 is independently selected from =O, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl , -C 3 -C 9 cycloalkyl, 3-10-membered heterocyclyl, C 6 -C 10 -membered aryl, 5-10-membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkane base, heteroarylalkyl, -OR b , -N(R b ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , - NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O)R b , -S(=O ) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b and -S(=O) 2 N(R b ) 2 , where Each R b is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu, -sec - Bu, -iso- Bu) and C3 - C9cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

在一些實施例中，各R9 獨立地選自=O、鹵基、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-C1 -C6 鹵烷基(例如， -CF3、-CHF2)、-C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)、3-10員雜環基(例如， 氧呾基、四氫哌喃基、四氫呋喃基、吖呾基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氮雜環庚烷基)、C6 -C10 芳基(例如， 苯基)、5-10員雜芳基(例如， 吡唑基、吡咯基、噻吩基、呋喃基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、三唑基、噻二唑基、噁二唑基)、環烷基烷基(例如， 環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基)、雜環基烷基(例如， 氧呾基甲基、氮丙啶基甲基、四氫呋喃基甲基、吡咯啶基甲基、四氫哌喃基甲基、哌啶基甲基、哌嗪基甲基、嗎啉基甲基、氮雜環庚烷基甲基)、芳基烷基(例如， 苯甲基)、雜芳基烷基(例如， 吡啶基甲基、噻唑基甲基、三唑基甲基、吡唑基甲基)、-ORb 、-N(Rb )2 、-C(=O)Rb 、-C(=O)ORb 、-NRb C(=O)Rb 、-NRb C(=O)ORb 、-C(=O)N(Rb )2 、-OC(=O)N(Rb )2 、-S(=O)Rb 、-S(=O)2 Rb 、-SRb 、-S(=O)(=NRb )Rb 、-NRb S(=O)2 Rb 及-S(=O)2 N(Rb )2 ，其中各Rb 如本文所定義。在其他實施例中，各Rb 為H或-Me。In some embodiments, each R 9 is independently selected from =O, halo, -CN, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu, -tBu , -sec -Bu, -iso -Bu), -C1 - C6 haloalkyl ( eg, -CF3, -CHF2), -C3 - C9 cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-10 membered heterocyclyl ( eg, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, acryl, pyrrolidinyl, piperidinyl, piperazinyl , morpholinyl, azepanyl), C 6 -C 10 aryl ( eg, phenyl), 5-10 membered heteroaryl ( eg, pyrazolyl, pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl), cycloalkylalkyl ( eg, cyclopropylmethyl, cyclobutylmethyl) cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl), heterocyclylalkyl ( e.g., oxanylmethyl, aziridinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl) group, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl), arylalkyl ( eg, benzyl), Heteroarylalkyl ( eg, pyridylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl), -ORb, -N(Rb ) 2 , -C(=O)R b , -C(=O)OR b , -NR b C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(= O)N(R b ) 2 , -S(=O)R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S (=O) 2 R b and -S(=O) 2 N(R b ) 2 , wherein each R b is as defined herein. In other embodiments, each R b is H or -Me.

在一個實施例中，本發明提供一種選自表1之化合物的化合物或其醫藥學上可接受之鹽。In one embodiment, the present invention provides a compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

本文所述之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物；或表1之化合物；或其醫藥學上可接受之鹽)可用作PRMT5之抑制劑(例如， MTA無競 爭性PRMT5抑制劑)。Compounds described herein ( eg, compounds of formula (I), (Ia), (Ib), (Ic), and (Id); or compounds of Table 1; or pharmaceutically acceptable salts thereof) can be used as PRMT5 ( eg, MTA uncompetitive PRMT5 inhibitor).

表1指示分別在存在SAM作為輔助因子之情況下、在無輔助因子之情況下及在MTA作為輔助因子之情況下示範性化合物針對PRMT5之IC50 值(μM)(第4-6列)。對於表1，「a」、「aa」及「aaa」分別指示在檢定中在SAM、無輔助因子及MTA之情況下小於50nM之IC50 ；「b」、「bb」及「bbb」分別指示在檢定中在SAM、無輔助因子及MTA之情況下50nM至小於500nM之IC50 ；「c」、「cc」及「ccc」分別指示在檢定中在SAM、無輔助因子及MTA之情況下大於或等於500nM之IC50 。Ki值可如實例部分所述由IC50 值計算。如實例部分詳述的，對於在存在SAM之情況下進行之檢定，IC 50 =Ki ×1.5(Ki=IC50 /1.5)。對於在存在MTA之情況下進行之檢定，IC 50 =Ki ×13.5(Ki=IC50 /13.5)。Table 1 indicates the IC50 values (μM) of exemplary compounds against PRMT5 in the presence of SAM as a cofactor, in the absence of a cofactor, and in the presence of MTA as a cofactor, respectively (columns 4-6). For Table 1, "a", "aa" and "aaa" indicate an IC50 of less than 50 nM in the assay with SAM, no cofactor and MTA, respectively; "b", "bb" and "bbb", respectively IC50 of 50 nM to less than 500 nM in the presence of SAM, no cofactor and MTA in the assay; "c", "cc" and "ccc" indicate greater than in the assay with SAM, no cofactor and MTA, respectively or equal to an IC50 of 500nM. Ki values can be calculated from IC50 values as described in the Examples section. As detailed in the Examples section, for assays performed in the presence of SAM, IC50 = Ki x 1.5 (Ki= IC50 / 1.5 ). For assays performed in the presence of MTA, IC50 = Ki x 13.5 (Ki= IC50 / 13.5).

表1亦指示在SDMA細胞內西方檢定中示範性化合物在MTAP同基因型細胞株對中之IC50 值(第7-8列)。HAP1 MTAP完整為表現內源性水準之MTAP的細胞株，且HAP1 MTAP缺失為MTAP無效細胞株。對於表1，在HAP1 MTAP完整及HAP1 MTAP缺失檢定中，分別地，「a* 」及「aa* 」指示<100nM之IC50 ，「b* 」及「bb* 」指示等於或大於100nM但小於1μM之IC50 ，且「c* 」及「cc* 」指示大於或等於1μM之IC50 。在第9列，「A」指示HAP1 MTAP完整細胞株及HAP1 MTAP缺失細胞株之IC50 之間大於或等於10倍的IC50 比率；「B」指示HAP1 MTAP完整細胞株及HAP1 MTAP缺失細胞株之IC50 之間大於或等於3倍但低於10倍的IC50 比率；「C」指示HAP1 MTAP完整細胞株及HAP1 MTAP缺失細胞株之IC50 之間小於3倍的IC50 比率。SDMA細胞內西方檢定中比率等於或大於3倍的化合物被認為具有MTAP選擇性。Table 1 also indicates IC50 values (columns 7-8) of exemplary compounds in MTAP isogenic cell line pairs in the SDMA in-cell western assay. HAP1 MTAP intact is a cell line expressing endogenous levels of MTAP, and HAP1 MTAP deletion is an MTAP null cell line. For Table 1, in the HAP1 MTAP intact and HAP1 MTAP deletion assays, respectively, "a * " and "aa * " indicate IC50s < 100 nM, and "b * " and "bb * " indicate equal to or greater than 100 nM but less than IC50 of 1 μM, and “c * ” and “cc * ” indicate IC50 greater than or equal to 1 μM. In column 9, "A" indicates an IC50 ratio greater than or equal to 10-fold between the IC50s of the HAP1 MTAP intact cell line and the HAP1 MTAP deficient cell line ; "B" indicates the HAP1 MTAP intact cell line and the HAP1 MTAP deficient cell line The IC50 ratio between the IC50 of HAP1 MTAP intact cell line and HAP1 MTAP deficient cell line is less than 3 -fold. Compounds with ratios equal to or greater than 3-fold in the SDMA intracellular Western assay were considered MTAP selective.

表1另外指示在MTAP缺失細胞株之活力檢定中之IC50 值(第10列)，指示使用化合物之治療對細胞存活之作用。在第10列，A* 之值指示小於1μM之IC50 ，B* 之值指示等於或大於1μM但小於10μM之IC50 ，且C* 之值指示大於或等 於10μM之IC50 。Table 1 additionally indicates IC50 values in viability assays of MTAP-deficient cell lines (column 10), indicating the effect of treatment with compounds on cell survival. In column 10, the value of A * indicates an IC50 of less than 1 μM, the value of B * indicates an IC50 of equal to or greater than 1 μM but less than 10 μM, and the value of C * indicates an IC50 of greater than or equal to 10 μM.

除非另外指示，否則所有掌性原子之絕對立體化學正如所描繪。用(或 )或(rel )標記之化合物為單一鏡像異構物，其中任意分配絕對立體化學(例如， 基於如實例部分中所述之掌性SFC溶離)。用(及 )或(外消旋 )標記之化合物為鏡像異構物之混合物，其中相對立體化學正如所示。用(abs )標記之化合物為單一鏡像異構物，其中絕對立體化學正如所指示。Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. Compounds labeled with ( or ) or ( rel ) are single enantiomers with arbitrary assignment of absolute stereochemistry ( eg, based on chiral SFC elution as described in the Examples section). Compounds labeled with ( and ) or ( racemic ) are mixtures of enantiomers with the relative stereochemistry as indicated. Compounds labeled with ( abs ) are single enantiomers with absolute stereochemistry as indicated.

Figure 110128222-A0202-12-0142-1158
Figure 110128222-A0202-12-0142-1158

Figure 110128222-A0202-12-0143-1159
Figure 110128222-A0202-12-0143-1159

Figure 110128222-A0202-12-0144-1160
Figure 110128222-A0202-12-0144-1160

Figure 110128222-A0202-12-0145-1161
Figure 110128222-A0202-12-0145-1161

Figure 110128222-A0202-12-0146-1162
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Figure 110128222-A0202-12-0147-1163
Figure 110128222-A0202-12-0147-1163

Figure 110128222-A0202-12-0148-1164
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Figure 110128222-A0202-12-0149-1165
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Figure 110128222-A0202-12-0150-1166
Figure 110128222-A0202-12-0150-1166

Figure 110128222-A0202-12-0151-1167
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Figure 110128222-A0202-12-0152-1168
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Figure 110128222-A0202-12-0153-1169
Figure 110128222-A0202-12-0153-1169

Figure 110128222-A0202-12-0154-1170
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Figure 110128222-A0202-12-0155-1171
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Figure 110128222-A0202-12-0156-1172
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Figure 110128222-A0202-12-0157-1173
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Figure 110128222-A0202-12-0158-1174
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Figure 110128222-A0202-12-0159-1175
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Figure 110128222-A0202-12-0160-1176
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Figure 110128222-A0202-12-0161-1177
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Figure 110128222-A0202-12-0162-1178
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Figure 110128222-A0202-12-0163-1179
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Figure 110128222-A0202-12-0164-1180
Figure 110128222-A0202-12-0164-1180

Figure 110128222-A0202-12-0165-1181
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Figure 110128222-A0202-12-0166-1182
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Figure 110128222-A0202-12-0167-1183
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Figure 110128222-A0202-12-0168-1184
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Figure 110128222-A0202-12-0169-1185
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Figure 110128222-A0202-12-0170-926
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Figure 110128222-A0202-12-0171-927
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Figure 110128222-A0202-12-0172-928
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Figure 110128222-A0202-12-0173-929
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Figure 110128222-A0202-12-0174-930
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Figure 110128222-A0202-12-0175-931
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Figure 110128222-A0202-12-0176-932
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Figure 110128222-A0202-12-0177-933
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Figure 110128222-A0202-12-0178-934
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Figure 110128222-A0202-12-0179-935
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Figure 110128222-A0202-12-0180-936
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Figure 110128222-A0202-12-0181-937
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Figure 110128222-A0202-12-0182-938
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Figure 110128222-A0202-12-0183-939
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Figure 110128222-A0202-12-0184-940
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Figure 110128222-A0202-12-0185-941
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Figure 110128222-A0202-12-0186-942
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Figure 110128222-A0202-12-0187-943
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Figure 110128222-A0202-12-0188-944
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Figure 110128222-A0202-12-0191-947
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Figure 110128222-A0202-12-0192-948
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Figure 110128222-A0202-12-0193-949
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Figure 110128222-A0202-12-0194-950
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Figure 110128222-A0202-12-0195-951
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Figure 110128222-A0202-12-0198-954
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Figure 110128222-A0202-12-0199-955
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Figure 110128222-A0202-12-0200-956
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Figure 110128222-A0202-12-0201-957
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Figure 110128222-A0202-12-0202-958
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Figure 110128222-A0202-12-0203-959
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Figure 110128222-A0202-12-0204-960
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Figure 110128222-A0202-12-0205-961
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Figure 110128222-A0202-12-0206-962
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Figure 110128222-A0202-12-0207-963
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Figure 110128222-A0202-12-0208-964
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Figure 110128222-A0202-12-0209-965
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Figure 110128222-A0202-12-0210-966
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Figure 110128222-A0202-12-0211-967
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Figure 110128222-A0202-12-0212-968
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Figure 110128222-A0202-12-0213-969
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Figure 110128222-A0202-12-0214-970
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Figure 110128222-A0202-12-0215-971
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Figure 110128222-A0202-12-0216-972
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Figure 110128222-A0202-12-0217-973
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Figure 110128222-A0202-12-0218-974
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Figure 110128222-A0202-12-0219-975
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Figure 110128222-A0202-12-0220-976
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Figure 110128222-A0202-12-0221-977
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Figure 110128222-A0202-12-0222-978
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Figure 110128222-A0202-12-0223-979
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Figure 110128222-A0202-12-0224-980
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Figure 110128222-A0202-12-0225-981
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Figure 110128222-A0202-12-0226-982
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Figure 110128222-A0202-12-0227-983
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Figure 110128222-A0202-12-0228-984
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Figure 110128222-A0202-12-0230-986
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Figure 110128222-A0202-12-0231-987
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Figure 110128222-A0202-12-0232-988
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Figure 110128222-A0202-12-0234-990
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Figure 110128222-A0202-12-0235-991
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Figure 110128222-A0202-12-0238-994
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Figure 110128222-A0202-12-0239-995
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Figure 110128222-A0202-12-0240-996
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Figure 110128222-A0202-12-0241-997
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Figure 110128222-A0202-12-0242-998
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Figure 110128222-A0202-12-0243-999
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Figure 110128222-A0202-12-0244-1000
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Figure 110128222-A0202-12-0245-1001
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Figure 110128222-A0202-12-0246-1002
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Figure 110128222-A0202-12-0247-1003
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Figure 110128222-A0202-12-0248-1004
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Figure 110128222-A0202-12-0249-1005
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Figure 110128222-A0202-12-0250-1006
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Figure 110128222-A0202-12-0251-1007
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Figure 110128222-A0202-12-0252-1008
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Figure 110128222-A0202-12-0253-1009
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Figure 110128222-A0202-12-0254-1010
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Figure 110128222-A0202-12-0255-1011
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Figure 110128222-A0202-12-0256-1012
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Figure 110128222-A0202-12-0257-1013
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Figure 110128222-A0202-12-0258-1014
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Figure 110128222-A0202-12-0259-1015
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Figure 110128222-A0202-12-0260-1016
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Figure 110128222-A0202-12-0261-1017
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Figure 110128222-A0202-12-0262-1018
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Figure 110128222-A0202-12-0263-1019
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Figure 110128222-A0202-12-0264-1020
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Figure 110128222-A0202-12-0265-1021
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Figure 110128222-A0202-12-0266-1022
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Figure 110128222-A0202-12-0267-1023
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Figure 110128222-A0202-12-0268-1024
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Figure 110128222-A0202-12-0269-1025
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Figure 110128222-A0202-12-0270-1026
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Figure 110128222-A0202-12-0271-1027
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Figure 110128222-A0202-12-0272-1028
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Figure 110128222-A0202-12-0273-1029
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Figure 110128222-A0202-12-0274-1030
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Figure 110128222-A0202-12-0276-1032
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Figure 110128222-A0202-12-0277-1033
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Figure 110128222-A0202-12-0278-1034
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Figure 110128222-A0202-12-0279-1035
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Figure 110128222-A0202-12-0280-1036
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Figure 110128222-A0202-12-0281-1037
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Figure 110128222-A0202-12-0282-1038
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Figure 110128222-A0202-12-0283-1039
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Figure 110128222-A0202-12-0284-1040
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Figure 110128222-A0202-12-0298-1054
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Figure 110128222-A0202-12-0299-1055
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Figure 110128222-A0202-12-0300-1056
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Figure 110128222-A0202-12-0301-1057
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Figure 110128222-A0202-12-0303-1059
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Figure 110128222-A0202-12-0304-1060
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Figure 110128222-A0202-12-0305-1061
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Figure 110128222-A0202-12-0306-1062
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Figure 110128222-A0202-12-0307-1063
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Figure 110128222-A0202-12-0308-1064
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Figure 110128222-A0202-12-0309-1065
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Figure 110128222-A0202-12-0310-1066
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Figure 110128222-A0202-12-0311-1067
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Figure 110128222-A0202-12-0312-1068
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Figure 110128222-A0202-12-0315-1071
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Figure 110128222-A0202-12-0324-1080
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Figure 110128222-A0202-12-0330-1086
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Figure 110128222-A0202-12-0331-1087
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Figure 110128222-A0202-12-0335-1091
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Figure 110128222-A0202-12-0340-1096
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Figure 110128222-A0202-12-0341-773
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Figure 110128222-A0202-12-0345-777
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Figure 110128222-A0202-12-0350-782
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Figure 110128222-A0202-12-0351-783
Figure 110128222-A0202-12-0351-783

Figure 110128222-A0202-12-0352-784
Figure 110128222-A0202-12-0352-784

Figure 110128222-A0202-12-0353-785
Figure 110128222-A0202-12-0353-785

Figure 110128222-A0202-12-0354-786
Figure 110128222-A0202-12-0354-786

Figure 110128222-A0202-12-0355-787
Figure 110128222-A0202-12-0355-787

Figure 110128222-A0202-12-0356-788
Figure 110128222-A0202-12-0356-788

Figure 110128222-A0202-12-0357-789
Figure 110128222-A0202-12-0357-789

Figure 110128222-A0202-12-0358-790
Figure 110128222-A0202-12-0358-790

Figure 110128222-A0202-12-0359-791
Figure 110128222-A0202-12-0359-791

Figure 110128222-A0202-12-0360-792
Figure 110128222-A0202-12-0360-792

Figure 110128222-A0202-12-0361-793
Figure 110128222-A0202-12-0361-793

Figure 110128222-A0202-12-0362-794
Figure 110128222-A0202-12-0362-794

Figure 110128222-A0202-12-0363-795
Figure 110128222-A0202-12-0363-795

Figure 110128222-A0202-12-0364-796
Figure 110128222-A0202-12-0364-796

Figure 110128222-A0202-12-0365-797
Figure 110128222-A0202-12-0365-797

Figure 110128222-A0202-12-0366-798
Figure 110128222-A0202-12-0366-798

Figure 110128222-A0202-12-0367-799
Figure 110128222-A0202-12-0367-799

Figure 110128222-A0202-12-0368-800
Figure 110128222-A0202-12-0368-800

Figure 110128222-A0202-12-0369-801
Figure 110128222-A0202-12-0369-801

Figure 110128222-A0202-12-0370-802
Figure 110128222-A0202-12-0370-802

Figure 110128222-A0202-12-0371-803
Figure 110128222-A0202-12-0371-803

Figure 110128222-A0202-12-0372-804
Figure 110128222-A0202-12-0372-804

Figure 110128222-A0202-12-0373-805
Figure 110128222-A0202-12-0373-805

Figure 110128222-A0202-12-0374-806
Figure 110128222-A0202-12-0374-806

Figure 110128222-A0202-12-0375-807
Figure 110128222-A0202-12-0375-807

Figure 110128222-A0202-12-0376-808
Figure 110128222-A0202-12-0376-808

Figure 110128222-A0202-12-0377-809
Figure 110128222-A0202-12-0377-809

Figure 110128222-A0202-12-0378-810
Figure 110128222-A0202-12-0378-810

Figure 110128222-A0202-12-0379-811
Figure 110128222-A0202-12-0379-811

Figure 110128222-A0202-12-0380-812
Figure 110128222-A0202-12-0380-812

Figure 110128222-A0202-12-0381-813
Figure 110128222-A0202-12-0381-813

Figure 110128222-A0202-12-0382-814
Figure 110128222-A0202-12-0382-814

Figure 110128222-A0202-12-0383-815
Figure 110128222-A0202-12-0383-815

Figure 110128222-A0202-12-0384-816
Figure 110128222-A0202-12-0384-816

Figure 110128222-A0202-12-0385-817
Figure 110128222-A0202-12-0385-817

Figure 110128222-A0202-12-0386-818
Figure 110128222-A0202-12-0386-818

Figure 110128222-A0202-12-0387-819
Figure 110128222-A0202-12-0387-819

Figure 110128222-A0202-12-0388-820
Figure 110128222-A0202-12-0388-820

Figure 110128222-A0202-12-0389-821
Figure 110128222-A0202-12-0389-821

Figure 110128222-A0202-12-0390-822
Figure 110128222-A0202-12-0390-822

Figure 110128222-A0202-12-0391-823
Figure 110128222-A0202-12-0391-823

Figure 110128222-A0202-12-0392-824
Figure 110128222-A0202-12-0392-824

Figure 110128222-A0202-12-0393-825
Figure 110128222-A0202-12-0393-825

Figure 110128222-A0202-12-0394-826
Figure 110128222-A0202-12-0394-826

Figure 110128222-A0202-12-0395-827
Figure 110128222-A0202-12-0395-827

Figure 110128222-A0202-12-0396-828
Figure 110128222-A0202-12-0396-828

Figure 110128222-A0202-12-0397-829
Figure 110128222-A0202-12-0397-829

Figure 110128222-A0202-12-0398-830
Figure 110128222-A0202-12-0398-830

Figure 110128222-A0202-12-0399-831
Figure 110128222-A0202-12-0399-831

Figure 110128222-A0202-12-0400-832
Figure 110128222-A0202-12-0400-832

Figure 110128222-A0202-12-0401-833
Figure 110128222-A0202-12-0401-833

Figure 110128222-A0202-12-0402-834
Figure 110128222-A0202-12-0402-834

Figure 110128222-A0202-12-0403-835
Figure 110128222-A0202-12-0403-835

Figure 110128222-A0202-12-0404-836
Figure 110128222-A0202-12-0404-836

Figure 110128222-A0202-12-0405-837
Figure 110128222-A0202-12-0405-837

Figure 110128222-A0202-12-0406-838
Figure 110128222-A0202-12-0406-838

Figure 110128222-A0202-12-0407-839
Figure 110128222-A0202-12-0407-839

Figure 110128222-A0202-12-0408-840
Figure 110128222-A0202-12-0408-840

Figure 110128222-A0202-12-0409-841
Figure 110128222-A0202-12-0409-841

Figure 110128222-A0202-12-0410-842
Figure 110128222-A0202-12-0410-842

Figure 110128222-A0202-12-0411-843
Figure 110128222-A0202-12-0411-843

Figure 110128222-A0202-12-0412-844
Figure 110128222-A0202-12-0412-844

Figure 110128222-A0202-12-0413-845
Figure 110128222-A0202-12-0413-845

Figure 110128222-A0202-12-0414-846
Figure 110128222-A0202-12-0414-846

Figure 110128222-A0202-12-0415-847
Figure 110128222-A0202-12-0415-847

Figure 110128222-A0202-12-0416-848
Figure 110128222-A0202-12-0416-848

Figure 110128222-A0202-12-0417-849
Figure 110128222-A0202-12-0417-849

Figure 110128222-A0202-12-0418-850
Figure 110128222-A0202-12-0418-850

Figure 110128222-A0202-12-0419-851
Figure 110128222-A0202-12-0419-851

Figure 110128222-A0202-12-0420-852
Figure 110128222-A0202-12-0420-852

Figure 110128222-A0202-12-0421-853
Figure 110128222-A0202-12-0421-853

Figure 110128222-A0202-12-0422-854
Figure 110128222-A0202-12-0422-854

Figure 110128222-A0202-12-0423-855
Figure 110128222-A0202-12-0423-855

Figure 110128222-A0202-12-0424-856
Figure 110128222-A0202-12-0424-856

Figure 110128222-A0202-12-0425-857
Figure 110128222-A0202-12-0425-857

Figure 110128222-A0202-12-0426-858
Figure 110128222-A0202-12-0426-858

Figure 110128222-A0202-12-0427-859
Figure 110128222-A0202-12-0427-859

Figure 110128222-A0202-12-0428-860
Figure 110128222-A0202-12-0428-860

Figure 110128222-A0202-12-0429-861
Figure 110128222-A0202-12-0429-861

Figure 110128222-A0202-12-0430-862
Figure 110128222-A0202-12-0430-862

Figure 110128222-A0202-12-0431-863
Figure 110128222-A0202-12-0431-863

Figure 110128222-A0202-12-0432-864
Figure 110128222-A0202-12-0432-864

Figure 110128222-A0202-12-0433-865
Figure 110128222-A0202-12-0433-865

Figure 110128222-A0202-12-0434-866
Figure 110128222-A0202-12-0434-866

Figure 110128222-A0202-12-0435-867
Figure 110128222-A0202-12-0435-867

Figure 110128222-A0202-12-0436-868
Figure 110128222-A0202-12-0436-868

Figure 110128222-A0202-12-0437-869
Figure 110128222-A0202-12-0437-869

Figure 110128222-A0202-12-0438-870
Figure 110128222-A0202-12-0438-870

Figure 110128222-A0202-12-0439-871
Figure 110128222-A0202-12-0439-871

Figure 110128222-A0202-12-0440-872
Figure 110128222-A0202-12-0440-872

Figure 110128222-A0202-12-0441-873
Figure 110128222-A0202-12-0441-873

Figure 110128222-A0202-12-0442-874
Figure 110128222-A0202-12-0442-874

Figure 110128222-A0202-12-0443-875
Figure 110128222-A0202-12-0443-875

Figure 110128222-A0202-12-0444-876
Figure 110128222-A0202-12-0444-876

Figure 110128222-A0202-12-0445-877
Figure 110128222-A0202-12-0445-877

Figure 110128222-A0202-12-0446-878
Figure 110128222-A0202-12-0446-878

Figure 110128222-A0202-12-0447-879
Figure 110128222-A0202-12-0447-879

Figure 110128222-A0202-12-0448-880
Figure 110128222-A0202-12-0448-880

Figure 110128222-A0202-12-0449-881
Figure 110128222-A0202-12-0449-881

Figure 110128222-A0202-12-0450-882
Figure 110128222-A0202-12-0450-882

Figure 110128222-A0202-12-0451-883
Figure 110128222-A0202-12-0451-883

Figure 110128222-A0202-12-0452-884
Figure 110128222-A0202-12-0452-884

Figure 110128222-A0202-12-0453-885
Figure 110128222-A0202-12-0453-885

Figure 110128222-A0202-12-0454-886
Figure 110128222-A0202-12-0454-886

Figure 110128222-A0202-12-0455-887
Figure 110128222-A0202-12-0455-887

Figure 110128222-A0202-12-0456-888
Figure 110128222-A0202-12-0456-888

Figure 110128222-A0202-12-0457-889
Figure 110128222-A0202-12-0457-889

Figure 110128222-A0202-12-0458-890
Figure 110128222-A0202-12-0458-890

Figure 110128222-A0202-12-0459-891
Figure 110128222-A0202-12-0459-891

Figure 110128222-A0202-12-0460-892
Figure 110128222-A0202-12-0460-892

Figure 110128222-A0202-12-0461-893
Figure 110128222-A0202-12-0461-893

Figure 110128222-A0202-12-0462-894
Figure 110128222-A0202-12-0462-894

Figure 110128222-A0202-12-0463-895
Figure 110128222-A0202-12-0463-895

Figure 110128222-A0202-12-0464-896
Figure 110128222-A0202-12-0464-896

Figure 110128222-A0202-12-0465-897
Figure 110128222-A0202-12-0465-897

Figure 110128222-A0202-12-0466-898
Figure 110128222-A0202-12-0466-898

Figure 110128222-A0202-12-0467-899
Figure 110128222-A0202-12-0467-899

Figure 110128222-A0202-12-0468-900
Figure 110128222-A0202-12-0468-900

Figure 110128222-A0202-12-0469-901
Figure 110128222-A0202-12-0469-901

Figure 110128222-A0202-12-0470-902
Figure 110128222-A0202-12-0470-902

Figure 110128222-A0202-12-0471-903
Figure 110128222-A0202-12-0471-903

Figure 110128222-A0202-12-0472-904
Figure 110128222-A0202-12-0472-904

Figure 110128222-A0202-12-0473-905
Figure 110128222-A0202-12-0473-905

Figure 110128222-A0202-12-0474-906
Figure 110128222-A0202-12-0474-906

Figure 110128222-A0202-12-0475-907
Figure 110128222-A0202-12-0475-907

Figure 110128222-A0202-12-0476-908
Figure 110128222-A0202-12-0476-908

Figure 110128222-A0202-12-0477-909
Figure 110128222-A0202-12-0477-909

Figure 110128222-A0202-12-0478-910
Figure 110128222-A0202-12-0478-910

Figure 110128222-A0202-12-0479-911
Figure 110128222-A0202-12-0479-911

Figure 110128222-A0202-12-0480-912
Figure 110128222-A0202-12-0480-912

Figure 110128222-A0202-12-0481-913
Figure 110128222-A0202-12-0481-913

Figure 110128222-A0202-12-0482-914
Figure 110128222-A0202-12-0482-914

Figure 110128222-A0202-12-0483-915
Figure 110128222-A0202-12-0483-915

Figure 110128222-A0202-12-0484-916
Figure 110128222-A0202-12-0484-916

Figure 110128222-A0202-12-0485-917
Figure 110128222-A0202-12-0485-917

Figure 110128222-A0202-12-0486-918
Figure 110128222-A0202-12-0486-918

Figure 110128222-A0202-12-0487-919
Figure 110128222-A0202-12-0487-919

Figure 110128222-A0202-12-0488-920
Figure 110128222-A0202-12-0488-920

Figure 110128222-A0202-12-0489-921
Figure 110128222-A0202-12-0489-921

Figure 110128222-A0202-12-0490-922
Figure 110128222-A0202-12-0490-922

Figure 110128222-A0202-12-0491-923
Figure 110128222-A0202-12-0491-923

在一些實施例中，本文所述之式(I)及(Ia)化合物可使用方案1中所述之方法製備。In some embodiments, the compounds of Formula (I) and (Ia) described herein can be prepared using the methods described in Scheme 1 .

方案1.plan 1.

Figure 110128222-A0202-12-0492-924
Figure 110128222-A0202-12-0492-924

Figure 110128222-A0202-12-0493-925
Figure 110128222-A0202-12-0493-925

如方案1中所示，式(Ia)、(Ib)、(Ic)及(Id)化合物可自式(I)化合物之混合物分離，其中R1 、R2 、R3 、R4 、R6 、R7、 R8 及n如本文所述，R1a 選自R1 及-NH-PG，且R2a 選自R2 及-NH-PG，其中PG為如本文所定義之氮保護基(例如， -Boc)。在某 些實施例中(例如， 當R1a 為NH-PG且R1 為-NH2 ，或R2a 為NH-PG且R2 為-NH2 時)，採用去保護步驟將R1a 轉化成R1 或將R2a 轉化成R2 。去保護步驟可在分離步驟之前或之後進行。用於移除保護基-PG(例如， -Boc)之條件可採用例如酸性條件(例如， 水/二噁烷、於質子性溶劑(例如，甲醇 )中之鹽酸、於非質子性溶劑(例如， 二噁烷)中之鹽酸、於非質子性溶劑(例如，二氯甲烷 、氯仿等)中之TFA)。As shown in Scheme 1, compounds of formula (Ia), (Ib), (Ic) and (Id) can be isolated from a mixture of compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and n are as described herein, R 1a is selected from R 1 and -NH-PG, and R 2a is selected from R 2 and -NH-PG, wherein PG is a nitrogen protecting group as defined herein ( For example, -Boc). In certain embodiments ( eg, when R 1a is NH-PG and R 1 is -NH 2 , or R 2a is NH-PG and R 2 is -NH 2 ), a deprotection step is used to convert R 1a into R 1 or convert R 2a into R 2 . The deprotection step can be performed before or after the separation step. Conditions for removing the protecting group -PG ( e.g., -Boc) can employ, for example, acidic conditions ( e.g., water/dioxane, hydrochloric acid in a protic solvent ( e.g., methanol ), in an aprotic solvent ( e.g. , , hydrochloric acid in dioxane), TFA) in an aprotic solvent ( eg, dichloromethane , chloroform, etc.).

式(I)化合物可藉由使式I-6化合物經歷醯胺鍵偶合條件來製備。在一些實施例中，式(I)化合物透過式I-6化合物與式I-7化合物之醯胺鍵偶合來製備。已知由式I-6及式I-7化合物生成式I化合物之條件之實例包括但不限於：添加偶合劑(諸如CDI、HATU、HOBT、HBTU或PyBOP)、鹼(諸如氫化物鹼(例如 NaH或KH)、胺鹼(諸如DBU、NEt3 及NEt( i Pr)2 )或碳酸鹽鹼(例如， Na2 CO3 、K2 CO3 或Cs2 CO3 ))；以及在一個實施例中在0℃至室溫下或在另一個實施例中在70℃或更高溫度下(例如在70℃至110℃範圍內或在70℃至80℃範圍內的溫度下、或在80℃下)攪拌反應物。可在諸如但不限於DMF及MTBE之溶劑中進行反應。在一些實施例中，式(I)化合物透過式I-6化合物與式I-8化合物之醯胺鍵偶合來製備。已知由式I-6及式I-8化合物生成式I化合物之條件之實例包括但不限於：添加鹼，諸如有機鋰鹼(例如，n -BuLi、t -BuLi、二異丙基醯胺鋰(LDA)、雙(三甲基矽基)醯胺鋰(LiHMDS))、氫化物鹼(例如， NaH或KH)、胺鹼(諸如DBU、NEt3 及NEt( i Pr)2 )或碳酸鹽鹼(例如， Na2 CO3 、K2 CO3 或Cs2 CO3 )；以及在一個實施例中在0℃至室溫下或在另一個實施例中在70℃或更高溫度下(例如在70℃至110℃範圍內或在70℃至80℃範圍內的溫度下或在80℃下)攪拌反應物。可在諸如但不限於THF、Et2 O、TMEDA、DME及MTBE或其混合物之溶劑中進行反應。Compounds of formula (I) can be prepared by subjecting compounds of formula 1-6 to amide coupling conditions. In some embodiments, compounds of formula (I) are prepared by amide coupling of a compound of formula 1-6 with a compound of formula 1-7. Examples of conditions known to generate compounds of formula I from compounds of formula 1-6 and 1-7 include, but are not limited to, the addition of a coupling agent such as CDI, HATU, HOBT, HBTU or PyBOP, a base such as a hydride base ( eg NaH or KH), amine bases (such as DBU, NEt 3 and NEt( i Pr) 2 ), or carbonate bases ( eg, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 )); and in one embodiment at 0°C to room temperature, or in another embodiment at 70°C or higher (eg, at a temperature in the range of 70°C to 110°C, or at a temperature in the range of 70°C to 80°C, or at 80°C bottom) to stir the reaction. The reaction can be carried out in solvents such as, but not limited to, DMF and MTBE. In some embodiments, compounds of formula (I) are prepared by amide coupling of compounds of formula 1-6 with compounds of formula 1-8. Examples of conditions known to generate compounds of formula I from compounds of formula 1-6 and 1-8 include, but are not limited to, the addition of a base, such as an organolithium base ( eg, n -BuLi, t -BuLi, diisopropylamide Lithium (LDA), lithium bis(trimethylsilyl)amide (LiHMDS)), hydride bases ( eg, NaH or KH), amine bases (such as DBU, NEt 3 and NEt( iPr ) 2 ), or carbonic acid saline ( eg, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 ); and in one embodiment at 0°C to room temperature or in another embodiment at 70°C or higher ( The reaction is stirred, for example, at a temperature in the range from 70°C to 110°C or at a temperature in the range from 70°C to 80°C or at 80°C). The reaction can be carried out in solvents such as, but not limited to, THF, Et2O , TMEDA, DME and MTBE or mixtures thereof.

在一些實施例中，式I-5化合物經歷去保護、環化及還原之序列以製備式I-6化合物。用於移除保護基(PG)(例如， MoM或Boc)之條件為熟悉此項技術者已知的。例如，Boc去保護可包含用酸處理。示範性酸包括TFA及HCl，且示 範性溶劑包括質子性溶劑(諸如甲醇)、鹵化溶劑(諸如DCM及六氟異丙醇)或醚溶劑(諸如二噁烷及二甲醚)。在一些實施例中，在將式I-5化合物去保護時可經歷自發環化以形成環狀亞胺。環狀亞胺之還原可使用還原劑諸如氫化物還原劑(例如， NaBH4 或LiAlH4 )、矽還原劑(例如， Cl3 SiH)或在存在催化劑(例如 Ir催化劑、Ru催化劑、Pd催化劑(例如， Pd/C、Pd(OAc)2 ))之情況下的H2 還原來完成。In some embodiments, compounds of formula 1-5 undergo a sequence of deprotection, cyclization and reduction to prepare compounds of formula 1-6. Conditions for removing protecting groups (PG) ( eg, MoM or Boc) are known to those skilled in the art. For example, Boc deprotection can comprise treatment with an acid. Exemplary acids include TFA and HCl, and exemplary solvents include protic solvents such as methanol, halogenated solvents such as DCM and hexafluoroisopropanol, or ethereal solvents such as dioxane and dimethyl ether. In some embodiments, compounds of formula 1-5 may undergo spontaneous cyclization upon deprotection to form cyclic imines. Cyclic imines can be reduced using reducing agents such as hydride reducing agents ( eg, NaBH 4 or LiAlH 4 ), silicon reducing agents ( eg, Cl 3 SiH), or in the presence of catalysts ( eg , Ir catalysts, Ru catalysts, Pd catalysts ( For example, H 2 reduction in the case of Pd/C, Pd(OAc) 2 )) is accomplished.

式I-5化合物可藉由對式I-4化合物之親核加成來製備。親核加成可使用格任亞試劑(Grignard reagent)(例如 R6 MgBr)來完成。親核加成反應可在諸如但不限於THF、Et2 O、TMEDA、DME及MTBE或其混合物之溶劑中進行。Compounds of formula 1-5 can be prepared by nucleophilic addition to compounds of formula 1-4. Nucleophilic additions can be accomplished using Grignard reagents such as R6MgBr . Nucleophilic addition reactions can be carried out in solvents such as, but not limited to, THF, Et2O , TMEDA, DME, and MTBE, or mixtures thereof.

替代地，式I-6化合物可經由式I-3化合物之還原來製備。式I-3化合物之還原可使用還原劑諸如氫化物還原劑(例如， NaBH4 或LiAlH4 )、矽還原劑(例如， Cl3 SiH)或在存在催化劑(例如 Ir催化劑、Ru催化劑、Pd催化劑(例如， Pd/C、Pd(OAc)2 ))之情況下的H2 還原來完成。Alternatively, compounds of formula 1-6 can be prepared via reduction of compounds of formula 1-3. Reduction of compounds of formula I-3 can use reducing agents such as hydride reducing agents ( eg, NaBH 4 or LiAlH 4 ), silicon reducing agents ( eg, Cl 3 SiH) or in the presence of catalysts ( eg , Ir catalysts, Ru catalysts, Pd catalysts) ( eg, Pd/C, Pd(OAc) 2 )) by H 2 reduction.

在一些實施例中，式I-2化合物可經歷去保護/雙鍵遷移以得到式I-3化合物。用於移除保護基(PG)(例如， MoM或Boc)之條件為熟悉此項技術者已知的。例如，Boc去保護可包含用酸處理。示範性酸包括TFA及HCl，且示範性溶劑包括質子性溶劑(諸如甲醇)、鹵化溶劑(諸如DCM及六氟異丙醇)或醚溶劑(諸如二噁烷及二甲醚)。In some embodiments, compounds of formula 1-2 can undergo deprotection/double bond migration to yield compounds of formula 1-3. Conditions for removing protecting groups (PG) ( eg, MoM or Boc) are known to those skilled in the art. For example, Boc deprotection can comprise treatment with an acid. Exemplary acids include TFA and HCl, and exemplary solvents include protic solvents such as methanol, halogenated solvents such as DCM and hexafluoroisopropanol, or ethereal solvents such as dioxane and dimethyl ether.

在一些實施例中，I-2化合物可透過式I-1化合物(其中X為脫離基，例如， 鹵素或-OSO2 CF3 )與合適的交叉偶合配偶體之交叉偶合來製備。在一些實施例中，合適的交叉偶合配偶體包括但不限於含硼交叉偶合配偶體，例如R6 B(OH)2 或R6 Bpin。In some embodiments, compounds of 1-2 can be prepared by cross-coupling of compounds of formula 1-1 (wherein X is a leaving group, eg, halogen or -OSO2CF3 ) with a suitable cross - coupling partner. In some embodiments, suitable cross-coupling partners include, but are not limited to, boron-containing cross-coupling partners, such as R6B (OH)2 or R6Bpin .

替代性實施例Alternative Embodiment

在一個替代性實施例中，本文所述之化合物亦可包含一或多個同位素取代。例如，氫可為2 H(D或氘)或3 H(T或氚)；碳可為例如13 C或14 C；氧可為例 如18 O；氮可為例如15 N及其類似者。在其他實施例中，特定同位素(例如， 3 H、13 C、14 C、18 O或15 N)可表示佔據化合物之特定位點之元素的總同位素豐度之至少1%、至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少99%或至少99.9%。In an alternative embodiment, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen can be2H (D or deuterium) or3H (T or tritium); carbon can be, for example, 13C or14C ; oxygen can be, for example, 18O ; nitrogen can be, for example, 15N and the like. In other embodiments, a particular isotope ( eg, 3 H, 13 C, 14 C, 18 O, or 15 N) may represent at least 1%, at least 5%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75% %, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%.

醫藥組成物Pharmaceutical composition

在另一個態樣中，本發明提供一種醫藥組成物，其包含醫藥學上可接受之載劑及有效量之本文所述之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)或其醫藥學上可接受之鹽。In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein ( eg, formula (I), (Ia), (Ib), (Ic) and (Id) compounds or compounds of Table 1) or pharmaceutically acceptable salts thereof.

術語「醫藥學上可接受之載劑或佐劑」係指可連同本文所提供之化合物一起向患者投與，且不會破壞其藥理學活性並在以足以傳遞治療量之化合物之劑量投與時無毒的載劑或佐劑。The term "pharmaceutically acceptable carrier or adjuvant" refers to a compound provided herein that can be administered to a patient without destroying its pharmacological activity and at a dose sufficient to deliver a therapeutic amount of the compound nontoxic carrier or adjuvant.

可用於本文所提供之醫藥組成物之醫藥學上可接受之載劑、佐劑及媒劑包括但不限於離子交換劑、氧化鋁、硬脂酸鋁、卵燐脂、自乳化藥物遞送系統(SEDDS)(諸如d-α-生育酚聚乙二醇1000琥珀酸酯)、醫藥劑型中所用之界面活性劑(諸如Tween或其他類似聚合物遞送基質)、血清蛋白(諸如人類血清白蛋白)、緩衝物質(諸如磷酸鹽)、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸之部分甘油混合物、水、鹽或電解質，諸如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽、膠體二氧化矽、三矽酸鎂、聚乙烯基吡咯啶酮、基於纖維素之物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯聚氧丙烯嵌段聚合物、聚乙二醇及羊毛脂。環糊精(諸如α-環糊精、β-環糊精及γ-環糊精)或經化學修飾之衍生物(諸如羥基烷基環糊精，包括2-羥丙基-β-環糊精及3-羥基丙基-β-環糊精)或其他溶解之衍生物亦可有利地用於增強本文所述之各式化合物的遞送。Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems ( SEDDS) (such as d-alpha-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (such as Tween or other similar polymeric delivery matrices), serum proteins (such as human serum albumin), Buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glycerol mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chloride Sodium, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxy Propylene block polymer, polyethylene glycol and lanolin. Cyclodextrins (such as alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin) or chemically modified derivatives (such as hydroxyalkylcyclodextrins, including 2-hydroxypropyl-beta-cyclodextrin) and 3-hydroxypropyl-beta-cyclodextrin) or other solubilized derivatives can also be advantageously used to enhance the delivery of the various compounds described herein.

當用作藥物時，本文所提供之化合物通常以醫藥組成物之形式投與。此類組成物可以醫藥技術中熟知之方式製備且包含至少一種活性化合物。When used as medicines, the compounds provided herein are typically administered in the form of pharmaceutical compositions. Such compositions may be prepared in a manner well known in the pharmaceutical art and contain at least one active compound.

在一個實施例中，關於醫藥組成物，載劑為腸胃外載劑、經口或局部載劑。In one embodiment, with regard to pharmaceutical compositions, the carrier is a parenteral, oral or topical carrier.

本發明亦係關於一種本文所述之化合物(例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)(或其醫藥組成物)，其用作藥物或藥劑(例如， 用於治療有需要之個體之MTAP缺乏及/或MTA累積疾病的藥劑)。在一個實施例中，疾病為增殖性疾病。在另一個實施例中，疾病為MTAP缺乏及/或MTA累積癌症。在一個實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。The invention also relates to a compound described herein ( eg, a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) (or a pharmaceutical composition thereof) for use as a medicament or medicament ( eg, a medicament for the treatment of MTAP deficiency and/or MTA accumulation disease in a subject in need thereof). In one embodiment, the disease is a proliferative disease. In another embodiment, the disease is MTAP deficiency and/or MTA accumulating cancer. In one embodiment, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

本發明亦係關於一種本文所述之化合物(例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)(或其醫藥組成物)，其用於治療有需要之個體之MTAP缺乏及/或MTA累積疾病。在一個實施例中，疾病為增殖性疾病。在另一個實施例中，疾病為MTAP缺乏及/或MTA累積癌症。在一個實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳 癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。The invention also relates to a compound described herein ( eg, a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) (or a pharmaceutical composition thereof) for the treatment of MTAP deficiency and/or MTA accumulation disease in an individual in need thereof. In one embodiment, the disease is a proliferative disease. In another embodiment, the disease is MTAP deficiency and/or MTA accumulating cancer. In one embodiment, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

本發明亦係關於一種本文所述之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)(或其醫藥組成物)，其用於製造藥物或藥劑(例如， 用於治療有需要之個體之MTAP缺乏及/或MTA累積疾病的藥劑)。在一個實施例中，疾病為增殖性疾病。在另一個實施例中，疾病為MTAP缺乏及/或MTA累積癌症。在一個實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。The invention also relates to a compound described herein ( eg, a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) (or a pharmaceutical composition thereof) for the manufacture of a medicament or medicament ( eg, a medicament for the treatment of MTAP deficiency and/or MTA accumulation disease in a subject in need thereof). In one embodiment, the disease is a proliferative disease. In another embodiment, the disease is MTAP deficiency and/or MTA accumulating cancer. In one embodiment, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

一般而言，本文所提供之化合物以治療有效量投與。實際投與之化合物之量通常將由臨床醫師根據相關情形來確定，包括欲治療之疾患、所選投與路徑、所投與之實際化合物、個別患者之年齡、體重及反應、患者症狀之嚴重性及其類似者。Generally, the compounds provided herein are administered in a therapeutically effective amount. The actual amount of compound administered will generally be determined by the clinician according to the relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like.

本文所提供之醫藥組成物可經口、腸胃外、藉由吸入噴霧、局部、經直腸、經鼻、經頰、經陰道或經由植入儲集囊(implanted reservoir)、較佳藉由經口投與或藉由注射投與來投與。本文所提供之醫藥組成物可含有任何習知無毒的醫藥學上可接受之載劑、佐劑或媒劑。在一些情況下，調配物之pH可利用醫藥學上可接受之酸、鹼或緩衝液調節以增強經調配之化合物或其遞送形式之穩定性。如本文所用之術語腸胃外包括皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內及顱內注射或輸注技術。The pharmaceutical compositions provided herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally or via an implanted reservoir, preferably by oral administered or administered by injection. The pharmaceutical compositions provided herein can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

用於經口投與之組成物可採用散裝液體溶液或懸浮液或者散裝粉末 之形式。然而，更通常，組成物以單位劑型呈現以有助於精確給藥。術語「單位劑型」係指作為整體劑量適用於人類個體及其他哺乳動物的物理上離散之單位，各單位含有經計算以產生所要治療效果之預定量之活性物質以及合適的醫藥賦形劑。典型的單位劑型包括液體組成物之經預填充、預量測之安瓿或注射器或者在固體組成物之情況下的丸劑、錠劑、膠囊或其類似者。在此類組成物中，化合物通常為微量組分(約0.1重量%至約50重量%或較佳約1重量%至約40重量%)，其餘部分為有助於形成所要給藥形式之各種媒劑或載劑及加工助劑。Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders the form of. More generally, however, the compositions are presented in unit dosage form to facilitate precise administration. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions or, in the case of solid compositions, pills, lozenges, capsules, or the like. In such compositions, the compound is usually a minor component (about 0.1% to about 50% by weight or preferably about 1% to about 40% by weight), with the remainder being various components that aid in forming the desired administration form Vehicles or carriers and processing aids.

適用於經口投與之液體形式可包括具有緩衝液、懸浮劑及分散劑、著色劑、調味劑及其類似者之合適水性或非水性媒劑。固體形式可包括例如任何以下成分或具有類似性質之化合物：黏合劑，諸如微晶纖維素、黃蓍膠或明膠；賦形劑，諸如澱粉或乳糖；崩解劑，諸如海藻酸、Primogel或玉米澱粉；潤滑劑，諸如硬脂酸鎂；助滑劑，諸如膠體二氧化矽；甜味劑，諸如蔗糖或糖精；或調味劑，諸如薄荷、柳酸甲酯或橙調味劑。Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles with buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following ingredients or compounds of similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; slip agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavor.

可注射組成物通常基於可注射無菌鹽水或磷酸鹽緩衝鹽水或此項技術中已知之其他可注射載劑。與先前一樣，此類組成物中之活性化合物通常為微量組分，通常為約0.05重量%至10重量%，其餘部分為可注射載劑及其類似者。醫藥組成物可呈無菌可注射製劑形式，例如呈無菌可注射水性或油性懸浮液形式。此懸浮液可根據此項技術中已知之技術使用合適分散劑或潤濕劑(諸如例如Tween 80)及懸浮劑調配。無菌可注射製劑亦可為於無毒腸胃外可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液，例如呈於1,3-丁二醇中之溶液。可採用的可接受之媒劑及溶劑為甘露醇、水、林格氏溶液及等滲氯化鈉溶液。此外，慣例上採用無菌不揮發油作為溶劑或懸浮介質。出於此目的，可採用任何品牌之不揮發油，包括合成單甘油酯或雙甘油酯。脂肪酸(諸如油酸及其甘油衍生物)可用於製備可注射劑，天然的醫藥學上可接受之油(諸如橄欖油或蓖麻油，尤其 是其聚氧乙基化版本)也一樣。這些油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑或者羧甲基纖維素或類似分散劑，其常用於調配醫藥學上可接受之劑型，諸如乳液及懸浮液。其他常用界面活性劑(諸如Tween或Span)及/或常用於製造醫藥學上可接受之固體、液體或其他劑型之其他類似乳化劑或生物可用度增強劑亦可用於調配目的。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions will generally be minor components, usually about 0.05% to 10% by weight, with the remainder being the injectable vehicle and the like. Pharmaceutical compositions can be in the form of sterile injectable preparations, eg, sterile injectable aqueous or oily suspensions. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents such as, for example, Tween 80 and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glycerol derivatives are useful in the preparation of injectables, natural pharmaceutically acceptable oils such as olive oil or castor oil, especially is its polyoxyethylated version) as well. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and suspensions. Other commonly used surfactants such as Tween or Span and/or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

經皮組成物通常調配為含有活性成分之局部軟膏或霜劑，活性成分之量之範圍通常為約0.01重量%至約20重量%，較佳約0.1重量%至約20重量%，較佳約0.1重量%至約10重量%，且更佳約0.5重量%至約15重量%。當調配為軟膏時，通常將活性成分與石蠟或水混溶性軟膏基底組合。替代地，可用例如水包油軟膏基底以霜劑的形式調配活性成分。此類經皮調配物為此項技術中熟知的且通常包括增強活性成分或調配物之皮膚滲透或穩定性的額外成分。所有此類已知經皮調配物及成分均包括在本文所提供之範圍內。Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient, usually in an amount ranging from about 0.01% to about 20% by weight, preferably from about 0.1% to about 20% by weight, preferably about 0.1 wt% to about 10 wt%, and more preferably about 0.5 wt% to about 15 wt%. When formulated as an ointment, the active ingredient is usually combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with a base such as an oil-in-water ointment. Such transdermal formulations are well known in the art and typically include additional ingredients that enhance skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

本文所提供之化合物亦可藉由經皮裝置來投與。因此，經皮投與可使用一片儲集囊或多孔膜類型或固體基質種類來完成。The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be accomplished using a one-piece reservoir bag or porous membrane type or solid matrix type.

本文所提供之醫藥組成物亦可以用於經直腸投與之栓劑形式投與。這些組成物可藉由將本文所提供之化合物與合適非刺激賦形劑混合來製備，該等賦形劑在室溫下為固體但在直腸溫度下為液體且因此將在直腸內融化以釋放活性組分。此類材料包括但不限於可可脂、蜜蠟及聚乙二醇。The pharmaceutical compositions provided herein can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound provided herein with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum for release active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

本文所提供之醫藥組成物可藉由經鼻氣溶膠或吸入來投與。此類組成物係根據醫藥調配技術中熟知之技術來製備且可採用苯甲醇或其他適合防腐劑、增強生物可用度之吸收促進劑、氟碳化合物及/或此項技術中已知之其他溶解劑或分散劑製備成於鹽水中之溶液。The pharmaceutical compositions provided herein can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may employ benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and/or other solubilizers known in the art Or dispersants are prepared as solutions in saline.

用於可經口投與、可注射或可局部投與、可經直腸投與及可經鼻投與組成物之上述組分僅為代表性的。其他材料以及加工技術及其類似者陳述於Remington's Pharmaceutical Sciences ，第17版，1985,Mack Publishing Company,Easton,Pennsylvania之第8部分中，該文獻以引用方式併入本文。The foregoing components for orally, injectable or topically, rectally, and nasally administrable compositions are representative only. Additional materials and processing techniques and the like are set forth in Remington's Pharmaceutical Sciences , 17th Ed., 1985, Mack Publishing Company, Easton, Pennsylvania, Section 8, which is incorporated herein by reference.

本發明之化合物亦可以持續釋放形式或自持續釋放藥物遞送系統投與。代表性持續釋放材料之描述可見於Remington's Pharmaceutical Sciences 。The compounds of the present invention may also be administered in sustained release form or from sustained release drug delivery systems. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences .

當本文所提供之組成物包含本文所述之各化合物與一或多種額外治療劑或預防劑之組合時，化合物及額外劑存在的劑量水準應在單一療法方案中通常投與之劑量之約1%至100%之間且更佳約5%至95%之間。額外劑可作為多劑量方案之一部分與本文所提供之化合物分開投與。替代地，那些劑可為單一劑型之一部分，與本文所提供之化合物一起混合在單一組成物中。When the compositions provided herein comprise each of the compounds described herein in combination with one or more additional therapeutic or prophylactic agents, the compounds and additional agents are present at dosage levels that are typically administered in a monotherapy regimen at about 1 Between % and 100% and more preferably between about 5% and 95%. Additional agents can be administered separately from the compounds provided herein as part of a multiple dose regimen. Alternatively, those agents may be part of a single dosage form, mixed with the compounds provided herein in a single composition.

本發明亦係關於本文所述之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)之醫藥學上可接受之酸加成鹽。The present invention also relates to pharmaceutically acceptable acid additions of compounds described herein ( eg, compounds of formula (I), (Ia), (Ib), (Ic), and (Id) or compounds of Table 1 ) Salt.

可用於製備醫藥學上可接受之鹽的酸為形成無毒酸加成鹽之酸，亦即含有藥理學上可接受之陰離子之鹽，陰離子諸如鹽酸根、氫碘酸根、氫溴酸根、硝酸根、硫酸根、硫酸氫根、磷酸根、乙酸根、乳酸根、檸檬酸根、酒石酸根、琥珀酸根、順丁烯二酸根、反丁烯二酸根、苯甲酸根、對甲苯磺酸根及其類似者。Acids useful in the preparation of pharmaceutically acceptable salts are those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as hydrochloride, hydroiodate, hydrobromide, nitrate , sulfate, hydrogen sulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate and the like .

本文所述之化合物可以例如藉由靜脈內、動脈內、表皮下、腹膜內、肌肉內或皮下注射；或經口、經頰、經鼻、經黏膜、局部、以眼用製劑或藉由吸入來投與，其劑量範圍為約0.5mg/kg體重至約100mg/kg體重，替代地劑量為1mg/劑量與1000mg/劑量之間，每4至120小時投與一次或根據特定藥物之要求。本文中之方法涵蓋投與有效量之化合物或化合物組成物以達成所要或所述效果。通常，本文所提供之醫藥組成物將每天投與約1至約6次，或替代地作為連續輸注投與。此種投與可用作長期或短期療法。可與載劑材料組合以產生單一劑型之活性成分的量將根據所治療之宿主及特定投與模式而改變。典型的製劑 將含有約5%至約95%的活性化合物(w/w)。替代地，此類製劑含有約20%至約80%的活性化合物。The compounds described herein may be administered, for example, by intravenous, intraarterial, subepidermal, intraperitoneal, intramuscular, or subcutaneous injection; or by oral, buccal, nasal, transmucosal, topical, in ophthalmic formulations, or by inhalation to be administered in doses ranging from about 0.5 mg/kg body weight to about 100 mg/kg body weight, alternatively at doses between 1 mg/dose and 1000 mg/dose, administered every 4 to 120 hours or as required by a particular drug. The methods herein encompass the administration of an effective amount of a compound or composition of compounds to achieve the desired or stated effect. Typically, the pharmaceutical compositions provided herein will be administered from about 1 to about 6 times per day, or alternatively as a continuous infusion. Such administration can be used as long-term or short-term therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. typical preparation Will contain from about 5% to about 95% active compound (w/w). Alternatively, such formulations contain from about 20% to about 80% active compound.

可能需要低於或高於上述劑量之劑量。用於任何特定患者之特定劑量及治療方案將取決於多種因素，包括所採用之特定化合物之活性、年齡、體重、一般健康狀態、性別、膳食、投與時間、排洩速率、藥物組合、疾病之嚴重性及病程、疾患或症狀、患者對疾病、疾患或症狀之處置及治療醫師之判斷。Doses lower or higher than those listed above may be required. The particular dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, disease status. Severity and course of disease, disease or symptom, patient's treatment of disease, disease or symptom, and judgment of treating physician.

在患者之疾患改善後，必要時，可投與本文所提供之化合物、組成物或組合之維持劑量。隨後，可以根據症狀減少投與劑量或頻率或二者至當症狀已緩解至所要水準時保留經改善疾患之水準。然而，患者可能在疾病症狀之任何復發後長期需要間歇性治療。After the patient's condition improves, a maintenance dose of a compound, composition or combination provided herein can be administered, as necessary. Subsequently, the dose or frequency of administration, or both, may be reduced according to symptoms to a level that retains the ameliorated disease when symptoms have been alleviated to the desired level. However, patients may require intermittent treatment long term following any recurrence of disease symptoms.

治療方法及用途Treatment methods and uses

MTAP缺乏及/或MTA累積增殖性病症之治療Treatment of MTAP deficiency and/or MTA accumulation proliferative disorders

在一個實施例中，本發明提供了治療患有或已診斷為患有MTAP缺乏症相關及/或MTA累積增殖性病症(例如， 癌症)之人類或動物個體的方法，其包含向有需要之個體投與治療有效量之本發明之化合物(例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)或其醫藥學上可接受之鹽。In one embodiment, the present invention provides a method of treating a human or animal subject having or having been diagnosed with an MTAP deficiency-related and/or MTA accumulating proliferative disorder ( eg, cancer), comprising administering to the individual in need thereof A therapeutically effective amount of a compound of the invention ( eg, a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1) or a pharmaceutically acceptable salt thereof is administered.

在一個實施例中，本發明提供了治療有需要之個體之MTAP缺乏症相關及/或MTA累積增殖性病症(例如， 癌症)的方法，其包含向個體投與治療有效量之本發明之化合物(例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)或其醫藥學上可接受之鹽。In one embodiment, the present invention provides a method of treating an MTAP deficiency-related and/or MTA accumulating proliferative disorder ( eg, cancer) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the present invention ( eg, compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of Table 1) or a pharmaceutically acceptable salt thereof.

在一個實施例中，本發明提供了治療患有或已診斷為患有MTAP缺乏症相關及/或MTA累積增殖性病症(例如， 癌症)之人類或動物個體的方法，其包含向有需要之個體投與治療有效量之本發明之醫藥組成物(例如， 包含式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽基醫藥學上 可接受之載劑的組成物)。在一個實施例中，化合物或組成物與第二治療劑組合投與。In one embodiment, the present invention provides a method of treating a human or animal subject having or having been diagnosed with an MTAP deficiency-related and/or MTA accumulating proliferative disorder ( eg, cancer), comprising administering to the individual in need thereof Administration of a therapeutically effective amount of a pharmaceutical composition of the present invention ( eg, comprising a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable composition in a pharmaceutically acceptable carrier). In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

在一個實施例中，本發明提供了治療有需要之個體之MTAP缺乏症相關及/或MTA累積增殖性病症(例如， 癌症)的方法，其包含向個體投與治療有效量之本發明之醫藥組成物(例如， 包含式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽基醫藥學上可接受之鹽的組成物)。在一個實施例中，化合物或組成物與第二治療劑組合投與。In one embodiment, the present invention provides a method of treating an MTAP deficiency-related and/or MTA accumulating proliferative disorder ( eg, cancer) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a medicament of the present invention A composition ( eg, comprising a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof composition). In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

在某些實施例中，疾病為MTAP缺乏及/或MTA累積癌症。In certain embodiments, the disease is MTAP deficiency and/or MTA accumulating cancer.

在一個實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如， 肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In one embodiment, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg, lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

在一個實施例中，癌症為MTAP缺乏及/或MTA累積神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In one embodiment, the cancer is MTAP deficient and/or MTA accumulating glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg , bladder urothelial carcinoma), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, Undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiocarcinoma, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urine Road cancer, liver cancer, soft tissue cancer, pleural or colorectal cancer or sarcoma.

本文所述之PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或 表1之化合物或其醫藥學上可接受之鹽)可用於抑制有需要之個體之MTAP缺乏細胞之增殖的方法中，該方法包含以有效抑制MTAP缺乏細胞之增殖的量向個體投與PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)。在一個實施例中，有需要之個體罹患選自以下之癌症：神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。PRMT5 inhibitors described herein ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg, formulae (I), (Ia), (Ib), (Ic) and (Id) ) compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof) can be used in a method of inhibiting the proliferation of MTAP deficient cells in an individual in need thereof, the method comprising administering to the individual an amount effective to inhibit the proliferation of MTAP deficient cells With PRMT5 inhibitors ( eg, MTA non-competitive, non-competitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg, compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof). In one embodiment, the individual in need has a cancer selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytes tumor, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer , Urinary tract cancer, liver cancer, soft tissue cancer, pleural or colorectal cancer or sarcoma.

本文所述之PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可用於抑制有需要之個體之MTAP累積細胞之增殖的方法中，該方法包含以有效抑制MTAP累積細胞之增殖的量向個體投與PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)。在一個實施例中，有需要之個體罹患選自以下之癌症：神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。PRMT5 inhibitors described herein ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg, formulae (I), (Ia), (Ib), (Ic) and (Id) ) compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof) can be used in a method of inhibiting the proliferation of MTAP accumulating cells in an individual in need thereof, the method comprising administering to the individual an amount effective to inhibit the proliferation of MTAP accumulating cells With PRMT5 inhibitors ( eg, MTA non-competitive, non-competitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg, compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof). In one embodiment, the individual in need has a cancer selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytes tumor, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer , Urinary tract cancer, liver cancer, soft tissue cancer, pleural or colorectal cancer or sarcoma.

本文所述之PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可用於抑制有需要之個體之MTAP缺乏及/或MTA累積細胞之增殖的方法中，該方法包含以有效抑制MTAP缺乏及/或MTA累積細胞之增殖的量向個體投與PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)。在一個實施例中，有需要之個體罹患選自以下之癌症：神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。PRMT5 inhibitors described herein ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg, formulae (I), (Ia), (Ib), (Ic) and (Id) ) compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof) can be used in a method for inhibiting the proliferation of MTAP-deficient and/or MTA-accumulating cells in an individual in need thereof, the method comprising effectively inhibiting MTAP-deficient and/or The amount of proliferation of MTA accumulating cells is administered to an individual with a PRMT5 inhibitor ( eg, an MTA uncompetitive, non-competitive or mixed mode PRMT5 inhibitor or an MTA synergistic binder, eg, formula (I), (Ia), (Ib) ), (Ic) and (Id) compounds or a compound of Table 1 or a pharmaceutically acceptable salt thereof). In one embodiment, the individual in need has a cancer selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytes tumor, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer , Urinary tract cancer, liver cancer, soft tissue cancer, pleural or colorectal cancer or sarcoma.

組合療法combination therapy

本發明提供了用PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)與第二治療劑之組合治療MTAP缺乏及/或MTA累積增殖性病症(例如， 癌症)之方法。The present invention provides use of PRMT5 inhibitors ( eg, MTA uncompetitive, non-competitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg, formulae (I), (Ia), (Ib), (Ic) and ( Id) Methods of treating MTAP deficiency and/or MTA accumulation proliferative disorders ( eg, cancer) in combination with a compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof) and a second therapeutic agent.

術語「組合」係指一個劑量單位形式之固定組合或組合投與，在該組合投與中可以獨立地同時或在時間間隔內單獨投與本發明之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)及組合配偶體(例如， 如下文所解釋之另一種藥物，亦稱為「治療劑」或「共劑」)，尤其其中此等時間間隔允許該組合配偶體顯示協同例如協同效應。單一組分可包 裝在套組中或單獨包裝。一種或兩種組分(例如， 粉劑或液體)可在投與前經重構或稀釋至所要劑量。如本文所用之術語「共同投與」或「組合投與」或其類似者意謂涵蓋向有需要之單一個體(例如， 患者)投與所選組合配偶體且意欲包括治療方案，其中該等劑不必藉由相同投與路徑投與或同時投與。如本文所用之術語「醫藥組合」意謂將多於一種治療劑混合或組合所得之產品且包括治療劑之固定及非固定組合。術語「固定組合」意謂同時以單一實體或劑量之形式向患者投與治療劑，例如本發明之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)及組合配偶體。術語「非固定組合」意謂作為單獨實體同時、並行或依次(無特定時間限制)向患者投與治療劑，例如本發明之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)及組合配偶體，其中此類投與在患者體內提供兩種化合物之治療有效水準。後者亦適用於雞尾酒療法，例如 投與三種或更多種治療劑。The term "combination" refers to a fixed combination or combined administration in one dosage unit form in which a compound of the invention ( e.g., formula (I), (Ia) may be administered independently simultaneously or separately at time intervals. ), (Ib), (Ic) and (Id) compounds or a compound of Table 1 or a pharmaceutically acceptable salt thereof) and a combination partner ( for example, another drug as explained below, also known as "therapeutic"agent" or "co-agent"), especially wherein such time intervals allow the combination partners to exhibit synergistic, eg, synergistic, effects. Individual components can be packaged in kits or individually. One or both components ( eg, powder or liquid) can be reconstituted or diluted to the desired dose prior to administration. The terms "co-administered" or "administered in combination" or the like, as used herein, are meant to encompass the administration of a selected combination of partners to a single individual ( eg, a patient) in need thereof and are intended to include therapeutic regimens wherein such The agents need not be administered by the same route of administration or administered simultaneously. The term "pharmaceutical combination" as used herein means a product resulting from mixing or combining more than one therapeutic agent and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that a therapeutic agent, such as a compound of the invention ( eg, Formula (I), (Ia), (Ib), (Ic), and (Id), is administered to a patient simultaneously in the form of a single entity or dose. compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof) and a combination partner. The term "non-fixed combination" means the simultaneous, concurrent or sequential (without specific time limitation) administration to a patient as separate entities of a therapeutic agent, such as a compound of the invention ( e.g., formula (I), (Ia), (Ib), Compounds (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) and a combination partner, wherein such administration provides therapeutically effective levels of both compounds in the patient. The latter also applies to cocktail therapy, such as the administration of three or more therapeutic agents.

術語「組合療法」係指投與兩種或更多種治療劑以治療本揭露中所述之治療性疾患或病症。此種投與涵蓋以實質上同時之方式，諸如以具有固定比率之活性成分之單一膠囊共同投與這些治療劑。替代地，此種投與涵蓋針對各活性成分以多個或單獨容器(例如， 錠劑、膠囊、粉劑或液體)共同投與。粉劑及/或液體可在投與前經重構或稀釋至所要劑量。此外，此種投與亦涵蓋以連續方式大約同時或在不同時間使用各類型之治療劑。The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic disorder or condition described in this disclosure. Such administration encompasses co-administration of the therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers ( eg, lozenges, capsules, powders, or liquids) for each active ingredient. Powders and/or liquids can be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner at about the same time or at different times.

在某些實施例中，本發明之化合物與其他治療劑組合，其他治療劑包括但不限於其他抗癌劑、抗過敏劑、止吐劑(或止吐劑)、鎮痛藥、細胞保護劑及其組合。In certain embodiments, the compounds of the present invention are combined with other therapeutic agents including, but not limited to, other anticancer agents, antiallergic agents, antiemetics (or antiemetics), analgesics, cytoprotective agents, and its combination.

認為用於組合療法中之一般化學治療劑包括阿納托唑(anastrozole)(Arimidex®)、比卡魯胺(bicalutamide)(Casodex®)、硫酸博萊黴素(Blenoxane®)、布他卡因(Myleran®)、布他卡因注射液(Busulfex®)、卡倍他濱 (Xeloda®)、N4-戊氧基羰基-5-去氧-5-氟胞苷、卡鉑(Paraplatin®)、雙氯乙基亞硝脲(BiCNU®)、氯芥苯丁酸(Leukeran®)、順鉑(Platinol®)、克拉利賓(Leustatin®)、環磷醯胺(Cytoxan®或Neosar®)、阿糖胞苷、胞嘧啶阿拉伯醣(Cytosar-U®)、阿糖胞苷脂質體注射液(DepoCyt®)、甲嗪咪唑胺(DTIC-Dome®)、放線菌素(放線菌素D、Cosmegan)、鹽酸道諾黴素(Cerubidine®)、檸檬酸道諾黴素脂質體注射液(DaunoXome®)、地塞米松、多烯紫杉醇(Taxotere®)、鹽酸多柔比星(Adriamycin®、Rubex®)、依託泊苷(Vepesid®)、磷酸氟達拉濱(Fludara®)、5-氟尿嘧啶(Adrucil®、Efudex®)、氟化醯胺(Eulexin®)、替紮他濱(tezacitibine)、吉西他濱(二氟去氧胞二磷膽鹼)、羥基脲(Hydrea®)、依達比星(Idarubicin)(Idamycin®)、依弗醯胺(IFEX®)、伊立替康(Camptosar®)、L-天冬醯胺酸酶(ELSPAR®)、亞葉酸鈣、黴法蘭(Alkeran®)、6-巰基嘌呤(Purinethol®)、胺甲喋呤(Folex®)、米托蒽醌(Novantrone®)、米羅他(mylotarg)、紫杉醇(Taxol®)、白蛋白結合型紫杉醇(nab-paclitaxel)(Abraxane®)、phoenix(Yttrium90/MX-DTPA)、噴司他丁、具有雙氯乙基亞硝脲植入物之聚苯丙生20(Gliadel®)、檸檬酸他莫西芬(Nolvadex®)、替尼泊苷(Vumon®)、6-硫代鳥嘌呤、噻替派、替拉紮明(Tirazone®)、注射用鹽酸拓撲替康(Hycamptin®)、長春鹼(Velban®)、長春新鹼(Oncovin®)及長春瑞濱(Navelbine®)。Common chemotherapeutic agents considered for use in combination therapy include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), butacaine ( Myleran®), Butacaine Injection (Busulfex®), Capecitabine (Xeloda®), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), bischloroethyl nitrosourea (BiCNU®), chloramphenicol (Leukeran®) ), cisplatin (Platinol®), claribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinose (Cytosar-U®), cytarabine lipid Body Injection (DepoCyt®), Methazolamide (DTIC-Dome®), Actinomycin (Actinomycin D, Cosmegan), Daunomycin Hydrochloride (Cerubidine®), Daunomycin Citrate Liposome Injection Liquid (DaunoXome®), Dexamethasone, Docetaxel (Taxotere®), Doxorubicin Hydrochloride (Adriamycin®, Rubex®), Etoposide (Vepesid®), Fludarabine Phosphate (Fludara®), 5 - Fluorouracil (Adrucil®, Efudex®), amide fluoride (Eulexin®), tezacitibine (tezacitibine), gemcitabine (citicoline difluorodeoxycitabine), hydroxyurea (Hydrea®), idarubicin Idarubicin (Idamycin®), Efamide (IFEX®), Irinotecan (Camptosar®), L-asparaginase (ELSPAR®), Calcium Folinate, Alkeran® , 6-mercaptopurine (Purinethol®), ammethopterin (Folex®), mitoxantrone (Novantrone®), milostat (mylotarg), paclitaxel (Taxol®), nab-paclitaxel ) (Abraxane®), phoenix (Yttrium90/MX-DTPA), pentostatin, polystyrene 20 with diclofenac implant (Gliadel®), tamoxifen citrate (Nolvadex) ®), teniposide (Vumon®), 6-thioguanine, thiatepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), Vincristine (Oncovin®) and Vinorelbine (Navelbine®).

與本發明之化合物組合的特別感興趣之其他化合物包括：EGFR抑制劑，諸如西妥昔單抗(cetuximab)、帕尼單抗(panitumimab)、厄羅替尼(erlotinib)、吉非替尼(gefitinib)及EGFRi NOS；MAPK路徑抑制劑，諸如BRAFi、panRAFi、MEKi、ERKi；PI3K-mTOR路徑抑制劑，諸如α特異性PI3Ki、泛I類PI3Ki及mTOR/PI3Ki，特別為依維莫司(everolimus)及其衍生物。Other compounds of particular interest in combination with the compounds of the invention include: EGFR inhibitors such as cetuximab, panitumimab, erlotinib, gefitinib ( gefitinib) and EGFRi NOS; MAPK pathway inhibitors such as BRAFi, panRAFi, MEKi, ERKi; PI3K-mTOR pathway inhibitors such as alpha-specific PI3Ki, pan-class I PI3Ki and mTOR/PI3Ki, in particular everolimus ) and its derivatives.

經由特定機制起作用之特定化合物及化合物類別可特別有效地與PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA 協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)結合。例如，已知PRMT5與SWI/SNF染色質重建複合物連同其他共阻遏蛋白分子(如HDAC2)締合。當離胺酸殘基由HDAC酶去乙醯化時，PRMT5對靶標H4R3及H3R8之活性得到增強。因此，當與PRMT5抑制劑結合使用時，HDAC抑制劑可為有效的(例如， 協同)(WO 011/079236)。Particular compounds and classes of compounds that act via specific mechanisms can be particularly effective with PRMT5 inhibitors ( eg, MTA uncompetitive, non-competitive or mixed mode PRMT5 inhibitors or MTA synergistic binders such as formula (I), (Ia) ), (Ib), (Ic) and (Id) compounds or a compound of Table 1 or a pharmaceutically acceptable salt thereof) combined. For example, PRMT5 is known to associate with the SWI/SNF chromatin remodeling complex along with other co-repressor molecules such as HDAC2. The activity of PRMT5 towards targets H4R3 and H3R8 is enhanced when lysine residues are deacetylated by HDAC enzymes. Thus, HDAC inhibitors can be effective ( eg, synergistic) when used in combination with PRMT5 inhibitors (WO 011/079236).

因此，本揭露之PRMT5抑制劑可與例如以下之化合物組合使用：HDAC抑制劑或DNA甲基轉移酶抑制劑。在一些實施例中，HDAC抑制劑為曲古黴素A。在一些實施例中，DNA甲基轉移酶抑制劑為5-氮雜胞苷。Thus, PRMT5 inhibitors of the present disclosure can be used in combination with compounds such as HDAC inhibitors or DNA methyltransferase inhibitors. In some embodiments, the HDAC inhibitor is trichostatin A. In some embodiments, the DNA methyltransferase inhibitor is 5-azacytidine.

PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)亦可與MAT2A抑制劑一起投與或以任何次序共同投與。PRMT5 inhibitors ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of formula (I), (Ia), (Ib), (Ic) and (Id) 1 or a pharmaceutically acceptable salt thereof) can also be administered with a MAT2A inhibitor or co-administered in any order.

PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)亦可與和PRMT5功能相互作用或為其所需要的蛋白質之抑制劑(包括但不限於pICIN、WDR77或RIOK1)一起投與或以任何次序共同投與。PRMT5 inhibitors ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of formula (I), (Ia), (Ib), (Ic) and (Id) 1 or a pharmaceutically acceptable salt thereof) can also be administered together or in any order with inhibitors of proteins that interact with or are required for PRMT5 function (including but not limited to pICIN, WDR77 or RIOK1). vote.

PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可與HDM2抑制劑及/或5-FU組合投與。由於CDKN2A缺失引起了HDM2活化，所以觀測到野生型p53之損失。這與MTAP缺失細胞不能自內生甲基-硫腺苷(MTA)再利用ATP及甲硫胺酸有關。因此，腫瘤細胞針對5-FU及其他嘌呤類似物(例如， 6-硫鳥嘌呤、6-巰基嘌呤)具有不同敏感性。PRMT5 inhibitors ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of formula (I), (Ia), (Ib), (Ic) and (Id) 1 or a pharmaceutically acceptable salt thereof) can be administered in combination with an HDM2 inhibitor and/or 5-FU. Loss of wild-type p53 was observed due to HDM2 activation due to CDKN2A deletion. This is related to the inability of MTAP-deficient cells to reuse ATP and methionine from endogenous methyl-thioadenosine (MTA). Thus, tumor cells have differential sensitivity to 5-FU and other purine analogs ( eg, 6-thioguanine, 6-mercaptopurine).

考慮到CDKN2A/MTAP損失亦導致p16/CDK4/6路徑失調，PRMT5抑 制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可與CDK4抑制劑組合投與，CDK4抑制劑包括但不限於LEE011或CDK 4/6抑制劑(例如， 帕博西尼(Ibrance®)、瑞博西尼(ribociclib)(Kisqali®)及玻瑪西尼(Verzenio®))。Considering that CDKN2A/MTAP loss also results in deregulation of the p16/CDK4/6 pathway, PRMT5 inhibitors ( e.g., MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders such as formula (I), (Ia) ), (Ib), (Ic) and (Id) compounds or a compound of Table 1 or a pharmaceutically acceptable salt thereof) can be administered in combination with a CDK4 inhibitor, including but not limited to LEE011 or CDK 4/ 6 Inhibitors ( eg, palbociclib (Ibrance®), ribociclib (Kisqali®), and pomacetinib (Verzenio®)).

PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可與取決於個別靶腫瘤對相關路徑之依賴性的靶向治療組合投與，如藉由合適預測標記所確定，該等標記包括但不限於：HDM2i、PI3K/mTOR-I、MAPKi、RTKi、EGFRi、FGFRi、METi、IGFiRi、JAKi及WNTi之抑制劑。PRMT5 inhibitors ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of formula (I), (Ia), (Ib), (Ic) and (Id) 1 or a pharmaceutically acceptable salt thereof) can be administered in combination with targeted therapy depending on the dependence of the individual target tumor on the relevant pathway, as determined by suitable predictive markers, including but not limited to : Inhibitors of HDM2i, PI3K/mTOR-I, MAPKi, RTKi, EGFRi, FGFRi, METi, IGFiRi, JAKi and WNTi.

PRMT5抑制劑(例如， MTA無競爭性PRMT5抑制劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可與免疫療法組合投與。PRMT5 inhibitors ( eg, MTA uncompetitive PRMT5 inhibitors such as compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof ) can be administered in combination with immunotherapy.

在一些實施例中，本文所述之化合物與癌症免疫療法(例如， 檢查點阻斷抗體)一起用於治療例如 患有本文所述之疾病或病症(例如， 本文所述之癌症))之個體(例如， 人類個體)。In some embodiments, the compounds described herein are used in conjunction with cancer immunotherapy ( e.g., checkpoint blocking antibodies) to treat, e.g. , individuals with a disease or disorder described herein ( e.g., cancer described herein) ( eg, human individuals).

在一些實施例中，免疫治療劑為抗CTLA-4抗體(例如，伊匹單抗( ipilimumab)、曲美單抗(tremelimumab))。In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody ( eg, ipilimumab , tremelimumab).

在一些實施例中，免疫治療劑為抗PD-1配體(例如， PD-LI(例如， B7-HI或CD274)；或PD-L2(例如， B7-DC或CD273))。在一些實施例中，免疫治療劑為抗PD-1抗體(例如， 抗PD-1或抗PD-L1，例如 納武單抗(nivolumab)(亦即MDX-1106、BMS-936558、ONO-4538)；CT-011；AMP-224；派姆單抗(pembrolizumab)；皮立珠單抗(pidilizumab)；或MK-3475)。在一些實施例中，免 疫治療劑為抗PD-L1抗體(例如， BMS936559(亦即，MDX-1105)；MEDI4736；MSB0010718C(阿維魯單抗(avelumab))；或MPDL-3280A)。In some embodiments, the immunotherapeutic agent is an anti-PD-1 ligand ( eg, PD-LI ( eg, B7-HI or CD274); or PD-L2 ( eg, B7-DC or CD273)). In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody ( eg, anti-PD-1 or anti-PD-L1, eg , nivolumab) (ie, MDX-1106, BMS-936558, ONO-4538 ); CT-011; AMP-224; pembrolizumab; pidilizumab; or MK-3475). In some embodiments, the immunotherapeutic agent is an anti-PD-L1 antibody ( eg, BMS936559 (ie, MDX-1105); MEDI4736; MSB0010718C (avelumab); or MPDL-3280A).

在一些實施例中，免疫治療劑為檢查點阻斷抗體(例如， 抗TIM3、抗LAG3、抗TIGIT包括IMP321及MGA271)。In some embodiments, the immunotherapeutic agent is a checkpoint blocking antibody ( eg, anti-TIM3, anti-LAG3, anti-TIGIT including IMP321 and MGA271).

在一些實施例中，免疫治療劑為基於細胞之療法。在一些實施例中，基於細胞之療法為CAR-T療法。In some embodiments, the immunotherapeutic agent is cell-based therapy. In some embodiments, the cell-based therapy is CAR-T therapy.

在一些實施例中，免疫治療劑為共刺激抗體(例如， 抗4-1BB、抗OX40、抗GITR、抗CD27、抗CD40)。In some embodiments, the immunotherapeutic agent is a costimulatory antibody ( eg, anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

在一些實施例中，免疫治療劑為癌症疫苗，諸如新抗原。這些疫苗使用肽或RNA(例如，) 來開發。In some embodiments, the immunotherapeutic agent is a cancer vaccine, such as a neoantigen. These vaccines are developed using peptides or RNA ( eg, ) .

在一些實施例中，免疫治療劑為溶瘤病毒。In some embodiments, the immunotherapeutic agent is an oncolytic virus.

在一些實施例中，免疫治療劑為STING路徑促效劑。示範性STING促效劑包括MK-1454及ADU-S100。In some embodiments, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可與疾病特異性huMAB(例如抗HER3 huMAB)組合投與。PRMT5 inhibitors ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of formula (I), (Ia), (Ib), (Ic) and (Id) 1 or a pharmaceutically acceptable salt thereof) can be administered in combination with a disease-specific huMAB (eg, an anti-HER3 huMAB).

PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可與依賴於相關表面靶標在感興趣之靶腫瘤上之表現的ADC/ADCC組合投與。PRMT5 inhibitors ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of formula (I), (Ia), (Ib), (Ic) and (Id) A compound of 1, or a pharmaceutically acceptable salt thereof) can be administered in combination with ADC/ADCC that depends on the expression of the relevant surface target on the target tumor of interest.

一些患者可能在投與期間或之後經歷對本發明之化合物及/或其他抗癌劑之過敏反應；因此，通常投與抗過敏劑以使過敏反應之風險最小化。合適抗過敏劑包括皮質類固醇，包括但不限於地塞米松(例如， Decadron®)、氯地米 松(例如， Beclovent®)、氫皮質酮(亦稱為皮質酮、氫皮質酮琥珀酸鈉、氫皮質酮硫酸鈉，且以商品名Ala-Cort®、磷酸、Solu-Cortef®、Hydrocort Acetate®及Lanacort®銷售)、普賴蘇濃(以商品名Delta-Cortel®、Orapred®、Pediapred®及Prelone®銷售)、普賴蘇(以商品名Deltasone®、Liquid Red®、Meticorten®及Orasone®銷售)、甲基普賴蘇穠(亦稱為6-甲基普賴蘇穠、甲基普賴蘇穠乙酸酯、甲基普賴蘇穠琥珀酸鈉，以商品名Duralone®、Medralone®、Medrol®、M-Prednisol®及Solu-Medrol®銷售)；抗組胺劑，諸如苯海拉明(例如， Benadryl®)、羥嗪及塞浦西他啶；及支氣管擴張劑，諸如β-腎上腺素受體促效劑、阿布叔醇(albuterol)(例如， Proventil®)及叔丁喘甯(terbutaline)(Brethine®)。Some patients may experience allergic reactions to the compounds of the invention and/or other anticancer agents during or after administration; therefore, antiallergic agents are typically administered to minimize the risk of allergic reactions. Suitable antiallergic agents include corticosteroids, including but not limited to dexamethasone ( eg, Decadron®), beclomethasone ( eg, Beclovent®), hydrocorticosterone (also known as corticosterone, hydrocorticosterone sodium succinate, hydrocortisone Sodium corticosterone sulfate, sold under the tradenames Ala-Cort®, Phosphoric Acid, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), Presolum (under the tradenames Delta-Cortel®, Orapred®, Pediapred®, and Prelone ® sold under the trade names Deltasone®, Liquid Red®, Meticorten® and Orasone®), Methyl Prisul (also known as 6-Methyl Prisul, Methyl Prisul Acetate, Sodium Methylpresulin Succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol®, and Solu-Medrol®); antihistamines, such as diphenhydramine ( For example, Benadryl®), hydroxyzine, and cypricitidine; and bronchodilators, such as beta-adrenergic agonists, albuterol ( eg, Proventil®), and terbutaline (Brethine®).

一些患者可能在投與本發明之化合物及/或其他抗癌劑期間及之後經歷乾嘔；因此，在預防乾嘔(上胃)及嘔吐時使用止吐劑。合適止吐劑包括阿瑞吡坦(Emend®)、奧丹西隆(ondansetron)(Zofran®)、格拉息沖HCl(Kytril®)、勞拉西泮(Ativan®)、地塞米松(Decadron®)、普魯氯嗪(Compazine®)、卡索匹坦(casopitant)(Rezonic®及Zunrisa®)及其組合。Some patients may experience retching during and after administration of the compounds of the invention and/or other anticancer agents; therefore, antiemetics are used to prevent retching (upper stomach) and vomiting. Suitable antiemetics include aprepitant (Emend®), ondansetron (Zofran®), glazide HCl (Kytril®), lorazepam (Ativan®), dexamethasone (Decadron®) ), prochlorazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof.

通常開具緩解在治療期期間經歷之疼痛的藥劑之處方以使患者更舒適。通常使用常用成藥止痛劑，諸如Tylenol®。然而，類鴉片止痛劑亦可用於中度或重度疼痛，其包括但不限於氫可酮/乙醯胺苯酚或氫可酮/乙醯胺苯酚(例如， Vicodin®)、嗎啡(例如， Astramorph®或Avinza®)、羥考酮(例如，OxyContin ®或Percocet®)、鹽酸氧化嗎啡酮(Opana®)及酚太尼(例如， Duragesic®)。Medications to relieve pain experienced during the treatment period are often prescribed to make the patient more comfortable. Common over-the-counter pain relievers such as Tylenol® are often used. However, opioid analgesics may also be used for moderate or severe pain, including but not limited to hydrocodone/acetaminophen or hydrocodone/acetaminophen ( eg, Vicodin®), morphine ( eg, Astramorph®) or Avinza®), oxycodone ( eg, OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), and fentanyl ( eg, Duragesic®).

為了保護正常細胞免於治療毒性且限制器官毒性，可使用細胞保護劑(諸如神經保護劑、自由基清除劑、心臟保護劑、蒽環外滲中和劑、營養素等)作為輔助療法。合適細胞保護劑包括阿咪福汀(Ethyol®)、麩醯胺、地美司(dimesna)(Tavocept®)、美司納(mesna)(Mesnex®)、地拉佐生(dexrazoxane)(Zinecard®或Totect®)、紮利羅登(xaliproden)(Xaprila®)及菊白葉酸(亦稱為菊白 葉酸鈣、嗜橙菌因子及醛葉酸)。To protect normal cells from therapeutic toxicity and limit organ toxicity, cytoprotective agents (such as neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) can be used as adjunctive therapy. Suitable cytoprotective agents include amifotine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard®) or Totect®), xaliproden (Xaprila®) and chrysanthemum folic acid (also known as chrysanthemum Calcium folic acid, citronella factor and aldehyde folic acid).

藉由編碼、通用名或商標名識別之活性化合物之結構可自實際版本之標準綱要「The Merck Index」或資料庫(例如， Patents International(例如， IMS World Publications))獲得。Structures of active compounds identified by code, generic or trade name can be obtained from actual editions of the standard compendium "The Merck Index" or from databases ( eg, Patents International ( eg, IMS World Publications)).

可與本發明之化合物組合使用之上述化合物可如此項技術中所述來製備及投與，包括但不限於上文引用之文獻。The aforementioned compounds that can be used in combination with the compounds of the present invention can be prepared and administered as described in the art, including but not limited to the references cited above.

在一個實施例中，本發明提供醫藥組成物，其包含本發明之至少一種化合物(例如， PRMT5抑制劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)或其醫藥學上可接受之鹽連同適用於單獨或連同其他抗癌劑一起向人類或動物個體投與之醫藥學上可接受之載劑。In one embodiment, the present invention provides pharmaceutical compositions comprising at least one compound of the present invention ( eg, a PRMT5 inhibitor, eg, a compound of formula (I), (Ia), (Ib), (Ic), and (Id) or a compound of Table 1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, alone or in combination with other anticancer agents.

在一個實施例中，本發明提供了治療患有或已診斷為患有MTAP缺乏及/或MTA累積增殖性病症(例如， 癌症)之人類或動物個體的方法，其包含向有需要之個體投與治療有效量之本發明之化合物(例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)或其醫藥學上可接受之鹽與第二治療劑之組合。In one embodiment, the present invention provides a method of treating a human or animal subject having or having been diagnosed with MTAP deficiency and/or an MTA accumulating proliferative disorder ( eg, cancer) comprising administering to an individual in need thereof A therapeutically effective amount of a compound of the present invention ( eg, a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1) or a pharmaceutically acceptable salt thereof and a second Combination of therapeutic agents.

在一個實施例中，本發明提供了治療有需要之個體中之MTAP缺乏及/或MTA累積增殖性病症(例如， 癌症)的方法，其包含向個體投與治療有效量之本發明之化合物(例如，式 (I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)或其醫藥學上可接受之鹽與第二治療劑之組合。In one embodiment, the invention provides a method of treating an MTAP deficiency and/or MTA accumulation proliferative disorder ( eg, cancer) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention ( For example, a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1) or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent.

具體而言，組成物將一起經調配為組合治療劑或經單獨投與。Specifically, the compositions will be formulated together as a combination therapeutic or administered separately.

在組合療法中，本發明之化合物及其他抗癌劑可同時、並行或依次(無特定時間限制)投與，其中此種投與在患者體內提供兩種化合物之治療有效水準。In combination therapy, the compounds of the present invention and other anticancer agents can be administered simultaneously, concurrently, or sequentially (without a specific time limit), wherein such administration provides therapeutically effective levels of both compounds in the patient.

在一較佳實施例中，本發明之化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)及其他抗癌劑通常藉由輸 注或經口以任何次序依次投與。給藥方案可根據疾病之狀態、患者之身體健適、個別藥物之安全性概況及個別藥物之耐受性以及主治醫師及投與該組合之開業醫生熟知之標準而改變。本發明之化合物及其他抗癌劑可根據用於治療之特定週期在彼此間隔數分鐘、數小時、數天或甚至數周投與。此外，週期可包括在治療週期期間且在每次藥物投與之不同劑量下一種藥物比另一種藥物更頻繁投與。In a preferred embodiment, a compound of the present invention ( eg, a compound of formula (I), (Ia), (Ib), (Ic), and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof ) and other anticancer agents are administered sequentially in any order, typically by infusion or orally. Dosage regimens may vary depending on the state of the disease, the physical fitness of the patient, the safety profile of the individual drug and the tolerability of the individual drug and criteria well known to the attending physician and the medical practitioner administering the combination. The compounds of the present invention and other anticancer agents can be administered minutes, hours, days, or even weeks apart from each other depending on the particular cycle used for treatment. In addition, a cycle may include administering one drug more frequently than the other during a treatment cycle and at a different dose each time the drug is administered.

在本發明之另一態樣中，提供了套組，其包括本發明之一或多種化合物(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)及如本文所揭示之第二治療劑。代表性套組包括：(a)本發明之化合物或其醫藥學上可接受之鹽(例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)；(b)至少一種其他治療劑，例如 ，如上文所指示，由此此種套組可包含包裝插頁或其他標籤，包括投與指導。In another aspect of the invention, kits are provided comprising one or more compounds of the invention ( eg, compounds of formula (I), (Ia), (Ib), (Ic), and (Id) or a compound of formula (I), (Ia), (Ib), (Ic), and (Id) 1 or a pharmaceutically acceptable salt thereof) and a second therapeutic agent as disclosed herein. Representative kits include: (a) a compound of the invention or a pharmaceutically acceptable salt thereof ( eg, a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 compound or a pharmaceutically acceptable salt thereof); (b) at least one other therapeutic agent, eg , as indicated above, whereby such a kit may include a package insert or other label, including administration instructions.

本發明之化合物(例如， 式(I)、(1a)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)亦可與已知治療過程(例如，激素或尤其輻射之投與)組合使用。本發明之化合物可特別用作輻射增敏劑，尤其用於治療對輻射療法表現出較差敏感性之腫瘤。Compounds of the invention ( eg, compounds of formulae (I), (1a), (Ib), (Ic) and (Id) or compounds of Table 1 or pharmaceutically acceptable salts thereof) can also be combined with known therapeutic procedures (eg administration of hormones or especially radiation). The compounds of the present invention are particularly useful as radiosensitizers, especially for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

在某些情況下，本發明之化合物與其他治療劑組合，其他治療劑包括但不限於其他抗癌劑、抗過敏劑、止吐劑(或止吐劑)、鎮痛藥、細胞保護劑及其組合。In certain instances, the compounds of the present invention are combined with other therapeutic agents, including, but not limited to, other anticancer agents, antiallergic agents, antiemetics (or antiemetics), analgesics, cytoprotective agents, and the like combination.

PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)亦可與一或多種DNA損傷路徑抑制劑一起投與或以任何次序共同投與。在一些實施例中，DNA損傷路徑抑制劑選自由以下組成之群：博來黴素、ATM抑制劑(例如，AZD1390)、USP1抑制劑、WEE1抑制劑(例 如，AZD1775)及Chk1抑制劑(例如，AZD7762)。在一些實施例中，DNA損傷路徑抑制劑為DNA烷基化劑。PRMT5 inhibitors ( eg, MTA uncompetitive, uncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders, eg compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of formula (I), (Ia), (Ib), (Ic) and (Id) A compound of 1, or a pharmaceutically acceptable salt thereof) may also be administered with one or more DNA damage pathway inhibitors or co-administered in any order. In some embodiments, the DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (eg, AZD1390), a USP1 inhibitor, a WEE1 inhibitor (eg, AZD1775), and a Chk1 inhibitor (eg, AZD1775) , AZD7762). In some embodiments, the DNA damage pathway inhibitor is a DNA alkylating agent.

在一個實施例中，本發明提供醫藥組成物，其包含本發明之至少一種化合物(例如， PRMT5抑制劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物)或其醫藥學上可接受之鹽連同適用於單獨或連同PARP抑制劑一起向人類或動物個體投與之醫藥學上可接受之載劑。在一些實施例中，PARP抑制劑選自由以下組成之群：奧拉帕尼(olaprib)、盧卡帕尼(rucaparib)、尼拉帕尼(niraparib)、他拉唑帕尼(talazoparib)、維利帕尼(veliparib)、帕米帕尼(pamiparib)、CEP 9722、E7016、伊尼帕利蔔(iniparib)及3-胺基苯甲醯胺。In one embodiment, the present invention provides pharmaceutical compositions comprising at least one compound of the present invention ( eg, a PRMT5 inhibitor, eg, a compound of formula (I), (Ia), (Ib), (Ic), and (Id) or a compound of Table 1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, alone or in combination with a PARP inhibitor. In some embodiments, the PARP inhibitor is selected from the group consisting of olaprib, rucaparib, niraparib, talazoparib, vitamin C Veliparib, pamiparib, CEP 9722, E7016, iniparib and 3-aminobenzamide.

患者選擇及監測Patient selection and monitoring

在一個態樣中，本發明提供一種確定患有或已診斷為患有癌症之個體(例如， 癌症患者)是否將對使用PRMT5抑制劑(例如， MTA-無競爭性PRMT5抑制劑，例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之治療有反應的方法，其包含以下步驟：In one aspect, the invention provides a method for determining whether an individual with or diagnosed with cancer ( eg, a cancer patient) will use a PRMT5 inhibitor ( eg, an MTA-uncompetitive PRMT5 inhibitor, eg, formula ( I), (Ia), (Ib), (Ic) and (Id) a compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof) responsive method, comprising the steps of:

a)使自該個體獲得之測試樣品與能夠偵測具有MTAP缺乏及/或MTA累積之人類癌細胞之試劑接觸；及a) contacting a test sample obtained from the individual with an agent capable of detecting human cancer cells with MTAP deficiency and/or MTA accumulation; and

b)比較測試樣品與參考物(例如， 取自非癌或正常對照個體之參考樣品)，其中該測試樣品中存在MTAP缺乏及/或MTA累積指示個體將對使用PRMT5抑制劑(例如， MTA-無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之治療性治療有反應。b) Comparing the test sample to a reference ( eg, a reference sample taken from a non-cancer or normal control subject), wherein the presence of MTAP deficiency and/or MTA accumulation in the test sample indicates that the subject will be treated with a PRMT5 inhibitor ( eg, MTA- Non-competitive, non-competitive or mixed mode PRMT5 inhibitors or MTA synergistic binders such as compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of Table 1 or pharmaceutics thereof response to therapeutic treatment with the above acceptable salts).

在一個態樣中，本發明提供一種確定癌症是否將對使用PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受 之鹽)之治療有反應的方法，其包含以下步驟：In one aspect, the invention provides a method for determining whether a cancer will respond to the use of a PRMT5 inhibitor ( eg, MTA uncompetitive, non-competitive or mixed mode PRMT5 inhibitor or MTA synergistic binder, eg, formula (I), (Ia) ), (Ib), (Ic) and (Id) compounds or a compound of Table 1 or a pharmaceutically acceptable salt thereof) is responsive to a method comprising the steps of:

a)使自患有或已診斷為患有該癌症之個體獲得之測試樣品與能夠偵測具有MTAP缺乏及/或MTA累積之人類癌細胞之試劑接觸；及a) contacting a test sample obtained from an individual with or diagnosed with the cancer with an agent capable of detecting human cancer cells with MTAP deficiency and/or MTA accumulation; and

b)比較測試樣品與參考物(例如， 取自非癌或正常對照個體之參考樣品)，其中該測試樣品中存在MTAP缺乏及/或MTA累積指示癌症將對使用PRMT5抑制劑(例如， MTA-無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之治療性治療有反應。在一些實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。在一些實施例中，該方法進一步包含確定癌細胞中PRMT5之水準的步驟。當確定PRMT5抑制劑之治療有效劑量時，可考慮PRMT5表現水準。b) Comparing the test sample to a reference ( eg, a reference sample taken from a non-cancer or normal control individual), wherein the presence of MTAP deficiency and/or MTA accumulation in the test sample indicates that the cancer will respond to PRMT5 inhibitors ( eg, MTA- Non-competitive, non-competitive or mixed mode PRMT5 inhibitors or MTA synergistic binders such as compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of Table 1 or pharmaceutics thereof response to therapeutic treatment with the above acceptable salts). In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma. In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells. The level of PRMT5 expression can be considered when determining a therapeutically effective dose of a PRMT5 inhibitor.

在一個態樣中，本發明提供一種確定癌細胞對PRMT5抑制(例如， 使用MTA無競爭性PRMT5抑制劑，例如，式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽進行抑制)之敏感性的方法，其包含以下步驟：In one aspect, the invention provides a method for determining PRMT5 inhibition by cancer cells ( eg, using an MTA uncompetitive PRMT5 inhibitor, eg, formula (I), (Ia), (Ib), (Ic), and (Id) A method for inhibiting the sensitivity of a compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof, comprising the following steps:

a)檢定該癌細胞中MTAP之產生、水準、活性、表現或存在；a) assaying the production, level, activity, expression or presence of MTAP in the cancer cells;

b)比較癌細胞中MTAP之產生、水準、活性、表現或存在與分別非癌或正常對照細胞中MTAP之產生、水準、活性、表現或存在，其中癌細胞中水準、活性或表現降低指示MTAP缺乏，且其中MTAP缺乏指示該癌細胞對PRMT5抑制劑敏感。b) comparing the production, level, activity, expression or presence of MTAP in cancer cells to the production, level, activity, expression or presence of MTAP in non-cancer or normal control cells, respectively, wherein a decrease in level, activity or expression in cancer cells is indicative of MTAP Deficiency, and wherein MTAP deficiency, indicates that the cancer cells are sensitive to PRMT5 inhibitors.

在一些實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

在一個實施例中，本發明提供一種確定癌細胞對PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之敏感性的方法，其包含以下步驟：In one embodiment, the present invention provides a method for determining the ability of cancer cells to respond to a PRMT5 inhibitor ( eg, MTA non-competitive, non-competitive, or mixed-mode PRMT5 inhibitor or MTA synergistic binder, eg, formula (I), (Ia), (Ib), (Ic) and (Id) compound or the compound of Table 1 or its pharmaceutically acceptable salt) susceptibility method, it comprises the following steps:

a)檢定癌細胞及正常對照細胞中MTAP基因或其基因產物之水準、活性或表現，其中癌細胞中水準、活性或表現降低指示MTAP缺乏；b)檢定該癌細胞中之PRMT5表現；c)比較癌細胞及正常對照細胞中之PRMT5表現與PRMT5表現；其中PRMT5表現之相似性及該癌細胞中該MTAP缺乏之存在指示該細胞對PRMT5抑制劑敏感。a) assaying the level, activity or expression of the MTAP gene or its gene product in cancer cells and normal control cells, wherein a decrease in the level, activity or expression in cancer cells is indicative of MTAP deficiency; b) assaying PRMT5 expression in the cancer cells; c) PRMT5 expression in cancer cells and normal control cells was compared to PRMT5 expression; wherein the similarity in PRMT5 expression and the presence of the MTAP deficiency in the cancer cells indicated that the cells were sensitive to PRMT5 inhibitors.

在一些實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

在一個態樣中，本發明提供一種治療患有或已診斷為患有癌症(例 如， 與MTAP缺乏及/或MTA累積相關之癌症)之個體的治療性方法，其包含以下步驟：In one aspect, the present invention provides a therapeutic method of treating an individual suffering from or diagnosed with cancer ( eg , cancer associated with MTAP deficiency and/or MTA accumulation) comprising the steps of:

a)評定自該個體獲得之測試樣品中MTAP及/或MTA之水準(例如，藉由使樣品與能夠偵測自該個體獲得之測試樣品中之人類MTAP缺乏及/或MTA累積癌細胞的試劑接觸)，其中MTA水準可直接(例如，藉由 ELISA或LC-MS/MS)或間接(例如， 藉由SDMA修飾之蛋白ELISA或IHC或藉由RNA剪接)評定；a) assessing the level of MTAP and/or MTA in a test sample obtained from the individual (eg, by subjecting the sample to an agent capable of detecting human MTAP deficiency and/or MTA accumulating cancer cells in a test sample obtained from the individual) contact), wherein MTA levels can be assessed directly ( eg, by ELISA or LC-MS/MS) or indirectly ( eg, by SDMA-modified protein ELISA or IHC or by RNA splicing);

b)比較測試樣品與參考物(例如，取自非癌或正常對照個體之參考樣品)，其中該測試樣品中之MTAP缺乏及/或MTA累積指示該個體將對使用PRMT5抑制劑之治療性治療有反應；及b) Comparing the test sample to a reference (eg, a reference sample taken from a non-cancer or normal control individual), wherein MTAP deficiency and/or MTA accumulation in the test sample is indicative of the individual being responsive to therapeutic treatment with a PRMT5 inhibitor respond; and

c)向步驟b)中鑑別之個體投與治療有效量之PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)。c) administering to the individual identified in step b) a therapeutically effective amount of a PRMT5 inhibitor ( eg, MTA non-competitive, non-competitive or mixed mode PRMT5 inhibitor or MTA synergistic binder, eg formula (I), (Ia) ), (Ib), (Ic) and (Id) compounds or a compound of Table 1 or a pharmaceutically acceptable salt thereof).

在一個態樣中，本發明提供一種治療有需要之個體之癌症(例如， 與MTAP缺乏及/或MTA累積相關之癌症)的治療性方法，其包含以下步驟：In one aspect, the present invention provides a therapeutic method of treating cancer ( eg, cancer associated with MTAP deficiency and/or MTA accumulation) in an individual in need thereof, comprising the steps of:

a)評定自該個體獲得之測試樣品中MTAP及/或MTA之水準(例如，藉由使樣品與能夠偵測人類MTAP缺乏及/或MTA累積癌細胞的試劑接觸)，其中MTA水準可直接(例如，藉由ELISA或LC-MS/MS)或間接(例如，藉由SDMA修飾之蛋白ELISA或IHC或藉由RNA剪接)評定；a) assessing the level of MTAP and/or MTA in a test sample obtained from the individual (eg, by contacting the sample with an agent capable of detecting human MTAP-deficient and/or MTA-accumulating cancer cells), wherein MTA levels can be directly ( Assessed, for example, by ELISA or LC-MS/MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC or by RNA splicing);

b)比較測試樣品與參考物(例如，取自非癌或正常對照個體之參考樣品)，其中該測試樣品中之MTAP缺乏及/或MTA累積指示該癌症將對使用PRMT5抑制劑(例如MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑)之治療性治療有反應；及b) Comparing the test sample to a reference (eg, a reference sample taken from a non-cancer or normal control individual), wherein MTAP deficiency and/or MTA accumulation in the test sample indicates that the cancer will respond to treatment with a PRMT5 inhibitor (eg, MTA-free) Competitive, non-competitive or mixed mode PRMT5 inhibitor or MTA synergistic binder) responds to therapeutic treatment; and

c)向步驟b)中鑑別之個體投與治療有效量之PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、 (Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)。c) administering to the individual identified in step b) a therapeutically effective amount of a PRMT5 inhibitor ( eg, MTA non-competitive, non-competitive or mixed mode PRMT5 inhibitor or MTA synergistic binder, eg formula (I), (Ia) ), (Ib), (Ic) and (Id) compounds or a compound of Table 1 or a pharmaceutically acceptable salt thereof).

在一些實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

在一些實施例中，該方法進一步包含確定癌細胞中PRMT5之水準的步驟。In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells.

在一個態樣中，本發明提供一種治療患有或已診斷為患有與MTAP缺乏及/或MTA累積相關之癌症之個體的治療性方法，其包含以下步驟：In one aspect, the present invention provides a therapeutic method of treating an individual having or diagnosed with a cancer associated with MTAP deficiency and/or MTA accumulation, comprising the steps of:

a)評定自該個體獲得之測試樣品中MTAP及/或MTA之水準(例如，藉由使樣品與能夠偵測人類MTAP缺乏及/或MTA累積癌細胞的試劑接觸)，其中MTA水準可直接(例如，藉由ELISA或LC-MS/MS)或間接(例如，藉由SDMA修飾之蛋白ELISA或IHC或藉由RNA剪接)評定；a) assessing the level of MTAP and/or MTA in a test sample obtained from the individual (eg, by contacting the sample with an agent capable of detecting human MTAP-deficient and/or MTA-accumulating cancer cells), wherein MTA levels can be directly ( Assessed, for example, by ELISA or LC-MS/MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC or by RNA splicing);

b)比較測試樣品與參考樣品(例如，取自非癌或正常對照個體之參考樣品)，其中該測試樣品中之MTAP缺乏及/或MTA累積指示該癌症將對使用PRMT5樣品抑制劑(例如MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑)之治療性治療有反應；及b) Comparing the test sample to a reference sample (eg, a reference sample taken from a non-cancer or normal control individual), wherein MTAP deficiency and/or MTA accumulation in the test sample indicates that the cancer will be treated with a PRMT5 sample inhibitor (eg MTA) Responds to therapeutic treatment with non-competitive, non-competitive or mixed-mode PRMT5 inhibitors or MTA co-binders); and

c)向步驟b)中鑑別之個體投與治療有效量之組成物，其包含PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)。c) administering to the individual identified in step b) a therapeutically effective amount of a composition comprising a PRMT5 inhibitor ( eg, an MTA non-competitive, non-competitive or mixed-mode PRMT5 inhibitor or an MTA synergistic binder, such as a formula ( I), (Ia), (Ib), (Ic) and (Id) compounds or compounds of Table 1 or pharmaceutically acceptable salts thereof).

在一個態樣中，本發明提供一種治療有需要之個體之與MTAP缺乏及 /或MTA累積相關之癌症的治療性方法，其包含以下步驟：In one aspect, the present invention provides a method of treating an individual in need thereof with MTAP deficiency and A therapeutic method for cancer associated with MTA accumulation, comprising the steps of:

a)評定自該個體獲得之測試樣品中MTAP及/或MTA之水準(例如，藉由使樣品與能夠偵測人類MTAP缺乏及/或MTA累積癌細胞的試劑接觸)，其中MTA水準可直接(例如，藉由ELISA或LC-MS/MS)或間接(例如，藉由SDMA修飾之蛋白ELISA或IHC或藉由RNA剪接)評定；a) assessing the level of MTAP and/or MTA in a test sample obtained from the individual (eg, by contacting the sample with an agent capable of detecting human MTAP-deficient and/or MTA-accumulating cancer cells), wherein MTA levels can be directly ( Assessed, for example, by ELISA or LC-MS/MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC or by RNA splicing);

b)比較測試樣品與參考樣品(例如，取自非癌或正常對照個體之參考樣品)，其中該測試樣品中之MTAP缺乏及/或MTA累積指示該癌症將對使用PRMT5樣品抑制劑(例如MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑)之治療性治療有反應；及b) Comparing the test sample to a reference sample (eg, a reference sample taken from a non-cancer or normal control individual), wherein MTAP deficiency and/or MTA accumulation in the test sample indicates that the cancer will be treated with a PRMT5 sample inhibitor (eg MTA) Responds to therapeutic treatment with non-competitive, non-competitive or mixed-mode PRMT5 inhibitors or MTA co-binders); and

c)向步驟b)中鑑別之個體投與治療有效量之組成物，其包含PRMT5抑制劑(例如， MTA無競爭性PRMT5抑制劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)。c) administering to the individual identified in step b) a therapeutically effective amount of a composition comprising a PRMT5 inhibitor ( eg, an MTA uncompetitive PRMT5 inhibitor, eg, formula (I), (Ia), (Ib), ( Ic) and (Id) compounds or compounds of Table 1 or pharmaceutically acceptable salts thereof).

在一些實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

在一些實施例中，該方法進一步包含確定癌細胞中PRMT5之水準的步驟。In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells.

在一個態樣中，本發明提供一種確定患有或已診斷為患有與MTAP缺乏及/或MTA累積相關之癌症的個體是否將對使用PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、 (Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之治療有反應的方法，其包含以下步驟：In one aspect, the invention provides a method for determining whether an individual with or diagnosed with a cancer associated with MTAP deficiency and/or MTA accumulation will be treated with a PRMT5 inhibitor ( eg, MTA non-competitive, non-competitive or Treatment of mixed-mode PRMT5 inhibitors or MTA co-binders, such as compounds of formula (I), (Ia), (Ib), (Ic), and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) A reactive method comprising the following steps:

a)評定自該個體獲得之測試樣品中MTAP及/或MTA之水準(例如，藉由使樣品與能夠偵測人類MTAP缺乏及/或MTA累積癌細胞的試劑接觸)，其中MTA水準可直接(例如，藉由ELISA或LC-MS/MS)或間接(例如，藉由SDMA修飾之蛋白ELISA或IHC或藉由RNA剪接)評定；a) assessing the level of MTAP and/or MTA in a test sample obtained from the individual (eg, by contacting the sample with an agent capable of detecting human MTAP-deficient and/or MTA-accumulating cancer cells), wherein MTA levels can be directly ( Assessed, for example, by ELISA or LC-MS/MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC or by RNA splicing);

b)比較測試樣品與參考物(例如，取自非癌或正常對照個體之參考樣品)，其中該測試樣品中之MTAP缺乏及/或MTA累積指示該個體將對使用PRMT5抑制劑(例如MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑)之治療性治療有反應；及b) Comparing the test sample to a reference (eg, a reference sample taken from a non-cancer or normal control individual), wherein MTAP deficiency and/or MTA accumulation in the test sample indicates that the individual will respond to the use of a PRMT5 inhibitor (eg, MTA-free) Competitive, non-competitive or mixed mode PRMT5 inhibitor or MTA synergistic binder) responds to therapeutic treatment; and

在一個態樣中，本發明提供一種確定與MTAP缺乏及/或MTA累積相關之癌症是否將對使用PRMT5抑制劑(例如，MTA無競爭性PRMT5抑制劑，例如， 式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之治療有反應的方法，其包含以下步驟：In one aspect, the invention provides a method for determining whether a cancer associated with MTAP deficiency and/or MTA accumulation will be treated with a PRMT5 inhibitor (eg, an MTA-uncompetitive PRMT5 inhibitor, eg, formula (I), (Ia) , (Ib), (Ic) and (Id) compounds or compounds of Table 1 or pharmaceutically acceptable salts thereof) are responsive to a method comprising the steps of:

a)評定自患有或已診斷為患有該癌症之個體獲得之測試樣品中MTAP及/或MTA之水準(例如，藉由使樣品與能夠偵測人類MTAP缺乏及/或MTA累積癌細胞的試劑接觸)，其中MTA水準可直接(例如，藉由ELISA或LC-MS/MS)或間接(例如，藉由SDMA修飾之蛋白ELISA或IHC或藉由RNA剪接)評定；a) Assessing levels of MTAP and/or MTA in test samples obtained from individuals with or diagnosed with the cancer (eg, by subjecting the samples to reagents capable of detecting human MTAP-deficient and/or MTA-accumulating cancer cells contact), wherein MTA levels can be assessed directly (eg, by ELISA or LC-MS/MS) or indirectly (eg, by SDMA-modified protein ELISA or IHC or by RNA splicing);

b)比較測試樣品與參考物(例如，取自非癌或正常對照個體之參考樣品)，其中該測試樣品中之MTAP缺乏及/或MTA累積指示該癌症將對使用PRMT5抑制劑(例如MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑)之治療性治療有反應；及b) Comparing the test sample to a reference (eg, a reference sample taken from a non-cancer or normal control individual), wherein MTAP deficiency and/or MTA accumulation in the test sample indicates that the cancer will respond to treatment with a PRMT5 inhibitor (eg, MTA-free) Competitive, non-competitive or mixed mode PRMT5 inhibitor or MTA synergistic binder) responds to therapeutic treatment; and

在一些實施例中，癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿 路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urothelial carcinoma) , pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, Diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer , pleural or colorectal cancer or sarcoma.

在一些實施例中，該方法進一步包含確定癌細胞中PRMT5之水準的步驟。In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells.

樣品製備Sample Preparation

本發明進一步提供用於偵測MTAP缺乏及/或MTA累積之檢定。其可包括偵測例如體液諸如血液(例如， 血清或血漿)、骨髓、腦脊髓液、腹膜液/胸膜液、淋巴液、腹水、漿液、痰、淚液、糞便及尿或在諸如腫瘤組織之組織中涉及MTAP缺乏及/或MTA累積之突變。腫瘤組織可為新鮮組織或保存組織(例如， 福馬林固定組織，例如， 石蠟包埋組織)。The present invention further provides assays for detecting MTAP deficiency and/or MTA accumulation. It can include detection of, for example, body fluids such as blood ( eg, serum or plasma), bone marrow, cerebrospinal fluid, peritoneal/pleural fluid, lymph, ascites, serous fluid, sputum, tears, feces, and urine or in tissues such as tumor tissue. Mutations involving MTAP deficiency and/or MTA accumulation. Tumor tissue can be fresh tissue or preserved tissue ( eg, formalin-fixed tissue, eg, paraffin-embedded tissue).

體液樣品可使用此項技術中已知之任何方法自個體獲得。用於自體液樣品提取細胞DNA之方法為此項技術中熟知的。通常，用清潔劑裂解細胞。在細胞裂解後，使用各種蛋白酶自DNA移除蛋白質。然後用苯酚提取DNA，使其在醇中沉澱，且將其溶解於水性溶液中。用於自體液樣品提取非細胞DNA之方法亦為此項技術中已知的。通常，將體液樣品中之細胞DNA自細胞分離，在醇中沉澱，且溶解於水性溶液中。A body fluid sample can be obtained from an individual using any method known in the art. Methods for extracting cellular DNA from bodily fluid samples are well known in the art. Typically, cells are lysed with detergent. Following cell lysis, proteins are removed from DNA using various proteases. The DNA was then extracted with phenol, precipitated in alcohol, and dissolved in an aqueous solution. Methods for extraction of acellular DNA from bodily fluid samples are also known in the art. Typically, cellular DNA in a body fluid sample is isolated from cells, precipitated in alcohol, and dissolved in an aqueous solution.

PRMT5選擇性之偵測Selective detection of PRMT5

一旦製備了樣品，即可針對MTAP缺乏及/或MTA累積進行測試，其任一者或二者指示樣品對使用PRMT5抑制劑之治療敏感。可藉由此項技術中已知之技術確定細胞為MTA累積的；用於偵測MTA的方法包括(作為非限制性實例)液相層析-電噴霧電離-串聯式質譜法(LC-ESI-MS/MS)，如Stevens等人2010.J. Chromatogr.A.1217：3282-3288；及Kirovski等人2011 Am.J.Pathol.178：1145-1152及本文引用之參考文獻中所述。MTAP缺乏之偵測可藉由任何多種方式進行，例如：DNA定序、基於PCR之方法(包括RT-PCR)、微陣列分析、南方墨點、北方墨點、下一代定序及試紙條分析(dip stick analysis)。在一些實施例中，可藉由此項技術中已知之任何技術評估MTAP缺乏，該等技術例如利用抗MTAP抗體或其衍生物之免疫組織化學、及/或基因體定序、或核酸雜交、或利用至少一種包含MTAP序列之至少12個連續核苷酸(nt)之序列的探針或引子之擴增，其中引子不長於約30 nt。Once a sample is prepared, it can be tested for MTAP deficiency and/or MTA accumulation, either or both of which indicate that the sample is susceptible to treatment with a PRMT5 inhibitor. Cells can be determined to be MTA-accumulating by techniques known in the art; methods for detecting MTA include, by way of non-limiting example, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI- MS/MS), as in Stevens et al. 2010.J. Chromatogr. A. 1217: 3282-3288; and Kirovski et al. 2011 Am. J. Pathol. 178: 1145-1152 and references cited herein. Detection of MTAP deficiency can be performed by any of a variety of means, such as: DNA sequencing, PCR-based methods (including RT-PCR), microarray analysis, southern blots, northern blots, next-generation sequencing, and test strips Dip stick analysis. In some embodiments, MTAP deficiency can be assessed by any technique known in the art, such as immunohistochemistry using anti-MTAP antibodies or derivatives thereof, and/or genome sequencing, or nucleic acid hybridization, Or amplification using at least one probe or primer comprising a sequence of at least 12 contiguous nucleotides (nt) of the MTAP sequence, wherein the primer is no longer than about 30 nt.

聚合酶鏈反應(PCR)可用於由自腫瘤組織提取之基因體DNA或RNA進行擴增並鑑別MTAP缺乏。PCR為此項技術中熟知的且詳細描述於Saiki等人，Science 1988,239：487中。Polymerase chain reaction (PCR) can be used to amplify and identify MTAP deficiency from genomic DNA or RNA extracted from tumor tissue. PCR is well known in the art and is described in detail in Saiki et al., Science 1988, 239:487.

提供了藉由雜交偵測MTAP缺乏之方法。該方法包含藉由其不能與MTAP核酸雜交來鑑別樣品中之MTAP缺乏。核酸探針用標記諸如放射性同位素、螢光劑或顯色劑可偵測地標記。放射性同位素可包括但不限於3H、32P、33P及35S等。螢光劑可包括但不限於：FITC、德克薩斯紅、玫瑰紅等。Methods for detecting MTAP deficiency by hybridization are provided. The method comprises identifying MTAP deficiency in a sample by its inability to hybridize to MTAP nucleic acid. Nucleic acid probes are detectably labeled with labels such as radioisotopes, fluorescent agents, or chromogenic agents. Radioisotopes may include, but are not limited to, 3H, 32P, 33P, and 35S, among others. Fluorescent agents may include, but are not limited to: FITC, Texas Red, Rose Bengal, and the like.

用於偵測且能夠與MTAP核酸雜交之探針可為約8個核苷酸至約100個核苷酸、約10個核苷酸至約75個核苷酸、約15個核苷酸至約50個核苷酸或約20至約30個核苷酸。套組亦可提供用於分析患者癌症樣品之說明書，其中MTAP缺乏之存在或不存在指示個體對使用PRMT5抑制劑之治療敏感或不敏感。Probes for detection and capable of hybridizing to MTAP nucleic acids can range from about 8 nucleotides to about 100 nucleotides, about 10 nucleotides to about 75 nucleotides, about 15 nucleotides to About 50 nucleotides or about 20 to about 30 nucleotides. The kit may also provide instructions for analyzing a patient's cancer sample, wherein the presence or absence of MTAP deficiency indicates that the individual is sensitive or insensitive to treatment with a PRMT5 inhibitor.

單股構型多型性(SSCP)亦可用於偵測MTAP缺乏。此技術充分描述於Orita等人，PNAS 1989,86：2766-2770中。Single-strand configuration polymorphism (SSCP) can also be used to detect MTAP deficiency. This technique is fully described in Orita et al., PNAS 1989, 86:2766-2770.

基因表現之量測Measurement of gene expression

可使用此項技術中已知之任何方法或試劑進行MTAP缺乏之評估及MTAP基因表現之量測以及PRMT5基因表現之量測。Assessment of MTAP deficiency and measurement of MTAP gene expression and measurement of PRMT5 gene expression can be performed using any method or reagent known in the art.

基因表現之偵測可藉由任何適當方法進行，該等方法包括例如偵測自基因轉錄之mRNA之量、或由自基因轉錄之mRNA之逆轉錄所產生之cDNA之量、或由基因編碼之多肽或蛋白質之量。這些方法可藉由抽樣基礎(sample basis)對樣品進行或經修改以用於高通量分析。例如，使用AffymetrixTM U133微陣列晶片。Detection of gene expression can be performed by any suitable method including, for example, detecting the amount of mRNA transcribed from the gene, or the amount of cDNA produced by reverse transcription of mRNA transcribed from the gene, or the amount of cDNA encoded by the gene. The amount of polypeptide or protein. These methods can be performed on samples on a sample basis or modified for high throughput analysis. For example, Affymetrix ™ U133 microarray wafers are used.

在一個態樣中，偵測基因表現且藉由與同針對該生物標誌物之適當探針特異性雜交之探針雜交來定量。探針亦可連接至固體支持物以用於使用此項技術中已知之方法進行高通量篩選檢定。In one aspect, gene expression is detected and quantified by hybridization to a probe that specifically hybridizes to an appropriate probe for the biomarker. Probes can also be attached to solid supports for high throughput screening assays using methods known in the art.

在一個態樣中，透過將核酸樣品暴露於經探針修飾之晶片來確定基因之表現水準。較佳在擴增步驟期間，例如用螢光標籤標記所提取之核酸。In one aspect, the expression level of the gene is determined by exposing the nucleic acid sample to the probe-modified wafer. Preferably during the amplification step, the extracted nucleic acids are labeled, for example, with a fluorescent tag.

在適當嚴格性水準下進行經標記之樣品之雜交。使用偵測裝置定量地量測探針-核酸雜交程度。Hybridization of labeled samples is performed at appropriate levels of stringency. The degree of probe-nucleic acid hybridization is quantitatively measured using a detection device.

替代地，可使用已知技術確定基因拷貝數、轉錄或轉譯中之任一者。例如，擴增方法諸如PCR可為有用的。PCR之一般程序教示於MacPherson等人，PCR：A Practical Approach,(IRL Press at Oxford University Press(1991))中。然而，各應用反應之PCR條件係憑經驗確定的。許多參數影響反應之成功。該等參數為退火溫度及時間、延長時間、Mg2+及/或ATP濃度、pH以及引子、模板及去氧核糖核苷酸之相對濃度。擴增之後，可藉由瓊脂糖凝膠電泳，接著用溴化乙錠染色及紫外線照明進行可視化來偵測所得DNA片段。在一個實施例中，藉由偵測連接至樣品核酸之一或多種標記來偵測經雜交之核酸。標記可藉由熟習此項技術者熟知之多種手段中之任一者來併入。然而，在一個態樣中，標記在製備樣品核酸之擴增步驟期間同時併入。因此，例如，使用經標記之引子或經標記之核苷酸之聚合酶鏈反應(PCR)將提供經標記之擴增產物。在一單獨實施例中，使用經標記之核苷酸(例如，經螢光素標記之UTP及/或CTP)進行之如上文所述之轉 錄擴增將標記併入至經轉錄之核酸中。Alternatively, any of gene copy number, transcription or translation can be determined using known techniques. For example, amplification methods such as PCR may be useful. General procedures for PCR are taught in MacPherson et al., PCR: A Practical Approach, (IRL Press at Oxford University Press (1991)). However, PCR conditions for each application reaction are determined empirically. Many parameters affect the success of the reaction. These parameters are annealing temperature and time, extension time, Mg2+ and/or ATP concentration, pH, and relative concentrations of primer, template and deoxyribonucleotides. After amplification, the resulting DNA fragments can be detected by agarose gel electrophoresis followed by visualization with ethidium bromide staining and UV illumination. In one embodiment, the hybridized nucleic acid is detected by detecting one or more labels attached to the sample nucleic acid. Labels can be incorporated by any of a variety of means well known to those skilled in the art. However, in one aspect, the label is simultaneously incorporated during the amplification step of preparing the sample nucleic acid. Thus, for example, polymerase chain reaction (PCR) using labeled primers or labeled nucleotides will provide labeled amplification products. In a separate embodiment, the transformation as described above is performed using labeled nucleotides (eg, luciferin labeled UTP and/or CTP). Transcriptional amplification incorporates a marker into the transcribed nucleic acid.

替代地，標記可直接添加至初始核酸樣品(例如，mRNA、polyA、mRNA、cDNA等)或在擴增完成之後添加至擴增產物中。將標記連接至核酸之手段為熟習此項技術者熟知的且包括例如藉由將核酸進行激酶化且隨後將連接樣品核酸之核酸連接子連接(attachment/ligation)至標記(例如螢光團)來進行鏈裂移位或末端標記(例如，使用經標記之RNA)。Alternatively, the label can be added directly to the initial nucleic acid sample (eg, mRNA, polyA, mRNA, cDNA, etc.) or to the amplification product after amplification is complete. Means of attaching a label to a nucleic acid are well known to those skilled in the art and include, for example, by kinasening the nucleic acid and then attaching/ligation to the label (e.g., a fluorophore) a nucleic acid linker ligating the sample nucleic acid. Strand translocation or end labeling (eg, using labeled RNA) is performed.

在一個實例中，可透過原位雜交方案量測基因表現，原位雜交方案可偵測含有組織切片或細胞之載玻片上之RNA分子(例如，透過RNAscope®)。In one example, gene expression can be measured by in situ hybridization protocols that can detect RNA molecules on slides containing tissue sections or cells (eg, by RNAscope®).

適用於本發明中之可偵測標記包括可藉由分光、光化學、生物化學、免疫化學、電、光學或化學手段偵測之任何組成物。本發明中之有用標記包括用於用經標記之卵白素綴合物進行染色之生物素、磁性珠粒(例如DynabeadsTM )、螢光染料(例如螢光素、德克薩斯紅、玫瑰紅、綠色螢光素蛋白及其類似者)、放射性標記(例如，3H、125I、35S、14C或32P)、酶(例如辣根過氧化物酶、鹼性磷酸酶及ELISA中常用之其他酶)及熱量標記諸如膠態金或有色玻璃或塑膠(例如，聚苯乙烯、聚丙烯、乳膠等)珠粒。Detectable labels suitable for use in the present invention include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Useful labels in the present invention include biotin for staining with labeled avidin conjugates, magnetic beads (eg Dynabeads ™ ), fluorescent dyes (eg luciferin, Texas Red, Rose Bengal) , green luciferin and its analogs), radiolabels (eg, 3H, 125I, 35S, 14C, or 32P), enzymes (eg, horseradish peroxidase, alkaline phosphatase, and other enzymes commonly used in ELISA) and thermal markers such as colloidal gold or colored glass or plastic (eg, polystyrene, polypropylene, latex, etc.) beads.

標記之偵測為熟習此項技術者熟知的。因此，例如，放射性標記可使用照相膠片或閃爍計數器偵測，螢光標誌物可使用偵測發射光的光偵測器進行偵測。酶標記通常藉由為酶提供受質且偵測由酶對受質之作用所產生之反應產物來偵測，且藉由簡單可視化有色標記來偵測熱量標記。可偵測標記可在雜交之前或之後添加至靶(樣品)核酸，如WO 97/10365中所述。這些可偵測標記在雜交之前直接連接或併入至靶(樣品)核酸。相比之下，「間接標記」在雜交之後連接至雜種雙鏈體。一般而言，間接標記連接至在雜交之前已連接至靶核酸的結合部分。例如，靶核酸可在雜交之前經生物素化。在雜交之後，抗生物素蛋白綴合之螢光團將結合攜帶生物素之雜種雙連體，從而提供易於偵測之標記。 對於標記核酸且偵測經標記之經雜交核酸之方法的詳細綜述，參見Laboratory Techniques in Biochemistry and Molecular Biology，第24卷：Hybridization with Nucleic Acid Probes,P.Tijssen編Elsevier,N.Y.(1993)。Detection of markers is well known to those skilled in the art. Thus, for example, radioactive labels can be detected using photographic film or scintillation counters, and fluorescent labels can be detected using photodetectors that detect emitted light. Enzyme labels are typically detected by providing a substrate for the enzyme and detecting the reaction product resulting from the action of the enzyme on the substrate, and caloric labels by simply visualizing the colored label. A detectable label can be added to the target (sample) nucleic acid before or after hybridization, as described in WO 97/10365. These detectable labels are directly ligated or incorporated into the target (sample) nucleic acid prior to hybridization. In contrast, "indirect labels" are attached to hybrid duplexes after hybridization. Generally, the indirect label is attached to a binding moiety that has been attached to the target nucleic acid prior to hybridization. For example, the target nucleic acid can be biotinylated prior to hybridization. Following hybridization, the avidin-conjugated fluorophore will bind to the biotin-bearing hybrid duplex, providing an easily detectable label. For a detailed review of methods of labeling nucleic acids and detecting labeled hybridized nucleic acids, see Laboratory Techniques in Biochemistry and Molecular Biology, Vol. 24: Hybridization with Nucleic Acid Probes, Ed. P. Tijssen Elsevier, N.Y. (1993).

多肽之偵測Detection of peptides

可藉由檢查蛋白質表現或蛋白質產物來確定MTAP之蛋白質水準。確定蛋白質水準涉及量測在選擇性識別且結合自個體獲得之樣品中生物標誌物之多肽的抗體之間發生之任何免疫特異性結合之量，及比較此量與對照樣品中至少一種生物標誌物之免疫特異性結合的量。The protein level of MTAP can be determined by examining protein expression or protein product. Determining protein levels involves measuring the amount of any immunospecific binding that occurs between antibodies that selectively recognize and bind to a polypeptide of a biomarker in a sample obtained from an individual, and comparing this amount to at least one biomarker in a control sample the amount of immunospecific binding.

在此項技術中多種技術可用於蛋白質分析。該等技術包括但不限於放射性免疫檢定、ELISA(酶聯免疫吸附檢定)、「三明治」免疫檢定、免疫放射量檢定、原位免疫檢定(使用例如膠態金、酶或放射性同位素標記)、西方墨點分析、免疫沉澱檢定、免疫螢光檢定、流動式細胞測量術、免疫組織化學、HPLC、質譜、共軛焦顯微鏡、酶檢定、表面電漿子共振及PAGE-SDS。Various techniques are available for protein analysis in this art. Such techniques include, but are not limited to, radioimmunoassays, ELISA (enzyme-linked immunosorbent assays), "sandwich" immunoassays, immunodosimetry, in situ immunoassays (using, for example, colloidal gold, enzyme or radioisotope labeling), Western Ink dot analysis, immunoprecipitation assay, immunofluorescence assay, flow cytometry, immunohistochemistry, HPLC, mass spectrometry, conjugate focus microscopy, enzyme assay, surface plasmon resonance and PAGE-SDS.

相鄰生物標誌物Adjacent Biomarkers

若干其他生物標誌物在染色體9上在MTAP附近或與其相鄰。CDKN2A常常(若非總是)連同MTAP一起缺失。此區域中之額外基因或偽基因包括：C9orf53、ERVFRD-3、TUBB8P1、KHSRPP1、MIR31及MIR31HG。Several other biomarkers are near or adjacent to MTAP on chromosome 9. CDKN2A is often, if not always, deleted along with MTAP. Additional genes or pseudogenes in this region include: C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31 and MIR31HG.

在該等方法之一些實施例中，MTAP缺乏之細胞亦缺乏CDKN2A。在一些實施例中，MTAP缺乏之細胞亦缺乏以下中之一或多者：CDKN2A、C9orf53、ERVFRD-3、TUBB8P1、KHSRPP1、MIR31及MIR31HG。In some embodiments of these methods, the cells deficient in MTAP are also deficient in CDKN2A. In some embodiments, the MTAP-deficient cells are also deficient in one or more of CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

因此，在涉及評估細胞之MTAP缺乏或確定細胞是否為MTAP缺乏之步驟的各種方法中，此步驟可包含確定細胞是否缺乏這些標記中之一或多者之步驟：CDKN2A、C9orf53、ERVFRD-3、TUBB8P1、KHSRPP1、MIR31及MIR31HG。Thus, in various methods involving the step of assessing a cell for MTAP deficiency or determining whether a cell is MTAP deficient, this step may comprise the step of determining whether a cell lacks one or more of these markers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31 and MIR31HG.

因此，在一些實施例中，本揭露涵蓋：一種確定患有或已診斷為患 有癌症之個體是否將對使用PRMT5抑制劑(例如，MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑)之治療性治療有反應的方法，其包含以下步驟：Accordingly, in some embodiments, the present disclosure covers: a patient determined to have or has been diagnosed with A method for whether an individual with cancer will respond to therapeutic treatment with a PRMT5 inhibitor (eg, an MTA uncompetitive, non-competitive or mixed mode PRMT5 inhibitor or an MTA synergistic binder) comprising the steps of:

a)評估自該個體獲得之測試樣品之MTAP缺乏且評估自非癌或正常對照個體之參考樣品之MTAP缺乏，其中測試樣品中相對於參考樣品之MTAP缺乏指示個體將對使用PRMT5抑制劑(例如，MTA無競爭性PRMT5抑制劑，例如，式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之治療性治療有反應；其中藉由評估以下生物標誌物中之一或多者之缺乏來評估MTAP缺乏：CDKN2A、C9orf53、ERVFRD-3、TUBB8P1、KHSRPP1、MIR31及MIR31HG，且其中該方法可進一步包含以下步驟：a) assessing MTAP deficiency in a test sample obtained from the subject and assessing MTAP deficiency in a reference sample from a non-cancer or normal control subject, wherein the MTAP deficiency in the test sample relative to the reference sample is indicative of the subject's use of a PRMT5 inhibitor (e.g. , MTA uncompetitive PRMT5 inhibitors, for example, the therapeutic properties of compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or compounds of Table 1 or pharmaceutically acceptable salts thereof) responsive to treatment; wherein MTAP deficiency is assessed by assessing the absence of one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31 and MIR31HG, and wherein the method can further comprise the steps of :

b)確定個體之MTAP之水準，其中步驟a)及b)可以任何次序進行；b) determining the level of MTAP of the individual, wherein steps a) and b) can be performed in any order;

c)向個體投與治療有效量之PRMT5抑制劑(例如， MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)；及c) administering to the subject a therapeutically effective amount of a PRMT5 inhibitor ( eg, MTA uncompetitive, non-competitive or mixed mode PRMT5 inhibitor or MTA synergistic binder, eg, formula (I), (Ia), (Ib), (Ic) and (Id) a compound or a compound of Table 1 or a pharmaceutically acceptable salt thereof); and

d)在步驟c)後確定個體之PRMT5活性水準，其中PRMT5活性水準降低與癌症增殖之抑制相關，且其中步驟c)及d)在步驟a)及b)後進行。d) determining the level of PRMT5 activity in the individual after step c), wherein a reduced level of PRMT5 activity correlates with inhibition of cancer proliferation, and wherein steps c) and d) are performed after steps a) and b).

在一些實施例中，本揭露涵蓋：一種確定癌症是否將對使用PRMT5抑制劑(例如，MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑)之治療性治療有反應的方法，其包含以下步驟：In some embodiments, the present disclosure encompasses: a method for determining whether a cancer will respond to therapeutic treatment with a PRMT5 inhibitor (eg, an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA synergistic binder) method, which includes the following steps:

a)評估自患有或已診斷為患有癌症之個體獲得之測試樣品之MTAP缺乏且評估自非癌或正常對照個體之參考樣品之MTAP缺乏，其中測試樣品中相對於參考樣品之MTAP缺乏指示癌症將對使用PRMT5抑制劑(例如，MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之治療性治療有反 應；其中藉由評估以下生物標誌物中之一或多者之缺乏來評估MTAP缺乏：CDKN2A、C9orf53、ERVFRD-3、TUBB8P1、KHSRPP1、MIR31及MIR31HG，且其中該方法可進一步包含以下步驟：a) assessing MTAP deficiency in test samples obtained from individuals with or diagnosed with cancer and assessing MTAP deficiency in reference samples from non-cancerous or normal control individuals, wherein MTAP deficiency in the test sample relative to the reference sample is indicative of cancer PRMT5 inhibitors (eg, MTA uncompetitive, noncompetitive or mixed mode PRMT5 inhibitors or MTA synergistic binders such as formula (I), (Ia), (Ib), (Ic) and (Id) will be used The compound or the compound of Table 1 or a pharmaceutically acceptable salt thereof) is contraindicated in the therapeutic treatment should; wherein MTAP deficiency is assessed by assessing the absence of one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31 and MIR31HG, and wherein the method may further comprise the steps of:

b)確定個體之MTAP之水準，其中步驟a)及b)可以任何次序進行；b) determining the level of MTAP of the individual, wherein steps a) and b) can be performed in any order;

c)向個體投與治療有效量之PRMT5抑制劑(例如， MTA無競爭性PRMT5抑制劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)；及c) administering to the subject a therapeutically effective amount of a PRMT5 inhibitor ( eg, an MTA uncompetitive PRMT5 inhibitor, such as a compound of formula (I), (Ia), (Ib), (Ic) and (Id) or of Table 1 compound or a pharmaceutically acceptable salt thereof); and

d)在步驟c)後確定個體之PRMT5活性水準，其中PRMT5活性水準降低與癌症增殖之抑制相關，且其中步驟c)及d)在步驟a)及b)後進行。d) determining the level of PRMT5 activity in the individual after step c), wherein a reduced level of PRMT5 activity correlates with inhibition of cancer proliferation, and wherein steps c) and d) are performed after steps a) and b).

檢定生物標誌物及PRMT5抑制劑治療Characterization of biomarkers and PRMT5 inhibitor therapy

許多患者分層策略可用於找到可能對使用MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑(例如，本發明之PRMT5抑制劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)之PRMT5抑制敏感的患者，包括但不限於測試MTAP缺乏及/或MTA累積。A number of patient stratification strategies can be used to find non-competitive, non-competitive, or mixed-mode PRMT5 inhibitors or MTA synergistic binders (eg, PRMT5 inhibitors of the invention, such as formula (I), (Ia), Patients susceptible to PRMT5 inhibition of compounds (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof), including but not limited to testing for MTAP deficiency and/or MTA accumulation.

一旦已檢定了患者之MTAP缺乏及/或MTA累積且預測對使用PRMT5抑制劑之治療敏感，向患者投與任何PRMT5抑制劑(例如，MTA無競爭性、非競爭性或混合模式PRMT5抑制劑或MTA協同結合劑，例如式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物或表1之化合物或其醫藥學上可接受之鹽)可在整個治療時程中以一個劑量連續或間歇地實現。確定最有效的投與手段及劑量之方法為熟習此項技術者熟知的且將根據用於療法之組成物、療法之目的、欲治療之靶細胞及正治療之個體而變化。單次或多次投與可以由治療醫師選擇之劑量水準及模式進行。可憑經驗調節投與該等劑之合適劑量調配物及方法。Once a patient has been determined for MTAP deficiency and/or MTA accumulation and is predicted to be susceptible to treatment with a PRMT5 inhibitor, administer any PRMT5 inhibitor (eg, MTA uncompetitive, uncompetitive, or mixed-mode PRMT5 inhibitor or MTA synergistic binders, such as compounds of formula (I), (Ia), (Ib), (Ic) and (Id) or a compound of Table 1 or a pharmaceutically acceptable salt thereof) can be used throughout the course of treatment with A dose is delivered continuously or intermittently. Methods of determining the most effective means of administration and dosage are well known to those skilled in the art and will vary depending on the composition used for the therapy, the purpose of the therapy, the target cells to be treated, and the individual being treated. Single or multiple administrations can be carried out at the dose level and pattern selected by the treating physician. Suitable dosage formulations and methods of administering these agents can be adjusted empirically.

套組set

在一些實施例中，提供了與本發明之方法相關之套組。In some embodiments, kits are provided in connection with the methods of the present invention.

在一個實施例中，提供了一種用於預測患有或已診斷為患有MTAP缺乏相關癌症之個體對使用PRMT5抑制劑之治療的敏感性的方法。套組包含：i)能夠偵測人類MTAP缺乏及/或MTA累積癌細胞之試劑；及ii)關於如何使用該套組之說明書。In one embodiment, a method is provided for predicting susceptibility to treatment with a PRMT5 inhibitor in an individual having or diagnosed with a cancer associated with MTAP deficiency. The kit includes: i) an agent capable of detecting human MTAP deficient and/or MTA accumulating cancer cells; and ii) instructions on how to use the kit.

實例Example

為了使本文所述之本發明可得到更完整理解，闡述以下實例。提供了本申請案中描述之合成及生物學實例以說明本文所提供之化合物、醫藥組成物及方法且不應以任何方式解釋為限制其範圍。在以下合成實例中，以數字次序列出反應序列內實驗程序之描述。In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed in any way to limit their scope. In the following synthetic examples, descriptions of experimental procedures within reaction sequences are listed in numerical order.

縮寫abbreviation

總則General

ADDP 1,1'-(氮雜二羰基)二哌啶ADDP 1,1'-(azadicarbonyl)dipiperidine

anhy. 無水anhy. anhydrous

aq. 水性aq. water-based

satd. 飽和satd.

min(s) 分鐘min(s) minutes

hr(s) 小時hr(s) hours

mL 毫升mL milliliter

mmol 毫莫耳mmol millimoles

mol 莫耳mol mole

MS 質譜MS mass spectrometry

NMR 核磁共振NMR nuclear magnetic resonance

TLC 薄層層析TLC thin layer chromatography

HPLC 高效液相層析HPLC High Performance Liquid Chromatography

Me 甲基Me methyl

i -Pr 異丙基 i -Pr isopropyl

t -Bu 第三丁基 t -Bu tertiary butyl

t BuXPhos 2-二-第三丁基膦基-2',4',6'-三異丙基聯苯 t BuXPhos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

Ph 苯基Ph phenyl

Et 乙基Et ethyl

Bz 苯甲醯基Bz benzyl

RuPhos 2-二環己基膦基-2',6'-二異丙氧基聯苯RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

光譜spectrum

Hz 赫茲Hz Hertz

δ 化學位移δ chemical shift

J 偶合常數J coupling constant

s 單峰s singlet

d 雙峰d double peak

t 三重峰t triplet

q 四重峰q quartet

m 多重峰m multiplet

br 寬峰br broad peak

qd 雙峰之四重峰quartet of qd doublet

dquin 四重峰之雙峰dquin quartet of twin peaks

dd 雙峰之雙峰dd Twin Peaks of Twin Peaks

dt 三重峰之雙峰double peak of dt triplet

溶劑及試劑Solvents and Reagents

DAST 二乙胺基硫三氟化物DAST diethylaminosulfur trifluoride

CHCl3 氯仿CHCl 3 chloroform

DCM 二氯甲烷DCM dichloromethane

DMF 二甲基甲醯胺DMF Dimethylformamide

Et2 O 乙醚Et 2 O ether

EtOH 乙醇EtOH Ethanol

EtOAc 乙酸乙酯EtOAc Ethyl acetate

MeOH 甲醇MeOH methanol

MeCN 乙腈MeCN Acetonitrile

PE 石油醚PE petroleum ether

THF 四氫呋喃THF tetrahydrofuran

DMSO 二甲亞碸DMSO dimethyl sulfoxide

t -BuOK 第三丁醇鉀 t -BuOK potassium tertiary butoxide

9-BBN 9-硼雜雙環[3.3.1]壬烷9-BBN 9-borabicyclo[3.3.1]nonane

AcOH 乙酸AcOH acetic acid

HCl 鹽酸HCl hydrochloric acid

H2 SO4 硫酸H 2 SO 4 Sulfuric acid

NH4 Cl 氯化銨NH 4 Cl Ammonium Chloride

KOH 氫氧化鉀KOH Potassium Hydroxide

NaOH 氫氧化鈉NaOH sodium hydroxide

K2 CO3 碳酸鉀K 2 CO 3 Potassium Carbonate

Na2 CO3 碳酸鈉Na 2 CO 3 Sodium Carbonate

TFA 三氟乙酸TFA trifluoroacetic acid

Na2 SO4 硫酸鈉Na 2 SO 4 Sodium Sulfate

NaBH4 硼氫化鈉NaBH 4 sodium borohydride

NaHCO3 碳酸氫鈉NaHCO 3 Sodium Bicarbonate

LiHMDS 六甲基二矽基醯胺化鋰LiHMDS Lithium Hexamethyldisilazide

NaBH4 硼氫化鈉NaBH 4 sodium borohydride

Et3 N 三乙胺Et 3 N triethylamine

Py 吡啶Py pyridine

PCC 氯鉻酸吡啶PCC Pyridine Chlorochromate

DMAP 4-(二甲胺基)吡啶DMAP 4-(dimethylamino)pyridine

DIPEA N,N-二異丙基乙胺DIPEA N,N-Diisopropylethylamine

BINAP 2,2'-雙(二苯基磷烷基)-1,1'-聯萘BINAP 2,2'-bis(diphenylphosphonyl)-1,1'-binaphthyl

dppf 1,1'-雙(二苯基膦基)二茂鐵dppf 1,1'-bis(diphenylphosphino)ferrocene

PEP 磷(烯醇)丙酮酸PEP phosphorus(enol)pyruvic acid

LDH 乳酸去氫酶LDH lactate dehydrogenase

DTT DL-二硫蘇糖醇DTT DL-Dithiothreitol

BSA 牛血清白蛋白BSA bovine serum albumin

NADH 經還原之β -菸鹼醯胺腺嘌呤二核苷酸NADH reduced beta -nicotinamide adenine dinucleotide

Pd(t -Bu3 P)2 雙(第三丁基膦)鈀(0)Pd( t - Bu3P )2bis(tert - butylphosphine)palladium(0)

AcCl 乙醯氯AcCl Acetyl chloride

i -PrMgCl 異丙基氯化鎂 i -PrMgCl isopropyl magnesium chloride

TBSCl 第三丁基(氯)二甲基矽烷TBSCl tert-butyl(chloro)dimethylsilane

(i -PrO)4 Ti 四異丙醇鈦( i -PrO) 4 Ti titanium tetraisopropoxide

BHT 2,6-二-第三丁基-4-甲基苯氧化物BHT 2,6-di-tert-butyl-4-methylphenoxide

BzCl 苯甲醯氯BzCl benzyl chloride

CsF 氟化銫CsF Cesium Fluoride

DCC 二環己基碳二亞胺DCC dicyclohexylcarbodiimide

DMP 戴斯-馬丁高碘烷(Dess-Martin periodinane)DMP Dess-Martin periodinane

EtMgBr 乙基溴化鎂EtMgBr Ethylmagnesium Bromide

EtOAc 乙酸乙酯EtOAc Ethyl acetate

TEA 三乙胺TEA triethylamine

AlaOH 丙胺酸AlaOH Alanine

TBAF 四正丁基氟化銨TBAF Tetra-n-butylammonium fluoride

TBS 第三丁基二甲基矽基TBS tert-butyldimethylsilyl

TMS 三甲基矽基TMS trimethylsilyl

TMSCF3 (三氟甲基)三甲基矽烷TMSCF 3 (trifluoromethyl)trimethylsilane

Ts 對甲苯磺醯基Ts p-toluenesulfonyl

Bu 丁基Bu Butyl

Ti(O i Pr)4 四異丙氧基鈦Ti(O i Pr) 4 tetraisopropoxide titanium

LAH 氫化鋰鋁LAH Lithium Aluminum Hydride

LDA 二異丙基醯胺化鋰LDA Lithium Diisopropylamide

LiOH.H2 O 氫氧化鋰水合物LiOH.H 2 O Lithium Hydroxide Hydrate

MAD 雙(2,6-二-第三丁基-4-甲基苯氧化物)甲基鋁MAD bis(2,6-di-tert-butyl-4-methylphenoxide)methylaluminum

NBS N-溴琥珀醯亞胺NBS N-bromosuccinimide

Na2 SO4 硫酸鈉Na 2 SO 4 Sodium Sulfate

Na2 S2 O3 硫代硫酸鈉Na 2 S 2 O 3 Sodium Thiosulfate

PE 石油醚PE petroleum ether

MeCN 乙腈MeCN Acetonitrile

Boc 第三丁氧基羰基Boc tertiary butoxycarbonyl

MTBE 甲基第三丁基醚MTBE methyl tertiary butyl ether

DIAD 氮雜二甲酸二異丙酯DIAD Diisopropyl azadicarboxylate

一般實驗說明：General experiment instructions:

在以下實例中，化學試劑購自商業來源(諸如Alfa、Acros、Sigma Aldrich、TCI及Shanghai Chemical Reagent Company)，且不經進一步純化即使用。In the following examples, chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company) and used without further purification.

在一些實例中，使用HPLC(H2 O-MeOH；裝備有DAD及質量偵測器之Agilent 1260 Infinity系統，Waters Sunfire C18 OBD製備型管柱，100Å，5μm，19mm X 100mm及SunFire C18製備型保護筒，100Å，10μm，19mm X 10mm)進行中間物及最終化合物之純化。將材料溶解於0.7mL DMSO中。流速：30mL/min。經由分析性LCMS檢查所獲得級分之純度。當以溶液形式在層析之後直接獲得級分之後，記錄其光譜。加熱至80℃之後，在N2 流動下蒸發溶劑。基於層析後LCMS分析，將級分聯合。將固體級分溶解於0.5mL MeOH中且將其轉移至經預稱量之標記小瓶中。加熱至80℃之後，在N2 流動下再次蒸發所獲得之溶液。乾燥之後，使產物經歷使用乙腈-水混合物之凍乾且最終藉由LCMS及1 H NMR表徵。In some examples, HPLC (H 2 O-MeOH; Agilent 1260 Infinity system equipped with DAD and mass detector, Waters Sunfire C18 OBD preparative column, 100Å, 5 μm, 19mm×100mm, and SunFire C18 preparative protection was used cylinder, 100Å, 10μm, 19mm X 10mm) for purification of intermediates and final compounds. The material was dissolved in 0.7 mL of DMSO. Flow rate: 30 mL/min. The purity of the obtained fractions was checked via analytical LCMS. After the fractions were obtained directly after chromatography in solution, their spectra were recorded. After heating to 80 °C, the solvent was evaporated under N2 flow. Fractions were combined based on post-chromatographic LCMS analysis. The solid fraction was dissolved in 0.5 mL of MeOH and transferred to a pre-weighed labeled vial. After heating to 80 °C, the obtained solution was evaporated again under N2 flow. After drying, the product was subjected to lyophilization using an acetonitrile-water mixture and finally characterized by LCMS and 1 H NMR.

使用Brucker AVANCE DRX 500、Bruker 400分光計或Varian UNITYplus 400記錄核磁共振(NMR)光譜。使用溶劑殘留峰(CHCl3 ：7.27ppm)(甲醇-d 4 ：3.31ppm)(DMSO-d 6 ：2.50ppm)或四甲基矽烷(0.00ppm)作為內標準來將質子之化學位移報告為δ 標度之百萬分之一。在δ 標度上自CDCl3 之中央峰(77.00ppm)(甲醇-d 4 ：49.15ppm)(DMSO-d 6 ：39.51ppm)以ppm為單位報告13 C NMR光譜之化學位移。如下表示資料：化學位移、多重性(s=單峰，d=雙峰，t=三重峰，q=四重峰，qn=五重峰，sx=六重峰，sp=七重峰，m=多重峰，br=寬峰)、偶合常數(J ,Hz)及積分。Nuclear Magnetic Resonance (NMR) spectra were recorded using a Bruker AVANCE DRX 500, Bruker 400 Spectrometer or Varian UNITYplus 400. Chemical shifts of protons are reported as delta using solvent residual peaks ( CHCl3 : 7.27 ppm) (methanol - d4 : 3.31 ppm) ( DMSO - d6 : 2.50 ppm) or tetramethylsilane (0.00 ppm) as internal standards One millionth of a scale. Chemical shifts of13C NMR spectra are reported in ppm on the delta scale from the central peak of CDCl3 (77.00 ppm) (methanol - d4 : 49.15 ppm) ( DMSO - d6 : 39.51 ppm). Data are represented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, sx=sextet, sp=septet, m= Multiplet, br=broad), coupling constant ( J , Hz) and integration.

在某些實例中，在具有DAD\ELSD及Agilent LC\MSD VL(G1956A)、SL(G1956B)質譜儀之Agilent 1100系列LC/MSD系統或具有DAD\ELSD及Agilent LC\MSD SL(G6130A)、SL(G6140A)質譜儀之Agilent 1200 系列LC/MSD系統上記錄質譜。In certain instances, on an Agilent 1100 series LC/MSD system with DAD\ELSD and Agilent LC\MSD VL (G1956A), SL (G1956B) mass spectrometers or with DAD\ELSD and Agilent LC\MSD SL (G6130A), Agilent 1200 for SL (G6140A) mass spectrometer Mass spectra were recorded on a serial LC/MSD system.

使用陽性/陰性模式交換獲得所有LC/MS資料。All LC/MS data were obtained using a positive/negative mode exchange.

管柱Zorbax SB-C18 1.8μm 4.6x15mm快速解析筒(PN 821975-932)Column Zorbax SB-C18 1.8μm 4.6x15mm Rapid Resolution Cartridge (PN 821975-932)

流動相A-乙腈、0.1%甲酸Mobile phase A-acetonitrile, 0.1% formic acid

B-水(0.1%甲酸)B-water (0.1% formic acid)

流速3ml/minFlow rate 3ml/min

梯度0min-100% BGradient 0min-100% B

0.01min-100% B0.01min-100% B

1.5min-0% B1.5min-0% B

1.8min-0% B1.8min-0% B

1.81min-100% B1.81min-100% B

注入體積1μlInjection volume 1 μl

離子化模式大氣壓化學離子化(APCI)Ionization Mode Atmospheric Pressure Chemical Ionization (APCI)

掃描範圍m/z 80-1000。Scan range m/z 80-1000.

其他示範性分析性LC/MS儀器反條件描述於下文中：Other exemplary analytical LC/MS instrumental counter-conditions are described below:

儀器：Agilent LC1100-MS6100系列G1956B；管柱：Xbridge Shield RP-18，50 * 2.1mm * 5μm；流動相A：具有0.05% NH3 -H2 O(v%)之H2 O；流動相B：MeCN；流速：1.0mL/min；波長：UV 220nm、254nm；管柱溫度：30℃；MS離子化：ESI。Instrument: Agilent LC1100-MS6100 Series G1956B; Column: Xbridge Shield RP-18, 50*2.1mm*5μm; Mobile Phase A: H2O with 0.05% NH3 - H2O (v%); Mobile Phase B : MeCN; flow rate: 1.0 mL/min; wavelength: UV 220 nm, 254 nm; column temperature: 30°C; MS ionization: ESI.

0-30CD：梯度：在2分鐘內0%~30% B且在30%下保持0.48分鐘；0-30CD: Gradient: 0%~30% B in 2 minutes and hold at 30% for 0.48 minutes;

0-60CD：梯度：在2分鐘內0%~60% B且在60%下保持0.48分鐘；0-60CD: Gradient: 0%~60% B in 2 minutes and hold at 60% for 0.48 minutes;

10-80CD：梯度：在2分鐘內10%~80% B且在80%下保持0.48分鐘；10-80CD: Gradient: 10%~80% B in 2 minutes and hold at 80% for 0.48 minutes;

30-90CD：梯度：在2分鐘內30%~90% B且在90%下保持0.48分鐘；30-90CD: Gradient: 30%~90% B in 2 minutes and hold at 90% for 0.48 minutes;

50-100CD：梯度：在2分鐘內50%~100% B且在100%下保持0.48分鐘；50-100CD: Gradient: 50%~100% B in 2 minutes and hold at 100% for 0.48 minutes;

儀器：Agilent LC1100-MS6100系列G1956B；管柱：Xtimate C18，30 * 2.1mm * 3μm；流動相A：具有0.0375% TFA(v%)之H2 O；流動相B：具有0.01875% TFA(v%)之MeCN；流速：0.8mL/min；波長：UV 220nm、254nm；管柱溫度：50℃；MS離子化：ESI。Instrument: Agilent LC1100-MS6100 Series G1956B; Column: Xtimate C18, 30*2.1mm*3μm; Mobile Phase A: H2O with 0.0375% TFA (v%); Mobile Phase B: with 0.01875% TFA (v%) ) of MeCN; flow rate: 0.8 mL/min; wavelength: UV 220 nm, 254 nm; column temperature: 50° C.; MS ionization: ESI.

0-30AB：梯度：在3分鐘內0%~30% B且在30%下保持0.5分鐘；0-30AB: Gradient: 0%~30% B in 3 minutes and hold at 30% for 0.5 minutes;

0-60AB：梯度：在3分鐘內0%~60% B且在30%下保持0.5分鐘；0-60AB: Gradient: 0%~60% B in 3 minutes and hold at 30% for 0.5 minutes;

10-80AB：梯度：在3分鐘內10%~80% B且在30%下保持0.5分鐘；10-80AB: Gradient: 10%~80% B in 3 minutes and hold at 30% for 0.5 minutes;

30-90AB：梯度：在3分鐘內0%~30% B且在30%下保持0.5分鐘；30-90AB: Gradient: 0%~30% B in 3 minutes and hold at 30% for 0.5 minutes;

50-100AB：梯度：在3分鐘內50%~100% B且在100%下保持0.5分鐘；50-100AB: Gradient: 50%~100% B in 3 minutes and hold at 100% for 0.5 minutes;

儀器：Shimadzu LC20-MS2010；管柱：Agilent Pursit 5 C18 20 * 2.0mm；流動相A：具有0.0375% TFA(v%)之H2 O；流動相B：具有0.01875% TFA(v%)之MeCN；梯度：在0.7分鐘內5~95% B且在95%下保持0.4分鐘；流速：1.5mL/min；波長：UV 220nm、254nm、215nm；管柱溫度：50℃；MS離子化：ESI。Instrument: Shimadzu LC20-MS2010; Column: Agilent Pursit 5 C18 20*2.0mm; Mobile Phase A: H2O with 0.0375% TFA (v%); Mobile Phase B: MeCN with 0.01875% TFA (v%) ; Gradient: 5~95% B in 0.7 min and hold at 95% for 0.4 min; Flow rate: 1.5 mL/min; Wavelength: UV 220nm, 254nm, 215nm; Column temperature: 50°C; MS ionization: ESI.

儀器：Shimadzu LC20-MS2020；管柱：Agilent Pursit 5 C18 20 * 2.0mm；流動相A：具有0.0375% TFA(v%)之H2 O；流動相B：具有0.01875% TFA(v%)之MeCN；梯度：在0.7分鐘內5~95% B且在95%下保持0.4分鐘；流速：1.5mL/min；波長：UV 220nm、254nm；管柱溫度：50℃；MS離子化：ESI。Instrument: Shimadzu LC20-MS2020; Column: Agilent Pursit 5 C18 20*2.0mm; Mobile Phase A: H2O with 0.0375% TFA (v%); Mobile Phase B: MeCN with 0.01875% TFA (v%) ; Gradient: 5 to 95% B in 0.7 min and hold at 95% for 0.4 min; flow rate: 1.5 mL/min; wavelength: UV 220 nm, 254 nm; column temperature: 50°C; MS ionization: ESI.

示範性HPLC儀器反條件Exemplary HPLC Instrument Counter Conditions

儀器：Shimadzu LC20；管柱：YMC-Pack ODS-A 150 * 4.6mm；流動相A：具有0.06875% TFA(v%)之H2 O；流動相B：具有0.0625% TFA(v%)之MeCN：流速：1.5mL/min；波長：UV 220nm、215nm、254nm；管柱溫度：40℃。Instrument: Shimadzu LC20; Column: YMC-Pack ODS-A 150*4.6mm; Mobile Phase A: H2O with 0.06875% TFA (v%); Mobile Phase B: MeCN with 0.0625% TFA (v%) : Flow rate: 1.5mL/min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40°C.

0-30：梯度：在10分鐘內0~30% B且在30%下保持5分鐘；0-30: Gradient: 0~30% B in 10 minutes and hold at 30% for 5 minutes;

0~60：梯度：在10分鐘內0~60% B且在60%下保持5分鐘；0~60: Gradient: 0~60% B in 10 minutes and hold at 60% for 5 minutes;

0-95：梯度：在10分鐘內0~95% B且在95%下保持5分鐘；0-95: Gradient: 0~95% B in 10 minutes and hold at 95% for 5 minutes;

10-80：梯度：在10分鐘內10~80% B且在80%下保持5分鐘；10-80: Gradient: 10-80% B in 10 minutes and hold at 80% for 5 minutes;

30-90：梯度：在10分鐘內30~90% B且在90%下保持5分鐘；30-90: Gradient: 30-90% B in 10 minutes and hold at 90% for 5 minutes;

50-100：梯度：在10分鐘內50~100% B且在100%下保持5分鐘。50-100: Gradient: 50-100% B in 10 minutes and hold at 100% for 5 minutes.

儀器：Shimadzu LC20；管柱：Xbridge Shield RP-18 50 * 2.1mm，5μm；流動相A：具有0.01% NH3 -H2 O之H2 O；流動相B：MeCN；流速：1.2mL/min；波長：UV 220nm、215nm、254nm；管柱溫度：40℃。Instrument: Shimadzu LC20; Column: Xbridge Shield RP-18 50*2.1 mm, 5 μm; Mobile Phase A: H2O with 0.01% NH3 - H2O ; Mobile Phase B: MeCN; Flow Rate: 1.2 mL/min ; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40°C.

0-30CD：梯度：在6分鐘內0~30% B且在30%下保持2分鐘；0-30CD: Gradient: 0~30% B in 6 minutes and hold at 30% for 2 minutes;

0-60CD：梯度：在6分鐘內0~60% B且在60%下保持2分鐘；0-60CD: Gradient: 0~60% B in 6 minutes and hold at 60% for 2 minutes;

10-80CD：梯度：在6分鐘內10~80% B且在80%下保持2分鐘；10-80CD: Gradient: 10-80% B in 6 minutes and hold at 80% for 2 minutes;

30-90CD：梯度：在6分鐘內30~90% B且在90%下保持2分鐘；30-90CD: Gradient: 30-90% B in 6 minutes and hold at 90% for 2 minutes;

50-100CD：梯度：在6分鐘內10~80% B且在100%下保持2分鐘。50-100 CD: Gradient: 10-80% B in 6 minutes and hold at 100% for 2 minutes.

儀器：Shimadzu LC20；管柱：Ultimate C18 50 * 3mm，3μm；流動相A：具有0.06875% TFA(v%)之H2 O；流動相B：具有0.0625% TFA(v%)之MeCN：流速：1.2mL/min；波長：UV 220nm、215nm、254nm；管柱溫度：40℃。Instrument: Shimadzu LC20; Column: Ultimate C18 50*3mm, 3μm; Mobile Phase A: H2O with 0.06875% TFA (v%); Mobile Phase B: MeCN with 0.0625% TFA (v%): Flow Rate: 1.2mL/min; wavelength: UV 220nm, 215nm, 254nm; column temperature: 40°C.

0-30AB：梯度：在2.5分鐘內0~30% B且在30%下保持0.75分鐘；0-30AB: Gradient: 0~30% B in 2.5 minutes and hold at 30% for 0.75 minutes;

0-60AB：梯度：在2.5分鐘內0~60% B且在60%下保持0.75分鐘；0-60AB: Gradient: 0~60% B in 2.5 minutes and hold at 60% for 0.75 minutes;

5-95AB：梯度：在2.5分鐘內5~95% B且在95%下保持0.75分鐘。5-95AB: Gradient: 5~95% B in 2.5 minutes and hold at 95% for 0.75 minutes.

儀器：Shimadzu LC20；管柱：Ultimate C18 50 * 3mm，3μm；流動相A：具有0.06875% TFA(v%)之H2 O；流動相B：具有0.0625% TFA(v%)之MeCN：流速：1.2mL/min；波長：UV 220nm、215nm、254nm；管柱溫度：40℃。Instrument: Shimadzu LC20; Column: Ultimate C18 50*3mm, 3μm; Mobile Phase A: H2O with 0.06875% TFA (v%); Mobile Phase B: MeCN with 0.0625% TFA (v%): Flow Rate: 1.2mL/min; wavelength: UV 220nm, 215nm, 254nm; column temperature: 40°C.

10-80AB：梯度：在4分鐘內10~80% B且在80%下保持2分鐘。10-80AB: Gradient: 10-80% B in 4 minutes and hold at 80% for 2 minutes.

示範性TLC、濃度及正相層析。Exemplary TLC, concentration and normal phase chromatography.

使用矽膠60 F254鋁盤進行分析性薄層層析(TLC)。在UV燈(254nm)下且藉由碘或浸漬在乙醇磷鉬酸(PMA)或過錳酸鉀(KMnO4 )、接著使用熱風槍加熱來進行可視化。藉由在20~40℃下旋轉蒸發來濃縮有機溶液。通常藉由使用230-400目矽膠或Agela急驟二氧化矽管柱的急驟管柱層析來進行反應產物之純化。Analytical thin layer chromatography (TLC) was performed using silica gel 60 F254 aluminum pans. Visualization was performed under UV lamp (254 nm) by iodine or immersion in ethanolic phosphomolybdic acid (PMA) or potassium permanganate (KMnO4 ) followed by heating with a heat gun. The organic solution was concentrated by rotary evaporation at 20-40°C. Purification of the reaction product is typically performed by flash column chromatography using 230-400 mesh silica gel or an Agela flash silica column.

示範性掌性SFC分析方法Exemplary palmar SFC analysis method

管柱：Chiralpak AD-3 150×4.6mm I.D.，3μm；流動相：A：超臨界CO2 ；流動相B：EtOH(0.05% DEA)；梯度：在5min內5%至40% B且在40%下保持2.5min，然後5% B達2.5min；流速：2.5mL/min；管柱溫度：35℃；ABPR：1500psi。Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Mobile Phase: A: Supercritical CO2 ; Mobile Phase B: EtOH (0.05% DEA); Gradient: 5% to 40% B in 5 min and at 40 % for 2.5 min, then 5% B for 2.5 min; flow rate: 2.5 mL/min; column temperature: 35°C; ABPR: 1500 psi.

管柱：Chiralpak AD-3 100×4.6mm I.D.，3μm；流動相：A：超臨界CO2 ；流動相B：EtOH(0.1%乙醇胺)；梯度：在4.5min內5%至40% B且在40%下保持2.5min，然後5% B達1min；流速：2.8mL/min；管柱溫度：40℃。Column: Chiralpak AD-3 100 x 4.6 mm ID, 3 μm; Mobile Phase: A: Supercritical CO2 ; Mobile Phase B: EtOH (0.1% ethanolamine); Gradient: 5% to 40% B in 4.5 min and in Hold at 40% for 2.5 min, then 5% B for 1 min; flow rate: 2.8 mL/min; column temperature: 40°C.

示範性製備型HPLC分離方法Exemplary Preparative HPLC Separation Method

鹼性條件(NH3 -H2 O)：儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Waters Xbridge 150×25mm×5μm；流動相A：具有0.05% NH3 -H2 O(v%)之H2 O；流動相B：MeCN；梯度：在9.5min內22%至52% B，保持100% B達1min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm。Basic conditions ( NH3 - H2O ): Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile Phase A: with 0.05% NH3 - H2O (v%) in H2O ; Mobile Phase B: MeCN; Gradient: 22% to 52% B in 9.5 min, hold 100% B for 1 min; Flow Rate: 25 mL/min; Column Temperature : 30℃; Wavelength: 220nm, 254nm.

酸條件(HCOOH)：儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Agela Durashell C18 150 * 25mm 5μm；流動相A：H2 O(0.0225% HCOOH)；流動相B：MeCN；梯度：在9min內7%至37% B，保持100% B達0min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm。Acid Conditions (HCOOH): Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Agela Durashell C18 150*25mm 5μm; Mobile Phase A: H2O (0.0225% HCOOH); Mobile phase B: MeCN; gradient: 7% to 37% B in 9 min, hold 100% B for 0 min; flow rate: 25 mL/min; column temperature: 30°C; wavelength: 220 nm, 254 nm.

酸條件(HCl)：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Xtimate C18150 * 25mm * 5μm；流動相A：具有0.05% HCl(v%)之H2 O；流動相B：MeCN；梯度：在6.5min內0%至30% B，保持100% B達2.5min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)。Acid Conditions (HCl): Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Xtimate C18150*25mm*5μm; Mobile Phase A: H2O with 0.05% HCl (v%) ; Mobile phase B: MeCN; Gradient: 0% to 30% B in 6.5min, hold 100% B for 2.5min; Flow rate: 25mL/min; Column temperature: 30°C; Wavelength: 220nm, 254nm).

中性條件(NH4 HCO3 )：(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Waters Xbridge 150×25mm×5μm；流動相A：具有10mmol NH4 HCO3 之H2 O；流動相B：MeCN；梯度：在10min內39%至69% B，保持100% B達2.5min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)。Neutral conditions (NH 4 HCO 3 ): (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile Phase A: with 10 mmol NH 4 H2O in HCO3 ; Mobile Phase B: MeCN; Gradient: 39% to 69% B in 10min, hold 100% B for 2.5min; Flow Rate: 25mL/min; Column Temperature: 30°C; Wavelength: 220nm, 254nm).

示範性大規模分離Exemplary Mass Separation

鹼性條件：儀器：Shimadzu LC-8A泵，Shimadzu SCL-10A VP系統控制器，Shimadzu SPD-20AV UV/VIS偵測器；管柱：Phenomenex Gemini C18 250 * 50mm * 10μm；流動相A：水(0.04% NH3 -H2 O+10mM NH4 HCO3 )；流動相B：MeCN；梯度：在26min內65%至95% B，保持100% B達3min；流速：110mL/min；管柱溫度：30℃；波長：220nm，254nm。Alkaline conditions: Instrument: Shimadzu LC-8A pump, Shimadzu SCL-10A VP system controller, Shimadzu SPD-20AV UV/VIS detector; Column: Phenomenex Gemini C18 250*50mm*10μm; Mobile phase A: water ( 0.04% NH3 - H2O + 10 mM NH4HCO3 ) ; mobile phase B: MeCN; gradient: 65% to 95% B in 26 min, hold 100% B for 3 min; flow rate: 110 mL/min; column temperature : 30℃; Wavelength: 220nm, 254nm.

酸條件(TFA)：儀器：Shimadzu LC-20AP泵，Shimadzu CBM-20A系統控制器，Shimadzu SPD-20AV UV/VIS偵測器；管柱：Phenomenex luna C18 250×50mm×10μm；流動相A：具有0.1% TFA(v%)之H2 O；流動相B：MeCN；梯度：在15min內0%至25% B，保持100% B達4min；流速：120mL/min；管柱溫度：30℃；波長：220nm，254nm。Acid condition (TFA): Instrument: Shimadzu LC-20AP pump, Shimadzu CBM-20A system controller, Shimadzu SPD-20AV UV/VIS detector; Column: Phenomenex luna C18 250×50mm×10μm; Mobile phase A: with 0.1% TFA (v%) in H 2 O; mobile phase B: MeCN; gradient: 0% to 25% B in 15 min, hold 100% B for 4 min; flow rate: 120 mL/min; column temperature: 30 °C; Wavelength: 220nm, 254nm.

示範性製備型掌性SFC方法：Exemplary preparative chiral SFC method:

可用於分離/純化本文所提供之鏡像異構物/非鏡像異構物之示範性掌性管柱包括但不限於CHIRALPAK® AD-10、CHIRALCEL® OB、CHIRALCEL® OB-H、CHIRALCEL® OD、CHIRALCEL® OD-H、CHIRALCEL® OF、CHIRALCEL® OG、CHIRALCEL® OJ及CHIRALCEL® OK。Exemplary chiral columns that can be used to separate/purify the Spiegelmers/Astereoisomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

在某些實例中，在以下條件下進行掌性分離：儀器：Thar 80；管柱：Daicel Chiralpak AD。250×30mm I.D.10μm；流動相：超臨界CO2 /MeOH(0.1% NH3 -H2 O，v%)=60/40；流速：70mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm。In certain instances, chiral separations were performed under the following conditions: Instrument: Thar 80; Column: Daicel Chiralpak AD. 250×30mm ID10μm; mobile phase: supercritical CO 2 /MeOH (0.1% NH 3 -H 2 O, v%)=60/40; flow rate: 70 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar ; Nozzle temperature: 60°C; Evaporator temperature: 20°C; Dresser temperature: 25°C; Wavelength: 220nm.

材料及方法Materials and Methods

可使用以下一般方法及程序由容易獲得之起始材料製備本文所提供之化合物。應瞭解，除非另外說明，否則在給予典型或較佳製程條件(亦即反應溫度、時間、反應物之莫耳比、溶劑、壓力等)之情況下，亦可使用其他製程條件。最佳之反應條件可隨所使用之特定反應物或溶劑而變，但該等條件可由熟習此項技術者藉藉由常規最佳化來確定。The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that other process conditions may also be used, given typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvents, pressure, etc.) unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

另外，如熟習此項技術者將顯而易見，習知保護基可能是必要的，以防止某些官能基經歷不希望之反應。特定官能基之合適保護基之選擇以及針對保護及去保護之合適條件為此項技術中熟知的。例如，許多保護基以及其引入及移除描述於T.W.Greene及P.G.M.Wuts,Protecting Groups in Organic Synthesis ,Second Edition,Wiley,New York,1991及在其中提及之參考文獻中。Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for particular functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and PGMWuts, Protecting Groups in Organic Synthesis , Second Edition, Wiley, New York, 1991 and references mentioned therein.

本文所提供之化合物可藉由已知標準程序分離及純化。此類程序包括(但不限於)重結晶、管柱層析、HPLC或超臨界流體層析(SFC)。以下方案呈現出關於製備本文中已列出之代表性吡唑的詳情。本文所提供之化合物可由熟習有機合成之技術者由已知或商業可獲得之起始材料及試劑製備。The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC or supercritical fluid chromatography (SFC). The following schemes present details on the preparation of representative pyrazoles already listed herein. The compounds provided herein can be prepared by one skilled in organic synthesis from known or commercially available starting materials and reagents.

製備型HPLC之示範性一般方法：管柱：Waters RBridge製備型10μm C18，19*250mm。流動相：乙腈、水(NH4 HCO3 )(30L水、24g NH4 HCO3 、30mL NH3 .H2 O)。流速：25mL/minExemplary general method for preparative HPLC: Column: Waters RBridge Prep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water ( NH4HCO3 ) ( 30 L water, 24 g NH4HCO3 , 30 mL NH3.H2O). Flow rate: 25mL/min

分析性HPLC之示範性一般方法：流動相：A：水(10mM NH4 HCO3 )， B：乙腈；梯度：在1.6或2min內5%-95% B；流速：1.8或2mL/min；管柱：XBridge C18，4.6*50mm，3.5μm，在45℃下。Exemplary general method for analytical HPLC: mobile phase: A: water (10 mM NH4HCO3 ) , B: acetonitrile; gradient: 5%-95% B in 1.6 or 2 min; flow rate: 1.8 or 2 mL/min; tube Column: XBridge C18, 4.6*50mm, 3.5μm, at 45°C.

1.常見中間物之合成1. Synthesis of common intermediates

1A. (S)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成1A. Synthesis of (S)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-0540-1186
Figure 110128222-A0202-12-0540-1186

步驟1：4-界基-5-側氧基戊酸甲酯之合成Step 1: Synthesis of methyl 4-jieryl-5-side oxyvalerate

向99%哌啶(293.22g，3.44mol，340.16mL)及碳酸鉀顆粒(95.19g，688.72mmol，41.57mL)之攪拌混合物中逐滴添加丙醛(100g，1.72mol，123.46mL)。將反應混合物在室溫下攪拌18小時。18小時後，透過Na2 SO4 墊過濾反應混合物，且用MTBE(1000mL)洗滌。將濾液經Na2 SO4 乾燥，過濾且在減壓下濃縮。將所獲得之粗品烯胺溶解於MeCN(1000mL)中且在室溫下將丙-2-烯酸甲酯(296.46g，3.44mol，310.10mL)逐滴添加到溶液中。將所得反應混合物回流16小時。16小時後，(小心)添加乙酸(206.79g，3.44mol，196.94mL)，接著添加水(1000mL)，且將所得溶液在回流下再加熱16小時。然後，將混合物冷卻至室溫，用NaCl飽和且用MTBE(2x1000mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得粗產物4-甲基-5-側氧基-戊酸甲酯(264g，粗品)。粗產物不經任何進一步純化即用於下一步。To a stirred mixture of 99% piperidine (293.22 g, 3.44 mol, 340.16 mL) and potassium carbonate particles (95.19 g, 688.72 mmol, 41.57 mL) was added propionaldehyde (100 g, 1.72 mol, 123.46 mL) dropwise. The reaction mixture was stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was filtered through a pad of Na2SO4 and washed with MTBE (1000 mL). The filtrate was dried over Na2SO4 , filtered and concentrated under reduced pressure. The obtained crude enamine was dissolved in MeCN (1000 mL) and methyl prop-2-enoate (296.46 g, 3.44 mol, 310.10 mL) was added dropwise to the solution at room temperature. The resulting reaction mixture was refluxed for 16 hours. After 16 hours, acetic acid (206.79 g, 3.44 mol, 196.94 mL) was (caution) added, followed by water (1000 mL), and the resulting solution was heated at reflux for an additional 16 hours. Then, the mixture was cooled to room temperature, saturated with NaCl and extracted with MTBE (2 x 1000 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain the crude 4-methyl-5-pentoxy-pentanoic acid methyl ester (264 g, crude). The crude product was used in the next step without any further purification.

1 H NMR(CDCl3 ,500MHz)：δ 1.09(d,3H),1.60-1.72(m,1H),1.94-2.00(m,1H),2.29-2.42(m,3H),3.64(s,3H),9.59(s,1H)。 1 H NMR (CDCl 3 , 500MHz): δ 1.09(d,3H), 1.60-1.72(m,1H), 1.94-2.00(m,1H), 2.29-2.42(m,3H), 3.64(s,3H) ), 9.59(s, 1H).

步驟2：(3R,8S,8aR)-8-甲基-3-苯基四氫-2H-噁唑并[3,2-a]吡啶-5(3H)-酮之合成Step 2: Synthesis of (3R,8S,8aR)-8-methyl-3-phenyltetrahydro-2H-oxazolo[3,2-a]pyridin-5(3H)-one

將4-甲基-5-側氧基-戊酸甲酯(67.8g，470.28mmol)、(2R )-2-胺基-2-苯基-乙醇(64.51g，470.28mmol)及無水硫酸鈉(66.80g，470.28mmol)於DCM(800mL)及乙醚(200mL)中之混合物在0℃下攪拌5小時。5小時之後，過濾所得懸浮液，且在減壓下濃縮濾液。藉由管柱層析(Interchim；800g SiO2 ；氯仿/乙腈，其中乙腈為0至15%，流速=120ml/min，Rv=4-10cv.)純化殘餘物，以得到呈淡黃色膠狀物之產物(3R ,8S ,8aR )-8-甲基-3-苯基四氫-2H -噁唑并[3,2-a]吡啶-5(3H )-酮(59.8g，258.55mmol，54.98%產率)。4-Methyl-5-oxy-pentanoic acid methyl ester (67.8g, 470.28mmol), ( 2R )-2-amino-2-phenyl-ethanol (64.51g, 470.28mmol) and anhydrous sulfuric acid A mixture of sodium (66.80 g, 470.28 mmol) in DCM (800 mL) and diethyl ether (200 mL) was stirred at 0 °C for 5 h. After 5 hours, the resulting suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Interchim; 800 g SiO2 ; chloroform/acetonitrile with 0 to 15% acetonitrile, flow rate = 120 ml/min, Rv = 4-10 cv.) to give a pale yellow gum The product ( 3R , 8S , 8aR )-8-methyl-3-phenyltetrahydro- 2H -oxazolo[3,2-a]pyridin-5( 3H )-one (59.8g , 258.55 mmol, 54.98% yield).

1 H NMR(CDCl3 ,500MHz)：δ 1.20(d,J =6.3Hz,3H),1.42-1.56(m,1H),1.86-2.00(m,2H),2.22-2.44(m,2H),4.00(dd,J =8.8,1.2Hz,1H),4.07-4.17(m,1H),4.42(dd,J =8.9,3.2Hz,1H),4.87-4.95(m,1H),7.17-7.32(m,5H)。 1 H NMR (CDCl 3 , 500 MHz): δ 1.20 (d, J =6.3 Hz, 3H), 1.42-1.56 (m, 1H), 1.86-2.00 (m, 2H), 2.22-2.44 (m, 2H), 4.00(dd, J =8.8,1.2Hz,1H),4.07-4.17(m,1H),4.42(dd, J =8.9,3.2Hz,1H),4.87-4.95(m,1H),7.17-7.32( m, 5H).

LCMS(ESI)：[M+H]+ m/z：計算值231.1；實測值232.2；Rt=1.12min。LCMS (ESI): [M+H] + m/z: calculated 231.1; found 232.2; Rt=1.12 min.

步驟3：(S)-1-((R)-2-羥基-1-苯基乙基)-5-甲基哌啶-2-酮之合成Step 3: Synthesis of (S)-1-((R)-2-hydroxy-1-phenylethyl)-5-methylpiperidin-2-one

將三乙基矽烷(1.51g，12.97mmol，2.07mL)及四氯化鈦(3.69g，19.46mmol)添加到(3R ,8S ,8aR )-8-甲基-3-苯基四氫-2H -噁唑并[3,2-a]吡啶-5(3H )-酮(1g，4.32mmol)於無水DCM(25mL)中之溶液中且將混合物在40℃下攪拌24小時。然後，添加額外的四氯化鈦(3.69g，19.46mmol，764.36μL)及三乙基矽烷(1.51g，12.97mmol，2.07mL)，且在50℃下繼續攪拌24小時。將混合物倒入飽和NaHCO3 (100mL)水溶液中。經矽藻土過濾水相並用CH2 Cl2 萃取。將經合併之有機萃取物經Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由管柱層析(Companion Combiflash；40g SiO2 ；MTBE/甲醇，其中甲醇為0至8%，流速=40mL/min，Rv=9-11 cv.)進行純化，以得到呈無色油狀物之產物(S) -1-((R )-2-羥基-1-苯基乙基)-5-甲基哌啶-2-酮(0.51g，2.19mmol，50.56%產率)。Triethylsilane (1.51 g, 12.97 mmol, 2.07 mL) and titanium tetrachloride (3.69 g, 19.46 mmol) were added to ( 3R , 8S , 8aR )-8-methyl-3-phenyltetrakis A solution of hydrogen- 2H -oxazolo[3,2-a]pyridin-5( 3H )-one (1 g, 4.32 mmol) in dry DCM (25 mL) and the mixture was stirred at 40 °C for 24 h . Then, additional titanium tetrachloride (3.69 g, 19.46 mmol, 764.36 μL) and triethylsilane (1.51 g, 12.97 mmol, 2.07 mL) were added and stirring was continued at 50° C. for 24 hours. The mixture was poured into saturated aqueous NaHCO3 (100 mL). The aqueous phase was filtered through celite and extracted with CH2Cl2 . The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (Companion Combiflash; 40 g SiO 2 ; MTBE/methanol with 0 methanol to 8%, flow rate = 40 mL/min, Rv = 9-11 cv.) for purification to give the product (S) -1-((( R )-2-hydroxy-1-phenylethyl) as a colorless oil yl)-5-methylpiperidin-2-one (0.51 g, 2.19 mmol, 50.56% yield).

1 H NMR(CDCl3 ,400MHz)：δ 0.93(d,J =6.4Hz,3H),1.44-1.54(m,1H),1.77-1.86(m,2H),2.40-2.62(m,2H),2.83(t,J =11.0Hz,1H),2.92-2.99(m,1H),4.04-4.21 (m,2H),5.71-5.79(m,2H),7.17-7.37(m,5H) 1 H NMR (CDCl 3 , 400 MHz): δ 0.93 (d, J = 6.4 Hz, 3H), 1.44-1.54 (m, 1H), 1.77-1.86 (m, 2H), 2.40-2.62 (m, 2H), 2.83(t, J =11.0Hz,1H), 2.92-2.99(m,1H), 4.04-4.21(m,2H), 5.71-5.79(m,2H), 7.17-7.37(m,5H)

LCMS(ESI)：[M+H]+ m/z：計算值233.1；實測值234.2；Rt=0.98min。LCMS (ESI): [M+H] + m/z: calculated 233.1; found 234.2; Rt=0.98 min.

步驟4：(S)-5-甲基哌啶-2-酮之合成Step 4: Synthesis of (S)-5-methylpiperidin-2-one

在-78℃下，向裝備有冷指冷凝器且裝入乾冰-丙酮之1000mL三頸圓底燒瓶中冷凝氨(500mL)。添加(S )-1-((R )-2-羥基-1-苯基乙基)-5-甲基哌啶-2-酮(17.2g，73.72mmol)於無水THF(100mL)中之溶液，且將溫度升高至-33℃。小批量添加鈉(5.08g，221.17mmol)，直到藍色持續存在，且將混合物在-33℃下攪拌3分鐘。藉由添加固體NH4 Cl淬滅反應物，直至藍色消失，然後在室溫下將混合物攪拌5小時。添加CH2 Cl2 ，過濾固體，且在減壓下移除溶劑，以得到呈淡黃色油狀物之(S )-5-甲基哌啶-2-酮(15g，粗品)。殘餘物不經任何進一步純化即用於下一步。Ammonia (500 mL) was condensed at -78°C in a 1000 mL three neck round bottom flask equipped with a cold finger condenser and charged with dry ice-acetone. A solution of ( S )-1-((( R )-2-hydroxy-1-phenylethyl)-5-methylpiperidin-2-one (17.2 g, 73.72 mmol) in dry THF (100 mL) was added , and the temperature was raised to -33°C. Sodium (5.08 g, 221.17 mmol) was added in small batches until blue color persisted and the mixture was stirred at -33 °C for 3 min. The reaction was quenched by addition of solid NH4Cl until the blue color disappeared, then the mixture was stirred at room temperature for 5 hours. CH2Cl2 was added, the solid was filtered, and the solvent was removed under reduced pressure to give ( S )-5-methylpiperidin- 2 -one (15 g, crude) as a pale yellow oil. The residue was used in the next step without any further purification.

1 H NMR(DMSO-d 6 ,400MHz)：δ 1.01(d,J=6.6Hz,3H,CH3 ),1.45-1.51(m,1H,H-4),1.83-1.99(m,2H,H-4,H-5),2.34(ddd,J=17.8,10.8,6.4Hz,1H,H-3),2.43(ddd,J=17.8,6.4,3.5Hz,1H,H-3),2.92(t,J=10.8Hz,1H,H-6),3.26-3.33(m,1H,H-6),6.10(br.s,1H,NH) 1 H NMR (DMSO- d 6 , 400 MHz): δ 1.01 (d, J=6.6 Hz, 3H, CH 3 ), 1.45-1.51 (m, 1H, H-4), 1.83-1.99 (m, 2H, H -4,H-5),2.34(ddd,J=17.8,10.8,6.4Hz,1H,H-3),2.43(ddd,J=17.8,6.4,3.5Hz,1H,H-3),2.92( t,J=10.8Hz,1H,H-6),3.26-3.33(m,1H,H-6),6.10(br.s,1H,NH)

步驟5：(S)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of (S)-3-butyl 5-methyl-2-oxypiperidine-1-carboxylate

在21℃下，向(S )-5-甲基哌啶-2-酮(15g，79.54mmol，粗品)及DMAP(971.67mg，7.95mmol)於DCM(500mL)中之溶液中逐滴添加二碳酸二-第三丁酯(17.36g，79.54mmol，18.25mL)。在同一溫度下將所得反應混合物攪拌1小時。1小時之後，所得溶液用10%水性HCl及鹽水稀釋，經Na2 SO4 乾燥且在減壓下濃縮，以獲得粗產物，其藉由管柱層析(Companion Combiflash，330g SiO2，石油醚/MTBE，其中MTBE為10~25%，流速=100mL/min，Rv=6 CV)進行純化，以獲得呈黃色固體之產物(S )-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(9g，42.20mmol，53.06%產率)。To a solution of ( S )-5-methylpiperidin-2-one (15 g, 79.54 mmol, crude) and DMAP (971.67 mg, 7.95 mmol) in DCM (500 mL) at 21 °C was added two dropwise Di-tert-butyl carbonate (17.36 g, 79.54 mmol, 18.25 mL). The resulting reaction mixture was stirred at the same temperature for 1 hour. After 1 hour, the resulting solution was diluted with 10% aqueous HCl and brine, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (Companion Combiflash, 330 g SiO , petroleum ether/ MTBE, wherein MTBE was 10~25%, flow rate=100 mL/min, Rv=6 CV) was purified to obtain the product ( S )-5-methyl-2-oxypiperidine-1- as a yellow solid 3-Butyl formate (9 g, 42.20 mmol, 53.06% yield).

1 H NMR(400MHz,DMSO-d 6 )δ 0.96(d,J =6.6Hz,3H),1.42(s,9H),),1.74-1.86(m,1H),1.87-1.97(m,1H),2.30-2.39(m,2H),2.98-3.11(m,1H),3.12(s,1H),3.60-3.68(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ 0.96(d, J =6.6Hz, 3H), 1.42(s, 9H), ), 1.74-1.86(m, 1H), 1.87-1.97(m, 1H) , 2.30-2.39(m, 2H), 2.98-3.11(m, 1H), 3.12(s, 1H), 3.60-3.68(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值213.2；實測值158.2；Rt=1.24min(t -Bu斷裂)LCMS (ESI): [M+H] + m/z: calculated 213.2; found 158.2; Rt=1.24min ( t -Bu fracture)

1B. 3-甲基-6-(((三氟甲基)磺醯基)氧基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成1B. Synthesis of 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-0543-679
Figure 110128222-A0202-12-0543-679

步驟1：5-甲基哌啶-2-酮之合成Step 1: Synthesis of 5-methylpiperidin-2-one

在高壓釜中，在50℃、100atm氫氣壓力下，在存在5%氫氧化鈀/碳(15g，106.81mmol)之情況下，將5-甲基-1H -吡啶-2-酮(102g，934.70mmol)於MeOH(1000mL)中之溶液氫化12h。使反應混合物冷卻，過濾掉催化劑，在真空中蒸發濾液，以得到呈白色固體之5-甲基哌啶-2-酮(105g，927.91mmol，99.27%產率)。5-Methyl- 1H -pyridin-2-one (102 g, 934.70 mmol) in the presence of 5% palladium hydroxide on carbon (15 g, 106.81 mmol) in an autoclave at 50 °C under 100 atm hydrogen pressure mmol) in MeOH (1000 mL) was hydrogenated for 12 h. The reaction mixture was cooled, the catalyst was filtered off, and the filtrate was evaporated in vacuo to give 5-methylpiperidin-2-one (105 g, 927.91 mmol, 99.27% yield) as a white solid.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.94(d,3H),1.38(m,1H),1.77(m,2H),2.12(d,2H),2.74(m,1H),3.12(m,1H),7.37(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.94(d,3H), 1.38(m,1H), 1.77(m,2H), 2.12(d,2H), 2.74(m,1H), 3.12 (m, 1H), 7.37 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值113.2；實測值114.2；Rt=0.701min。LCMS (ESI): [M] + m/z: calculated 113.2; found 114.2; Rt=0.701 min.

步驟2：5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate

在25℃下，將二碳酸二-第三丁酯(212.64g，974.31mmol，223.60mL)添加到5-甲基哌啶-2-酮(105g，927.91mmol)及N,N -二甲基吡啶-4-胺(11.34g，92.79mmol)於THF(1000mL)中之經攪拌之混合物中。將反應混合物在25℃下攪拌24h，然後在真空中蒸發。將殘餘物溶解於二氯甲烷(1500ml)中且用5%硫酸氫鈉水溶液(400ml)及水(400ml)連續洗滌。將有機層分離，經硫酸鈉乾燥且在 真空中蒸發，以得到呈淡黃色油狀物之粗品5-甲基-2-側氧基-哌啶-1-甲酸第三丁酯(199g，粗品)，其直接用於下一步驟中。At 25°C, di-tert-butyl dicarbonate (212.64 g, 974.31 mmol, 223.60 mL) was added to 5-methylpiperidin-2-one (105 g, 927.91 mmol) and N,N -dimethyl In a stirred mixture of pyridin-4-amine (11.34 g, 92.79 mmol) in THF (1000 mL). The reaction mixture was stirred at 25 °C for 24 h, then evaporated in vacuo. The residue was dissolved in dichloromethane (1500ml) and washed successively with 5% aqueous sodium bisulfate (400ml) and water (400ml). The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to give crude 5-methyl-2-pendoxo-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (199 g, crude ), which is used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.03(d,3H),1.48(m,1H),1.58(s,9H),1.92(m,2H),2.56(m,2H),3.11(t,1H),3.80(d,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.03(d, 3H), 1.48(m, 1H), 1.58(s, 9H), 1.92(m, 2H), 2.56(m, 2H), 3.11( t, 1H), 3.80(d, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值113.2；實測值114.2；Rt=1.275min。LCMS (ESI): [M-Boc] + m/z: calculated 113.2; found 114.2; Rt=1.275 min.

步驟3：3-甲基-6-(((三氟甲基)磺醯基)氧基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: Synthesis of 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

在氬氣下，將LiHMDS(588.42g，703.32mmol，653.80mL，20%純度)(1.08M於THF/乙苯中)逐滴添加到冷卻至-78℃的5-甲基-2-側氧基-哌啶-1-甲酸第三丁酯(100g，468.88mmol)於THF(1000mL)中之溶液中。將所得溶液在-78℃下攪拌1.5h，然後一次性添加1,1,1-三氟-N -苯基-N -(三氟甲基磺醯基)甲磺醯胺(209.39g，586.10mmol)。使反應混合物升溫至25℃且攪拌12h，然後用水(300ml)及MTBE(1500ml)稀釋。將有機層分離，另外用MTBE(300ml)萃取水層。將經合併之有機萃取物用10%氫氧化鈉水溶液(3*500ml)洗滌，經碳酸鉀乾燥，且在真空中蒸發。殘餘物用己烷/MTBE混合物(4/1，1500mL，重複三次)稀釋且攪拌0.5h。將所得混濁溶液自油狀殘餘物傾析，透過短矽胺墊過濾且在真空中蒸發，以得到呈淡黃色油狀物之3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(147g，425.67mmol，90.78%產率)。Under argon, LiHMDS (588.42 g, 703.32 mmol, 653.80 mL, 20% purity) (1.08 M in THF/ethylbenzene) was added dropwise to 5-methyl-2-oxoside cooled to -78 °C A solution of tert-butyl-piperidine-1-carboxylate (100 g, 468.88 mmol) in THF (1000 mL). The resulting solution was stirred at -78 °C for 1.5 h, then 1,1,1-trifluoro- N -phenyl- N- (trifluoromethylsulfonyl)methanesulfonamide (209.39 g, 586.10 g was added in one portion) mmol). The reaction mixture was warmed to 25°C and stirred for 12h, then diluted with water (300ml) and MTBE (1500ml). The organic layer was separated and the aqueous layer was additionally extracted with MTBE (300 ml). The combined organic extracts were washed with 10% aqueous sodium hydroxide solution (3*500ml), dried over potassium carbonate and evaporated in vacuo. The residue was diluted with a hexane/MTBE mixture (4/1, 1500 mL, repeated three times) and stirred for 0.5 h. The resulting cloudy solution was decanted from the oily residue, filtered through a short pad of silicone and evaporated in vacuo to give 3-methyl-6-(trifluoromethylsulfonyloxy as a pale yellow oil )-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (147 g, 425.67 mmol, 90.78% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.01(d,3H),1.49(s,9H),1.87(m,2H),2.38(d,1H),3.01(d,1H),3.89(d,1H),5.26(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.01(d,3H), 1.49(s,9H), 1.87(m,2H), 2.38(d,1H), 3.01(d,1H), 3.89( d, 1H), 5.26 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值245.3；實測值246.2；Rt=1.719min。LCMS (ESI): [M-Boc] + m/z: calculated 245.3; found 246.2; Rt=1.719 min.

2.常見側氧基乙酸吡啶酯中間物之合成2. Synthesis of common side oxyacetic acid pyridyl ester intermediates

Figure 110128222-A0202-12-0545-680
Figure 110128222-A0202-12-0545-680

2A. 2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯及2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸鋰鹽之合成2A. 2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-side oxyacetic acid 2,2,2-trifluoroethyl ester and 2-((5-aminocarbamoylpyridine Synthesis of -3-yl)amino)-2-oxoacetate lithium salt

Figure 110128222-A0202-12-0545-681
Figure 110128222-A0202-12-0545-681

步驟1：5-胺基吡啶-3-甲醯胺之合成Step 1: Synthesis of 5-aminopyridine-3-carboxamide

將5-胺基吡啶-3-甲酸甲酯(鹽酸鹽)(5g，32.86mmol)溶解於25% NH3 (水溶液)(50mL)中且將所得反應混合物在室溫下攪拌18小時。18小時之後，在減壓下濃縮反應混合物且將所得殘餘物用水(20mL)洗滌，在70℃下乾燥10小時，以獲得呈白色粉末之5-胺基吡啶-3-甲醯胺(2.8g，20.42mmol，62.13%產率)。Methyl 5-aminopyridine-3-carboxylate (hydrochloride) (5 g, 32.86 mmol) was dissolved in 25% NH3 (aq) (50 mL) and the resulting reaction mixture was stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was washed with water (20 mL), dried at 70 °C for 10 hours to obtain 5-aminopyridine-3-carboxamide (2.8 g) as a white powder. , 20.42 mmol, 62.13% yield).

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)5.49(brs,2H),7.30(t,1H),7.36(brs,1H),7.93(brs,1H),8.02(d,1H),8.18(s,1H) 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 5.49 (brs, 2H), 7.30 (t, 1H), 7.36 (brs, 1H), 7.93 (brs, 1H), 8.02 (d, 1H) ,8.18(s,1H)

LCMS(ESI)：[M+H]+ m/z：計算值137.1；實測值138.2；Rt=0.139min。LCMS (ESI): [M+H] + m/z: calculated 137.1; found 138.2; Rt=0.139 min.

步驟2：2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 2: Synthesis of 2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester

在0℃下，向5-胺基吡啶-3-甲醯胺(0.65g，4.74mmol)及DIPEA(918.84mg，7.11mmol，1.24mL)於無水THF(15mL)中之攪拌溶液中逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(993.23mg，5.21mmol)。將反應混合物在室溫下攪拌12小時，然後過濾。在真空下濃縮濾液，以獲得2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(1.7g，粗品)。粗產物不經任何進一步純化即用於下 一步反應。To a stirred solution of 5-aminopyridine-3-carboxamide (0.65 g, 4.74 mmol) and DIPEA (918.84 mg, 7.11 mmol, 1.24 mL) in dry THF (15 mL) was added dropwise at 0 °C 2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (993.23 mg, 5.21 mmol). The reaction mixture was stirred at room temperature for 12 hours and then filtered. The filtrate was concentrated in vacuo to obtain 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxyacetate 2,2,2-trifluoroethyl ester (1.7 g, crude) . The crude product was used without any further purification one-step reaction.

LCMS(ESI)：[M +H] +m/z：計算值291.0；實測值292.2；Rt=0.815min。 LCMS (ESI): [M + H] + m/z: calculated 291.0; found 292.2; Rt=0.815 min.

步驟3：2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸鋰鹽之合成Step 3: Synthesis of 2-((5-aminocarboxypyridin-3-yl)amino)-2-oxoacetate lithium salt

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(1.1g，3.78mmol)及98%氫氧化鋰單水合物(174.38mg，4.16mmol)一起混合在THF(10mL)及H2 O(2.5mL)中。將所得混合物攪拌隔夜。將所得混合物用10mL THF稀釋。過濾出沉澱且將其風乾，以得到呈白色粉末之2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸鋰鹽(0.74g，3.44mmol，91.07%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (1.1 g, 3.78 mmol) and 98% lithium hydroxide The monohydrate (174.38 mg, 4.16 mmol) was mixed together in THF (10 mL) and H2O (2.5 mL). The resulting mixture was stirred overnight. The resulting mixture was diluted with 10 mL of THF. The precipitate was filtered off and air-dried to give lithium 2-((5-aminocarboxypyridin-3-yl)amino)-2-oxoacetate salt (0.74 g, 3.44 mmol, 91.07 g) as a white powder %Yield).

1 H NMR(400MHz,DMSO-d6 )δ 7.56(s,1H),8.12(s,1H),8.66(m,2H),8.98(s,1H),10.58(m,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.56 (s, 1H), 8.12 (s, 1H), 8.66 (m, 2H), 8.98 (s, 1H), 10.58 (m, 1H).

2B.2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基] 胺基] 2B. 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl] amino ] -2-側氧基乙酸2,2,2-三氟乙酯 - 2,2,2-trifluoroethyl 2-oxoacetate 及2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸之合成And the synthesis of 2-[[6-(3rd-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0546-682
Figure 110128222-A0202-12-0546-682

步驟1：N-(3-甲基-5-硝基-2-吡啶基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-(3-methyl-5-nitro-2-pyridyl)carbamate

在0℃下，向3-甲基-5-硝基-吡啶-2-胺(60g，391.80mmol)於DMF(525mL)中之溶液中分批添加於礦物油中之氫化鈉(油分散物)60%分散物(16.51g，412.88mmol，60%純度)。將所得混合物攪拌0.5h(直至氣體逸出結束)且逐滴添加二碳酸二-第三丁酯(89.79g，411.39mmol，94.41mL)於DMF(75mL)中之溶液。將所得混合物在25℃下攪拌18h。將混合物用水(1000mL)淬滅，過濾出所形成之沉澱且在真空中乾燥以獲得粗產物(100g)。藉由矽膠梯度層析(以CHCl3 -MTBE作為溶析液)純化此材料，以獲得N-(3-甲基-5-硝基-2-吡啶基)胺甲 酸第三丁酯(46g，181.64mmol，46.36%產率)。To a solution of 3-methyl-5-nitro-pyridin-2-amine (60 g, 391.80 mmol) in DMF (525 mL) was added portionwise sodium hydride (oil dispersion) in mineral oil at 0 °C ) 60% dispersion (16.51 g, 412.88 mmol, 60% pure). The resulting mixture was stirred for 0.5 h (until gas evolution ceased) and a solution of di-tert-butyl dicarbonate (89.79 g, 411.39 mmol, 94.41 mL) in DMF (75 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 18 h. The mixture was quenched with water (1000 mL), the formed precipitate was filtered off and dried in vacuo to obtain crude product (100 g). This material was purified by silica gel gradient chromatography (with CHCl3 -MTBE as eluent) to obtain tert-butyl N-(3-methyl-5-nitro-2-pyridyl)carbamate (46 g, 181.64 mmol, 46.36% yield).

1 H NMR(DMSO-d6,400MHz)：δ 1.49(s,9H),2.32(s,3H),8.37(s,1H),8.97(s,1H),9.59(s,1H) 1 H NMR (DMSO-d6, 400MHz): δ 1.49(s, 9H), 2.32(s, 3H), 8.37(s, 1H), 8.97(s, 1H), 9.59(s, 1H)

LCMS(ESI)：[M-CH2C(CH3)+H]+ m/z：計算值253.26；實測值198.2；Rt=1.272min。LCMS(ESI): [M-CH2C(CH3)+H] + m/z: calculated 253.26; found 198.2; Rt=1.272 min.

步驟2：N-(5-胺基-3-甲基-2-吡啶郵胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-(5-amino-3-methyl-2-pyridinecarbamic acid)

向N-(3-甲基-5-硝基-2-吡啶基)胺甲酸第三丁酯(46g，181.64mmol)於MeOH(600mL)中之溶液中添加10%鈀/活性碳(4.60g，43.22mmol)。在氫氣氛下攪拌所得混合物24h。過濾催化劑且在真空中蒸發溶劑，將殘餘物溶解於DCM(500ml)中，經Na2 SO4 乾燥且在真空中蒸發，以獲得N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(38g，170.20mmol，93.70%產率)。To a solution of tert-butyl N-(3-methyl-5-nitro-2-pyridyl)carbamate (46 g, 181.64 mmol) in MeOH (600 mL) was added 10% palladium on activated carbon (4.60 g) , 43.22 mmol). The resulting mixture was stirred under a hydrogen atmosphere for 24 h. The catalyst was filtered and the solvent was evaporated in vacuo, the residue was dissolved in DCM (500ml), dried over Na2SO4 and evaporated in vacuo to give N-(5-amino-3-methyl-2-pyridine) (38 g, 170.20 mmol, 93.70% yield).

1 H NMR(DMSO-d6,400MHz)：δ 1.40(s,9H),2.03(s,3H),3.30(brs,2H),6.80(s,1H),7.54(s,1H),8.52(s,1H) 1 H NMR (DMSO-d6, 400MHz): δ 1.40(s, 9H), 2.03(s, 3H), 3.30(brs, 2H), 6.80(s, 1H), 7.54(s, 1H), 8.52(s ,1H)

LCMS(ESI)：[M+H]+ m/z：計算值223.2；實測值224.2；Rt=0.67min。LCMS (ESI): [M+H] + m/z: calculated 223.2; found 224.2; Rt=0.67 min.

步驟3：2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 3: 2,2,2-trifluoroethyl acetate synthesis

在0℃、氬氣下，向N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(17.6g，78.83mmol)及DIPEA(15.28g，118.24mmol，20.60mL)於ACN(250mL)中之溶液中逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(17.27g，90.65mmol)。然後在室溫下將反應混合物攪拌24h，然後在真空中蒸發，將殘餘物用水(575mL)稀釋。過濾出所形成之沉澱，用水洗滌且在真空中乾燥，以得到產物2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(30g，粗品)。To 3-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (17.6 g, 78.83 mmol) and DIPEA (15.28 g, 118.24 mmol, 20.60 mmol) at 0°C under argon mL) in ACN (250 mL) was added dropwise 2,2,2-trifluoroethyl 2-chloro-2- oxyacetate (17.27 g, 90.65 mmol). The reaction mixture was then stirred at room temperature for 24 h, then evaporated in vacuo and the residue was diluted with water (575 mL). The resulting precipitate was filtered off, washed with water and dried in vacuo to give the product 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridinyl]amino]-2- Pendant 2,2,2-trifluoroethyl acetate (30 g, crude).

1 H NMR(DMSO-d6,400MHz)：δ 1.42(s,9H),2.15(s,3H),4.96(q,2H),7.93(s,1H),8.49(s,1H),9.03(s,1H),11.06(s,1H) 1 H NMR (DMSO-d6, 400MHz): δ 1.42(s, 9H), 2.15(s, 3H), 4.96(q, 2H), 7.93(s, 1H), 8.49(s, 1H), 9.03(s ,1H),11.06(s,1H)

LCMS(ESI)：[M-CH2C(CH3)+H]+ m/z：計算值377.32；實測值322.0；Rt=1.274min。LCMS(ESI): [M-CH2C(CH3)+H] + m/z: calculated 377.32; found 322.0; Rt=1.274 min.

步驟4：2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸之合成Step 4: Synthesis of 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid

在5℃下，以TLC對照(DCM-MeOH 5：1作為溶析液)，攪拌2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(30g，79.51mmol)及氫氧化鋰單水合物(6.67g，159.02mmol，4.42mL)於THF(120mL)-甲醇(120mL)-水(120mL)中之混合物。起始材料完全消耗(2h)之後，旋轉蒸發揮發性有機溶劑。將殘餘物用硫酸氫鈉單水合物(21.96g，159.02mmol)酸化至pH 5，且過濾出所形成之沉澱，用水洗滌且在真空中乾燥，以得到產物2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(23g，77.89mmol，97.96%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridinyl]amine was stirred at 5°C with TLC control (DCM-MeOH 5:1 as eluent) 2,2,2-trifluoroethyl acetate (30 g, 79.51 mmol) and lithium hydroxide monohydrate (6.67 g, 159.02 mmol, 4.42 mL) in THF (120 mL)-methanol ( 120 mL)-water (120 mL). After complete consumption of starting material (2h), the volatile organic solvent was rotary evaporated. The residue was acidified to pH 5 with sodium bisulfate monohydrate (21.96 g, 159.02 mmol) and the resulting precipitate was filtered off, washed with water and dried in vacuo to give the product 2-[[6-(tert-butylene Oxycarbonylamino)-5-methyl-3-pyridinyl]amino]-2-side oxyacetic acid (23 g, 77.89 mmol, 97.96% yield).

1 H NMR(DMSO-d6,400MHz)：δ 1.44(s,9H),2.16(s,3H),7.97(s,1H),8.51(s,1H),8.98(s,1H),10.70(s,1H) 1 H NMR (DMSO-d6, 400MHz): δ 1.44(s, 9H), 2.16(s, 3H), 7.97(s, 1H), 8.51(s, 1H), 8.98(s, 1H), 10.70(s ,1H)

LCMS(ESI)：[M-CH2C(CH3)+H]+ m/z：計算值295.29；實測值240.0；Rt=0.829min。LCMS(ESI): [M-CH2C(CH3)+H] + m/z: calculated 295.29; found 240.0; Rt=0.829 min.

2C. 2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯及2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸之合成2C. 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-side oxyacetic acid 2,2,2-trifluoroethyl ester and 2-[(5 -Synthesis of aminocarboxy-6-methoxy-3-pyridyl)amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0548-683
Figure 110128222-A0202-12-0548-683

步驟1：2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1: Synthesis of 2-[(5-Aminocarboxy-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester

在0℃下，向5-胺基-2-甲氧基吡啶-3-甲醯胺(10.06g，60.18mmol)及三乙胺(6.09g，60.18mmol，8.39mL)於無水THF(250mL)中之溶液中添加於50ml 無水THF中之2-氯-2-側氧基乙酸2,2，2-三氟乙酯(12.04g，63.19mmol)。在室溫下攪拌12h之後，將所得混合物蒸發至乾，以得到呈淡粉色固體之2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(29g，粗品)，其不經進一步純化即用於下一步驟。1 H NMR(DMSO-d6,500MHz)：δ 1.47(s,9H),3.3(s,2H),8.81(s,1H),9.15(s,1H),9.88(s,1H)To 5-amino-2-methoxypyridine-3-carboxamide (10.06 g, 60.18 mmol) and triethylamine (6.09 g, 60.18 mmol, 8.39 mL) in dry THF (250 mL) at 0 °C To the solution was added 2,2,2-trifluoroethyl 2-chloro-2-oxoacetate (12.04 g, 63.19 mmol) in 50 ml of dry THF. After stirring at room temperature for 12 h, the resulting mixture was evaporated to dryness to give 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2- as a pale pink solid Pendant 2,2,2-trifluoroethyl acetate (29 g, crude), which was used in the next step without further purification. 1 H NMR (DMSO-d6, 500MHz): δ 1.47(s, 9H), 3.3(s, 2H), 8.81(s, 1H), 9.15(s, 1H), 9.88(s, 1H)

1 H NMR(DMSO-d6,400MHz)：δ 3.97(s,3H),5.00(q,2H),7.75(brs,2H),8.55(s,1H),8.63(s,1H),11.21(s,1H) 1 H NMR (DMSO-d6, 400MHz): δ 3.97(s, 3H), 5.00(q, 2H), 7.75(brs, 2H), 8.55(s, 1H), 8.63(s, 1H), 11.21(s ,1H)

步驟2：2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸之合成Step 2: Synthesis of 2-[(5-Aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid

向2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(15g，46.70mmol)於MeOH(400mL)中之溶液中添加98%氫氧化鋰單水合物(3.92g，93.40mmol，2.60mL)，且將所得混合物在室溫下攪拌1h。然後將所得混合物蒸發至乾，溶解於水中。用鹽酸水溶液將水酸化至pH=1，且過濾沉澱。將沉澱懸浮於MeOH中且添加三乙胺(9.45g，93.40mmol，13.02mL)，直到溶液變得澄清。將所得混合物蒸發至乾，以得到呈米色固體之2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(10.35g，30.41mmol，65.12%產率，Et3N)。To 2-[(5-aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetate 2,2,2-trifluoroethyl ester (15 g, 46.70 mmol) was added To a solution in MeOH (400 mL) was added 98% lithium hydroxide monohydrate (3.92 g, 93.40 mmol, 2.60 mL) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then evaporated to dryness and dissolved in water. The water was acidified to pH=1 with aqueous hydrochloric acid, and the precipitate was filtered. The precipitate was suspended in MeOH and triethylamine (9.45 g, 93.40 mmol, 13.02 mL) was added until the solution became clear. The resulting mixture was evaporated to dryness to give 2-[(5-aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-pendoxoacetic acid (10.35 g, 30.41 g) as a beige solid mmol, 65.12% yield, Et3N).

1 H NMR(DMSO-d6,400MHz)：δ 1.17(s,12H),3.06(q,6H),3.92(s,3H),7.70(d,2H),8.60(s,1H),10.34(s,1H),10.34(brs,1H) 1 H NMR (DMSO-d6, 400MHz): δ 1.17(s, 12H), 3.06(q, 6H), 3.92(s, 3H), 7.70(d, 2H), 8.60(s, 1H), 10.34(s ,1H),10.34(brs,1H)

2D. 2-[(5-氯-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸之合成2D. Synthesis of 2-[(5-Chloro-6-methyl-3-pyridyl)amino]-2-oxoacetic acid

Figure 110128222-A0202-12-0549-684
Figure 110128222-A0202-12-0549-684

步驟1：2-[(5-氯-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸甲酯之合成Step 1: Synthesis of methyl 2-[(5-chloro-6-methyl-3-pyridinyl)amino]-2-oxoacetate

將5-氯-6-甲基吡啶-3-胺(3g，21.04mmol)及TEA(2.13g，21.04mmol，2.93mL)溶解於DCM(50mL)中且冷卻至0℃，隨後逐滴添加2-氯-2-側氧基乙酸甲酯(2.84g，23.14mmol，2.13mL)。反應完成之後，將混合物用DCM(50 mL)稀釋，用H2 O(40mL)及鹽水(50mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到2-[(5-氯-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸甲酯(3.5g，15.31mmol，72.76%產率)。5-Chloro-6-methylpyridin-3-amine (3 g, 21.04 mmol) and TEA (2.13 g, 21.04 mmol, 2.93 mL) were dissolved in DCM (50 mL) and cooled to 0 °C, followed by dropwise addition of 2 - Methyl chloro-2-oxoacetate (2.84 g, 23.14 mmol, 2.13 mL). After completion of the reaction, the mixture was diluted with DCM (50 mL), washed with H2O (40 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give methyl 2-[(5-chloro-6-methyl-3-pyridinyl)amino]-2-oxoacetate (3.5 g, 15.31 mmol, 72.76% yield).

1 H NMR(500MHz,DMSO-d6 )δ 2.52(s,3H),3.86(s,3H),8.24(s,1H),8.79(s,1H),11.14(s,1H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.52(s,3H), 3.86(s,3H), 8.24(s,1H), 8.79(s,1H), 11.14(s,1H).

步驟2：2-[(5-氯-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸之合成Step 2: Synthesis of 2-[(5-Chloro-6-methyl-3-pyridyl)amino]-2-oxoacetic acid

將2-[(5-氯-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸甲酯(3.49g，15.26mmol)溶解於THF(50mL)中，隨後添加98%氫氧化鋰單水合物(768.26mg，18.31mmol，508.78μL)且再攪拌隔夜。反應完成之後，過濾混合物，將所獲得之固體風乾且用CCl4(200mL)再蒸發至乾，以得到2-[(5-氯-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸(2.5g，11.28mmol，73.96%產率，Li+)。Methyl 2-[(5-chloro-6-methyl-3-pyridinyl)amino]-2-oxyacetate (3.49 g, 15.26 mmol) was dissolved in THF (50 mL) followed by the addition of 98% Lithium hydroxide monohydrate (768.26 mg, 18.31 mmol, 508.78 μL) and stirred overnight. After the reaction was complete, the mixture was filtered, the solid obtained was air-dried and re-evaporated to dryness with CCl (200 mL) to give 2-[(5-chloro-6-methyl-3-pyridinyl)amino]-2- Pendant oxyacetic acid (2.5 g, 11.28 mmol, 73.96% yield, Li+).

1 H NMR(400MHz,DMSO-d6 )δ 2.43(s,3H),8.28(s,1H),8.73(s,1H),10.47(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.43 (s, 3H), 8.28 (s, 1H), 8.73 (s, 1H), 10.47 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值214.0；實測值215.0；Rt=0.751minLCMS(ESI): [M+H] + m/z: Calculated 214.0; Measured 215.0; Rt=0.751min

2E. 2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯及2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸之合成2E. 2,2,2-trifluoroethyl acetate Synthesis of 2-[(6-Amino-5-ethyl-3-pyridyl)amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0550-685
Figure 110128222-A0202-12-0550-685

步驟1：N-(3-溴-5-硝基-2-吡啶基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-(3-bromo-5-nitro-2-pyridyl)carbamate

在0℃下，向3-溴-5-硝基-吡啶-2-胺(30g，137.61mmol)於DMF(200mL)中之溶液中分批添加於礦物油中之氫化鈉(油分散物)60%分散物(5.54g， 138.42mmol，60%純度)。將所得混合物攪拌0.5h(直至氣體逸出結束)且逐滴添加二碳酸二-第三丁酯(31.53g，144.49mmol，33.16mL)於DMF(50mL)中之溶液。將所得混合物在25℃下攪拌12h。將混合物用水(1000ml)淬滅，過濾沉澱且將其溶解於EtOAc(900ml)+THF(100ml)中，用鹽水(2*300ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得白色晶體沉澱。過濾此沉澱，用EtOAc(30ml)、MTBE(2*50ml)洗滌且乾燥，以獲得N-(3-溴-5-硝基-2-吡啶基)胺甲酸第三丁酯(32g，100.59mmol，73.10%產率)。To a solution of 3-bromo-5-nitro-pyridin-2-amine (30 g, 137.61 mmol) in DMF (200 mL) was added portionwise sodium hydride in mineral oil (oil dispersion) at 0 °C 60% dispersion (5.54 g, 138.42 mmol, 60% pure). The resulting mixture was stirred for 0.5 h (until gas evolution ceased) and a solution of di-tert-butyl dicarbonate (31.53 g, 144.49 mmol, 33.16 mL) in DMF (50 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 12 h. The mixture was quenched with water (1000ml), the precipitate was filtered and dissolved in EtOAc (900ml) + THF (100ml), washed with brine (2*300ml), dried over Na2SO4 and evaporated in vacuo to obtain White crystals precipitated. The precipitate was filtered, washed with EtOAc (30ml), MTBE (2*50ml) and dried to give tert-butyl N-(3-bromo-5-nitro-2-pyridyl)carbamate (32g, 100.59mmol) , 73.10% yield).

1 H NMR(DMSO-d6,500MHz)：δ 1.47(s,9H),3.3(s,2H),8.81(s,1H),9.15(s,1H),9.88(s,1H) 1 H NMR (DMSO-d6, 500MHz): δ 1.47(s, 9H), 3.3(s, 2H), 8.81(s, 1H), 9.15(s, 1H), 9.88(s, 1H)

LCMS(ESI)：[M-CH2C(CH3)+H]+ m/z：計算值318.1；實測值264.0；Rt=1.152min。LCMS (ESI): [M-CH2C(CH3)+H] + m/z: calculated 318.1; found 264.0; Rt=1.152 min.

步驟2：N-(5-硝基-3-乙烯基-2-吡啶基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-(5-nitro-3-vinyl-2-pyridyl)carbamate

將N-(3-溴-5-硝基-2-吡啶基)胺甲酸第三丁酯(27g，84.87mmol)、乙烯基三氟硼酸鉀(13.64g，101.85mmol)及碳酸鉀(58.65g，424.36mmol，25.61mL)於二噁烷(400mL)及水(100mL)中之溶液抽真空且用氬氣再填充三次。向此溶液中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(3.47g，4.24mmol)且將所得混合物在80℃下攪拌2h。將所得混合物冷卻，過濾，移除溶劑。將殘餘物用水(350ml)溶解且用EtOAc-THF 9：1(3*300ml)萃取。將有機層經Na2 SO4 乾燥。移除90%溶劑且過濾所形成之沉澱，用MTBE洗滌且乾燥，以得到N-(5-硝基-3-乙烯基-2-吡啶基)胺甲酸第三丁酯(13.5g，50.89mmol，59.96%產率)。Combine tert-butyl N-(3-bromo-5-nitro-2-pyridyl)carbamate (27 g, 84.87 mmol), potassium vinyltrifluoroborate (13.64 g, 101.85 mmol) and potassium carbonate (58.65 g) , 424.36 mmol, 25.61 mL) in dioxane (400 mL) and water (100 mL) was evacuated and refilled three times with argon. To this solution was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (3.47 g, 4.24 mmol) and the resulting mixture was heated at 80 °C under stirring for 2h. The resulting mixture was cooled, filtered and the solvent was removed. The residue was dissolved in water (350ml) and extracted with EtOAc-THF 9:1 (3*300ml). The organic layer was dried over Na2SO4 . 90% solvent was removed and the resulting precipitate was filtered, washed with MTBE and dried to give tert-butyl N-(5-nitro-3-vinyl-2-pyridyl)carbamate (13.5 g, 50.89 mmol) , 59.96% yield).

1 H NMR(DMSO-d6,400MHz)：δ 1.45(s,9H),3.3(s,2H),5.54(d,1H),6.06(d,1H),6.75(dd,1H),8.07(s,1H),9.08(s,1H),9.93(s,1H) 1 H NMR (DMSO-d6, 400MHz): δ 1.45(s, 9H), 3.3(s, 2H), 5.54(d, 1H), 6.06(d, 1H), 6.75(dd, 1H), 8.07(s ,1H),9.08(s,1H),9.93(s,1H)

LCMS(ESI)：[M-CH2C(CH3)+H]+ m/z：計算值265.1；實測值210.0；Rt=1.311min。LCMS(ESI): [M-CH2C(CH3)+H] + m/z: calculated 265.1; found 210.0; Rt=1.311 min.

步驟3：N-(5-胺基-3-乙烯-2-吡啶基)胺甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl N-(5-amino-3-vinyl-2-pyridyl)carbamate

向N-(5-硝基-3-乙烯基-2-吡啶基)胺甲酸第三丁酯(13g，49.01mmol)於甲醇(400mL)中之溶液中添加鈀(10%於碳上)(52.15g，49.01mmol，10%純度)。在氫氣氛、25℃下攪拌所得混合物24h。過濾催化劑且在真空中蒸發溶劑，將殘餘物溶解於ACN(150ml)中且在真空中蒸發，以獲得N-(5-胺基-3-乙基-2-吡啶基)胺甲酸第三丁酯(11g，46.36mmol，94.59%產率)。To a solution of tert-butyl N-(5-nitro-3-vinyl-2-pyridinyl)carbamate (13 g, 49.01 mmol) in methanol (400 mL) was added palladium (10% on carbon) ( 52.15 g, 49.01 mmol, 10% pure). The resulting mixture was stirred under a hydrogen atmosphere at 25 °C for 24 h. The catalyst was filtered and the solvent was evaporated in vacuo, the residue was dissolved in ACN (150ml) and evaporated in vacuo to obtain tert-butyl N-(5-amino-3-ethyl-2-pyridyl)carbamate Ester (11 g, 46.36 mmol, 94.59% yield).

1 H NMR(DMSO-d6,400MHz)：δ 1.03(t,3H),1.36(s,9H),2.37(q,2H),3.3(s,2H),6.76(s,1H),7.52(s,1H),8.40(s,1H) 1 H NMR (DMSO-d6, 400MHz): δ 1.03(t, 3H), 1.36(s, 9H), 2.37(q, 2H), 3.3(s, 2H), 6.76(s, 1H), 7.52(s ,1H),8.40(s,1H)

LCMS(ESI)：[M+H]+ m/z：計算值237.3；實測值238.2；Rt=0.901min。LCMS (ESI): [M+H] + m/z: calculated 237.3; found 238.2; Rt=0.901 min.

步驟4：2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 4: 2,2,2-trifluoroethyl 2-[[6-(Third-butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-oxoacetic acid synthesis

在0℃、氬氣下，向N-(5-胺基-3-乙基-2-吡啶基)胺甲酸第三丁酯(11g，46.36mmol)及DIPEA(8.99g，69.53mmol，12.11mL)於ACN(350mL)中之溶液中逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(10.16g，53.31mmol)。然後在室溫下將反應混合物攪拌24h，然後在真空中蒸發，將殘餘物用水(575mL)稀釋。將沉澱研磨24h，過濾出所形成之沉澱，用水、EtOAc洗滌且在真空中乾燥，以得到產物2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(13g，粗品)。To 3-butyl N-(5-amino-3-ethyl-2-pyridyl)carbamate (11 g, 46.36 mmol) and DIPEA (8.99 g, 69.53 mmol, 12.11 mL) at 0°C under argon ) in ACN (350 mL) was added dropwise 2,2,2-trifluoroethyl 2-chloro-2-oxyacetate (10.16 g, 53.31 mmol). The reaction mixture was then stirred at room temperature for 24 h, then evaporated in vacuo and the residue was diluted with water (575 mL). The precipitate was triturated for 24h, the formed precipitate was filtered off, washed with water, EtOAc and dried in vacuo to give the product 2-[[6-(tert-butoxycarbonylamino)-5-ethyl-3-pyridyl ]amino]-2-oxoacetate 2,2,2-trifluoroethyl ester (13 g, crude).

LCMS光譜顯示所要產物及經Boc去保護之產物之混合物。LCMS spectrum showed a mixture of desired product and Boc deprotected product.

此產物不經純化即用於下一步驟。This product was used in the next step without purification.

步驟4：2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸之合成Step 4: Synthesis of 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid

根據LCMS，起始材料部分經Boc去保護。According to LCMS, the starting material was partially deprotected with Boc.

向2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(13g，33.22mmol)於甲醇(100mL)及THF(100mL)中之溶液中添加氫氧化鋰單水合物(2.79g，66.44mmol，1.85mL)於水(200mL)中之溶液。將 所得混合物在0℃下攪拌3h，移除有機溶劑，用硫酸氫鈉單水合物(9.63g，69.76mmol)於水(50mL)中之溶液酸化水溶液。過濾所形成之沉澱且乾燥，以獲得2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(8.7g，粗品)。To 2-[[6-(Third-butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (13 g , 33.22 mmol) in methanol (100 mL) and THF (100 mL) was added a solution of lithium hydroxide monohydrate (2.79 g, 66.44 mmol, 1.85 mL) in water (200 mL). Will The resulting mixture was stirred at 0 °C for 3 h, the organic solvent was removed, and the aqueous solution was acidified with a solution of sodium bisulfate monohydrate (9.63 g, 69.76 mmol) in water (50 mL). The resulting precipitate was filtered and dried to obtain 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid (8.7 g, crude).

在添加Et3 N之情況下，取得於作為溶劑之CD3OD中之NMR光譜。此化合物不經純化即用於下一步驟。NMR spectra were obtained in CD3OD as solvent with the addition of Et3N . This compound was used in the next step without purification.

1 H NMR(CD3OD,400MHz)：δ 1.22(t,3H),2.47(q,2H),7.65(s,1H),8.19(s,1H) 1 H NMR (CD3OD, 400MHz): δ 1.22(t,3H), 2.47(q,2H), 7.65(s,1H), 8.19(s,1H)

2F. 2-[[6-甲基-5-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸之合成2F. Synthesis of 2-[[6-methyl-5-(trifluoromethyl)-3-pyridyl]amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0553-686
Figure 110128222-A0202-12-0553-686

步驟1：2-[5-硝基-3-(三氟甲基)-2-吡啶基]丙二酸二乙酯之合成Step 1: Synthesis of diethyl 2-[5-nitro-3-(trifluoromethyl)-2-pyridyl]malonate

在-10℃下，向丙二酸二乙酯(1.41g，8.83mmol，1.33mL)於THF(50mL)中之經攪拌之溶液中添加第三丁醇鉀(2.97g，26.49mmol)，且將混合物在同一溫度下攪拌10min，隨後在室溫下攪拌30min。在0℃下，將2-氯-5-硝基-3-(三氟甲基)吡啶(2g，8.83mmol)緩慢添加到混合物中，且將所得混合物在室溫下攪拌4h。將混合物用氯化銨水溶液淬滅且用乙酸乙酯萃取兩次。將經合併之有機層用水洗滌，隨後用鹽水洗滌，且經無水硫酸鈉乾燥。將溶液過濾，濃縮，以得到2-[5-硝基-3-(三氟甲基)-2-吡啶基]丙二酸二乙酯(2.3g，6.57mmol，74.38%產率).粗品胺同樣用於下一步驟。To a stirred solution of diethyl malonate (1.41 g, 8.83 mmol, 1.33 mL) in THF (50 mL) at -10 °C was added potassium tert-butoxide (2.97 g, 26.49 mmol), and The mixture was stirred at the same temperature for 10 min, then at room temperature for 30 min. 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) was slowly added to the mixture at 0 °C, and the resulting mixture was stirred at room temperature for 4 h. The mixture was quenched with aqueous ammonium chloride and extracted twice with ethyl acetate. The combined organic layers were washed with water, followed by brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give diethyl 2-[5-nitro-3-(trifluoromethyl)-2-pyridyl]malonate (2.3 g, 6.57 mmol, 74.38% yield). Crude The amine was also used in the next step.

1 H NMR(500MHz,DMSO-d6 )δ 1.15(m,6H),4.18(m,4H),5.37(s,1H),8.87(s,1H),9.63(s,1H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 1.15 (m, 6H), 4.18 (m, 4H), 5.37 (s, 1H), 8.87 (s, 1H), 9.63 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值350.1；實測值351.0；Rt=1.379min。LCMS (ESI): [M+H] + m/z: calculated 350.1; found 351.0; Rt=1.379 min.

步驟2：2-甲基-5-硝基-3-(三氟甲基)吡啶之合成Step 2: Synthesis of 2-methyl-5-nitro-3-(trifluoromethyl)pyridine

將2-[5-硝基-3-(三氟甲基)-2-吡啶基]丙二酸二乙酯(2.3g，6.57mmol)於水(23mL)及H2 SO4 (23mL)中之溶液在90℃下加熱2-3h。將混合物冷卻至0℃且用3N NaOH溶液鹼化。用DCM萃取水溶液兩次。將經合併之有機層用鹽水洗滌且經無水硫酸鈉乾燥。將溶液過濾，濃縮，以得到2-甲基-5-硝基-3-(三氟甲基)吡啶(0.6g，2.91mmol，44.33%產率)。Diethyl 2-[5-nitro-3-(trifluoromethyl)-2-pyridyl]malonate (2.3 g, 6.57 mmol) in water (23 mL) and H2SO4 ( 23 mL) The solution was heated at 90°C for 2-3h. The mixture was cooled to 0°C and basified with 3N NaOH solution. The aqueous solution was extracted twice with DCM. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give 2-methyl-5-nitro-3-(trifluoromethyl)pyridine (0.6 g, 2.91 mmol, 44.33% yield).

1 H NMR(500MHz,DMSO-d6 )δ 2.77(s,3H),8.71(s,1H),9.48(s,1H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.77 (s, 3H), 8.71 (s, 1H), 9.48 (s, 1H).

GCMS(EI)：[M+H]+ m/z：計算值206.0；實測值206.0；Rt=5.223min。GCMS (EI): [M+H] + m/z: calculated 206.0; found 206.0; Rt=5.223 min.

步驟3：6-甲基-5-(三氟甲基)吡啶-3-胺之合成Step 3: Synthesis of 6-methyl-5-(trifluoromethyl)pyridin-3-amine

在50℃下，向2-甲基-5-硝基-3-(三氟甲基)吡啶(0.6g，2.91mmol)於HCl(0.1mL)、水(1mL)及EtOH(10mL)中之溶液中分批添加鐵(1.30g，23.29mmol，165.45μL)。此後，將所得混合物攪拌隔夜。將溶液透過矽膠來過濾且蒸發，以得到6-甲基-5-(三氟甲基)吡啶-3-胺(0.5g，2.84mmol，97.52%產率)。To 2-methyl-5-nitro-3-(trifluoromethyl)pyridine (0.6 g, 2.91 mmol) in HCl (0.1 mL), water (1 mL) and EtOH (10 mL) at 50 °C Iron (1.30 g, 23.29 mmol, 165.45 [mu]L) was added portionwise to the solution. After this time, the resulting mixture was stirred overnight. The solution was filtered through silica gel and evaporated to give 6-methyl-5-(trifluoromethyl)pyridin-3-amine (0.5 g, 2.84 mmol, 97.52% yield).

1 H NMR(400MHz,DMSO-d6 )δ 2.37(s,3H),5.52(s,2H),7.15(s,1H),7.99(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 3H), 5.52 (s, 2H), 7.15 (s, 1H), 7.99 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值176.1；實測值177.2；Rt=0.711min。LCMS (ESI): [M+H] + m/z: calculated 176.1; found 177.2; Rt=0.711 min.

步驟4：2-[[6-甲基-5-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸乙酯之合成Step 4: Synthesis of ethyl 2-[[6-methyl-5-(trifluoromethyl)-3-pyridinyl]amino]-2-oxoacetate

向6-甲基-5-(三氟甲基)吡啶-3-胺(0.5g，2.84mmol)於DCM(10mL)中之溶液中添加TEA(344.69mg，3.41mmol，474.79μL)。此後，將溶液冷卻至0℃且逐滴添加2-氯-2-側氧基乙酸乙酯(465.09mg，3.41mmol，381.22μL)。在室溫下將所得混合物攪拌3h。將反應混合物用水及鹽水洗滌，經無水硫酸鈉乾燥。將溶液過濾，濃縮，以得到2-[[6-甲基-5-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸乙酯(0.68g，2.46mmol，86.73%產率)。To a solution of 6-methyl-5-(trifluoromethyl)pyridin-3-amine (0.5 g, 2.84 mmol) in DCM (10 mL) was added TEA (344.69 mg, 3.41 mmol, 474.79 μL). After this time, the solution was cooled to 0°C and ethyl 2-chloro-2-pendoxoacetate (465.09 mg, 3.41 mmol, 381.22 μL) was added dropwise. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was washed with water and brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give ethyl 2-[[6-methyl-5-(trifluoromethyl)-3-pyridyl]amino]-2-oxoacetate (0.68 g, 2.46 mmol, 86.73% yield).

1 H NMR(500MHz,DMSO-d6 )δ 1.30(t,3H),2.58(s,3H),4.32(q,2H),8.46(s,1H),9.04(s,1H),11.23(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.30(t, 3H), 2.58(s, 3H), 4.32(q, 2H), 8.46(s, 1H), 9.04(s, 1H), 11.23(s , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值276.1；實測值277.2；Rt=1.045min。LCMS (ESI): [M+H] + m/z: calculated 276.1; found 277.2; Rt=1.045 min.

步驟5：2-[[6-甲基-5-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸之合成Step 5: Synthesis of 2-[[6-Methyl-5-(trifluoromethyl)-3-pyridyl]amino]-2-pendoxoacetic acid

將2-[[6-甲基-5-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸乙酯(0.68g，2.46mmol)於水(5mL)及THF(5mL)中之溶液冷卻。在0℃下，添加氫氧化鋰單水合物(123.97mg，2.95mmol，82.10μL)。然後將反應混合物在室溫下攪拌隔夜。旋轉蒸發有機溶劑。將殘餘物用HCl酸化至pH 2且過濾，以得到2-[[6-甲基-5-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸(2.5g，10.72mmol，56.01%產率)。Ethyl 2-[[6-methyl-5-(trifluoromethyl)-3-pyridinyl]amino]-2-oxoacetate (0.68 g, 2.46 mmol) in water (5 mL) and THF The solution in (5 mL) was cooled. At 0°C, lithium hydroxide monohydrate (123.97 mg, 2.95 mmol, 82.10 μL) was added. The reaction mixture was then stirred at room temperature overnight. Rotary evaporation of organic solvents. The residue was acidified with HCl to pH 2 and filtered to give 2-[[6-methyl-5-(trifluoromethyl)-3-pyridinyl]amino]-2-oxoacetic acid (2.5 g , 10.72 mmol, 56.01% yield).

1 H NMR(400MHz,DMSO-d6 )δ 2.58(s,3H),8.51(s,1H),9.06(s,1H),11.14(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.58 (s, 3H), 8.51 (s, 1H), 9.06 (s, 1H), 11.14 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值248.0；實測值249.2；Rt=0.729min。LCMS (ESI): [M+H] + m/z: calculated 248.0; found 249.2; Rt=0.729 min.

2G. 2-[[5-甲基-6-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸之合成2G. Synthesis of 2-[[5-methyl-6-(trifluoromethyl)-3-pyridyl]amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0555-687
Figure 110128222-A0202-12-0555-687

步驟1：2-[[5-甲基-6-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸甲酯之合成Step 1: Synthesis of methyl 2-[[5-methyl-6-(trifluoromethyl)-3-pyridinyl]amino]-2-oxoacetate

將5-甲基-6-(三氟甲基)吡啶-3-胺(3.00g，17.03mmol)及TEA(1.72g，17.03mmol，2.37mL)溶解於DCM(50mL)中且冷卻至0℃，隨後逐滴添加2-氯-2-側氧基乙酸甲酯(2.30g，18.74mmol，1.73mL)。反應完成之後，將混合物用DCM(50mL)稀釋，用H2 O(40mL)及鹽水(50mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到2-[[5-甲基-6-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸甲酯(4g，15.26mmol，89.57%產率)。5-Methyl-6-(trifluoromethyl)pyridin-3-amine (3.00 g, 17.03 mmol) and TEA (1.72 g, 17.03 mmol, 2.37 mL) were dissolved in DCM (50 mL) and cooled to 0 °C , followed by the dropwise addition of methyl 2-chloro-2-oxoacetate (2.30 g, 18.74 mmol, 1.73 mL). After the reaction was complete, the mixture was diluted with DCM (50 mL), washed with H2O (40 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give 2-[[5-methyl-6-(trifluoromethyl)-3-pyridinyl]amino]-2-pendoxyloxy Methyl acetate (4 g, 15.26 mmol, 89.57% yield).

1 H NMR(500MHz,DMSO-d6 )δ 2.49(s,3H),3.87(s,3H),8.28(s,1H),8.86(s,1H),11.20(s,1H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.49(s,3H), 3.87(s,3H), 8.28(s,1H), 8.86(s,1H), 11.20(s,1H).

步驟2：2-[[5-甲基-6-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸之合成Step 2: Synthesis of 2-[[5-methyl-6-(trifluoromethyl)-3-pyridinyl]amino]-2-pendoxoacetic acid

將2-[[5-甲基-6-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸甲酯(4g，15.26mmol)溶解於THF(50mL)中，隨後添加98%氫氧化鋰單水合物(768.26mg， 18.31mmol，508.78μL)且再攪拌隔夜。反應完成之後，過濾混合物，將所獲得之固體風乾且用CCl4 (200mL)再蒸發至乾，以得到2-[[5-甲基-6-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸(3.4g，13.33mmol，87.36%產率，Li+)。Methyl 2-[[5-methyl-6-(trifluoromethyl)-3-pyridinyl]amino]-2-oxoacetate (4 g, 15.26 mmol) was dissolved in THF (50 mL), 98% Lithium hydroxide monohydrate (768.26 mg, 18.31 mmol, 508.78 μL) was then added and stirred overnight. After the reaction was complete, the mixture was filtered, the solid obtained was air-dried and re-evaporated to dryness with CCl 4 (200 mL) to give 2-[[5-methyl-6-(trifluoromethyl)-3-pyridyl] Amino]-2-pendant oxyacetic acid (3.4 g, 13.33 mmol, 87.36% yield, Li+).

1 H NMR(400MHz,DMSO-d6 )δ 2.38(s,3H),8.25(s,1H),8.82(s,1H),10.56(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.38 (s, 3H), 8.25 (s, 1H), 8.82 (s, 1H), 10.56 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值248.0；實測值249.0；Rt=0.948min。LCMS (ESI): [M+H] + m/z: calculated 248.0; found 249.0; Rt=0.948 min.

2H. 2-[[6-(二氟甲基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸之合成2H. Synthesis of 2-[[6-(difluoromethyl)-5-methyl-3-pyridyl]amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0556-688
Figure 110128222-A0202-12-0556-688

步驟1：2-[[6-(二氟甲基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸甲酯之合成Step 1: Synthesis of methyl 2-[[6-(difluoromethyl)-5-methyl-3-pyridyl]amino]-2-oxoacetate

將6-(二氟甲基)-5-甲基吡啶-3-胺(3g，18.97mmol)及TEA(1.92g，18.97mmol，2.64mL)溶解於DCM(50mL)中且冷卻至0℃，隨後逐滴添加2-氯-2-側氧基乙酸甲酯(2.56g，20.87mmol，1.92mL)。反應完成之後，將混合物用DCM(50mL)稀釋，用H2 O(40mL)及鹽水(50mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到2-[[6-(二氟甲基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸甲酯(3.3g，13.51mmol，71.24%產率)。6-(Difluoromethyl)-5-methylpyridin-3-amine (3 g, 18.97 mmol) and TEA (1.92 g, 18.97 mmol, 2.64 mL) were dissolved in DCM (50 mL) and cooled to 0 °C, Then methyl 2-chloro-2-pendoxoacetate (2.56 g, 20.87 mmol, 1.92 mL) was added dropwise. After the reaction was complete, the mixture was diluted with DCM (50 mL), washed with H2O (40 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give 2-[[6-(difluoromethyl)-5-methyl-3-pyridinyl]amino]-2-pendoxyloxy Methyl acetate (3.3 g, 13.51 mmol, 71.24% yield).

1 H NMR(500MHz,DMSO-d6 )δ 2.43(s,3H),3.87(s,3H),6.98(t,1H),8.16(s,1H),8.80(s,1H),11.19(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 2.43(s, 3H), 3.87(s, 3H), 6.98(t, 1H), 8.16(s, 1H), 8.80(s, 1H), 11.19(s , 1H).

步驟2：2-[[6-(二氟甲基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸之合成Step 2: Synthesis of 2-[[6-(difluoromethyl)-5-methyl-3-pyridinyl]amino]-2-oxoacetic acid

將2-[[6-(二氟甲基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸甲酯(3.3g，13.51mmol)溶解於THF(50mL)中，隨後添加98%氫氧化鋰單水合物(680.45mg，16.22mmol，450.63μL)且再攪拌隔夜。反應完成之後，過濾混合物，將所獲得之固體風乾且用CCl4 (200mL)再蒸發至乾，以得到2-[[6-(二氟甲基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(2.2g，9.28mmol，68.66%產率，Li+)。Methyl 2-[[6-(difluoromethyl)-5-methyl-3-pyridinyl]amino]-2-oxoacetate (3.3 g, 13.51 mmol) was dissolved in THF (50 mL) , followed by the addition of 98% lithium hydroxide monohydrate (680.45 mg, 16.22 mmol, 450.63 μL) and stirring overnight. After the reaction was complete, the mixture was filtered, the solid obtained was air-dried and re-evaporated to dryness with CCl 4 (200 mL) to give 2-[[6-(difluoromethyl)-5-methyl-3-pyridyl] Amino]-2-pendant oxyacetic acid (2.2 g, 9.28 mmol, 68.66% yield, Li+).

1 H NMR(400MHz,DMSO-d6 )δ 2.28(s,3H),6.75(t,1H),8.02(s,1H),8.34(s,1H),未觀察到NH及OH。 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.28(s,3H), 6.75(t,1H), 8.02(s,1H), 8.34(s,1H), NH and OH were not observed.

LCMS(ESI)：[M+H]+ m/z：計算值230.0；實測值231.0；Rt=0.807min。LCMS (ESI): [M+H] + m/z: calculated 230.0; found 231.0; Rt=0.807 min.

2I. 2-[[5-(二氟甲基)-6-甲基-3-吡啶基]胺基]-2-側氧基乙酸之合成2I. Synthesis of 2-[[5-(difluoromethyl)-6-methyl-3-pyridyl]amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0557-689
Figure 110128222-A0202-12-0557-689

步驟1：5-溴-2-甲基吡啶-3-甲酸甲酯之合成Step 1: Synthesis of methyl 5-bromo-2-methylpyridine-3-carboxylate

將5-溴-2-甲基吡啶-3-甲酸(4g，18.52mmol)溶解於MeOH(100mL)中且逐滴添加亞硫醯氯(6.61g，55.55mmol，4mL)，將反應混合物回流隔夜。在真空下濃縮反應混合物，將所獲得之殘餘物溶解於DCM中，且用Na2 CO3 (水溶液)、水洗滌，經Na2 SO4 乾燥，過濾且在真空下過濾，以得到5-溴-2-甲基吡啶-3-甲酸甲酯(3.54g，15.39mmol，83.10%產率)，其不經進一步純化即用於下一步驟。5-Bromo-2-methylpyridine-3-carboxylic acid (4 g, 18.52 mmol) was dissolved in MeOH (100 mL) and thionine chloride (6.61 g, 55.55 mmol, 4 mL) was added dropwise and the reaction mixture was refluxed overnight . The reaction mixture was concentrated under vacuum, the obtained residue was dissolved in DCM and washed with Na2CO3 ( aq ), water, dried over Na2SO4 , filtered and filtered under vacuum to give 5-bromo -Methyl 2-methylpyridine-3-carboxylate (3.54 g, 15.39 mmol, 83.10% yield), which was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 2.78(s,3H),3.92(s,3H),8.32(s,1H),8.66(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 2.78 (s, 3H), 3.92 (s, 3H), 8.32 (s, 1H), 8.66 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值229.0；實測值230.0；Rt=1.231min。LCMS (ESI): [M+H] + m/z: calculated 229.0; found 230.0; Rt=1.231 min.

步驟2：(5-溴-2-甲基-3-吡啶基)甲醇之合成Step 2: Synthesis of (5-bromo-2-methyl-3-pyridyl)methanol

將5-溴-2-甲基吡啶-3-甲酸甲酯(3.54g，15.39mmol)溶解於MeOH(60mL)中且在用冰水冷卻下分批添加硼氫化鈉(1.75g，46.16mmol，1.63mL)。將反應混合物加熱至室溫且攪拌12h。添加NH4 Cl(水溶液)且蒸發甲醇，將水層用 DCM(3* 30ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在45℃下在真空下蒸發，以得到(5-溴-2-甲基-3-吡啶基)甲醇(2.5g，12.37mmol，80.41%產率)，其不經進一步純化即用於下一步驟。Methyl 5-bromo-2-methylpyridine-3-carboxylate (3.54 g, 15.39 mmol) was dissolved in MeOH (60 mL) and sodium borohydride (1.75 g, 46.16 mmol, 1.63 mL). The reaction mixture was warmed to room temperature and stirred for 12 h. NH4Cl (aq) was added and methanol was evaporated, the aqueous layer was extracted with DCM (3 * 30ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated under vacuum at 45°C to give ( 5-Bromo-2-methyl-3-pyridinyl)methanol (2.5 g, 12.37 mmol, 80.41% yield) was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 2.41(s,3H),4.72(s,2H),7.86(s,1H),8.32(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 2.41 (s, 3H), 4.72 (s, 2H), 7.86 (s, 1H), 8.32 (s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值202.0；實測值204.0；Rt=0.678min。LCMS (ESI): [M+2H] + m/z: calculated 202.0; found 204.0; Rt=0.678 min.

步驟3：5-溴-2-甲基吡啶-3-甲醛之合成Step 3: Synthesis of 5-bromo-2-methylpyridine-3-carbaldehyde

將戴斯-馬丁高碘烷(8.79g，20.71mmol)於DCM(15mL)中之漿液用tBuOH(2mL)處理，且將混合物在室溫下攪拌15min，然後在5min內添加(5-溴-2-甲基-3-吡啶基)甲醇(3.1g，15.34mmol)於DCM(15mL)中之溶液。將混合物在室溫下攪拌2h，然後用乙酸乙酯及1N NaOH溶液稀釋，且攪拌10min。分離各層且將有機層用水、鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮，以得到5-溴-2-甲基吡啶-3-甲醛(3.1g，粗品)，其不經進一步純化即用於下一步驟。A slurry of Dess-Martin periodane (8.79 g, 20.71 mmol) in DCM (15 mL) was treated with tBuOH (2 mL) and the mixture was stirred at room temperature for 15 min before (5-bromo- 2-Methyl-3-pyridyl)methanol (3.1 g, 15.34 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate and IN NaOH solution and stirred for 10 min. The layers were separated and the organic layer was washed with water, brine, dried over Na2SO4 , filtered and concentrated to give 5 -bromo-2-methylpyridine-3-carbaldehyde (3.1 g, crude) which was used without further purification for the next step.

1 H NMR(500MHz,CDCl3 )δ 2.83(s,3H),8.17(s,1H),8.72(s,1H),10.27(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 2.83 (s, 3H), 8.17 (s, 1H), 8.72 (s, 1H), 10.27 (s, 1H).

步驟4：5-溴-3-(二氟甲基)-2-甲基吡啶之合成Step 4: Synthesis of 5-bromo-3-(difluoromethyl)-2-methylpyridine

在室溫下，向5-溴-2-甲基吡啶-3-甲醛(3.1g，15.50mmol)於DCM(120mL)中之溶液中添加二乙胺基三氟化硫(19.98g，123.98mmol，16.38mL)。將所得反應混合物在室溫下攪拌隔夜，然後濃縮，以得到5-溴-3-(二氟甲基)-2-甲基吡啶(1.90g，8.57mmol，55.28%產率)，其不經進一步純化即用於下一步驟。To a solution of 5-bromo-2-methylpyridine-3-carbaldehyde (3.1 g, 15.50 mmol) in DCM (120 mL) was added diethylaminosulfur trifluoride (19.98 g, 123.98 mmol) at room temperature , 16.38mL). The resulting reaction mixture was stirred at room temperature overnight, then concentrated to give 5-bromo-3-(difluoromethyl)-2-methylpyridine (1.90 g, 8.57 mmol, 55.28% yield) which was Further purification was used in the next step.

1 H NMR(400MHz,CDCl3 )δ 2.55(s,3H),6.71(t,1H),7.91(s,1H),8.77(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 2.55 (s, 3H), 6.71 (t, 1H), 7.91 (s, 1H), 8.77 (s, 1H).

步驟5：N-[5-(二氟甲基)-6-甲基-3-吡啶基]-1,1-二苯基甲亞胺之合成Step 5: Synthesis of N-[5-(difluoromethyl)-6-methyl-3-pyridyl]-1,1-diphenylmethaneimine

藉由將氬氣鼓泡到5-溴-3-(二氟甲基)-2-甲基吡啶(1.55g，6.98mmol)、二苯基甲亞胺(1.39g，7.68mmol，1.29mL)、Xantphos(1.21g，2.09mmol)、Pd2 (dba)3 (319.64mg，349.05μmol)及碳酸銫(6.82g，20.94mmol)於二噁烷(100mL)中之混合物中若干分鐘來對混合物進行除氣。在90℃、Ar氣氛下，將反應混 合物攪拌12h。將反應混合物冷卻至室溫且過濾。在真空中濃縮濾液且用水稀釋殘餘物。將混合物用乙酸乙酯萃取。將經合併之有機層用水洗滌，經Na2 SO4 乾燥，過濾且濃縮，以得到N-[5-(二氟甲基)-6-甲基-3-吡啶基]-1,1-二苯基甲亞胺(3.8g，粗品)，其不經進一步純化即用於下一步驟。By bubbling argon through 5-bromo-3-(difluoromethyl)-2-methylpyridine (1.55 g, 6.98 mmol), diphenylmethaneimine (1.39 g, 7.68 mmol, 1.29 mL) The mixture was subjected to a mixture of , Xantphos (1.21 g, 2.09 mmol), Pd2(dba )3 ( 319.64 mg, 349.05 μmol) and cesium carbonate (6.82 g, 20.94 mmol) in dioxane (100 mL) for several minutes Degassing. The reaction mixture was stirred for 12 h at 90 °C under Ar atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was diluted with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na 2 SO 4 , filtered and concentrated to give N-[5-(difluoromethyl)-6-methyl-3-pyridinyl]-1,1-di Phenylcarbimide (3.8 g, crude) was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 2.52(s,3H),6.64(t,1H),6.75(s,1H),7.36(m,10H),7.98(s,1H) 1 H NMR (500MHz, CDCl 3 )δ 2.52(s,3H), 6.64(t,1H), 6.75(s,1H), 7.36(m,10H), 7.98(s,1H)

LCMS(ESI)：[M+H]+ m/z：計算值322.1；實測值323.2；Rt=1.358min。LCMS (ESI): [M+H] + m/z: calculated 322.1; found 323.2; Rt=1.358 min.

步驟6：5-(二氟甲基)-6-甲基吡啶-3-胺之合成Step 6: Synthesis of 5-(difluoromethyl)-6-methylpyridin-3-amine

將N-[5-(二氟甲基)-6-甲基-3-吡啶基]-1,1-二苯基甲亞胺(3.8g，11.79mmol)溶解於DCM(20mL)及HCl(1M)(20mL)中且在40℃下攪拌12h。分離DCM層，用額外DCM洗滌水，將水層用Na2 CO3 鹼化且用DCM萃取兩次，將鹼化後經合併之DCM經Na2 SO4 乾燥，過濾且蒸發，以得到5-(二氟甲基)-6-甲基吡啶-3-胺(0.715g，4.52mmol，38.35%產率)，其不經進一步純化即用於下一步驟。N-[5-(Difluoromethyl)-6-methyl-3-pyridinyl]-1,1-diphenylmethaneimine (3.8 g, 11.79 mmol) was dissolved in DCM (20 mL) and HCl ( 1M) (20 mL) and stirred at 40 °C for 12 h. The DCM layer was separated, the water was washed with additional DCM, the aqueous layer was basified with Na2CO3 and extracted twice with DCM, the basified combined DCMs were dried over Na2SO4 , filtered and evaporated to give 5- (Difluoromethyl)-6-methylpyridin-3-amine (0.715 g, 4.52 mmol, 38.35% yield), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ 2.48(s,3H),3.65(s,2H),6.69(t,1H),7.11(s,1H),8.06(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 2.48 (s, 3H), 3.65 (s, 2H), 6.69 (t, 1H), 7.11 (s, 1H), 8.06 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值158.1；實測值159.0；Rt=0.346min。LCMS (ESI): [M+H] + m/z: calculated 158.1; found 159.0; Rt=0.346 min.

步驟7：2-[[5-(二氟甲基)-6-甲基-3-吡啶基]胺基]-2-側氧基乙酸甲酯之合成Step 7: Synthesis of methyl 2-[[5-(difluoromethyl)-6-methyl-3-pyridinyl]amino]-2-oxoacetate

將5-(二氟甲基)-6-甲基吡啶-3-胺(0.79g，5.00mmol)及TEA(505.48mg，5.00mmol，696.25μL)溶解於DCM(15mL)中且冷卻至20℃，隨後逐滴添加2-氯-2-側氧基乙酸甲酯(673.16mg，5.49mmol)，且將反應混合物在20℃下攪拌12h。將混合物用DCM稀釋，用水及鹽水(50mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到2-[[5-(二氟甲基)-6-甲基-3-吡啶基]胺基]-2-側氧基乙酸甲酯(1.22g，5.00mmol，100.00%產率)。5-(Difluoromethyl)-6-methylpyridin-3-amine (0.79 g, 5.00 mmol) and TEA (505.48 mg, 5.00 mmol, 696.25 μL) were dissolved in DCM (15 mL) and cooled to 20 °C , then methyl 2-chloro-2-oxoacetate (673.16 mg, 5.49 mmol) was added dropwise, and the reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with DCM, washed with water and brine (50 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give 2-[[5-(difluoromethyl)-6-methyl-3-pyridinyl]amino]-2-pendoxyloxy Methyl acetate (1.22 g, 5.00 mmol, 100.00% yield).

1 H NMR(400MHz,CDCl3 )δ 2.66(s,3H),3.99(s,3H),6.79(t,1H),8.30(s,1H),8.78 (s,1H),9.09(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 2.66(s,3H), 3.99(s,3H), 6.79(t,1H), 8.30(s,1H), 8.78(s,1H), 9.09(s,1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值244.1；實測值245.0；Rt=0.777min。LCMS (ESI): [M+H] + m/z: calculated 244.1; found 245.0; Rt=0.777 min.

步驟8：2-[[5-(二氟甲基)-6-甲基-3-吡啶基]胺基]-2-側氧基乙酸之合成Step 8: Synthesis of 2-[[5-(difluoromethyl)-6-methyl-3-pyridinyl]amino]-2-pendoxoacetic acid

將2-[[5-(二氟甲基)-6-甲基-3-吡啶基]胺基]-2-側氧基乙酸甲酯(1.22g，5.00mmol)溶解於THF(20mL)中，隨後添加98%氫氧化鋰單水合物(251.56mg，6.00mmol，166.60μL)且將反應混合物在20℃下12h。過濾反應混合物，將所獲得之固體風乾且用CCl4 再蒸發至乾，以得到2-[[5-(二氟甲基)-6-甲基-3-吡啶基]胺基]-2-側氧基乙酸(1.09g，4.60mmol，92.01%產率，Li)Methyl 2-[[5-(difluoromethyl)-6-methyl-3-pyridyl]amino]-2-oxoacetate (1.22 g, 5.00 mmol) was dissolved in THF (20 mL) , followed by the addition of 98% lithium hydroxide monohydrate (251.56 mg, 6.00 mmol, 166.60 μL) and the reaction mixture was left at 20 °C for 12 h. The reaction mixture was filtered, the solid obtained was air-dried and re-evaporated to dryness with CCl to give 2 -[[5-(difluoromethyl)-6-methyl-3-pyridinyl]amino]-2- Pendant oxyacetic acid (1.09 g, 4.60 mmol, 92.01% yield, Li)

LCMS(ESI)：[M+H]+ m/z：計算值230.0；實測值231.0；Rt=0.558min。LCMS (ESI): [M+H] + m/z: calculated 230.0; found 231.0; Rt=0.558 min.

LCMS(ESI)：[M+H]+ m/z：計算值456.2；實測值457.2；Rt=1.022min。LCMS (ESI): [M+H] + m/z: calculated 456.2; found 457.2; Rt=1.022 min.

2J. 5-碘-3-(氧呾-3-基)吡啶-2-胺之合成2J. Synthesis of 5-iodo-3-(oxygen-3-yl)pyridin-2-amine

Figure 110128222-A0202-12-0560-690
Figure 110128222-A0202-12-0560-690

步驟1：3-(氧呾-3-基)吡啶-2-胺之合成：Step 1: Synthesis of 3-(oxo-3-yl)pyridin-2-amine:

將反式-2-胺基環己醇(198.13mg，1.72mmol)及碘化鎳(II)(537.58mg，1.72mmol)添加到(2-胺基-3-吡啶基)硼酸(5g，28.67mmol，HCl)於異丙醇(50mL)中之溶液中。然後，逐滴添加雙(三甲基矽基)醯胺化鈉(40%於THF中)(39.43g，86.01mmol，44.11mL，40%純度)，接著添加3-碘氧呾(7.91g，43.01mmol，3.70mL)。將反應燒瓶用氬氣吹掃且將所得混合物在75℃下攪拌8h。在減壓下移除揮發物且藉由梯度管柱層析純化殘餘物。Companion combiflash；80g SiO2 ，CHCl3 -MeOH 0~100%，流速=60mL/min，cv=5獲得呈黃色油狀物之3-(氧呾-3-基)吡啶-2-胺(1g，6.66mmol，23.22%產率)。Trans-2-aminocyclohexanol (198.13 mg, 1.72 mmol) and nickel(II) iodide (537.58 mg, 1.72 mmol) were added to (2-amino-3-pyridyl)boronic acid (5 g, 28.67 g mmol, HCl) in isopropanol (50 mL). Then, sodium bis(trimethylsilyl)amide (40% in THF) (39.43 g, 86.01 mmol, 44.11 mL, 40% purity) was added dropwise, followed by 3-iodooxane (7.91 g, 43.01 mmol, 3.70 mL). The reaction flask was purged with argon and the resulting mixture was stirred at 75 °C for 8 h. Volatiles were removed under reduced pressure and the residue was purified by gradient column chromatography. Companion combiflash; 80g SiO 2 , CHCl 3 -MeOH 0~100%, flow rate=60mL/min, cv=5 to obtain 3-(oxo-3-yl)pyridin-2-amine (1g, 6.66 mmol, 23.22% yield).

1 H NMR(400MHz,DMSO-d6 )δ 4.12(q,1H),4.62(dd,2H),4.90(dd,2H),5.69(s,2H),6.62(dd,1H),7.45(s,1H),7.83(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 4.12(q,1H), 4.62(dd,2H), 4.90(dd,2H), 5.69(s,2H), 6.62(dd,1H), 7.45(s , 1H), 7.83(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值150.2；實測值151.0；Rt=0.166min。LCMS (ESI): [M+H] + m/z: calculated 150.2; found 151.0; Rt=0.166 min.

步驟2：5-碘-3-(氧呾-3-基)吡啶-2-胺之合成：Step 2: Synthesis of 5-iodo-3-(oxo-3-yl)pyridin-2-amine:

將3-(氧呾-3-基)吡啶-2-胺(0.8g，5.33mmol)溶解於DMFA(15mL)中，接著分批添加1-碘吡咯啶-2,5-二酮(1.60g，7.11mmol)。將反應混合物攪拌隔夜且在減壓下濃縮。將殘餘物溶解於DCM中且將有機層用Na2 S2O3 水溶液及水洗滌多次。分離DCM層，將其經Na2 SO4 乾燥且在減壓下濃縮。獲得呈黃色固體之純5-碘-3-(氧呾-3-基)吡啶-2-胺(0.6g，2.17mmol，40.80%產率)。3-(Oxygen-3-yl)pyridin-2-amine (0.8 g, 5.33 mmol) was dissolved in DMFA (15 mL), followed by portionwise addition of 1-iodopyrrolidine-2,5-dione (1.60 g) , 7.11 mmol). The reaction mixture was stirred overnight and concentrated under reduced pressure. The residue was dissolved in DCM and the organic layer was washed several times with aqueous Na2S2O3 and water. The DCM layer was separated, dried over Na2SO4 and concentrated under reduced pressure. Pure 5-iodo-3-(oxon-3-yl)pyridin-2-amine (0.6 g, 2.17 mmol, 40.80% yield) was obtained as a yellow solid.

1 H NMR(400MHz,DMSO-d6 )δ 4.15(q,1H),4.56(dd,2H),4.87(dd,2H),5.87(s,1H),7.66(s,1H),7.98(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 4.15(q, 1H), 4.56(dd, 2H), 4.87(dd, 2H), 5.87(s, 1H), 7.66(s, 1H), 7.98(s , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值277.0；實測值277.0；Rt=0.563min。LCMS (ESI): [M+H] + m/z: calculated 277.0; found 277.0; Rt=0.563 min.

2K. 2-[(5-胺甲醯基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸之合成2K. Synthesis of 2-[(5-aminocarboxy-6-methyl-3-pyridyl)amino]-2-side oxyacetic acid

步驟1.2-苯甲氧基-5-溴-吡啶之合成Step 1. Synthesis of 2-benzyloxy-5-bromo-pyridine

Figure 110128222-A0202-12-0561-691
Figure 110128222-A0202-12-0561-691

在0℃下，向5-胺基-2-甲基吡啶-3-甲醯胺(975mg，6.45mmol)及三乙胺(652.66mg，6.45mmol，898.99μL)於THF(25mL)中之溶液中添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(1.23g，6.45mmol)。在20℃下攪拌18h之後，將所得混合物蒸發至乾，以得到呈黃色固體之2-[(5-胺甲醯基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(2.21g，粗品)，其不經進一步純化即用於下一步驟。To a solution of 5-amino-2-methylpyridine-3-carboxamide (975 mg, 6.45 mmol) and triethylamine (652.66 mg, 6.45 mmol, 898.99 μL) in THF (25 mL) at 0 °C To this was added 2,2,2-trifluoroethyl 2-chloro-2-oxoacetate (1.23 g, 6.45 mmol). After stirring at 20 °C for 18 h, the resulting mixture was evaporated to dryness to give 2-[(5-aminocarboxy-6-methyl-3-pyridinyl)amino]-2-oxygen as a yellow solid 2,2,2-trifluoroethyl acetate (2.21 g, crude), which was used in the next step without further purification.

LCMS(ESI)：[M+1]+ m/z：計算值305.2；實測值306.0；Rt=0.714min。LCMS (ESI): [M+1] + m/z: calculated 305.2; found 306.0; Rt=0.714 min.

步驟2.2-[(5-胺甲醯基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸之合成Step 2. Synthesis of 2-[(5-aminocarbamoyl-6-methyl-3-pyridyl)amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0562-692
Figure 110128222-A0202-12-0562-692

向2-[(5-胺甲醯基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(440mg，1.44mmol)於MeOH(10mL)中之溶液中添加98%氫氧化鋰單水合物(120.98mg，2.88mmol，80.12μL)且將所得混合物在室溫下攪拌1h。然後將所得混合物蒸發至乾，溶解於水中，用DCM洗滌三次。將水酸化至pH=1且過濾沉澱且用水(2*10ml)、EA(25ml)洗滌，且風乾，以獲得2-[(5-胺甲醯基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸(96mg，粗品)。To 2-[(5-aminocarbamoyl-6-methyl-3-pyridinyl)amino]-2-oxoacetate 2,2,2-trifluoroethyl ester (440 mg, 1.44 mmol) in MeOH To the solution in (10 mL) was added 98% lithium hydroxide monohydrate (120.98 mg, 2.88 mmol, 80.12 μL) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then evaporated to dryness, dissolved in water and washed three times with DCM. The water was acidified to pH=1 and the precipitate was filtered and washed with water (2*10ml), EA (25ml), and air-dried to obtain 2-[(5-aminocarbamoyl-6-methyl-3-pyridyl) Amino]-2-side oxyacetic acid (96 mg, crude).

1 H NMR(400MHz,DMSO-d6)δ(ppm)7.56(s,1H),7.99(s,1H),8.12(s,1H),8.83(s,1H),10.97(s,1H)。 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.56 (s, 1H), 7.99 (s, 1H), 8.12 (s, 1H), 8.83 (s, 1H), 10.97 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值223.2；實測值224.0；Rt=0.174min。LCMS (ESI): [M+1] + m/z: calculated 223.2; found 224.0; Rt=0.174 min.

2L. 2-[[5-胺甲醯基-6-(三氟甲氧基)-3-吡啶基]胺基]-2-側氧基乙酸之合成2L. Synthesis of 2-[[5-aminocarboxy-6-(trifluoromethoxy)-3-pyridyl]amino]-2-side oxyacetic acid

2-[[5-胺甲醯基-6-(三氟甲氧基)-3-吡啶基]胺基]-2-側氧基乙酸之合成Synthesis of 2-[[5-Aminocarboxy-6-(trifluoromethoxy)-3-pyridyl]amino]-2-side oxyacetic acid

Figure 110128222-A0202-12-0562-693
Figure 110128222-A0202-12-0562-693

步驟1-2.2-苯甲氧基-5-溴-吡啶之合成Step 1-2. Synthesis of 2-benzyloxy-5-bromo-pyridine

Figure 110128222-A0202-12-0562-694
Figure 110128222-A0202-12-0562-694

在-78℃下，將丁基鋰(1.20g，18.75mmol，7.51mL)逐滴添加到6-(三氟甲氧基)吡啶-3-胺(1.67g，9.38mmol)於THF(20mL)中之溶液中，接著在1min 後添加氯三甲基矽烷(2.14g，19.69mmol，2.50mL)。使反應混合物達到25℃達2h，之後過濾到矽藻土墊上。移除溶劑且在真空(101-103 0C/1毫巴)下蒸餾粗品油狀物，以得到6-(三氟甲氧基)-N,N-雙(三甲基矽基)吡啶-3-胺(2.93g，粗品)。在0℃下，將丁基鋰(1.18g，18.43mmol，7.38mL)逐滴添加到二異丙胺(1.95g，19.31mmol，2.72mL)於THF(56mL)中之溶液中。在-780℃下，逐滴添加6-(三氟甲氧基)-N,N-雙(三甲基矽基)吡啶-3-胺(2.83g，8.78mmol)於THF(2mL)中之溶液且將反應混合物在此溫度下攪拌1h。然後透過具有硫酸之乾燥容器將CO2鼓泡到溶液中達15min。在-78℃下30min之後，使溶液達到室溫。蒸發溶劑。藉由管柱層析(MTBE/甲醇)純化所得粗材料，以獲得5-胺基-2-(三氟甲氧基)吡啶-3-甲酸(0.1g，450.20umol，5.13%產率)。Butyllithium (1.20 g, 18.75 mmol, 7.51 mL) was added dropwise to 6-(trifluoromethoxy)pyridin-3-amine (1.67 g, 9.38 mmol) in THF (20 mL) at -78 °C in solution, followed by 1 min Chlorotrimethylsilane (2.14 g, 19.69 mmol, 2.50 mL) was then added. The reaction mixture was allowed to reach 25 °C for 2 h before being filtered onto a pad of celite. The solvent was removed and the crude oil was distilled under vacuum (101-103 OC/1 mbar) to give 6-(trifluoromethoxy)-N,N-bis(trimethylsilyl)pyridine-3 - Amine (2.93 g, crude). Butyllithium (1.18 g, 18.43 mmol, 7.38 mL) was added dropwise to a solution of diisopropylamine (1.95 g, 19.31 mmol, 2.72 mL) in THF (56 mL) at 0 °C. A solution of 6-(trifluoromethoxy)-N,N-bis(trimethylsilyl)pyridin-3-amine (2.83 g, 8.78 mmol) in THF (2 mL) was added dropwise at -780°C solution and the reaction mixture was stirred at this temperature for 1 h. CO2 was then bubbled into the solution through a drying vessel with sulfuric acid for 15 min. After 30 min at -78°C, the solution was allowed to reach room temperature. Evaporate the solvent. The resulting crude material was purified by column chromatography (MTBE/methanol) to obtain 5-amino-2-(trifluoromethoxy)pyridine-3-carboxylic acid (0.1 g, 450.20 umol, 5.13% yield).

1 H NMR(500MHz,DMSO-d6)δ(ppm)5.20-5.30(brs,2H),7.35(s,1H),7.65(s,1H)。 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 5.20-5.30 (brs, 2H), 7.35 (s, 1H), 7.65 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值222.0；實測值223.0；Rt=0.641min。LCMS (ESI): [M+1] + m/z: calculated 222.0; found 223.0; Rt=0.641 min.

步驟2. 5-胺基-2-(三氟甲氧基)吡啶-3-甲醯胺之合成Step 2. Synthesis of 5-amino-2-(trifluoromethoxy)pyridine-3-carboxamide

Figure 110128222-A0202-12-0563-695
Figure 110128222-A0202-12-0563-695

將5-胺基-2-(三氟甲氧基)吡啶-3-甲酸(90mg，405.18umol)、碳酸銨(116.80mg，1.22mmol)、三乙胺(205.00mg，2.03mmol，282.37uL)混合到DMF(2mL)中，然後添加HATU(231.09mg，607.78umol)。將所得混合物在25℃下攪拌13h。將溶劑蒸發，以獲得粗產物，其藉由HPLC(35-55%(甲醇)-2-10min，流速：30ml/min)進行純化，以獲得5-胺基-2-(三氟甲氧基)吡啶-3-甲醯胺(18.9mg，85.47umol，21.09%產率)。5-amino-2-(trifluoromethoxy)pyridine-3-carboxylic acid (90 mg, 405.18 umol), ammonium carbonate (116.80 mg, 1.22 mmol), triethylamine (205.00 mg, 2.03 mmol, 282.37 uL) Mix into DMF (2 mL), then add HATU (231.09 mg, 607.78 umol). The resulting mixture was stirred at 25 °C for 13 h. The solvent was evaporated to obtain crude product, which was purified by HPLC (35-55% (methanol)-2-10 min, flow rate: 30 ml/min) to obtain 5-amino-2-(trifluoromethoxy) ) pyridine-3-carboxamide (18.9 mg, 85.47 umol, 21.09% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)5.19(d,1H),5.37(s,2H),5.65(d,1H),6.63(m, 1H),6.78(d,1H),7.24-7.63(m,5),7.71(d,1H),8.19(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ(ppm) 5.19(d, 1H), 5.37(s, 2H), 5.65(d, 1H), 6.63(m, 1H), 6.78(d, 1H), 7.24- 7.63(m,5), 7.71(d,1H), 8.19(s,1H).

LCMS(ESI)：[M+1]+ m/z：計算值221.0；實測值222.0；Rt=0.727min。LCMS (ESI): [M+1] + m/z: calculated 221.0; found 222.0; Rt=0.727 min.

步驟3. 2-[[5-胺甲醯基-6-(三氟甲氧基)-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯Step 3. 2,2,2-trifluoroethyl acetate

Figure 110128222-A0202-12-0564-696
Figure 110128222-A0202-12-0564-696

將5-胺基-2-(三氟甲氧基)吡啶-3-甲醯胺(318mg，1.44mmol)及三乙胺(145.51mg，1.44mmol，200.43μL)溶解於THF(7mL)中且將所得溶液在冰/甲醇浴中冷卻至0℃。在0℃下，逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(273.95mg，1.44mmol)於THF(0.5mL)中之溶液。添加完成之後，使反應混合物升溫至室溫且攪拌隔夜。將反應混合物在真空中濃縮。將殘餘物轉移至過濾器且用水(2*25ml)、DCM(25ml)沖洗且風乾，以獲得2-[[5-胺甲醯基-6-(三氟甲氧基)-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(355mg，946.21μmol，65.80%產率)。5-Amino-2-(trifluoromethoxy)pyridine-3-carboxamide (318 mg, 1.44 mmol) and triethylamine (145.51 mg, 1.44 mmol, 200.43 μL) were dissolved in THF (7 mL) and The resulting solution was cooled to 0°C in an ice/methanol bath. A solution of 2,2,2-trifluoroethyl 2-chloro-2-pendoxoacetic acid (273.95 mg, 1.44 mmol) in THF (0.5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo. The residue was transferred to a filter and rinsed with water (2*25ml), DCM (25ml) and air-dried to obtain 2-[[5-aminocarboxy-6-(trifluoromethoxy)-3-pyridyl ]amino]-2-oxoacetate 2,2,2-trifluoroethyl ester (355 mg, 946.21 μmol, 65.80% yield).

1 H NMR(400MHz,DMSO-d6)δ(ppm)4.97(q,2H),7.74(s,1H),7.92(s,1H),8.42(s,1H),8.72(s,1H),11.36(s,1H)。 1 H NMR (400MHz, DMSO-d6) δ(ppm) 4.97(q, 2H), 7.74(s, 1H), 7.92(s, 1H), 8.42(s, 1H), 8.72(s, 1H), 11.36 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值375.2；實測值376.2；Rt=1.054min。LCMS (ESI): [M+1] + m/z: calculated 375.2; found 376.2; Rt=1.054 min.

步驟4. 2-[[5-胺甲醯基-6-(三氟甲氧基)-3-吡啶基]胺基]-2-側氧基乙酸Step 4. 2-[[5-Aminocarboxy-6-(trifluoromethoxy)-3-pyridyl]amino]-2-pendoxoacetic acid

Figure 110128222-A0202-12-0564-1188
Figure 110128222-A0202-12-0564-1188

將2-[[5-胺甲醯基-6-(三氟甲氧基)-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(473.7mg，1.26mmol)溶解於MeOH(15mL)中且向其中添加98%氫氧化鋰單水合物(105.97mg，2.53mmol，70.18μL)。攪拌所得混合物1h。在真空中濃縮反應混合物，且將殘餘物溶解於水(10ml)中。將所得混合物用HCl 酸化且過濾沉澱，用水(10ml)沖洗，且風乾，以獲得2-[[5-胺甲醯基-6-(三氟甲氧基)-3-吡啶基]胺基]-2-側氧基乙酸(232mg，791.39μmol，62.68%產率)。2-[[5-Aminocarbamoyl-6-(trifluoromethoxy)-3-pyridyl]amino]-2-trifluoroethyl acetate (473.7 mg , 1.26 mmol) was dissolved in MeOH (15 mL) and to it was added 98% lithium hydroxide monohydrate (105.97 mg, 2.53 mmol, 70.18 μL). The resulting mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water (10 ml). The resulting mixture was treated with HCl Acidify and filter the precipitate, rinse with water (10 ml), and air dry to give 2-[[5-aminocarboxy-6-(trifluoromethoxy)-3-pyridinyl]amino]-2-oxo acetic acid (232 mg, 791.39 μmol, 62.68% yield).

1 H NMR(400MHz,DMSO-d6)δ(ppm)7.80(s,1H),7.99(s,1H),8.44(s,1H),8.72(s,1H),11.19(s,1H)。 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.80 (s, 1H), 7.99 (s, 1H), 8.44 (s, 1H), 8.72 (s, 1H), 11.19 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值293.2；實測值294.2；Rt=0.728min。LCMS (ESI): [M+1] + m/z: calculated 293.2; found 294.2; Rt=0.728 min.

3.雜項哌啶中間物合成3. Miscellaneous Piperidine Intermediates Synthesis

3A.5-甲基-2-(1-甲基-1H -吡唑-5-基)哌啶之合成 3A. Synthesis of 5-methyl-2-(1-methyl- 1H -pyrazol-5-yl)piperidine

Figure 110128222-A0202-12-0565-698
Figure 110128222-A0202-12-0565-698

步驟1：(2-甲基-5-(1-甲基-1H吡唑-5-基)-5-側氧基戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (2-methyl-5-(1-methyl-1Hpyrazol-5-yl)-5-oxypentyl)carbamate

在-75℃下，將正丁基鋰(10.19g，36.57mmol，14.98mL，23%純度)(2.5M於己烷中)逐滴添加到1-甲基吡唑(3.00g，36.57mmol，3.04mL)於THF(60mL)中之經攪拌之溶液中。將所得重懸浮液在-75℃下攪拌1h，然後在-75℃下逐滴添加5-甲基-2-側氧基-哌啶-1-甲酸第三丁酯(7.8g，36.57mmol)，且使反應混合物升溫至0℃且將其攪拌1h。將所得懸浮液用水(50ml)及MTBE(100ml)稀釋，轉移至分液漏斗，且分離上部有機層。另外用MTBE(50ml)萃取水層。將經合併之有機萃取物用水(20ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色油狀物之N -[2-甲基-5-(2-甲基吡唑-3-基)-5-側氧基戊基]胺甲酸第三丁 酯(9g，30.47mmol，83.31%產率)，其直接用於下一步驟中。At -75°C, n-butyllithium (10.19 g, 36.57 mmol, 14.98 mL, 23% purity) (2.5 M in hexanes) was added dropwise to 1-methylpyrazole (3.00 g, 36.57 mmol, 3.04 mL) in a stirred solution of THF (60 mL). The resulting resuspension was stirred at -75 °C for 1 h, then 5-methyl-2-pendoxo-piperidine-1-carboxylic acid tert-butyl ester (7.8 g, 36.57 mmol) was added dropwise at -75 °C , and the reaction mixture was warmed to 0 °C and stirred for 1 h. The resulting suspension was diluted with water (50 ml) and MTBE (100 ml), transferred to a separatory funnel, and the upper organic layer was separated. The aqueous layer was additionally extracted with MTBE (50 ml). The combined organic extracts were washed with water (20ml), dried over sodium sulfate and evaporated in vacuo to give N- [2-methyl-5-(2-methylpyrazole-3 as a yellow oil -yl)-5-oxypentyl]carbamic acid tert- butyl ester (9 g, 30.47 mmol, 83.31% yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.95(d,3H),1.44(s,9H),1.78(m,2H),2.88(m,2H),3.05(m,2H),3.98(m,1H),4.15(s,3H),4.68(m,1H),6.85(d,1H),7.45(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.95(d, 3H), 1.44(s, 9H), 1.78(m, 2H), 2.88(m, 2H), 3.05(m, 2H), 3.98( m, 1H), 4.15 (s, 3H), 4.68 (m, 1H), 6.85 (d, 1H), 7.45 (d, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值195.3；實測值196.2；Rt=1.351min。LCMS (ESI): [M-Boc] + m/z: calculated 195.3; found 196.2; Rt=1.351 min.

步驟2：3-甲基-6-(1-甲基-1H-吡唑-5-基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydropyridine

將N -[2-甲基-5-(2-甲基吡唑-3-基)-5-側氧基戊基]胺甲酸第三丁 酯(3 g，10.16mmol)於三氟乙酸(23.16g，203.13mmol，15.65mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(20g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色油狀物之3-甲基-6-(2-甲基吡唑-3-基)-2,3,4,5-四氫吡啶(1.7g，9.59mmol，94.43%產率)，其直接用於下一步驟中。 N- [2-Methyl-5-(2-methylpyrazol-3-yl)-5-oxypentyl]carbamic acid tert- butyl ester (3 g, 10.16 mmol) was dissolved in trifluoroacetic acid ( The solution in 23.16 g, 203.13 mmol, 15.65 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (20 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 3-methyl-6-(2-methylpyrazol-3-yl)-2,3,4 as a yellow oil , 5-tetrahydropyridine (1.7 g, 9.59 mmol, 94.43% yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.14(d,3H),1.38(m,1H),1.68(m,1H),1.88(m,1H),2.49(m,1H),2.67(m,1H),3.25(m,1H),3.97(m,1H),4.13(s,3H),6.44(d,1H),7.41(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.14(d,3H), 1.38(m,1H), 1.68(m,1H), 1.88(m,1H), 2.49(m,1H), 2.67( m, 1H), 3.25 (m, 1H), 3.97 (m, 1H), 4.13 (s, 3H), 6.44 (d, 1H), 7.41 (d, 1H).

LCMS(ESI)：[M+1]m/z：計算值177.2；實測值178.2；Rt=0.624min。LCMS (ESI): [M+1] m/z: calculated 177.2; found 178.2; Rt=0.624 min.

步驟3：5-甲基-2-(1-甲基-1H-吡唑-5-基)哌啶之合成Step 3: Synthesis of 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)piperidine

在0℃下，將硼氫化鈉(725.67mg，19.18mmol，678.20μL)一次性添加到3-甲基-6-(2-甲基吡唑-3-基)-2,3,4,5-四氫吡啶(1.7g，9.59mmol)於甲醇(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色油狀物之5-甲基-2-(2-甲基吡唑-3-基)哌啶(1.3g，7.25mmol，75.61%產率)，其直接用於下一步驟中。Sodium borohydride (725.67 mg, 19.18 mmol, 678.20 μL) was added in one portion to 3-methyl-6-(2-methylpyrazol-3-yl)-2,3,4,5 at 0 °C - Tetrahydropyridine (1.7 g, 9.59 mmol) in a stirred solution of methanol (20 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-methyl-2-(2-methylpyrazol-3-yl)piperidine as a yellow oil (1.3 g, 7.25 mmol, 75.61% yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.89(d,3H),1.15(m,2H),1.58(m,2H),1.88(m,2H),2.37(m,1H),3.11(m,1H),3.64(m,1H),3.88(s,3H),6.14(d,1H),7.37(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.89(d,3H), 1.15(m,2H), 1.58(m,2H), 1.88(m,2H), 2.37(m,1H), 3.11( m, 1H), 3.64 (m, 1H), 3.88 (s, 3H), 6.14 (d, 1H), 7.37 (d, 1H).

LCMS(ESI)：[M+1]m/z：計算值179.2；實測值180.2；Rt=0.749minLCMS(ESI): [M+1]m/z: Calculated value 179.2; Measured value 180.2; Rt=0.749min

3B.5-甲基-2-(1-甲基-1H-吡唑-5-基)哌啶之合成 3B. Synthesis of 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)piperidine

Figure 110128222-A0202-12-0567-699
Figure 110128222-A0202-12-0567-699

步驟1：2-(甲氧基(甲基)胺甲醯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 2-(methoxy(methyl)aminocarboxy)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在25℃下，將CDI(8.80g，54.25mmol)一次性添加到1-第三丁氧基 羰基-5-甲基-哌啶-2-甲酸(11g，45.21mmol)於THF(200mL)中之經攪拌之溶液中。在25℃下攪拌所得混合物，直到二氧化碳逸出完成，然後添加甲氧基(甲基)胺鹽酸鹽(8.82g，90.42mmol)及三乙胺(9.15g，90.42mmol，12.60mL)。將反應混合物在50℃下攪拌12h，然後冷卻且在真空中蒸發。將殘餘物用5%硫酸氫鈉水溶液(200ml)稀釋且用二氯甲烷(2*100ml)萃取。將經合併之有機萃取物用水(100ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈白色固體之2-[甲氧基(甲基)胺甲醯基]-5-甲基哌啶-1-甲酸第三丁酯(11.2g，39.11mmol，86.51%產率)，其直接用於下一步驟中。CDI (8.80 g, 54.25 mmol) was added in one portion to 1 -tert- butoxycarbonyl-5-methyl-piperidine-2-carboxylic acid (11 g, 45.21 mmol) in THF (200 mL) at 25 °C in the stirred solution. The resulting mixture was stirred at 25°C until carbon dioxide evolution was complete, then methoxy(methyl)amine hydrochloride (8.82 g, 90.42 mmol) and triethylamine (9.15 g, 90.42 mmol, 12.60 mL) were added. The reaction mixture was stirred at 50 °C for 12 h, then cooled and evaporated in vacuo. The residue was diluted with 5% aqueous sodium bisulfate solution (200ml) and extracted with dichloromethane (2*100ml). The combined organic extracts were washed with water (100 ml), dried over sodium sulfate and evaporated in vacuo to give 2-[methoxy(methyl)aminocarbamoyl]-5-methylpiperidine as a white solid 3-butyl pyridine-1-carboxylate (11.2 g, 39.11 mmol, 86.51% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.17(m,2H),1.46(s,9H),1.74(m,2H),2.03(m,1H),3.09(m,1H),3.18(s,3H),3.84(s,3H),3.99(m,1H),5.03(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d, 3H), 1.17(m, 2H), 1.46(s, 9H), 1.74(m, 2H), 2.03(m, 1H), 3.09( m, 1H), 3.18 (s, 3H), 3.84 (s, 3H), 3.99 (m, 1H), 5.03 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值186.3；實測值187.2；Rt=1.443min。LCMS (ESI): [M-Boc] + m/z: calculated 186.3; found 187.2; Rt=1.443 min.

步驟2：5-甲基-2-丙炔醯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl 5-methyl-2-propynylpiperidine-1-carboxylate

在-40℃下，將2-[甲氧基(甲基)胺甲醯基]-5-甲基哌啶-1-甲酸第三丁酯(11.2g，39.11mmol)於THF(200mL)中之溶液逐滴添加到乙炔基溴化鎂(25.08g，195.55mmol，400mL)之經攪拌之溶液中。使所得混合物升溫至25℃且在此溫度下攪拌12h，然後倒入硫酸氫鈉(46.96g，391.11mmol)水溶液(500g)中。將所得混合物攪拌0.5h，然後轉移到分液漏斗中。分離上部有機層，另外用乙酸 乙酯(2*200ml)萃取水層。將經合併之有機萃取物用鹽水(2*200ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈紅色油狀物之5-甲基-2-丙-2-炔醯基-哌啶-1-甲酸第三丁酯(9.6g，38.20mmol，97.67%產率)，其直接用於下一步驟中。2-[Methoxy(methyl)aminocarboxy]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (11.2 g, 39.11 mmol) in THF (200 mL) at -40 °C This solution was added dropwise to a stirred solution of ethynylmagnesium bromide (25.08 g, 195.55 mmol, 400 mL). The resulting mixture was warmed to 25 °C and stirred at this temperature for 12 h, then poured into aqueous sodium bisulfate (46.96 g, 391.11 mmol) solution (500 g). The resulting mixture was stirred for 0.5 h and then transferred to a separatory funnel. The upper organic layer was separated with additional acetic acid The aqueous layer was extracted with ethyl ester (2*200ml). The combined organic extracts were washed with brine (2*200ml), dried over sodium sulfate and evaporated in vacuo to give 5-methyl-2-prop-2-ynyl-piperidine as a red oil 3-butyl pyridine-1-carboxylate (9.6 g, 38.20 mmol, 97.67% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.07(m,2H),1.46(s,9H),1.62(m,2H),2.51(m,2H),3.30(d,1H),4.07(m,1H),4.91(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d,3H), 1.07(m,2H), 1.46(s,9H), 1.62(m,2H), 2.51(m,2H), 3.30( d, 1H), 4.07 (m, 1H), 4.91 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值151.3；實測值152.2；Rt=1.501min。LCMS (ESI): [M-Boc] + m/z: calculated 151.3; found 152.2; Rt=1.501 min.

步驟3：(E)-2-(3-(二乙胺基)丙烯醯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of (E)-3-(3-(diethylamino)acryloyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將5-甲基-2-丙-2-炔醯基哌啶-1-甲酸第三丁酯(9.6g，38.20mmol)用二乙胺(4.47g，61.12mmol，6.33mL)於乙醇(100mL)中之溶液稀釋。將所得溶液在25℃下攪拌1h，然後在真空中蒸發，以得到呈紅色膠狀物之2-[(E )-3-(二乙胺基)丙-2-烯醯基]-5-甲基哌啶-1-甲酸第三丁酯(12.2g，37.60mmol，98.44%產率)，其直接用於下一步驟中。The tert-butyl 5-methyl-2-prop-2-ynylpiperidine-1-carboxylate (9.6 g, 38.20 mmol) was dissolved in ethanol (100 mL) with diethylamine (4.47 g, 61.12 mmol, 6.33 mL). ) in the solution dilution. The resulting solution was stirred at 25°C for 1 h, then evaporated in vacuo to give 2-[( E )-3-(diethylamino)prop-2-enyl]-5- as a red gum Methylpiperidine-1-carboxylate tert-butyl ester (12.2 g, 37.60 mmol, 98.44% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.22(m,8H),1.48(s,9H),2.11(m,1H),2.52(m,2H),3.27(m,5H),4.07(m,1H),4.59(m,1H),5.21(d,1H),7.67(d,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d,3H), 1.22(m,8H), 1.48(s,9H), 2.11(m,1H), 2.52(m,2H), 3.27( m, 5H), 4.07 (m, 1H), 4.59 (m, 1H), 5.21 (d, 1H), 7.67 (d, 1H).

LCMS(ESI)：[M+1]m/z：計算值324.4；實測值325.2；Rt=1.506min。LCMS (ESI): [M+1] m/z: calculated 324.4; found 325.2; Rt=1.506 min.

步驟4：5-甲基-2-(1-甲基-1H-吡唑-5-基)哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester

將甲基肼(795.18mg，17.26mmol)添加到2-[(E )-3-(二乙胺基)丙-2-烯醯基]-5-甲基哌啶-1-甲酸第三丁酯(3.5g，10.79mmol)及乙酸(1.04g，17.26mmol，987.12μL)於乙醇(50mL)中之經攪拌之溶液中。將反應混合物在80℃下用回流冷凝器攪拌12h，然後冷卻且在真空中蒸發。將殘餘物用水(30ml)稀釋且用MTBE(2*30ml)萃取。將經合併之有機萃取物用水(30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈紅色油狀物之粗品5-甲基-2-(2-甲基吡唑-3-基)哌啶-1-甲酸第三丁酯(2.7g，9.66mmol，89.59%產率)，其直接用於下一步驟中。Methylhydrazine (795.18 mg, 17.26 mmol) was added to tert-butyl 2-[( E )-3-(diethylamino)prop-2-enyl]-5-methylpiperidine-1-carboxylic acid In a stirred solution of ester (3.5 g, 10.79 mmol) and acetic acid (1.04 g, 17.26 mmol, 987.12 μL) in ethanol (50 mL). The reaction mixture was stirred at 80 °C with a reflux condenser for 12 h, then cooled and evaporated in vacuo. The residue was diluted with water (30ml) and extracted with MTBE (2*30ml). The combined organic extracts were washed with water (30 ml), dried over sodium sulfate and evaporated in vacuo to give crude 5-methyl-2-(2-methylpyrazol-3-yl as a red oil) ) tert-butyl piperidine-1-carboxylate (2.7 g, 9.66 mmol, 89.59% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.22(m,2H),1.44(s,9H),1.56(m,2H),1.74(m,1H),1.92(m,1H),2.08(m,1H),2.26(m,1H),3.86(s,3H),6.24(d,1H),7.39(d,1H)。LCMS(ESI)：[M+1]m/z：計算值279.3；實測值280.2；Rt=1.378min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d, 3H), 1.22(m, 2H), 1.44(s, 9H), 1.56(m, 2H), 1.74(m, 1H), 1.92( m, 1H), 2.08 (m, 1H), 2.26 (m, 1H), 3.86 (s, 3H), 6.24 (d, 1H), 7.39 (d, 1H). LCMS (ESI): [M+1] m/z: calculated 279.3; found 280.2; Rt=1.378 min.

步驟5：5-甲基-2-(1-甲基-1H-吡唑-5-基)哌啶之合成Step 5: Synthesis of 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)piperidine

將於二噁烷中之4.0M氯化氫溶液(42.00g，160.12mmol，40mL，13.9%純度)添加到5-甲基-2-(2-甲基吡唑-3-基)哌啶-1-甲酸第三丁 酯(2.7g，9.66mmol)於二氯甲烷(30mL)中之經攪拌之溶液中。將反應混合物在25℃下攪拌2h，然後在真空中蒸發。將殘餘物用氯仿(30ml)稀釋且攪拌1h。過濾沉澱，用氯仿(5ml)洗滌且在真空中乾燥，以得到呈白色固體之5-甲基-2-(2-甲基吡唑-3-基)哌啶(1.9g，7.53mmol，77.96%產率，2HCl)。A 4.0M solution of hydrogen chloride in dioxane (42.00 g, 160.12 mmol, 40 mL, 13.9% pure) was added to 5-methyl-2-(2-methylpyrazol-3-yl)piperidine-1- A stirred solution of tert -butyl formate (2.7 g, 9.66 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at 25 °C for 2 h, then evaporated in vacuo. The residue was diluted with chloroform (30 ml) and stirred for 1 h. The precipitate was filtered, washed with chloroform (5 ml) and dried in vacuo to give 5-methyl-2-(2-methylpyrazol-3-yl)piperidine (1.9 g, 7.53 mmol, 77.96 g) as a white solid % yield, 2HCl).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.13(d,3H),1.22(m,1H),1.96(m,3H),2.05(m,1H),2.91(m,1H),3.17(m,1H),3.91(s,3H),4.55(m,1H),6.63(d,1H),8.97(d,1H),10.13(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.13(d,3H), 1.22(m,1H), 1.96(m,3H), 2.05(m,1H), 2.91(m,1H), 3.17(m,1H), 3.91(s,3H), 4.55(m,1H), 6.63(d,1H), 8.97(d,1H), 10.13(m,1H).

LCMS(ESI)：[M+1]m/z：計算值179.2；實測值180.2；Rt=0.654min。LCMS (ESI): [M+1] m/z: calculated 179.2; found 180.2; Rt=0.654 min.

3C.N-[5-(5-甲基-2-哌啶基)-2-噻吩基]乙醯胺之合成 3C. Synthesis of N-[5-(5-methyl-2-piperidinyl)-2-thienyl]acetamide

Figure 110128222-A0202-12-0569-700
Figure 110128222-A0202-12-0569-700

步驟1：5-溴噻吩-2-羰基氯之合成Step 1: Synthesis of 5-bromothiophene-2-carbonyl chloride

將5-溴噻吩-2-甲酸(8g，38.64mmol)及二甲基甲醯胺(282.41mg，3.86mmol，299.17μL)懸浮於二氯甲烷(100mL)中且在0℃下逐滴添加於二氯甲烷(100mL)中之草醯氯(9.81g，77.28mmol，6.72mL)。將所得混合物在0℃下攪拌8h。 當氣體逸出停止時，在減壓下濃縮所得澄清溶液。將殘餘物再溶解於己烷(150ml)中，過濾且在真空中蒸發，以得到產物5-溴噻吩-2-羰基氯(7.8g，34.59mmol，89.52%產率)。5-Bromothiophene-2-carboxylic acid (8 g, 38.64 mmol) and dimethylformamide (282.41 mg, 3.86 mmol, 299.17 μL) were suspended in dichloromethane (100 mL) and added dropwise at 0 °C to Oxalyl chloride (9.81 g, 77.28 mmol, 6.72 mL) in dichloromethane (100 mL). The resulting mixture was stirred at 0 °C for 8 h. When gas evolution ceased, the resulting clear solution was concentrated under reduced pressure. The residue was redissolved in hexanes (150 ml), filtered and evaporated in vacuo to give the product 5-bromothiophene-2-carbonyl chloride (7.8 g, 34.59 mmol, 89.52% yield).

1 H NMR(500MHz,CDCl3 )δ 7.1(d,1H),7.74(d,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 7.1 (d, 1H), 7.74 (d, 1H).

步驟2：3-(5-溴噻吩-2-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-(5-bromothiophene-2-carbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

在-78℃下，將用己烷穩定之雙(三甲基矽基)醯胺化鋰(12.73g，76.10mmol，33mL)逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(7.38g，34.59mmol)於THF(100mL)中之經預冷卻之溶液中。添加完成之後，將其在同一溫度下攪拌1h。此後，一次性添加5-溴噻吩-2-羰基氯(7.8g，34.59mmol)且移除冷卻浴。將所得混合物緩慢升高至0℃且在此溫度下攪拌2h。然後，將其用15%NaHSO4 水溶液(250ml)淬滅且用乙酸乙酯(300ml)萃取。將有機層用20%NaCl水溶液(2* 250ml)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以得到3-(5-溴噻吩-2-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(9.8g，24.36mmol，70.42%產率)。Lithium bis(trimethylsilyl)amide (12.73 g, 76.10 mmol, 33 mL) stabilized with hexane was added dropwise to 3-Butyl 1-carboxylate (7.38 g, 34.59 mmol) in a precooled solution in THF (100 mL). After the addition was complete, it was stirred at the same temperature for 1 h. After this time, 5-bromothiophene-2-carbonyl chloride (7.8 g, 34.59 mmol) was added in one portion and the cooling bath was removed. The resulting mixture was slowly raised to 0 °C and stirred at this temperature for 2 h. It was then quenched with 15% aqueous NaHSO4 (250ml) and extracted with ethyl acetate (300ml). The organic layer was washed with 20% aqueous NaCl (2 * 250ml), dried over Na2SO4 and evaporated under reduced pressure to give 3-(5-bromothiophene-2-carbonyl)-5-methyl-2- 3-butyl pendant-oxypiperidine-1-carboxylate (9.8 g, 24.36 mmol, 70.42% yield).

1 H NMR(500MHz,CDCl3 )δ 1.20(m,4H),1.56(s,9H),2.04(m,2H),3.23(m,1H),3.88(m,1H),4.27(m,1H),7.13(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ 1.20(m, 4H), 1.56(s, 9H), 2.04(m, 2H), 3.23(m, 1H), 3.88(m, 1H), 4.27(m, 1H) ), 7.13 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值302.2；實測值304.0；Rt=1.429min。LCMS (ESI): [M-Boc] + m/z: calculated 302.2; found 304.0; Rt=1.429 min.

步驟3：6-(5-溴-2-噻吩基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-(5-Bromo-2-thienyl)-3-methyl-2,3,4,5-tetrahydropyridine

將CH3 COOH(100mL)及ACS級36-38%鹽酸(80.00g，2.19mol，100mL)懸浮且將所得混合物在110℃下攪拌且逐滴添加3-(5-溴噻吩-2-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(8.6g，21.38mmol)。將所得混合物在110℃下攪拌14h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(50ml)與DCM(2* 40ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至pH

Figure 110128222-A0202-12-0570-557
10且用DCM(2* 50ml)萃取。分離DCM溶液，經K2 CO3 乾燥且在減壓下蒸發，以得到6-(5-溴-2-噻吩 基)-3-甲基-2,3,4,5-四氫吡啶(4.5g，17.43mmol，81.54%產率)。 CH3COOH (100 mL) and ACS grade 36-38% hydrochloric acid (80.00 g, 2.19 mol, 100 mL) were suspended and the resulting mixture was stirred at 110 °C and 3-(5-bromothiophene-2-carbonyl) was added dropwise - 3-butyl 5-methyl-2-pendoxopiperidine-1-carboxylate (8.6 g, 21.38 mmol). The resulting mixture was stirred at 110 °C for 14 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (50ml) and DCM (2 * 40ml). The organic layer was separated and discarded. The aqueous layer was basified to pH with 10% NaOH
Figure 110128222-A0202-12-0570-557
10 and extracted with DCM (2 * 50ml). The DCM solution was separated, dried over K2CO3 and evaporated under reduced pressure to give 6-( 5 -bromo- 2 -thienyl)-3-methyl-2,3,4,5-tetrahydropyridine (4.5 g, 17.43 mmol, 81.54% yield).

1 H NMR(500MHz,CDCl3 )δ 0.98(d,3H),1.37(m,1H),1.71(m,2H),2.71(m,2H),3.19(m,1H),3.88(m,1H),6.99(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ 0.98(d,3H), 1.37(m,1H), 1.71(m,2H), 2.71(m,2H), 3.19(m,1H), 3.88(m,1H) ), 6.99 (m, 2H).

LCMS(ESI)；[M+2H]+ m/z：計算值258.2；實測值260.0；Rt=0.835min。LCMS (ESI); [M+2H] + m/z: calculated 258.2; found 260.0; Rt=0.835 min.

步驟4：2-(5-溴-2-噻吩基)-5-甲基哌啶之合成Step 4: Synthesis of 2-(5-Bromo-2-thienyl)-5-methylpiperidine

在15分鐘內，將硼氫化鈉(989.06mg，26.14mmol，924.35μL)分批添加到6-(5-溴-2-噻吩基)-3-甲基-2,3,4,5-四氫吡啶(4.5g，17.43mmol)於甲醇(100mL)中之溶液中。將所得溶液在0℃下攪拌14h。然後，在減壓下移除溶劑且將殘餘物分配於水(40ml)與DCM(80ml)之間。分離有機層，經Na2 SO4 乾燥且在真空中蒸發，得到2-(5-溴-2-噻吩基)-5-甲基哌啶(3.1g，11.91mmol，68.36%產率)。Sodium borohydride (989.06 mg, 26.14 mmol, 924.35 μL) was added portionwise to 6-(5-bromo-2-thienyl)-3-methyl-2,3,4,5-tetrakis over 15 minutes Hydropyridine (4.5 g, 17.43 mmol) in methanol (100 mL). The resulting solution was stirred at 0 °C for 14 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (40ml) and DCM (80ml). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to give 2-(5-bromo-2-thienyl)-5-methylpiperidine (3.1 g, 11.91 mmol, 68.36% yield).

1 H NMR(400MHz,CDCl3 )δ 0.97(d,3H),1.16(m,2H),1.56(m,2H),1.85(m,2H),2.35(t,1H),3.08(m,1H),3.74(m,1H),6.65(d,1H),6.84(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.97(d,3H), 1.16(m,2H), 1.56(m,2H), 1.85(m,2H), 2.35(t,1H), 3.08(m,1H) ), 3.74(m, 1H), 6.65(d, 1H), 6.84(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值259.2；實測值260.0；Rt=0.911min。LCMS (ESI): [M+H] + m/z: calculated 259.2; found 260.0; Rt=0.911 min.

步驟5：2-(5-溴-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of 2-(5-bromo-2-thienyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在0℃下，將二碳酸二-第三丁酯(1.37g，6.27mmol，1.44mL)逐滴添加到2-(5-溴-2-噻吩基)-5-甲基哌啶(1.6g，6.15mmol)及TEA(684.47mg，6.76mmol，942.80μL)於DCM(20mL)中之經攪拌之懸浮液中。將所得混合物在室溫下攪拌6h，然後在真空中蒸發，倒入水(100ml)中且用DCM(2* 50ml)萃取。將經合併之有機萃取物用水(2* 30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物2-(5-溴-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(1.8g，5.00mmol，81.24%產率)。At 0°C, di-tert-butyl dicarbonate (1.37 g, 6.27 mmol, 1.44 mL) was added dropwise to 2-(5-bromo-2-thienyl)-5-methylpiperidine (1.6 g , 6.15 mmol) and TEA (684.47 mg, 6.76 mmol, 942.80 μL) in a stirred suspension of DCM (20 mL). The resulting mixture was stirred at room temperature for 6h, then evaporated in vacuo, poured into water (100ml) and extracted with DCM (2 * 50ml). The combined organic extracts were washed with water (2 * 30ml), dried over sodium sulfate and evaporated in vacuo to give the product 2-(5-bromo-2-thienyl)-5-methylpiperidine-1- 3-Butyl formate (1.8 g, 5.00 mmol, 81.24% yield).

1 H NMR(400MHz,CDCl3 )δ 0.99(m,2H),1.46(m,2H),1.50(d,9H),1.84(m,3H),2.32(m,1H),2.99(m,1H),3.71(m,1H),5.47(m,1H),6.58(d,1H),6.87(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.99(m, 2H), 1.46(m, 2H), 1.50(d, 9H), 1.84(m, 3H), 2.32(m, 1H), 2.99(m, 1H) ), 3.71(m, 1H), 5.47(m, 1H), 6.58(d, 1H), 6.87(d, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值259.2；實測值260.0；Rt=1.660min。LCMS (ESI): [M-Boc] + m/z: calculated 259.2; found 260.0; Rt=1.660 min.

步驟6：2-(5-乙醯胺基-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 6: Synthesis of 2-(5-acetamido-2-thienyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將2-(5-溴-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(2.8g，7.77mmol)、乙醯胺(918.03mg，15.54mmol)、Cu(246.91mg，3.89mmol)、CuI(148.00mg，777.11μmol，26.33μL)、碳酸鉀(2.15g，15.54mmol，938.03μL)及(1R,2R)-N1,N2-二甲基環己-1,2-二胺(110.54mg，777.11μmol)混合在用Ar吹掃15分鐘的28%氫氧化銨溶液(40mL)中，然後在密封管中在110℃下加熱16h。將反應混合物在真空中蒸發且倒入水(40ml)中且用EtOAc(2* 10ml)萃取。將經合併之有機萃取物用28%氫氧化銨溶液(40mL)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物2-(5-乙醯胺基-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(2.2g，6.50mmol，83.64%產率)。2-(5-Bromo-2-thienyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2.8 g, 7.77 mmol), acetamide (918.03 mg, 15.54 mmol), Cu (246.91 mmol) mg, 3.89 mmol), CuI (148.00 mg, 777.11 μmol, 26.33 μL), potassium carbonate (2.15 g, 15.54 mmol, 938.03 μL) and (1R,2R)-N1,N2-dimethylcyclohexyl-1,2 - The diamine (110.54 mg, 777.11 μmol) was mixed in 28% ammonium hydroxide solution (40 mL) purged with Ar for 15 min, then heated in a sealed tube at 110 °C for 16 h. The reaction mixture was evaporated in vacuo and poured into water (40ml) and extracted with EtOAc (2 * 10ml). The combined organic extracts were washed with 28% ammonium hydroxide solution (40 mL), dried over sodium sulfate and evaporated in vacuo to give the product 2-(5-acetamido-2-thienyl)-5- Methylpiperidine-1-carboxylate tert-butyl ester (2.2 g, 6.50 mmol, 83.64% yield).

1 H NMR(400MHz,CDCl3 )δ 1.00(d,3H),1.45(s,9H),1.83(m,3H),2.13(m,2H),3.07(m,2H),3.70(m,2H),5.49(m,2H),6.48(d,1H),6.53(d,1H),8.12(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.00(d,3H), 1.45(s,9H), 1.83(m,3H), 2.13(m,2H), 3.07(m,2H), 3.70(m,2H) ), 5.49(m, 2H), 6.48(d, 1H), 6.53(d, 1H), 8.12(m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值238.2；實測值239.0；Rt=1.366min。LCMS (ESI): [M-Boc] + m/z: calculated 238.2; found 239.0; Rt=1.366 min.

步驟7：N-[5-(5-甲基-2-哌啶基)-2-噻吩基]乙醯胺之合成Step 7: Synthesis of N-[5-(5-methyl-2-piperidinyl)-2-thienyl]acetamide

將於DCM(10mL)中之2-(5-乙醯胺基-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(1.05g，3.10mmol)添加到99%三氟乙酸(10g，87.70mmol，6.76mL)中。將反應混合物在20℃下攪拌8h，然後在真空中蒸發，以得到N-[5-(5-甲基-2-哌啶基)-2-噻吩基]乙醯胺(1.4g，粗品，CF3 COOH)。To 99% tributyl 2-(5-acetamido-2-thienyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.05 g, 3.10 mmol) in DCM (10 mL) was added Fluoroacetic acid (10 g, 87.70 mmol, 6.76 mL). The reaction mixture was stirred at 20 °C for 8 h, then evaporated in vacuo to give N-[5-(5-methyl-2-piperidinyl)-2-thienyl]acetamide (1.4 g, crude, CF3COOH ).

LCMS(ESI)：[M+H]+ m/z：計算值238.2；實測值239.0；Rt=0.708min。LCMS (ESI): [M+H] + m/z: calculated 238.2; found 239.0; Rt=0.708 min.

3D. 外消旋 -5-((2R,5S )-5-甲基哌啶-2-基)噻吩-2-甲醯胺之合成 3D. Synthesis of racemic -5-(( 2R,5S )-5-methylpiperidin-2-yl)thiophene-2-carboxamide

Figure 110128222-A0202-12-0572-701
Figure 110128222-A0202-12-0572-701

步驟1：外消旋-(2R,5S)-2-(5-胺甲醯基噻吩-2-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of racemic-(2R,5S)-2-(5-aminocarboxythiophen-2-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5S )-2-(5-溴-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(800mg，2.22mmol)(如上文所製備)溶解於在MeOH中之2M氨(15.74g，39.74mmol，20mL，4.3%純度)中且添加Pd(dppf)Cl2 *DCM(90.66mg，111.02μmol)。將所得混合物在130℃、CO(30巴)氣氛下攪拌48h。在減壓下移除溶劑且將殘餘物溶解於乙酸乙酯(40ml)中。透過短矽膠墊過濾出不溶性固體且在減壓下濃縮濾液。將所獲得之混合物(大約50/50醯胺/甲酯)再溶解於MeOH(30mL)中，在0-5℃下用無水氨飽和且在高壓釜中在130℃下攪拌24h。然後，將其在真空中濃縮，得到(2R,5S )-2-(5-胺甲醯基-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(800mg，粗品)。( 2R,5S )-2-(5-bromo-2-thienyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (800 mg, 2.22 mmol) (prepared as above) was dissolved in MeOH To the 2M ammonia (15.74 g, 39.74 mmol, 20 mL, 4.3% purity) was added Pd(dppf)Cl2*DCM (90.66 mg , 111.02 μmol). The resulting mixture was stirred at 130°C under CO (30 bar) atmosphere for 48h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (40 ml). The insoluble solids were filtered through a short pad of silica gel and the filtrate was concentrated under reduced pressure. The obtained mixture (approximately 50/50 amide/methyl ester) was redissolved in MeOH (30 mL), saturated with anhydrous ammonia at 0-5 °C and stirred in an autoclave at 130 °C for 24 h. It was then concentrated in vacuo to give ( 2R,5S )-2-(5-aminocarboxy-2-thienyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (800 mg, crude ).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.91(d,3H),1.31(m,1H),1.38(s,9H),1.49(m,1H),1.91(m,3H),2.91(m,1H),3.31(m,1H),5.38(m,1H),6.86(d,1H),7.59(m,2H),7.91(d,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.91(d,3H), 1.31(m,1H), 1.38(s,9H), 1.49(m,1H), 1.91(m,3H), 2.91(m,1H), 3.31(m,1H), 5.38(m,1H), 6.86(d,1H), 7.59(m,2H), 7.91(d,1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值224.2；實測值225.2；Rt=1.400min。LCMS (ESI): [M-Boc] + m/z: calculated 224.2; found 225.2; Rt=1.400 min.

步驟2：外消旋-5-((2R,5S)-5-甲基哌啶-2-基)噻吩-2-甲醯胺之合成Step 2: Synthesis of racemic-5-((2R,5S)-5-methylpiperidin-2-yl)thiophene-2-carboxamide

將於99% 1,4-二噁烷中之4M氯化氫(10.10g，27.70mmol，12.62mL，10%純度)添加到(2R,5S )-2-(5-胺甲醯基-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(800mg，2.47mmol)於DCM(15mL)中之溶液中且將所得混合物在20℃下攪拌5h。然後，在減壓下移除溶劑且將殘餘物再溶解於水(20ml)中。透過棉花塞過濾出不溶性焦油。將濾液用固體K2 CO3 鹼化至pH

Figure 110128222-A0202-12-0573-558
10且用乙酸乙酯(2x15ml)萃取。將經合併之有機層經Na2 SO4 乾燥且在減壓下濃縮，得到5-[(2R,5S )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(370mg，1.65mmol，66.89%產率)。4M hydrogen chloride in 99% 1,4-dioxane (10.10 g, 27.70 mmol, 12.62 mL, 10% purity) was added to ( 2R,5S )-2-(5-aminocarbamoyl-2-thiophene yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (800 mg, 2.47 mmol) in DCM (15 mL) and the resulting mixture was stirred at 20 °C for 5 h. Then, the solvent was removed under reduced pressure and the residue was redissolved in water (20 ml). Filter out the insoluble tar through a cotton plug. The filtrate was basified to pH with solid K2CO3
Figure 110128222-A0202-12-0573-558
10 and extracted with ethyl acetate (2x15ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 5-[( 2R,5S )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (370 mg, 1.65 mmol, 66.89% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.82(d,3H),1.11(m,1H),1.34(m,1H),1.48(m,1H),1.78(d,1H),1.86(d,1H),2.23(t,1H),2.95(m,1H),3.70(d,1H),6.94(d,1H), 7.54(d,1H),7.70(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.82(d,3H), 1.11(m,1H), 1.34(m,1H), 1.48(m,1H), 1.78(d,1H), 1.86( d, 1H), 2.23 (t, 1H), 2.95 (m, 1H), 3.70 (d, 1H), 6.94 (d, 1H), 7.54 (d, 1H), 7.70 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值224.2；實測值225.2；Rt=0.523min。LCMS (ESI): [M] + m/z: calculated 224.2; found 225.2; Rt=0.523 min.

3E. 外消旋 -N -甲基-5-((2R,5S )-5-甲基哌啶-2-基)噻吩-2-甲醯胺之合成 3E. Synthesis of racemic - N -methyl-5-(( 2R,5S )-5-methylpiperidin-2-yl)thiophene-2-carboxamide

Figure 110128222-A0202-12-0574-702
Figure 110128222-A0202-12-0574-702

步驟1：外消旋-5-((2R,5S)-1-(第三丁氧基羰基)-5-甲基哌啶-2-基)噻吩-2-甲酸之合成Step 1: Synthesis of racemic-5-((2R,5S)-1-(3-butoxycarbonyl)-5-methylpiperidin-2-yl)thiophene-2-carboxylic acid

在氬氣氣氛下，向-75℃的(2R,5S )-2-(5-溴-2-噻吩基)-5-甲基哌啶-1-甲酸第三丁酯(5g，13-88mmol)(如上文所述製備)於THF(50mL)中之經攪拌之溶液中逐滴添加於己烷中之23%正丁基鋰(2.5M)(4.25g，15.26mmol，6.13mL，23%純度)。將所得溶液在同一溫度下攪拌15分鐘。15分鐘之後，將填充有二氧化碳(3.66g，83.26mmol)之氣球連接至反應容器且用CO2 吹出殘餘氬氣。此後，關閉反應燒瓶且將所得溶液在-75℃下攪拌40min。然後，使其升溫至室溫且將其分配於10% NaHSO4 水溶液(100ml)與MTBE(100ml)之間。將有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，得到5-[(2R,5S )-1-第三丁氧基 羰基-5-甲基-2-哌啶基]噻吩-2-甲酸(4.6g，粗品)。Add ( 2R,5S )-2-(5-bromo-2-thienyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (5 g, 13-88 mmol) to -75 °C under argon atmosphere. ) (prepared as described above) to a stirred solution in THF (50 mL) was added dropwise 23% n-butyllithium (2.5 M) in hexanes (4.25 g, 15.26 mmol, 6.13 mL, 23% purity). The resulting solution was stirred at the same temperature for 15 minutes. After 15 minutes, a balloon filled with carbon dioxide (3.66 g, 83.26 mmol) was attached to the reaction vessel and residual argon was purged with CO2 . After this time, the reaction flask was closed and the resulting solution was stirred at -75°C for 40 min. It was then allowed to warm to room temperature and partitioned between 10% aqueous NaHSO4 (100ml) and MTBE (100ml). The organic layer was washed with brine (50 ml), dried over Na 2 SO 4 and concentrated under reduced pressure to give 5-[( 2R,5S )-1 -tert -butoxycarbonyl-5-methyl-2-piperidine Peridyl]thiophene-2-carboxylic acid (4.6 g, crude).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.79(m,1H),0.96(d,3H),1.39(s,9H),1.69(m,1H),1.82(m,1H),1.96(m,1H),2.07(m,1H),2.92(d,1H),3.65(d,1H),5.44(m,1H),6.95(d,1H),7.61(d,1H),12.96(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.79(m, 1H), 0.96(d, 3H), 1.39(s, 9H), 1.69(m, 1H), 1.82(m, 1H), 1.96(m, 1H), 2.07(m, 1H), 2.92(d, 1H), 3.65(d, 1H), 5.44(m, 1H), 6.95(d, 1H), 7.61(d, 1H), 12.96 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值225.2；實測值226.2；Rt=1.487min。LCMS (ESI): [M-Boc] + m/z: calculated 225.2; found 226.2; Rt=1.487 min.

步驟2：外消旋-(2R,5S)-5-甲基-2-(5-(甲基胺甲醯基)噻吩-2-基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of rac-(2R,5S)-5-methyl-2-(5-(methylaminocarboxy)thiophen-2-yl)piperidine-1-carboxylic acid tert-butyl ester

將羰基二咪唑(934.26mg，5.76mmol)添加到5-[(2R,5S )-1-第三丁氧基 羰基-5-甲基-2-哌啶基]噻吩-2-甲酸(1.5g，4.61mmol)於THF(20mL)中之溶液中。將所得溶液簡單加熱至50℃達10分鐘。然後，使其冷卻至室溫且添加於THF中之2M甲胺(19.88g，46.09mmol，23.09mL，7.2%純度)。將所得混合物在20℃下攪拌4h。此後，在減壓下移除溶劑且將殘餘物再溶解於乙酸乙酯(30ml)中且用10%NaHSO4 水溶液(2x10ml)洗滌。將EA溶液經Na2 SO4 乾燥且在真空中濃縮，得到(2R,5S )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]哌啶-1-甲酸第三丁酯(1.4g，4.14mmol，89.74%產率)。Carbonyldiimidazole (934.26 mg, 5.76 mmol) was added to 5-[( 2R,5S )-1 -tert -butoxycarbonyl-5-methyl-2-piperidinyl]thiophene-2-carboxylic acid (1.5 g , 4.61 mmol) in THF (20 mL). The resulting solution was briefly heated to 50°C for 10 minutes. It was then cooled to room temperature and 2M methylamine in THF (19.88 g, 46.09 mmol, 23.09 mL, 7.2% purity) was added. The resulting mixture was stirred at 20 °C for 4 h. After this time, the solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate (30 ml) and washed with 10% aqueous NaHSO 4 (2×10 ml). The EA solution was dried over Na2SO4 and concentrated in vacuo to give ( 2R,5S )-5-methyl-2-[5-(methylaminocarboxy)-2-thienyl]piperidine-1 - tert-butyl formate (1.4 g, 4.14 mmol, 89.74% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.32(m,1H),1.42(s,9H),1.70(m,1H),1.82(m,1H),1.98(m,1H),2.05(m,1H),2.72(d,3H),2.93(d,1H),3.61(d,1H),5.43(m,1H),6.91(d,1H),7.55(d,1H),8.37(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.32(m,1H), 1.42(s,9H), 1.70(m,1H), 1.82(m,1H), 1.98(m, 1H), 2.05(m, 1H), 2.72(d, 3H), 2.93(d, 1H), 3.61(d, 1H), 5.43(m, 1H), 6.91(d, 1H), 7.55 (d, 1H), 8.37 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值238.2；實測值239.2；Rt=1.279min。LCMS (ESI): [M-Boc] + m/z: calculated 238.2; found 239.2; Rt=1.279 min.

步驟3：外消旋-N-甲基-5-((2R,5S)-5-甲基哌啶-2-基)噻吩-2-甲醯胺之合成Step 3: Synthesis of Racemic-N-methyl-5-((2R,5S)-5-methylpiperidin-2-yl)thiophene-2-carboxamide

將於99% 1,4-二噁烷中之4M氯化氫(15.15g，41.55mmol，18.94mL，10%純度)添加到(2R,5S )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]哌啶-1-甲酸第三丁酯(1.4g，4.14mmol)於DCM(20mL)中之溶液中。將所得混合物在20℃下攪拌15h。然後，在減壓下移除揮發物且將殘餘物分配於20%K2 CO3 水溶液(20ml)與乙酸乙酯(40ml)之間。分離有機層，經Na2 SO4 乾燥且在真空中濃縮，得到N -甲基-5-[(2R,5S )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(760mg，3.19mmol，77.09%產率)。4M hydrogen chloride in 99% 1,4-dioxane (15.15 g, 41.55 mmol, 18.94 mL, 10% purity) was added to ( 2R,5S )-5-methyl-2-[5-(methyl) Aminocarboxy)-2-thienyl]piperidine-1-carboxylic acid tert-butyl ester (1.4 g, 4.14 mmol) in DCM (20 mL). The resulting mixture was stirred at 20 °C for 15 h. Then, the volatiles were removed under reduced pressure and the residue was partitioned between 20 % aqueous K2CO3 (20ml) and ethyl acetate (40ml). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to give N -methyl-5-[( 2R,5S )-5-methyl-2-piperidinyl]thiophene-2-carboxamide ( 760 mg, 3.19 mmol, 77.09% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.80(d,3H),0.88(m,1H),1.05(m,1H),1.32(m,1H),1.48(m,1H),1.73(m,1H),1.84(m,1H),2.21(t,1H),2.71(d,3H),2.93(d,1H),3.70(d,1H),6.92(d,1H),7.47(d,1H),8.26(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.80(d, 3H), 0.88(m, 1H), 1.05(m, 1H), 1.32(m, 1H), 1.48(m, 1H), 1.73(m, 1H), 1.84(m, 1H), 2.21(t, 1H), 2.71(d, 3H), 2.93(d, 1H), 3.70(d, 1H), 6.92(d, 1H), 7.47 (d, 1H), 8.26 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值238.2；實測值239.2；Rt=0.569min。LCMS (ESI): [M] + m/z: calculated 238.2; found 239.2; Rt=0.569 min.

3F.2-環己基-5-甲基哌啶之合成 3F. Synthesis of 2-cyclohexyl-5-methylpiperidine

Figure 110128222-A0202-12-0576-703
Figure 110128222-A0202-12-0576-703

步驟1：2-(環已烯-1-基)-5-甲基吡啶之合成Step 1: Synthesis of 2-(cyclohexen-1-yl)-5-methylpyridine

將2-溴-5-甲基吡啶(2.86g，16.63mmol)及2-(環己烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(4.15g，19.95mmol，4.32mL)溶解於THF(50mL)中。添加碳酸銫(13.54g，41.56mmol)於水(5mL)中之溶液。然後，添加PdCl2* dppf* CH2 Cl2 (83.13μmol)且將反應燒瓶炔速抽真空且用氬氣再填充。將所得混合物在80℃下攪拌16h。此後，使其冷卻且蒸發。將殘餘物分配於EtOAc與水之間。將有機層用鹽水洗滌，經Na2 SO4 乾燥且蒸發。使殘餘物經歷管柱層析(SiO2(80g)管柱，Hex-MTBE作為流動相)，以獲得2-(環己烯-1-基)-5-甲基吡啶(2g，11.54mnmol，69.43%產率)。2-Bromo-5-methylpyridine (2.86 g, 16.63 mmol) and 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxo Bororolane (4.15 g, 19.95 mmol, 4.32 mL) was dissolved in THF (50 mL). A solution of cesium carbonate (13.54 g, 41.56 mmol) in water (5 mL) was added. Then, PdCl2 * dppf * CH2Cl2 (83.13 μmol) was added and the reaction flask was quickly evacuated and refilled with argon. The resulting mixture was stirred at 80 °C for 16 h. After that, it was cooled and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was subjected to column chromatography (SiO2 (80 g) column, Hex-MTBE as mobile phase) to obtain 2-(cyclohexen-1-yl)-5-methylpyridine (2 g, 11.54 mmol, 69.43 %Yield).

1 H NMR(DMSO-d6 ,400MHz)δ(ppm)1.59(m,2H),1.68(m,2H),2.18(t,2H),2.25(s,3H),2.41(t,2H),6.62(s,1H),7.38(d,1H),7.51(d,1H),8.32(s,1H)。 1 H NMR(DMSO-d 6 , 400MHz)δ(ppm)1.59(m,2H),1.68(m,2H),2.18(t,2H),2.25(s,3H),2.41(t,2H), 6.62(s, 1H), 7.38(d, 1H), 7.51(d, 1H), 8.32(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值173.2；實測值174.2；Rt=0.899min。LCMS (ESI): [M+H] + m/z: calculated 173.2; found 174.2; Rt=0.899 min.

步驟2：2-環己基-5-甲基哌啶之合成Step 2: Synthesis of 2-cyclohexyl-5-methylpiperidine

將乾燥的487型鈀(10%於碳上)(24.57mg，230.88μmol)添加到2-(環己烯-1-基)-5-甲基吡啶(2g，11.54mmol)於MeOH(50mL)中之溶液中且將所得混合物在50atm.壓力及50℃下氫化48h。在起始材料(HNMR對照)消耗之後，使所得混合物冷卻至室溫且過濾。將濾液蒸發至乾。使殘餘物經歷HPLC(裝備有DAD及質量偵測器之Agilent 1260 Infinity系統；Waters SunFire C18 OBD製備型管柱，100A，5mkm，19* 100mm with SunFire C18製備型保護筒，100A，10mkm，19* 100mm；1-30% 1.5-5min；水-乙腈作為流動相；流速30mL/min；(裝載泵4mL/min水)；目標質量181)，以獲得2-環己基-5-甲基哌啶(1.5g，6.89mmol，59.67%產率， HCl)。Dry palladium Form 487 (10% on carbon) (24.57 mg, 230.88 μmol) was added to 2-(cyclohexen-1-yl)-5-methylpyridine (2 g, 11.54 mmol) in MeOH (50 mL) in solution and the resulting mixture was hydrogenated at 50 atm. pressure and 50 °C for 48 h. After consumption of starting material (HNMR control), the resulting mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness. The residue was subjected to HPLC (Agilent 1260 Infinity system equipped with DAD and mass detector; Waters SunFire C18 OBD prep column, 100A, 5mkm, 19 * 100mm with SunFire C18 prep cartridge, 100A, 10mkm, 19 * 100mm; 1-30% 1.5-5min; water-acetonitrile as mobile phase; flow rate 30mL/min; (loading pump 4mL/min water); target mass 181) to obtain 2-cyclohexyl-5-methylpiperidine ( 1.5 g, 6.89 mmol, 59.67% yield, HCl).

1 H NMR(DMSO-d6 ,400MHz)δ(ppm)0.95(s,3H),1.12(m,6H),1.51(m,4H),1.84(m,6H),2.77(m,2H),3.09(m,2H),8.88(s,1H)。 1 H NMR(DMSO-d 6 , 400MHz)δ(ppm)0.95(s,3H),1.12(m,6H),1.51(m,4H),1.84(m,6H),2.77(m,2H), 3.09 (m, 2H), 8.88 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值181.2；實測值182.4；Rt=2.315min。LCMS (ESI): [M+H] + m/z: calculated 181.2; found 182.4; Rt=2.315 min.

3G.外消旋-N-甲基-4-[(2S,5R)-5-甲基-2-哌啶基]苯胺之合成 3G. Synthesis of racemic-N-methyl-4-[(2S,5R)-5-methyl-2-piperidinyl]aniline

Figure 110128222-A0202-12-0577-704
Figure 110128222-A0202-12-0577-704

步驟1：外消旋-(2S,5R)-2-[4-(第三丁氧基羰基胺基)苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of racemic-(2S,5R)-2-[4-(tert-butoxycarbonylamino)phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將外消旋-4-[(2S,5R)-5-甲基-2-哌啶基]苯胺(1g，3.80mmol，2HCl)溶解於DCM(30mL)中。將所得混合物在室溫下攪拌5min且添加TEA(1.54g，15.20mmol，2.12mL)。將反應混合物用冰水浴冷卻，隨後逐滴添加碳酸第三丁氧基羰基第三丁酯(3.32g，15.20mmol，3.49mL)。在SiO2 上用MTBE-Hex(50/50%)沖洗粗品化合物，得到外消旋-(2S,5R)-2-[4-(第三丁氧基羰基胺基)苯基]-5-甲基哌啶-1-甲酸第三丁酯(1.1g，2.82mmol，74.14%產率)。Racemic-4-[(2S,5R)-5-methyl-2-piperidinyl]aniline (1 g, 3.80 mmol, 2HCl) was dissolved in DCM (30 mL). The resulting mixture was stirred at room temperature for 5 min and TEA (1.54 g, 15.20 mmol, 2.12 mL) was added. The reaction mixture was cooled with an ice-water bath, followed by the dropwise addition of tert-butyl tert-butoxycarbonyl carbonate (3.32 g, 15.20 mmol, 3.49 mL). Rinse the crude compound with MTBE-Hex (50/50%) on SiO to give rac-(2S,5R)-2-[4-(tert-butoxycarbonylamino)phenyl]-5- Methylpiperidine-1-carboxylate tert-butyl ester (1.1 g, 2.82 mmol, 74.14% yield).

LCMS(ES1)：[M-Boc]+ m/z：計算值290.2；實測值291.2；Rt=1.615min。LCMS (ES1): [M-Boc] + m/z: calculated 290.2; found 291.2; Rt=1.615 min.

步驟2：外消旋-(2S,5R)-2-[4-[第三丁氧基羰基(甲基)胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Racemic-(2S,5R)-2-[4-[tert-butoxycarbonyl(methyl)amino]phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester synthesis

將外消旋 -(2S,5R)-2-[4-(第三丁氧基羰基胺基)苯基]-5-甲基哌啶-1-甲酸第三丁酯(1.1g，2.82mmol)溶解於THF(30mL)中。用Ar吹掃燒瓶且小心少量添加NaH(129.52mg，3.38mmol，60%純度)。在劇烈攪拌1h之後，經由注射器逐滴添加MeI(439.79mg，3.10mmol)，然後攪拌隔夜。將最終混合物用1mL水淬滅，然後濃縮。將粗產物用水處理且用MTBE萃取，經Na2 SO4 乾燥且在真空中 蒸發，以得到(2S,5R)-2-[4-[第三丁氧基羰基(甲基)胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(1.3g，粗品)。 rac- (2S,5R)-2-[4-(tert-butoxycarbonylamino)phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.82 mmol ) was dissolved in THF (30 mL). The flask was purged with Ar and NaH (129.52 mg, 3.38 mmol, 60% purity) was added carefully in small amounts. After vigorous stirring for 1 h, MeI (439.79 mg, 3.10 mmol) was added dropwise via syringe and then stirred overnight. The final mixture was quenched with 1 mL of water and concentrated. The crude product was treated with water and extracted with MTBE, dried over Na 2 SO 4 and evaporated in vacuo to give (2S,5R)-2-[4-[tert-butoxycarbonyl(methyl)amino]benzene yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.3 g, crude).

1 H NMR(400MHz,CDCl3 )δ 7.01(d,3H),1.43(s,18H),1.60(m,3H),2.01(m,2H),2.96(m,1H),3.23(s,3H),3.70(m,1H),5.28(m,1H),7.16(m,4H)。 1 H NMR (400MHz, CDCl 3 )δ 7.01(d,3H), 1.43(s,18H), 1.60(m,3H), 2.01(m,2H), 2.96(m,1H), 3.23(s,3H) ), 3.70 (m, 1H), 5.28 (m, 1H), 7.16 (m, 4H).

LCMS(ESI)：[M-Boc]+ m/z：計算值304.2；實測值305.2；Rt=1.784min。LCMS (ESI): [M-Boc] + m/z: calculated 304.2; found 305.2; Rt=1.784 min.

步驟3：外消旋-N-甲基-4-[(2S,5R)-5-甲基-2-哌啶基]苯胺之合成Step 3: Synthesis of Racemic-N-methyl-4-[(2S,5R)-5-methyl-2-piperidinyl]aniline

將外消旋 -(2S,5R)-2-[4-[第三丁氧基羰基(甲基)胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(1.3g，3.21mmol)溶解於10mL甲醇中，然後添加10mL於二噁烷中之HCl(4.0M溶液)。將混合物攪拌隔夜，然後在真空中濃縮。將粗產物用MTBE處理且過濾出來。將所獲得之沉澱風乾，以得到外消旋 -N-甲基-4-[(2S,5R)-5-甲基-2-哌啶基]苯胺(0.65g，2.34mmol，72.96%產率，2HCl)。The rac- (2S,5R)-2-[4-[tert-butoxycarbonyl(methyl)amino]phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.3 g, 3.21 mmol) was dissolved in 10 mL of methanol, then 10 mL of HCl in dioxane (4.0 M solution) was added. The mixture was stirred overnight, then concentrated in vacuo. The crude product was treated with MTBE and filtered off. The obtained precipitate was air-dried to give rac -N-methyl-4-[(2S,5R)-5-methyl-2-piperidinyl]aniline (0.65 g, 2.34 mmol, 72.96% yield) , 2HCl).

LCMS(ESI)：[M+H]+ m/z：計算值204.1；實測值205.2；Rt=0.608min。LCMS (ESI): [M+H] + m/z: calculated 204.1; found 205.2; Rt=0.608 min.

3H. 外消旋 -(2R,5R )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶之合成 3H. Synthesis of racemic- ( 2R,5R )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidine

Figure 110128222-A0202-12-0578-705
Figure 110128222-A0202-12-0578-705

步驟1：(E)-1-(3,4-二氟苯基)戊-1-烯-3-酮之合成Step 1: Synthesis of (E)-1-(3,4-difluorophenyl)pent-1-en-3-one

在Ar氣氛下，向1,2-二氟-4-碘苯(20g，83.34mmol)及TEA(12.23g，120.84mmol，16.84mL)之混合物中添加戊-1-烯-3-酮(14.02g，166.67mmol)，隨後添加乙酸鈀(II)(935.49mg，4.17mmol)及MeCN(100mL)。將混合物回流12h。移除溶劑且將殘餘物溶解於水(150ml)中且用MTBE(3*100ml)萃取。將有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮，以得到(E )-1-(3,4-二氟苯基)戊-1-烯-3-酮(18g，粗品)，其不經進一步純化即用於下一步驟。To a mixture of 1,2-difluoro-4-iodobenzene (20 g, 83.34 mmol) and TEA (12.23 g, 120.84 mmol, 16.84 mL) was added pent-1-en-3-one (14.02 g) under Ar atmosphere g, 166.67 mmol), followed by the addition of palladium(II) acetate (935.49 mg, 4.17 mmol) and MeCN (100 mL). The mixture was refluxed for 12 h. The solvent was removed and the residue was dissolved in water (150ml) and extracted with MTBE (3*100ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give ( E )-1-(3,4-difluorophenyl)pent-1-en-3-one (18 g, crude product), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.18(t,3H),2.69(m,2H),6.65(d,1H),7.18(d,1H),7.27(s,1H),7.36(d,1H),7.45(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.18(t, 3H), 2.69(m, 2H), 6.65(d, 1H), 7.18(d, 1H), 7.27(s, 1H), 7.36( d, 1H), 7.45 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值196.2；實測值197.2；Rt=1.449min。LCMS (ESI): [M] + m/z: calculated 196.2; found 197.2; Rt=1.449 min.

步驟2：(E)-1-(3,4-三氟苯基)-5-(三甲胺基)-4-甲基戊-1-烯-3-酮之合成Step 2: Synthesis of (E)-1-(3,4-trifluorophenyl)-5-(trimethylamino)-4-methylpent-1-en-3-one

將(E )-1-(3,4-二氟苯基)戊-1-烯-3-酮(18g，91.75mmol)、1,3,5-三噁烷(5.51g，183.49mmol，4.71mL，300%純度)、二甲胺鹽酸鹽(7.48g，91.75mmol)及36% w/w鹽酸水溶液(9.16g，91.75mmol，11.46mL，36.5%純度)於EtOH(150mL)中之溶液在80℃下攪拌12h。在真空中移除溶劑，以得到(E )-1-(3,4-二氟苯基)-5-(二甲胺基)-4-甲基-戊-1-烯-3-酮(30g，粗品，HCl)，其不經進一步純化即用於下一步驟。Combine ( E )-1-(3,4-difluorophenyl)pent-1-en-3-one (18 g, 91.75 mmol), 1,3,5-trioxane (5.51 g, 183.49 mmol, 4.71 g) mL, 300% purity), dimethylamine hydrochloride (7.48 g, 91.75 mmol) and a solution of 36% w/w aqueous hydrochloric acid (9.16 g, 91.75 mmol, 11.46 mL, 36.5% purity) in EtOH (150 mL) Stir at 80°C for 12h. The solvent was removed in vacuo to give ( E )-1-(3,4-difluorophenyl)-5-(dimethylamino)-4-methyl-pent-1-en-3-one ( 30 g, crude, HCl), which was used in the next step without further purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.17(d,3H),2.68(s,6H),3.45(m,1H),4.47(m,2H),6.85(d,1H),7.10(d,1H),7.62(s,1H),7.83(d,1H),7.92(d,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.17(d,3H), 2.68(s,6H), 3.45(m,1H), 4.47(m,2H), 6.85(d,1H), 7.10(d,1H), 7.62(s,1H), 7.83(d,1H), 7.92(d,1H).

LCMS(ESI)：[M]+ m/z：計算值253.2；實測值254.2；Rt=0.795min。LCMS (ESI): [M] + m/z: calculated 253.2; found 254.2; Rt=0.795 min.

步驟3：外消旋-(2R,5R)-2-(3,4-三氟苯基)-5-甲基哌啶-4-酮之合成Step 3: Synthesis of Racemic-(2R,5R)-2-(3,4-trifluorophenyl)-5-methylpiperidin-4-one

將(E )-1-(3,4-二氟苯基)-5-(二甲胺基)-4-甲基-戊-1-烯-3-酮(30g，118.44mmol)溶解於水(150mL)及NH3 水溶液(150mL)中，然後將反應混合物在80℃下攪拌12h。將反應混合物用1N HCl酸化，用MTBE(2*150ml)萃取，然後將水層用1N NaOH鹼化且用DCM(3*100ml)萃取。將DCM層經Na2 SO4 乾燥，過濾且在真空下蒸發，以得到(2S,5S )-2-(3,4-二氟苯基)-5-甲基哌啶-4-酮(5.5g，粗品)，其不經進一步純化即用於下一步驟。( E )-1-(3,4-Difluorophenyl)-5-(dimethylamino)-4-methyl-pent-1-en-3-one (30 g, 118.44 mmol) was dissolved in water (150 mL) and aqueous NH3 (150 mL), then the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was acidified with 1N HCl, extracted with MTBE (2*150ml), then the aqueous layer was basified with 1N NaOH and extracted with DCM (3*100ml). The DCM layer was dried over Na2SO4 , filtered and evaporated in vacuo to give ( 2S,5S )-2-(3,4-difluorophenyl)-5-methylpiperidin-4-one (5.5 g, crude), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.03(d,3H),1.26(m,1H),2.48(m,2H),2.65(m,2H),3.45(m,1H),3.88(d,1H),7.07(m,2H),7.24(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.03(d, 3H), 1.26(m, 1H), 2.48(m, 2H), 2.65(m, 2H), 3.45(m, 1H), 3.88( d, 1H), 7.07 (m, 2H), 7.24 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值225.2；實測值226.2；Rt=0.570min。LCMS (ESI): [M] + m/z: calculated 225.2; found 226.2; Rt=0.570 min.

步驟4：外消旋-(2R,5R)-1-苯甲基-2-(3,4-三氟苯基)-5-甲基哌啶-4-酮之合成Step 4: Synthesis of Racemic-(2R,5R)-1-benzyl-2-(3,4-trifluorophenyl)-5-methylpiperidin-4-one

將(2S,5S )-2-(3,4-二氟苯基)-5-甲基哌啶-4-酮(5.5g，24.42mmol)、99%無水碳酸鉀(10.12g，73.26mmol，4.42mL)及溴甲基苯(4.59g，26.86mmol，3.19mL)溶解於DMF(25mL)中且在60℃下攪拌12h。將反應混合物溶解於水(150ml)中且用MTBE(3*50ml)萃取。將有機相用鹽水(3*50ml)洗滌。將有機相經Na2 SO4 乾燥，過濾且在真空中濃縮，以得到粗產物(7g)，其藉由急驟管柱層析(己烷-MTBE)進行純化，以得到(2S,5S )-1-苯甲基-2-(3,4-二氟苯基)-5-甲基哌啶-4-酮(2.0g，6.34mmol，25.97%產率)。藉由2D-NMR實驗證明標題化合物之結構。( 2S,5S )-2-(3,4-difluorophenyl)-5-methylpiperidin-4-one (5.5 g, 24.42 mmol), 99% anhydrous potassium carbonate (10.12 g, 73.26 mmol, 4.42 mL) and bromomethylbenzene (4.59 g, 26.86 mmol, 3.19 mL) were dissolved in DMF (25 mL) and stirred at 60 °C for 12 h. The reaction mixture was dissolved in water (150ml) and extracted with MTBE (3*50ml). The organic phase was washed with brine (3*50ml). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product (7 g), which was purified by flash column chromatography (hexane-MTBE) to give ( 2S,5S )- 1-Benzyl-2-(3,4-difluorophenyl)-5-methylpiperidin-4-one (2.0 g, 6.34 mmol, 25.97% yield). The structure of the title compound was confirmed by 2D-NMR experiments.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.94(d,3H),2.02(m,1H),2.48(m,1H),2.62(m,1H),2.75(m,1H),2.90(m,1H),3.17(m,1H),3.53(m,1H),3.79(m,1H),7.17(m,1H),7.32(m,7H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.94(d,3H), 2.02(m,1H), 2.48(m,1H), 2.62(m,1H), 2.75(m,1H), 2.90( m, 1H), 3.17 (m, 1H), 3.53 (m, 1H), 3.79 (m, 1H), 7.17 (m, 1H), 7.32 (m, 7H).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=1.428min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=1.428 min.

步驟5：外消旋-(2R,5R)-1-苯甲基-2-(3,4-二氟苯基)-4,4-三氟-5-甲基哌啶之合成Step 5: Synthesis of Racemic-(2R,5R)-1-benzyl-2-(3,4-difluorophenyl)-4,4-trifluoro-5-methylpiperidine

將(2S,5S )-1-苯甲基-2-(3,4-二氟苯基)-5-甲基哌啶-4-酮(2g，6.34mmol)、HF(1.27g，63.42mmol)及SF4 (1.37g，12.68mmol)在不鏽鋼高壓釜中在70℃下加熱12h。反應完成之後，排出氣體產物，將反應混合物倒入冰上且用10% K2 CO3 水溶液中和。將產物用MTBE(3×100mL)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥，且在減壓下濃縮，以得到(2S,5S )-1-苯甲基-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶(2g，5.93mmol，93.48%產率)，其不經進一步純化即用於下一步驟。Combine ( 2S,5S )-1-benzyl-2-(3,4-difluorophenyl)-5-methylpiperidin-4-one (2 g, 6.34 mmol), HF (1.27 g, 63.42 mmol) ) and SF4 (1.37 g, 12.68 mmol) were heated in a stainless steel autoclave at 70 °C for 12 h. After the reaction was complete, the gaseous product was vented, the reaction mixture was poured onto ice and neutralized with 10 % aqueous K2CO3. The product was extracted with MTBE (3 x 100 mL). The combined organic extracts were washed with brine, dried over Na2SO4 , and concentrated under reduced pressure to give ( 2S,5S )-1-benzyl-2-(3,4-difluorophenyl) )-4,4-difluoro-5-methylpiperidine (2 g, 5.93 mmol, 93.48% yield), which was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.97(d,3H),2.02(m,2H),2.22(m,2H),2.85(d,2H),3.45(d,1H),3.72(d,1H),7.14(m,2H),7.25(m,3H),7.31(m,3H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.97(d,3H), 2.02(m,2H), 2.22(m,2H), 2.85(d,2H), 3.45(d,1H), 3.72( d, 1H), 7.14 (m, 2H), 7.25 (m, 3H), 7.31 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值337.2；實測值338.2；Rt=1.718min。LCMS (ESI): [M] + m/z: calculated 337.2; found 338.2; Rt=1.718 min.

步驟6：外消旋-(2R,5R)-2-(3,4-三氟苯基)-4,4-二氟-5-甲基哌啶之合成Step 6: Synthesis of Racemic-(2R,5R)-2-(3,4-trifluorophenyl)-4,4-difluoro-5-methylpiperidine

在存在活性催化劑於H2 O中之雷氏鎳2800漿液(507.92mg，5.93 mmol)之情況下，將(2S,5S )-1-苯甲基-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶(2g，5.93mmol)於MeOH(60mL)中之溶液回流4h且透過SiO2 薄層過濾。向溶液中添加乾燥的487型鈀(10%於碳上)(630.91mg，5.93mmol)且在室溫下用H2 (40atm)氫化48h。透過矽藻土過濾反應混合物且在真空中濃縮濾液，以得到(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶(0.9g，3.64mmol，61.40%產率)，其不經進一步純化即用於下一步驟。( 2S,5S )-1-benzyl-2-(3,4-difluorophenyl) in the presence of a slurry of Raj's Nickel 2800 (507.92 mg, 5.93 mmol) of the active catalyst in H2O (507.92 mg, 5.93 mmol) )-4,4-difluoro-5-methylpiperidine (2 g, 5.93 mmol) in MeOH (60 mL) was refluxed for 4 h and filtered through a thin layer of SiO2 . To the solution was added dry palladium type 487 (10% on carbon) (630.91 mg, 5.93 mmol) and hydrogenated with H2 (40 atm) at room temperature for 48 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give ( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidine (0.9 g, 3.64 mmol, 61.40% yield), which was used in the next step without further purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.90(d,3H),1.72(m,1H),1.97(m,1H),2.16(m,1H),2.39(t,1H),2.69(bds,1H),2.98(d,1H),3.71(d,1H),7.21(s,1H),7.35(d,1H),7.45(d,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.90(d,3H), 1.72(m,1H), 1.97(m,1H), 2.16(m,1H), 2.39(t,1H), 2.69(bds, 1H), 2.98(d, 1H), 3.71(d, 1H), 7.21(s, 1H), 7.35(d, 1H), 7.45(d, 1H).

LCMS(ESI)：[M]+ m/z：計算值247.2；實測值248.2；Rt=0.981min。LCMS (ESI): [M] + m/z: calculated 247.2; found 248.2; Rt=0.981 min.

3I. 外消旋 -4,4 -二氟-5-甲基-2-苯基哌啶之合成 3I. Synthesis of racemic - 4,4 -difluoro-5-methyl-2-phenylpiperidine

Figure 110128222-A0202-12-0581-706
Figure 110128222-A0202-12-0581-706

步驟1：(E)-1-苯基基-1-烯-3-酮之合成Step 1: Synthesis of (E)-1-phenyl-1-en-3-one

在室溫下，向碘苯(30g，147.05mmol，16.39mL)及TEA(21.58g，213.23mmol，29.72mL)之混合物中添加戊-1-烯-3-酮(24.74g，294.11mmol)，隨後添加乙酸鈀(II)(1.65g，7.35mmol)及MeCN(150mL)。將混合物回流12h，然後添加乙酸乙酯(30mL)及水(30mL)。將有機層用水洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮，以得到(E)-1-苯基戊-1-烯-3-酮(27.66g，粗品)，其不經進一步純化即用於下一步驟。To a mixture of iodobenzene (30 g, 147.05 mmol, 16.39 mL) and TEA (21.58 g, 213.23 mmol, 29.72 mL) was added pent-1-en-3-one (24.74 g, 294.11 mmol) at room temperature, Palladium(II) acetate (1.65 g, 7.35 mmol) and MeCN (150 mL) were then added. The mixture was refluxed for 12 h, then ethyl acetate (30 mL) and water (30 mL) were added. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (E)-1-phenylpent-1-en-3-one (27.66 g, crude) without further purification i.e. for the next step.

LCMS(ESI)：[M-tBu]+ m/z：計算值160.2；實測值161.4；Rt=3.422min。LCMS (ESI): [M-tBu] + m/z: calculated 160.2; found 161.4; Rt=3.422 min.

步驟2：(E)-5-(三甲胺基)-4-甲基-1-苯基-戊-1-烯-3-酮之合成Step 2: Synthesis of (E)-5-(trimethylamino)-4-methyl-1-phenyl-pent-1-en-3-one

將(E)-1-苯基戊-1-烯-3-酮(27g，168.53mmol)、N-甲基甲胺(13.74g，168.53mmol，17.73mL，HCl)及用7-8%甲醇穩定之37%w/w甲醛水溶液(10.63g，353.91mmol，9.84mL)在乙醇(300mL)+HCl(水溶液)(30mL)中加熱回流4小時。Combine (E)-1-phenylpent-1-en-3-one (27 g, 168.53 mmol), N-methylmethylamine (13.74 g, 168.53 mmol, 17.73 mL, HCl) with 7-8% methanol Stabilized 37% w/w aqueous formaldehyde (10.63 g, 353.91 mmol, 9.84 mL) was heated to reflux in ethanol (300 mL) + HCl(aq) (30 mL) for 4 hours.

將反應混合物在真空中濃縮，以得到(E)-5-(二甲胺基)-4-甲基-1-苯基-戊-1-烯-3-酮(41g，粗品)，其不經進一步純化即用於下一步驟。The reaction mixture was concentrated in vacuo to give (E)-5-(dimethylamino)-4-methyl-1-phenyl-pent-1-en-3-one (41 g, crude) which was not It was used in the next step after further purification.

LCMS(ESI)：[M+1]+ m/z：計算值217.1；實測值218.4；Rt=2.136min。LCMS (ESI): [M+1] + m/z: calculated 217.1; found 218.4; Rt=2.136 min.

步驟3：5-甲基-2-苯基哌啶-4-酮之合成Step 3: Synthesis of 5-methyl-2-phenylpiperidin-4-one

將(E)-5-(二甲胺基)-4-甲基-1-苯基-戊-1-烯-3-酮(46g，181.27mmol，HCl)溶解於水(150mL)及NH3 (水溶液)(150mL)中，然後將反應混合物在80℃下攪拌20h。將反應混合物用1N HCl酸化，用MTBE(2*20ml)萃取，然後將水層用1N NaOH鹼化且用DCM(2*20ml)萃取。將DCM層經Na2 SO4 乾燥，過濾且在真空下蒸發，以得到5-甲基-2-苯基哌啶-4-酮(8.15g，43.06mmol，23.76%產率)，其不經進一步純化即用於下一步驟。(E)-5-(dimethylamino)-4-methyl-1-phenyl-pent-1-en-3-one (46 g, 181.27 mmol, HCl) was dissolved in water (150 mL) and NH 3 (aq) (150 mL), then the reaction mixture was stirred at 80 °C for 20 h. The reaction mixture was acidified with 1N HCl, extracted with MTBE (2*20ml), then the aqueous layer was basified with 1N NaOH and extracted with DCM (2*20ml). The DCM layer was dried over Na 2 SO 4 , filtered and evaporated in vacuo to give 5-methyl-2-phenylpiperidin-4-one (8.15 g, 43.06 mmol, 23.76% yield) which was Further purification was used in the next step.

LCMS(ESI)：[M+1]+ m/z：計算值190,2；實測值190,4；Rt=1.152minLCMS(ESI): [M+1] + m/z: Calculated 190,2; Measured 190,4; Rt=1.152min

步驟4：1-苯甲基-5-甲基-2-苯基哌啶-4-酮之合成Step 4: Synthesis of 1-benzyl-5-methyl-2-phenylpiperidin-4-one

將5-甲基-2-苯基哌啶-4-酮(1.15g，6.08mmol)、99%苯甲基溴(1.14g，6.68mmol，793.88μL)及99%無水碳酸鉀(2.52g，18.23mmol，1.10mL)溶解於DMF(3mL)中且在60℃下攪拌12h。添加乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由急驟管柱層析進行純化，以得到1-苯甲基-5-甲基-2-苯基哌啶-4-酮(0.52g，1.86mmol，30.63%產率)。5-Methyl-2-phenylpiperidin-4-one (1.15 g, 6.08 mmol), 99% benzyl bromide (1.14 g, 6.68 mmol, 793.88 μL) and 99% anhydrous potassium carbonate (2.52 g, 18.23 mmol, 1.10 mL) was dissolved in DMF (3 mL) and stirred at 60 °C for 12 h. Ethyl acetate was added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product, which was purified by flash column chromatography to give 1-benzyl-5-methyl- 2-Phenylpiperidin-4-one (0.52 g, 1.86 mmol, 30.63% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.93(m,3H),1.53(s,1H),2.00(t,1H),2.51(d, 1H),2.71(m,1H),2.84(m,1H),3.17(m,1H),3.51(d,1H),3.79(d,1H),7.23-7.45(m,10H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.93 (m, 3H), 1.53 (s, 1H), 2.00 (t, 1H), 2.51 (d, 1H), 2.71 (m, 1H), 2.84 (m, 1H), 3.17 (m, 1H), 3.51 (d, 1H), 3.79 (d, 1H), 7.23-7.45 (m, 10H).

LCMS(ESI)：[M+1]+ m/z：計算值279.2；實測值280.4；Rt=2.905minLCMS(ESI): [M+1] + m/z: Calculated 279.2; Measured 280.4; Rt=2.905min

步驟5：1-苯甲基-4,4-二氟-5-甲基-2-苯基哌啶之合成Step 5: Synthesis of 1-benzyl-4,4-difluoro-5-methyl-2-phenylpiperidine

將1-苯甲基-5-甲基-2-苯基哌啶-4-酮(0.52g，1.86mmol)、HF(372.38mg，18.61mmol)及SF4(402.41mg，3.72mmol)在不鏽鋼高壓釜中在70℃下加熱12h。反應完成之後，排出氣體產物，將反應混合物倒入冰上且用10% K2 CO3 水溶液中和。將產物用MTBE(3×100mL)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥，且在減壓下濃縮，以得到1-苯甲基-4,4-二氟-5-甲基-2-苯基哌啶(0.4g，1.33mmol，71.31%產率)，其不經進一步純化即用於下一步驟。1-Benzyl-5-methyl-2-phenylpiperidin-4-one (0.52 g, 1.86 mmol), HF (372.38 mg, 18.61 mmol) and SF4 (402.41 mg, 3.72 mmol) were combined in a stainless steel high pressure The kettle was heated at 70°C for 12h. After the reaction was complete, the gaseous product was vented, the reaction mixture was poured onto ice and neutralized with 10 % aqueous K2CO3. The product was extracted with MTBE (3 x 100 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to give 1-benzyl-4,4-difluoro-5-methyl-2-phenylpiperin pyridine (0.4 g, 1.33 mmol, 71.31% yield), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ 0.96(m,3H),1.99(m,1H),2.10(m,2H),2.23(m,1H),2.83(m,2H),3.46(d,1H),3.76(d,1H),7.23-7.46(m,10H) 1 H NMR (400MHz, CDCl 3 )δ 0.96(m,3H), 1.99(m,1H), 2.10(m,2H), 2.23(m,1H), 2.83(m,2H), 3.46(d,1H) ),3.76(d,1H),7.23-7.46(m,10H)

LCMS(ESI)：[M+1]+ m/z：計算值301.4；實測值302.2；Rt=1.356minLCMS(ESI): [M+1] + m/z: Calculated 301.4; Measured 302.2; Rt=1.356min

步驟6：4,4-三氟-5-甲基-2-苯基哌啶之合成Step 6: Synthesis of 4,4-Trifluoro-5-methyl-2-phenylpiperidine

將1-苯甲基-4,4-二氟-5-甲基-2-苯基哌啶(0.4g，1.33mmol)溶解於MeOH(10mL)中且添加10% Pd/C(0.1g，53.09μmol)且在室溫下用H2 (30atm)氫化60h。透過矽藻土過濾反應混合物且在45℃下在真空中濃縮濾液，以得到4,4-二氟-5-甲基-2-苯基哌啶(0.2g，946.75μmol，71.33%產率)，其不經進一步純化即用於下一步驟。1-Benzyl-4,4-difluoro-5-methyl-2-phenylpiperidine (0.4 g, 1.33 mmol) was dissolved in MeOH (10 mL) and 10% Pd/C (0.1 g, 53.09 μmol) and hydrogenated with H2 (30 atm) for 60 h at room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo at 45 °C to give 4,4-difluoro-5-methyl-2-phenylpiperidine (0.2 g, 946.75 μmol, 71.33% yield) , which was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 1.06(m,3H),1.83-2.30(m,3H),2.71(t,1H),3.13(m,1H),3.92(d,2H),7.23-7.46(m,5H) 1 H NMR (500 MHz, CDCl 3 ) δ 1.06 (m, 3H), 1.83-2.30 (m, 3H), 2.71 (t, 1H), 3.13 (m, 1H), 3.92 (d, 2H), 7.23-7.46 (m,5H)

LCMS(ESI)：[M+1]+ m/z：計算值211.2；實測值212.2；Rt=0.714minLCMS(ESI): [M+1] + m/z: Calculated 211.2; Measured 212.2; Rt=0.714min

3J.(2R,5R)-5-甲基-2-苯基哌啶-4-醇之合成 3J. Synthesis of (2R,5R)-5-methyl-2-phenylpiperidin-4-ol

Figure 110128222-A0202-12-0584-707
Figure 110128222-A0202-12-0584-707

步驟1：(2R,5R)-5-甲基-4-側氧基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,5R)-5-methyl-4-oxo-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

將5-甲基-2-苯基哌啶-4-酮(2.8g，14.80mmol)(如上文所述製備)及TEA(2.25g，22.19mmol，3.09mL)溶解於DCM(40mL)中且逐滴添加二碳酸二-第三丁酯(3.23g，14.80mmol，3.40mL)，然後將反應混合物在室溫下攪拌12h。將反應混合物用NaHSO4 (水溶液)洗滌，將有機層經Na2 SO4 乾燥，過濾且在真空下濃縮，以得到粗產物，其藉由HPLC(2-10min 10-50% MeCN+NH3 ，30ml/min(裝載泵4ml MeCN)管柱：TRIART C18 100*20mm)進行純化，以得到(2R,5R)-5-甲基-4-側氧基-2-苯基哌啶-1-甲酸第三丁酯(0.317g，1.10mmol，7.40%產率)。5-Methyl-2-phenylpiperidin-4-one (2.8 g, 14.80 mmol) (prepared as above) and TEA (2.25 g, 22.19 mmol, 3.09 mL) were dissolved in DCM (40 mL) and Di-tert-butyl dicarbonate (3.23 g, 14.80 mmol, 3.40 mL) was added dropwise and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was washed with NaHSO 4 (aq), the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product, which was purified by HPLC (2-10 min 10-50% MeCN+NH 3 , 30ml/min (loading pump 4ml MeCN) column: TRIART C18 100*20mm) for purification to give (2R,5R)-5-methyl-4-oxy-2-phenylpiperidine-1-carboxylic acid Tertiary butyl ester (0.317 g, 1.10 mmol, 7.40% yield).

LCMS(ESI)：[M-tBu+1]+ m/z：計算值289.2；實測值234.2；Rt=3.784minLCMS(ESI): [M-tBu+1] + m/z: Calculated 289.2; Measured 234.2; Rt=3.784min

步驟2：(2R,5R)-4-羥基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5R)-4-hydroxy-5-methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5R)-5-甲基-4-側氧基-2-苯基哌啶-1-甲酸第三丁酯(0.31g，1.07mmol)溶解於MeOH(7mL)中。將反應混合物用冷水冷卻且添加硼氫化鈉(60.79mg，1.61mmol，56.82μL)。將反應混合物在室溫下攪拌隔夜。在真空下移除溶劑。將殘餘物用NH4 Cl(水溶液)稀釋且用DCM(2x20ml)萃取，將DCM經Na2 SO4 乾燥，過濾且在真空下濃縮，以得到呈DM之(2R,5R)-4-羥基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯(0.244g，837.38μmol，78.17%產率)，其不經進一步純化即用於下一步驟。(2R,5R)-3-butyl 5-methyl-4-oxo-2-phenylpiperidine-1-carboxylate (0.31 g, 1.07 mmol) was dissolved in MeOH (7 mL). The reaction mixture was cooled with cold water and sodium borohydride (60.79 mg, 1.61 mmol, 56.82 μL) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was diluted with NH4Cl (aq) and extracted with DCM (2x20ml), the DCM was dried over Na2SO4 , filtered and concentrated in vacuo to give (2R,5R)-4-hydroxy- as DM 5-Methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.244 g, 837.38 μmol, 78.17% yield) was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ 1.50(m,3H),1.35(m,9H),1.71-2.50(m,4H),3.50(m,1H),3.67(m,1H),3.87(m,1H),5.12-5.55(m,1H),7.31(m,5H)。 1 H NMR (400MHz, CDCl 3 ) δ 1.50 (m, 3H), 1.35 (m, 9H), 1.71-2.50 (m, 4H), 3.50 (m, 1H), 3.67 (m, 1H), 3.87 (m , 1H), 5.12-5.55 (m, 1H), 7.31 (m, 5H).

LCMS(ESI)：[M+Na]+ m/z：計算值314.2；實測值291.2；Rt=3.635minLCMS(ESI): [M+Na] + m/z: Calculated 314.2; Found 291.2; Rt=3.635min

步驟3：(2R,5R)-5-甲基-2-苯基哌啶-4-醇之合成Step 3: Synthesis of (2R,5R)-5-methyl-2-phenylpiperidin-4-ol

將(2R,5R)-4-羥基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯(0.244g， 837.38μmol)溶解於二噁烷/HCl(7mL)中且攪拌4h。將反應混合物在真空下濃縮，以得到呈DM之(2R,5R)-5-甲基-2-苯基哌啶-4-醇(0.19g，834.32μmol，99.63%產率，HCl)，其不經進一步純化即用於下一步驟。(2R,5R)-4-hydroxy-5-methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.244 g, 837.38 μmol) was dissolved in dioxane/HCl (7 mL) and stirred for 4 h. The reaction mixture was concentrated in vacuo to give (2R,5R)-5-methyl-2-phenylpiperidin-4-ol as DM (0.19 g, 834.32 μmol, 99.63% yield, HCl) as DM Used in the next step without further purification.

1 H NMR(500MHz,DMSO)δ 0.91-1.02(m,3H),1.83-2.30(m,3H),2.73(q,1H),2.97-3.21(m,2H),4.39(m,1H),7.40-7.50(m,5H),9.13-9.47(m,2H) 1 H NMR(500MHz, DMSO)δ 0.91-1.02(m,3H), 1.83-2.30(m,3H), 2.73(q,1H), 2.97-3.21(m,2H), 4.39(m,1H), 7.40-7.50(m,5H),9.13-9.47(m,2H)

LCMS(ESI)：[M+1]+ m/z：計算值191.2；實測值192.4；Rt=1.023minLCMS(ESI): [M+1] + m/z: Calculated 191.2; Measured 192.4; Rt=1.023min

3K. 外消旋 -(2R,5R )-5-氟-5-甲基-2-苯基哌啶之合成 3K. Synthesis of racemic- ( 2R,5R )-5-fluoro-5-methyl-2-phenylpiperidine

Figure 110128222-A0202-12-0585-708
Figure 110128222-A0202-12-0585-708

上文給出1-苯甲基-5-甲基-2-苯基哌啶-4-酮之製備。The preparation of 1-benzyl-5-methyl-2-phenylpiperidin-4-one is given above.

步驟1：外消旋-(2R,5R)-1-苯甲基-5-甲基-2-苯基哌啶-4-醇之合成Step 1: Synthesis of Racemic-(2R,5R)-1-benzyl-5-methyl-2-phenylpiperidin-4-ol

將(2R,5R )-1-苯甲基-5-甲基-2-苯基哌啶-4-酮(350.00mg，1.25mmol)溶解於MeOH(7mL)中。將反應混合物用冷水冷卻且添加硼氫化鈉(71.09mg，1.88mmol，66.44μL)。將反應混合物在室溫下攪拌隔夜。在真空下移除溶劑。將殘餘物用NH4 Cl(水溶液)稀釋且用DCM(2x20ml)萃取，將DCM經Na2 SO4 乾燥，過濾且在真空下濃縮，以得到呈DM之(2R,5R )-1-苯甲基-5-甲基-2-苯基哌啶-4-醇(0.28g，995.06μmol，79.43%產率)，其不經進一步純化即用於下一步驟。( 2R,5R )-1-benzyl-5-methyl-2-phenylpiperidin-4-one (350.00 mg, 1.25 mmol) was dissolved in MeOH (7 mL). The reaction mixture was cooled with cold water and sodium borohydride (71.09 mg, 1.88 mmol, 66.44 μL) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was diluted with NH4Cl (aq) and extracted with DCM (2x20ml), the DCM was dried over Na2SO4 , filtered and concentrated in vacuo to give ( 2R,5R )-1-benzyl as DM yl-5-methyl-2-phenylpiperidin-4-ol (0.28 g, 995.06 μmol, 79.43% yield), which was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.94(d,3H),1.47(m,1H),1.70(m,2H),1.96(m,1H),2.09(m,1H),2.76(m,1H),2.88(m,1H),3.24(m,1H),3.76(m,1H),7.25(m,10H),7.45(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.94(d,3H), 1.47(m,1H), 1.70(m,2H), 1.96(m,1H), 2.09(m,1H), 2.76( m, 1H), 2.88 (m, 1H), 3.24 (m, 1H), 3.76 (m, 1H), 7.25 (m, 10H), 7.45 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值281.2；實測值282.2；Rt=1.327min。LCMS (ESI): [M] + m/z: calculated 281.2; found 282.2; Rt=1.327 min.

步驟2：外消旋-(2R,5R)-1-苯甲基-5-氟-5-甲基-2-苯基哌啶之合成Step 2: Synthesis of Racemic-(2R,5R)-1-benzyl-5-fluoro-5-methyl-2-phenylpiperidine

將(2R,5R )-1-苯甲基-5-甲基-2-苯基哌啶-4-醇(0.28g，995.06μmol)、HF(199.07mg，9.95mmol)及SF4 (215.13mg，1.99mmol)在不鏽鋼高壓釜中在70 ℃下加熱12h。反應完成之後，排出氣體產物，將反應混合物倒入冰上且用10% K2 CO3 水溶液中和。將產物用MTBE(3×100mL)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以得到粗產物，其藉由HPLC(2-10min50-60% MeOH/H2 O 30ml/min(裝載泵4ml MeOH)管柱：SunFire 100*19mm，5微米)進行純化，以得到(2R,4S,5R )-1-苯甲基-4-氟-5-甲基-2-苯基哌啶(0.065g，229.37μmol，23.05%產率)及(2R,5R )-1-苯甲基-5-氟-5-甲基-2-苯基哌啶(0.044g，155.27μmol，15.60%產率)。( 2R,5R )-1-benzyl-5-methyl-2-phenylpiperidin-4-ol (0.28 g, 995.06 μmol), HF (199.07 mg, 9.95 mmol) and SF 4 (215.13 mg) were combined , 1.99 mmol) in a stainless steel autoclave at 70 °C for 12 h. After the reaction was complete, the gaseous product was vented, the reaction mixture was poured onto ice and neutralized with 10 % aqueous K2CO3. The product was extracted with MTBE (3 x 100 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product, which was obtained by HPLC (2-10 min 50-60% MeOH/H 2 O 30 ml/min (loading) Pump 4ml MeOH) column: SunFire 100*19mm, 5 microns) for purification to give ( 2R,4S,5R )-1-benzyl-4-fluoro-5-methyl-2-phenylpiperidine ( 0.065 g, 229.37 μmol, 23.05% yield) and ( 2R,5R )-1-benzyl-5-fluoro-5-methyl-2-phenylpiperidine (0.044 g, 155.27 μmol, 15.60% yield) ).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.23(d,3H),1.68(m,2H),1.78(m,2H),2.12(m,1H),2.88(m,2H),3.18(m,1H),3.68(m,1H),7.23(m,6H),7.36(m,2H),7.48(m,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.23(d,3H), 1.68(m,2H), 1.78(m,2H), 2.12(m,1H), 2.88(m,2H), 3.18 (m, 1H), 3.68 (m, 1H), 7.23 (m, 6H), 7.36 (m, 2H), 7.48 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值283.2；實測值284.2；Rt=1.011min。LCMS (ESI): [M] + m/z: calculated 283.2; found 284.2; Rt=1.011 min.

步驟3：外消旋-(2R,5R)-5-氟-5-甲基-2-苯基哌啶之合成Step 3: Synthesis of Racemic-(2R,5R)-5-fluoro-5-methyl-2-phenylpiperidine

將(2R,5R)-1-苯甲基-5-氟-5-甲基-2-苯基哌啶(0.044g，155.27μmol)溶解於MeOH(4mL)中且添加10% Pd/C(0.006g，155.27μmol)且在室溫下用H2 (1atm)氫化36h。透過矽藻土過濾反應混合物且在真空中在45℃下濃縮濾液，以得到(2R,5R )-5-氟-5-甲基-2-苯基哌啶(0.014g，72.44μmol，46.66%產率)，其不經進一步純化即用於下一步驟。(2R,5R)-1-benzyl-5-fluoro-5-methyl-2-phenylpiperidine (0.044 g, 155.27 μmol) was dissolved in MeOH (4 mL) and 10% Pd/C ( 0.006 g, 155.27 μmol) and hydrogenated with H 2 (1 atm) at room temperature for 36 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo at 45 °C to give ( 2R,5R )-5-fluoro-5-methyl-2-phenylpiperidine (0.014 g, 72.44 μmol, 46.66% yield), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.29(d,3H),1.98(m,4H),2.86(m,1H),3.18(m,1H),3.66(m,1H),7.35(m,5H)。LCMS(ESI)：[M]+ m/z：計算值193.2；實測值194.2；Rt=1.143min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.29(d,3H), 1.98(m,4H), 2.86(m,1H), 3.18(m,1H), 3.66(m,1H), 7.35( m, 5H). LCMS (ESI): [M] + m/z: calculated 193.2; found 194.2; Rt=1.143 min.

3L. 外消旋 -(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基哌啶之合成 3L. Synthesis of racemic- ( 2R,5S )-2-(3-chloro-4,5-difluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0586-709
Figure 110128222-A0202-12-0586-709

步驟1：3-氯-4,5-二氟苯甲醯氯之合成Step 1: Synthesis of 3-chloro-4,5-difluorobenzyl chloride

將草醯氯(1.98g，15.58mmol，1.35mL)逐滴添加到3-氯-4,5-二氟苯甲酸(2g，10.39mmol)於DCM(20mL)中之經攪拌之懸浮液中。然後，向其中添加DMF(94.40mg，1.29mmol，0.1mL)且將所得混合物在20℃下攪拌3h。在減壓下移除揮發物。將殘餘物再溶解於己烷(40mL)中，過濾且在真空中濃縮，得到3-氯-4,5-二氟苯甲醯氯(2.1g，9.95mmol，95.82%產率)。Oxalyl chloride (1.98 g, 15.58 mmol, 1.35 mL) was added dropwise to a stirred suspension of 3-chloro-4,5-difluorobenzoic acid (2 g, 10.39 mmol) in DCM (20 mL). Then, DMF (94.40 mg, 1.29 mmol, 0.1 mL) was added thereto and the resulting mixture was stirred at 20 °C for 3 h. The volatiles were removed under reduced pressure. The residue was redissolved in hexanes (40 mL), filtered and concentrated in vacuo to give 3-chloro-4,5-difluorobenzyl chloride (2.1 g, 9.95 mmol, 95.82% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)7.88(s,1H),8.02(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 7.88 (s, 1H), 8.02 (s, 1H).

GCMS：計算值210.2；實測值210.2；Rt=5.122min。GCMS: Calculated 210.2; Found 210.2; Rt=5.122min.

步驟2：3-(3-氯-4,5-三氟苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-(3-chloro-4,5-trifluorobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

在-78℃下，將雙(三甲基矽基)醯胺化鈉(40%於THF中)(9.58g，20.90mmol，10.72mL，40%純度)逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2.12g，9.95mmol)於THF(30mL)中之經預冷卻之溶液中。添加完成之後，將其在同一溫度下攪拌1h。此後，逐滴添加於己烷(8mL)中之3-氯-4,5-二氟苯甲醯氯(2.1g，9.95mmol)溶液，且移除冷卻浴。將所得混合物緩慢升高至20℃且在此溫度下攪拌1h。然後，將其用15%NaHSO4 水溶液(40ml)淬滅且用乙酸乙酯(40ml)萃取。將有機層用20%NaCl水溶液(2x30ml)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，得到3-(3-氯-4,5-二氟苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(3.8g，9.80mmol，98.45%產率)。Sodium bis(trimethylsilyl)amide (40% in THF) (9.58 g, 20.90 mmol, 10.72 mL, 40% pure) was added dropwise to 5-methyl-2 at -78 °C - Pendant oxypiperidine-1-carboxylic acid tert-butyl ester (2.12 g, 9.95 mmol) in a precooled solution in THF (30 mL). After the addition was complete, it was stirred at the same temperature for 1 h. After this time, a solution of 3-chloro-4,5-difluorobenzyl chloride (2.1 g, 9.95 mmol) in hexanes (8 mL) was added dropwise and the cooling bath was removed. The resulting mixture was slowly raised to 20 °C and stirred at this temperature for 1 h. It was then quenched with 15% aqueous NaHSO 4 (40 ml) and extracted with ethyl acetate (40 ml). The organic layer was washed with 20% aqueous NaCl (2 x 30 ml), dried over Na 2 SO 4 and evaporated under reduced pressure to give 3-(3-chloro-4,5-difluorobenzyl)-5-methyl - 3-Butyl 2-Pendoxopiperidine-1-carboxylate (3.8 g, 9.80 mmol, 98.45% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.96(d,3H),1.56(s,9H),2.22(m,4H),3.17(m,1H),3.86(m,1H),7.57(s,1H),7.85(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.96(d,3H), 1.56(s,9H), 2.22(m,4H), 3.17(m,1H), 3.86(m,1H), 7.57( s, 1H), 7.85 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值287.2；實測值288.2；Rt=1.596min。LCMS (ESI): [M-Boc] + m/z: calculated 287.2; found 288.2; Rt=1.596 min.

步驟3：6-(3-氯-4,5-三氟苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-(3-Chloro-4,5-trifluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將3-(3-氯-4,5-二氟苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(3.8g，9.80mmol)溶解於乙酸(20mL)中且逐滴添加30%鹽酸水溶液(23.00g，189.24mmol，20mL，30%純度)。添加完成之後，將所得混合物在100℃下攪拌 5h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(50ml)與EA(20ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至ph

Figure 110128222-A0202-12-0588-559
10且用DCM(2x30ml)萃取。分離DCM溶液，經K2 CO3 乾燥且在減壓下蒸發，得到6-(3-氯-4,5-二氟苯基)-3-甲基-2,3,4,5-四氫吡啶(1.5g，6.16mmol，62.82%產率)。3-(3-Chloro-4,5-difluorobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (3.8 g, 9.80 mmol) was dissolved in acetic acid (20 mL) and 30% aqueous hydrochloric acid (23.00 g, 189.24 mmol, 20 mL, 30% purity) was added dropwise. After the addition was complete, the resulting mixture was stirred at 100 °C for 5 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (50ml) and EA (20ml). The organic layer was separated and discarded. The aqueous layer was basified to pH with 10% NaOH
Figure 110128222-A0202-12-0588-559
10 and extracted with DCM (2x30ml). The DCM solution was separated, dried over K2CO3 and evaporated under reduced pressure to give 6-( 3 -chloro-4,5-difluorophenyl)-3-methyl-2,3,4,5-tetrahydro Pyridine (1.5 g, 6.16 mmol, 62.82% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.96(d,3H),1.36(m,1H),1.68(m,1H),1.91(m,1H),2.48(m,1H),2.68(m,1H),3.26(m,1H),3.99(m,1H),7.54(s,1H),7.61(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.96(d,3H), 1.36(m,1H), 1.68(m,1H), 1.91(m,1H), 2.48(m,1H), 2.68( m, 1H), 3.26 (m, 1H), 3.99 (m, 1H), 7.54 (s, 1H), 7.61 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值243.2；實測值244.2；Rt=1.026min。LCMS (ESI): [M] + m/z: calculated 243.2; found 244.2; Rt=1.026 min.

步驟4：外消旋-(2R,5S)-2-(3-氯-4,5-二氟苯基)-5-甲基哌啶之合成Step 4: Synthesis of racemic-(2R,5S)-2-(3-chloro-4,5-difluorophenyl)-5-methylpiperidine

在15分鐘內，將硼氫化鈉(349.30mg，9.23mmol，326.45μL)分批添加到6-(3-氯-4,5-二氟苯基)-3-甲基-2,3,4,5-四氫吡啶(1.5g，6.16mmol)於MeOH(30mL)中之溶液中。將所得溶液在20℃下攪拌2h。然後，在減壓下移除溶劑且將殘餘物分配於水(30ml)與DCM(30ml)之間。分離有機層，經K2 CO3 乾燥且在真空中蒸發，得到(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基哌啶(1.48g，6.02mmol，97.86%產率)。Sodium borohydride (349.30 mg, 9.23 mmol, 326.45 μL) was added portionwise to 6-(3-chloro-4,5-difluorophenyl)-3-methyl-2,3,4 over 15 minutes , 5-tetrahydropyridine (1.5 g, 6.16 mmol) in MeOH (30 mL). The resulting solution was stirred at 20 °C for 2 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (30ml) and DCM (30ml). The organic layer was separated, dried over K2CO3 and evaporated in vacuo to give ( 2R,5S )-2-( 3 -chloro-4,5-difluorophenyl)-5-methylpiperidine (1.48 g, 6.02 mmol, 97.86% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.86(d,3H),1.12(m,1H),1.41(m,1H),1.82(m,4H),2.36(t,1H),3.11(d,1H),3.56(d,1H),7.08(s,1H),7.19(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.86(d,3H), 1.12(m,1H), 1.41(m,1H), 1.82(m,4H), 2.36(t,1H), 3.11( d, 1H), 3.56 (d, 1H), 7.08 (s, 1H), 7.19 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值245.2；實測值246.2；Rt=0.921min。LCMS (ESI): [M] + m/z: calculated 245.2; found 246.2; Rt=0.921 min.

3M. 外消旋 -2-甲基-5-((2R,5S )-5-甲基哌啶-2-基)苯酚之合成 3M. Synthesis of racemic -2-methyl-5-((2R ,5S )-5-methylpiperidin-2-yl)phenol

Figure 110128222-A0202-12-0588-710
Figure 110128222-A0202-12-0588-710

步驟1：3-(3-甲氧基-4-甲基苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-(3-methoxy-4-methylbenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

向5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(19g，89.09mmol)於THF (350mL)中之經預冷卻之(-78℃)溶液中逐滴添加LiHMDS(189mmol，178mL)。將所得混合物在-78℃下攪拌1h。一次性添加3-甲氧基-4-甲基-苯甲醯氯(16.45g，89.09mmol)之溶液。使反應混合物升溫至室溫且在該溫度下攪拌4h。將反應混合物用NaHSO4 (45g；10%溶液)淬滅且用DCM(3*150ml)萃取。將有機層用水洗滌，經Na2 SO4 乾燥。將DCM蒸發，以得到3-(3-甲氧基-4-甲基苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(38g，粗品)。To a pre-cooled (-78°C) solution of 5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (19 g, 89.09 mmol) in THF (350 mL) was added dropwise LiHMDS ( 189 mmol, 178 mL). The resulting mixture was stirred at -78 °C for 1 h. A solution of 3-methoxy-4-methyl-benzyl chloride (16.45 g, 89.09 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred at this temperature for 4 h. The reaction mixture was quenched with NaHSO4 (45 g; 10% solution) and extracted with DCM (3*150 ml). The organic layer was washed with water, dried over Na2SO4 . The DCM was evaporated to give 3-(3-methoxy-4-methylbenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (38 g, crude) .

1 H NMR(400MHz,CDCl3 )δ(ppm)0.96(d,3H),1.18(m,1H),1.49(s,9H),1.98(m,2H),2.24(s,3H),2.56(m,1H),3.23(m,1H),3.86(s,3H),4.54(m,1H),7.24(m,2H),7.44(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.96(d,3H), 1.18(m,1H), 1.49(s,9H), 1.98(m,2H), 2.24(s,3H), 2.56( m, 1H), 3.23 (m, 1H), 3.86 (s, 3H), 4.54 (m, 1H), 7.24 (m, 2H), 7.44 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值261.4；實測值262.2；Rt=1.443min。LCMS (ESI): [M-Boc] + m/z: calculated 261.4; found 262.2; Rt=1.443 min.

步驟2：2-甲基-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯酚之合成Step 2: Synthesis of 2-methyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenol

將3-(3-甲氧基-4-甲基苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2g，5.53mmol)溶解於乙酸(20mL)中且分批添加溴化氫水溶液(48重量%)(20mL)。添加完成之後，將所得混合物在100℃下攪拌14h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(5ml)與DCM(20ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至ph

Figure 110128222-A0202-12-0589-560
10且用EtOAc(3x30ml)萃取。分離EtOAc溶液，經Na2 SO4 乾燥且在減壓下濃縮，得到2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(400mg，1.97mmol，35.56%產率)。3-(3-Methoxy-4-methylbenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (2 g, 5.53 mmol) was dissolved in acetic acid ( 20 mL) and aqueous hydrogen bromide (48 wt %) (20 mL) was added portionwise. After the addition was complete, the resulting mixture was stirred at 100 °C for 14 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (5ml) and DCM (20ml). The organic layer was separated and discarded. The aqueous layer was basified to pH with 10% NaOH
Figure 110128222-A0202-12-0589-560
10 and extracted with EtOAc (3x30ml). The EtOAc solution was separated, dried over Na 2 SO 4 and concentrated under reduced pressure to give 2-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (400 mg , 1.97 mmol, 35.56% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.96(d,3H),1.38(m,2H),1.69(m,1H),1.86(m,1H),2.24(s,3H),2.51(m,1H),2.70(m,1H),3.19(m,1H),3.94(m,1H),7.02(m,2H),7.33(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.96(d,3H), 1.38(m,2H), 1.69(m,1H), 1.86(m,1H), 2.24(s,3H), 2.51( m, 1H), 2.70 (m, 1H), 3.19 (m, 1H), 3.94 (m, 1H), 7.02 (m, 2H), 7.33 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值203.4；實測值204.2；Rt=0.893min。LCMS (ESI): [M] + m/z: calculated 203.4; found 204.2; Rt=0.893 min.

步驟3：外消旋-2-甲基-5-((2R,5S)-5-甲基哌啶-2-基)苯酚之合成Step 3: Synthesis of racemic-2-methyl-5-((2R,5S)-5-methylpiperidin-2-yl)phenol

在25℃下，向2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(400mg， 1.97mmol)於MeOH(20mL)中之溶液中分批添加硼氫化鈉(74.44mg，1.97mmol，69.57μL)。將所得混合物在25℃下攪拌2h且在真空中蒸發。將殘餘物用氯化氫二噁烷溶液處理。然後蒸發二噁烷。將沉澱用THF洗滌，在真空中乾燥，以得到2-甲基-5-[(2S,5R )-5-甲基-2-哌啶基]苯酚(450mg，1.86mmol，94.60%產率，HCl)。To a solution of 2-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (400 mg, 1.97 mmol) in MeOH (20 mL) at 25 °C Sodium borohydride (74.44 mg, 1.97 mmol, 69.57 μL) was added portionwise. The resulting mixture was stirred at 25 °C for 2 h and evaporated in vacuo. The residue was treated with a solution of hydrogen chloride in dioxane. Dioxane was then evaporated. The precipitate was washed with THF and dried in vacuo to give 2-methyl-5-[( 2S,5R )-5-methyl-2-piperidinyl]phenol (450 mg, 1.86 mmol, 94.60% yield, HCl).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.96(d,3H),1.22(m,1H),1.86(m,4H),2.14(s,3H),2.48(m,1H),2.56(m,1H),3.14(m,1H),5.74(m,1H),6.81(m,1H),7.01(m,1H),7.18(m,1H),9.01(bds,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.96(d,3H), 1.22(m,1H), 1.86(m,4H), 2.14(s,3H), 2.48(m,1H), 2.56( m, 1H), 3.14 (m, 1H), 5.74 (m, 1H), 6.81 (m, 1H), 7.01 (m, 1H), 7.18 (m, 1H), 9.01 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值205.4；實測值206.2；Rt=0.895min。LCMS (ESI): [M] + m/z: calculated 205.4; found 206.2; Rt=0.895 min.

3N. 4-[(2S,5R)-5-甲基-2-哌啶基]-N-(2,2,2-三氟乙基)苯胺 之合成 3N. Synthesis of 4-[(2S,5R)-5-methyl-2-piperidinyl]-N-(2,2,2-trifluoroethyl)aniline

Figure 110128222-A0202-12-0590-711
Figure 110128222-A0202-12-0590-711

步驟1：4-溴苯甲醯氯之合成Step 1: Synthesis of 4-bromobenzyl chloride

將4-溴苯甲酸(20g，99.49mmol)及草醯氯(18.94g，149.24mmol，12.97mL)懸浮於二氯甲烷(200mL)中。然後，分3批向其中添加二甲基甲醯胺(94.40mg，1.29mmol，0.1mL)。將所得混合物在25℃下攪拌2h。當氣體逸出停止時，在減壓下濃縮所得澄清溶液。將殘餘物再溶解於己烷(150mL)中，過濾且在真空中蒸發，得到4-溴苯甲醯氯(21.5g，97.97mmol，98.46%產率)。4-Bromobenzoic acid (20 g, 99.49 mmol) and oxalic chloride (18.94 g, 149.24 mmol, 12.97 mL) were suspended in dichloromethane (200 mL). Then, dimethylformamide (94.40 mg, 1.29 mmol, 0.1 mL) was added thereto in 3 batches. The resulting mixture was stirred at 25 °C for 2 h. When gas evolution ceased, the resulting clear solution was concentrated under reduced pressure. The residue was redissolved in hexanes (150 mL), filtered and evaporated in vacuo to give 4-bromobenzyl chloride (21.5 g, 97.97 mmol, 98.46% yield).

1 H NMR(500MHz,CDCl3 )δ 7.66(d,2H),7.97(d,2H)。 1 H NMR (500 MHz, CDCl 3 ) δ 7.66 (d, 2H), 7.97 (d, 2H).

GCMS：[M+H]+ m/z：計算值219.2；實測值219.9；Rt=5.646min。GCMS: [M+H] + m/z: calculated 219.2; found 219.9; Rt=5.646 min.

步驟2：3-(4-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-(4-Bromobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

在-78℃下，將LiHMDS(20%於THF/乙苯中)(172.12g，205.73mmol， 194.05mL，20%純度)逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(20.89g，97.97mmol)於四氫呋喃(150mL)中之經預冷卻之溶液中。添加完成之後，將其在同一溫度下攪拌1h。此後，一次性添加4-溴苯甲醯氯(21.5g，97.97mmol)且移除冷卻浴。將所得混合物緩慢升高至20℃且在此溫度下攪拌1h。然後，將其用15%NaHSO4 水溶液(250mL)淬滅且用乙酸乙酯(300mL)萃取。將有機層用20%NaCl水溶液(2* 250mL)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，得到3-(4-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(41.7g，粗品)。LiHMDS (20% in THF/ethylbenzene) (172.12 g, 205.73 mmol, 194.05 mL, 20% purity) was added dropwise to 5-methyl-2-pendoxopiperidine-1 at -78°C - tert-butyl formate (20.89 g, 97.97 mmol) in a precooled solution in tetrahydrofuran (150 mL). After the addition was complete, it was stirred at the same temperature for 1 h. After this time, 4-bromobenzyl chloride (21.5 g, 97.97 mmol) was added in one portion and the cooling bath was removed. The resulting mixture was slowly raised to 20 °C and stirred at this temperature for 1 h. It was then quenched with 15% aqueous NaHSO 4 (250 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 20% aqueous NaCl (2 * 250 mL), dried over Na2SO4 and evaporated under reduced pressure to give 3-( 4 -bromobenzyl)-5-methyl-2-oxo tert-butyl piperidine-1-carboxylate (41.7 g, crude).

1 H NMR(400MHz,CDCl3 )δ 1.12(m,3H),1.62(s,9H),1.87(m,3H),3.14(m,1H),3.82(m,1H),4.46(m,1H),7.18(d,1H),7.54(d,1H),7.66(d,1H),7.82(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.12(m,3H), 1.62(s,9H), 1.87(m,3H), 3.14(m,1H), 3.82(m,1H), 4.46(m,1H) ), 7.18(d, 1H), 7.54(d, 1H), 7.66(d, 1H), 7.82(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.1；實測值396.0；Rt=1.363min。LCMS (ESI): [M+H] + m/z: calculated 395.1; found 396.0; Rt=1.363 min.

步驟3：6-(4-溴苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-(4-Bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將3-(4-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(40.4g，101.95mmol)溶解於乙酸(300mL)中且分批添加30% w/w鹽酸水溶液(345.00g，2.84mol，300mL，30%純度)(小心！會形成泡沫)。添加完成之後，將所得混合物在100℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(500mL)與DCM(400mL)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至pH 10且用DCM(2* 200mL)萃取。分離DCM溶液，經K2 CO3 乾燥且在減壓下蒸發，得到6-(4-溴苯基)-3-甲基-2,3,4,5-四氫吡啶(17.2g，68.21mmol，66.91%產率)。3-(4-Bromobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (40.4 g, 101.95 mmol) was dissolved in acetic acid (300 mL) and batched Add 30% w/w aqueous hydrochloric acid (345.00 g, 2.84 mol, 300 mL, 30% purity) (be careful! foam will form). After the addition was complete, the resulting mixture was stirred at 100 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (500 mL) and DCM (400 mL). The organic layer was separated and discarded. The aqueous layer was basified to pH 10 with 10% NaOH and extracted with DCM (2 * 200 mL). The DCM solution was separated, dried over K2CO3 and evaporated under reduced pressure to give 6-( 4 -bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (17.2 g, 68.21 mmol , 66.91% yield).

1 H NMR(400MHz,CDCl3 )δ0.97(m,3H),1.35(m,1H),1.69(m,1H),1.89(m,1H),2.52(m,1H),2.70(m,1H),3.22(m,1H),3.96(m,1H),7.48(d,2H),7.62(d,2H)。 1 H NMR (400MHz, CDCl 3 )δ0.97(m,3H), 1.35(m,1H), 1.69(m,1H), 1.89(m,1H), 2.52(m,1H), 2.70(m, 1H), 3.22 (m, 1H), 3.96 (m, 1H), 7.48 (d, 2H), 7.62 (d, 2H).

LCMS(ESI)：[M+3H]+ m/z：計算值251.1；實測值254.0；Rt=0.864min。LCMS (ESI): [M+3H] + m/z: calculated 251.1; found 254.0; Rt=0.864 min.

步驟4：外消旋-(2R,5S)-2-(4-溴苯基)-5-甲基哌啶之合成Step 4: Synthesis of Racemic-(2R,5S)-2-(4-bromophenyl)-5-methylpiperidine

在15分鐘內，將硼氫化鈉(2.58g，68.21mmol，2.41mL)分批添加到6-(4-溴苯基)-3-甲基-2,3,4,5-四氫吡啶(17.2g，68.21mmol)於甲醇(250mL)中之溶 液中。將所得溶液在20℃下攪拌2h。然後，在減壓下移除溶劑且將殘餘物分配於水(100mL)與DCM(200mL)之間。分離有機層，經Na2 SO4 乾燥且在真空中蒸發，得到外消旋-(2R,5S)-2-(4-溴苯基)-5-甲基哌啶(17.3g，68.07mmol，99.78%產率)。其含有12%順式-雜質。Sodium borohydride (2.58 g, 68.21 mmol, 2.41 mL) was added portionwise to 6-(4-bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine ( 17.2 g, 68.21 mmol) in methanol (250 mL). The resulting solution was stirred at 20 °C for 2 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (100 mL) and DCM (200 mL). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to give rac-(2R,5S)-2-(4-bromophenyl)-5-methylpiperidine (17.3 g, 68.07 mmol, 99.78% yield). It contains 12% cis-impurity.

1 H NMR(500MHz,CDCl3 )δ 0.90(m,3H),1.15(m,2H),1.48(m,1H),1.59(m,1H),1.65(m,1H),1.86(m,1H),2.41(t,1H),3.13(m,1H),3.51(m,1H),7.24(m,2H),7.43(d,2H)。 1 H NMR (500MHz, CDCl 3 )δ 0.90 (m, 3H), 1.15 (m, 2H), 1.48 (m, 1H), 1.59 (m, 1H), 1.65 (m, 1H), 1.86 (m, 1H) ), 2.41(t, 1H), 3.13(m, 1H), 3.51(m, 1H), 7.24(m, 2H), 7.43(d, 2H).

LCMS(ESI)：[M+3H]+ m/z：計算值253.1；實測值256.0；Rt=0.821min。LCMS (ESI): [M+3H] + m/z: calculated 253.1; found 256.0; Rt=0.821 min.

步驟5：(2R,5S)-2-(4-溴苯基)-5-甲基哌啶1-甲酸第三丁酯之合成Step 5: Synthesis of tert-butyl (2R,5S)-2-(4-bromophenyl)-5-methylpiperidine 1-carboxylate

將(2R,5S)-2-(4-溴苯基)-5-甲基哌啶(17.3g，68.07mmol)溶解於二氯甲烷(250mL)中且逐滴添加二碳酸二-第三丁酯(15.15g，69.43mmol，15.93mL)(劇烈氣體逸出！)。將所得混合物在25℃下攪拌4h。然後，在減壓下移除揮發物，得到(2R,5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(24.3g，粗品)。(2R,5S)-2-(4-bromophenyl)-5-methylpiperidine (17.3 g, 68.07 mmol) was dissolved in dichloromethane (250 mL) and di-tert-butyldicarbonate was added dropwise Ester (15.15 g, 69.43 mmol, 15.93 mL) (vigorous gas evolution!). The resulting mixture was stirred at 25 °C for 4 h. Then, the volatiles were removed under reduced pressure to give tert-butyl (2R,5S)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylate (24.3 g, crude).

1 H NMR(500MHz,CDCl3 )δ 1.05(d,3H),1.29(m,1H),1.45(s,9H),1.58(m,1H),1.83(m,1H),1.97(m,1H),2.12(m,1H),2.97(d,1H),3.72(d,1H),5.26(m,1H),7.12(d,2H),7.45(d,2H)。 1 H NMR (500MHz, CDCl 3 )δ 1.05(d,3H), 1.29(m,1H), 1.45(s,9H), 1.58(m,1H), 1.83(m,1H), 1.97(m,1H) ), 2.12(m, 1H), 2.97(d, 1H), 3.72(d, 1H), 5.26(m, 1H), 7.12(d, 2H), 7.45(d, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值253.2；實測值256.0；Rt=1.691min。LCMS (ESI): [M-Boc] + m/z: calculated 253.2; found 256.0; Rt=1.691 min.

步驟6：(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]哌啶-1-甲酸第三丁酯之合成Step 6: Synthesis of (2S,5R)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]piperidine-1-carboxylic acid tert-butyl ester

將(2S,5R)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(1.6g，4.52mmol)、2,2,2-三氟乙胺(1.57g，15.81mmol，l.25mL)及第三丁醇鈉(651.01mg，6.77mmol)一起混合在甲苯(15mL)中。將反應燒瓶簡單抽真空且用氬氣再填充且在氬氣流下添加PdG3XPhos(191.14mg，225.81μmol)及XPhos(107.65mg，225.81μmol)。將所得混合物在100℃下在密封容器中攪拌16h。然後，將其冷卻至室溫且倒入10%NH4 Cl水溶液(10ml)中。將所獲得之混合物用乙酸乙酯(20ml) 萃取。將有機層分離且用Pd-清除劑(0.5g)處理3h。經Na2 SO4 乾燥之後，在減壓下移除溶劑，得到(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]哌啶-1-甲酸第三丁酯(1.85g，粗品)。Combine (2S,5R)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.6 g, 4.52 mmol), 2,2,2-trifluoroethylamine ( 1.57 g, 15.81 mmol, 1.25 mL) and sodium tert-butoxide (651.01 mg, 6.77 mmol) were mixed together in toluene (15 mL). The reaction flask was briefly evacuated and refilled with argon and PdG3XPhos (191.14 mg, 225.81 μmol) and XPhos (107.65 mg, 225.81 μmol) were added under argon flow. The resulting mixture was stirred at 100 °C in a sealed vessel for 16 h. It was then cooled to room temperature and poured into 10% aqueous NH4Cl (10 ml). The obtained mixture was extracted with ethyl acetate (20 ml). The organic layer was separated and treated with Pd-scavenger (0.5 g) for 3 h. After drying over Na 2 SO 4 , the solvent was removed under reduced pressure to give (2S,5R)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]piperidine 3-butyl pyridine-1-carboxylate (1.85 g, crude).

1 H NMR(400MHz,CDCl3 )δ 0.75(m,1H),1.01(d,3H),1.26(m,2H),1.44(s,9H),1.76(m,2H),2.04(m,2H),2.90(m,1H),3.72(m,2H),5.25(m,1H),6.64(d,2H),7.04(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ 0.75(m, 1H), 1.01(d, 3H), 1.26(m, 2H), 1.44(s, 9H), 1.76(m, 2H), 2.04(m, 2H) ), 2.90(m, 1H), 3.72(m, 2H), 5.25(m, 1H), 6.64(d, 2H), 7.04(m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值272.2；實測值273.2；Rt=1.621min。LCMS (ESI): [M-Boc] + m/z: calculated 272.2; found 273.2; Rt=1.621 min.

步驟7：4-[(2S,5R)-5-甲基-2-哌啶基]-N-(2,2,2-三氟乙基)苯胺之合成Step 7: Synthesis of 4-[(2S,5R)-5-methyl-2-piperidinyl]-N-(2,2,2-trifluoroethyl)aniline

將(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]哌啶-1-甲酸第三丁酯(1.85g，4.97mmol)溶解於二氯甲烷(20mL)中且添加於二噁烷中之4.0M氯化氫溶液(18.11g，49.67mmol，17.93mL，10%純度)。將所得混合物在25℃下攪拌15h，且在減壓下濃縮。將殘餘物用乙酸乙酯(25ml)研磨。將所獲得之灰色沉澱過濾且乾燥，得到4-[(2S,5R)-5-甲基-2-哌啶基]-N-(2,2,2-三氟乙基)苯胺(1.2g，3.48mmol，69.97%產率，2HCl)。(2S,5R)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.85 g, 4.97 mmol) Dissolve in dichloromethane (20 mL) and add a 4.0 M solution of hydrogen chloride in dioxane (18.11 g, 49.67 mmol, 17.93 mL, 10% purity). The resulting mixture was stirred at 25 °C for 15 h and concentrated under reduced pressure. The residue was triturated with ethyl acetate (25 ml). The obtained grey precipitate was filtered and dried to give 4-[(2S,5R)-5-methyl-2-piperidinyl]-N-(2,2,2-trifluoroethyl)aniline (1.2 g , 3.48 mmol, 69.97% yield, 2HCl).

1 H NMR(400MHz,DMSO-d6 )δ 0.87(m,1H),1.05(d,3H),1.49(m,1H),1.75(m,2H),1.97(m,2H),2.83(m,1H),3.09(m,1H),3.88(m,2H),4.04(m,1H),5.74(s,1H),6.71(d,2H),7.26(d,2H),8.53(m,1H),9.43(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.87(m, 1H), 1.05(d, 3H), 1.49(m, 1H), 1.75(m, 2H), 1.97(m, 2H), 2.83(m ,1H),3.09(m,1H),3.88(m,2H),4.04(m,1H),5.74(s,1H),6.71(d,2H),7.26(d,2H),8.53(m, 1H), 9.43 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值272.2；實測值273.2；Rt=0.967min。LCMS (ESI): [M+H] + m/z: calculated 272.2; found 273.2; Rt=0.967 min.

3O.N,N-二甲基-2-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]乙醯胺之合成 3O. Synthesis of N,N-dimethyl-2-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]acetamide

Figure 110128222-A0202-12-0593-712
Figure 110128222-A0202-12-0593-712

步驟1：(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: (2S,5R)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]-5-methylpiperidine-1-carboxylic acid Synthesis of tertiary butyl ester

將(2S,5R)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(1.5g，4.23mmol)(如上文所示製備)、2-胺基-N,N-二甲基乙醯胺(475.68mg，4.66mmol，HCl)及第三丁醇鈉(1.02g，10.58mmol)一起混合在甲苯(20mL)中。將反應燒瓶抽真空且用氬氣再填充3次且在氬氣流下添加PdG3XPhos(179.19mg，211.70μmol)及XPhos(100.92mg，211.70μmol)。將所得混合物在100℃下攪拌16h。然後，將其冷卻至室溫且倒入10%NH4 Cl水溶液(15ml)中。將所獲得之混合物用乙酸乙酯(25ml)萃取。將有機層分離且用Pd-清除劑(0.5g)處理3h。經Na2 SO4 乾燥之後，在減壓下移除溶劑，得到(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(1.58g，4.21mmol，99.38%產率)。Combine (2S,5R)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.23 mmol) (prepared as above), 2-amino -N,N-Dimethylacetamide (475.68 mg, 4.66 mmol, HCl) and sodium tert-butoxide (1.02 g, 10.58 mmol) were mixed together in toluene (20 mL). The reaction flask was evacuated and refilled 3 times with argon and PdG3XPhos (179.19 mg, 211.70 μmol) and XPhos (100.92 mg, 211.70 μmol) were added under argon flow. The resulting mixture was stirred at 100 °C for 16 h. It was then cooled to room temperature and poured into 10% aqueous NH4Cl (15 ml). The obtained mixture was extracted with ethyl acetate (25 ml). The organic layer was separated and treated with Pd-scavenger (0.5 g) for 3 h. After drying over Na 2 SO 4 , the solvent was removed under reduced pressure to give (2S,5R)-2-[4-[[2-(dimethylamino)-2- pendant oxyethyl]amino] Phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.58 g, 4.21 mmol, 99.38% yield).

1 H NMR(400MHz,CDCl3 )δ 1.01(m,4H),1.28(m,3H),1.44(s,9H),1.77(m,3H),2.35(m,1H),2.95(m,2H),3.01(s,3H),3.67(m,1H),3.84(m,2H),5.26(m,1H),6.62(d,1H),7.03(m,1H),7.14(m,1H),7.22(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.01 (m, 4H), 1.28 (m, 3H), 1.44 (s, 9H), 1.77 (m, 3H), 2.35 (m, 1H), 2.95 (m, 2H) ), 3.01(s, 3H), 3.67(m, 1H), 3.84(m, 2H), 5.26(m, 1H), 6.62(d, 1H), 7.03(m, 1H), 7.14(m, 1H) , 7.22 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值275.2；實測值276.2；Rt=1.392min。LCMS (ESI): [M-Boc] + m/z: calculated 275.2; found 276.2; Rt=1.392 min.

步驟2：N,N-三甲基-2-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]乙醯胺之合成Step 2: Synthesis of N,N-trimethyl-2-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]acetamide

將(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(1.58g，4.21mmol)溶解於二氯甲烷(15mL)中且添加於二噁烷中之4.0M氯化氫溶液(15.34g，42.08mmol，15.19mL，10%純度)。將所得混合物在25℃下攪拌15h，且在減壓下濃縮。將殘餘物用乙酸乙酯(20ml)研磨。將所獲得之灰色沉澱過濾且乾燥，得到N,N-二甲基-2-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]乙醯胺(1.2g，3.45mmol，81.88%產率，2HCl)。(2S,5R)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]-5-methylpiperidine-1-carboxylic acid 3 The butyl ester (1.58 g, 4.21 mmol) was dissolved in dichloromethane (15 mL) and a 4.0 M solution of hydrogen chloride in dioxane (15.34 g, 42.08 mmol, 15.19 mL, 10% pure) was added. The resulting mixture was stirred at 25 °C for 15 h and concentrated under reduced pressure. The residue was triturated with ethyl acetate (20 ml). The grey precipitate obtained was filtered and dried to give N,N-dimethyl-2-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]acetamide (1.2 g, 3.45 mmol, 81.88% yield, 2HCl).

1 H NMR(400MHz,DMSO-d6 )δ 0.93(d,3H),1.17(m,2H),1.98(m,2H),2.65(m,1H),2.87(s,3H),3.14(s,3H),3.98(m,2H),4.52(m,1H),6.82(d,2H),7.35(d,2H),7.71(m,1H),9.13(m,1H),9.35(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.93(d,3H), 1.17(m,2H), 1.98(m,2H), 2.65(m,1H), 2.87(s,3H), 3.14(s ,3H),3.98(m,2H),4.52(m,1H),6.82(d,2H),7.35(d,2H),7.71(m,1H),9.13(m,1H),9.35(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值275.2；實測值276.2；Rt=0.842min。LCMS (ESI): [M+H] + m/z: calculated 275.2; found 276.2; Rt=0.842 min.

3P.1-甲基-3-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]吡咯啶-2-酮之合成 3P. Synthesis of 1-methyl-3-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]pyrrolidin-2-one

Figure 110128222-A0202-12-0595-713
Figure 110128222-A0202-12-0595-713

步驟1：(2S,5R)-5-甲基-2-[4-[(1-甲基-2-側氧基-吡咯啶-3-基)胺基]苯基]哌啶-1-甲酸第三丁酯之合成Step 1: (2S,5R)-5-Methyl-2-[4-[(1-methyl-2-oxy-pyrrolidin-3-yl)amino]phenyl]piperidine-1- Synthesis of tert-butyl formate

將(2S,5R)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(1.5g，4.23mmol)(如上文所述製備)、3-胺基-1-甲基-吡咯啶-2-酮(531.61mg，4.66mmol，HCl)及第三丁醇鈉(1.02g，10.58mmol)一起混合在甲苯(20mL)中。將反應燒瓶抽真空且用氬氣再填充3次且在氬氣流下添加PdG3XPhos(179.19mg，211.70μmol)及XPhos(100.92mg，211.70μmol)。將所得混合物在100℃下攪拌16h。然後，將其冷卻至室溫且倒入10%NH4 Cl水溶液(15ml)中。將所獲得之混合物用乙酸乙酯(25ml)萃取。將有機層分離且用Pd-清除劑(0.5g)處理3h。經Na2 SO4 乾燥之後，在減壓下移除溶劑，得到(2S,5R)-5-甲基-2-[4-[(1-甲基-2-側氧基-吡咯啶-3-基)胺基1苯基]哌啶-1-甲酸第三丁酯(1.66g，粗品)。Combine (2S,5R)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.23 mmol) (prepared as described above), 3-amino -1-Methyl-pyrrolidin-2-one (531.61 mg, 4.66 mmol, HCl) and sodium tert-butoxide (1.02 g, 10.58 mmol) were mixed together in toluene (20 mL). The reaction flask was evacuated and refilled 3 times with argon and PdG3XPhos (179.19 mg, 211.70 μmol) and XPhos (100.92 mg, 211.70 μmol) were added under argon flow. The resulting mixture was stirred at 100 °C for 16 h. It was then cooled to room temperature and poured into 10% aqueous NH4Cl (15 ml). The obtained mixture was extracted with ethyl acetate (25 ml). The organic layer was separated and treated with Pd-scavenger (0.5 g) for 3 h. After drying over Na 2 SO 4 , the solvent was removed under reduced pressure to give (2S,5R)-5-methyl-2-[4-[(1-methyl-2-oxo-pyrrolidine-3 -yl)aminolphenyl]piperidine-l-carboxylic acid tert-butyl ester (1.66 g, crude).

1 H NMR(400MHz,CDCl3 )δ 1.01(m,4H),1.28(m,4H),1.44(s,9H),2.02(m,4H),2.66(m,1H),2.92(s,3H),3.39(m,1H),3.69(m,1H),3.90(m,1H),5.22(m,1H),6.64(d,1H),7.05(m,2H),7.15(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.01 (m, 4H), 1.28 (m, 4H), 1.44 (s, 9H), 2.02 (m, 4H), 2.66 (m, 1H), 2.92 (s, 3H) ), 3.39(m, 1H), 3.69(m, 1H), 3.90(m, 1H), 5.22(m, 1H), 6.64(d, 1H), 7.05(m, 2H), 7.15(m, 1H) .

LCMS(ESI)：[M-Boc]+ m/z：計算值287.2；實測值288.2；Rt=1.381min。LCMS (ESI): [M-Boc] + m/z: calculated 287.2; found 288.2; Rt=1.381 min.

步驟2：1-甲基-3-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]吡咯啶-2-酮之合成Step 2: Synthesis of 1-methyl-3-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]pyrrolidin-2-one

將(2S,5R)-5-甲基-2-[4-[(1-甲基-2-側氧基-吡咯啶-3-基)胺基]苯基]哌啶-1-甲酸第三丁酯(1.66g，4.28mmol)溶解於二氯甲烷(20mL)中且添加於二噁烷中之4.0M氯化氫溶液(15.62g，42.84mmol，15.46mL，10%純度)。將所得混合物在25℃下攪拌15h，且在減壓下濃縮。將殘餘物用乙酸乙酯(25ml)研磨。將 所獲得之灰色沉澱過濾且乾燥，得到1-甲基-3-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]吡咯啶-2-酮(1.24g，3.44mmol，80.34%產率，2HCl)。(2S,5R)-5-methyl-2-[4-[(1-methyl-2-oxy-pyrrolidin-3-yl)amino]phenyl]piperidine-1-carboxylic acid Tributyl ester (1.66 g, 4.28 mmol) was dissolved in dichloromethane (20 mL) and a 4.0 M solution of hydrogen chloride in dioxane (15.62 g, 42.84 mmol, 15.46 mL, 10% pure) was added. The resulting mixture was stirred at 25 °C for 15 h and concentrated under reduced pressure. The residue was triturated with ethyl acetate (25 ml). Will The grey precipitate obtained was filtered and dried to give 1-methyl-3-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]pyrrolidin-2-one (1.24 g , 3.44 mmol, 80.34% yield, 2HCl).

1 H NMR(400MHz,DMSO-d6 )δ 0.87(d,3H),1.07(m,2H),1.94(m,2H),2.56(m,2H),2.73(s,3H),3.09(m,2H),3.27(m,2H),3.52(s,2H),4.08(m,1H),5.62(m,1H),6.72(d,2H),7.39(d,2H),9.10(m,1H),9.38(m,1H),9.78(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.87(d,3H), 1.07(m,2H), 1.94(m,2H), 2.56(m,2H), 2.73(s,3H), 3.09(m ,2H),3.27(m,2H),3.52(s,2H),4.08(m,1H),5.62(m,1H),6.72(d,2H),7.39(d,2H),9.10(m, 1H), 9.38 (m, 1H), 9.78 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值287.2；實測值288.2；Rt=0.847min。LCMS (ESI): [M+H] + m/z: calculated 287.2; found 288.2; Rt=0.847 min.

3Q.N,N-二甲基-2-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]丙醯胺之合成 3Q. Synthesis of N,N-dimethyl-2-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]propionamide

Figure 110128222-A0202-12-0596-714
Figure 110128222-A0202-12-0596-714

步驟1：(2S,5R)-2-[4-[[2-(二甲胺基)-1-甲基-2-側氧基乙基]胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: (2S,5R)-2-[4-[[2-(dimethylamino)-1-methyl-2-oxyethyl]amino]phenyl]-5-methylpiperidine Synthesis of tert-butyl pyridine-1-carboxylate

將(2S,5R)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(820mg，2.31mmol)(如上文所述製備)、(2S)-2-胺基-N,N-二甲基丙醯胺(388.58mg，2.55mmol，HCl)及第三丁醇鈉(556.07mg，5.79mmol)一起混合在甲苯(15mL)中。將反應燒瓶抽真空且用氬氣再填充3次且在氬氣流下添加PdG3XPhos(97.96mg，115.73μmol)及XPhos(55.17mg，115.73μmol)。將所得混合物在100℃下攪拌16h。然後，將其冷卻至室溫且倒入10%NH4 Cl水溶液(10ml)中。將所獲得之混合物用乙酸乙酯(20ml)萃取。將有機層分離且用Pd-清除劑(0.5g)處理3h。經Na2 SO4 乾燥之後，在減壓下移除溶劑，得到(2S,5R)-2-[4-[[2-(二甲胺基)-1-甲基-2-側氧基乙基]胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(940mg，粗品)。Combine (2S,5R)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (820 mg, 2.31 mmol) (prepared as above), (2S)-2 -Amino-N,N-dimethylpropionamide (388.58 mg, 2.55 mmol, HCl) and sodium tert-butoxide (556.07 mg, 5.79 mmol) were mixed together in toluene (15 mL). The reaction flask was evacuated and refilled 3 times with argon and PdG3XPhos (97.96 mg, 115.73 μmol) and XPhos (55.17 mg, 115.73 μmol) were added under argon flow. The resulting mixture was stirred at 100 °C for 16 h. It was then cooled to room temperature and poured into 10% aqueous NH4Cl (10 ml). The obtained mixture was extracted with ethyl acetate (20 ml). The organic layer was separated and treated with Pd-scavenger (0.5 g) for 3 h. After drying over Na 2 SO 4 , the solvent was removed under reduced pressure to give (2S,5R)-2-[4-[[2-(dimethylamino)-1-methyl-2-pendoxoethyl (940 mg, crude).

1 H NMR(400MHz,CDCl3 )δ 1.00(d,3H),1.27(m,2H),1.35(m,3H),1.43(s,9H),1.75(m,2H),1.97(m,2H),2.96(m,3H),3.08(s,3H),3.65(m,1H),4.40(m,1H),5.24(m,1H),6.63(d,2H),7.02(d,2H),7.24(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.00(d,3H), 1.27(m,2H), 1.35(m,3H), 1.43(s,9H), 1.75(m,2H), 1.97(m,2H) ), 2.96(m, 3H), 3.08(s, 3H), 3.65(m, 1H), 4.40(m, 1H), 5.24(m, 1H), 6.63(d, 2H), 7.02(d, 2H) , 7.24 (m, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值333.2；實測值334.2；Rt=1.477min。LCMS (ESI): [M-tBu] + m/z: calculated 333.2; found 334.2; Rt=1.477 min.

步驟2：N,N-三甲基-2-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]丙醯胺之合成Step 2: Synthesis of N,N-trimethyl-2-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]propionamide

將(2S,5R)-2-[4-[[2-(二甲胺基)-1-甲基-2-側氧基乙基]胺基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(0.94g，2.41mmol)溶解於二氯甲烷(10mL)中且添加於二噁烷中之4.0M氯化氫溶液(8.80g，24.13mmol，8.71mL，10%純度)。將所得混合物在25℃下攪拌15h，且在減壓下濃縮。將殘餘物用乙酸乙酯(10ml)研磨。 將所獲得之灰色沉澱過濾且乾燥，得到N,N-二甲基-2-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]丙醯胺(0.69g，1.90mmol，78.91%產率，2HCl)。(2S,5R)-2-[4-[[2-(dimethylamino)-1-methyl-2-oxyethyl]amino]phenyl]-5-methylpiperidine- 3-Butyl 1-carboxylate (0.94 g, 2.41 mmol) was dissolved in dichloromethane (10 mL) and a 4.0 M solution of hydrogen chloride in dioxane (8.80 g, 24.13 mmol, 8.71 mL, 10% purity) was added. The resulting mixture was stirred at 25 °C for 15 h and concentrated under reduced pressure. The residue was triturated with ethyl acetate (10 ml). The obtained grey precipitate was filtered and dried to give N,N-dimethyl-2-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]propionamide (0.69 g, 1.90 mmol, 78.91% yield, 2HCl).

1 H NMR(400MHz,DMSO-d6 )δ 0.91(d,3H),1.10(m,1H),1.25(m,4H),1.82(m,3H),2.01(m,2H),2.65(m,1H),2.82(s,3H),3.07(s,3H),3.17(m,1H),3.56(m,1H),4.55(m,1H),6.78(d,2H),7.34(d,2H),9.05(m,1H),9.28(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.91(d,3H), 1.10(m,1H), 1.25(m,4H), 1.82(m,3H), 2.01(m,2H), 2.65(m ,1H),2.82(s,3H),3.07(s,3H),3.17(m,1H),3.56(m,1H),4.55(m,1H),6.78(d,2H),7.34(d, 2H), 9.05 (m, 1H), 9.28 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值289.2；實測值290.2；Rt=0.765min。LCMS (ESI): [M+H] + m/z: calculated 289.2; found 290.2; Rt=0.765 min.

3R.5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成 3R. 5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidinyl]-2-oxygen Synthesis of Acetyl]amino]pyridine-3-carbamoylamine

Figure 110128222-A0202-12-0597-715
Figure 110128222-A0202-12-0597-715

步驟1：(2S,5R)-5-甲基-2-[4-(2-四氫哌喃-2-基吡唑-3-基)苯基]哌啶-1-甲酸第三丁酯之合成Step 1: (2S,5R)-5-methyl-2-[4-(2-tetrahydropyran-2-ylpyrazol-3-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester synthesis

將(2S,5R)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(1.5g，4.23mmol)(如上文所述製備)、1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑(1.30g，4.66mmol)、碳酸鈉(1.35g，12.70mmol，532.11μL)於二噁烷(30mL)及水(5mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加 [1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(172.88mg，211.70μmol)。將所得混合物除氣，用Ar再填充且在90℃下攪拌12h。過濾出沉澱，用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於50ml水中且用EtOAc(2*50ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(2.5g)。藉由梯度層析(己烷-MTBE)純化粗產物，以獲得(2S,5R)-5-甲基-2-[4-(2-四氫哌喃-2-基吡唑-3-基)苯基]啶啶-1-甲酸第三丁酯(0.4g，939.93μmol，22.20%產率)。Combine (2S,5R)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.23 mmol) (prepared as described above), 1-tetrahydro Piran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole (1.30 g, 4.66 mmol) , a suspension of sodium carbonate (1.35 g, 12.70 mmol, 532.11 μL) in dioxane (30 mL) and water (5 mL) was degassed and refilled three times with Ar. To this solution was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (172.88 mg, 211.70 [mu]mol). The resulting mixture was degassed, refilled with Ar and stirred at 90 °C for 12 h. The precipitate was filtered off and washed with dioxane (50 ml). The solvent was evaporated in vacuo and the residue was dissolved in 50 ml of water and extracted with EtOAc (2*50 ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (2.5 g). The crude product was purified by gradient chromatography (hexane-MTBE) to obtain (2S,5R)-5-methyl-2-[4-(2-tetrahydropyran-2-ylpyrazol-3-yl] )phenyl]pyridine-1-carboxylic acid tert-butyl ester (0.4 g, 939.93 μmol, 22.20% yield).

1 H NMR(DMSO-d6,500MHz)：0.91(d,3H),1.31(s,9H),1.47(m,4H),1.72(m,2H),1.99(m,4H),2.31(m,1H),2.90(m,1H),3.47(m,2H),3.90(m,1H),5.07(m,1H),5.13(m,1H),6.24(d,1H),7.21(m,2H),7.38(m,3H), 1 H NMR (DMSO-d6, 500MHz): 0.91 (d, 3H), 1.31 (s, 9H), 1.47 (m, 4H), 1.72 (m, 2H), 1.99 (m, 4H), 2.31 (m, 1H), 2.90(m, 1H), 3.47(m, 2H), 3.90(m, 1H), 5.07(m, 1H), 5.13(m, 1H), 6.24(d, 1H), 7.21(m, 2H) ),7.38(m,3H),

LCMS(ESI)：[M+Na]+ m/z：計算值425.3；實測值448.2；Rt=1.736min。LCMS (ESI): [M+Na] + m/z: calculated 425.3; found 448.2; Rt=1.736 min.

步驟2：(2S,5R)-5-甲基2-[4-(1H-吡唑-5-基)苯基]哌啶之合成Step 2: Synthesis of (2S,5R)-5-methyl 2-[4-(1H-pyrazol-5-yl)phenyl]piperidine

向(2S,5R)-5-甲基-2-[4-(2-四氫哌喃-2-基吡唑-3-基)苯基]哌啶-1-甲酸第三丁酯(0.4g，939.93μmol)於DCM(10mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌24h，且在減壓下蒸發。將殘餘物用1：1 EtOH及MTBE(3ml)研磨且過濾沉澱，以得到(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]哌啶(0.25g，795.54μmol，84.64%產率，2HCl)。To (2S,5R)-5-methyl-2-[4-(2-tetrahydropyran-2-ylpyrazol-3-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.4 g, 939.93 μmol) in DCM (10 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (8.00 g, 219.41 mmol, 10 mL). The resulting mixture was stirred at 25 °C for 24 h and evaporated under reduced pressure. The residue was triturated with 1:1 EtOH and MTBE (3 ml) and the precipitate was filtered to give (2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]piperidine pyridine (0.25 g, 795.54 μmol, 84.64% yield, 2HCl).

1 H NMR(DMSO-d6,400MHz)：0.91(d,3H),1.32(m,2H),1.90(m,3H),2.01(m,2H),2.67(m,1H),3.22(m,1H),4.13(m,2H),6.73(d,1H),7.56(d,1H),7.71(d,1H),7.84(d,1H)。 1 H NMR (DMSO-d6, 400MHz): 0.91 (d, 3H), 1.32 (m, 2H), 1.90 (m, 3H), 2.01 (m, 2H), 2.67 (m, 1H), 3.22 (m, 1H), 4.13 (m, 2H), 6.73 (d, 1H), 7.56 (d, 1H), 7.71 (d, 1H), 7.84 (d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值241.2；實測值242.2；Rt=0.919min。LCMS (ESI): [M+H] + m/z: calculated 241.2; found 242.2; Rt=0.919 min.

3S.外消旋-(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]哌啶之合成 3S. Synthesis of racemic-(2S,5R)-5-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]piperidine

Figure 110128222-A0202-12-0599-716
Figure 110128222-A0202-12-0599-716

步驟1：(2S,5R)-5-甲基-2-[4-(1-四氫哌喃-2-基吡唑-4-基)苯基]哌啶-1-甲酸第三丁酯之合成Step 1: (2S,5R)-5-methyl-2-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester synthesis

將(2S,5R)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(1g，2.82mmol)(如上文所述製備)、1-四氫哌喃-2-基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑(785.13mg，2.82mmol)及碳酸鈉(448.75mg，4.23mmol，177.37μL)一起混合在二噁烷(8mL)及水(2mL)中。將反應燒瓶抽真空且用氬氣再填充3次且在氬氣流下添加PdCl2 *dppf*DCM(92.20mg，112.90μmol)。將所得混合物在90℃下攪拌20h。然後，在減壓下移除溶劑且將殘餘物再溶解於MTBE(30ml)中。透過短矽膠墊過濾此溶液且在真空中蒸發殘餘物，得到(2S,5R)-5-甲基-2-[4-(1-四氫哌喃-2-基吡唑-4-基)苯基]哌啶-1-甲酸第三丁酯(1.49g，粗品)。Combine (2S,5R)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1 g, 2.82 mmol) (prepared as described above), 1-tetrahydropiperidine Pyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole (785.13 mg, 2.82 mmol) and Sodium carbonate (448.75 mg, 4.23 mmol, 177.37 μL) was mixed together in dioxane (8 mL) and water (2 mL). The reaction flask was evacuated and refilled 3 times with argon and PdCl2 *dppf*DCM (92.20 mg, 112.90 μmol) was added under argon flow. The resulting mixture was stirred at 90 °C for 20 h. Then, the solvent was removed under reduced pressure and the residue was redissolved in MTBE (30 ml). The solution was filtered through a short pad of silica gel and the residue was evaporated in vacuo to give (2S,5R)-5-methyl-2-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl) Phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.49 g, crude).

1 H NMR(CDCl3 ,400MHz)：1.02(d,3H),1.04(m,1H),1.17(s,9H),1.43(m,2H),1.61(m,2H),1.69(m,2H),1.81(m,1H),2.03(m,4H),2.99(m,1H),3.71(m,2H),4.06(m,1H),5.40(m,1H),7.22(m,2H),7.43(m,2H),7.79(s,1H),7.82(s,1H)。 1 H NMR (CDCl 3 , 400MHz): 1.02 (d, 3H), 1.04 (m, 1H), 1.17 (s, 9H), 1.43 (m, 2H), 1.61 (m, 2H), 1.69 (m, 2H) ), 1.81(m, 1H), 2.03(m, 4H), 2.99(m, 1H), 3.71(m, 2H), 4.06(m, 1H), 5.40(m, 1H), 7.22(m, 2H) , 7.43(m, 2H), 7.79(s, 1H), 7.82(s, 1H).

LCMS(ESI)：[M+Na]+ m/z：計算值425.3；實測值448.2；Rt=1.679min。LCMS (ESI): [M+Na] + m/z: calculated 425.3; found 448.2; Rt=1.679 min.

步驟2：(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]哌啶)之合成Step 2: Synthesis of (2S,5R)-5-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]piperidine)

將於二噁烷中之4.0M氯化氫溶液(12.75g，34.97mmol，12.62mL，10%純度)添加到(2S,5R)-5-甲基-2-[4-(1-四氫哌喃-2-基吡唑-4-基)苯基]哌啶-1-甲酸第三丁酯(1.49g，3.50mmol)於甲醇(15mL)中之溶液中。將所得混合物在20℃下攪拌15h，且在減壓下濃縮。將殘餘物用乙酸乙酯(25ml)研磨。過濾所得沉 澱，用冰冷的乙醇(15ml)沖洗且乾燥，得到(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]哌啶(580mg，1.85mmol，52.78%產率，2HCl)。A 4.0 M solution of hydrogen chloride in dioxane (12.75 g, 34.97 mmol, 12.62 mL, 10% purity) was added to (2S,5R)-5-methyl-2-[4-(1-tetrahydropyran) -2-ylpyrazol-4-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.49 g, 3.50 mmol) in methanol (15 mL). The resulting mixture was stirred at 20 °C for 15 h and concentrated under reduced pressure. The residue was triturated with ethyl acetate (25 ml). Filtered sink The precipitate was washed with ice cold ethanol (15ml) and dried to give (2S,5R)-5-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]piperidine (580mg, 1.85mmol). , 52.78% yield, 2HCl).

1 H NMR(DMSO-d6,400MHz)：0.91(d,3H),1.08(m,1H),1.29(m,1H),1.89(m,3H),2.02(m,2H),2.63(m,1H),3.18(m,1H),4.17(m,2H),7.52(d,1H),7.62(d,1H),8.08(s,2H),9.23(s,1H),9.42(s,1H)。 1 H NMR (DMSO-d6, 400MHz): 0.91(d,3H), 1.08(m,1H), 1.29(m,1H), 1.89(m,3H), 2.02(m,2H), 2.63(m, 1H), 3.18(m, 1H), 4.17(m, 2H), 7.52(d, 1H), 7.62(d, 1H), 8.08(s, 2H), 9.23(s, 1H), 9.42(s, 1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值241.19實測值242.2；Rt=0.819min。LCMS (ESI): [M+H] + m/z: calculated 241.19 found 242.2; Rt=0.819 min.

3T.外消旋-4-[(2R,5S)-5-甲基-2-哌啶基]苯甲酸甲酯之合成 3T. Synthesis of rac-4-[(2R,5S)-5-methyl-2-piperidinyl]benzoic acid methyl ester

Figure 110128222-A0202-12-0600-717
Figure 110128222-A0202-12-0600-717

步驟1：(2R,5S)-2-(4-甲氧基羰基苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,5S)-2-(4-methoxycarbonylphenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(1.00g，2.82mmol)溶解於甲醇(30mL)中。向其中添加三乙胺(285.62mg，2.82mmol，393.42μL)及PdCl2*dppf*dcm(141.13μmol)。將所得混合物在135℃、CO(30巴)氣氛下攪拌16h。然後，在減壓下蒸發溶劑。將殘餘物用MTBE(50ml)稀釋且透過短矽膠墊過濾。在真空中濃縮濾液，得到(2R,5S)-2-(4-甲氧基羰基苯基)-5-甲基哌啶-1-甲酸第三丁酯。(2R,5S)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.82 mmol) was dissolved in methanol (30 mL). To this were added triethylamine (285.62 mg, 2.82 mmol, 393.42 μL) and PdCl2*dppf*dcm (141.13 μmol). The resulting mixture was stirred at 135°C under CO (30 bar) atmosphere for 16 h. Then, the solvent was evaporated under reduced pressure. The residue was diluted with MTBE (50 ml) and filtered through a short pad of silica gel. The filtrate was concentrated in vacuo to give tert-butyl (2R,5S)-2-(4-methoxycarbonylphenyl)-5-methylpiperidine-1-carboxylate.

1 H NMR(DMSO-d6,500MHz)：0.97(d,3H),1.15(m,1H),1.37(s,9H),1.53(m,1H),1.81(m,1H),2.07(m,2H),2.98(m,1H),3.62(m,1H),3.84(s,3H),5.18(m,1H),7.37(m,2H),7.95(m,2H)。 1 H NMR (DMSO-d6, 500MHz): 0.97(d,3H), 1.15(m,1H), 1.37(s,9H), 1.53(m,1H), 1.81(m,1H), 2.07(m, 2H), 2.98 (m, 1H), 3.62 (m, 1H), 3.84 (s, 3H), 5.18 (m, 1H), 7.37 (m, 2H), 7.95 (m, 2H).

步驟2：4-[(2R,5S)-5-甲基-2-哌啶基]苯甲酸甲酯之合成Step 2: Synthesis of methyl 4-[(2R,5S)-5-methyl-2-piperidinyl]benzoate

將(2R,5S)-2-(4-甲氧基羰基苯基)-5-甲基哌啶-1-甲酸第三丁酯(800.00mg，2.40mmol)於二噁烷/HCl(10mL)中之溶液在20℃下攪拌12h。將所得混合 物蒸發至乾。將殘餘物用碳酸鉀稀釋且用DCM(2*20ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且蒸發，以獲得粗品4-[(2R,5S)-5-甲基-2-哌啶基]苯甲酸甲酯，其不經純化即用於下一步驟。(2R,5S)-2-(4-Methoxycarbonylphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (800.00 mg, 2.40 mmol) in dioxane/HCl (10 mL) The solution was stirred at 20 °C for 12 h. mix the result Evaporate to dryness. The residue was diluted with potassium carbonate and extracted with DCM (2*20ml). The combined organic extracts were dried over sodium sulfate and evaporated to give crude methyl 4-[(2R,5S)-5-methyl-2-piperidinyl]benzoate which was used in the next step without purification one step.

步驟3：4-[(2R,5S)-5-甲基-2-哌啶基]苯甲酸甲酯之合成Step 3: Synthesis of methyl 4-[(2R,5S)-5-methyl-2-piperidinyl]benzoate

在0℃下，將鋁酸鋰(lithium alumanuide)(97.61mg，2.57mmol)添加到4-[(2R,5S)-5-甲基-2-哌啶基]苯甲酸甲酯(300.00mg，1.29mmol)於無水THF中之經攪拌之溶液中且使其升溫至室溫，然後攪拌12h。將反應混合物用飽和硫酸鈉溶液淬滅且攪拌30min。透過矽藻土過濾反應混合物，分離有機層且在真空中濃縮，以獲得[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]甲醇(0.1g，487.10μmol，37.88%產率)。At 0°C, lithium alumanuide (97.61 mg, 2.57 mmol) was added to methyl 4-[(2R,5S)-5-methyl-2-piperidinyl]benzoate (300.00 mg, 1.29 mmol) in a stirred solution of dry THF and allowed to warm to room temperature, then stirred for 12 h. The reaction mixture was quenched with saturated sodium sulfate solution and stirred for 30 min. The reaction mixture was filtered through celite, the organic layer was separated and concentrated in vacuo to give [4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]methanol (0.1 g, 487.10 μmol , 37.88% yield).

1 H NMR(CDCl3 ,400MHz)：0.89(d,3H),1.06(m,2H),1.62(m,2H),1.82(m,2H),2.49(t,1H),3.13(m,1H),3.52(m,1H),3.75(m,1H),4.52(s,2H),7.37(m,2H),7.42(m,2H)。 1 H NMR (CDCl 3 , 400MHz): 0.89 (d, 3H), 1.06 (m, 2H), 1.62 (m, 2H), 1.82 (m, 2H), 2.49 (t, 1H), 3.13 (m, 1H) ), 3.52(m, 1H), 3.75(m, 1H), 4.52(s, 2H), 7.37(m, 2H), 7.42(m, 2H).

3U.2-側氧基-2-(2-苯基-1-哌啶基)乙酸之合成 3U. Synthesis of 2-oxygen-2-(2-phenyl-1-piperidinyl)acetic acid

Figure 110128222-A0202-12-0601-718
Figure 110128222-A0202-12-0601-718

步驟1：2-(5-甲基-2-苯基1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1: Synthesis of 2,2,2-trifluoroethyl 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid

在-10℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(5.43g，28.53mmol)逐滴添加到5-甲基-2-苯基哌啶(5g，28.53mmol)及三乙胺(2.89g，28.53mmol，3.98mL)於THF(50mL)中之溶液中。將所得混合物升溫至室溫且攪拌12h。過濾出所得沉澱。將濾液蒸發，以獲得2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(9g，27.33mmol，95.80%產率)，其不經純化即用於下一步驟。2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (5.43 g, 28.53 mmol) was added dropwise to 5-methyl-2-phenylpiperidine ( 5 g, 28.53 mmol) and triethylamine (2.89 g, 28.53 mmol, 3.98 mL) in THF (50 mL). The resulting mixture was warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered off. The filtrate was evaporated to obtain 2,2,2-trifluoroethyl 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyacetate (9 g, 27.33 mmol, 95.80%) yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.19(m,3H),1.33(m,1H),1.91(m,4H),3.10(m, 2H),5.10(m,3H),7.19(d,1H),7.21(d,1H),7.40(m,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.19(m, 3H), 1.33(m, 1H), 1.91(m, 4H), 3.10(m, 2H), 5.10(m, 3H), 7.19(d , 1H), 7.21 (d, 1H), 7.40 (m, 3H).

LCMS(ESI)：[M+H]+ m/z：計算值329.1；實測值330.1；Rt=1.496min。LCMS (ESI): [M+H] + m/z: calculated 329.1; found 330.1; Rt=1.496 min.

步驟2：2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸之合成Step 2: Synthesis of 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid

將氫氧化鋰(654.50mg，27.33mmol)添加到2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(9g，27.33mmol)於THF(100mL)及水(10mL)中之溶液中。將所得混合物在20℃下攪拌12h。然後，將混合物蒸發至乾，以獲得2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸(5g，19.67mmol，71.96%產率，Li+)，其不經純化即用於下一步驟。Lithium hydroxide (654.50 mg, 27.33 mmol) was added to 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester ( 9 g, 27.33 mmol) in THF (100 mL) and water (10 mL). The resulting mixture was stirred at 20 °C for 12 h. Then, the mixture was evaporated to dryness to obtain 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid (5 g, 19.67 mmol, 71.96% yield, Li+), It was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.13(m,3H),1.30(m,1H),1.63(m,2H),2.01(m,2H),3.56(m,2H),5.04(m,1H),7.16(m,3H),7.32(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.13(m, 3H), 1.30(m, 1H), 1.63(m, 2H), 2.01(m, 2H), 3.56(m, 2H), 5.04(m , 1H), 7.16 (m, 3H), 7.32 (m, 2H).

LCMS(ESI)：酸[M+H]+ m/z：計算值.247.1.1；實測值248.2；Rt=1.133min。LCMS (ESI): acid [M+H] + m/z: calcd. 247.1.1; found 248.2; Rt=1.133 min.

3V.N-(6- 胺基-5-甲基-3-吡 啶基)-2-[(2R,5S)-5-甲基-2-(6- 側氧基-5H-1,5- 萘啶-2-基)-1-哌啶基]-2-側氧基乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯胺之合成 3V. N-(6- amino-5-methyl-3 -pyridyl)-2-[(2R,5S)-5-methyl-2-(6 - oxy-5H-1,5 -Naphthyridin-2 - yl)-1-piperidinyl]-2-oxyacetamide and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S, Synthesis of 5R)-5-methyl-2-(6-oxo-5H-1,5-naphthyridin-2-yl)-1-piperidinyl]-2-oxoacetamide

Figure 110128222-A0202-12-0602-719
Figure 110128222-A0202-12-0602-719

步驟1：3-甲基-6-(4,4,5,5-四甲基-1,3,2-三氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: 3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-trioxaborol-2-yl)-3,4-dihydro- Synthesis of 2H-pyridine-1-carboxylic acid tert-butyl ester

向3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5g，14.5mmol)於二噁烷(30mL)中之混合物中添加B2 pin2 (5.5g，21.7mmol)、PdCl2 (PPh3 )2 (305mg，0.435mmol)、PPh3 (228mg，0.869mmol)及K2 CO3 (3g，21.7mmol)。在85℃、氮氣下將所得混合物攪拌12小時。將反應混合物用H2 O(50 mL)稀釋，用EtOAc(50mL * 3)萃取。將經合併之有機層用鹽水(100mL * 2)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；80g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~10%，流速=45mL/min，I2 )進行純化，以得到呈無色油狀物之3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.6g，98.3%產率)。LCMS(ESI)[M+H]+ m/z：計算值324.2，實測值324.1。To 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 g, 14.5 mmol) in dioxane (30 mL) ) was added B 2 pin 2 (5.5 g, 21.7 mmol), PdCl 2 (PPh 3 ) 2 (305 mg, 0.435 mmol), PPh 3 (228 mg, 0.869 mmol) and K 2 CO 3 (3 g, 21.7 mmol) ). The resulting mixture was stirred at 85°C under nitrogen for 12 hours. The reaction mixture was diluted with H2O (50 mL), extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product, which was purified by flash chromatography ( ISCO® ; 80 g AgelaFlash® II Silica flash column, petroleum ether/EtOAc with 0-10% EtOAc, flow rate = 45 mL/min, I 2 ) was purified to give 3-methyl-6-(4,4 as a colorless oil ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.6g , 98.3% yield). LCMS (ESI) [M+H] + m/z: calcd 324.2, found 324.1.

步驟2：6-.溴-1H-1,5-萘啶-2-酮之合成Step 2: Synthesis of 6-.bromo-1H-1,5-naphthyridin-2-one

向3-(3-胺基-6-溴-2-吡啶基)丙-2-烯酸乙酯(2.2g，8.11mmol)於EtOH(20mL)中之溶液中添加DBU(6.1mL，40.9mmol)。然後在100℃、氮氣下將混合物攪拌16小時。在減壓下濃縮混合物，以得到粗產物，其藉由急驟層析(ISCO® ；40g AgelaFlash® 二氧化矽急驟管柱，DCM/MeOH，其中MeOH為0~0.5%，流速=50mL/min，254nm)進行純化，以得到呈棕色固體之6-溴-1H-1,5-萘啶-2-酮(3.5g，粗品)。LCMS(ESI)[M+H]+ m/z：計算值227.0，實測值227.0。To a solution of 3-(3-amino-6-bromo-2-pyridyl)prop-2-enoic acid ethyl ester (2.2 g, 8.11 mmol) in EtOH (20 mL) was added DBU (6.1 mL, 40.9 mmol) ). The mixture was then stirred at 100°C for 16 hours under nitrogen. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® ; 40 g AgelaFlash® silica flash column, DCM/MeOH with 0-0.5% MeOH, flow rate = 50 mL/min, 254 nm) to give 6-bromo-lH-l,5-naphthyridin-2-one (3.5 g, crude) as a brown solid. LCMS (ESI) [M+H] + m/z: Calculated 227.0, found 227.0.

步驟3：6-溴-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮之合成Step 3: Synthesis of 6-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one

在0℃下，向6-溴-1H-1,5-萘啶-2-酮(3.5g，15.6mmol)於THF(30mL)中之溶液中添加NaH(1.3g，32.5mmol，60重量%於礦物油中)。將混合物在20℃下攪拌0.5小時。添加SEMCl(3.3mL，18.7mmol)，且將混合物在20℃下攪拌12小時。在LCMS上，反應物未完全轉化。在0℃下，添加NaH(1.3g，32.5mmol，60重量%於礦物油中)且將混合物在20℃下攪拌30分鐘。添加SEMCl(3.3mL，18.7mmol)，且將混合物在20℃下攪拌14小時。添加SEMCl(3.3mL，18.7mmol)，且將混合物在20℃下攪拌5小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；24g SepaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~13%，35mL/min，254nm)進行純化，以得到呈白 色固體之6-溴-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(1.92g，34.8%產率)。To a solution of 6-bromo-1H-1,5-naphthyridin-2-one (3.5 g, 15.6 mmol) in THF (30 mL) at 0 °C was added NaH (1.3 g, 32.5 mmol, 60 wt%) in mineral oil). The mixture was stirred at 20°C for 0.5 hour. SEMCl (3.3 mL, 18.7 mmol) was added, and the mixture was stirred at 20°C for 12 hours. On LCMS, the reaction was not completely converted. At 0 °C, NaH (1.3 g, 32.5 mmol, 60 wt% in mineral oil) was added and the mixture was stirred at 20 °C for 30 minutes. SEMCl (3.3 mL, 18.7 mmol) was added, and the mixture was stirred at 20°C for 14 hours. SEMCl (3.3 mL, 18.7 mmol) was added, and the mixture was stirred at 20°C for 5 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® ; 24g SepaFlash® silica flash column, petroleum ether/ EtOAc, where EtOAc was 0~13%, 35 mL/min, 254 nm) was purified to give 6-bromo-1-(2-trimethylsilylethoxymethyl)-1,5- as a white solid Naphthyridin-2-one (1.92 g, 34.8% yield).

1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.97(d,J =8.4Hz,1H),7.91(d,J =9.8Hz,1H),7.74(d,J =8.9Hz,1H),6.92(d,J =9.8Hz,1H),5.76(s,2H),3.65-3.68(m,2H),0.90-0.93(m,2H),0.02(s,9H)；LCMS(ESI)[M+H]+ m/z：計算值357.0，實測值356.9。 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.97 (d, J =8.4 Hz, 1H), 7.91 (d, J =9.8 Hz, 1H), 7.74 (d, J =8.9 Hz, 1H), 6.92 (d, J =9.8Hz,1H),5.76(s,2H),3.65-3.68(m,2H),0.90-0.93(m,2H),0.02(s,9H); LCMS(ESI)[M+ H] + m/z: Calculated 357.0, found 356.9.

步驟4：3-甲基-6-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 4: 3-Methyl-6-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-yl]-3,4- Synthesis of tert-butyl dihydro-2H-pyridine-1-carboxylate

將3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.3g，7.12mmol)、6-溴-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(1.9g，5.35mmol)、Pd(OAc)2 (240mg，1.07mmol)、PPh3 (561mg，2.14mmol)、Cs2 CO3 (3.5g，10.7mmol)、二噁烷(20mL)及H2 O(2mL)之混合物在100℃下攪拌12小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用鹽水(100mL * 2)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；80g SepaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~45%，45mL/min，254nm)進行純化，以得到呈黃色油狀物之3-甲基-6-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(600mg，23.8%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.95-8.09(m,2H),7.60(d,J =8.8Hz,1H),6.91(d,J =9.8Hz,1H),5.81(s,2H),5.75(s,1H),3.99(d,J =9.5Hz,1H),3.71-3.77(m,1H),3.63-3.70(m,2H),2.46-2.57(m,1H),2.02-2.11(m,1H),1.91-2.00(m,1H),1.20(s,9H),1.06(d,J =6.8Hz,3H),0.87-0.92(m,2H),-0.04(s,9H)；LCMS(ESI)[M+H]+ m/z：計算值472.3，實測值472.4。3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-2H- 3-butyl pyridine-1-carboxylate (2.3 g, 7.12 mmol), 6-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one (1.9 g, 5.35 mmol), Pd(OAc) 2 (240 mg, 1.07 mmol), PPh 3 (561 mg, 2.14 mmol), Cs 2 CO 3 (3.5 g, 10.7 mmol), dioxane (20 mL) and H 2 O ( 2 mL) of the mixture was stirred at 100°C for 12 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product, which was purified by flash chromatography ( ISCO® ; 80 g SepaFlash® II Silica flash column, petroleum ether/EtOAc, where EtOAc was 0-45%, 45 mL/min, 254 nm) was purified to give 3-methyl-6-[6-pendoxo- as a yellow oil 5-(2-Trimethylsilylethoxymethyl)-1,5-naphthyridin-2-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (600 mg, 23.8% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.95-8.09 (m, 2H), 7.60 (d, J =8.8Hz, 1H), 6.91 (d, J =9.8Hz, 1H), 5.81 (s, 2H), 5.75(s, 1H), 3.99(d, J =9.5Hz, 1H), 3.71-3.77(m, 1H), 3.63-3.70(m, 2H), 2.46-2.57(m, 1H), 2.02 -2.11(m, 1H), 1.91-2.00(m, 1H), 1.20(s, 9H), 1.06(d, J =6.8Hz, 3H), 0.87-0.92(m, 2H), -0.04(s, 9H); LCMS (ESI) [M+H] + m/z: calcd 472.3, found 472.4.

步驟5：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮之合成Step 5: 6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthalene Synthesis of pyridin-2-ones

向3-甲基-6-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2- 基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(580mg，1.23mmol)於DCM(30mL)中之溶液中添加ZnBr2 (554mg，2.46mmol)。在20℃、氮氣下將混合物攪拌12小時。所得混合物藉由添加水(30mL)來淬滅且用DCM(30mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色固體之6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(650mg，粗品)，其不經進一步純化即直接使用。LCMS(ESI)[M+H]+ m/z：計算值372.2，實測值372.2。to 3-methyl-6-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-yl]-3,4-dihydro To a solution of -2H-pyridine-1-carboxylic acid tert-butyl ester (580 mg, 1.23 mmol) in DCM (30 mL) was added ZnBr2 (554 mg , 2.46 mmol). The mixture was stirred at 20°C under nitrogen for 12 hours. The resulting mixture was quenched by adding water (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 6-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a yellow solid (650 mg, crude), which was used without further purification. LCMS (ESI) [M+H] + m/z: calcd 372.2, found 372.2.

步驟6：6-(5-甲基-2-哌啶基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮之合成Step 6: Synthesis of 6-(5-methyl-2-piperidinyl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one

在0℃下，向6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(600mg，1.61mmol)於MeOH(10mL)中之溶液中添加NaBH4 (92mg，2.43mmol)。將混合物在0℃下攪拌30分鐘。將所得混合物在減壓下濃縮，以得到呈棕色固體之6-(5-甲基-2-哌啶基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(800mg，粗品)，其不經進一步純化即直接使用。LCMS(ESI)[M+H]+ m/z：計算值374.2，實測值374.2。At 0 °C, to 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1-(2-trimethylsilylethoxymethyl)-1, To a solution of 5-naphthyridin-2-one (600 mg, 1.61 mmol) in MeOH ( 10 mL) was added NaBH4 (92 mg, 2.43 mmol). The mixture was stirred at 0°C for 30 minutes. The resulting mixture was concentrated under reduced pressure to give 6-(5-methyl-2-piperidinyl)-1-(2-trimethylsilylethoxymethyl)-1,5 as a brown solid - Naphthyridin-2-one (800 mg, crude), which was used without further purification. LCMS (ESI) [M+H] + m/z: calcd 374.2, found 374.2.

3W.2-環戊基-5-甲基哌啶之合成 3W. Synthesis of 2-cyclopentyl-5-methylpiperidine

Figure 110128222-A0202-12-0605-720
Figure 110128222-A0202-12-0605-720

步驟1：5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate

將二碳酸二-第三丁酯(21.22g，97.21mmol，22.31mL)逐滴添加到5-甲基哌啶-2-酮(10g，88.37mmol)及4-二甲胺基吡啶(539.82mg，4.42mmol)於MeCN(100mL)中之溶液中。將所得溶液在25℃下攪拌12h。然後蒸發溶劑且將所得粗材料用DCM(50ml)稀釋且用飽和碳酸氫鈉溶液(2x100ml)洗滌。將有機相經硫酸鈉乾燥且在減壓下蒸發，以獲得5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(16.5g，77.37mmol，87.54%產率)。Di-tert-butyl dicarbonate (21.22 g, 97.21 mmol, 22.31 mL) was added dropwise to 5-methylpiperidin-2-one (10 g, 88.37 mmol) and 4-dimethylaminopyridine (539.82 mg) , 4.42 mmol) in MeCN (100 mL). The resulting solution was stirred at 25 °C for 12 h. The solvent was then evaporated and the resulting crude material was diluted with DCM (50ml) and washed with saturated sodium bicarbonate solution (2x100ml). The organic phase was dried over sodium sulfate and evaporated under reduced pressure to obtain tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (16.5 g, 77.37 mmol, 87.54% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.99(d,3H),1.39(m,1H),1.49(s,9H),1.89(m,2H),2.48(m,2H),3.09(t,1H),3.75(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.99(d, 3H), 1.39(m, 1H), 1.49(s, 9H), 1.89(m, 2H), 2.48(m, 2H), 3.09( t, 1H), 3.75(d, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值113.2；實測值114.2；Rt=1.223min。LCMS (ESI): [M-Boc] + m/z: calculated 113.2; found 114.2; Rt=1.223 min.

步驟2：(4-環戊基-2-甲基-4-側氧基丁基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl (4-cyclopentyl-2-methyl-4-oxybutyl)carbamate

向鎂(2.26g，92.84mmol，1.30mL)於THF(100mL)中之懸浮液中添加溴環戊烷(14.99g，100.58mmol，10.78mL)。將反應混合物攪拌45min，以得到灰色溶液。將此溶液逐滴轉移至5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(16.5g，77.37mmol)於THF(200mL)中之冷(-78℃)懸浮液中。將反應混合物在-78℃下攪拌1h，之後使其升溫至室溫且攪拌12h。將反應物用MTBE(500ml)稀釋且用100mL飽和氯化鈉水溶液緩慢萃取。將有機相用飽和碳酸氫鈉水溶液(2x200ml)洗滌。將經合併之水性級分用MTBE反萃取兩次。將經合併之有機級分經硫酸鈉乾燥，且藉由旋轉蒸發來濃縮，以獲得粗材料，其藉由管柱層析(120g SiO2 ，己烷/MTBE，其中MTBE為0~15%，流速=80mL/min)進行純化，以獲得N -(4-環戊基-2-甲基-4-側氧基-丁基)胺甲酸第三丁 酯(3.55g，13.18mmol，17.03%產率)。To a suspension of magnesium (2.26 g, 92.84 mmol, 1.30 mL) in THF (100 mL) was added bromocyclopentane (14.99 g, 100.58 mmol, 10.78 mL). The reaction mixture was stirred for 45 min to give a grey solution. This solution was transferred dropwise to a cold (-78°C) suspension of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (16.5 g, 77.37 mmol) in THF (200 mL) . The reaction mixture was stirred at -78 °C for 1 h, after which it was allowed to warm to room temperature and stirred for 12 h. The reaction was diluted with MTBE (500 ml) and slowly extracted with 100 mL of saturated aqueous sodium chloride. The organic phase was washed with saturated aqueous sodium bicarbonate solution (2x200ml). The combined aqueous fractions were back extracted twice with MTBE. The combined organic fractions were dried over sodium sulfate and concentrated by rotary evaporation to obtain crude material, which was chromatographed by column (120 g SiO2 , hexane/MTBE, where MTBE was 0-15%, flow rate = 80 mL/min) for purification to obtain tert-butyl N- (4-cyclopentyl-2-methyl-4-oxy-butyl) carbamate (3.55 g, 13.18 mmol, 17.03% yield) Rate).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.86(s,3H),1.41(s,9H),1.63(m,9H),2.45(m,2H),2.84(m,1H),2.98(m,2H),4.64(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.86(s, 3H), 1.41(s, 9H), 1.63(m, 9H), 2.45(m, 2H), 2.84(m, 1H), 2.98( m, 2H), 4.64 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值183.4；實測值184.2；Rt=1.457min。LCMS (ESI): [M-Boc] + m/z: calculated 183.4; found 184.2; Rt=1.457 min.

步驟3：6-環戊基-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-cyclopentyl-3-methyl-2,3,4,5-tetrahydropyridine

將N-(4-環戊基-2-甲基-4-側氧基丁基)胺甲酸第三丁 酯(3.55g，13.18mmol)於TFA(20mL)及DCM(20mL)中之溶液在25℃下攪拌11h。將飽和硫酸鈉水溶液添加到該溶液(50ml)中，然後用DCM(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得6-環戊基-3-甲基-2,3,4,5-四氫吡啶(1.6g，9.68mmol，73.46%產率)。A solution of tert-butyl N-(4-cyclopentyl-2-methyl-4-oxybutyl) carbamate (3.55 g, 13.18 mmol) in TFA (20 mL) and DCM (20 mL) was Stir at 25°C for 11h. Saturated aqueous sodium sulfate solution was added to the solution (50ml), then extracted with DCM (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain 6-cyclopentyl-3-methyl-2,3,4,5-tetrahydropyridine (1.6 g, 9.68 mmol, 73.46% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.91(s,3H),1.22(m,1H),1.60(m,7H),1.81(m, 3H),2.14(m,1H),2.24(m,1H),2.55(m,1H),2.99(m,1H),3.69(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.91(s, 3H), 1.22(m, 1H), 1.60(m, 7H), 1.81(m, 3H), 2.14(m, 1H), 2.24( m, 1H), 2.55 (m, 1H), 2.99 (m, 1H), 3.69 (m, 1H).

步驟4：2-環戊基-5-甲基哌啶之合成Step 4: Synthesis of 2-cyclopentyl-5-methylpiperidine

將硼氫化鈉(732.50mg，19.36mmol，684.58μL)分批添加到6-環戊基-3-甲基-2,3,4,5-四氫吡啶(1.6g，9.68mmol)於MeOH(20mL)中之溶液中。將混合物在室溫下攪拌12h。添加水(50ml)且將所得混合物用EtOAc(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得2-環戊基-5-甲基哌啶(1.55g，粗品)。Sodium borohydride (732.50 mg, 19.36 mmol, 684.58 μL) was added portionwise to 6-cyclopentyl-3-methyl-2,3,4,5-tetrahydropyridine (1.6 g, 9.68 mmol) in MeOH ( 20mL) in the solution. The mixture was stirred at room temperature for 12 h. Water (50ml) was added and the resulting mixture was extracted with EtOAc (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 2-cyclopentyl-5-methylpiperidine (1.55 g, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.78(s,3H),1.03(m,4H),1.62(m,11H),2.16(m,2H),2.96(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 0.78 (s, 3H), 1.03 (m, 4H), 1.62 (m, 11H), 2.16 (m, 2H), 2.96 (m, 1H).

GCMS：[M]+ m/z：計算值167.4；實測值168.2；Rt=6.657min。GCMS: [M] + m/z: calculated 167.4; found 168.2; Rt=6.657 min.

3X.(2S ,4R )-2-苯基哌啶-4-甲腈之合成 3X. Synthesis of ( 2S , 4R )-2-phenylpiperidine-4-carbonitrile

Figure 110128222-A0202-12-0607-721
Figure 110128222-A0202-12-0607-721

步驟1：(2S,4R)-4-胺甲醯基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (2S,4R)-4-aminocarbamoyl-2-phenylpiperidine-1-carboxylate

向(2S ,4R )-1-第三丁氧基羰基-2-苯基哌啶-4-甲酸(1g，3.27mmol)於CH3 CN(100mL)中之經攪拌之溶液中添加羰基二咪唑(690.29mg，4.26mmol)。然後將反應混合物攪拌1小時。1小時之後，分批添加碳酸銨(1.43g，8.19mmol)且將所得反應混合物在室溫下攪拌隔夜。然後將反應混合物在真空中蒸發，添加水且用DCM(2 x 40mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以得到呈黃色油狀物之(2S, 4R )-4-胺甲醯基-2-苯基哌啶-1-甲酸第三丁酯(0.7g，2.30mmol，70.23%產率)。To a stirred solution of ( 2S , 4R )-1-tert-butoxycarbonyl-2-phenylpiperidine-4-carboxylic acid (1 g, 3.27 mmol) in CH3CN (100 mL) was added carbonyl Diimidazole (690.29 mg, 4.26 mmol). The reaction mixture was then stirred for 1 hour. After 1 hour, ammonium carbonate (1.43 g, 8.19 mmol) was added portionwise and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then evaporated in vacuo, water was added and extracted with DCM (2 x 40 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give ( 2S, 4R )-4-aminocarboxy-2-phenylpiperidine-1 as a yellow oil - tert-butyl formate (0.7 g, 2.30 mmol, 70.23% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值304.2；實測值249.2(t-Bu裂解之產物質量)；Rt=1.313min。LCMS (ESI): [M+Boc] + m/z: calculated 304.2; found 249.2 (product mass of t-Bu cleavage); Rt=1.313 min.

步驟2：(2S,4R)-4-氰基2-苯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2S,4R)-4-cyano 2-phenylpiperidine-1-carboxylic acid tert-butyl ester

向(2S ,4R )-4-胺甲醯基-2-苯基哌啶-1-甲酸第三丁酯(0.7g，2.30mmol)於DCM(10mL)中之經攪拌之溶液中添加Et3 N(1.05g，10.35mmol，1.44mL)且將所得黃色溶液冷卻至0℃。在5分鐘內將三氟乙酸酐(724.52mg，3.45mmol，486.26μL)逐滴添加到反應混合物中且將所得反應混合物攪拌30分鐘。30分鐘之後，將粗反應混合物用飽和碳酸氫鈉溶液及二氯甲烷稀釋。分離兩層。將水層用二氯甲烷萃取且將經合併之有機相用飽和碳酸氫鈉溶液、鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以得到呈黃色油狀物之(2S ,4R )-4-氰基-2-苯基哌啶-1-甲酸第三丁酯(0.6g，2.10mmol，91.11%產率)。To a stirred solution of ( 2S , 4R )-4-aminocarbamoyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.7 g, 2.30 mmol) in DCM (10 mL) was added Et3N (1.05 g, 10.35 mmol, 1.44 mL) and the resulting yellow solution was cooled to 0 °C. Trifluoroacetic anhydride (724.52 mg, 3.45 mmol, 486.26 μL) was added dropwise to the reaction mixture over 5 minutes and the resulting reaction mixture was stirred for 30 minutes. After 30 minutes, the crude reaction mixture was diluted with saturated sodium bicarbonate solution and dichloromethane. Separate the two layers. The aqueous layer was extracted with dichloromethane and the combined organic phases were washed with saturated sodium bicarbonate solution, brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give ( 2S , 4R )-4-Cyano-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.6 g, 2.10 mmol, 91.11 % yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值286.2；實測值231.2(t -Bu裂解之產物質量)；Rt=1.411min。LCMS (ESI): [M+Boc] + m/z: calculated 286.2; found 231.2 ( t -Bu cleavage product mass); Rt=1.411 min.

步驟3：(2S,4R)-2-苯基哌啶-4-甲腈之合成Step 3: Synthesis of (2S,4R)-2-phenylpiperidine-4-carbonitrile

向(2S ,4R )-4-氰基-2-苯基哌啶-1-甲酸第三丁酯(0.6g，2.10mmol)於MeOH(10mL)中之經攪拌之溶液中添加於二噁烷中之HCl(2.10mmol，5mL)。將所得反應混合物在室溫下攪拌隔夜。然後在真空中蒸發反應物，以得到(2S ,4R )-2-苯基哌啶-4-甲腈(0.36g，1.93mmol，92.25%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of ( 2S , 4R )-4-cyano-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.6 g, 2.10 mmol) in MeOH (10 mL) was added diethyl ether. HCl in oxane (2.10 mmol, 5 mL). The resulting reaction mixture was stirred at room temperature overnight. The reaction was then evaporated in vacuo to give ( 2S , 4R )-2-phenylpiperidine-4-carbonitrile (0.36 g, 1.93 mmol, 92.25% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值186.1；實測值187.1；Rt=0.558min。LCMS (ESI): [M+H] + m/z: calculated 186.1; found 187.1; Rt=0.558 min.

3Y. 外消旋 -(2R,5S )-2-(3-溴苯基)-5-甲基哌啶之合成 3Y. Synthesis of racemic- ( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0608-722
Figure 110128222-A0202-12-0608-722

步驟1：3-(3-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-(3-bromobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

向5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(13g，60.95mmol)於THF(250mL)中之經預冷卻之(-78℃)溶液中逐滴添加LiHMDS(115mL)。將所得混合 物在-78℃下攪拌1h。一次性添加3-溴苯甲醯氯(13.38g，60.95mmol，8.06mL)之溶液。使反應混合物升溫至室溫且在該溫度下攪拌5h。將反應混合物用NaHSO4 (35g；10%溶液)淬滅且用DCM(3*150ml)萃取。將有機層用水洗滌，經Na2 SO4 乾燥。將DCM蒸發，以得到3-(3-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(29g，粗品)。To a pre-cooled (-78°C) solution of 5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (13 g, 60.95 mmol) in THF (250 mL) was added dropwise LiHMDS ( 115mL). The resulting mixture was stirred at -78 °C for 1 h. A solution of 3-bromobenzyl chloride (13.38 g, 60.95 mmol, 8.06 mL) was added in one portion. The reaction mixture was warmed to room temperature and stirred at this temperature for 5 h. The reaction mixture was quenched with NaHSO4 (35 g; 10% solution) and extracted with DCM (3*150 ml). The organic layer was washed with water, dried over Na2SO4 . The DCM was evaporated to give 3-(3-bromobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (29 g, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.08(d,3H),1.28(m,1H),1.48(s,9H),1.98(m,2H),2.14(m,1H),2.41(m,1H),4.51(m,1H),7.31(m,3H),7.65(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.08(d,3H), 1.28(m,1H), 1.48(s,9H), 1.98(m,2H), 2.14(m,1H), 2.41( m, 1H), 4.51 (m, 1H), 7.31 (m, 3H), 7.65 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值296.4；實測值297.2；Rt=1.563min。LCMS (ESI): [M-Boc] + m/z: calculated 296.4; found 297.2; Rt=1.563 min.

步驟2：6-(3-溴-4-甲基苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3-bromo-4-methylphenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將3-(3-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(29g，73.18mmol)溶解於乙酸(150mL)中且分批添加氯化氫水溶液(250mL，30%純度)。添加完成之後，將所得混合物在100℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(150ml)與DCM(100ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至ph

Figure 110128222-A0202-12-0609-561
10且用EtOAc(3x150ml)萃取。分離EtOAc溶液，經Na2 SO4 乾燥且在減壓下蒸發，得到6-(3-溴苯基)-3-甲基-2,3,4,5-四氫吡啶(10g，39.66mmol，54.19%產率)。3-(3-Bromobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (29 g, 73.18 mmol) was dissolved in acetic acid (150 mL) and added portionwise Aqueous hydrogen chloride solution (250 mL, 30% purity). After the addition was complete, the resulting mixture was stirred at 100 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (150ml) and DCM (100ml). The organic layer was separated and discarded. The aqueous layer was basified to pH with 10% NaOH
Figure 110128222-A0202-12-0609-561
10 and extracted with EtOAc (3x150ml). The EtOAc solution was separated, dried over Na2SO4 and evaporated under reduced pressure to give 6-(3-bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (10 g, 39.66 mmol, 54.19% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.98(d,3H),1.38(m,1H),1.69(m,1H),1.93(m,1H),2.55(m,1H),2.73(m,1H),3.27(m,1H),4.01(m,1H),7.22(t,1H),7.49(d,1H),7.65(d,1H),7.93(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.38(m,1H), 1.69(m,1H), 1.93(m,1H), 2.55(m,1H), 2.73( m, 1H), 3.27 (m, 1H), 4.01 (m, 1H), 7.22 (t, 1H), 7.49 (d, 1H), 7.65 (d, 1H), 7.93 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值252.4；實測值253.2；Rt=0.886min。LCMS (ESI): [M] + m/z: calculated 252.4; found 253.2; Rt=0.886 min.

步驟3：外消旋-(2R,5S)-2-(3-溴苯基)-5-甲基哌啶之合成Step 3: Synthesis of Racemic-(2R,5S)-2-(3-bromophenyl)-5-methylpiperidine

在0℃下，向6-(3-溴苯基)-3-甲基-2,3,4,5-四氫吡啶(10g，39.66mmol)於MeOH(100mL)中之溶液中分批添加硼氫化鈉(1.73g，45.61mmol，1.61mL)。將所得混合物在25℃下攪拌2h且在真空中蒸發。將殘餘物溶解於MeOH(50mL) 中且用於二噁烷中之4.0M氯化氫溶液(14.46g，396.59mmol，18.08mL)處理且將反應混合物攪拌15min。蒸發溶劑。將沉澱用THF洗滌，在真空中乾燥，以得到(2S,5R)-2-(3-溴苯基)-5-甲基哌啶(10g，34.41mmol，86.76%產率，HCl)。產物含有2.78g(約30%)NaCl。To a solution of 6-(3-bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (10 g, 39.66 mmol) in MeOH (100 mL) was added portionwise at 0 °C Sodium borohydride (1.73 g, 45.61 mmol, 1.61 mL). The resulting mixture was stirred at 25 °C for 2 h and evaporated in vacuo. The residue was dissolved in MeOH (50 mL) was treated with 4.0 M hydrogen chloride solution in dioxane (14.46 g, 396.59 mmol, 18.08 mL) and the reaction mixture was stirred for 15 min. Evaporate the solvent. The precipitate was washed with THF and dried in vacuo to give (2S,5R)-2-(3-bromophenyl)-5-methylpiperidine (10 g, 34.41 mmol, 86.76% yield, HCl). The product contained 2.78 g (about 30%) NaCl.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.22(m,1H),1.95(m,3H),2.16(m,1H),2.63(m,1H),3.19(m,1H),4.15(m,1H),7.37(t,1H),7.57(d,1H),7.67(d,1H),7.91(s,1H),9.69(bds,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.22(m,1H), 1.95(m,3H), 2.16(m,1H), 2.63(m,1H), 3.19(m,1H), 4.15(m,1H), 7.37(t,1H), 7.57(d,1H), 7.67(d,1H), 7.91(s,1H), 9.69(bds,1H).

LCMS(ESI)：[M]+ m/z：計算值253.4；實測值254.2；Rt=0.815min。LCMS (ESI): [M] + m/z: calculated 253.4; found 254.2; Rt=0.815 min.

3Z. 外消旋 -6-((2R,5S )-5-甲基哌啶-2-基)螺[3.3 ]庚-2-醇之合成 3Z. Synthesis of racemic -6-(( 2R,5S )-5-methylpiperidin-2-yl)spiro[ 3.3 ]heptan-2-ol

Figure 110128222-A0202-12-0610-723
Figure 110128222-A0202-12-0610-723

步驟1：3-(6-(苯甲氧基)螺[3.3]庚烷-2-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-(6-(benzyloxy)spiro[3.3]heptane-2-carbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

向5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(8.65g，40.56mmol)於THF(200mL)中之經預冷卻之(-78℃)溶液中逐滴添加LiHMDS(80.4mL)。將所得混合物在-78℃下攪拌1h。一次性添加2-苯甲氧基螺[3.3 ]庚烷-6-羰基氯(10.74g，40.56mmol，8.06mL)之溶液。使反應混合物升溫至室溫且在該溫度下攪拌5h。將反應混合物用NaHSO4 (30g；10%溶液)淬滅且用DCM(3*150ml)萃取。將有機層用水洗滌，經Na2 SO4 乾燥。將DCM蒸發，以得到3-(2-苯甲氧基螺[3.3 ]庚烷-6-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(33g，粗品)。To a pre-cooled (-78°C) solution of 5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (8.65 g, 40.56 mmol) in THF (200 mL) was added LiHMDS dropwise (80.4 mL). The resulting mixture was stirred at -78 °C for 1 h. A solution of 2-benzyloxyspiro[ 3.3 ]heptane-6-carbonyl chloride (10.74 g, 40.56 mmol, 8.06 mL) was added in one portion. The reaction mixture was warmed to room temperature and stirred at this temperature for 5 h. The reaction mixture was quenched with NaHSO4 (30 g; 10% solution) and extracted with DCM (3*150 ml). The organic layer was washed with water, dried over Na2SO4 . The DCM was evaporated to give 3-(2-benzyloxyspiro[ 3.3 ]heptane-6-carbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (33 g, Crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.05(d,3H),1.53(s,9H),2.11(m,10H),2.65(m,2H),3.12(m,2H),3.76(m,1H),3.96(m,1H),4.38(s,2H),7.31(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.05(d, 3H), 1.53(s, 9H), 2.11(m, 10H), 2.65(m, 2H), 3.12(m, 2H), 3.76( m, 1H), 3.96 (m, 1H), 4.38 (s, 2H), 7.31 (m, 5H).

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=1.625min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=1.625 min.

步驟2：6-(5-甲基-3,4,5,6-四氫吡啶-2-基).螺[3.3]庚-2-醇之合成Step 2: Synthesis of 6-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl).spiro[3.3]hept-2-ol

將3-(2-苯甲氧基螺[3.3 ]庚烷-6-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(33g，74.74mmol)溶解於乙酸(150mL)中且分批添加氯化氫水溶液(250mL，30%純度)。添加完成之後，將所得混合物在100℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(150ml)與DCM(100ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至ph

Figure 110128222-A0202-12-0611-562
10且用EtOAc(3x150ml)萃取。分離EtOAc溶液，經Na2 SO4 乾燥且在減壓下濃縮，得到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)螺[3.3]庚-2-醇(4.5g，21.71mmol，29.04%產率)。3-(2-Benzyloxyspiro[ 3.3 ]heptane-6-carbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (33 g, 74.74 mmol) was dissolved in To acetic acid (150 mL) and aqueous hydrogen chloride solution (250 mL, 30% purity) were added portionwise. After the addition was complete, the resulting mixture was stirred at 100 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (150ml) and DCM (100ml). The organic layer was separated and discarded. The aqueous layer was basified to pH with 10% NaOH
Figure 110128222-A0202-12-0611-562
10 and extracted with EtOAc (3x150ml). The EtOAc solution was separated, dried over Na2SO4 and concentrated under reduced pressure to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)spiro[3.3]hept-2- Alcohol (4.5 g, 21.71 mmol, 29.04% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.23(m,2H),1.54(m,1H),1.70(m,1H),1.80(m,1H),1.92(m,1H),2.02(m,5H),2.22(m,1H),2.48(m,1H),2.95(m,2H),3.67(m,1H),4.15(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.86(d, 3H), 1.23(m, 2H), 1.54(m, 1H), 1.70(m, 1H), 1.80(m, 1H), 1.92(m,1H), 2.02(m,5H), 2.22(m,1H), 2.48(m,1H), 2.95(m,2H), 3.67(m,1H), 4.15(m,1H).

LCMS(ESI)：[M]+ m/z：計算值207.2；實測值208.2；Rt=0.628min。LCMS (ESI): [M] + m/z: calculated 207.2; found 208.2; Rt=0.628 min.

步驟3：外消旋-6-((2R,5S)-5-甲基哌啶-2-基)螺[3.3]庚-2-醇之合成Step 3: Synthesis of racemic-6-((2R,5S)-5-methylpiperidin-2-yl)spiro[3.3]heptan-2-ol

在0℃下，向6-(3-甲基-2,3,4,5-四氫吡啶-6-基)螺[3.3 ]庚-2-醇(4.5g，21.71mmol)於MeOH(50mL)中之溶液中分批添加硼氫化鈉(944.33mg，24.96mmol，882.55μL)。將所得混合物在25℃下攪拌2h且在真空中蒸發。將殘餘物用水(100ml)稀釋且將產物用EtOAc(3*30ml)萃取。將經合併之有機層經Na2 SO4 乾燥。將EtOAc蒸發，以得到6-[(2S,5R )-5-甲基-2-哌啶基]螺[3.3 ]庚-2-醇(3.5g，16.72mmol，77.03%產率)。To 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)spiro[ 3.3 ]heptan-2-ol (4.5 g, 21.71 mmol) in MeOH (50 mL) at 0 °C ) was added portionwise sodium borohydride (944.33 mg, 24.96 mmol, 882.55 μL). The resulting mixture was stirred at 25 °C for 2 h and evaporated in vacuo. The residue was diluted with water (100ml) and the product was extracted with EtOAc (3*30ml). The combined organic layers were dried over Na2SO4 . The EtOAc was evaporated to give 6-[( 2S,5R )-5-methyl-2-piperidinyl]spiro[ 3.3 ]heptan-2-ol (3.5 g, 16.72 mmol, 77.03% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.81(d,3H),0.95(m,2H),1.22(m,1H),1.52(m,3H),1.95(m,7H),2.21(m,3H),2.44(m,2H),2.95(m,1H),4.22(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.81(d,3H), 0.95(m,2H), 1.22(m,1H), 1.52(m,3H), 1.95(m,7H), 2.21( m, 3H), 2.44 (m, 2H), 2.95 (m, 1H), 4.22 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值209.2；實測值210.2；Rt=0.600min。LCMS (ESI): [M] + m/z: calculated 209.2; found 210.2; Rt=0.600 min.

3AA.(2R,4S)-N-苯甲基-2-苯基哌啶-4-胺之合成 3AA. Synthesis of (2R,4S)-N-benzyl-2-phenylpiperidin-4-amine

Figure 110128222-A0202-12-0612-724
Figure 110128222-A0202-12-0612-724

步驟1：(2R,4S)-4-(苯甲基胺基)-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,4S)-4-(benzylamino)-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

將4-側氧基-2-苯基哌啶-1-甲酸第三丁酯(3g，10.90mmol)及苯基甲胺(1.17g，10.90mmol)混合於DCM(30mL)中。向其中添加4A分子篩(10g)且在不攪拌之情況下使所得混合物在20℃下反應。12h之後，HNMR顯示形成亞胺。過濾所得混合物。在真空中移除所有揮發物。將殘餘物溶解於無水MeOH(30mL)中。在劇烈攪拌下分批添加硼氫化鈉(412.21mg，10.90mmol，385.24μL)且將所得混合物在20℃下攪拌3小時。蒸發所得混合物。將殘餘物分配於EtOAc(30ml)與水(30ml)之間。將水層用DCM(2x20ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且蒸發，以獲得(2R,4S)-4-(苯甲基胺基)-2-苯基哌啶-1-甲酸第三丁酯(4.5g，粗品)，其不經純化即用於下一步驟。Combine tert-butyl 4-oxy-2-phenylpiperidine-1-carboxylate (3 g, 10.90 mmol) and phenylmethylamine (1.17 g, 10.90 mmol) in DCM (30 mL). To this was added 4A molecular sieves (10 g) and the resulting mixture was allowed to react at 20°C without stirring. After 12h, HNMR showed formation of an imine. The resulting mixture was filtered. All volatiles were removed in vacuo. The residue was dissolved in dry MeOH (30 mL). Sodium borohydride (412.21 mg, 10.90 mmol, 385.24 μL) was added portionwise with vigorous stirring and the resulting mixture was stirred at 20° C. for 3 hours. The resulting mixture was evaporated. The residue was partitioned between EtOAc (30ml) and water (30ml). The aqueous layer was extracted with DCM (2x20ml). The combined organic extracts were dried over sodium sulfate and evaporated to give tert-butyl (2R,4S)-4-(benzylamino)-2-phenylpiperidine-1-carboxylate (4.5 g, crude product), which was used in the next step without purification.

1 H NMR(DMSO-d6,400MHz)：1.20(s,9H),1.29(m,2H),1.49(m,1H),1.89(m,1H),2.12(m,1H),2.81(m,1H),3.35(m,1H),3.57(s,2H),3.85(m,1H),4.82(m,1H),7.16(m,10H)。 1 H NMR (DMSO-d6, 400MHz): 1.20(s, 9H), 1.29(m, 2H), 1.49(m, 1H), 1.89(m, 1H), 2.12(m, 1H), 2.81(m, 1H), 3.35 (m, 1H), 3.57 (s, 2H), 3.85 (m, 1H), 4.82 (m, 1H), 7.16 (m, 10H).

LCMS(ESI)：[M+H]+ m/z：計算值366.3；實測值367.2；Rt=1.148min。LCMS (ESI): [M+H] + m/z: calculated 366.3; found 367.2; Rt=1.148 min.

步驟2：(2R,4S)-N-苯甲基-2-苯基哌啶-4-胺之合成Step 2: Synthesis of (2R,4S)-N-benzyl-2-phenylpiperidin-4-amine

將(2R,4S)-4-(苯甲基胺基)-2-苯基哌啶-1-甲酸第三丁酯(4.5g，12.28mmol)於二噁烷/HCl(25mL)中之溶液在20℃下攪拌12h。將所得混合物蒸發至乾，以獲得粗品(2R,4S)-N-苯甲基-2-苯基哌啶-4-胺(3.7g，10.90mmol，88.81%產率，2HCl)，其不經純化即用於下一步驟。A solution of (2R,4S)-4-(benzylamino)-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (4.5 g, 12.28 mmol) in dioxane/HCl (25 mL) Stir at 20°C for 12h. The resulting mixture was evaporated to dryness to obtain crude (2R,4S)-N-benzyl-2-phenylpiperidin-4-amine (3.7 g, 10.90 mmol, 88.81% yield, 2HCl) which was not purified by Purification was used in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值266.22；實測值267.2；Rt=0.703min。LCMS (ESI): [M+H] + m/z: calculated 266.22; found 267.2; Rt=0.703 min.

3BB.4-(5-甲基-2-哌啶基)苯磺醯胺之合成 3BB. Synthesis of 4-(5-methyl-2-piperidinyl)benzenesulfonamide

Figure 110128222-A0202-12-0613-725
Figure 110128222-A0202-12-0613-725

步驟1：4-(1-第三丁氧基羰基-5-甲基-2-哌啶基)苯亞磺酸鹽之合成Step 1: Synthesis of 4-(1-tert-butoxycarbonyl-5-methyl-2-piperidinyl)benzenesulfinate

將於己烷中之23%正丁基鋰(2.5M)(1.73g，6.21mmol，2.50mL，23%純度)逐滴添加到冷卻至-75℃之2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(2g，5.65mmol)於四氫呋喃(30mL)中之溶液。添加完成之後，將混合物在-75℃下攪拌30分鐘。然後將二氧化硫(1.81g，28.23mmol)鼓泡到溶液中且將所得溶液在-60℃下攪拌1h。此後，在減壓下移除揮發物，留下4-(1-第三丁氧基羰基-5-甲基-2-哌啶基)苯亞磺酸鹽(1.9g，5.50mmol，97.45%產率，Li+)。23% n-butyllithium (2.5M) in hexanes (1.73 g, 6.21 mmol, 2.50 mL, 23% purity) was added dropwise to 2-(4-bromophenyl)-cooled to -75°C. A solution of tert-butyl 5-methylpiperidine-1-carboxylate (2 g, 5.65 mmol) in tetrahydrofuran (30 mL). After the addition was complete, the mixture was stirred at -75°C for 30 minutes. Sulfur dioxide (1.81 g, 28.23 mmol) was then bubbled into the solution and the resulting solution was stirred at -60 °C for 1 h. After this time, the volatiles were removed under reduced pressure, leaving 4-(1-tert-butoxycarbonyl-5-methyl-2-piperidinyl)benzenesulfinate (1.9 g, 5.50 mmol, 97.45%) yield, Li+).

LCMS(ESI)：[M+H-Boc]+ m/z：計算值339.2；實測值239.2；Rt=1.248min。LCMS (ESI): [M+H-Boc] + m/z: calculated 339.2; found 239.2; Rt=1.248 min.

步驟2：2-(4-氯磺醯基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 2-(4-Chlorosulfonylphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將N-氯琥珀醯亞胺(771.32mg，5.78mmol，467.46μL)分批添加到4-(1-第三丁氧基羰基-5-甲基-2-哌啶基)苯亞磺酸鹽(1.9g，5.50mmol，Li+)於水(30mL)及二氯甲烷(30mL)中之冰冷溶液中。添加完成之後，將所得混合物在5℃下攪拌1h。然後，分離DCM層，經Na2 SO4 乾燥且在減壓下濃縮，得到2-(4-氯磺醯基苯基)-5-甲基哌啶-1-甲酸第三丁酯(2g，5.35mmol，97.24%產率)。N-Chlorosuccinimide (771.32 mg, 5.78 mmol, 467.46 μL) was added portionwise to 4-(1-tert-butoxycarbonyl-5-methyl-2-piperidinyl)benzenesulfinate (1.9 g, 5.50 mmol, Li+) in an ice-cold solution of water (30 mL) and dichloromethane (30 mL). After the addition was complete, the resulting mixture was stirred at 5°C for 1 h. Then, the DCM layer was separated, dried over Na 2 SO 4 and concentrated under reduced pressure to give tert-butyl 2-(4-chlorosulfonylphenyl)-5-methylpiperidine-1-carboxylate (2 g, 5.35 mmol, 97.24% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值373.1；實測值272.0；Rt=1.206min。LCMS (ESI): [M-Boc] + m/z: calculated 373.1; found 272.0; Rt=1.206 min.

步驟3：5-甲基-2-(4-胺磺醯基苯基)哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl 5-methyl-2-(4-sulfamonophenyl)piperidine-1-carboxylate

將於THF溶液中之氨(0.5M)(13.66g，8.02mmol，16.08mL，1%純度)逐滴添加到2-(4-氯磺醯基苯基)-5-甲基哌啶-1-甲酸第三丁酯(1g，2.67mmol)於四氫呋喃(20mL)中之溶液中。添加完成之後，將所得混合物在20℃下攪拌1h。然後，透過短矽膠墊過濾該混合物且在減壓下濃縮濾液，得到5-甲基-2-(4-胺磺醯基苯基)哌啶-1-甲酸第三丁酯(0.87g，2.45mmol，91.77%產率)。Ammonia (0.5M) in THF solution (13.66 g, 8.02 mmol, 16.08 mL, 1% purity) was added dropwise to 2-(4-chlorosulfonylphenyl)-5-methylpiperidine-1 - A solution of tert-butyl formate (1 g, 2.67 mmol) in tetrahydrofuran (20 mL). After the addition was complete, the resulting mixture was stirred at 20 °C for 1 h. The mixture was then filtered through a short pad of silica gel and the filtrate was concentrated under reduced pressure to give tert-butyl 5-methyl-2-(4-aminosulfonylphenyl)piperidine-1-carboxylate (0.87 g, 2.45 g mmol, 91.77% yield).

LCMS(ESI)：[M+Na]+ m/z：計算值354.2；實測值377.0；Rt=1.319min。LCMS (ESI): [M+Na] + m/z: calculated 354.2; found 377.0; Rt=1.319 min.

步驟4：4-(5-甲基-2-哌啶基)苯磺醯胺之合成Step 4: Synthesis of 4-(5-Methyl-2-piperidinyl)benzenesulfonamide

將於二噁烷中之4.0M氯化氫溶液(10.10g，27.70mmol，10mL，10%純度)添加到5-甲基-2-(4-胺磺醯基苯基)哌啶-1-甲酸第三丁酯(870mg，2.45mmol)於二氯甲烷(20mL)中之溶液中。將所得混合物在20℃下攪拌4h。然後，在減壓下移除溶劑，留下4-(5-甲基-2-哌啶基)苯磺醯胺(700mg，2.41mmol，98.07%產率，HCl)。A 4.0M solution of hydrogen chloride in dioxane (10.10 g, 27.70 mmol, 10 mL, 10% purity) was added to 5-methyl-2-(4-sulfamonophenyl)piperidine-1-carboxylic acid A solution of tributyl ester (870 mg, 2.45 mmol) in dichloromethane (20 mL). The resulting mixture was stirred at 20 °C for 4 h. Then, the solvent was removed under reduced pressure to leave 4-(5-methyl-2-piperidinyl)benzenesulfonamide (700 mg, 2.41 mmol, 98.07% yield, HCl).

LCMS(ESI)：[M+H]+ m/z：計算值254.1；實測值255.2；Rt=0754min。LCMS (ESI): [M+H] + m/z: calculated 254.1; found 255.2; Rt=0754 min.

3CC.N-甲基-4-(5-甲基-2-哌啶基)苯磺醯胺之合成 3CC. Synthesis of N-methyl-4-(5-methyl-2-piperidinyl)benzenesulfonamide

Figure 110128222-A0202-12-0614-726
Figure 110128222-A0202-12-0614-726

步驟1：5-甲基-2-[4-(甲基胺磺醯基)苯基]哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 5-methyl-2-[4-(methylaminosulfonyl)phenyl]piperidine-1-carboxylic acid tert-butyl ester

將於THF中之2M甲胺(5.77g，13.37mmol，6.70mL，7.2%純度)逐滴添加到2-(4-氯磺醯基苯基)-5-甲基哌啶-1-甲酸第三丁酯(1g，2.67mmol)(如上文所述製備)於四氫呋喃(20mL)中之溶液中。添加完成之後，將所得混合物在20℃下攪拌1h。然後，透過短矽膠墊過濾該混合物且在減壓下濃縮濾液，得到5-甲基-2-[4-(甲基胺磺醯基)苯基]哌啶-1-甲酸第三丁酯(0.92g，2.50mmol，93.35% 產率)。2M methylamine in THF (5.77 g, 13.37 mmol, 6.70 mL, 7.2% purity) was added dropwise to 2-(4-chlorosulfonylphenyl)-5-methylpiperidine-1-carboxylic acid A solution of tributyl ester (1 g, 2.67 mmol) (prepared as described above) in tetrahydrofuran (20 mL). After the addition was complete, the resulting mixture was stirred at 20 °C for 1 h. Then, the mixture was filtered through a short pad of silica gel and the filtrate was concentrated under reduced pressure to give tert-butyl 5-methyl-2-[4-(methylaminosulfonyl)phenyl]piperidine-1-carboxylate ( 0.92g, 2.50mmol, 93.35% Yield).

LCMS(ESI)：[M+H-Boc]+ m/z：計算值368.2；實測值269.0；Rt=1.411min。LCMS (ESI): [M+H-Boc] + m/z: calculated 368.2; found 269.0; Rt=1.411 min.

步驟2：N-甲基-4-(5-甲基-2-哌啶基)苯磺醯胺之合成Step 2: Synthesis of N-methyl-4-(5-methyl-2-piperidinyl)benzenesulfonamide

將於二噁烷中之4.0M氯化氫溶液(10.10g，27.70mmol，10mL，10%純度)添加到5-甲基-2-[4-(甲基胺磺醯基)苯基]哌啶-1-甲酸第三丁酯(920mg，2.50mmol)於二氯甲烷(20mL)中之溶液中。將所得混合物在20℃下攪拌4h。然後，在減壓下移除溶劑，留下N-甲基-4-(5-甲基-2-哌啶基)苯磺醯胺(740mg，2.43mmol，97.23%產率，HCl)。A 4.0 M solution of hydrogen chloride in dioxane (10.10 g, 27.70 mmol, 10 mL, 10% purity) was added to 5-methyl-2-[4-(methylaminosulfonyl)phenyl]piperidine- A solution of tert-butyl 1-carboxylate (920 mg, 2.50 mmol) in dichloromethane (20 mL). The resulting mixture was stirred at 20 °C for 4 h. Then, the solvent was removed under reduced pressure to leave N-methyl-4-(5-methyl-2-piperidinyl)benzenesulfonamide (740 mg, 2.43 mmol, 97.23% yield, HCl).

LCMS(ESI)：[M+H]+ m/z：計算值268.2；實測值269.1；Rt=0.774minLCMS(ESI): [M+H] + m/z: Calculated 268.2; Found 269.1; Rt=0.774min

3DD. (2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基哌啶之合成 3DD . Synthesis of (2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0615-727
Figure 110128222-A0202-12-0615-727

步驟1：4-氰基-2,2-二氟戊酸乙酯之合成Step 1: Synthesis of ethyl 4-cyano-2,2-difluorovalerate

在20℃下，向銅(9.47g，149.06mmol)、2-甲基丙-2-烯腈(5g，74.53mmol)及2-溴-2,2-二氟乙酸乙酯(27.23g，134.15mmol，17.23mL)於THF(64mL)中之經攪拌之混合物中依次添加TMEDA(4.33g，37.26mmol，5.59mL)及乙酸 (4.48g，74.53mmol，4.26mL)。將混合物在室溫下攪拌1小時，然後使用Et2O作為溶析液經矽藻土過濾。將飽和氯化銨溶液添加到混合物中且將產物用Et2O(50ml)萃取。將有機相用飽和氯化銨及碳酸氫鈉水溶液洗滌若干次，以移除最後痕量之銅鹽。然後蒸發有機層且用CC(OK.Interchim,330g SiO2，石油醚/MtBE，其中MtBE為5~35%，流速=130mL/min，Rv=6 CV)純化粗殘餘物，以獲得4-氰基-2,2-二氟戊酸乙酯(10g，52.31mmol，70.19%產率)。To copper (9.47 g, 149.06 mmol), 2-methylprop-2-enenitrile (5 g, 74.53 mmol) and ethyl 2-bromo-2,2-difluoroacetate (27.23 g, 134.15 mmol) at 20 °C To a stirred mixture of mmol, 17.23 mL) in THF (64 mL) was added TMEDA (4.33 g, 37.26 mmol, 5.59 mL) followed by acetic acid (4.48 g, 74.53 mmol, 4.26 mL). The mixture was stirred at room temperature for 1 hour and then filtered through celite using Et2O as the eluent. Saturated ammonium chloride solution was added to the mixture and the product was extracted with Et2O (50 ml). The organic phase was washed several times with saturated aqueous ammonium chloride and sodium bicarbonate to remove last traces of copper salts. The organic layer was then evaporated and the crude residue was purified with CC (OK.Interchim, 330 g SiO2, petroleum ether/MtBE, where MtBE was 5~35%, flow rate=130 mL/min, Rv=6 CV) to obtain 4-cyano - Ethyl 2,2-difluorovalerate (10 g, 52.31 mmol, 70.19% yield).

1 H NMR(CDCl3 ,500MHz)：1.32(d,3H),1.45(t,3H),2.28(q,1H),2.54(q,1H),2.98(m,1H),4.37(q,2H)。 1 H NMR (CDCl 3 , 500MHz): 1.32(d,3H), 1.45(t,3H), 2.28(q,1H), 2.54(q,1H), 2.98(m,1H), 4.37(q,2H) ).

步驟2：4,4-二氟-5-(4-氟苯基)-2-甲基-5-側氧基戊腈之合成Step 2: Synthesis of 4,4-difluoro-5-(4-fluorophenyl)-2-methyl-5-oxovaleronitrile

在-10℃下，向1-溴-4-氟苯(8.70g，49.69mmol，5.47mL)於Et2O(50mL)及THF(50mL)中之溶液中逐滴添加於己烷中之2.5M正丁基鋰(2.5M，19.88mL)。有機鋰物質形成後接著進行1 H-NMR。在-10℃下，向所得溶液中逐滴添加於Et2O(50mL)中之化合物4-氰基-2,2-二氟戊酸乙酯(9.5g，49.69mmol)。將混合物在-10℃下攪拌2h。將反應物用飽和氯化銨水溶液淬滅，添加EtOAc且分離各相。用EtOAc(2 x 5mL)進一步萃取水相。將經合併之有機相經MgSO4乾燥，過濾，在真空中濃縮，以得到4,4-二氟-5-(4-氟苯基)-2-甲基-5-側氧基戊腈(8.5g，35.24mmol，70.91%產率)，其不經純化即用於下一步驟。To a solution of 1-bromo-4-fluorobenzene (8.70 g, 49.69 mmol, 5.47 mL) in Et2O (50 mL) and THF (50 mL) was added dropwise 2.5 M n-hexane in hexane at -10 °C Butyllithium (2.5M, 19.88 mL). The formation of the organolithium species was followed by 1 H-NMR. To the resulting solution was added the compound ethyl 4-cyano-2,2-difluorovalerate (9.5 g, 49.69 mmol) in Et2O (50 mL) dropwise at -10 °C. The mixture was stirred at -10 °C for 2 h. The reaction was quenched with saturated aqueous ammonium chloride, EtOAc was added and the phases were separated. The aqueous phase was further extracted with EtOAc (2 x 5 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to give 4,4-difluoro-5-(4-fluorophenyl)-2-methyl-5-oxopentanenitrile (8.5 g, 35.24 mmol, 70.91% yield), which was used in the next step without purification.

1 H NMR(CDCl3 ,400MHz)：1.52(d,3H),2.42(m,1H),2.61(m,1H),3.18(m,1H),7.19(m,2H),8.20(m,2H)。 1 H NMR (CDCl 3 , 400MHz): 1.52(d,3H), 2.42(m,1H), 2.61(m,1H), 3.18(m,1H), 7.19(m,2H), 8.20(m,2H) ).

步驟3：N-[4,4-二氟-5-(4-氟苯基)-5-羥基-2-甲基戊基]胺甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl N-[4,4-difluoro-5-(4-fluorophenyl)-5-hydroxy-2-methylpentyl]carbamate

將4,4-二氟-5-(4-氟苯基)-2-甲基-5-側氧基戊腈(8.5g，35.24mmol)及碳酸第三丁氧基羰基第三丁酯(23.07g，105.72mmol，24.26mL)溶解於MeOH(20mL)中且冷卻至-10℃，接著分多批添加98%氯化鎳(II)六水合物(2.00g，7.05mmol，1.04mL)及硼氫化鈉(13.33g，352.39mmol，12.46mL)，保持溫度低於-5 ℃。在氣體逸出停止後，過濾出混合物且在減壓下蒸發。在減壓下蒸發經合併之有機溶劑；將粗產物溶解於MTBE(20mL)中且用飽和NH4 Cl水溶液洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以得到N-[4,4-二氟-5-(4-氟苯基)-5-羥基-2-甲基戊基]胺甲酸第三丁酯(6.5g，18.71mmol，53.10%產率)，其不經純化即用於下一步驟。4,4-Difluoro-5-(4-fluorophenyl)-2-methyl-5-oxyvaleronitrile (8.5 g, 35.24 mmol) and tert-butoxycarbonyl tert-butyl carbonate ( 23.07 g, 105.72 mmol, 24.26 mL) was dissolved in MeOH (20 mL) and cooled to -10°C, followed by addition of 98% nickel(II) chloride hexahydrate (2.00 g, 7.05 mmol, 1.04 mL) and Sodium borohydride (13.33 g, 352.39 mmol, 12.46 mL), keeping the temperature below -5 °C. After gas evolution ceased, the mixture was filtered off and evaporated under reduced pressure. The combined organic solvents were evaporated under reduced pressure; the crude product was dissolved in MTBE (20 mL) and washed with saturated aqueous NH4Cl , dried over Na2SO4 and evaporated under reduced pressure to give N-[ 4 , 3-butyl 4-difluoro-5-(4-fluorophenyl)-5-hydroxy-2-methylpentyl]carbamate (6.5 g, 18.71 mmol, 53.10% yield) without purification for the next step.

LCMS(ESI)：[M+Na]+ m/z：計算值347.2；實測值370.2；Rt=1.291min。LCMS (ESI): [M+Na] + m/z: calculated 347.2; found 370.2; Rt=1.291 min.

步驟4：N-[4,4-二氟-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 4: Synthesis of N-[4,4-difluoro-5-(4-fluorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

將N-[4,4-二氟-5-(4-氟苯基)-5-羥基-2-甲基戊基]胺甲酸第三丁酯(6.5g，18.71mmol)溶解於DCM(20mL)中，隨後添加戴斯-馬丁高碘烷(9.52g，22.45mmol)。反應完成之後，過濾出沉澱且在減壓下蒸發。用CC(己烷/EtOAc 9：1)純化粗混合物，以得到N-[4,4-二氟-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(1.2g，3.47mmol，18.57%產率)。3-Butyl N-[4,4-difluoro-5-(4-fluorophenyl)-5-hydroxy-2-methylpentyl]carbamate (6.5 g, 18.71 mmol) was dissolved in DCM (20 mL) ) followed by the addition of Dess-Martin periodinane (9.52 g, 22.45 mmol). After the reaction was complete, the precipitate was filtered off and evaporated under reduced pressure. The crude mixture was purified with CC (hexane/EtOAc 9:1) to give N-[4,4-difluoro-5-(4-fluorophenyl)-2-methyl-5-pendoxopentyl] tert-butyl carbamate (1.2 g, 3.47 mmol, 18.57% yield).

1 H NMR(400MHz,CDCl3 )1.12(d,3H),1.48(s,9H),2.08(m,2H),2.31(m,1H),3.12(m,2H),4.89(m,1H),7.18(m,2H),8.16(m,2H)。 1 H NMR (400MHz, CDCl 3 ) 1.12(d,3H), 1.48(s,9H), 2.08(m,2H), 2.31(m,1H), 3.12(m,2H), 4.89(m,1H) , 7.18 (m, 2H), 8.16 (m, 2H).

LCMS(ESI)：[M+Na]+ m/z：計算值345.2；實測值368.2；Rt=1.437min。LCMS (ESI): [M+Na] + m/z: calculated 345.2; found 368.2; Rt=1.437 min.

步驟5：5,5-三氟-6-(4-氟苯基)-3-甲基-3,4-二氫-2H-吡啶之合成Step 5: Synthesis of 5,5-trifluoro-6-(4-fluorophenyl)-3-methyl-3,4-dihydro-2H-pyridine

將N-[4,4-二氟-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(1.1g，3.19mmol)溶解於DCM(20mL)中，隨後添加TFA(1.82g，15.93mmol，1.23mL)。在反應完成(氣體逸出停止)之後，將混合物用10% K2 CO3 水溶液鹼化至pH 10，經Na2 SO4 乾燥且在減壓下蒸發，以得到5,5-二氟-6-(4-氟苯基)-3-甲基-3,4-二氫-2H-吡啶(0.8g，粗品)其不經純化即用於下一步驟。3-butyl N-[4,4-Difluoro-5-(4-fluorophenyl)-2-methyl-5-oxypentyl]carbamate (1.1 g, 3.19 mmol) was dissolved in DCM (20 mL) followed by TFA (1.82 g, 15.93 mmol, 1.23 mL). After the reaction was complete (gas evolution ceased), the mixture was basified to pH 10 with 10 % aqueous K2CO3, dried over Na2SO4 and evaporated under reduced pressure to give 5,5-difluoro-6 -(4-Fluorophenyl)-3-methyl-3,4-dihydro-2H-pyridine (0.8 g, crude) which was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )1.02(d,3H),1.67(m,1H),2.10(m,1H),2.42(m,1H),3.24(m,1H),4.17(m,1H),7.08(m,2H),7.89(m,2H)。 1 H NMR (400MHz, CDCl 3 ) 1.02(d,3H), 1.67(m,1H), 2.10(m,1H), 2.42(m,1H), 3.24(m,1H), 4.17(m,1H) , 7.08 (m, 2H), 7.89 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值227.1；實測值228.2；Rt=1.269min。LCMS (ESI): [M+H] + m/z: calculated 227.1; found 228.2; Rt=1.269 min.

步驟6：(2S,5S)-3,3-三氟-2-(4-氟苯基)-5-甲基哌啶之合成Step 6: Synthesis of (2S,5S)-3,3-trifluoro-2-(4-fluorophenyl)-5-methylpiperidine

將5,5-二氟-6-(4-氟苯基)-3-甲基-3,4-二氫-2H-吡啶(0.8g，3.52mmol)溶解於MeOH(20mL)中且冷卻至0℃，隨後分幾批添加硼氫化鈉(399.60mg，10.56mmol，373.45μL)。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH=2且在減壓下蒸發有機溶劑。將粗混合物溶解於H2 O(10mL)中，用MTBE(10mL)洗滌，用10% K2 CO3 水溶液酸化至pH=10且用DCM(20mL)萃取3次。蒸發有機溶劑，得到(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基哌啶，其不經純化即用於下一步驟。5,5-Difluoro-6-(4-fluorophenyl)-3-methyl-3,4-dihydro-2H-pyridine (0.8 g, 3.52 mmol) was dissolved in MeOH (20 mL) and cooled to At 0°C, sodium borohydride (399.60 mg, 10.56 mmol, 373.45 μL) was then added in several portions. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl and the organic solvent was evaporated under reduced pressure. The crude mixture was dissolved in H2O (10 mL), washed with MTBE (10 mL), acidified to pH=10 with 10 % aqueous K2CO3 and extracted 3 times with DCM (20 mL). Evaporation of the organic solvent gave (2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methylpiperidine, which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值229.1；實測值230.0；Rt=0.733min。LCMS (ESI): [M+H] + m/z: calculated 229.1; found 230.0; Rt=0.733 min.

3EE.(2S,5S)-3-氟-2-(4-氟苯基)-5-甲基哌啶之合成 3EE. Synthesis of (2S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0618-728
Figure 110128222-A0202-12-0618-728

步驟1：3-氟-5-甲基2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-fluoro-5-methyl 2-oxypiperidine-1-carboxylic acid tert-butyl ester

將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(5g，23.44mmol)溶解於THF(5mL)中且冷卻至-78℃，接著逐滴添加六甲基二矽氮烷鋰(1.1M，23.44mL)。10min之後，一次性添加N-(苯磺醯基)-N-氟苯磺醯胺(7.39g，23.44mmol)且使反應混合物升溫至-10℃。反應完成之後，將混合物倒入飽和NH4 Cl水溶液上，且用EtOAc(10mL)萃取。蒸發溶劑，得到粗產物。用CC(Companion combiflash,220g SiO2，石油醚/MtBE，其中MtBE為10~35%，流速=100mL/min，Rv=7 CV)純化，得到3-氟-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(1.5g，6.49mmol，27.67%產率)。Tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (5 g, 23.44 mmol) was dissolved in THF (5 mL) and cooled to -78°C, followed by dropwise addition of hexamethyldisilazane Lithium azane (1.1 M, 23.44 mL). After 10 min, N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (7.39 g, 23.44 mmol) was added in one portion and the reaction mixture was warmed to -10 °C. After the reaction was complete, the mixture was poured onto saturated aqueous NH4Cl and extracted with EtOAc (10 mL). Evaporation of the solvent gave crude product. Purify with CC (Companion combiflash, 220g SiO2, petroleum ether/MtBE, wherein MtBE is 10~35%, flow rate=100mL/min, Rv=7 CV) to obtain 3-fluoro-5-methyl-2-side oxygen 3-Butyl piperidine-1-carboxylate (1.5 g, 6.49 mmol, 27.67% yield).

1 H NMR(CDCl3 ,500MHz)：1.02(d,3H),1.41(s,9H),1.79(m,1H),2.22(m,2H),3.22(m,1H),3.75(m,1H),4.91(m,1H)。 1 H NMR (CDCl 3 , 500MHz): 1.02(d,3H), 1.41(s,9H), 1.79(m,1H), 2.22(m,2H), 3.22(m,1H), 3.75(m,1H) ), 4.91(m, 1H).

步驟2：N-[4-氟-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 2: Synthesis of N-[4-fluoro-5-(4-fluorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

在存在催化量之I2之情況下，將1-溴-4-氟苯(1.36g，7.78mmol)及鎂(315.35mg，12.97mmol，181.24μL)於THF(20mL)中回流2h。將所獲得之深色溶液冷卻至室溫且轉移至滴液漏斗。1-Bromo-4-fluorobenzene (1.36 g, 7.78 mmol) and magnesium (315.35 mg, 12.97 mmol, 181.24 μL) were refluxed in THF (20 mL) for 2 h in the presence of a catalytic amount of I2. The obtained dark solution was cooled to room temperature and transferred to a dropping funnel.

將3-氟-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(1.5g，6.49mmol)溶解於THF(20mL)中且在Ar下冷卻至-78℃。在同一溫度下緩慢添加所獲得之格任亞試劑。反應完成之後，將混合物用飽和NH4 Cl水溶液淬滅且用EtOAc(3*100mL)萃取。將經合併之有機層用鹽水(3*30mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以得到粗產物，其藉由CC(Ok.Companion combiflash；40g SiO2；石油醚/MtBE，其中MtBE為0至38%，流速=40ml/min，Rv=11-12cv.)進行純化，以得到N-[4-氟-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(1.1g，3.36mmol，51.81%產率)。3-Fluoro-5-methyl-2-pendoxopiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.49 mmol) was dissolved in THF (20 mL) and cooled to -78 °C under Ar. The obtained Grignard reagent was slowly added at the same temperature. After the reaction was complete, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3*100 mL). The combined organic layers were washed with brine (3*30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give crude product, which was purified by CC (Ok. Companion combiflash; 40 g SiO 2 ; petroleum ether/MtBE , with MtBE from 0 to 38%, flow rate=40ml/min, Rv=11-12cv.) was purified to give N-[4-fluoro-5-(4-fluorophenyl)-2-methyl-5 - tert-butyl pendant oxypentyl]carbamate (1.1 g, 3.36 mmol, 51.81% yield).

LCMS(ESI)：[M+Na]+ m/z：計算值327.2；實測值350.2；Rt=1.322min。LCMS (ESI): [M+Na] + m/z: calculated 327.2; found 350.2; Rt=1.322 min.

步驟3：5-氟-6-(4-氟苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 5-fluoro-6-(4-fluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將N-[4-氟-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(1.1g，3.36mmol)溶解於DCM(20mL)中，隨後添加TFA(1.92g，16.80mmol，1.29mL)。反應完成(氣體逸出停止)之後，將混合物用10% K2 CO3 水溶液鹼化至pH=10，經Na2 SO4 乾燥且在減壓下蒸發，以得到5-氟-6-(4-氟苯基)-3-甲基-2,3,4,5-四氫吡啶，其不經純化即用於下一步驟。3-Butyl N-[4-fluoro-5-(4-fluorophenyl)-2-methyl-5-oxypentyl]carbamate (1.1 g, 3.36 mmol) was dissolved in DCM (20 mL) , followed by the addition of TFA (1.92 g, 16.80 mmol, 1.29 mL). After the reaction was complete (gas evolution ceased), the mixture was basified with 10% aqueous K 2 CO 3 to pH=10, dried over Na 2 SO 4 and evaporated under reduced pressure to give 5-fluoro-6-(4 -Fluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine, which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值209.1；實測值210.2；Rt=0.728min。LCMS (ESI): [M+H] + m/z: calculated 209.1; found 210.2; Rt=0.728 min.

步驟4：(2S,5S)-3-氟-2-(4-氟苯基)-5-甲基哌啶之合成Step 4: Synthesis of (2S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methylpiperidine

將5-氟-6-(4-氟苯基)-3-甲基-2,3,4,5-四氫吡啶(736.66mg，3.52mmol) 溶解於MeOH(20mL)中且冷卻至0℃，隨後分幾批次添加硼氫化鈉(399.60mg，10.56mmol，373.45μL)。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH=2且在減壓下蒸發有機溶劑。將粗混合物溶解於H2 O(10mL)中，用MTBE(10mL)洗滌，用10% K2 CO3 水溶液酸化至pH=10且用DCM(20mL)萃取3次。蒸發有機溶劑，得到(2S,5S)-3-氟-2-(4-氟苯基)-5-甲基哌啶(0.5g，2.37mmol，67.23%產率)，其不經純化即用於下一步驟。5-Fluoro-6-(4-fluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (736.66 mg, 3.52 mmol) was dissolved in MeOH (20 mL) and cooled to 0 °C , followed by the addition of sodium borohydride (399.60 mg, 10.56 mmol, 373.45 μL) in several batches. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl and the organic solvent was evaporated under reduced pressure. The crude mixture was dissolved in H2O (10 mL), washed with MTBE (10 mL), acidified to pH=10 with 10 % aqueous K2CO3 and extracted 3 times with DCM (20 mL). Evaporation of the organic solvent gave (2S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methylpiperidine (0.5 g, 2.37 mmol, 67.23% yield) which was used without purification in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值211.2；實測值212.0；Rt=0.726min。LCMS (ESI): [M+H] + m/z: calculated 211.2; found 212.0; Rt=0.726 min.

3FF.410 min。第三丁基(2R,5S)-5-甲基-2-[1-(1H-吡唑-3-基)吡唑-4-基]哌啶及(2R,5S)-5-甲基-2-(1H-吡唑-4-基)哌啶之合成 3FF. 410 min. tert-butyl(2R,5S)-5-methyl-2-[1-(1H-pyrazol-3-yl)pyrazol-4-yl]piperidine and (2R,5S)-5-methyl Synthesis of -2-(1H-pyrazol-4-yl)piperidine

Figure 110128222-A0202-12-0620-729
Figure 110128222-A0202-12-0620-729

步驟1. 6-二苯氧基磷醯氧基-3-甲基-3,4-三氫-2H-吡啶-1-甲酸第三丁酯Step 1. 6-Diphenoxyphosphoryloxy-3-methyl-3,4-trihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

在氬氣下，將雙(三甲基矽基)醯胺化鋰(49.04g，58.61mmol，54.48mL，20%純度)(1.08M於THF/乙苯中)逐滴添加到冷卻至-78℃之5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(10g，46.89mmol)於THF(100mL)中之溶液中。將所得溶液在-78℃下攪拌1.5h，然後逐滴添加[氯(苯氧基)磷醯基]氧基苯(12.60g，46.89mmol，9.69mL)，保持溫度低於-70℃。使反應混合物升溫(移除冷卻浴)至0℃，然後用水(20ml)及MTBE(100ml)稀釋。將有機層分離，另外用MTBE(50ml)萃取水層。將經合併之有機萃取物用10%氫氧化鈉水溶液(2*100ml)洗滌，經碳酸鉀乾燥，且在真空中濃縮。將殘餘物溶解於己烷/MTBE混合物(1/1，400ml)中且透過短矽膠墊過濾所得混濁溶液，且在真空中蒸發，以得到呈淡黃色油狀物之 粗品6-二苯氧基磷醯氧基-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(21g，粗品)，其直接用於下一步驟中。Under argon, lithium bis(trimethylsilyl)amide (49.04 g, 58.61 mmol, 54.48 mL, 20% purity) (1.08 M in THF/ethylbenzene) was added dropwise to a cooled to -78 A solution of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (10 g, 46.89 mmol) in THF (100 mL) at °C. The resulting solution was stirred at -78 °C for 1.5 h, then [chloro(phenoxy)phosphoryl]oxybenzene (12.60 g, 46.89 mmol, 9.69 mL) was added dropwise, keeping the temperature below -70 °C. The reaction mixture was warmed (cooling bath removed) to 0°C, then diluted with water (20ml) and MTBE (100ml). The organic layer was separated and the aqueous layer was additionally extracted with MTBE (50 ml). The combined organic extracts were washed with 10% aqueous sodium hydroxide solution (2*100ml), dried over potassium carbonate and concentrated in vacuo. The residue was dissolved in a hexane/MTBE mixture (1/1, 400 ml) and the resulting cloudy solution was filtered through a short pad of silica gel and evaporated in vacuo to give a pale yellow oil. Crude 6-diphenoxyphosphoryloxy-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (21 g, crude) was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.95(d,3H),1.41(s,9H),1.69(m,1H),1.87(m,1H),2.25(m,1H),2.97(dd,1H),5.05(t,1H),7.17-7.33(m,10H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.95(d,3H), 1.41(s,9H), 1.69(m,1H), 1.87(m,1H), 2.25(m,1H), 2.97 (dd, 1H), 5.05 (t, 1H), 7.17-7.33 (m, 10H).

LCMS(ESI)：[M-Boc]+ m/z：計算值445.4；實測值346.2；Rt=1.517min。LCMS (ESI): [M-Boc] + m/z: calculated 445.4; found 346.2; Rt=1.517 min.

步驟2. 6-(1-苯甲基吡唑-4-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯Step 2. 6-(1-Benzylpyrazol-4-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-二苯氧基磷醯氧基-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(17g，38.16mmol)、1-苯甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑(11.93g，41.98mmol)及碳酸鈉(12.1.4g，114.49mmol，4.80mL)添加到1,4-二噁烷(150mL)及水(50mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2．DCM(1.56g，1.91mmol)。將反應混合物在氬氣、80℃下攪拌18h，然後冷卻且過濾。將濾餅用二噁烷(2*50ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用己烷/MTBE梯度(0-35% MTBE)純化殘餘物，以得到呈淡黃色膠狀物之6-(1-苯甲基吡唑-4-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.6g，27.16mmol，71.17%產率)，其直接用於下一步驟中。6-Diphenoxyphosphoryloxy-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (17 g, 38.16 mmol), 1-benzyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole (11.93g, 41.98mmol) and sodium carbonate (12.1.4g, 114.49g) mmol, 4.80 mL) was added to a mixture of 1,4-dioxane (150 mL) and water (50 mL). The resulting mixture was evacuated and backfilled with argon. This operation was repeated three times, and then Pd(dppf)Cl2 was added under argon. DCM (1.56 g, 1.91 mmol). The reaction mixture was stirred under argon at 80 °C for 18 h, then cooled and filtered. The filter cake was washed with dioxane (2*50ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/MTBE gradient (0-35% MTBE) to give 6-(1-benzylpyridine as a pale yellow gum) Azol-4-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.6 g, 27.16 mmol, 71.17% yield), which was used directly in the next step middle.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.95(d,3H),1.04(s,9H),1.72(m,1H),1.84(m,1H),2.22(m,1H),2.85(dd,1H),3.78(d,1H),5.19(brs,2H),7.23-7.26(m,5H),7.51(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.95(d,3H), 1.04(s,9H), 1.72(m,1H), 1.84(m,1H), 2.22(m,1H), 2.85 (dd, 1H), 3.78 (d, 1H), 5.19 (brs, 2H), 7.23-7.26 (m, 5H), 7.51 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值353.4；實測值354.4；Rt=1.428min。LCMS (ESI): [M-Boc] + m/z: calculated 353.4; found 354.4; Rt=1.428 min.

步驟3. 6-(1-苯甲基吡唑-4-基)-3-甲基-2,3,4,5-四氫吡啶Step 3. 6-(1-Benzylpyrazol-4-yl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(1-苯甲基吡唑-4-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.6g，27.16mmol)於三氟乙酸(111.00g，973.51mmol，75mL)中之溶液在25℃下攪拌1h。1小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用冰冷水 (100mL)稀釋且用10% NaOH水溶液中和，直至pH=10。用二氯甲烷(2 x 100mL)萃取所得混合物。將經合併之有機相經硫酸鈉乾燥且在減壓下濃縮，以得到呈淡黃色膠狀物之6-(1-苯甲基吡唑-4-基)-3-甲基-2,3,4,5-四氫吡啶(6.3g，24.87mmol，91.56%產率)，其直接用於下一步驟中。6-(1-Benzylpyrazol-4-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.6 g, 27.16 mmol) in trifluoro A solution in acetic acid (111.00 g, 973.51 mmol, 75 mL) was stirred at 25 °C for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was washed with ice-cold water (100 mL) was diluted and neutralized with 10% aqueous NaOH until pH=10. The resulting mixture was extracted with dichloromethane (2 x 100 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 6-(1-benzylpyrazol-4-yl)-3-methyl-2,3 as a pale yellow gum ,4,5-tetrahydropyridine (6.3 g, 24.87 mmol, 91.56% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.05(s,3H),1.30(m,1H),1.60(m,1H),1.84(m,1H),2.45(m,1H),2.65(dd,1H),3.15(m,1H),3.95(d,1H),5.32(s,2H),7.23-7.34(m,5H),7.68(s,1H),7.79(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.05(s, 3H), 1.30(m, 1H), 1.60(m, 1H), 1.84(m, 1H), 2.45(m, 1H), 2.65( dd, 1H), 3.15 (m, 1H), 3.95 (d, 1H), 5.32 (s, 2H), 7.23-7.34 (m, 5H), 7.68 (s, 1H), 7.79 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值253.3；實測值254.2；Rt=0.715min。LCMS (ESI): [M-Boc] + m/z: calculated 253.3; found 254.2; Rt=0.715 min.

步驟4. (2R,5S)-2-(1-苯甲基吡唑-4-基)-5-甲基哌啶Step 4. (2R,5S)-2-(1-Benzylpyrazol-4-yl)-5-methylpiperidine

將6-(1-苯甲基吡唑-4-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.6g，27.16mmol)於三氟乙酸(111.00g，973.51mmol，75mL)中之溶液在25℃下攪拌1h。1小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用冰冷水(100mL)稀釋且用10% NaOH水溶液中和，直至pH=10。用二氯甲烷(2 x 100mL)萃取所得混合物。將經合併之有機相經硫酸鈉乾燥且在減壓下濃縮，以得到呈淡黃色膠狀物之6-(1-苯甲基吡唑-4-基)-3-甲基-2,3,4,5-四氫吡啶(6.3g，24.87mmol，91.56%產率)，其直接用於下一步驟中。6-(1-Benzylpyrazol-4-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.6 g, 27.16 mmol) in trifluoro A solution in acetic acid (111.00 g, 973.51 mmol, 75 mL) was stirred at 25 °C for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ice-cold water (100 mL) and neutralized with 10% aqueous NaOH until pH=10. The resulting mixture was extracted with dichloromethane (2 x 100 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 6-(1-benzylpyrazol-4-yl)-3-methyl-2,3 as a pale yellow gum ,4,5-tetrahydropyridine (6.3 g, 24.87 mmol, 91.56% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.75(s,3H),1.10(dd,1H),1.40(m,1H),1.50-1.70(brs,1H),1.87(t,2H),2.33(t,1H),3.03(d,1H),3.59(d,1H),5.25(s,2H),7.20(s,1H),7.29-7.32(m,5H),7.46(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.75(s, 3H), 1.10(dd, 1H), 1.40(m, 1H), 1.50-1.70(brs, 1H), 1.87(t, 2H), 2.33(t, 1H), 3.03(d, 1H), 3.59(d, 1H), 5.25(s, 2H), 7.20(s, 1H), 7.29-7.32(m, 5H), 7.46(s, 1H) .

LCMS(ESI)：[M-Boc]+ m/z：計算值255.3；實測值256.2；Rt=0.733min。LCMS (ESI): [M-Boc] + m/z: calculated 255.3; found 256.2; Rt=0.733 min.

步驟5. (2R,5S)-2-(1-苯甲基吡唑-4-基)-5-甲基哌啶-1-甲酸第三丁酯Step 5. tert-butyl (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-methylpiperidine-1-carboxylate

在25℃下，將二碳酸二-第三丁酯(5.47g，25.08mmol，5.76mL)一次性添加到(2R,5S)-2-(1-苯甲基吡唑-4-基)-5-甲基哌啶(6.1g，23.89mmol)於二氯甲烷(100mL)中之經攪拌之溶液中。將反應混合物在25℃下攪拌1h，然後在真空 中濃縮，以得到呈淡黃色膠狀物之粗品(2R,5S)-2-(1-苯甲基吡唑-4-基)-5-甲基哌啶-1-甲酸第三丁酯(8.4g，23.63mmol，98.92%產率)，其直接用於下一步驟中。At 25°C, di-tert-butyl dicarbonate (5.47 g, 25.08 mmol, 5.76 mL) was added in one portion to (2R,5S)-2-(1-benzylpyrazol-4-yl)- In a stirred solution of 5-methylpiperidine (6.1 g, 23.89 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 25 °C for 1 h, then under vacuum was concentrated to give crude (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester as a pale yellow gum ( 8.4 g, 23.63 mmol, 98.92% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.95(s,3H),1.10-1.40(m,12H),1.40-1.80(m,4H),2.10(t,1H),2.95(d,1H),3.75(d,1H),5.20(s,2H),5.40(s,1H),7.20-7.38(m,7H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.95(s, 3H), 1.10-1.40(m, 12H), 1.40-1.80(m, 4H), 2.10(t, 1H), 2.95(d, 1H) ), 3.75(d, 1H), 5.20(s, 2H), 5.40(s, 1H), 7.20-7.38(m, 7H).

LCMS(ES1)：[M+1]+ m/z：計算值355.5；實測值356.2；Rt=1.567min。LCMS (ES1): [M+1] + m/z: calculated 355.5; found 356.2; Rt=1.567 min.

步驟6. (2R,5S)-5-甲基-2-(1H-吡唑-4-基)哌啶-1-甲酸第三丁酯Step 6. (2R,5S)-5-Methyl-2-(1H-pyrazol-4-yl)piperidine-1-carboxylic acid tert-butyl ester

向(2R,5S)-2-(1-苯甲基吡唑-4-基)-5-甲基哌啶-1-甲酸第三丁酯(8.4g，23.63mmol)於甲醇(150mL)中之溶液中添加濕潤的10%鈀/碳(2.51g，23.63mmol)及乙酸(2.13g，35.45mmol，2.03mL)。將所得混合物抽真空，然後用氫氣回填。將反應混合物在氫氣氣氛(氣球壓力)、55℃下攪拌96h。等分試樣之HNMR顯示50%轉化。將10% Pd/碳A402028-10批號C-14557(1.5g，23.63mmol)添加到反應混合物中，且將其再次抽真空，然後用氫氣回填；然後在氫氣(氣球壓力)、55℃下攪拌48h。等分試樣之HNMR顯示反應完成。過濾出催化劑，在真空中濃縮濾液。將殘餘物溶解於二氯甲烷(100ml)中且用碳酸氫鈉(3g)於水(50ml)中之溶液洗滌。將有機層分離，經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色膠狀物之(2R,5S)-5-甲基-2-(1H-吡唑-4-基)哌啶-1-甲酸第三丁酯(6g，22.61mmol，95.69%產率)，其直接用於下一步驟中。To (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (8.4 g, 23.63 mmol) in methanol (150 mL) To this solution was added wet 10% palladium on carbon (2.51 g, 23.63 mmol) and acetic acid (2.13 g, 35.45 mmol, 2.03 mL). The resulting mixture was evacuated and backfilled with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) at 55 °C for 96 h. HNMR of an aliquot showed 50% conversion. 10% Pd/Carbon A402028-10 Lot C-14557 (1.5 g, 23.63 mmol) was added to the reaction mixture and it was evacuated again, then backfilled with hydrogen; then stirred under hydrogen (balloon pressure) at 55°C 48h. HNMR of an aliquot showed the reaction to be complete. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (100ml) and washed with a solution of sodium bicarbonate (3g) in water (50ml). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give (2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)piperidine- as a pale yellow gum 3-Butyl 1-carboxylate (6 g, 22.61 mmol, 95.69% yield) was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.03(d,3H),1.37(m,1H),1.48(s,9H),1.82(m,3H),2.13(m,1H),2.98(d,1H),3.72(d,1H),5.42(d,1H),7.43(s,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.03(d,3H), 1.37(m,1H), 1.48(s,9H), 1.82(m,3H), 2.13(m,1H), 2.98( d, 1H), 3.72 (d, 1H), 5.42 (d, 1H), 7.43 (s, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值265.2；實測值266.2；Rt=1.315min。LCMS (ESI): [M+1] + m/z: calculated 265.2; found 266.2; Rt=1.315 min.

步驟7. (2R,5S)-5-甲基-2-[1-(1-四氫哌喃-2-基吡唑-3-基)吡唑-4-基]哌啶-1-甲酸第三丁酯Step 7. (2R,5S)-5-Methyl-2-[1-(1-tetrahydropyran-2-ylpyrazol-3-yl)pyrazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester

將(2R,5S)-5-甲基-2-(1H-吡唑-4-基)哌啶-1-甲酸第三丁酯(3g，11.31 .mol)、3-碘-1-四氫哌喃-2-基-吡唑(4.3g，15.46mmol)、碘化銅(I)(1.50g，7.88mmol，266.90μL)、99%無水碳酸鉀(3.8g，27.49mmol，1.66mL)、N1,N2-二甲基環己-1,2-二胺(959.99mg，6.75mmol)、銅(400mg，6.29mmol)及甲苯(100mL)於100ml裝備有回流冷凝器及玻璃塞之單頸圓底燒瓶中之混合物抽真空，然後用氬氣回填。然後將反應混合物在氬氣、110℃下攪拌20h。將反應混合物冷卻，且添加50ml 25%氨水。將所得混合物攪拌10min，然後透過短矽酸鎂墊過濾。將濾餅另外用乙酸乙酯(2*50ml)洗滌且丟棄。將濾液轉移至分液漏斗，分離各層，將有機層另外用水(50ml)洗滌，經硫酸鈉乾燥，且在真空中濃縮，以得到呈淡黃色膠狀物之粗品(2R,5S)-5-甲基-2-[1-(1-四氫哌喃-2-基吡唑-3-基)吡唑-4-基]哌啶-1-甲酸第三丁酯(4.9g，粗品)，其直接用於下一步驟中。(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)piperidine-1-carboxylic acid tert-butyl ester (3 g, 11.31 .mol), 3-iodo-1-tetrahydropyran-2-yl-pyrazole (4.3 g, 15.46 mmol), copper(I) iodide (1.50 g, 7.88 mmol, 266.90 μL), 99% anhydrous carbonic acid Potassium (3.8 g, 27.49 mmol, 1.66 mL), N1,N2-dimethylcyclohexyl-1,2-diamine (959.99 mg, 6.75 mmol), copper (400 mg, 6.29 mmol) and toluene (100 mL) in 100 mL The mixture in a single neck round bottom flask equipped with a reflux condenser and glass stopper was evacuated and then backfilled with argon. The reaction mixture was then stirred under argon at 110 °C for 20 h. The reaction mixture was cooled and 50 ml of 25% aqueous ammonia was added. The resulting mixture was stirred for 10 min and then filtered through a pad of short magnesium silicate. The filter cake was additionally washed with ethyl acetate (2*50ml) and discarded. The filtrate was transferred to a separatory funnel, the layers were separated, the organic layer was washed with additional water (50 ml), dried over sodium sulfate, and concentrated in vacuo to give crude (2R,5S)-5- as a pale yellow gum Methyl-2-[1-(1-tetrahydropyran-2-ylpyrazol-3-yl)pyrazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester (4.9 g, crude), It is used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.47(s,9H),1.50-1.70(m,6H),1.70-1.90(m,3H),1.95-2.40(m,6H),3.00(d,1H),3.60-3.72(m,2.5H),4.10(m,1.50),5.28(d,1H),5.42(d,1H),6.54(s,1H),7.43(m,1H),7.40(s,1H),7.50(s,1H),7.90(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d, 3H), 1.47(s, 9H), 1.50-1.70(m, 6H), 1.70-1.90(m, 3H), 1.95-2.40(m ,6H),3.00(d,1H),3.60-3.72(m,2.5H),4.10(m,1.50),5.28(d,1H),5.42(d,1H),6.54(s,1H),7.43 (m, 1H), 7.40 (s, 1H), 7.50 (s, 1H), 7.90 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值415.2；實測值416.2；Rt=1.554min。LCMS (ESI): [M+1] + m/z: calculated 415.2; found 416.2; Rt=1.554 min.

步驟8. 第三丁基(2R,5S)-5-甲基2-[1-(1H-吡唑-3-基)吡唑-4-基]哌啶Step 8. Tert-Butyl(2R,5S)-5-methyl 2-[1-(1H-pyrazol-3-yl)pyrazol-4-yl]piperidine

在25℃下，將於二噁烷中之4.0M氯化氫溶液(26.25g，100.08mmol，25mL，13.9%純度)添加到(2R,5S)-5-甲基-2-[1-(1-四氫哌喃-2-基吡唑-3-基)吡唑-4-基]哌啶-1-甲酸第三丁酯(1.1g，2.65mmol)於甲醇(25mL)中之經攪拌之溶液中。將反應混合物在25℃下攪拌12h，然後在真空中濃縮，以得到呈淡黃色泡沫之粗品(2R,5S)-5-甲基-2-[1-(1H-吡唑-3-基)吡唑-4-基]哌啶(1.1g，粗品，3HCl)，其直接用於下一步驟中。A 4.0 M solution of hydrogen chloride in dioxane (26.25 g, 100.08 mmol, 25 mL, 13.9% purity) was added to (2R,5S)-5-methyl-2-[1-(1-) at 25°C A stirred solution of tetrahydropyran-2-ylpyrazol-3-yl)pyrazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.65 mmol) in methanol (25 mL) middle. The reaction mixture was stirred at 25 °C for 12 h, then concentrated in vacuo to give crude (2R,5S)-5-methyl-2-[1-(1H-pyrazol-3-yl) as a pale yellow foam Pyrazol-4-yl]piperidine (1.1 g, crude, 3HCl) was used directly in the next step.

1 H NMR(500MHz,DMSO)δ(ppm)0.87(d,3H),1.22(m,1H),1.26(m,1H),1.91(m,3H),2.60(m,2H),3.12(m,1H),4.13(t,1H),6.14(s,2H),7.79-7.87(m,2H), 8.40(s,1H),9.49(m,3H)。 1 H NMR (500MHz, DMSO)δ(ppm) 0.87(d,3H), 1.22(m,1H), 1.26(m,1H), 1.91(m,3H), 2.60(m,2H), 3.12(m , 1H), 4.13(t, 1H), 6.14(s, 2H), 7.79-7.87(m, 2H), 8.40(s, 1H), 9.49(m, 3H).

LCMS(ES1)：[M+1]+ m/z：計算值232.2；實測值231.2；Rt=0.672min。LCMS (ES1): [M+1] + m/z: calculated 232.2; found 231.2; Rt=0.672 min.

步驟9. (2R,5S)-5-甲基-2-(1H-吡唑-4-基)哌啶之合成 Step 9. Synthesis of (2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)piperidine

3GG.第三丁基6-(5-甲基-2-哌啶基)吡啶-3-胺之合成 3GG. Synthesis of tert-butyl 6-(5-methyl-2-piperidinyl)pyridin-3-amine

Figure 110128222-A0202-12-0625-730
Figure 110128222-A0202-12-0625-730

步驟1. (2S,5R)-1-第三丁氧基羰基-5-甲基哌啶-2-甲酸之合成Step 1. Synthesis of (2S,5R)-1-tert-butoxycarbonyl-5-methylpiperidine-2-carboxylic acid

將(2S,5R)-5-甲基哌啶-2-甲酸(14g，77.93mmol，HCl)溶解於水(150mL)中且向其中添加碳酸氫鈉(19.64g，233.80mmol，9.09mL)。將所得混合物用THF(150mL)稀釋且將二碳酸二-第三丁酯(20.41g，93.52mmol，21.46mL)逐滴添加到先前的混合物中。在室溫下攪拌所得混合物18h。在減壓下濃縮反應混合物且將殘餘物再溶解於水(50ml)中。將所得混合物用MTBE(3*50ml)萃取且將水層用NaHSO4 酸化。將所得混合物用DCM(2*50ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得呈白色固體之(2S,5R)-1-第三丁氧基羰基-5-甲基哌啶-2-甲酸(14g，57.54mmol，73.84%產率)。(2S,5R)-5-methylpiperidine-2-carboxylic acid (14 g, 77.93 mmol, HCl) was dissolved in water (150 mL) and to it was added sodium bicarbonate (19.64 g, 233.80 mmol, 9.09 mL). The resulting mixture was diluted with THF (150 mL) and di-tert-butyl dicarbonate (20.41 g, 93.52 mmol, 21.46 mL) was added dropwise to the previous mixture. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in water (50 ml). The resulting mixture was extracted with MTBE (3*50ml) and the aqueous layer was acidified with NaHSO4 . The resulting mixture was extracted with DCM (2*50ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to give (2S,5R)-1-tert-butoxycarbonyl- as a white solid 5-Methylpiperidine-2-carboxylic acid (14 g, 57.54 mmol, 73.84% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.88(d,3H),1.32(s,9H),1.31-1.42(m,2H),1.79(m,3H),3.04(m,1H),3.28(m,1H),3.47(d,1H),4.50(m,1H),12.65(brs,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.88(d, 3H), 1.32(s, 9H), 1.31-1.42(m, 2H), 1.79(m, 3H), 3.04(m, 1H) ), 3.28(m, 1H), 3.47(d, 1H), 4.50(m, 1H), 12.65(brs, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值243.3；實測值144.0；Rt=1.140min。LCMS (ESI): [M-Boc] + m/z: calculated 243.3; found 144.0; Rt=1.140 min.

步驟2. (2S,5R)-2-[甲氧基(甲基)胺甲醯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2. Synthesis of (2S,5R)-2-[methoxy(methyl)carbamoyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在25℃下，將羰基二咪唑(8.00g，49.32mmol)一次性添加到(2S,5R)-1-第三丁氧基羰基-5-甲基哌啶-2-甲酸(10g，41.10mmol)於THF(200mL)中之經攪 拌之溶液中。將所得混合物在25℃下攪拌，直到二氧化碳逸出完成，然後添加甲氧基(甲基)胺鹽酸鹽(8.02g，82.20mmol)及TEA(8.32g，82.20mmol，11.46mL)。將反應混合物在50℃下攪拌12h，然後冷卻且在真空中蒸發。將殘餘物用5%硫酸氫鈉水溶液(200ml)稀釋且用二氯甲烷(2*100ml)萃取。將經合併之有機萃取物用水(100ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈白色固體之(2S,5R)-2-[甲氧基(甲基)胺甲醯基]-5-甲基哌啶-1-甲酸第三丁酯(9g，31.43mmol，76.46%產率)，其直接用於下一步驟中。Carbonyldiimidazole (8.00 g, 49.32 mmol) was added in one portion to (2S,5R)-1-tert-butoxycarbonyl-5-methylpiperidine-2-carboxylic acid (10 g, 41.10 mmol) at 25 °C ) in THF (200 mL) by stirring mixed in the solution. The resulting mixture was stirred at 25°C until carbon dioxide evolution was complete, then methoxy(methyl)amine hydrochloride (8.02 g, 82.20 mmol) and TEA (8.32 g, 82.20 mmol, 11.46 mL) were added. The reaction mixture was stirred at 50 °C for 12 h, then cooled and evaporated in vacuo. The residue was diluted with 5% aqueous sodium bisulfate solution (200ml) and extracted with dichloromethane (2*100ml). The combined organic extracts were washed with water (100 ml), dried over sodium sulfate and evaporated in vacuo to give (2S,5R)-2-[methoxy(methyl)aminocarboxy] as a white solid - 3-butyl 5-methylpiperidine-1-carboxylate (9 g, 31.43 mmol, 76.46% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.87(d,3H),1.33(s,9H),1.56(m,3H),1.72(m,1H),1.84(m,1H),3.05(s,3H),3.39(m,2H),3.65(s,3H),4.71(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.87(d,3H), 1.33(s,9H), 1.56(m,3H), 1.72(m,1H), 1.84(m,1H), 3.05(s, 3H), 3.39(m, 2H), 3.65(s, 3H), 4.71(m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值286.4；實測值187.2；Rt=1.380min。LCMS (ESI): [M-Boc] + m/z: calculated 286.4; found 187.2; Rt=1.380 min.

步驟4. (2S,5R)-5-甲基-2-(5-硝基-2-吡啶基)哌啶-1-甲酸第三丁酯之合成Step 4. Synthesis of (2S,5R)-5-methyl-2-(5-nitro-2-pyridyl)piperidine-1-carboxylic acid tert-butyl ester

將(2S,5R)-2-乙醯基-5-甲基哌啶-1-甲酸第三丁酯(3.1g，12.85mmol)及1-甲基-3,5-二硝基-吡啶-2-酮(3.84g，19.27mmol)溶解於MeOH/NH3 (50mL)中。將反應混合物在90℃、高壓力下攪拌隔夜。然後將其冷卻且在真空中蒸發，以得到粗品(2S,5R)-5-甲基-2-(5-硝基-2-吡啶基)哌啶-1-甲酸第三丁酯(4g，12.45mmol，96.89%產率)，其不經純化即用於下一步驟。(2S,5R)-2-Acetyl-5-methylpiperidine-1-carboxylic acid tert-butyl ester (3.1 g, 12.85 mmol) and 1-methyl-3,5-dinitro-pyridine- The 2-one (3.84 g, 19.27 mmol) was dissolved in MeOH/ NH3 (50 mL). The reaction mixture was stirred at 90°C under high pressure overnight. It was then cooled and evaporated in vacuo to give crude (2S,5R)-5-methyl-2-(5-nitro-2-pyridyl)piperidine-1-carboxylic acid tert-butyl ester (4 g, 12.45 mmol, 96.89% yield), which was used in the next step without purification.

LCMS(ESI)：[M-Boc]+ m/z：計算值321.2；實測值222.2；Rt=1.328min。LCMS (ESI): [M-Boc] + m/z: calculated 321.2; found 222.2; Rt=1.328 min.

步驟5. (2S,5R)-2-(5-胺基-2-吡啶基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5. Synthesis of (2S,5R)-2-(5-amino-2-pyridyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2S,5R)-5-甲基-2-(5-硝基-2-吡啶基)哌啶-1-甲酸第三丁酯(4g，12.45mmol)溶解於MeOH(50mL)中且添加10%鈀/碳(662.29mg，622.33μmol，10%純度)。然後將反應混合物在25下攪拌24h。過濾催化劑。在真空中蒸發溶液，以得到粗品(2S,5R)-2-(5-胺基-2-吡啶基)-5-甲基哌啶-1-甲酸第三丁酯(3.6g，12.35mmol，99.26%產率)，其不經純化即用於下一步驟。(2S,5R)-5-methyl-2-(5-nitro-2-pyridyl)piperidine-1-carboxylic acid tert-butyl ester (4 g, 12.45 mmol) was dissolved in MeOH (50 mL) and added 10% palladium on carbon (662.29 mg, 622.33 μmol, 10% pure). The reaction mixture was then stirred at 25 for 24 h. Filter catalyst. The solution was evaporated in vacuo to give crude (2S,5R)-2-(5-amino-2-pyridyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (3.6 g, 12.35 mmol, 99.26% yield), which was used in the next step without purification.

LCMS(ESI)：[M-Boc]+ m/z：計算值291.2；實測值292.2；Rt=0.908min。LCMS (ESI): [M-Boc] + m/z: calculated 291.2; found 292.2; Rt=0.908 min.

步驟6. 第三丁基6-(5-甲基-2-哌啶基)吡啶-3-胺之合成Step 6. Synthesis of tert-butyl 6-(5-methyl-2-piperidinyl)pyridin-3-amine

將(2S,5R)-2-(5-胺基-2-吡啶基)-5-甲基哌啶-1-甲酸第三丁酯(1.9g，6.52mmol)溶解於二噁烷/HCl(15mL)中且在室溫下攪拌隔夜。然後在減壓下濃縮反應混合物。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5 mkm管柱及具有NH3 之H2 O-MeOH作為溶析液混合物)，以獲得純的6-(5-甲基-2-哌啶基)吡啶-3-胺(0.5g，2.61mmol，40.09%產率)。(2S,5R)-2-(5-amino-2-pyridyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.9 g, 6.52 mmol) was dissolved in dioxane/HCl ( 15 mL) and stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5 mkm column and H2O -MeOH with NH3 as eluent mixture) to obtain pure 6-(5-methyl-2-piperidine) Peridyl)pyridin-3-amine (0.5 g, 2.61 mmol, 40.09% yield).

LCMS(ESI)：[M+1]+ m/z：計算值191.2；實測值192.2；Rt=0.707min。LCMS (ESI): [M+1] + m/z: calculated 191.2; found 192.2; Rt=0.707 min.

3HH.2-(5-甲基-2-哌啶基)吡啶之合成 3HH. Synthesis of 2-(5-methyl-2-piperidinyl)pyridine

Figure 110128222-A0202-12-0627-731
Figure 110128222-A0202-12-0627-731

步驟1. 5-甲基-2-(2-吡啶基)哌啶-1-甲酸第三丁酯之合成Step 1. Synthesis of 3-butyl 5-methyl-2-(2-pyridyl)piperidine-1-carboxylate

將r[dF(CF3)ppy]2(dtbbpy)PF6(101.45mg，90.42μmol)、NiCl2甘醇二甲醚(198.68mg，904.24μmol)及dtbbpy(242.69mg，904.24μmol)一起混合在DMF(110mL)中。將1-第三丁氧基羰基-5-甲基哌啶-2-甲酸(2.2g，9.04mmol)、2-第三丁基-1,1,3,3-四甲基胍(1.55g，9.04mmol，1.82mL)及2-溴吡啶(1.43g，9.04mmol，876.48μL)添加到先前混合物中且藉由用氬氣吹掃來將所得混合物除氣15min。將小瓶密封，用石蠟膜纏繞且置於藍色LED光反應器中。將反應混合物在25℃下攪拌36h。在真空中濃縮反應混合物且將水(50ml)添加到殘餘物中。將所得混合物用EtOAc(2*50ml)萃取。將經合併之有機層用水(3*50ml)、鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由管柱層析純化殘餘物，以獲得呈順式及反式異構物(約1：1)之混合物形式之5-甲基-2-(2-吡啶基)哌啶-1-甲酸第三丁酯(1.45g，5.25mmol，58.02%產率)。r[dF(CF3)ppy]2(dtbbpy)PF6 (101.45 mg, 90.42 μmol), NiCl2 glyme (198.68 mg, 904.24 μmol) and dtbbpy (242.69 mg, 904.24 μmol) were mixed together in DMF (110 mL). )middle. Combine 1-tert-butoxycarbonyl-5-methylpiperidine-2-carboxylic acid (2.2 g, 9.04 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (1.55 g , 9.04 mmol, 1.82 mL) and 2-bromopyridine (1.43 g, 9.04 mmol, 876.48 μL) were added to the previous mixture and the resulting mixture was degassed by purging with argon for 15 min. The vial was sealed, wrapped with parafilm and placed in a blue LED photoreactor. The reaction mixture was stirred at 25 °C for 36 h. The reaction mixture was concentrated in vacuo and water (50 ml) was added to the residue. The resulting mixture was extracted with EtOAc (2*50ml). The combined organic layers were washed with water (3*50ml), brine, dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography to obtain 5-methyl-2-(2-pyridyl)piperidine-1-carboxylic acid as a mixture of cis and trans isomers (approximately 1:1) Tertiary butyl ester (1.45 g, 5.25 mmol, 58.02% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.77(d，對於1異構物1.5H)及1.04(d，對於 2異構物1.5H),1.40(s,9H),1.40-1.60(m,2H),1.60(m,1H),1.83(m,1H),2.13(m，對於1異構物0.5H),2.34(m,1H),2.68(m，對於1異構物0.5H),3.12(m，對於2異構物0.5H),3.66(m，對於2異構物0.5H),5.29(m,1H),7.15(m,2H),7.65(m,1H),8.88(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 0.77 (d, for 1 isomer 1.5H) and 1.04 (d, for 2 isomer 1.5H), 1.40 (s, 9H), 1.40-1.60 ( m, 2H), 1.60 (m, 1H), 1.83 (m, 1H), 2.13 (m, for 1 isomer 0.5H), 2.34 (m, 1H), 2.68 (m, for 1 isomer 0.5H ), 3.12 (m, for the 2 isomer 0.5H), 3.66 (m, for the 2 isomer 0.5H), 5.29 (m, 1H), 7.15 (m, 2H), 7.65 (m, 1H), 8.88 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值276.2；實測值277.0；Rt(異構物1)=1.277min,Rt(異構物2)=1.406min。LCMS (ESI): [M+1] + m/z: calculated 276.2; found 277.0; Rt(Isomer 1)=1.277 min, Rt(Isomer 2)=1.406 min.

步驟2. 2-(5-甲基-2-哌啶基)吡啶之合成Step 2. Synthesis of 2-(5-methyl-2-piperidinyl)pyridine

向5-甲基-2-(2-吡啶基)哌啶-1-甲酸第三丁酯(1.4g，5.07mmol)於MeOH(10mL)中之溶液中添加1,4-二噁烷HCl(7mL)且將混合物在室溫下攪拌隔夜。將溶劑蒸發，以獲得2-(5-甲基-2-哌啶基)吡啶(1.2g，粗品)LCMS(ESI)：[M+1]+ m/z：計算值176.2；實測值177.2；Rt(異構物1)=0.737min,Rt(異構物2)=0.767min。To a solution of tert-butyl 5-methyl-2-(2-pyridyl)piperidine-1-carboxylate (1.4 g, 5.07 mmol) in MeOH (10 mL) was added 1,4-dioxane HCl ( 7 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated to obtain 2-(5-methyl-2-piperidinyl)pyridine (1.2 g, crude) LCMS (ESI): [M+1] + m/z: calcd 176.2; found 177.2; Rt(Isomer 1)=0.737min, Rt(Isomer 2)=0.767min.

311. 外消旋 -(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基哌啶之合成 311. Synthesis of racemic- (2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0628-732
Figure 110128222-A0202-12-0628-732

步驟1：(E)-1-(4-氟苯基)戊-1-烯-3-酮之合成Step 1: Synthesis of (E)-1-(4-fluorophenyl)pent-1-en-3-one

向1-氟-4-碘苯(40g，180.18mmol，20.73mL)及TEA(18.23g，180.18mmol，25.11mL)之混合物中添加戊-1-烯-3-酮(30.31g，360.36mmol)，隨後在室溫下添加Pd(dppf)Cl2‧DCM(7.36g，9.01mmol)及MeCN(200mL)。將混合物回流12h。在真空下濃縮反應混合物。將所獲得之殘餘物用MTBE及水稀釋，分離有機層且將水層用額外MTBE洗滌，將經合併之有機層經無水硫酸鈉乾燥，過濾 且在真空中濃縮。(E)-1-(4-氟苯基)戊-1-烯-3-酮(25.1g，140.85mmol，78.17%產率)不經進一步純化即用於下一步驟。1 H NMR(400MHz,CDCl3 )δ(ppm)1.18(t,3H),2.69(m,2H),6.65(d,1H),7.18(d,1H),7.27(s,1H),7.36(d,1H),7.45(d,1H)。To a mixture of 1-fluoro-4-iodobenzene (40 g, 180.18 mmol, 20.73 mL) and TEA (18.23 g, 180.18 mmol, 25.11 mL) was added pent-1-en-3-one (30.31 g, 360.36 mmol) , followed by the addition of Pd(dppf)Cl2·DCM (7.36 g, 9.01 mmol) and MeCN (200 mL) at room temperature. The mixture was refluxed for 12 h. The reaction mixture was concentrated under vacuum. The obtained residue was diluted with MTBE and water, the organic layer was separated and the aqueous layer was washed with additional MTBE, the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. (E)-1-(4-Fluorophenyl)pent-1-en-3-one (25.1 g, 140.85 mmol, 78.17% yield) was used in the next step without further purification. 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.18(t, 3H), 2.69(m, 2H), 6.65(d, 1H), 7.18(d, 1H), 7.27(s, 1H), 7.36( d, 1H), 7.45 (d, 1H).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.17(d,3H),2.68(s,2H),6.69(d,1H),7.08(m,2H),7.54(m,3H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 1.17 (d, 3H), 2.68 (s, 2H), 6.69 (d, 1H), 7.08 (m, 2H), 7.54 (m, 3H).

LCMS(ESI)：[M+1]+ m/z：計算值178.2；實測值179.0；Rt=1.330min。LCMS (ESI): [M+1] + m/z: calculated 178.2; found 179.0; Rt=1.330 min.

步驟2：(E)-5-(二甲胺基)-1-(4-氟苯基)-4-甲基戊-1-烯-3-酮之合成Step 2: Synthesis of (E)-5-(dimethylamino)-1-(4-fluorophenyl)-4-methylpent-1-en-3-one

(E)-1-(4-氟苯基)戊-1-烯-3-酮(41.7g，234.00mmol)、N-甲基甲胺(19.08g，234.00mmol，24.62mL，HCl)及用7-8%甲醇穩定之37% w/w甲醛水溶液(14.76g，491.41mmol，13.66mL)在乙醇(500mL)及HCl(水溶液)(50mL)之混合物中，然後將其在80℃下攪拌12h。將反應混合物在真空中濃縮。(E)-5-(二甲胺基)-1-(4-氟苯基)-4-甲基戊-1-烯-3-酮(72.67g，粗品，HCl)不經進一步純化即用於下一步驟。(E)-1-(4-Fluorophenyl)pent-1-en-3-one (41.7 g, 234.00 mmol), N-methylmethanamine (19.08 g, 234.00 mmol, 24.62 mL, HCl) and mixed with 7-8% methanol stabilized 37% w/w aqueous formaldehyde solution (14.76 g, 491.41 mmol, 13.66 mL) in a mixture of ethanol (500 mL) and HCl(aq) (50 mL), which was then stirred at 80 °C for 12 h . The reaction mixture was concentrated in vacuo. (E)-5-(Dimethylamino)-1-(4-fluorophenyl)-4-methylpent-1-en-3-one (72.67 g, crude, HCl) was used without further purification in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.21(d,3H),2.68(s,6H),3.06(m,1H),3.44-3.55(m,1H),7.04(d,1H),7.26(m,1H),7.74(d,1H),7.84(m,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.21(d,3H), 2.68(s,6H), 3.06(m,1H), 3.44-3.55(m,1H), 7.04(d,1H) ), 7.26(m, 1H), 7.74(d, 1H), 7.84(m, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值235.2；實測值236.2；Rt=0.876min。LCMS (ESI): [M+1] + m/z: calculated 235.2; found 236.2; Rt=0.876 min.

步驟3：外消旋-(2R,5R)-2-(4-氟苯基)-5-甲基哌啶-4-酮之合成Step 3: Synthesis of Racemic-(2R,5R)-2-(4-fluorophenyl)-5-methylpiperidin-4-one

將(E)-5-(二甲胺基)-1-(4-氟苯基)-4-甲基戊-1-烯-3-酮(72.67g，267.41mmol，HCl)溶解於水(250mL)及NH3 (水溶液)(250mL)，然後將反應混合物在80℃下攪拌12h。將反應混合物用1N HCl酸化，用MTBE萃取，然後將水層用1N NaOH鹼化且用DCM萃取。將DCM層經Na2 SO4 乾燥，過濾且在真空下蒸發，以得到(2R,5R)-2-(4-氟苯基)-5-甲基哌啶-4-酮(22.9g，110.50mmol，41.32%產率)，其不經進一步純化即用於下一步驟。(E)-5-(dimethylamino)-1-(4-fluorophenyl)-4-methylpent-1-en-3-one (72.67 g, 267.41 mmol, HCl) was dissolved in water ( 250 mL) and NH3 (aq) (250 mL), then the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was acidified with 1N HCl, extracted with MTBE, then the aqueous layer was basified with 1N NaOH and extracted with DCM. The DCM layer was dried over Na2SO4 , filtered and evaporated in vacuo to give (2R,5R)-2-(4-fluorophenyl)-5-methylpiperidin-4-one (22.9 g, 110.50 g mmol, 41.32% yield), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.03(d,3H),1.26(m,1H),2.17(m,1H),2.51(m, 2H),2.64(m,2H),3.44(m,1H),3.88(d,1H),7.07(m,2H),7.33(m,2H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.03(d, 3H), 1.26(m, 1H), 2.17(m, 1H), 2.51(m, 2H), 2.64(m, 2H), 3.44( m, 1H), 3.88(d, 1H), 7.07(m, 2H), 7.33(m, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值207.2；實測值208.4；Rt=0.591min。LCMS (ESI): [M+1] + m/z: calculated 207.2; found 208.4; Rt=0.591 min.

步驟4：外消旋-(2R,5R)-2-(4-氟苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of racemic-(2R,5R)-2-(4-fluorophenyl)-5-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester

將(2R,5R)-2-(4-氟苯基)-5-甲基哌啶-4-酮(22.9g，110.50mmol)及TEA(16.77g，165.75mmol，23.10mL)溶解於DCM(330mL)中，然後在冰/水冷卻下逐滴添加二碳酸二-第三丁酯(27.73g，127.07mmol，29.16mL)，此後將反應混合物在20℃下攪拌12h。將反應混合物用NaHSO4 (水溶液)洗滌三次，將DCM層經Na2 SO4 乾燥，過濾且在真空下濃縮。藉由FCC(Companion combiflash；120g SiO2，Hex-MTBE 0~100%，流速=60mL/min，cv=12)純化粗產物。獲得呈棕色膠狀物之所要產物((2R,5R)-2-(4-氟苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯(13g，42.30mmol，38.28%產率))。(2R,5R)-2-(4-fluorophenyl)-5-methylpiperidin-4-one (22.9 g, 110.50 mmol) and TEA (16.77 g, 165.75 mmol, 23.10 mL) were dissolved in DCM ( 330 mL), then di-tert-butyl dicarbonate (27.73 g, 127.07 mmol, 29.16 mL) was added dropwise under ice/water cooling, after which the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was washed three times with NaHSO4 (aq), the DCM layer was dried over Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by FCC (Companion combiflash; 120 g SiO2, Hex-MTBE 0-100%, flow rate=60 mL/min, cv=12). The desired product ((2R,5R)-2-(4-fluorophenyl)-5-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester (13 g, 42.30 g) was obtained as a brown gum mmol, 38.28% yield)).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.01(d,3H),1.31(s,9H),2.35(m,1H),2.81(d,1H),2.81(d,1H),3.69(m,2H),5.28(m,1H),7.05(m,2H),7.23(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.01(d,3H), 1.31(s,9H), 2.35(m,1H), 2.81(d,1H), 2.81(d,1H), 3.69( m, 2H), 5.28 (m, 1H), 7.05 (m, 2H), 7.23 (m, 2H).

LCMS(ESI)：[M+Na]+ m/z：計算值307.2；實測值330.2；Rt=1.346min。LCMS (ESI): [M+Na] + m/z: calculated 307.2; found 330.2; Rt=1.346 min.

步驟5：外消旋-(2R,5R)-2-(4-氟苯基)-5-甲基哌啶-4-酮之合成Step 5: Synthesis of Racemic-(2R,5R)-2-(4-fluorophenyl)-5-methylpiperidin-4-one

將(2R,5R)-2-(4-氟苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯(1.7g，5.53mmol)溶解於DCM(17mL)中且一次性添加TFA(17mL)。將反應混合物在20℃下攪拌1h。在真空下濃縮反應混合物。所獲得之產物不經進一步純化即用於下一步驟中。獲得呈棕色膠狀物之所要產物((2R,5R)-2-(4-氟苯基)-5-甲基哌啶-4-酮(2.6g，粗品，CF3 COOH))。(2R,5R)-2-(4-fluorophenyl)-5-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester (1.7 g, 5.53 mmol) was dissolved in DCM (17 mL) TFA (17 mL) was added in one portion. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum. The product obtained was used in the next step without further purification. The desired product ((2R,5R)-2-(4-fluorophenyl)-5-methylpiperidin-4-one (2.6 g, crude, CF3COOH )) was obtained as a brown gum.

1 H NMR(400MHz,DMSO)δ(ppm)0.99(d,3H),2.59(m,1H),2.91(m,2H),3.12(m,2H),3.62(m,1H),4.80(m,1H),7.14(m,2H),7.25(m,3H),7.31(m,3H)。 1 H NMR (400MHz, DMSO)δ(ppm) 0.99(d,3H), 2.59(m,1H), 2.91(m,2H), 3.12(m,2H), 3.62(m,1H), 4.80(m , 1H), 7.14 (m, 2H), 7.25 (m, 3H), 7.31 (m, 3H).

LCMS(ESI)：[M+1]+ m/z：計算值207.2；實測值208.2；Rt=0.689min。LCMS (ESI): [M+1] + m/z: calculated 207.2; found 208.2; Rt=0.689 min.

步驟6：外消旋-(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基哌啶之合成Step 6: Synthesis of Racemic-(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methylpiperidine

將(2R,5R)-2-(4-氟苯基)-5-甲基哌啶-4-酮(2.6g，8.09mmol，CF3 COOH)、HF(1.62g，80.93mmol)及SF4(1.75g，16.19mmol)在不鏽鋼高壓釜中在70℃下加熱12h。反應完成之後，排出氣體產物，將反應混合物倒入冰上且用10% K2 CO3 水溶液中和。將產物用MTBE萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥，且在減壓下濃縮，以得到(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基哌啶(1.2g，5.23mmol，64.68%產率)，其不經進一步純化即用於下一步驟。(2R,5R)-2-(4-fluorophenyl)-5-methylpiperidin-4-one (2.6 g, 8.09 mmol, CF3COOH ), HF (1.62 g, 80.93 mmol) and SF4 ( 1.75 g, 16.19 mmol) in a stainless steel autoclave at 70 °C for 12 h. After the reaction was complete, the gaseous product was vented, the reaction mixture was poured onto ice and neutralized with 10 % aqueous K2CO3. The product was extracted with MTBE. The combined organic extracts were washed with brine, dried over Na2SO4 , and concentrated under reduced pressure to give (2R,5R)-4,4-difluoro-2-(4-fluorophenyl)- 5-Methylpiperidine (1.2 g, 5.23 mmol, 64.68% yield) was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.02(d,3H),1.80(m,2H),1.86(m,1H),2.01(m,1H),2.67(dd,1H),3.06(m,1H),3.86(d,1H),7.00(m,1H),7.32(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.80(m,2H), 1.86(m,1H), 2.01(m,1H), 2.67(dd,1H), 3.06( m, 1H), 3.86 (d, 1H), 7.00 (m, 1H), 7.32 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值229.2；實測值230.2；Rt=0.863min。LCMS (ESI): [M+1] + m/z: calculated 229.2; found 230.2; Rt=0.863 min.

3JJ.5-(5-甲基-2-哌啶基)-1H-吡唑并[4,3-b]吡啶之合成 3JJ. Synthesis of 5-(5-methyl-2-piperidinyl)-1H-pyrazolo[4,3-b]pyridine

Figure 110128222-A0202-12-0631-733
Figure 110128222-A0202-12-0631-733

步驟1. 5-溴-1-四氫哌喃-2-基-吡唑并[4,3-b]吡啶之合成Step 1. Synthesis of 5-bromo-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine

將5-溴-1H-吡唑并[4,3-b]吡啶(10g，50.50mmol)及3,4-二氫-2H-哌喃(12.74g，151.50mmol，13.76mL)溶解於CH3CN(200mL)中且向其中添加對甲苯磺酸單水合物(1.92g，10.10mmol，1.55mL)。將反應混合物攪拌12h。在真空中蒸發所得混合物，將其倒入NaHCO3 (濃)水溶液(150ml)中且用EtOAc(2x100ml)萃取。將經合併之有機萃取物用水(2*40ml)萃取，經硫酸鈉乾燥且在真空中蒸發，留下25g粗產物，25g粗產物藉由矽膠管柱層析，使用己烷/MTBE梯度 (10-100% MTBE)進行純化，以得到5-溴-1-四氫哌喃-2-基吡唑并[4,3-b]吡啶(6.4g，22.68mmol，44.92%產率)。5-Bromo-1H-pyrazolo[4,3-b]pyridine (10 g, 50.50 mmol) and 3,4-dihydro-2H-pyran (12.74 g, 151.50 mmol, 13.76 mL) were dissolved in CH3CN ( 200 mL) and to this was added p-toluenesulfonic acid monohydrate (1.92 g, 10.10 mmol, 1.55 mL). The reaction mixture was stirred for 12 h. The resulting mixture was evaporated in vacuo, poured into aqueous NaHCO3 (cone) (150ml) and extracted with EtOAc (2x100ml). The combined organic extracts were extracted with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 25g of crude product which was chromatographed on a silica gel column using a hexane/MTBE gradient (10 -100% MTBE) to give 5-bromo-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridine (6.4 g, 22.68 mmol, 44.92% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.66(m,4H),1.75(m,2H),2.43(m,1H),3.69(m,1H),3.95(m,1H),5.71(d,1H),7.38(d,1H),7.58(d,1H),8.13(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.66(m, 4H), 1.75(m, 2H), 2.43(m, 1H), 3.69(m, 1H), 3.95(m, 1H), 5.71( d, 1H), 7.38 (d, 1H), 7.58 (d, 1H), 8.13 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值282.0；實測值282.0；Rt=1.218min。LCMS (ESI): [M] + m/z: calculated 282.0; found 282.0; Rt=1.218 min.

步驟2. 3-甲基-6-(1-四氫哌喃-2-基吡唑并[4,3-b]吡啶-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2. 3-Methyl-6-(1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-yl)-3,4-dihydro-2H-pyridine-1 -Synthesis of tert-butyl formate

將3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(10.79g，33.39mmol)及5-溴-1-四氫哌喃-2-基吡唑并[4,3-b]吡啶(4.71g，16.69mmol)一起混合在t-BuOH(80mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加於t-BuOH(80mL)中之乙酸鈀(II)(187.40mg，834.70μmol)及CM-Phos(673.67mg，1.67mmol)。將反應混合物在氬氣、115℃下攪拌17h，然後冷卻且在真空中蒸發，將其倒入水(150ml)中且用EtOAc(2x80ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下10.5g粗產物，10.5g粗產物藉由矽膠管柱層析，使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到產物3-甲基-6-(1-四氫哌喃-2-基吡唑并[4,3-b]吡啶-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.6g，1.51mmol，9.02%產率)。3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-2H- 3-butyl pyridine-1-carboxylate (10.79 g, 33.39 mmol) and 5-bromo-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridine (4.71 g, 16.69 mmol) together Mix in t-BuOH (80 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then palladium(II) acetate (187.40 mg, 834.70 μmol) and CM-Phos ( 673.67 mg, 1.67 mmol). The reaction mixture was stirred under argon at 115°C for 17h, then cooled and evaporated in vacuo, poured into water (150ml) and extracted with EtOAc (2x80ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo to leave 10.5g of crude product which was chromatographed on a silica gel column using a hexane/MTBE gradient (10-100% MTBE) to give the product 3-methyl-6-(1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-yl)-3, 4-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.6 g, 1.51 mmol, 9.02% yield).

LCMS(ESI)：[M-tBu]+ m/z：計算值398.0；實測值399.2；Rt=1.405min。LCMS (ESI): [M-tBu] + m/z: calculated 398.0; found 399.2; Rt=1.405 min.

步驟3. 5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吡唑并[4,3-b]吡啶之合成Step 3. Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-pyrazolo[4,3-b]pyridine

將3-甲基-6-(1-四氫哌喃-2-基吡唑并[4,3-b]吡啶-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.6g，1.51mmol)於MeOH(20mL)及於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)中之溶液在115℃下攪拌17h，然後蒸發且向殘餘物中添加水(20ml)，且將pH用10%碳酸氫鈉水溶液調節至8。將所 得混合物用EtOAc(2*20mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吡唑并[4,3-b]吡啶(0.32g，1.49mmol，99.19%產率)3-Methyl-6-(1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid A solution of tert-butyl ester (0.6 g, 1.51 mmol) in MeOH (20 mL) and a 4.0 M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL) was stirred at 115 °C for 17 h, then evaporated and added to Water (20 ml) was added to the residue, and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate solution. will be The resulting mixture was extracted with EtOAc (2*20 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-pyrazolo[ 4,3-b]pyridine (0.32 g, 1.49 mmol, 99.19% yield)

LCMS(ESI)：[M+H]+ m/z：計算值214.1；實測值215.2；Rt=0.743min。LCMS (ESI): [M+H] + m/z: calculated 214.1; found 215.2; Rt=0.743 min.

步驟4. 5-(5-甲基-2-哌啶基)-1H-吡唑并[4,3-b]吡啶之合成Step 4. Synthesis of 5-(5-methyl-2-piperidinyl)-1H-pyrazolo[4,3-b]pyridine

在0℃下，將硼氫化鈉(113.00mg，2.99mmol，105.61μL)一次性添加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吡唑并[4,3-b]吡啶(0.32g，1.49mmol)於MeOH(15mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌5h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用二氯甲烷(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到5-(5-甲基-2-哌啶基)-1H-吡唑并[4,3-b]吡啶(0.24g，1.11mmol，74.30%產率)。At 0 °C, sodium borohydride (113.00 mg, 2.99 mmol, 105.61 μL) was added in one portion to 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H- In a stirred solution of pyrazolo[4,3-b]pyridine (0.32 g, 1.49 mmol) in MeOH (15 mL). The resulting mixture was stirred at 0 °C for 5 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl)-1H-pyrazolo[4,3-b]pyridine (0.24 g , 1.11 mmol, 74.30% yield).

LCMS(ESI)：[M+H]+ m/z：計算值216.2；實測值217.2；Rt=0.578min。LCMS (ESI): [M+H] + m/z: calculated 216.2; found 217.2; Rt=0.578 min.

3KK. 外消旋 -N -甲基-3-[(2R,5S )-5-甲基-2-哌啶基]哌啶-1-甲醯胺、外消旋 -1-[3-[(2R,5S )-5-甲基-2-哌啶基]-1-哌啶基]乙酮及外消旋 -1-甲基-3-[(2R,5S )-5-甲基-2-哌啶基]哌啶之合成 3KK. rac - N -methyl-3-[( 2R,5S )-5-methyl-2-piperidinyl]piperidine-1-carboxamide, rac -1-[3-[ ( 2R,5S )-5-methyl-2-piperidinyl]-1-piperidinyl]ethanone and racemic -1-methyl-3-[( 2R,5S )-5-methyl- Synthesis of 2-Piperidinyl] Piperidine

Figure 110128222-A0202-12-0633-734
Figure 110128222-A0202-12-0633-734

步驟1：5-甲基-5,6-二氫-[2,3'-聯吡啶]-1(4H)-甲酸第三丁酯之合成Step 1: Synthesis of 5-methyl-5,6-dihydro-[2,3'-bipyridine]-1(4H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(19g，55.02mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(10.26g，50.02mmol)、碳酸鈉(15.90g，150.05mmol，6.29mL)於二噁烷(100mL)及水(50mL)中之溶液抽真空且用Ar再填充三次。向此混合物中添加[1,1'-雙( 二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(2.04g，2.50mmol)且將所得混合物在95℃下攪拌12h，冷卻，過濾且蒸發。將殘餘物溶解於水(200ml)中且用MTBE(3*200ml)萃取。將有機層用鹽水(150ml)洗滌，經Na2 SO4 乾燥，透過SiO2 薄層過濾且在真空中蒸發，以得到3-甲基-6-(3-吡啶基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(10g，36.45mmol，72.87%產率)。此化合物不經進一步純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (19 g, 55.02 mmol), 3-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyridine (10.26 g, 50.02 mmol), sodium carbonate (15.90 g, 150.05 mmol, 6.29 mL) The solution in dioxane (100 mL) and water (50 mL) was evacuated and refilled three times with Ar. To this mixture was added [1,1'- bis( diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (2.04 g, 2.50 mmol) and the resulting mixture was stirred at 95 °C 12h, cooled, filtered and evaporated. The residue was dissolved in water (200ml) and extracted with MTBE (3*200ml). The organic layer was washed with brine (150 ml), dried over Na 2 SO 4 , filtered through a thin layer of SiO 2 and evaporated in vacuo to give 3-methyl-6-(3-pyridinyl)-3,4-di Hydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (10 g, 36.45 mmol, 72.87% yield). This compound was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.01(s,12H),1.86(m,1H),2.00(m,1H),2.41(m,1H),2.98(t,1H),4.06(d,1H),5.32(m,1H),7.20(m,1H),7.55(m,1H),8.45(m,1H),8.53(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.01(s, 12H), 1.86(m, 1H), 2.00(m, 1H), 2.41(m, 1H), 2.98(t, 1H), 4.06( d, 1H), 5.32 (m, 1H), 7.20 (m, 1H), 7.55 (m, 1H), 8.45 (m, 1H), 8.53 (s, 1H).

LCMS(ESI)：[M] +m/z：計算值274.2；實測值275.2；Rt=1.121min。 LCMS (ESI): [M] + m/z: calculated 274.2; found 275.2; Rt=1.121 min.

步驟2：5-甲基-3,4,5,6-四氫-2,3'-聯吡啶之合成Step 2: Synthesis of 5-methyl-3,4,5,6-tetrahydro-2,3'-bipyridine

將3-甲基-6-(3-吡啶基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(10g，36.45mmol)於TFA(60g，526.21mmol，40.54mL)中之溶液在25℃下攪拌2h。移除溶劑，冷卻殘餘物，將其溶解於100ml 10% NaOH溶液中且用DCM(3*100ml)萃取。將有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以得到3-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(6.2g，35.58mmol，97.62%產率)。3-Methyl-6-(3-pyridyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (10 g, 36.45 mmol) in TFA (60 g, 526.21 mmol, 40.54 mL) The solution was stirred at 25°C for 2h. The solvent was removed, the residue was cooled, dissolved in 100 ml of 10% NaOH solution and extracted with DCM (3*100 ml). The organic layer was washed with brine (100 ml), dried over Na 2 SO 4 and evaporated in vacuo to give 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine ( 6.2 g, 35.58 mmol, 97.62% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.98(d,3H),1.36(m,1H),1.70(m,1H),1.91(m,1H),2.57(m,1H),2.77(m,1H),3.22(m,1H),4.00(m,1H),7.26(t,1H),8.07(d,1H),8.57(d,1H),8.93(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.36(m,1H), 1.70(m,1H), 1.91(m,1H), 2.57(m,1H), 2.77( m, 1H), 3.22 (m, 1H), 4.00 (m, 1H), 7.26 (t, 1H), 8.07 (d, 1H), 8.57 (d, 1H), 8.93 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值174.2；實測值175.2；Rt=0.388min。LCMS (ESI): [M] + m/z: calculated 174.2; found 175.2; Rt=0.388 min.

步驟3：外消旋-3-((2R,5S)-5-甲基哌啶-2-基)吡啶)之合成Step 3: Synthesis of Racemic-3-((2R,5S)-5-methylpiperidin-2-yl)pyridine)

在0℃下，將硼氫化鈉(1.35g，35.58mmol，1.26mL)分批添加到3-(3- 甲基-2,3,4,5-四氫吡啶-6-基)吡啶(6.2g，35.58mmol)於MeOH(70mL)中之經攪拌之溶液中。將所得混合物攪拌2h，然後在真空中蒸發。將殘餘物用水(80ml)稀釋且用二氯甲烷(2*80ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以獲得3-[(2R,5S )-5-甲基-2-哌啶基]吡啶(6.2g，35.18mmol，98.86%產率)。Sodium borohydride (1.35 g, 35.58 mmol, 1.26 mL) was added portionwise to 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine (6.2 g, 35.58 mmol) in a stirred solution of MeOH (70 mL). The resulting mixture was stirred for 2 h, then evaporated in vacuo. The residue was diluted with water (80ml) and extracted with dichloromethane (2*80ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 3-[( 2R,5S )-5-methyl-2-piperidinyl]pyridine (6.2 g, 35.18 mmol, 98.86% yield) Rate).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.90(d,3H),1.12(m,1H),1.51(m,1H),1.65(m,1H),1.86(m,3H),2.41(m,1H),3.14(m,1H),3.58(m,1H),7.26(t,1H),7.69(d,1H),8.47(d,1H),8.57(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.90(d,3H), 1.12(m,1H), 1.51(m,1H), 1.65(m,1H), 1.86(m,3H), 2.41( m, 1H), 3.14 (m, 1H), 3.58 (m, 1H), 7.26 (t, 1H), 7.69 (d, 1H), 8.47 (d, 1H), 8.57 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值176.2；實測值177.2；Rt=0.331min。LCMS (ESI): [M] + m/z: calculated 176.2; found 177.2; Rt=0.331 min.

步驟4：外消旋-(2R,5S)-5-甲基-2-(吡啶-3-基)哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of racemic-(2R,5S)-5-methyl-2-(pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

向3-[(2R,5S )-5-甲基-2-哌啶基]吡啶(6.20g，35.18mmol)於DCM(70mL)中之溶液中添加二碳酸二-第三丁酯(7.68g，35.18mmol，8.07mL)。將所得混合物在25℃下攪拌12h，移除溶劑且藉由梯度層析(己烷-EtOAc)純化粗產物(12g)，以獲得(2R,5S )-5-甲基-2-(3-吡啶基)哌啶-1-甲酸第三丁酯(6g，21.71mmol，61.72%產率)。亦獲得具有順式異構物雜質之第二級分(2g)。對於下一步驟僅用純級分。To a solution of 3-[( 2R,5S )-5-methyl-2-piperidinyl]pyridine (6.20 g, 35.18 mmol) in DCM (70 mL) was added di-tert-butyl dicarbonate (7.68 g) , 35.18 mmol, 8.07 mL). The resulting mixture was stirred at 25 °C for 12 h, the solvent was removed and the crude product (12 g) was purified by gradient chromatography (hexane-EtOAc) to obtain ( 2R,5S )-5-methyl-2-(3- Pyridinyl)piperidine-1-carboxylic acid tert-butyl ester (6 g, 21.71 mmol, 61.72% yield). A second fraction (2 g) was also obtained with the cis isomer impurity. Only pure fractions were used for the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.07(d,3H),1.37(m,1H),1.46(s,9H),1.68(m,1H),1.72(m,1H),2.04(m,1H),2.18(m,1H),3.02(m,1H),3.75(m,1H),5.36(m,1H),7.26(m,1H),7.57(d,1H),8.49(d,1H),8.54(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.07(d,3H), 1.37(m,1H), 1.46(s,9H), 1.68(m,1H), 1.72(m,1H), 2.04( m, 1H), 2.18(m, 1H), 3.02(m, 1H), 3.75(m, 1H), 5.36(m, 1H), 7.26(m, 1H), 7.57(d, 1H), 8.49(d , 1H), 8.54(s, 1H).

步驟5：外消旋-(2R,5S)-5-甲基-2-(3-哌啶基)哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of racemic-(2R,5S)-5-methyl-2-(3-piperidinyl)piperidine-1-carboxylic acid tert-butyl ester

向(2R,5S )-5-甲基-2-(3-吡啶基)哌啶-1-甲酸第三丁酯(6g，21.71mmol)於MeOH(100mL)中之溶液中添加乾燥的487型鈀(10%於碳上)(0.8g，7.52mmol)。將所得混合物在高壓釜中在氫氣氣氛(100atm)、45℃下攪拌96h。藉由NMR監測反應進展。在獲得完全轉化時，過濾催化劑，在真空中移除溶劑。將 殘餘物溶解於DCM(50ml)中，經Na2 SO4 乾燥且移除溶劑，以獲得(2R,5S )-5-甲基-2-(3-哌啶基)哌啶-1-甲酸第三丁酯(5.7g，20.18mmol，92.97%產率)。藉由2D-NMR證明產物之結構為反式。 To a solution of ( 2R,5S )-5-methyl-2-(3-pyridyl)piperidine-1-carboxylic acid tert-butyl ester (6 g, 21.71 mmol) in MeOH (100 mL) was added dry type 487 Palladium (10% on carbon) (0.8 g, 7.52 mmol). The resulting mixture was stirred in an autoclave under a hydrogen atmosphere (100 atm) at 45 °C for 96 h. The progress of the reaction was monitored by NMR. When complete conversion was obtained, the catalyst was filtered and the solvent was removed in vacuo. The residue was dissolved in DCM (50 ml), dried over Na 2 SO 4 and the solvent was removed to obtain ( 2R,5S )-5-methyl-2-(3-piperidinyl)piperidine-1-carboxylic acid Tertiary butyl ester (5.7 g, 20.18 mmol, 92.97% yield). The structure of the product was confirmed to be trans by 2D-NMR.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),0.94(m,1H),1.18(m,1H),1.34(s,9H),1.49(m,1H),1.58(m,2H),1.77(m,2H),1.91(m,1H),2.19(m,1H),2.41(m,1H),2.90(m,3H),3.59(m,5H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.86(d, 3H), 0.94(m, 1H), 1.18(m, 1H), 1.34(s, 9H), 1.49(m, 1H), 1.58(m, 2H), 1.77(m, 2H), 1.91(m, 1H), 2.19(m, 1H), 2.41(m, 1H), 2.90(m, 3H), 3.59(m, 5H).

LCMS(ESI)：[M]+ m/z：計算值282.2；實測值283.2；Rt=0.932min。LCMS (ESI): [M] + m/z: calculated 282.2; found 283.2; Rt=0.932 min.

步驟6：外消旋-(2R,5S)-5-甲基-2-[1-(甲基胺甲醯基)-3-哌啶基]哌啶-1-甲酸第三丁酯之合成Step 6: Synthesis of racemic-(2R,5S)-5-methyl-2-[1-(methylaminocarboxy)-3-piperidinyl]piperidine-1-carboxylic acid tert-butyl ester

在0℃下，向(2R,5S )-5-甲基-2-(3-哌啶基)哌啶-1-甲酸第三丁酯(0.85g，3.01mmol)及TEA(456.83mg，4.51mmol，629.24μL)於DCM(50mL)中之溶液中分批添加N -甲基胺甲醯氯(337.73mg，3.61mmol)。將所得混合物攪拌3h，用鹽水(3*40ml)洗滌，經Na2 SO4 乾燥且在真空中移除溶劑，以獲得(2R,5S )-5-甲基-2-[1-(甲基胺甲醯基)-3-哌啶基]哌啶-1-甲酸第三丁酯(0.9g，2.65mmol，88.09%產率)。To ( 2R,5S )-5-methyl-2-(3-piperidinyl)piperidine-1-carboxylic acid tert-butyl ester (0.85 g, 3.01 mmol) and TEA (456.83 mg, 4.51 mmol) at 0 °C mmol, 629.24 μL) in DCM (50 mL) was added portionwise N -methylamine carboxyl chloride (337.73 mg, 3.61 mmol). The resulting mixture was stirred for 3h, washed with brine (3*40ml), dried over Na2SO4 and the solvent was removed in vacuo to obtain ( 2R,5S )-5-methyl-2-[1-(methyl) Aminocarboxy)-3-piperidinyl]piperidine-1-carboxylic acid tert-butyl ester (0.9 g, 2.65 mmol, 88.09% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.95(d,3H),1.09(m,3H),1.25(m,1H),1.41(s,9H),1.66(m,4H),1.78(m,1H),2.47(m,1H),2.66(m,1H),2.75(s,3H),2.84(m,1H),3.12(m,1H),3.57(m,1H),3.71(m,1H),3.86(m,1H),3.99(m,1H),4.45(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.95(d, 3H), 1.09(m, 3H), 1.25(m, 1H), 1.41(s, 9H), 1.66(m, 4H), 1.78( m, 1H), 2.47(m, 1H), 2.66(m, 1H), 2.75(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.57(m, 1H), 3.71(m , 1H), 3.86 (m, 1H), 3.99 (m, 1H), 4.45 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值339.2；實測值340.2；Rt=1.213min。LCMS (ESI): [M] + m/z: calculated 339.2; found 340.2; Rt=1.213 min.

步驟7：外消旋-N-甲基-3-[(2R,5S)-5-甲基-2-哌啶基]哌啶-1-甲醯胺之合成Step 7: Synthesis of Racemic-N-methyl-3-[(2R,5S)-5-methyl-2-piperidinyl]piperidine-1-carboxamide

將(2R,5S )-5-甲基-2-[1-(甲基胺甲醯基)-3-哌啶基]哌啶-1-甲酸第三丁酯(0.95g，2.80mmol)及於二噁烷中之4.0M氯化氫溶液(5g，137.13mmol，6.25mL)於DCM(20mL)中之溶液在25℃下攪拌12h。在真空中移除溶劑，以獲得N - 甲基-3-[(2R,5S )-5-甲基-2-哌啶基]哌啶-1-甲醯胺(0.75g，粗品，HCl)。此產物不經進一步純化即用於下一步驟。( 2R,5S )-5-methyl-2-[1-(methylaminocarboxy)-3-piperidinyl]piperidine-1-carboxylic acid tert-butyl ester (0.95 g, 2.80 mmol) and A solution of 4.0 M hydrogen chloride in dioxane (5 g, 137.13 mmol, 6.25 mL) in DCM (20 mL) was stirred at 25 °C for 12 h. The solvent was removed in vacuo to give N -methyl-3-[( 2R,5S )-5-methyl-2-piperidinyl]piperidin-1-carboxamide (0.75 g, crude, HCl) . This product was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.85(d,3H),1.09(m,1H),1.18(m,2H),1.28(m,2H),1.42(m,1H),1.61(m,2H),1.81(m,3H),2.49(s,3H),2.78(m,2H),3.11(m,2H),3.82(m,1H),4.11(m,1H),6.33(m,1H),8.97(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.85(d,3H), 1.09(m,1H), 1.18(m,2H), 1.28(m,2H), 1.42(m,1H), 1.61(m, 2H), 1.81(m, 3H), 2.49(s, 3H), 2.78(m, 2H), 3.11(m, 2H), 3.82(m, 1H), 4.11(m, 1H), 6.33 (m, 1H), 8.97 (m, 1H).

步驟8：外消旋-(2R,5S)-2-(1-乙醯基-3-哌啶基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 8: Synthesis of rac-(2R,5S)-2-(1-acetyl-3-piperidinyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在0℃下，向(2R,5S )-5-甲基-2-(3-哌啶基)哌啶-1-甲酸第三丁酯(0.8g，2.83mmol)及TEA(429.95mg，4.25mmol，592.22μL)於DCM(30mL)中之溶液中添加乙醯氯(266.83mg，3.40mmol，206.84μL)。將所得混合物攪拌2h，用水(3*20ml)洗滌，經Na2 SO4 乾燥且移除溶劑，以獲得(2R,5S )-2-(1-乙醯基-3-哌啶基)-5-甲基哌啶-1-甲酸第三丁酯(0.9g，2.77mmol，97.92%產率)。To ( 2R,5S )-5-methyl-2-(3-piperidinyl)piperidine-1-carboxylic acid tert-butyl ester (0.8 g, 2.83 mmol) and TEA (429.95 mg, 4.25 mmol) at 0 °C mmol, 592.22 μL) in DCM (30 mL) was added acetyl chloride (266.83 mg, 3.40 mmol, 206.84 μL). The resulting mixture was stirred for 2 h, washed with water (3*20 ml), dried over Na 2 SO 4 and the solvent was removed to obtain ( 2R,5S )-2-(1-acetyl-3-piperidinyl)-5 - tert-butyl methylpiperidine-1-carboxylate (0.9 g, 2.77 mmol, 97.92% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.87(d,3H),1.18(m,2H),1.34(s,9H),1.58(m,4H),1.75(m,2H),1.94(s,3H),2.22(m,1H),2.82(m,2H),3.32(m,2H),3.58(m,3H),4.01(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.87(d,3H), 1.18(m,2H), 1.34(s,9H), 1.58(m,4H), 1.75(m,2H), 1.94(s, 3H), 2.22(m, 1H), 2.82(m, 2H), 3.32(m, 2H), 3.58(m, 3H), 4.01(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值324.2；實測值325.2；Rt=1.263min。LCMS (ESI): [M] + m/z: calculated 324.2; found 325.2; Rt=1.263 min.

步驟9：外消旋-1-[3-[(2R,5S)-5-甲基-2-哌啶基]-1-哌啶基]乙酮之合成Step 9: Synthesis of Racemic-1-[3-[(2R,5S)-5-methyl-2-piperidinyl]-1-piperidinyl]ethanone

(2R,5S )-2-(1-乙醯基-3-哌啶基)-5-甲基哌啶-1-甲酸第三丁酯(0.9g，2.77mmol)及於二噁烷中之4.0M氯化氫溶液(4.00g，109.71mmol，5mL)於DCM(10mL)中之溶液。將所得混合物在25℃下攪拌4h。在真空中蒸發溶劑，以得到呈淡黃色固體之1-[3-[(2R,5S )-5-甲基-2-哌啶基]-1-哌啶基]乙酮(0.7g，2.68mmol，96.76%產率，HCl)。( 2R,5S )-2-(1-Acetyl-3-piperidinyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (0.9 g, 2.77 mmol) and in dioxane A solution of 4.0 M hydrogen chloride solution (4.00 g, 109.71 mmol, 5 mL) in DCM (10 mL). The resulting mixture was stirred at 25 °C for 4 h. The solvent was evaporated in vacuo to give 1-[3-[( 2R,5S )-5-methyl-2-piperidinyl]-1-piperidinyl]ethanone (0.7 g, 2.68 g) as a pale yellow solid mmol, 96.76% yield, HCl).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.08(m,2H),1.36(m,2H),1.76(m,6H),1.99(s,3H),2.82(m,2H),2.98(m,1H),3.11(m,1H),3.66(m,1H),4.28(m, 1H),4.75(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.86(d,3H), 1.08(m,2H), 1.36(m,2H), 1.76(m,6H), 1.99(s,3H), 2.82(m, 2H), 2.98(m, 1H), 3.11(m, 1H), 3.66(m, 1H), 4.28(m, 1H), 4.75(m, 2H).

LCMS(ESI)：[M]+ m/z：計算值224.2；實測值225.2；Rt=0.547min。LCMS (ESI): [M] + m/z: calculated 224.2; found 225.2; Rt=0.547 min.

LCMS(ESI)：[M]+ m/z：計算值239.2；實測值240.2；Rt=0.634min。LCMS (ESI): [M] + m/z: calculated 239.2; found 240.2; Rt=0.634 min.

步驟10：外消旋-(2R,5S)-5-甲基-2-(1-甲基-3-哌啶基)哌啶-1-甲酸第三丁酯之合成Step 10: Synthesis of racemic-(2R,5S)-5-methyl-2-(1-methyl-3-piperidinyl)piperidine-1-carboxylic acid tert-butyl ester

向(2R,5S )-5-甲基-2-(3-哌啶基)哌啶-1-甲酸第三丁酯(0.8g，2.83mmol)及碳酸鉀(1.17g，8.50mmol，512.87μL)於ACN(30mL)中之混合物中添加碘甲烷(442.27mg，3.12mmol，193.98μL)。將所得混合物在25℃下攪拌8h，過濾出沉澱且移除溶劑。將殘餘物溶解於DCM(30ml)中，過濾沉澱且在真空中移除溶劑，以得到(2R,5S )-5-甲基-2-(1-甲基-3-哌啶基)哌啶-1-甲酸第三丁酯(0.8g，2.70mmol，95.27%產率)。To ( 2R,5S )-5-methyl-2-(3-piperidinyl)piperidine-1-carboxylic acid tert-butyl ester (0.8 g, 2.83 mmol) and potassium carbonate (1.17 g, 8.50 mmol, 512.87 μL ) in ACN (30 mL) was added iodomethane (442.27 mg, 3.12 mmol, 193.98 μL). The resulting mixture was stirred at 25 °C for 8 h, the precipitate was filtered off and the solvent was removed. The residue was dissolved in DCM (30 ml), the precipitate was filtered and the solvent was removed in vacuo to give ( 2R,5S )-5-methyl-2-(1-methyl-3-piperidinyl)piperidine - 3-Butyl 1-carboxylate (0.8 g, 2.70 mmol, 95.27% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.96(d,3H),1.26(m,2H),1.42(s,9H),1.81(m,9H),2.26(s,3H),2.86(m,2H),3.50(m,3H),3.56(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.96(d, 3H), 1.26(m, 2H), 1.42(s, 9H), 1.81(m, 9H), 2.26(s, 3H), 2.86( m, 2H), 3.50 (m, 3H), 3.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值296.2；實測值297.2；Rt=1.008min。LCMS (ESI): [M] + m/z: calculated 296.2; found 297.2; Rt=1.008 min.

步驟11：外消旋-1-甲基-3-[(2R,5S)-5-甲基-2-哌啶基]哌啶之合成Step 11: Synthesis of racemic-1-methyl-3-[(2R,5S)-5-methyl-2-piperidinyl]piperidine

將(2R,5S )-5-甲基-2-(1-甲基-3-哌啶基)哌啶-1-甲酸第三丁酯(0.8g，2.70mmol)及於二噁烷中之4.0M氯化氫溶液(5g，137.13mmol，6.25mL)於DCM(15mL)中之溶液在25℃下攪拌5h。在真空中移除溶劑，以獲得1-甲基-3-[(2R,5S )-5-甲基-2-哌啶基]哌啶(0.7g，粗品，2HCl)。此產物不經進一步純化即用於下一步驟。( 2R,5S )-5-methyl-2-(1-methyl-3-piperidinyl)piperidine-1-carboxylic acid tert-butyl ester (0.8 g, 2.70 mmol) in dioxane A solution of 4.0 M hydrogen chloride solution (5 g, 137.13 mmol, 6.25 mL) in DCM (15 mL) was stirred at 25 °C for 5 h. The solvent was removed in vacuo to obtain 1-methyl-3-[( 2R,5S )-5-methyl-2-piperidinyl]piperidine (0.7 g, crude, 2HCl). This product was used in the next step without further purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.84(d,3H),1.09(m,3H),1.85(m,6H),2.65(s,3H),2.86(m,2H),3.11(m,3H),3.36(m,2H),4.28(m,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.84(d,3H), 1.09(m,3H), 1.85(m,6H), 2.65(s,3H), 2.86(m,2H), 3.11 (m, 3H), 3.36 (m, 2H), 4.28 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值196.2；實測值197.2；Rt=0.159min。LCMS (ESI): [M] + m/z: calculated 196.2; found 197.2; Rt=0.159 min.

3LL.外消旋-5-[(2R,5R)-4,4-二氟-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成 3LL. Synthesis of racemic-5-[(2R,5R)-4,4-difluoro-5-methyl-2-piperidinyl]-1,3-benzothiazole

Figure 110128222-A0202-12-0639-735
Figure 110128222-A0202-12-0639-735

步驟1. 2-(2-甲基-1,3-三氧環戊烷-2-基)丙酸乙酯之合成Step 1. Synthesis of ethyl 2-(2-methyl-1,3-trioxolan-2-yl)propanoate

將2-甲基-3-側氧基-丁酸乙酯(24.72g，171.47mmol，24.24mL)溶解於甲苯(250mL)中且向其中添加乙二醇(11.71g，188.61mmol，10.55mL)，隨後添加對甲苯磺酸單水合物(3.26g，17.15mmol，2.63mL)。將所得混合物回流3h。將反應混合物用NaHCO3 水溶液(2*100ml)洗滌且將有機層分離，經Na2 SO4 乾燥，過濾且蒸發。藉由分餾(bp=60℃，1mm Hg)純化殘餘物，以獲得2-(2-甲基-1,3-二氧環戊烷-2-基)丙酸乙酯(13.45g，71.44mmol，41.67%產率)。2-Methyl-3-pendoxo-butyric acid ethyl ester (24.72 g, 171.47 mmol, 24.24 mL) was dissolved in toluene (250 mL) and to it was added ethylene glycol (11.71 g, 188.61 mmol, 10.55 mL) , followed by the addition of p-toluenesulfonic acid monohydrate (3.26 g, 17.15 mmol, 2.63 mL). The resulting mixture was refluxed for 3 h. The reaction mixture was washed with aqueous NaHCO 3 (2*100 ml) and the organic layer was separated, dried over Na 2 SO 4 , filtered and evaporated. The residue was purified by fractional distillation (bp=60°C, 1 mm Hg) to obtain ethyl 2-(2-methyl-1,3-dioxolan-2-yl)propanoate (13.45 g, 71.44 mmol) , 41.67% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.20(d,3H),1.25(t,3H),1.38(s,3H),2.72(m,1H),3.90-3.97(m,4H),4.14(q,2H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.20 (d, 3H), 1.25 (t, 3H), 1.38 (s, 3H), 2.72 (m, 1H), 3.90-3.97 (m, 4H) , 4.14(q, 2H).

步驟2. 2-(2-甲基-1,3-三氧環戊烷-2-基)丙-1-醇之合成Step 2. Synthesis of 2-(2-methyl-1,3-trioxolan-2-yl)propan-1-ol

將氫化鋰鋁(5.42g，142.89mmol)懸浮於THF(150mL)中且逐滴添加2-(2-甲基-1,3-二氧環戊烷-2-基)丙酸乙酯(13.45g，71.44mmol)於THF(20mL)中之溶液。將反應混合物攪拌1h。將水(5.4ml)小心添加到反應混合物中，隨後添加20% KOH水溶液(5.4ml)及水(10.8ml)。過濾所得懸浮液且在真空中蒸發濾液。藉由急驟層析(己烷-EtOAc 2：1)純化殘餘物，以獲得2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-醇(6.79g，46.43mmol，65.00%產率)。Lithium aluminum hydride (5.42 g, 142.89 mmol) was suspended in THF (150 mL) and ethyl 2-(2-methyl-1,3-dioxolan-2-yl)propanoate (13.45 g was added dropwise) g, 71.44 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h. Water (5.4ml) was carefully added to the reaction mixture, followed by 20% aqueous KOH (5.4ml) and water (10.8ml). The resulting suspension was filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography (hexane-EtOAc 2:1) to give 2-(2-methyl-1,3-dioxolan-2-yl)propan-1-ol (6.79 g) , 46.43 mmol, 65.00% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.95(d,3H),1.27(s,3H),2.00(m,1H),2.90(s,1H),3.45(dd,1H),3.70(dd,1H),3.90-3.97(m,4H), 1 H NMR (CDCl 3 , 400MHz): δ(ppm) 0.95(d,3H), 1.27(s,3H), 2.00(m,1H), 2.90(s,1H), 3.45(dd,1H), 3.70 (dd,1H),3.90-3.97(m,4H),

步驟3. 甲磺酸2-(2-甲基-1,3-二氧環戊烷-2-基)丙酯之合成Step 3. Synthesis of 2-(2-methyl-1,3-dioxolan-2-yl)propyl methanesulfonate

將2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-醇(6.79g，46.45mmol)溶解於 DCM(60mL)中且向其中添加三乙胺(5.17g，51.09mmol，7.12mL)。將所得溶液在冰浴中冷卻至-5℃且逐滴添加甲磺醯氯(5.59g，48.77mmol，3.77mL)於DCM(10mL)中之溶液。使所得混合物升溫至室溫且攪拌隔夜。將水(25ml)添加到反應混合物中且將所得混合物轉移至分液漏斗中且分離有機層。將有機層用NaHSO4 水溶液(25ml)、水(25ml)洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得甲磺酸2-(2-甲基-1,3-二氧環戊烷-2-基)丙酯(10.36g，46.18mmol，99.41%產率)。2-(2-Methyl-1,3-dioxolan-2-yl)propan-1-ol (6.79 g, 46.45 mmol) was dissolved in DCM (60 mL) and to it was added triethylamine ( 5.17 g, 51.09 mmol, 7.12 mL). The resulting solution was cooled to -5°C in an ice bath and a solution of mesylate chloride (5.59 g, 48.77 mmol, 3.77 mL) in DCM (10 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. Water (25 ml) was added to the reaction mixture and the resulting mixture was transferred to a separatory funnel and the organic layer was separated. The organic layer was washed with aqueous NaHSO 4 (25 ml), water (25 ml), dried over Na 2 SO 4 , filtered and evaporated to obtain 2-(2-methyl-1,3-dioxolane methanesulfonate) -2-yl)propyl ester (10.36 g, 46.18 mmol, 99.41% yield).

1 H NMR(CDCl3 ,500MHz)：δ(ppm)1.10(d,3H),1.27(s,3H),2.17(m,1H),3.00(s,3H),3.90-3.97(m,4H),4.04(dd,1H),4.41(dd,1H)。 1 H NMR (CDCl 3 , 500MHz): δ(ppm) 1.10(d, 3H), 1.27(s, 3H), 2.17(m, 1H), 3.00(s, 3H), 3.90-3.97(m, 4H) , 4.04 (dd, 1H), 4.41 (dd, 1H).

步驟4. 2-(2-疊氮基-1-甲基乙基)-2-甲基-1,3-二氧環戊烷之合成Step 4. Synthesis of 2-(2-azido-1-methylethyl)-2-methyl-1,3-dioxolane

將甲磺酸2-(2-甲基-1,3-二氧環戊烷-2-基)丙酯(10.36g，46.18mmol)溶解於DMF(100mL)中且向其中添加疊氮化鈉(9.01g，138.53mmol，4.87mL)。將所得混合物在75℃下加熱24h。將反應混合物倒入水(150ml)中且將所得混合物用MTBE(2*100ml)萃取。將經合併之有機層用水(3*75ml)、鹽水(75ml)洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得2-(2-疊氮基-1-甲基乙基)-2-甲基-1,3-二氧環戊烷(6.59g，38.51mmol，83.40%產率)。2-(2-Methyl-1,3-dioxolan-2-yl)propyl methanesulfonate (10.36 g, 46.18 mmol) was dissolved in DMF (100 mL) and sodium azide was added to it (9.01 g, 138.53 mmol, 4.87 mL). The resulting mixture was heated at 75 °C for 24 h. The reaction mixture was poured into water (150ml) and the resulting mixture was extracted with MTBE (2*100ml). The combined organic layers were washed with water (3*75ml), brine (75ml), dried over Na2SO4 , filtered and evaporated to give 2-(2-azido-1-methylethyl)-2 - Methyl-1,3-dioxolane (6.59 g, 38.51 mmol, 83.40% yield).

1 H NMR(CDCl3 ,500MHz)：δ(ppm)1.07(d,3H),1.26(s,3H),1.97(m,1H),3.07(dd,1H),3.58(dd,1H),3.90-3.97(m,4H)。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 1.07 (d, 3H), 1.26 (s, 3H), 1.97 (m, 1H), 3.07 (dd, 1H), 3.58 (dd, 1H), 3.90 -3.97(m, 4H).

步驟5. 2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-胺之合成Step 5. Synthesis of 2-(2-methyl-1,3-dioxolan-2-yl)propan-1-amine

將2-(2-疊氮基-1-甲基乙基)-2-甲基-1,3-二氧環戊烷(6.59g，38.51mmol)溶解於THF(100mL)中且分批添加三苯基膦(10.61g，40.44mmol)。將所得混合物攪拌1小時且將水(10.6mL)添加到先前混合物中。將所得混合物攪拌隔夜。在真空中濃縮反應混合物，且將殘餘物溶解於DCM(100ml)中。將所得溶液用NaHSO4 水溶液(2*75ml)萃取且將經合併之水層用DCM(2*75ml)洗滌。將水層用NaOH鹼化且將所得混合物用MTBE(2*75ml)萃取。將經合併之有機層用 鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-胺(4.89g，33.65mmol，87.38%產率)。2-(2-Azido-1-methylethyl)-2-methyl-1,3-dioxolane (6.59 g, 38.51 mmol) was dissolved in THF (100 mL) and added portionwise Triphenylphosphine (10.61 g, 40.44 mmol). The resulting mixture was stirred for 1 hour and water (10.6 mL) was added to the previous mixture. The resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in DCM (100 ml). The resulting solution was extracted with aq. NaHSO4 (2*75ml) and the combined aqueous layers were washed with DCM (2*75ml). The aqueous layer was basified with NaOH and the resulting mixture was extracted with MTBE (2*75ml). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and evaporated to give 2-(2-methyl-1,3-dioxolan-2-yl)propan-1-amine (4.89 g, 33.65 mmol, 87.38% yield).

1 H NMR(CDCl3 ,600MHz)：δ(ppm)0.97(d,3H),1.22(s,3H),1.42(brs,2H),1.72(m,1H),2.49(dd,1H),2.87(dd,1H),3.89-3.91(m,4H)。 1 H NMR (CDCl 3 , 600MHz): δ (ppm) 0.97 (d, 3H), 1.22 (s, 3H), 1.42 (brs, 2H), 1.72 (m, 1H), 2.49 (dd, 1H), 2.87 (dd, 1H), 3.89-3.91 (m, 4H).

步驟6. 9-(1,3-苯并噻唑-5-基)-6-甲基-1,4-二氯雜-8-氮雜螺[4.5]癸烷之合成Step 6. Synthesis of 9-(1,3-benzothiazol-5-yl)-6-methyl-1,4-dichloro-8-azaspiro[4.5]decane

將2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-胺(2.14g，14.71mmol)溶解於苯(30mL)中且向其中添加1,3-苯并噻唑-5-甲醛(2.4g，14.71mmol)，隨後添加對甲苯磺酸單水合物(8.39g，44.12mmol，6.77mL)。將所得混合物加熱至回流且以迪安-斯塔克分離器(Dean-Stark trap)回流隔夜。將反應混合物冷卻且添加K2 CO3 水溶液(15ml)。將所得混合物轉移至分液漏斗且分離有機層。用EtOAc(35ml)萃取水層，且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發。將殘餘物溶解於CHCl3 (25ml)中且將所得混合物用NaHSO4 水溶液(1g於10ml水中，2*10ml)萃取。將經合併之水層用CHCl3 (2*30ml)洗滌，然後用K2 CO3 (6g)鹼化。將所得混合物用CHCl3 (2*40ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得9-(1,3-苯并噻唑-5-基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(1.7g，粗品)。2-(2-Methyl-1,3-dioxolan-2-yl)propan-1-amine (2.14 g, 14.71 mmol) was dissolved in benzene (30 mL) and 1,3- Benzothiazole-5-carbaldehyde (2.4 g, 14.71 mmol) followed by p-toluenesulfonic acid monohydrate (8.39 g, 44.12 mmol, 6.77 mL). The resulting mixture was heated to reflux and refluxed in a Dean-Stark trap overnight. The reaction mixture was cooled and aqueous K2CO3 ( 15 ml) was added. The resulting mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with EtOAc (35 ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated. The residue was dissolved in CHCl 3 (25 ml) and the resulting mixture was extracted with aqueous NaHSO 4 (1 g in 10 ml water, 2*10 ml). The combined aqueous layers were washed with CHCl3 ( 2 *30 ml), then basified with K2CO3 ( 6 g). The resulting mixture was extracted with CHCl 3 (2*40 ml) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to obtain 9-(1,3-benzothiazol-5-yl)-6- Methyl-1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, crude).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.89(d,3H),1.73(dd,1H),1.99(m,2H),2.80(t,1H),3.07(dd,1H),3.75(m,1H),3.96(m,5H),7.48(d,1H),7.88(d,1H),8.09(s,1H),8.97(s,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.89 (d, 3H), 1.73 (dd, 1H), 1.99 (m, 2H), 2.80 (t, 1H), 3.07 (dd, 1H), 3.75 (m, 1H), 3.96 (m, 5H), 7.48 (d, 1H), 7.88 (d, 1H), 8.09 (s, 1H), 8.97 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值290.1；實測值291.0；Rt=0.783min。LCMS (ESI): [M+1] + m/z: calculated 290.1; found 291.0; Rt=0.783 min.

步驟7. 外消旋-(2R,5R)-2-(苯并[d]噻唑-5-基)-5-甲基哌啶-4-酮之合成Step 7. Synthesis of racemic-(2R,5R)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-4-one

將9-(1,3-苯并噻唑-5-基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(1.65g，5.68mmol)溶解於6N HCl(30mL)中且將所得混合物在80℃下(於油浴中)加熱隔夜。將反應混合物冷卻且用K2 CO3 鹼化。將所得混合物用CHCl3 (2*50ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發。將殘餘物溶解於MTBE中且向 其中添加TFA(0.1ml)。過濾所得懸浮液，將濾餅用MTBE沖洗且在真空中乾燥，以獲得呈TFA鹽形式之外消旋-(2R,5R)-2-(苯并[d]噻唑-5-基)-5-甲基哌啶-4-酮 (1.1g，3.05mmol，53.72%產率，CF3 COOH)。9-(1,3-Benzothiazol-5-yl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane (1.65 g, 5.68 mmol) was dissolved in 6N HCl (30 mL) and the resulting mixture was heated at 80 °C (in an oil bath) overnight. The reaction mixture was cooled and basified with K2CO3. The resulting mixture was extracted with CHCl3 (2*50 ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated. The residue was dissolved in MTBE and TFA (0.1 ml) was added to it. The resulting suspension was filtered, the filter cake was rinsed with MTBE and dried in vacuo to obtain rac-(2R,5R)-2-(benzo[d]thiazol-5-yl)-5 as the TFA salt - Methylpiperidin-4-one (1.1 g, 3.05 mmol, 53.72% yield, CF3COOH ).

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.04(d,3H),2.68(d,1H),2.98(m,1H),3.23(m,4H),3.75(m,1H),4.98(m,1H),7.61(m,1H),9.63(brs,2H)。 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.04(d,3H), 2.68(d,1H), 2.98(m,1H), 3.23(m,4H), 3.75(m,1H), 4.98 (m, 1H), 7.61 (m, 1H), 9.63 (brs, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值246.1；實測值247.0；Rt=0.717min。LCMS (ESI): [M+1] + m/z: calculated 246.1; found 247.0; Rt=0.717 min.

步驟8. 外消旋-5-[(2R,5R)-4,4-二氟-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 8. Synthesis of racemic-5-[(2R,5R)-4,4-difluoro-5-methyl-2-piperidinyl]-1,3-benzothiazole

將2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-4-酮(1.1g，4.47mmol)溶解於HF(無水)(3.3mL)中且將所得混合物密封在不鏽鋼容器中，在液態N2中冷卻，且向其中添加SF4(3.3mL)。使所得混合物升溫至室溫且在室溫下攪拌隔夜。反應完成之後，將反應混合物倒入冰上且用NaHCO3 中和。將所得混合物用EtOAc(2*75ml)萃取且將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得5-[(2R,5R)-4,4-二氟-5-甲基-2-哌啶基]-1,3-苯并噻唑(480mg，粗品)。2-(1,3-Benzothiazol-5-yl)-5-methylpiperidin-4-one (1.1 g, 4.47 mmol) was dissolved in HF (dry) (3.3 mL) and the resulting mixture was sealed In a stainless steel vessel, cooled in liquid N2, and SF4 (3.3 mL) was added to it. The resulting mixture was warmed to room temperature and stirred at room temperature overnight. After the reaction was complete, the reaction mixture was poured onto ice and neutralized with NaHCO3 . The resulting mixture was extracted with EtOAc (2*75ml) and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated to give 5 -[(2R,5R)-4,4-difluoro -5-Methyl-2-piperidinyl]-1,3-benzothiazole (480 mg, crude).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.06(d,3H),2.03-2.20(m,3H),2.30(m,1H),2.72(t,1H),3.12(m,1H),4.04(d,1H),7.46(d,1H),7.89(d,1H),8.12(s,1H),8.97(s,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.06 (d, 3H), 2.03-2.20 (m, 3H), 2.30 (m, 1H), 2.72 (t, 1H), 3.12 (m, 1H) , 4.04(d, 1H), 7.46(d, 1H), 7.89(d, 1H), 8.12(s, 1H), 8.97(s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值268.1；實測值269.0；Rt=0.837min。LCMS (ESI): [M+1] + m/z: calculated 268.1; found 269.0; Rt=0.837 min.

3MM.外消旋-(2R,5R )-2-(3-氯苯基)-4,4-二氟-5-甲基哌啶之合成 3MM. Synthesis of racemic-( 2R,5R )-2-(3-chlorophenyl)-4,4-difluoro-5-methylpiperidine

Figure 110128222-A0202-12-0642-736
Figure 110128222-A0202-12-0642-736

步驟1：9-(3-氯苯基)-6-甲基-1,4-三氧雜-8-氮雜螺[4.5]癸烷之合成Step 1: Synthesis of 9-(3-chlorophenyl)-6-methyl-1,4-trioxa-8-azaspiro[4.5]decane

將2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-胺(2.76g，18.99mmol)(如上文所製備)溶解於苯(60mL)中且向其中添加3-氯苯甲醛(2.67g，18.99mmol，2.15 mL)，隨後添加對甲苯磺酸 單水合物(10.84g，56.98mmol，8.74mL)。將所得混合物加熱至回流且以迪安-斯塔克分離器回流隔夜。將反應混合物冷卻且添加K2 CO3 水溶液(15ml)。將所得混合物轉移至分液漏斗且分離有機層。用EtOAc(35ml)萃取水層，且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發。將殘餘物溶解於CHCl3 (25ml)中且將所得混合物用NaHSO4 水溶液(1g於10ml水中，2*10ml)萃取。將經合併之水層用CHCl3 (2*30ml)洗滌，然後用K2 CO3 (6g)鹼化。將所得混合物用CHCl3 (2*40ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得9-(3-氯苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5 ]癸烷(1.51g，粗品)。2-(2-Methyl-1,3-dioxolan-2-yl)propan-1-amine (2.76 g, 18.99 mmol) (prepared as above) was dissolved in benzene (60 mL) and added to To this was added 3-chlorobenzaldehyde (2.67 g, 18.99 mmol, 2.15 mL) followed by p-toluenesulfonic acid monohydrate (10.84 g, 56.98 mmol, 8.74 mL). The resulting mixture was heated to reflux and refluxed with a Dean-Stark separator overnight. The reaction mixture was cooled and aqueous K2CO3 ( 15 ml) was added. The resulting mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with EtOAc (35 ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated. The residue was dissolved in CHCl 3 (25 ml) and the resulting mixture was extracted with aqueous NaHSO 4 (1 g in 10 ml water, 2*10 ml). The combined aqueous layers were washed with CHCl3 ( 2 *30 ml), then basified with K2CO3 ( 6 g). The resulting mixture was extracted with CHCl 3 (2*40 ml) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to obtain 9-(3-chlorophenyl)-6-methyl-1,4 -Dioxa-8-azaspiro[ 4.5 ]decane (1.51 g, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.08(d,3H),1.26(m,2H),1.64(m,1H),2.54(m,2H),2.67(m,2H),3.07(m,1H),3.48(m,1H),3.92(m,2H),7.26(m,4H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.08(d, 3H), 1.26(m, 2H), 1.64(m, 1H), 2.54(m, 2H), 2.67(m, 2H), 3.07( m, 1H), 3.48 (m, 1H), 3.92 (m, 2H), 7.26 (m, 4H).

LCMS(ESI)：[M]+ m/z：計算值267.2；實測值268.2；Rt=0.915min。LCMS (ESI): [M] + m/z: calculated 267.2; found 268.2; Rt=0.915min.

步驟2：2-(3-氯苯基)-5-甲基哌啶-4-酮之合成Step 2: Synthesis of 2-(3-Chlorophenyl)-5-methylpiperidin-4-one

將9-(3-氯苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5 ]癸烷(1.51g，5.64mmol)溶解於6N HCl(30mL)中且將所得混合物在80℃下(於油浴中)加熱隔夜。將反應混合物冷卻且用K2 CO3 鹼化。將所得混合物用CHCl3 (2*50ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發。將殘餘物溶解於MTBE中且向其中添加TFA(0.1ml)。將所得懸浮液過濾，將濾餅用MTBE沖洗且在真空中乾燥，以獲得2-(3-氯苯基)-5-甲基哌啶-4-酮(1.3g，3.85mmol，68.26%產率，CF3 COOH)。9-(3-Chlorophenyl)-6-methyl-1,4-dioxa-8-azaspiro[ 4.5 ]decane (1.51 g, 5.64 mmol) was dissolved in 6N HCl (30 mL) and The resulting mixture was heated at 80°C (in an oil bath) overnight. The reaction mixture was cooled and basified with K2CO3. The resulting mixture was extracted with CHCl3 (2*50 ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated. The residue was dissolved in MTBE and TFA (0.1 ml) was added to it. The resulting suspension was filtered, the filter cake was rinsed with MTBE and dried in vacuo to obtain 2-(3-chlorophenyl)-5-methylpiperidin-4-one (1.3 g, 3.85 mmol, 68.26% yield). rate, CF 3 COOH).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.01(d,3H),2.62(m,2H),2.89(m,1H),3.02(m,1H),3.67(m,1H),4.78(m,1H),7.52(m,3H),7.63(m,1H),9.56(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.01(d,3H), 2.62(m,2H), 2.89(m,1H), 3.02(m,1H), 3.67(m,1H), 4.78 (m, 1H), 7.52 (m, 3H), 7.63 (m, 1H), 9.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值223.2；實測值224.2；Rt=0.729min。LCMS (ESI): [M] + m/z: calculated 223.2; found 224.2; Rt=0.729 min.

步驟3：外消旋-(2R,5R)-2-(3-氯苯基)-4,4-二氟-5-甲基哌啶之合成Step 3: Synthesis of Racemic-(2R,5R)-2-(3-chlorophenyl)-4,4-difluoro-5-methylpiperidine

將2-(3-氯苯基)-5-甲基哌啶-4-酮(1.3g，3.85mmol，CF3 COOH)溶解於HF(無水)(3.9mL)中且將所得混合物密封在不鏽鋼容器中，在液態N2 中冷卻且 向其中添加SF4 (3.9mL)。使所得混合物升溫至室溫且攪拌隔夜。反應完成之後，將反應混合物倒入冰上且用NaHCO3 中和。將所得混合物用EtOAc(2*75ml)萃取且將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得(2R,5R )-2-(3-氯苯基)-4,4-二氟-5-甲基哌啶(0.79g，3.22mmol，83.53%產率)。2-(3-Chlorophenyl)-5-methylpiperidin-4-one (1.3 g, 3.85 mmol, CF3COOH ) was dissolved in HF (anhydrous) (3.9 mL) and the resulting mixture was sealed in stainless steel In a vessel, cooled in liquid N2 and SF4 (3.9 mL) was added to it. The resulting mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was poured onto ice and neutralized with NaHCO3 . The resulting mixture was extracted with EtOAc (2*75ml) and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated to give ( 2R,5R )-2-(3-chlorophenyl) -4,4-Difluoro-5-methylpiperidine (0.79 g, 3.22 mmol, 83.53% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.05(d,3H),2.03(m,3H),2.69(m,1H),3.05(m,1H),3.84(m,1H),7.28(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.05(d,3H), 2.03(m,3H), 2.69(m,1H), 3.05(m,1H), 3.84(m,1H), 7.28( m, 5H).

LCMS(ESI)：[M]+ m/z：計算值245.2；實測值246.2；Rt=0.933min。LCMS (ESI): [M] + m/z: calculated 245.2; found 246.2; Rt=0.933 min.

3NN.(2R,5S)-5-乙基-2-(1H-吡唑-4-基)哌啶之合成 3NN. Synthesis of (2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)piperidine

Figure 110128222-A0202-12-0644-737
Figure 110128222-A0202-12-0644-737

步驟1. 2-苯甲氧基-5-溴-吡啶之合成Step 1. Synthesis of 2-benzyloxy-5-bromo-pyridine

將於礦物油中之氫化鈉(油分散物)60%分散物(11.48g，286.95mmol，60%純度)小批量添加到5-溴-2-氯-吡啶(50.2g，260.86mmol)及苯基甲醇(31.03g，286.95mmol，29.55mL)於二甲基甲醯胺(500mL)中之溶液中。H2逸出停止之後，將所得混合物在20℃下攪拌18h。然後，將其倒入冰冷的水(2000ml)中且用MTBE(2x800ml)萃取。將經合併之有機層連續用水(2x300ml)、鹽水(300ml)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，得到2-苯甲氧基-5-溴-吡啶(72.1g，粗品)。Sodium hydride (oil dispersion) 60% dispersion in mineral oil (11.48 g, 286.95 mmol, 60% pure) was added in small batches to 5-bromo-2-chloro-pyridine (50.2 g, 260.86 mmol) and benzene in dimethylformamide (500 mL). After H2 evolution ceased, the resulting mixture was stirred at 20 °C for 18 h. It was then poured into ice cold water (2000ml) and extracted with MTBE (2x800ml). The combined organic layers were washed successively with water (2x300ml), brine (300ml), dried over Na2SO4 and concentrated under reduced pressure to give 2-benzyloxy-5-bromo-pyridine (72.1 g, crude) .

1 H NMR(400MHz,CDCl3 )δ(ppm)5.33(s,2H),6.71(d,1H),7.36-7.42(m,5H), 7.65(d,1H),8.19(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 5.33 (s, 2H), 6.71 (d, 1H), 7.36-7.42 (m, 5H), 7.65 (d, 1H), 8.19 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值263.0；實測值264.2；Rt=1.498min。LCMS (ESI): [M-Boc] + m/z: calculated 263.0; found 264.2; Rt=1.498 min.

步驟2. 2-苯甲氧基-5-乙烯基-吡啶之合成Step 2. Synthesis of 2-benzyloxy-5-vinyl-pyridine

將三乙胺(49.72g，491.37mmol，68.49mL)添加到2-苯甲氧基-5-溴-吡啶(72.1g，245.69mmol)及三氟(乙烯基)硼氫化物(30.29g，319.39mmol)於乙醇(700mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2*dppf*dcm(2.01g，2.46mmol)。在78℃、惰性氣氛下將所得混合物攪拌20h。然後，將其在減壓下濃縮且將殘餘物用己烷/MTBE 1：1混合物(700ml)萃取。透過短矽膠墊過濾所獲得之溶液且在減壓下蒸發。在-30℃下，將粗產物自己烷(350ml)結晶且過濾(產物在室溫下為液體)，得到2-苯甲氧基-5-乙烯基吡啶(27.8g，131.59mmol，53.56%產率)。Triethylamine (49.72 g, 491.37 mmol, 68.49 mL) was added to 2-benzyloxy-5-bromo-pyridine (72.1 g, 245.69 mmol) and trifluoro(vinyl)borohydride (30.29 g, 319.39 g mmol) in ethanol (700 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl2*dppf*dcm (2.01 g, 2.46 mmol) was added under argon flow. The resulting mixture was stirred at 78 °C under an inert atmosphere for 20 h. It was then concentrated under reduced pressure and the residue was extracted with a hexane/MTBE 1:1 mixture (700 ml). The resulting solution was filtered through a short pad of silica gel and evaporated under reduced pressure. The crude product hexane (350 ml) was crystallized at -30°C and filtered (the product was liquid at room temperature) to give 2-benzyloxy-5-vinylpyridine (27.8 g, 131.59 mmol, 53.56% yield). Rate).

1 H NMR(400MHz,CDCl3 )δ(ppm)5.19(d,1H),5.37(s,2H),5.65(d,1H),6.63(m,1H),6.78(d,1H),7.24-7.63(m,5),7.71(d,1H),8.19(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 5.19(d,1H), 5.37(s,2H), 5.65(d,1H), 6.63(m,1H), 6.78(d,1H), 7.24- 7.63(m,5), 7.71(d,1H), 8.19(s,1H).

步驟3. 5-乙基哌啶-2-酮之合成Step 3. Synthesis of 5-ethylpiperidin-2-one

將鈀(10%於碳上)(2g，1.88mmol，10%純度)添加到2-苯甲氧基-5-乙烯基吡啶(27.8g，131.59mmol)於甲醇(350mL)中之溶液中。將所得混合物在氫氣氣氛、20℃及氣球壓力下攪拌18小時，然後在70℃及40巴下再攪拌18小時。此後，過濾出催化劑且在減壓下濃縮濾液。將殘餘物再溶解於於乙酸乙酯(300ml)中且用20%K2 CO3 水溶液(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，得到5-乙基哌啶-2-酮(15.3g，120.30mmol，91.42%產率)。Palladium (10% on carbon) (2 g, 1.88 mmol, 10% pure) was added to a solution of 2-benzyloxy-5-vinylpyridine (27.8 g, 131.59 mmol) in methanol (350 mL). The resulting mixture was stirred under a hydrogen atmosphere at 20°C and balloon pressure for 18 hours, then at 70°C and 40 bar for a further 18 hours. After this time, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (300ml) and washed with 20 % aqueous K2CO3 (50ml), dried over Na2SO4 and evaporated in vacuo to give 5 -ethylpiperidine-2- Ketone (15.3 g, 120.30 mmol, 91.42% yield).

1 H NMR(400MHz,DMSO-d6)δ(ppm)0.87(m,3H),1.27(m,3H),1.53(m,1H),1.76(m,1H),2.12(m,2H),2.74(m,1H),3.13(m,1H),7.37(s,1H)。 1 H NMR (400MHz, DMSO-d6)δ(ppm) 0.87(m,3H), 1.27(m,3H), 1.53(m,1H), 1.76(m,1H), 2.12(m,2H), 2.74 (m, 1H), 3.13 (m, 1H), 7.37 (s, 1H).

GCMS(EI)：[M-Boc]+ m/z：計算值127.2；實測值127；Rt=7.4min。GCMS (EI): [M-Boc] + m/z: calculated 127.2; found 127; Rt=7.4 min.

步驟4. 5-乙基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 4. Synthesis of 3-butyl 5-ethyl-2-oxypiperidine-1-carboxylate

將二碳酸二-第三丁酯(36.76g，168.42mmol，38.65mL)逐滴添加到5-乙基哌啶-2-酮(15.3g，120.30mmol)及4-二甲胺基吡啶(1.47g，12.03mmol)於四氫呋喃(200mL)中之溶液中。將所得溶液在40℃下攪拌15h。然後，添加水(30ml)且將混合物攪拌20分鐘。當CO2逸出停止時，其分配於5%NaHSO4 水溶液(150ml)與MTBE(250ml)之間。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。將殘餘物在1毫巴及90℃下乾燥，得到5-乙基-2-側氧基哌啶-1-甲酸第三丁酯(18.2g，80.07mmol，66.56%產率)。Di-tert-butyl dicarbonate (36.76 g, 168.42 mmol, 38.65 mL) was added dropwise to 5-ethylpiperidin-2-one (15.3 g, 120.30 mmol) and 4-dimethylaminopyridine (1.47 g g, 12.03 mmol) in tetrahydrofuran (200 mL). The resulting solution was stirred at 40 °C for 15 h. Then, water (30 ml) was added and the mixture was stirred for 20 minutes. When CO2 evolution ceased, it was partitioned between 5 % aqueous NaHSO4 (150ml) and MTBE (250ml). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was dried at 1 mbar and 90°C to give tert-butyl 5-ethyl-2-oxypiperidine-1-carboxylate (18.2 g, 80.07 mmol, 66.56% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.97(m,3H),1.35-1.45(m,3H),1.53(s,9H),1.73(m,1H),1.93(m,1H),2.47-2.55(m,2H),3.18(m,1H),3.85(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.97(m, 3H), 1.35-1.45(m, 3H), 1.53(s, 9H), 1.73(m, 1H), 1.93(m, 1H), 2.47-2.55 (m, 2H), 3.18 (m, 1H), 3.85 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值227.3；實測值228.2；Rt=1.299min。LCMS (ESI): [M-Boc] + m/z: calculated 227.3; found 228.2; Rt=1.299 min.

步驟5. 6-二苯氧基磷醯氧基-3-乙基-3,4-三氫-2H-吡啶-1-甲酸第三丁酯之合成Step 5. Synthesis of 6-diphenoxyphosphoryloxy-3-ethyl-3,4-trihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

在氬氣下，將雙(三甲基矽基)醯胺化鋰(20%於THF/乙苯中)(80.39g，96.08mmol，89.32mL，20%純度)逐滴添加到冷卻至-78℃之5-乙基-2-側氧基哌啶-1-甲酸第三丁酯(18.2g，80.07mmol)於四氫呋喃(150mL)中之溶液中。將所得溶液在-70℃下攪拌1h，然後逐滴添加[氯(苯氧基)磷醯基]氧基苯(22.59g，84.07mmol，17.37mL)，保持溫度低於-70℃。使反應混合物升溫(移除冷卻浴)至0℃，然後用水(100ml)及MTBE(200ml)稀釋。將有機層分離，另外用MTBE(100ml)萃取水層。將經合併之有機萃取物用10% K2 CO3 水溶液(2*100ml)洗滌，經碳酸鉀乾燥，且在真空中濃縮。將殘餘物溶解於己烷中且透過短矽膠墊過濾所得混濁溶液。在真空中蒸發濾液，以得到呈淡黃色油狀物之粗品6-二苯氧基磷醯氧基-3-乙基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(33.4g，72.69mmol，90.79%產率)，其直接用於下一步驟中。Under argon, lithium bis(trimethylsilyl)amide (20% in THF/ethylbenzene) (80.39 g, 96.08 mmol, 89.32 mL, 20% pure) was added dropwise to a cooled to -78 A solution of tert-butyl 5-ethyl-2-oxypiperidine-1-carboxylate (18.2 g, 80.07 mmol) in tetrahydrofuran (150 mL) at °C. The resulting solution was stirred at -70 °C for 1 h, then [chloro(phenoxy)phosphoryl]oxybenzene (22.59 g, 84.07 mmol, 17.37 mL) was added dropwise, keeping the temperature below -70 °C. The reaction mixture was warmed (cooling bath removed) to 0°C, then diluted with water (100ml) and MTBE (200ml). The organic layer was separated and the aqueous layer was additionally extracted with MTBE (100 ml). The combined organic extracts were washed with 10 % aqueous K2CO3 ( 2 *100 ml), dried over potassium carbonate, and concentrated in vacuo. The residue was dissolved in hexane and the resulting cloudy solution was filtered through a short pad of silica gel. The filtrate was evaporated in vacuo to give crude 6-diphenoxyphosphoryloxy-3-ethyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a pale yellow oil (33.4 g, 72.69 mmol, 90.79% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.94(s,3H),1.24(m,1H),1.25(m,1H),1.43(s,9H),1.73(m,1H),1.76(m,1H),2.31(m,1H),2.94(dd,1H),3.95(dd,1H),5.07(s, 1H),7.18-7.33(m,10H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.94(s, 3H), 1.24(m, 1H), 1.25(m, 1H), 1.43(s, 9H), 1.73(m, 1H), 1.76( m, 1H), 2.31 (m, 1H), 2.94 (dd, 1H), 3.95 (dd, 1H), 5.07 (s, 1H), 7.18-7.33 (m, 10H).

LCMS(ESI)：[M+1]+ m/z：計算值459.2；實測值460.2；Rt=1.723min。LCMS (ESI): [M+1] + m/z: calculated 459.2; found 460.2; Rt=1.723 min.

步驟6. 6-(1-苯甲基吡唑-4-基)-3-乙基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 6. Synthesis of 6-(1-benzylpyrazol-4-yl)-3-ethyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鉀(2.92g，21.11mmol，1.27mL)添加到6-二苯氧基磷醯氧基-3-乙基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.09g，11.09mmol)及1-苯甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑(3g，10.56mmol)於二噁烷(40mL)及水(15mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2*dppf*dcm(344.86mg，422.30μmol)。在90℃、惰性氣氛下將所得混合物攪拌18h。然後，將其在減壓下濃縮且將殘餘物用MTBE(60ml)萃取。透過短矽膠墊過濾所獲得之溶液且在減壓下蒸發，得到6-(1-苯甲基吡唑-4-基)-3-乙基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.68g，粗品)。Potassium carbonate (2.92 g, 21.11 mmol, 1.27 mL) was added to 6-diphenoxyphosphoryloxy-3-ethyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester ( 5.09 g, 11.09 mmol) and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole ( 3 g, 10.56 mmol) in dioxane (40 mL) and water (15 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl2*dppf*dcm (344.86 mg, 422.30 μmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 18 h. It was then concentrated under reduced pressure and the residue was extracted with MTBE (60 ml). The resulting solution was filtered through a short pad of silica gel and evaporated under reduced pressure to give 6-(1-benzylpyrazol-4-yl)-3-ethyl-3,4-dihydro-2H-pyridine-1 - tert-butyl formate (4.68 g, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.96(m,3H),1.17(s,9H),1.39(m,1H),1.74(m,2H),2.09(m,2H),2.36(m,1H),2.90(dd,1H),4.06(d,1H),5.25(s,2H),7.26-7.32(m,6H),7.47(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.96(m, 3H), 1.17(s, 9H), 1.39(m, 1H), 1.74(m, 2H), 2.09(m, 2H), 2.36( m, 1H), 2.90 (dd, 1H), 4.06 (d, 1H), 5.25 (s, 2H), 7.26-7.32 (m, 6H), 7.47 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值367.2；實測值368.3；Rt=1.657min。LCMS (ESI): [M+1]+ m/z: calculated 367.2; found 368.3; Rt=1.657 min.

步驟7. 6-(1-苯甲基吡唑-4-基)-3-乙基-2,3,4,5-四氫吡啶之合成Step 7. Synthesis of 6-(1-benzylpyrazol-4-yl)-3-ethyl-2,3,4,5-tetrahydropyridine

將30% w/w鹽酸水溶液(17. 25g，141. 93mmol，15mL，30%純度)添加到6-(1-苯甲基吡唑-4-基)-3-乙基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.68g，12.74mmol)於二噁烷(20mL)中之溶液中。將所得混合物在40℃下攪拌15h。然後，在減壓下移除揮發物且將殘餘物分配於水(50ml)與乙酸乙酯(35ml)之間。分離有機層且丟棄。將水層用固體K2 CO3 鹼化且用DCM(3x20ml)萃取。將經合併之有機層經K2 CO3 乾燥且在真空中濃縮，得到6-(1-苯甲基吡唑-4-基)-3-乙基-2,3,4,5-四氫吡啶(2.13g，7.97mmol，62.56%產率)。30% w/w aqueous hydrochloric acid (17.25 g , 141.93 mmol , 15 mL, 30% purity) was added to 6-(1-benzylpyrazol-4-yl)-3-ethyl-3,4- A solution of tert-butyl dihydro-2H-pyridine-1-carboxylate (4.68 g, 12.74 mmol) in dioxane (20 mL). The resulting mixture was stirred at 40 °C for 15 h. Then, the volatiles were removed under reduced pressure and the residue was partitioned between water (50ml) and ethyl acetate (35ml). The organic layer was separated and discarded. The aqueous layer was basified with solid K2CO3 and extracted with DCM ( 3x20ml ). The combined organic layers were dried over K2CO3 and concentrated in vacuo to give 6-(1-benzylpyrazol-4-yl)-3-ethyl-2,3,4,5-tetrahydro Pyridine (2.13 g, 7.97 mmol, 62.56% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.92(m,3H),1.21-1.32(m,3H),1.45(m,1H), 1.88(m,1H),2.43(m,1H),2.60(dd,1H),3.17(dd,1H),3.87(dd,1H),5.26(s,2H),7.20-7.32(m,5H),7.69(s,1H),7.77(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.92(m, 3H), 1.21-1.32(m, 3H), 1.45(m, 1H), 1.88(m, 1H), 2.43(m, 1H), 2.60(dd,1H),3.17(dd,1H),3.87(dd,1H),5.26(s,2H),7.20-7.32(m,5H),7.69(s,1H),7.77(s,1H) .

LCMS(ESI)：[M+1]+ m/z：計算值267.2；實測值268.2；Rt=0.863min。LCMS (ESI): [M+1] + m/z: calculated 267.2; found 268.2; Rt=0.863 min.

步驟8. (2R,5S)-2-(1-苯甲基吡唑-4-基)-5-乙基哌啶之合成Step 8. Synthesis of (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-ethylpiperidine

向6-(1-苯甲基吡唑-4-基)-3-乙基-2,3,4,5-四氫吡啶(2.13g，7.97mmol)於甲醇(40mL)中之經攪拌之溶液中分批添加硼氫化鈉(452.09mg，11.95mmol，422.52μL)。將所得混合物在20℃下攪拌2h。然後，在減壓下移除溶劑且將殘餘物分配於水(20ml)與乙酸乙酯(30ml)之間。將有機層分離，經Na2 SO4 乾燥且在真空中濃縮，得到(2R,5S)-2-(1-苯甲基吡唑-4-基)-5-乙基-哌啶(1.98g，7.35mmol，92.26%產率)。To a stirred solution of 6-(1-benzylpyrazol-4-yl)-3-ethyl-2,3,4,5-tetrahydropyridine (2.13 g, 7.97 mmol) in methanol (40 mL) To the solution was added sodium borohydride (452.09 mg, 11.95 mmol, 422.52 μL) in portions. The resulting mixture was stirred at 20 °C for 2 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (20ml) and ethyl acetate (30ml). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to give (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-ethyl-piperidine (1.98 g) , 7.35 mmol, 92.26% yield).

1 H NMR(500MHz,DMSO)δ(ppm)0.88(m,3H),1.19(m,1H),1.36(m,2H),1.36(m,1H),1.57(m,1H),1.90(m,3H),2.34(dd,1H),3.15(d,1H),3.56(d,1H),5.24(s,2H),7.20-7.32(m,6H),7.48(s,1H)。 1 H NMR(500MHz,DMSO)δ(ppm)0.88(m,3H),1.19(m,1H),1.36(m,2H),1.36(m,1H),1.57(m,1H),1.90(m , 3H), 2.34(dd, 1H), 3.15(d, 1H), 3.56(d, 1H), 5.24(s, 2H), 7.20-7.32(m, 6H), 7.48(s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值269.2；實測值270.1；Rt=0.944min。LCMS (ESI): [M+1] + m/z: calculated 269.2; found 270.1; Rt=0.944 min.

步驟9. (2R,5S)-2-(1-苯甲基吡唑-4-基)-5-乙基哌啶之合成Step 9. Synthesis of (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-ethylpiperidine

將二碳酸二-第三丁酯(1.76g，8.09mmol，1.86mL)添加到(2R,5S)-2-(1-苯甲基吡唑-4-基)-5-乙基哌啶(1.98g，7.35mmol)於二氯甲烷(30mL)中之溶液中。將所得混合物在20℃下攪拌4h。然後，在減壓下移除揮發物，且藉由梯度管柱層析(Hex-MTBE)純化殘餘物，得到(2R,5S)-2-(1-苯甲基吡唑-4-基)-5-乙基-哌啶-1-甲酸第三丁酯(2.2g，5.95mmol，81.01%產率)。Di-tert-butyl dicarbonate (1.76 g, 8.09 mmol, 1.86 mL) was added to (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-ethylpiperidine ( 1.98 g, 7.35 mmol) in dichloromethane (30 mL). The resulting mixture was stirred at 20 °C for 4 h. Then, the volatiles were removed under reduced pressure, and the residue was purified by gradient column chromatography (Hex-MTBE) to give (2R,5S)-2-(1-benzylpyrazol-4-yl) - 5-Ethyl-piperidine-1-carboxylic acid tert-butyl ester (2.2 g, 5.95 mmol, 81.01% yield).

1 H NMR(dmso,600MHz)：δ(ppm)0.87-0.90(m,4H),1.31(m,1H),1.44(m,10H),1.74(m,3H),1.98(m,1H),2.90(d,1H),3.83(d,1H),5.26(s,2H),5.33(s,1H),7.18(m,2H),7.33-7.38(m,5H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.87-0.90 (m, 4H), 1.31 (m, 1H), 1.44 (m, 10H), 1.74 (m, 3H), 1.98 (m, 1H), 2.90(d,1H), 3.83(d,1H), 5.26(s,2H), 5.33(s,1H), 7.18(m,2H), 7.33-7.38(m,5H).

LCMS(ESI)：[M+1]+ m/z：計算值369.2；實測值370.2；Rt=1.687min。LCMS (ESI): [M+1] + m/z: calculated 369.2; found 370.2; Rt=1.687 min.

步驟10. (2R,5S)-2-(1-苯甲基吡唑-4-基)-5-乙基哌啶-1-甲酸第三丁酯之合成Step 10. Synthesis of (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-ethylpiperidine-1-carboxylic acid tert-butyl ester

向(2R,5S)-2-(1-苯甲基吡唑-4-基)-5-乙基哌啶-1-甲酸第三丁酯(2.2g，5.95mmol)於甲醇(40mL)中之溶液中添加10% Pd/碳A402028-10批次C-14557(0.5g，469.84μmol，10%純度)及乙酸(5.05g，84.11mmol，4.81mL)。將所得混合物抽真空，然後用氫氣回填。將反應混合物在氫氣氣氛(氣球壓力)、55℃下攪拌18h。然後，過濾出催化劑且在真空中濃縮濾液，得到(2R,5S)-5-乙基-2-(1H-吡唑-4-基)哌啶-1-甲酸第三丁酯(1.75g，粗品)。To (2R,5S)-2-(1-benzylpyrazol-4-yl)-5-ethylpiperidine-1-carboxylic acid tert-butyl ester (2.2 g, 5.95 mmol) in methanol (40 mL) To this solution was added 10% Pd/carbon A402028-10 batch C-14557 (0.5 g, 469.84 μmol, 10% purity) and acetic acid (5.05 g, 84.11 mmol, 4.81 mL). The resulting mixture was evacuated and backfilled with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) at 55 °C for 18 h. Then, the catalyst was filtered off and the filtrate was concentrated in vacuo to give tert-butyl (2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)piperidine-1-carboxylate (1.75 g, Crude).

1 H NMR(dmso,400MHz)：δ(ppm)0.93(m,3H),1.34(m,1H),1.48(m,12H),1.77(m,2H),2.04(m,1H),2.90(d,1H),3.85(d,1H),5.39(s,1H),7.26(m,2H),7.44(s,1H)。 1 H NMR (dmso, 400MHz): δ (ppm) 0.93 (m, 3H), 1.34 (m, 1H), 1.48 (m, 12H), 1.77 (m, 2H), 2.04 (m, 1H), 2.90 ( d, 1H), 3.85 (d, 1H), 5.39 (s, 1H), 7.26 (m, 2H), 7.44 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值279.2；實測值280.2；Rt=1.278min。LCMS (ESI): [M+1] + m/z: calculated 279.2; found 280.2; Rt=1.278 min.

步驟11. (2R,5S)-5-乙基-2-(1H-吡唑-4-基)哌啶之合成Step 11. Synthesis of (2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)piperidine

將於二噁烷中之4.0M氯化氫溶液(15.15g，41.55mmol，15mL，10%純度)添加到(2R,5S)-5-乙基-2-(1H-吡唑-4-基)哌啶-1-甲酸第三丁酯(1.6g，5.73mmol)於甲醇(10mL)中之溶液中。將所得混合物在25℃下攪拌16h。然後，在減壓下移除揮發物，得到(2R,5S)-5-乙基-2-(1H-吡唑-4-基)哌啶(1.44g，5.71mmol，100.00%產率，2HCl)。A 4.0M solution of hydrogen chloride in dioxane (15.15 g, 41.55 mmol, 15 mL, 10% purity) was added to (2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)piperidine A solution of tert-butyl pyridine-1-carboxylate (1.6 g, 5.73 mmol) in methanol (10 mL). The resulting mixture was stirred at 25 °C for 16 h. Then, the volatiles were removed under reduced pressure to give (2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)piperidine (1.44 g, 5.71 mmol, 100.00% yield, 2HCl ).

1 H NMR(dmso,400MHz)：δ(ppm)0.84(m,3H),1.19(m,3H),1.70(m,1H),1.86(m,1H),1.96(m,1H),2.60(dd,1H),3.12(m,1H),4.07(t,1H),5.93(brs,2H),7.88(s,2H),9.47(s,1H)。 1 H NMR (dmso, 400MHz): δ (ppm) 0.84 (m, 3H), 1.19 (m, 3H), 1.70 (m, 1H), 1.86 (m, 1H), 1.96 (m, 1H), 2.60 ( dd, 1H), 3.12 (m, 1H), 4.07 (t, 1H), 5.93 (brs, 2H), 7.88 (s, 2H), 9.47 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值279.2；實測值280.2；Rt=1.278min。LCMS (ESI): [M+1] + m/z: calculated 279.2; found 280.2; Rt=1.278 min.

3OO.7-氟-5-(5-甲基-2-哌啶基)-1H-吲唑之合成 3OO. The synthesis of 7-fluoro-5-(5-methyl-2-piperidinyl)-1H-indazole

Figure 110128222-A0202-12-0650-738
Figure 110128222-A0202-12-0650-738

步驟1：(Z)-1-(5-溴-2,3-二氟苯基)-N-甲氧基甲亞胺之合成Step 1: Synthesis of (Z)-1-(5-bromo-2,3-difluorophenyl)-N-methoxymethimine

將碳酸鉀(7.50g，54.30mmol，3.28mL)添加到5-溴-2,3-二氟苯甲醛(10g，45.25mmol)基O-甲基羥基胺(4.16g，49.77mmol，HCl)於DME(115mL)中之溶液中，且使反應物在45℃下反應隔夜。冷卻至室溫之後，將其過濾，用乙酸乙酯洗滌，且蒸發。Potassium carbonate (7.50 g, 54.30 mmol, 3.28 mL) was added to 5-bromo-2,3-difluorobenzaldehyde (10 g, 45.25 mmol) based O-methylhydroxylamine (4.16 g, 49.77 mmol, HCl) to solution in DME (115 mL) and the reaction was allowed to react overnight at 45°C. After cooling to room temperature, it was filtered, washed with ethyl acetate, and evaporated.

1 H NMR(400MHz,CDCl3 )δ 3.99(s,3H),7.30(m,1H),7.73(s,1H),8.18(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.99 (s, 3H), 7.30 (m, 1H), 7.73 (s, 1H), 8.18 (s, 1H).

步驟2：5-溴-7-氟-1H-吲唑之合成Step 2: Synthesis of 5-bromo-7-fluoro-1H-indazole

將(Z)-1-(5-溴-2,3-二氟苯基)-N-甲氧基甲亞胺(10.7g，42.79mmol)、水合肼溶液(45mL)於THF(45mL)中之溶液加熱至90℃達120h。蒸發溶劑且將所得混合物用EtOAc稀釋，用水洗滌，經Na2 SO4 乾燥且在真空下濃縮，以得到粗產物。經由急驟管柱層析純化殘餘物，以得到1.95g。(Z)-1-(5-Bromo-2,3-difluorophenyl)-N-methoxymethimine (10.7 g, 42.79 mmol), hydrazine hydrate solution (45 mL) in THF (45 mL) The solution was heated to 90°C for 120h. The solvent was evaporated and the resulting mixture was diluted with EtOAc, washed with water, dried over Na2SO4 and concentrated in vacuo to give crude product. The residue was purified via flash column chromatography to give 1.95 g.

1 H NMR(400MHz,DMSO-d6 )δ 7.30(s,1H),7.76(s,1H),8.06(s,1H),13.72(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.30 (s, 1H), 7.76 (s, 1H), 8.06 (s, 1H), 13.72 (s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值215.0；實測值217.0；Rt=0.959min。LCMS (ESI): [M+2H] + m/z: calculated 215.0; found 217.0; Rt=0.959 min.

步驟3：5-溴-7-氟-1-四氫哌喃-2-基-吲唑之合成 向5-溴-7-氟-1H-吲唑(1.95g，9.07mmol)及3,4-二氫-2H-哌喃(915.40mg，10.88mmol，988.56μL)於CH2 Cl2 (40mL)中之溶液中添加對甲苯磺酸單水合物(172.51mg，906.88μmol，139.12μL)。在 室溫下將混合物攪拌隔夜。將混合物用DCM(250mL)稀釋且用水(3 x 80mL)洗滌。將有機層乾燥(Na2 SO4 )，過濾且在減壓下濃縮。 Step 3: Synthesis of 5-bromo-7-fluoro-1-tetrahydropyran-2-yl-indazole To 5-bromo-7-fluoro-1H-indazole (1.95 g, 9.07 mmol) and 3,4 - Dihydro-2H-pyran (915.40 mg, 10.88 mmol, 988.56 μL) in CH2Cl2 ( 40 mL) was added p-toluenesulfonic acid monohydrate (172.51 mg, 906.88 μmol, 139.12 μL). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (250 mL) and washed with water (3 x 80 mL). The organic layer was dried ( Na2SO4 ) , filtered and concentrated under reduced pressure.

1 H NMR(400MHz,CDCl3 )δ 1.71(m,2H),3.29(m,2H),3.71(m,2H),3.81(m,1H),4.50(m,1H),5.71(m,1H),7.50(d,1H),7.89(s,1H),8.36(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.71 (m, 2H), 3.29 (m, 2H), 3.71 (m, 2H), 3.81 (m, 1H), 4.50 (m, 1H), 5.71 (m, 1H) ), 7.50(d, 1H), 7.89(s, 1H), 8.36(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值；實測值；Rt=min。LCMS (ESI): [M+H] + m/z: calculated value; observed value; Rt=min.

步驟4：7-氟-1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 4: 7-Fluoro-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of base)indazole

將5-溴-7-氟-1-四氫哌喃-2-基吲唑(2.7g，9.03mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.29g，9.03mmol)及乙酸鉀(1.77g，18.05mmol，1.13mL)混合於二噁烷(60mL)中，且將所得混合物抽真空且用氬氣回填三次。向其中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(368.54mg，451.30μmol)且將反應混合物在100℃下加熱20h。冷卻反應混合物且過濾。在真空中濃縮濾液且藉由管柱層析純化，以獲得7-氟-1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑(1.87g，5.40mmol，59.84%產率)。5-Bromo-7-fluoro-1-tetrahydropyran-2-ylindazole (2.7 g, 9.03 mmol), 4,4,5,5-tetramethyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (2.29 g, 9.03 mmol) and potassium acetate (1.77 g, 18.05 mmol, 1.13 mL) were mixed in dioxane (60 mL), and the resulting mixture was evacuated and backfilled with argon three times. To this was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (368.54 mg, 451.30 μmol) and the reaction mixture was heated at 100 °C 20h. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo and purified by column chromatography to obtain 7-fluoro-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)indazole (1.87 g, 5.40 mmol, 59.84% yield).

1 H NMR(400MHz,CDCl3 )δ 1.20(m,2H),1.42(s,12H),1.70(m,2H),2.12(m,2H),2.60(m,1H),3.72(m,1H),5.91(m,1H),7.49(d,1H),8.08(s,1H),8.19(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.20(m, 2H), 1.42(s, 12H), 1.70(m, 2H), 2.12(m, 2H), 2.60(m, 1H), 3.72(m, 1H) ), 5.91(m, 1H), 7.49(d, 1H), 8.08(s, 1H), 8.19(s, 1H).

步驟5：6-(7-氟-1-四氫哌喃-2-基吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 5: 6-(7-Fluoro-1-tetrahydropyran-2-ylindazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl Synthesis of Esters

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.70g，4.91mmol)、7-氟-1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑(1.87g，5.40mmol)及碳酸鈉(1.04g，9.82mmol，411.43μL)一起混合於二噁烷(15mL)及水(5mL)之混合物中。將所得混合物抽真空且用氬氣回填三次，且向其中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之 複合物(200.50mg，245.52μmol)。將反應混合物在90℃下加熱18h。冷卻反應混合物且將其倒入水(50ml)中。將所得混合物用EtOAc(2*50ml)萃取且將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.70 g, 4.91 mmol), 7-fluoro- 1-Tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole (1.87g , 5.40 mmol) and sodium carbonate (1.04 g, 9.82 mmol, 411.43 μL) were mixed together in a mixture of dioxane (15 mL) and water (5 mL). The resulting mixture was evacuated and backfilled with argon three times, and to it was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (200.50 mg) , 245.52 μmol). The reaction mixture was heated at 90 °C for 18 h. The reaction mixture was cooled and poured into water (50 ml). The resulting mixture was extracted with EtOAc (2*50 ml) and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated.

LCMS(ESI)：[M-THP]+ m/z：計算值331.2；實測值332.2；Rt=1.407min。LCMS (ESI): [M-THP] + m/z: calculated 331.2; found 332.2; Rt=1.407 min.

步驟6：7-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-四氫哌喃-2-基吲唑之合成Step 6: Synthesis of 7-fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1-tetrahydropyran-2-ylindazole

將三氟乙酸(3.02g，26.47mmol，2.04mL)添加到於CH2Cl2(2mL)中之6-(7-氟-1-四氫哌喃-2-基-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.2g，5.29mmol)中。將反應混合物在25℃下攪拌18h，然後在真空中蒸發且倒入水(80ml)及碳酸氫鈉(4.45g，52.95mmol，2.06mL)中且用EtOAc(2x30ml)萃取。將經合併之有機萃取物用水(2*20ml)洗滌，經硫酸鈉乾燥且在真空中蒸發。Trifluoroacetic acid (3.02 g, 26.47 mmol, 2.04 mL) was added to 6-(7-fluoro-1-tetrahydropyran-2-yl-indazol-5-yl)-3 in CH2Cl2 (2 mL) - methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.2 g, 5.29 mmol). The reaction mixture was stirred at 25°C for 18h, then evaporated in vacuo and poured into water (80ml) and sodium bicarbonate (4.45g, 52.95mmol, 2.06mL) and extracted with EtOAc (2x30ml). The combined organic extracts were washed with water (2*20ml), dried over sodium sulfate and evaporated in vacuo.

LCMS(ESI)：[M+H]+ m/z：計算值315.2；實測值316.2；Rt=0.867min。LCMS (ESI): [M+H] + m/z: calculated 315.2; found 316.2; Rt=0.867 min.

步驟7：7-氟-5-(5-甲基-2-哌啶基)-1-四氫哌喃-2-基吲唑之合成Step 7: Synthesis of 7-fluoro-5-(5-methyl-2-piperidinyl)-1-tetrahydropyran-2-ylindazole

將7-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-四氫哌喃-2-基吲唑(1.45g，4.60mmol)溶解於MeOH(20mL)中且分批添加硼氫化鈉(521.78mg，13.79mmol，487.64μL)。將反應混合物攪拌18h。將反應混合物蒸發至乾。將殘餘物溶解於DCM(50ml)中且將所得混合物用NaHSO4 水溶液(2*50ml)萃取。將經合併之水層用DCM(3*50ml)洗滌，然後用K2CO3 鹼化。將所得混合物用DCM(2*100ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發。7-Fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1-tetrahydropyran-2-ylindazole (1.45 g, 4.60 mmol) was dissolved In MeOH (20 mL) was added sodium borohydride (521.78 mg, 13.79 mmol, 487.64 μL) portionwise. The reaction mixture was stirred for 18 h. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (50ml) and the resulting mixture was extracted with aq. NaHSO4 (2*50ml). The combined aqueous layers were washed with DCM ( 3 *50ml), then basified with K2CO3. The resulting mixture was extracted with DCM (2*100ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated.

LCMS(ESI)：[M+H]+ m/z：計算值317.2；實測值318.2；Rt=0.757min。LCMS (ESI): [M+H] + m/z: calculated 317.2; found 318.2; Rt=0.757 min.

步驟8：7-氟-5-(5-甲基-2-哌啶基)-1H-吲唑之合成Step 8: Synthesis of 7-fluoro-5-(5-methyl-2-piperidinyl)-1H-indazole

將7-氟-5-(5-甲基-2-哌啶基)-1-四氫哌喃-2-基-吲唑(0.74g，2.33mmol)溶解於於二噁烷中之4.0M氯化氫溶液(1.70g，2.13mL)中且將溶液攪拌12h。將反應混合物蒸發至乾。7-Fluoro-5-(5-methyl-2-piperidinyl)-1-tetrahydropyran-2-yl-indazole (0.74 g, 2.33 mmol) was dissolved in 4.0 M in dioxane hydrogen chloride solution (1.70 g, 2.13 mL) and the solution was stirred for 12 h. The reaction mixture was evaporated to dryness.

LCMS(ESI)：[M+H]+ m/z：計算值233.2；實測值234.2；Rt=0.619min。LCMS (ESI): [M+H] + m/z: calculated 233.2; found 234.2; Rt=0.619 min.

3PP.3PP. 5-甲基-2-(5-甲基-2-哌啶基)吡啶之合成Synthesis of 5-methyl-2-(5-methyl-2-piperidinyl)pyridine

Figure 110128222-A0202-12-0653-739
Figure 110128222-A0202-12-0653-739

步驟1：2-(1-苯甲基-5-甲基-2-吡啶基)-5-甲基溴化吡啶之合成Step 1: Synthesis of 2-(1-benzyl-5-methyl-2-pyridyl)-5-methylpyridinium bromide

將5-甲基-2-(5-甲基-2-吡啶基)吡啶(1g，5.43mmol)及苯甲基溴(2.48g，14.48mmol，1.72mL)於乙腈(10mL)中之混合物在密封管中在85℃下加熱18小時。18小時之後，在減壓下濃縮反應混合物。將所獲得之粗產物用MTBE研磨，將沉澱過濾，用MTBE洗滌且在真空下乾燥，以得到呈淡粉色粉末之2-(1-苯甲基-5-甲基-2-吡啶基)-5-甲基溴化吡啶(1.95g，粗品)。A mixture of 5-methyl-2-(5-methyl-2-pyridyl)pyridine (1 g, 5.43 mmol) and benzyl bromide (2.48 g, 14.48 mmol, 1.72 mL) in acetonitrile (10 mL) was placed in Heat in a sealed tube at 85°C for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure. The crude product obtained was triturated with MTBE, the precipitate was filtered, washed with MTBE and dried under vacuum to give 2-(1-benzyl-5-methyl-2-pyridinyl)- as a pale pink powder 5-Methylpyridine bromide (1.95 g, crude).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)2.44(s,3H),2.63(s,3H),6.24(s,2H),7.21(m,5H),7.59(d,1H),7.66(d,1H),7.91(d,1H),8.34(m,1H),8.60(s,1H),9.75(s,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 2.44 (s, 3H), 2.63 (s, 3H), 6.24 (s, 2H), 7.21 (m, 5H), 7.59 (d, 1H), 7.66 (d, 1H), 7.91 (d, 1H), 8.34 (m, 1H), 8.60 (s, 1H), 9.75 (s, 1H).

步驟2：2-(1-苯甲基-5-甲基-2-哌啶基)-5-甲基吡啶之合成Step 2: Synthesis of 2-(1-benzyl-5-methyl-2-piperidinyl)-5-methylpyridine

在高壓釜中，將2-(1-苯甲基-5-甲基-2-吡啶基)-5-甲基-溴化吡啶(1.9g，4.92mmol)及TEA(0.5g，4.94mmol，688.71μL)於甲醇(50mL)中之溶液在20atm H2 壓力、40℃下經PtO2 (0.05g，220.19μmol)氫化18小時。完成之後，透過矽藻土墊過濾反應混合物且在減壓下濃縮濾液。將所獲得之粗產物用MTBE研磨。過濾沉澱且在減壓下濃縮濾液，以獲得呈非鏡像異構物(約1：3)之混合物形式之2-(1-苯甲基-5-甲基-2-哌啶基)-5-甲基吡啶(1.3g，粗品)。In an autoclave, 2-(1-benzyl-5-methyl-2-pyridyl)-5-methyl-pyridine bromide (1.9 g, 4.92 mmol) and TEA (0.5 g, 4.94 mmol, 688.71 μL) in methanol (50 mL) was hydrogenated over PtO 2 (0.05 g, 220.19 μmol) at 20 atm H 2 pressure at 40 °C for 18 h. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product obtained was triturated with MTBE. The precipitate was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(1-benzyl-5-methyl-2-piperidinyl)-5 as a mixture of diastereoisomers (about 1:3) - Methylpyridine (1.3 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值280.2；實測值281.2；Rt=1.010min。LCMS (ESI): [M+H] + m/z: calculated 280.2; found 281.2; Rt=1.010 min.

步驟3：5-甲基-2-(5-甲基-2-哌啶基)吡啶之合成Step 3: Synthesis of 5-methyl-2-(5-methyl-2-piperidinyl)pyridine

在高壓釜中，將2-(1-苯甲基-5-甲基-2-哌啶基)-5-甲基吡啶(0.5g，1.78mmol)於甲醇(80mL)中之溶液在10atm H2 壓力、100℃下經10% Pd/C(1.78mmol) 氫化12小時。完成之後，透過矽藻土墊過濾反應混合物且在真空中濃縮濾液，以獲得5-甲基-2-(5-甲基-2-哌啶基)吡啶(0.33g，粗品)。將粗產物用於下一步驟反應中。In an autoclave, a solution of 2-(1-benzyl-5-methyl-2-piperidinyl)-5-methylpyridine (0.5 g, 1.78 mmol) in methanol (80 mL) was added at 10 atm H Hydrogenation over 10% Pd/C (1.78 mmol) at 2 pressure, 100°C for 12 hours. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to obtain 5-methyl-2-(5-methyl-2-piperidinyl)pyridine (0.33 g, crude). The crude product was used in the next step reaction.

LCMS(ESI)：[M+H]+ m/z：計算值190.2；實測值191.2；Rt=0.806-1.099min。LCMS (ESI): [M+H] + m/z: calculated 190.2; found 191.2; Rt=0.806-1.099 min.

3QQ. 外消旋 -5-((2R,5S )-5-甲基哌啶-2-基)-1H -噻吩并[3,2-c ]吡唑之合成 3QQ. Synthesis of racemic -5-(( 2R,5S )-5-methylpiperidin-2-yl)-1H-thieno[ 3,2 -c ]pyrazole

Figure 110128222-A0202-12-0654-740
Figure 110128222-A0202-12-0654-740

步驟1：5-溴-1H-噻吩并[3,2-c]吡唑之合成Step 1: Synthesis of 5-bromo-1H-thieno[3,2-c]pyrazole

將1-(5-溴噻吩并[3,2-c]吡唑-1-基)乙酮(10g，40.80mmol)溶解於二噁烷(50mL)中且與於H2 O(10mL)中之碳酸鉀(8.46g，61.20mmol，8.46mL)混合。將反應混合物加熱至70℃且攪拌48h(藉由H-NMR控制反應完成)。反應完成之後，在減壓下蒸發溶劑；將油狀殘餘物用H2 O(100mL)研磨且過濾。將所獲得之固體風乾，以得到5-溴-1H -噻吩并[3,2-c ]吡唑(7.5g，36.93mmol，90.53%產率)。1-(5-Bromothieno[3,2-c]pyrazol-1-yl)ethanone (10 g, 40.80 mmol) was dissolved in dioxane (50 mL) and dissolved in H2O (10 mL) and potassium carbonate (8.46 g, 61.20 mmol, 8.46 mL). The reaction mixture was heated to 70 °C and stirred for 48 h (reaction completion was controlled by H-NMR). After the reaction was complete, the solvent was evaporated under reduced pressure; the oily residue was triturated with H2O (100 mL) and filtered. The obtained solid was air-dried to give 5-bromo- 1H -thieno[ 3,2-c ]pyrazole (7.5 g, 36.93 mmol, 90.53% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.43(s,1H),7.83(s,1H),13.11(bds,1H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 7.43 (s, 1H), 7.83 (s, 1H), 13.11 (bds, 1H).

步驟2：5-溴-1-(四氫-2H-哌喃-2-基)-1H-噻吩并[3,2-c]吡唑之合成Step 2: Synthesis of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[3,2-c]pyrazole

將5-溴-1H -噻吩并[3,2-c ]吡唑(7.5g，36.93mmol)懸浮於3,4-二氫-2H -哌喃(31.07g，369.35mmol，33.55mL)中，隨後添加甲苯磺酸(636.02mg，3.69mmol)(小心！觀察到放熱)。反應完成之後，將混合物蒸發至乾且使其經歷CC(O OK.Interchim,330g SiO2，石油醚/MTBE，其中MTBE為5~15%，流速=135mL/min，Rv=6-10 CV)，以得到5-溴-1-四氫哌喃-2-基-噻吩并[3,2-c ]吡唑(6g， 20.89mmol，56.57%產率)。5-Bromo- 1H -thieno[ 3,2-c ]pyrazole (7.5 g, 36.93 mmol) was suspended in 3,4-dihydro- 2H -pyran (31.07 g, 369.35 mmol, 33.55 mL), Toluenesulfonic acid (636.02 mg, 3.69 mmol) was then added (be careful! exotherm observed). After the reaction was complete, the mixture was evaporated to dryness and subjected to CC (O OK. Interchim, 330 g SiO , petroleum ether/MTBE, where MTBE was 5-15%, flow rate=135 mL/min, Rv=6-10 CV), to give 5-bromo-1-tetrahydropyran-2-yl-thieno[ 3,2-c ]pyrazole (6 g, 20.89 mmol, 56.57% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.65(m,4H),2.15(m,2H),3.71(m,1H),4.07(m,1H),5.48(m,1H),7.13(s,1H),7.68(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.65(m, 4H), 2.15(m, 2H), 3.71(m, 1H), 4.07(m, 1H), 5.48(m, 1H), 7.13( s, 1H), 7.68 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值287.2；實測值288.2；Rt=1.239min。LCMS (ESI): [M] + m/z: calculated 287.2; found 288.2; Rt=1.239 min.

步驟3：(2-甲基-5-側氧基-5-(1-(四氫-2H-哌喃-2-基)-1H-噻吩并[3,2-c]吡唑-5-基)戊基)胺甲酸第三丁酯之合成Step 3: (2-Methyl-5-oxo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[3,2-c]pyrazole-5- Synthesis of tert-butyl)pentyl)carbamate

將5-溴-1-四氫哌喃-2-基-噻吩并[3,2-c ]吡唑(6g，20.89mmol)溶解於THF(30mL)中且在Ar下冷卻至-78℃。逐滴添加丁基鋰(2.5M，9.19mL)，將溫度保持在同一點下。再攪拌10min之後，添加5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(6.68g，31.34mmol)於THF(20mL)中之溶液。再攪拌10min之後，將反應物升溫至-10℃且用飽和NH4 Cl水溶液(30mL)萃取。將粗反應混合物分配於EtOAc(50mL)與H2 O(30mL)之間，將有機層經Na2 SO4 乾燥，蒸發至乾且用CC(OK.Companion combiflash；330g SiO2 ，氯仿/MeCN，其中MeCN為0~10%，流速=100mL/min，Rv=6.5 CV)純化，以得到N -[2-甲基-5-側氧基-5-(1-四氫哌喃-2-基噻吩并[3,2-c]吡唑-5-基)戊基]胺甲酸第三丁 酯(1.5g，3.56mmol，17.03%產率)。5-Bromo-1-tetrahydropyran-2-yl-thieno[ 3,2-c ]pyrazole (6 g, 20.89 mmol) was dissolved in THF (30 mL) and cooled to -78 °C under Ar. Butyllithium (2.5M, 9.19 mL) was added dropwise, keeping the temperature at the same point. After stirring for an additional 10 min, a solution of tert-butyl 5-methyl-2-pentoxypiperidine-1-carboxylate (6.68 g, 31.34 mmol) in THF (20 mL) was added. After stirring for an additional 10 min, the reaction was warmed to -10 °C and extracted with saturated aqueous NH4Cl (30 mL). The crude reaction mixture was partitioned between EtOAc (50 mL) and H 2 O (30 mL), the organic layer was dried over Na 2 SO 4 , evaporated to dryness and washed with CC (OK. Companion combiflash; 330 g SiO 2 , chloroform/MeCN, wherein MeCN is 0~10%, flow rate=100mL/min, Rv=6.5 CV) and purified to obtain N- [2-methyl-5-oxy-5-(1-tetrahydropyran-2-yl] Thieno[3,2-c]pyrazol-5-yl)pentyl]carbamate tert -butyl ester (1.5 g, 3.56 mmol, 17.03% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.92(d,3H),1.42(s,9H),1.78(m,7H),2.13(m,2H),2.31(m,1H),3.07(m,3H),3.75(m,1H),4.02(m,1H),4.66(m,1H),5.61(m,1H),7.69(s,1H),7.75(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.92(d, 3H), 1.42(s, 9H), 1.78(m, 7H), 2.13(m, 2H), 2.31(m, 1H), 3.07( m, 3H), 3.75 (m, 1H), 4.02 (m, 1H), 4.66 (m, 1H), 5.61 (m, 1H), 7.69 (s, 1H), 7.75 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.525min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.525min.

步驟4：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-1H-噻吩并[3,2-c]吡唑之合成Step 4: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1H-thieno[3,2-c]pyrazole

將N -[2-甲基-5-側氧基-5-(1-四氫哌喃-2-基噻吩并[3,2-c ]吡唑-5-基)戊基]胺甲酸第三丁 酯(1.5g，3.56mmol)溶解於DCM(10mL)中，隨後添加TFA(2.03g，17.79mmol，1.37mL)且攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且將有機溶劑蒸發，以得到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -噻吩 并[3,2-c ]吡唑(0.8g，粗品)，其不經純化即用於下一步驟。 N- [2-Methyl-5-oxy-5-(1-tetrahydropyran-2-ylthieno[ 3,2-c ]pyrazol- 5 -yl)pentyl]carbamic acid Tributyl ester (1.5 g, 3.56 mmol) was dissolved in DCM (10 mL), then TFA (2.03 g, 17.79 mmol, 1.37 mL) was added and stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH, and the organic solvent was evaporated to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H- thieno [ 3,2-c ]pyrazole (0.8 g, crude) was used in the next step without purification.

1 H NMR(600MHz,CDCl3 )δ(ppm)1.02(d,3H),1.56(m,1H),1.76(m,1H),1.95(m,1H),2.56(m,1H),2.86(m,1H),3.26(m,1H),3.96(m,1H),4.36(m,1H),7.28(s,1H),7.76(s,1H)。 1 H NMR (600MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.56(m,1H), 1.76(m,1H), 1.95(m,1H), 2.56(m,1H), 2.86( m, 1H), 3.26 (m, 1H), 3.96 (m, 1H), 4.36 (m, 1H), 7.28 (s, 1H), 7.76 (s, 1H).

步驟5：外消旋-5-((2R,5S)-5-甲基哌啶-2-基)-1H-噻吩并[3,2-c]吡唑之合成Step 5: Synthesis of Racemic-5-((2R,5S)-5-methylpiperidin-2-yl)-1H-thieno[3,2-c]pyrazole

將5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -噻吩并[3,2-c ]吡唑(0.8g，3.65mmol)溶解於MeOH(5mL)中且冷卻至0℃。將硼氫化鈉(138.0lmg，3.65mmol，128.98μL)分批添加到所獲得之混合物中且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH=2，用MTBE洗滌(2*10mL)，用10% NaOH水溶液鹼化至pH=10且用DCM(10mL)萃取。將經合併之有機層經Na2 SO4 乾燥且蒸發，以得到5-[(2S,5R )-5-甲基-2-哌啶基]-1H -噻吩并[3,2-c ]吡唑(0.9g，粗品)，其不經純化即用於下一步驟。5-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-thieno[ 3,2 -c ]pyrazole (0.8 g, 3.65 mmol) was dissolved in MeOH ( 5 mL) and cooled to 0 °C. Sodium borohydride (138.01 mg, 3.65 mmol, 128.98 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl, washed with MTBE (2*10 mL), basified with 10% aqueous NaOH to pH=10 and extracted with DCM (10 mL). The combined organic layers were dried over Na 2 SO 4 and evaporated to give 5-[( 2S,5R )-5-methyl-2-piperidinyl]-1H-thieno[ 3,2 -c ]pyridine azole (0.9 g, crude), which was used in the next step without purification.

1 H NMR(600MHz,CDCl3 )δ(ppm)0.98(d,3H),1.65(m,4H),1.95(m,2H),2.38(m,1H),3.16(m,1H),3.82(m,1H),6.82(s,1H),7.71(s,1H)。 1 H NMR (600MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.65(m,4H), 1.95(m,2H), 2.38(m,1H), 3.16(m,1H), 3.82( m, 1H), 6.82 (s, 1H), 7.71 (s, 1H).

3RR.外消旋-5-((2R,5S )-5-甲基哌啶-2-基)-1H -噻吩并[2,3-c ]吡唑之合成 3RR. Synthesis of racemic-5-(( 2R,5S )-5-methylpiperidin-2-yl)-1H- thieno [ 2,3-c ]pyrazole

Figure 110128222-A0202-12-0656-741
Figure 110128222-A0202-12-0656-741

步驟1：1-(四氫-2H-哌喃-2-基)-1H-噻吩并[2,3-c]吡唑-5-甲酸之合成Step 1: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid

將1H -噻吩并[2,3-c]吡唑-5-甲酸(5g，29.73mmol)懸浮於3,4-二氫-2H -哌喃(25.01g，297.31mmol，27.01mL)中，隨後添加甲苯磺酸(255.99mg，1.49 mmol)。劇烈攪拌0.5h之後，溶解所有固體，將澄清溶液蒸發至乾且將粗殘餘物溶解於50%KOH水溶液中。將所獲得之乳狀懸浮液用DCM(30mL)洗滌五次且用MTBE(30mL)洗滌2次。將澄清淡黃色溶液用10% NaHSO4 水溶液酸化至pH=2且用DCM(30mL)萃取2次。蒸發經合併之有機溶劑，得到呈位置異構物之混合物形式之1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-甲酸(7.2g，28.54mmol，95.99%產率)。 1H -thieno[2,3-c]pyrazole-5-carboxylic acid (5 g, 29.73 mmol) was suspended in 3,4-dihydro- 2H -pyran (25.01 g, 297.31 mmol, 27.01 mL), followed by Toluenesulfonic acid (255.99 mg, 1.49 mmol) was added. After vigorous stirring for 0.5 h, all solids were dissolved, the clear solution was evaporated to dryness and the crude residue was dissolved in 50% aqueous KOH. The milky suspension obtained was washed five times with DCM (30 mL) and twice with MTBE (30 mL). The clear pale yellow solution was acidified to pH=2 with 10% aqueous NaHSO 4 and extracted twice with DCM (30 mL). The combined organic solvents were evaporated to give 1-tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazole-5-carboxylic acid (7.2 g, 28.54 mmol, 95.99 g) as a mixture of positional isomers %Yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.95(m,6H),3.86(m,2H),5.56(m,1H),7.68(s,1H),8.28(s,1H),13.25(bds,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.95(m, 6H), 3.86(m, 2H), 5.56(m, 1H), 7.68(s, 1H), 8.28(s, 1H), 13.25 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值252.2；實測值253.2；Rt=1.089min。LCMS (ESI): [M] + m/z: calculated 252.2; found 253.2; Rt=1.089 min.

步驟2：(1H-咪唑-1-基)(1-(四氫-2H-哌喃-2-基)-1H-噻吩并[2,3-c]吡唑-5-基)甲酮之合成Step 2: (1H-imidazol-1-yl)(1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[2,3-c]pyrazol-5-yl)methanone synthesis

將1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-甲酸(7.2g，28.54mmol)溶解於DCM(100mL)中，隨後一次性添加CDI(6.94g，42.81mmol)。反應完成之後(藉由氣態副產物之最終逸出且藉由H-NMR推測)，將混合物用DCM(100mL)稀釋且用0.1M HCl水溶液洗滌(三次)。在減壓下蒸發有機溶劑，得到咪唑-1-基-(1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-基)甲酮(5.8g，19.18mmol，67.22%產率)，其立即用於下一步驟。1-Tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazole-5-carboxylic acid (7.2 g, 28.54 mmol) was dissolved in DCM (100 mL) followed by CDI (6.94 g, 42.81 mmol). After the reaction was complete (by eventual evolution of gaseous by-products and presumed by H-NMR), the mixture was diluted with DCM (100 mL) and washed with 0.1 M aqueous HCl (three times). The organic solvent was evaporated under reduced pressure to give imidazol-1-yl-(1-tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazol-5-yl)methanone (5.8 g, 19.18 mmol) , 67.22% yield), which was used immediately in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.95(m,6H),3.82(m,1H),4.08(m,1H),5.62(m,1H),7.19(s,1H),7.69(s,1H),7.82(s,1H),8.12(s,1H),8.32(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.95(m, 6H), 3.82(m, 1H), 4.08(m, 1H), 5.62(m, 1H), 7.19(s, 1H), 7.69(s, 1H), 7.82(s, 1H), 8.12(s, 1H), 8.32(s, 1H).

步驟3：5-甲基-2-側氧基-3-(1-(四氫-2H-哌喃-2-基)-1H-噻吩并[2,3-c]吡唑-5-羰基)哌啶-1-甲酸第三丁酯之合成Step 3: 5-Methyl-2-oxo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[2,3-c]pyrazole-5-carbonyl ) Synthesis of tert-butyl piperidine-1-carboxylate

將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(4.50g，21.10mmol)溶解於THF(40mL)中且在Ar下冷卻至-78℃，隨後逐滴添加六甲基二矽氮烷鋰(1.03M，22.35mL)。再攪拌10min之後，添加咪唑-1-基-(1-四氫哌喃-2-基噻吩并[2,3-c ]吡 唑-5-基)甲酮(5.8g，19.18mmol)於THF(40mL)中之溶液且將反應混合物升溫至室溫。反應完成之後，將混合物倒入飽和NH4 Cl水溶液中且用EtOAc(100mL)萃取三次。蒸發有機溶劑且用CC(OK.Interchim；220g SiO2 ，石油醚/乙酸乙酯，其中乙酸乙酯為10~75%，流速=100mL/min，Rv=7.7 CV)純化，產生呈異構物之混合物形式之5-甲基-2-側氧基-3-(1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-羰基)哌啶-1-甲酸第三丁酯(4.5g，10.05mmol，52.42%產率)。將單獨級分合併且用於下一步驟。3-Butyl 5-methyl-2-oxypiperidine-1-carboxylate (4.50 g, 21.10 mmol) was dissolved in THF (40 mL) and cooled to -78 °C under Ar, followed by dropwise addition of six Lithium methyldisilazane (1.03M, 22.35 mL). After stirring for an additional 10 min, imidazol-1-yl-(1-tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazol-5-yl)methanone (5.8 g, 19.18 mmol) in THF was added (40 mL) and the reaction mixture was warmed to room temperature. After the reaction was complete, the mixture was poured into saturated aqueous NH4Cl and extracted three times with EtOAc (100 mL). The organic solvent was evaporated and purified with CC (OK. Interchim; 220 g SiO2 , petroleum ether/ethyl acetate with 10-75% ethyl acetate, flow rate = 100 mL/min, Rv = 7.7 CV) to give isomers 5-Methyl-2-oxo-3-(1-tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazole-5-carbonyl)piperidine-1-carboxylic acid as a mixture of Tertiary butyl ester (4.5 g, 10.05 mmol, 52.42% yield). The individual fractions were combined and used in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.08(d,3H),1.53(s,9H),1.62(m,4H),2.15(m,6H),3.23(m,1H),3.85(m,2H),4.39(m,1H),5.55(m,1H),7.86(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.08(d, 3H), 1.53(s, 9H), 1.62(m, 4H), 2.15(m, 6H), 3.23(m, 1H), 3.85( m, 2H), 4.39 (m, 1H), 5.55 (m, 1H), 7.86 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值347.2；實測值348.2；Rt=1.384min。LCMS (ESI): [M-Boc] + m/z: calculated 347.2; found 348.2; Rt=1.384 min.

步驟4：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-1H-噻吩并[2,3-c]吡唑之合成Step 4: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1H-thieno[2,3-c]pyrazole

將5-甲基-2-側氧基-3-(1-四氫哌喃-2-基噻吩并[2,3-c]吡唑-5-羰基)哌啶-1-甲酸第三丁酯(4.5g，10.05mmol)溶解於乙酸(50mL)中且加熱至回流。逐滴添加HCl(10M，10.05mL)(小心！觀察到劇烈泡沫形成！)。氣體逸出停止之後，將混合物蒸發至乾，溶解於H2 O(50mL)中且用10% K2 CO3 水溶液鹼化至pH=10；將所獲得之不透明溶液用DCM(150mL)萃取，將其經Na2 SO4 乾燥且在減壓下蒸發，以得到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -噻吩并[2,3-c ]吡唑(1.6g，7.30mmol，72.56%產率)。5-Methyl-2-oxo-3-(1-tetrahydropyran-2-ylthieno[2,3-c]pyrazole-5-carbonyl)piperidine-1-carboxylic acid tertiary butyl The ester (4.5 g, 10.05 mmol) was dissolved in acetic acid (50 mL) and heated to reflux. HCl (10 M, 10.05 mL) was added dropwise (be careful! Vigorous foam formation was observed!). After gas evolution ceased, the mixture was evaporated to dryness, dissolved in H2O (50 mL) and basified to pH= 10 with 10 % aqueous K2CO3; the resulting opaque solution was extracted with DCM (150 mL), It was dried over Na 2 SO 4 and evaporated under reduced pressure to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H- thieno [ 2,3 -c ]pyrazole (1.6 g, 7.30 mmol, 72.56% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.02(d,3H),1.86(m,1H),1.95(m,2H),2.48(m,1H),2.86(m,1H),3.26(m,1H),4.02(m,1H),7.42(m,1H),7.82(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.86(m,1H), 1.95(m,2H), 2.48(m,1H), 2.86(m,1H), 3.26( m, 1H), 4.02 (m, 1H), 7.42 (m, 1H), 7.82 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值219.2；實測值220.2；Rt=0.802min。LCMS (ESI): [M] + m/z: calculated 219.2; found 220.2; Rt=0.802 min.

步驟5：外消旋-5-((2R,5S)-5-甲基哌啶-2-基)-1H-噻吩并[2,3-c]吡唑之合成Step 5: Synthesis of Racemic-5-((2R,5S)-5-methylpiperidin-2-yl)-1H-thieno[2,3-c]pyrazole

將5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -噻吩并[2,3-c ]吡唑(1.6g，7.30mmol)溶解於MeOH(20mL)中且冷卻至0℃。將硼氫化鈉(552.00mg，14.59 mmol，515.89μL)分批添加到所獲得之混合物中且再攪拌隔夜。反應完成之後，將反應混合物用10%HCl水溶液酸化至pH=2，用MTBE洗滌(2*10mL)，用10%NaOH水溶液鹼化至pH=10且用DCM(50mL)萃取。蒸發溶劑，得到純的5-[(2S,5R )-5-甲基-2-哌啶基]-2H -噻吩并[2,3-c]吡唑(1.3g，5.87mmol，80.51%產率)。5-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H- thieno [ 2,3-c ]pyrazole (1.6 g, 7.30 mmol) was dissolved in MeOH ( 20 mL) and cooled to 0 °C. Sodium borohydride (552.00 mg, 14.59 mmol, 515.89 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl, washed with MTBE (2*10 mL), basified with 10% aqueous NaOH to pH=10 and extracted with DCM (50 mL). The solvent was evaporated to give pure 5-[( 2S,5R )-5-methyl-2-piperidinyl] -2H -thieno[2,3-c]pyrazole (1.3 g, 5.87 mmol, 80.51% yield Rate).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.98(d,3H),1.56(m,2H),1.68(m,2H),1.92(m,1H),2.02(m,1H),2.44(m,1H),3.20(m,1H),3.86(m,1H),6.83(s,1H),7.61(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.56(m,2H), 1.68(m,2H), 1.92(m,1H), 2.02(m,1H), 2.44( m, 1H), 3.20 (m, 1H), 3.86 (m, 1H), 6.83 (s, 1H), 7.61 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值221.2；實測值222.2；Rt=0.711min。LCMS (ESI): [M] + m/z: calculated 221.2; found 222.2; Rt=0.711 min.

3SS. 外消旋 -(2R,5S )-5-甲基-2-(1H -吡唑-3-基)哌啶之合成 3SS. Synthesis of racemic- ( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)piperidine

Figure 110128222-A0202-12-0659-742
Figure 110128222-A0202-12-0659-742

步驟1：外消旋-(2R,5S)-2-(甲氧基(甲基)胺甲醯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of racemic-(2R,5S)-2-(methoxy(methyl)aminocarboxy)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在25℃下，將CDI(14.08g，86.81mmol)一次性添加到(2R,5S)-1-第三丁氧基羰基-5-甲基哌啶-2-甲酸(17.6g，72.34mmol)於THF(200mL)中之經攪拌之溶液中。將所得混合物在45℃下攪拌，直到二氧化碳逸出完成，然後添加甲氧基(甲基)胺鹽酸鹽(14.11g，144.68mmol)及TEA(14.64g，144.68mmol，20.17mL)。將反應混合物在50℃下攪拌12h，然後冷卻且在真空中蒸發。將殘餘物用5%硫酸氫鈉水溶液(200ml)稀釋且用DCM(2*100ml)萃取。將經合併之有機萃取物用水(100ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈無色膠狀物之 (2R,5S )-2-[甲氧基(甲基)胺甲醯基]-5-甲基 哌啶-1-甲酸第三丁酯(18g，62.86mmol，86.89%產率)，其直接用於下一步驟中。CDI (14.08 g, 86.81 mmol) was added in one portion to (2R,5S)-1-tert-butoxycarbonyl-5-methylpiperidine-2-carboxylic acid (17.6 g, 72.34 mmol) at 25 °C In a stirred solution in THF (200 mL). The resulting mixture was stirred at 45°C until carbon dioxide evolution was complete, then methoxy(methyl)amine hydrochloride (14.11 g, 144.68 mmol) and TEA (14.64 g, 144.68 mmol, 20.17 mL) were added. The reaction mixture was stirred at 50 °C for 12 h, then cooled and evaporated in vacuo. The residue was diluted with 5% aqueous sodium bisulfate (200ml) and extracted with DCM (2*100ml). The combined organic extracts were washed with water (100 ml), dried over sodium sulfate and evaporated in vacuo to give ( 2R,5S )-2-[methoxy(methyl)amine carboxamide as a colorless gum yl]-5 - methylpiperidine-1-carboxylic acid tert-butyl ester (18 g, 62.86 mmol, 86.89% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.36(m,1H),1.49(s,9H),1.72(m,1H),1.80(m,1H),1.97(m,2H),3.17(s,3H),3.66(m,2H),3.73(s,3H),4.91(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d, 3H), 1.36(m, 1H), 1.49(s, 9H), 1.72(m, 1H), 1.80(m, 1H), 1.97( m, 2H), 3.17 (s, 3H), 3.66 (m, 2H), 3.73 (s, 3H), 4.91 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值186.2；實測值187.2；Rt=1.381min。LCMS (ESI): [M-Boc] + m/z: calculated 186.2; found 187.2; Rt=1.381 min.

步驟2：外消旋-(2R,5S)-5-甲基-2-丙炔醯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of racemic-(2R,5S)-5-methyl-2-propynylpiperidine-1-carboxylic acid tert-butyl ester

在-40℃下，將(2R,5S )-2-[甲氧基(甲基)胺甲醯基]-5-甲基哌啶-1-甲酸第三丁酯(18g，62.86mmol)於THF(200mL)中之溶液逐滴添加乙炔基溴化鎂(587.50g，314.85mmol，625mL，6.872%純度)(0.5M於THF溶液中)之經攪拌之溶液。使所得混合物升溫至25℃且在此溫度下攪拌12h，然後倒入於水(675mL)中之硫酸氫鈉(75.47g，628.57mmol)中。將所得混合物攪拌30min，然後轉移至分液漏斗中。分離上部有機層；另外用乙酸乙酯(2*300ml)萃取水層。將經合併之有機萃取物用鹽水(2*200ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈紅色油狀物之(2R,5S )-5-甲基-2-丙-2-炔醯基哌啶-1-甲酸第三丁酯(15g，59.68mmol，94.95%產率)，其直接用於下一步驟中。At -40°C, ( 2R,5S )-2-[methoxy(methyl)aminocarboxy]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (18 g, 62.86 mmol) was added to The solution in THF (200 mL) was added dropwise to a stirred solution of ethynylmagnesium bromide (587.50 g, 314.85 mmol, 625 mL, 6.872% pure) (0.5 M in THF). The resulting mixture was warmed to 25 °C and stirred at this temperature for 12 h, then poured into sodium bisulfate (75.47 g, 628.57 mmol) in water (675 mL). The resulting mixture was stirred for 30 min and then transferred to a separatory funnel. The upper organic layer was separated; the aqueous layer was additionally extracted with ethyl acetate (2*300ml). The combined organic extracts were washed with brine (2*200ml), dried over sodium sulfate and evaporated in vacuo to give ( 2R,5S )-5-methyl-2-propan-2 as a red oil -Alkynylpiperidine-1-carboxylic acid tert-butyl ester (15 g, 59.68 mmol, 94.95% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(m,1H),0.96(d,3H),1.36(m,1H),1.49(s,9H),1.57(m,1H),1.95(m,2H),2.08(m,1H),3.24(m,1H),3.52(m,1H),4.58(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(m, 1H), 0.96(d, 3H), 1.36(m, 1H), 1.49(s, 9H), 1.57(m, 1H), 1.95( m, 2H), 2.08 (m, 1H), 3.24 (m, 1H), 3.52 (m, 1H), 4.58 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值151.2；實測值152.2；Rt=1.467min。LCMS (ESI): [M-Boc] + m/z: calculated 151.2; found 152.2; Rt=1.467 min.

步驟3：外消旋-(2R,5S)-2-((E)-3-(二乙胺基)丙烯醯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of racemic-(2R,5S)-2-((E)-3-(diethylamino)acryloyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5S )-5-甲基-2-丙-2-炔醯基哌啶-1-甲酸第三丁酯(15.00g，59.68mmol)用二乙胺(6.98g，95.50mmol，9.89mL)於乙醇(200mL)中之溶液稀釋。將所得溶液在25℃下攪拌1h，然後在真空中蒸發，以得到呈紅色膠狀物之 (2R,5S )-2-[(E )-3-(二乙胺基)丙-2-烯醯基]-5-甲基哌啶-1-甲酸第三丁酯(19.8g，粗品)，其直接用於下一步驟中。( 2R,5S )-5-methyl-2-prop-2-ynylpiperidine-1-carboxylic acid tert-butyl ester (15.00 g, 59.68 mmol) was treated with diethylamine (6.98 g, 95.50 mmol, 9.89 mL) in ethanol (200 mL). The resulting solution was stirred at 25 °C for 1 h, then evaporated in vacuo to give ( 2R,5S )-2-[( E )-3-(diethylamino)prop-2-ene as a red gum Acyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (19.8 g, crude), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.98(d,3H),1.15(m,6H),1.36(m,1H),1.45(s,9H),1.56(m,1H),1.80(m,2H),2.10(m,1H),3.09(m,1H),3.25(m,4H),3.69(m,1H),4.57(m,1H),5.20(d,1H),7.65(d,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.98(d, 3H), 1.15(m, 6H), 1.36(m, 1H), 1.45(s, 9H), 1.56(m, 1H), 1.80( m, 2H), 2.10(m, 1H), 3.09(m, 1H), 3.25(m, 4H), 3.69(m, 1H), 4.57(m, 1H), 5.20(d, 1H), 7.65(d , 1H).

LCMS(ESI)：[M]+ m/z：計算值324.2；實測值325.2；Rt=1.372min。LCMS (ESI): [M] + m/z: calculated 324.2; found 325.2; Rt=1.372 min.

步驟4：外消旋-(2R,5S)-5-甲基-2-(1H-吡唑-3-基)哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of racemic-(2R,5S)-5-methyl-2-(1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

將單水合肼(6.89g，88.15mmol，6.69mL)添加到(2R,5S )-2-[(E )-3-(二乙胺基)丙-2-烯醯基]-5-甲基哌啶-1-甲酸第三丁酯(14.3g，44.07mmol)及乙酸(5.29g，88.15mmol，5.04mL)於乙醇(300mL)中之經攪拌之溶液中。將反應混合物在80℃下用回流冷凝器攪拌36h，然後冷卻且在真空中蒸發。將殘餘物用水(100ml)稀釋且用MTBE(2*100ml)萃取。將經合併之有機萃取物用水(50ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈紅色膠狀物之粗品(2R,5S )-5-甲基-2-(1H -吡唑-3-基)哌啶-1-甲酸第三丁酯(10g，37.69mmol，85.51%產率)，其直接用於下一步驟中。Hydrazine monohydrate (6.89 g, 88.15 mmol, 6.69 mL) was added to ( 2R,5S )-2-[( E )-3-(diethylamino)prop-2-enyl]-5-methyl In a stirred solution of tert-butyl piperidine-1-carboxylate (14.3 g, 44.07 mmol) and acetic acid (5.29 g, 88.15 mmol, 5.04 mL) in ethanol (300 mL). The reaction mixture was stirred at 80 °C with a reflux condenser for 36 h, then cooled and evaporated in vacuo. The residue was diluted with water (100ml) and extracted with MTBE (2*100ml). The combined organic extracts were washed with water (50 ml), dried over sodium sulfate and evaporated in vacuo to give crude ( 2R,5S )-5-methyl-2-( 1H -pyrazole as a red gum -3-yl)piperidine-1-carboxylic acid tert-butyl ester (10 g, 37.69 mmol, 85.51% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.03(d,3H),1.47(s,9H),1.83(m,2H),2.00(m,1H),2.12(m,2H),2.91(m,1H),3.71(m,1H),5.42(m,1H),6.18(d,1H),7.51(d,1H),8.89(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.03(d, 3H), 1.47(s, 9H), 1.83(m, 2H), 2.00(m, 1H), 2.12(m, 2H), 2.91( m, 1H), 3.71 (m, 1H), 5.42 (m, 1H), 6.18 (d, 1H), 7.51 (d, 1H), 8.89 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值165.2；實測值166.2；Rt=1.293min。LCMS (ESI): [M-Boc] + m/z: calculated 165.2; found 166.2; Rt=1.293 min.

步驟5：外消旋-(2R,5S)-5-甲基-2-(1H-吡唑-3-基)哌啶之合成Step 5: Synthesis of Racemic-(2R,5S)-5-methyl-2-(1H-pyrazol-3-yl)piperidine

在25℃下，將於二噁烷中之4.0M氯化氫溶液(7.35g，28.02mmol，7.00mL，13.9%純度)添加到(2R,5S )-5-甲基-2-(1H -吡唑-3-基)哌啶-1-甲酸第三丁酯(700mg，2.64mmol)於MeOH(30mL)中之經攪拌之溶液中。將反應混合物在25℃下攪拌3h，然後在真空中濃縮，以得到呈米色固體之(2R,5S )-5-甲基-2-(1H - 吡唑-3-基)哌啶(530mg，2.63mmol，99.61%產率，HCl)，其不經進一步純化即用於下一步驟。A 4.0 M solution of hydrogen chloride in dioxane (7.35 g, 28.02 mmol, 7.00 mL, 13.9% purity) was added to ( 2R,5S )-5-methyl-2-( 1H -pyrazole at 25 °C -3-yl)piperidine-1-carboxylic acid tert-butyl ester (700 mg, 2.64 mmol) in a stirred solution of MeOH (30 mL). The reaction mixture was stirred at 25 °C for 3 h, then concentrated in vacuo to give ( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)piperidine as a beige solid (530 mg, 2.63 mmol, 99.61% yield, HCl), which was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.36(m,1H),1.95(m,4H),2.67(m,1H),3.13(m,1H),4.19(m,1H),6.49(d,1H),7.74(d,1H),9.43(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.36(m,1H), 1.95(m,4H), 2.67(m,1H), 3.13(m,1H), 4.19 (m, 1H), 6.49 (d, 1H), 7.74 (d, 1H), 9.43 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值165.2；實測值166.2；Rt=0.653min。LCMS (ESI): [M] + m/z: calculated 165.2; found 166.2; Rt=0.653 min.

3TT. 外消旋 -3-((2R,5S )-5-甲基哌啶-2-基)-1'H -1,3'-聯吡唑之合成 3TT. Synthesis of racemic -3-(( 2R,5S )-5-methylpiperidin-2-yl)-1'H- 1,3' -bipyrazole

Figure 110128222-A0202-12-0662-743
Figure 110128222-A0202-12-0662-743

步驟1：外消旋-(2R,5S)-5-甲基-2-(1'-(四氫-2H-哌喃-2-基)-1'H-[1,3'-聯吡唑]-3-基)哌啶-1-甲酸第三丁酯之合成Step 1: Racemic-(2R,5S)-5-methyl-2-(1'-(tetrahydro-2H-pyran-2-yl)-1'H-[1,3'-bipyridine Synthesis of 3-butyl oxazol]-3-yl)piperidine-1-carboxylate

將(2R,5S )-5-甲基-2-(1H -吡唑-3-基)哌啶-1-甲酸第三丁酯(3.7g，13.94mmol)、3-碘-1-四氫哌喃-2-基吡唑(4.74g，17.03mmol)、碘化銅(I)(1.85g，9.71mmol，329.18μL)、99%無水碳酸鉀(4.44g，32.13mmol，1.94mL)、N 1 ,N 2 -二甲基環己-1,2-二胺(1.18g，8.32mmol)、銅(444.00mg，6.99mmol)及甲苯(100mL)於100ml裝備有回流冷凝器及玻璃塞之單頸圓底燒瓶中之混合物抽真空，然後用氬氣回填。然後將反應混合物在氬氣、110℃下攪拌72h。等分試樣之LCMS顯示25.67%目標化合物。將反應混合物冷卻，且添加50ml 25%氨水。將所得混合物攪拌0.5h，然後透過短矽酸鎂墊過濾。將濾餅另外用乙酸乙酯(2*25ml)洗滌且丟棄。將濾液轉移至分液漏斗，將有機層分離，經硫酸鈉乾燥且在真空中蒸發。藉由矽膠管柱層析，使用己烷/乙酸乙酯梯度(0-100%乙酸乙酯)純化殘餘物，以得到呈淡黃色油狀物之粗品(2R,5S )-5-甲基-2-[1-(1-四氫哌喃-2-基吡唑-3-基)吡唑-3-基]哌啶-1-甲酸第三丁酯(3.5g，8.42mmol，60.41%產率)，其直接用於下一步驟中。( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (3.7 g, 13.94 mmol), 3-iodo-1-tetrahydro Piran-2-ylpyrazole (4.74 g, 17.03 mmol), copper(I) iodide (1.85 g, 9.71 mmol, 329.18 μL), 99% anhydrous potassium carbonate (4.44 g, 32.13 mmol, 1.94 mL), N 1 ,N 2 -Dimethylcyclohexyl-1,2-diamine (1.18 g, 8.32 mmol), copper (444.00 mg, 6.99 mmol) and toluene (100 mL) in a 100 mL aliquot equipped with a reflux condenser and glass stopper The mixture in the necked round bottom flask was evacuated and then backfilled with argon. The reaction mixture was then stirred under argon at 110 °C for 72 h. LCMS of an aliquot showed 25.67% of the title compound. The reaction mixture was cooled and 50 ml of 25% aqueous ammonia was added. The resulting mixture was stirred for 0.5 h, then filtered through a pad of magnesium short silicate. The filter cake was additionally washed with ethyl acetate (2*25ml) and discarded. The filtrate was transferred to a separatory funnel, the organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a hexane/ethyl acetate gradient (0-100% ethyl acetate) to give crude ( 2R,5S )-5-methyl- 2-[1-(1-Tetrahydropyran-2-ylpyrazol-3-yl)pyrazol-3-yl]piperidine-1-carboxylic acid tert-butyl ester (3.5 g, 8.42 mmol, 60.41% yield rate), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.02(d,3H),1.36(m,1H),1.49(s,9H),1.96(m,5H),2.22(m,6H),3.72(m,2H),4.09(m,2H),5.42(m,1H),6.18(d,1H),6.32(d,1H),6.55(d,1H),8.04(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.36(m,1H), 1.49(s,9H), 1.96(m,5H), 2.22(m,6H), 3.72( m, 2H), 4.09 (m, 2H), 5.42 (m, 1H), 6.18 (d, 1H), 6.32 (d, 1H), 6.55 (d, 1H), 8.04 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.696min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.696 min.

步驟2：外消旋-3-((2R,5S)-5-甲基哌啶-2-基)-1'H-1,3'-聯吡唑之合成Step 2: Synthesis of racemic-3-((2R,5S)-5-methylpiperidin-2-yl)-1'H-1,3'-bipyrazole

在25℃下，將於二噁烷中之4.0M氯化氫溶液(52.50g，200.15mmol，50mL，13.9%純度)添加到(2R,5S )-5-甲基-2-[1-(1-四氫哌喃-2-基吡唑-3-基)吡唑-3-基]哌啶-1-甲酸第三丁酯(2.5g，6.02mmol)於MeOH(50mL)中之經攪拌之溶液中。將反應混合物在25℃下攪拌48h，然後在真空中濃縮。將殘餘物與DCM(50ml)一起蒸發，以得到呈淡黃色膠狀物之粗品(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]哌啶(2g，5.87mmol，97.58%產率，3HCl)，其直接用於下一步驟中。A 4.0 M solution of hydrogen chloride in dioxane (52.50 g, 200.15 mmol, 50 mL, 13.9% purity) was added to ( 2R,5S )-5-methyl-2-[1-(1-) at 25°C A stirred solution of tetrahydropyran-2-ylpyrazol-3-yl)pyrazol-3-yl]piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 6.02 mmol) in MeOH (50 mL) middle. The reaction mixture was stirred at 25 °C for 48 h, then concentrated in vacuo. The residue was evaporated with DCM (50ml) to give crude ( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl)pyrazole- as a pale yellow gum 3-yl]piperidine (2 g, 5.87 mmol, 97.58% yield, 3HCl), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.36(m,1H),2.07(m,4H),2.36(m,1H),2.59(m,1H),4.16(m,1H),6.44(d,1H),6.79(d,1H),7.82(d,1H),8.26(d,1H),9.58(m,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.36(m,1H), 2.07(m,4H), 2.36(m,1H), 2.59(m,1H), 4.16(m,1H), 6.44(d,1H), 6.79(d,1H), 7.82(d,1H), 8.26(d,1H), 9.58(m,2H).

LCMS(ESI)：[M]+ m/z：計算值231.2；實測值232.2；Rt=0.629min。LCMS (ESI): [M] + m/z: calculated 231.2; found 232.2; Rt=0.629 min.

3UU.外消旋-5-[(2S,5S)-4,4-二氟-5-甲基-2-哌啶基]-2-甲基吡啶之合成 3UU. Synthesis of racemic-5-[(2S,5S)-4,4-difluoro-5-methyl-2-piperidinyl]-2-methylpyridine

Figure 110128222-A0202-12-0663-744
Figure 110128222-A0202-12-0663-744

步驟1：(E)-1-(6-甲基吡啶-3-基)戊-1-烯-3-酮之合成Step 1: Synthesis of (E)-1-(6-methylpyridin-3-yl)pent-1-en-3-one

在氬氣氣氛下，向5-碘-2-甲基吡啶(15g，68.49mmol)及三乙胺(10.05 g，99.30mmol，13.84mL)之混合物中添加戊-1-烯-3-酮(11.52g，136.97mmol，13.54mL)，隨後添加乙酸鈀(II)(768.79mg，3.42mmol)及MeCN(300mL)。將混合物回流12h。移除溶劑且將殘餘物溶解於水(150mL)中且用MTBE(3*100mL)萃取。將有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮，以得到(E)-1-(6-甲基-3-吡啶基)戊-1-烯-3-酮(12g，68.48mmol，100.00%產率)，其不經進一步純化即用於下一步驟。To 5-iodo-2-methylpyridine (15 g, 68.49 mmol) and triethylamine (10.05 mmol) under argon atmosphere g, 99.30 mmol, 13.84 mL) was added pent-1-en-3-one (11.52 g, 136.97 mmol, 13.54 mL) followed by palladium(II) acetate (768.79 mg, 3.42 mmol) and MeCN (300 mL) ). The mixture was refluxed for 12 h. The solvent was removed and the residue was dissolved in water (150 mL) and extracted with MTBE (3*100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (E)-1-(6-methyl-3-pyridyl)pent-1-en-3-one (12 g) , 68.48 mmol, 100.00% yield), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ 1.14(t,3H),2.47(s,3H),2.66(q,2H),6.71(m,1H),7.16(m,1H),7.47(m,1H),7.72(m,1H),8.80(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.14 (t, 3H), 2.47 (s, 3H), 2.66 (q, 2H), 6.71 (m, 1H), 7.16 (m, 1H), 7.47 (m, 1H) ), 7.72(m, 1H), 8.80(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值175.2；實測值176.2；Rt=0.721min。LCMS (ESI): [M+H] + m/z: calculated 175.2; found 176.2; Rt=0.721 min.

步驟2：(E)-5-(二甲胺基)-4-甲基-1-(6-甲基-3-吡啶基)戊-1-烯-3-酮之合成Step 2: Synthesis of (E)-5-(dimethylamino)-4-methyl-1-(6-methyl-3-pyridyl)pent-1-en-3-one

將(E)-1-(6-甲基-3-吡啶基)戊-1-烯-3-酮(12g，68.48mmol)、98% 1,3,5-三噁烷(4.11g，136.97mmol，3.51mL，300%純度)、二甲胺鹽酸鹽(5.58g，68.48mmol)及36% w/w鹽酸水溶液(6.94g，68.48mmol，5.78mL，36%純度)於乙醇(120mL)中之溶液在80℃下攪拌12h。在真空中移除溶劑，以得到(E)-5-(二甲胺基)-4-甲基-1-(6-甲基-3-吡啶基)戊-1-烯-3-酮(22g，粗品，2HCl)，其不經進一步純化即用於下一步驟。(E)-1-(6-methyl-3-pyridinyl)pent-1-en-3-one (12 g, 68.48 mmol), 98% 1,3,5-trioxane (4.11 g, 136.97 mmol, 3.51 mL, 300% pure), dimethylamine hydrochloride (5.58 g, 68.48 mmol) and 36% w/w aqueous hydrochloric acid (6.94 g, 68.48 mmol, 5.78 mL, 36% pure) in ethanol (120 mL) The solution was stirred at 80 °C for 12 h. The solvent was removed in vacuo to give (E)-5-(dimethylamino)-4-methyl-1-(6-methyl-3-pyridyl)pent-1-en-3-one ( 22 g, crude, 2HCl), which was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值232.2；實測值233.2；Rt=0.164min。LCMS (ESI): [M+H] + m/z: calculated 232.2; found 233.2; Rt=0.164 min.

步驟3：外消旋-(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)哌啶-4-酮之合成Step 3: Synthesis of Racemic-(2S,5S)-5-methyl-2-(6-methyl-3-pyridyl)piperidin-4-one

將(E)-5-(二甲胺基)-4-甲基-1-(6-甲基-3-吡啶基)戊-1-烯-3-酮(22g，94.70mmol)溶解於水(120mL)及NH3 (水溶液)(120mL)中，然後將反應混合物在80℃下攪拌12h。將反應混合物用1N HCl酸化，用MTBE(3*150mL)萃取，然後將水層用1N NaOH鹼化且用DCM(3*100ml)萃取。將DCM層經Na2 SO4 乾燥，過濾且在真空下蒸發，以得到(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)哌啶-4-酮(14g，粗品)，其不經進一步純化即用於下一步驟。(E)-5-(dimethylamino)-4-methyl-1-(6-methyl-3-pyridyl)pent-1-en-3-one (22 g, 94.70 mmol) was dissolved in water (120 mL) and NH3 (aq) (120 mL), then the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was acidified with 1N HCl, extracted with MTBE (3*150 mL), then the aqueous layer was basified with 1N NaOH and extracted with DCM (3*100 ml). The DCM layer was dried over Na 2 SO 4 , filtered and evaporated in vacuo to give (2S,5S)-5-methyl-2-(6-methyl-3-pyridyl)piperidin-4-one ( 14 g, crude), which was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值204.2；實測值205.2；Rt=0.196min。LCMS (ESI): [M+H] + m/z: calculated 204.2; found 205.2; Rt=0.196 min.

步驟4：外消旋-(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)-4-側氧基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of racemic-(2S,5S)-5-methyl-2-(6-methyl-3-pyridyl)-4-oxypiperidine-1-carboxylic acid tert-butyl ester

將(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)哌啶-4-酮(14g，68.54mmol)及二碳酸二-第三丁酯(14.96g，68.54mmol，15.73mL)於DCM(150mL)中之溶液在25℃下攪拌12h。在真空中移除溶劑且藉由梯度層析(DCM-MeCN)純化殘餘物(20g)且再純化(MTBE-MeCN)，以獲得(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)-4-側氧基哌啶-1-甲酸第三丁酯(1.9g，6.24mmol，9.11%產率)及級分0.5g70%純度。(2S,5S)-5-methyl-2-(6-methyl-3-pyridyl)piperidin-4-one (14 g, 68.54 mmol) and di-tert-butyl dicarbonate (14.96 g, A solution of 68.54 mmol, 15.73 mL) in DCM (150 mL) was stirred at 25 °C for 12 h. The solvent was removed in vacuo and the residue (20 g) was purified by gradient chromatography (DCM-MeCN) and repurified (MTBE-MeCN) to obtain (2S,5S)-5-methyl-2-(6- Methyl-3-pyridyl)-4-oxypiperidine-1-carboxylic acid tert-butyl ester (1.9 g, 6.24 mmol, 9.11% yield) and fractions 0.5 g 70% pure.

1 H NMR(400MHz,CDCl3 )δ 1.16(m,3H),1.42(s,9H),2.52(m,1H),2.55(s,3H),2.80(m,1H),2.99(m,1H),3.56(m,1H),3.77(m,1H),5.57(m,1H),7.10(d,1H),7.42(d,1H),8.39(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.16(m, 3H), 1.42(s, 9H), 2.52(m, 1H), 2.55(s, 3H), 2.80(m, 1H), 2.99(m, 1H) ), 3.56(m, 1H), 3.77(m, 1H), 5.57(m, 1H), 7.10(d, 1H), 7.42(d, 1H), 8.39(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值304.2；實測值305.2；Rt=0.935min。LCMS (ESI): [M+H] + m/z: calculated 304.2; found 305.2; Rt=0.935 min.

步驟5：外消旋-(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)哌啶-4-酮之合成Step 5: Synthesis of Racemic-(2S,5S)-5-methyl-2-(6-methyl-3-pyridyl)piperidin-4-one

將(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)-4-側氧基哌啶-1-甲酸第三丁酯(1.9g，6.24mmol)及三氟乙酸(15g，131.55mmol，10.14mL)於DCM(10mL)中之溶液在25℃下攪拌3h，以得到(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)哌啶-4-酮(3g，粗品，2TFA)。(2S,5S)-5-methyl-2-(6-methyl-3-pyridyl)-4-oxypiperidine-1-carboxylic acid tert-butyl ester (1.9 g, 6.24 mmol) and tris A solution of fluoroacetic acid (15 g, 131.55 mmol, 10.14 mL) in DCM (10 mL) was stirred at 25 °C for 3 h to give (2S,5S)-5-methyl-2-(6-methyl-3-pyridine) yl)piperidin-4-one (3 g, crude, 2TFA).

1 H NMR(500MHz,DMSO-d6 )δ 1.01(d,3H),2.63(s,3H),2.92(m,1H),3.19(m,2H),3.71(m,1H),4.92(m,1H),7.73(d,1H),8.24(d,1H),8.74(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.01(d,3H), 2.63(s,3H), 2.92(m,1H), 3.19(m,2H), 3.71(m,1H), 4.92(m , 1H), 7.73(d, 1H), 8.24(d, 1H), 8.74(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值204.2；實測值205.2；Rt=0.311min。LCMS (ESI): [M+H] + m/z: calculated 204.2; found 205.2; Rt=0.311 min.

步驟6：外消旋-5-[(2S,5S)-4,4-二氟-5-甲基-2-哌啶基]-2-甲基吡啶之合成Step 6: Synthesis of Racemic-5-[(2S,5S)-4,4-difluoro-5-methyl-2-piperidinyl]-2-methylpyridine

將外消旋-(2S,5S)-5-甲基-2-(6-甲基-3-吡啶基)哌啶-4-酮(3g，6.97mmol，2TFA)、HF(1.39g，69.72mmol)及四氟化硫(1.51g，13.94mmol)在不鏽鋼高壓釜中在70℃下加熱12h。反應完成之後，排出氣體產物，將反應混合物倒 入冰上且用10% K2 CO3 水溶液中和。將產物用MTBE(3×100mL)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥，且在減壓下濃縮，以得到5-[(2S,5S)-4,4-二氟-5-甲基-2-哌啶基]-2-甲基吡啶(1.5g，6.63mmol，95.09%產率)，其不經進一步純化即用於下一步驟。藉由2D NMR確認結構。Mix rac-(2S,5S)-5-methyl-2-(6-methyl-3-pyridinyl)piperidin-4-one (3 g, 6.97 mmol, 2TFA), HF (1.39 g, 69.72 g) mmol) and sulfur tetrafluoride (1.51 g, 13.94 mmol) were heated in a stainless steel autoclave at 70 °C for 12 h. After the reaction was complete, the gaseous product was vented, the reaction mixture was poured onto ice and neutralized with 10 % aqueous K2CO3. The product was extracted with MTBE (3 x 100 mL). The combined organic extracts were washed with brine, dried over Na2SO4 , and concentrated under reduced pressure to give 5-[(2S,5S)-4,4-difluoro-5-methyl-2- Piperidinyl]-2-methylpyridine (1.5 g, 6.63 mmol, 95.09% yield), which was used in the next step without further purification. The structure was confirmed by 2D NMR.

1 H NMR(400MHz,CDCl3 )δ 1.02(d,3H),1.79(m,1H),1.88(m,2H),2.52(s,3H),2.67(t,1H),3.07(m,1H),3.86(m,1H),7.11(d,1H),7.58(d,1H),8.45(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.02(d,3H), 1.79(m,1H), 1.88(m,2H), 2.52(s,3H), 2.67(t,1H), 3.07(m,1H) ), 3.86(m, 1H), 7.11(d, 1H), 7.58(d, 1H), 8.45(s, 1H).

LCMS(ES1)：[M+H]+ m/z：計算值226.2；實測值227.0；Rt=0.540min。LCMS (ES1): [M+H] + m/z: calculated 226.2; found 227.0; Rt=0.540 min.

3VV.6-(4-氟苯基)-5-氮雜螺[2.5]辛烷之合成 3VV. Synthesis of 6-(4-fluorophenyl)-5-azaspiro[2.5]octane

Figure 110128222-A0202-12-0666-745
Figure 110128222-A0202-12-0666-745

步驟1：(1-(((第三丁基二甲基矽基)氧基)甲基)環丙基)甲醇之合成Step 1: Synthesis of (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol

在0℃下，將第三丁基 二甲基矽基氯(15.50g，102.81mmol)添加到化合物1(10.00g，97.92mmol)及咪唑(10.00g，146.90mmol)於CH2 Cl2 (816mL)中之經攪拌之溶液中。在室溫下攪拌混合物(16小時)。藉由添加飽和NaHCO3 水溶液(250mL)來淬滅反應混合物。使用EtOAc(3x)萃取混合物，將其經MgSO4 乾燥，過濾，然後濃縮。藉由矽膠管柱層析(EtOAc/己烷，1：5)純化殘餘物，以得到呈無色油狀物之化合物3 (11.00g，52%)。At 0°C, tert-butyldimethylsilyl chloride (15.50 g, 102.81 mmol) was added to compound 1 (10.00 g, 97.92 mmol) and imidazole (10.00 g, 146.90 mmol) in CH 2 Cl 2 (816 mL) ) in a stirred solution. The mixture was stirred at room temperature (16 hours). The reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (250 mL). The mixture was extracted with EtOAc (3x), dried over MgSO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane, 1:5) to give compound 3 (11.00 g, 52%) as a colorless oil.

1 H NMR(CDCl3 ,400MHz)δ 3.61(s,2H),3.56(d,J =5.3Hz,2H),2.75(t,J =5.3Hz,1H),0.90(s,9H),0.51-044(m,4H),0.05(s,6H)。 1 H NMR(CDCl 3 , 400MHz)δ 3.61(s, 2H), 3.56(d, J =5.3Hz, 2H), 2.75(t, J =5.3Hz, 1H), 0.90(s, 9H), 0.51- 044(m, 4H), 0.05(s, 6H).

步驟2：1-(((第三丁基三甲基矽基)氧基)甲基)環丙烷-1-甲醛之合成Step 2: Synthesis of 1-(((tert-butyltrimethylsilyl)oxy)methyl)cyclopropane-1-carbaldehyde

將戴斯-馬丁高碘烷(13.80g，32.5mmol)添加到(1-(((第三丁基二甲基矽基)氧基)甲基)環丙基)甲醇(2 )(6.40g，29.60mmol)於CH2 Cl2 (296mL)中之冰冷溶液中。將反應混合物在室溫下攪拌1h，用混合飽和Na2S2O3水溶液(200mL)及飽和NaHCO3 水溶液(200mL)稀釋，然後用乙醚(3 x 200mL)萃取。將經合併之有機相用鹽水洗滌，乾燥(Na2 SO4 )，過濾且在減壓下濃縮。殘餘物不經進一步純化即使用。Dess-Martin periodinane (13.80 g, 32.5 mmol) was added to (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol ( 2 ) (6.40 g , 29.60 mmol) in an ice-cold solution of CH2Cl2 ( 296 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with a mixture of saturated aqueous Na2S2O3 (200 mL) and saturated aqueous NaHCO3 (200 mL), then extracted with ether (3 x 200 mL). The combined organic phases were washed with brine, dried ( Na2SO4 ) , filtered and concentrated under reduced pressure. The residue was used without further purification.

步驟3：(E)-3-(1-(((第三丁基二甲基矽基)氧基)甲基)環丙基)丙烯酸乙酯之合成Step 3: Synthesis of (E)-ethyl 3-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)acrylate

向氫化鈉(1.54mg，38.50mmol，60%於油中)於四氫呋喃(75mL)中之溶液中逐滴添加三乙基磷酸乙酯(7.96g，35.50mmol)，且將混合物升溫至室溫達20min。將1-(((第三丁基二甲基矽基)氧基)甲基)環丙烷-1-甲醛(3 )(6.35g，29.60mmol)於四氫呋喃(39mL)中之溶液逐滴添加先前溶液中。添加完成之後，在室溫下進行反應達2小時。將水(150mL)添加到反應混合物中，且蒸發揮發物。使用CH2 Cl2 (3x)萃取混合物，將其經MgSO4 乾燥，過濾，然後濃縮。藉由矽膠管柱層析(EtOAc/己烷，0/1至1：3)純化殘餘物，以得到呈無色油狀物之(E)-3-(1-(((第三丁基二甲基矽基)氧基)甲基)環丙基)丙烯酸乙酯(4 )(6.700g，80%)。To a solution of sodium hydride (1.54 mg, 38.50 mmol, 60% in oil) in tetrahydrofuran (75 mL) was added ethyl triethyl phosphate (7.96 g, 35.50 mmol) dropwise and the mixture was warmed to room temperature 20min. A solution of 1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropane-1-carbaldehyde ( 3 ) (6.35 g, 29.60 mmol) in tetrahydrofuran (39 mL) was added dropwise as previously in solution. After the addition was complete, the reaction was carried out at room temperature for 2 hours. Water (150 mL) was added to the reaction mixture and the volatiles were evaporated. The mixture was extracted with CH2Cl2 ( 3x), dried over MgSO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/Hexane, 0/1 to 1:3) to give (E)-3-(1-(((tert-butylbismuth as a colorless oil) Methylsilyl)oxy)methyl)cyclopropyl)ethyl acrylate ( 4 ) (6.700 g, 80%).

1 H NMR(CDCl3 ,400MHz)δ 6.66(d,J =15.9Hz,1H),5.82(d,J =15.9Hz,1H),4.17(q,J =7.2Hz,CH3 CH2 O),3.66(s,2H),1.28(t,J =7.2Hz,CH 3 CH2 O),0.97-0.93(m,2H),0.88(s,9H),0.80-0.76(m,2H),0.05(s,3H)。 1 H NMR (CDCl 3 , 400MHz) δ 6.66(d, J =15.9Hz, 1H), 5.82(d, J =15.9Hz, 1H), 4.17(q, J =7.2Hz, CH 3 CH 2 O), 3.66(s, 2H), 1.28(t, J =7.2Hz, CH 3 CH 2 O), 0.97-0.93(m, 2H), 0.88(s, 9H), 0.80-0.76(m, 2H), 0.05 (s, 3H).

步驟4：(E)-3-(1-(羥甲基)環丙基)丙烯酸乙酯之合成Step 4: Synthesis of (E)-ethyl 3-(1-(hydroxymethyl)cyclopropyl)acrylate

將1M HCl水溶液(1.18mL，1.18mmol)添加到(E)-3-(1-(((第三丁基二甲基矽基)氧基)甲基)環丙基)丙烯酸乙酯(4 )(6.70g，23.55mmol)之乙醇(62mL， 1M)溶液中。將溶液在室溫下攪拌(4h)。蒸發揮發物且藉由矽膠管柱層析(EtOAc/己烷，0/1至5/5)純化殘餘物，以得到呈無色油狀物之(E)-3-(1-(羥甲基)環丙基)丙烯酸乙酯(5 )(6.700g，80%)。Aqueous 1M HCl (1.18 mL, 1.18 mmol) was added to (E)-ethyl 3-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)acrylate ( 4 ) (6.70 g, 23.55 mmol) in ethanol (62 mL, 1 M). The solution was stirred at room temperature (4h). The volatiles were evaporated and the residue was purified by silica gel column chromatography (EtOAc/hexane, 0/1 to 5/5) to give (E)-3-(1-(hydroxymethyl) as a colorless oil ) cyclopropyl) ethyl acrylate ( 5 ) (6.700 g, 80%).

1 H NMR(CDCl3 ,400MHz)δ 6.62(d,J =15.9Hz,1H),5.96(d,J =15.9Hz,1H),4.17(q,J =7.1Hz,CH3 CH2 O),3.66(s,2H),1.28(t,J =7.1Hz,CH 3 CH2 O),0.97-0.92(m,2H),0.91-0.87(m,2H)。 1 H NMR (CDCl 3 , 400MHz) δ 6.62(d, J =15.9Hz, 1H), 5.96(d, J =15.9Hz, 1H), 4.17(q, J =7.1Hz, CH 3 CH 2 O), 3.66 (s, 2H), 1.28 (t, J = 7.1 Hz, CH3CH2O ), 0.97-0.92 (m, 2H), 0.91-0.87 (m, 2H).

步驟5：(E)-3-(1-(((甲基磺醯基)氧基)甲基)環丙基)丙烯酸乙酯之合成Step 5: Synthesis of (E)-ethyl 3-(1-(((methylsulfonyl)oxy)methyl)cyclopropyl)acrylate

在0℃下，將甲磺醯氯(1.81mL，23.30mmol)逐滴添加到DMAP(237mg，1.94mmol)、三乙胺(7.57mL，54.30mmol)及(E)-3-(1-(羥甲基)環丙基)丙烯酸乙酯(5 )(3.30g，19.40mmol)之CH2 Cl2 (39mL，0.5M)溶液中。在室溫下攪拌反應物(2h)。添加飽和NaHCO3 水溶液(30mL)。分離各層，且用CH2 Cl2 (x2)洗滌水層。將有機層合併，乾燥(Na2 SO4 )且在真空下濃縮。殘餘物不經進一步純化即用於下一步驟中。At 0 °C, mesylate chloride (1.81 mL, 23.30 mmol) was added dropwise to DMAP (237 mg, 1.94 mmol), triethylamine (7.57 mL, 54.30 mmol) and (E)-3-(1-( Hydroxymethyl)cyclopropyl)ethyl acrylate ( 5 ) (3.30 g, 19.40 mmol) in CH2Cl2 ( 39 mL, 0.5 M). The reaction was stirred at room temperature (2h). Saturated aqueous NaHCO3 (30 mL) was added. The layers were separated and the aqueous layer was washed with CH2Cl2 ( x2 ). The organic layers were combined, dried ( Na2SO4 ) and concentrated in vacuo. The residue was used in the next step without further purification.

步驟6：(E)-3-(1-(疊氮基甲基)環丙基)丙烯酸乙酯之合成Step 6: Synthesis of (E)-ethyl 3-(1-(azidomethyl)cyclopropyl)acrylate

將前一步驟中獲得之粗品(E)-3-(1-(甲基磺醯基氧基甲基)環丙基)丙-2-烯酸酯(6 )(4.54g，19.4mmol)添加到反應容器中，添加二甲基甲醯胺(16.2mL)及疊氮化鈉(2.52g，38.8mmol)。將混合物在室溫下攪拌(隔夜)。將DMF在真空下濃縮且添加乙酸乙酯及水。分離各層且用乙酸乙酯(2x)洗滌水層。將有機層合併，乾燥(Na2 SO4 )且在真空下濃縮。藉由矽膠管柱層析(EtOAc/環己烷)純化殘餘物，以得到(E)-3-(1-(疊氮基甲基)環丙基)丙烯酸乙酯(7 )黃色油狀物(18.0g，產率92.3%)。The crude (E)-3-(1-(methylsulfonyloxymethyl)cyclopropyl)prop-2-enoate ( 6 ) (4.54 g, 19.4 mmol) obtained in the previous step was added To the reaction vessel, dimethylformamide (16.2 mL) and sodium azide (2.52 g, 38.8 mmol) were added. The mixture was stirred at room temperature (overnight). DMF was concentrated under vacuum and ethyl acetate and water were added. The layers were separated and the aqueous layer was washed with ethyl acetate (2x). The organic layers were combined, dried ( Na2SO4 ) and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/cyclohexane) to give (E)-ethyl 3-(1-(azidomethyl)cyclopropyl)acrylate ( 7 ) as a yellow oil (18.0 g, 92.3% yield).

1 H NMR(CDCl3 ,400MHz)δ 6.56(d,J =15.9Hz,1H),5.90(d,J =15.9Hz,1H),4.19(q,J =7.1Hz,CH3 CH2 O,2H),3.36(s,2H),1.29(t,J =7.1Hz,CH 3 CH2 O),1.03-1.00(m,2H),0.97-0.94(m,2H)。 1 H NMR (CDCl 3 , 400 MHz) δ 6.56 (d, J =15.9 Hz, 1H), 5.90 (d, J =15.9 Hz, 1H), 4.19 (q, J =7.1 Hz, CH 3 CH 2 O, 2H ), 3.36 (s, 2H), 1.29 (t, J = 7.1 Hz, CH 3 CH 2 O), 1.03-1.00 (m, 2H), 0.97-0.94 (m, 2H).

步驟7：5-氮雜螺[2.5]辛-6-酮之合成Step 7: Synthesis of 5-azaspiro[2.5]octan-6-one

向(E)-3-(1-(疊氮基甲基)環丙基)丙-2-烯酸乙酯(7 )(2.6g，14.0mmol)之乙醇(48mL)溶液中添加Pd/c(260mg)。在H2 氣氛(氣球)下攪拌反應混合物(16h)。透過針筒過濾器過濾反應混合物且在真空下濃縮濾液。獲得呈蠟狀白色固體之5-氮雜螺[2.5]辛-6-酮(8 )(1.60g，89%)。To a solution of (E)-ethyl 3-(1-(azidomethyl)cyclopropyl)prop-2-enoate ( 7 ) (2.6 g, 14.0 mmol) in ethanol (48 mL) was added Pd/c (260mg). The reaction mixture was stirred (16h) under H2 atmosphere (balloon). The reaction mixture was filtered through a syringe filter and the filtrate was concentrated under vacuum. 5-Azaspiro[2.5]octan-6-one ( 8 ) (1.60 g, 89%) was obtained as a waxy white solid.

1 H NMR(CDCl3 ,400MHz)δ 6.69-6.57(br s,1H),3.09(dJ =1.9Hz,2H),2.43(t,J =6.6Hz,2H),1.61(t,J =6.6Hz,2H),0.49(s,4H)。 1 H NMR(CDCl 3 , 400MHz)δ 6.69-6.57(br s, 1H), 3.09(d J =1.9Hz, 2H), 2.43(t, J =6.6Hz, 2H), 1.61(t, J =6.6 Hz, 2H), 0.49 (s, 4H).

步驟8：6-側氧基-5-氮雜螺[2.5]辛烷-5-甲酸苯甲酯之合成Step 8: Synthesis of benzyl 6-oxy-5-azaspiro[2.5]octane-5-carboxylate

將5-氮雜螺[2.5]辛-6-酮(8 )(1.0g，8.0mmol)溶解於THF(100mL)中且在78℃下添加LiHMDS(10.4mL於THF中之1M溶液，10.4mmol)。攪拌30min之後，添加Cbz-OSu(2.6g,10.4mmol)且將所得混合物在室溫下攪拌隔夜。將反應物用水(30mL)及CH2 Cl2 (30mL)淬滅。分離各層，且用CH2 Cl2 (2*30mL)洗滌水層。將經合併之有機層乾燥(Na2 SO4 )，過濾，且在真空中濃縮。藉由矽膠管柱層析(10/0環己烷/乙酸乙酯至6/4)純化殘餘物，以得到呈無色油狀物之6-側氧基-5-氮雜螺[2.5]辛烷-5-甲酸苯甲酯(9 )(400mg，20%)。5-Azaspiro[2.5]octan-6-one ( 8 ) (1.0 g, 8.0 mmol) was dissolved in THF (100 mL) and LiHMDS (10.4 mL of a 1M solution in THF, 10.4 mmol) was added at 78°C ). After stirring for 30 min, Cbz-OSu (2.6 g, 10.4 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and CH2Cl2 ( 30 mL). The layers were separated and the aqueous layer was washed with CH2Cl2 ( 2 *30 mL). The combined organic layers were dried ( Na2SO4 ) , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10/0 cyclohexane/ethyl acetate to 6/4) to give 6-oxy-5-azaspiro[2.5]octane as a colorless oil Benzyl alkane-5-carboxylate ( 9 ) (400 mg, 20%).

1 H NMR(CDCl3 ,400MHz)δ 7.46-7.29(m,5H),5.27(s,2H),3.51(s,2H),2.65(t,J =6.9Hz,2H),1.69(t,J =6.9Hz,2H),0.62-0.57(m,2H),0.55-0.51(m,2H)。 1 H NMR (CDCl 3 , 400MHz)δ 7.46-7.29(m, 5H), 5.27(s, 2H), 3.51(s, 2H), 2.65(t, J =6.9Hz, 2H), 1.69(t, J =6.9Hz,2H),0.62-0.57(m,2H),0.55-0.51(m,2H).

步驟9：6-(((三氟甲基)磺醯基)氧基)-5-氮雜螺[2.5]辛6-烯-5-甲酸苯甲酯之合成Step 9: Synthesis of benzyl 6-(((trifluoromethyl)sulfonyl)oxy)-5-azaspiro[2.5]oct6-ene-5-carboxylate

將6-側氧基-5-氮雜螺[2.5]辛烷-5-甲酸苯甲酯(9 )(200mg，0.83mmol)於無水THF(4.8mL)中之溶液冷卻至-78℃。在5min內添加1M LiHMDS溶液(1.04mL於THF中之1M溶液，1.04mmol)，且將混合物攪拌70min。添加經蒸餾之HMPA(288μL，1.66mmol)，且將溶液再攪拌30min，然後添加PhNTf2 (370mg，1.04mmol)於無水THF(0.5mL)中之溶液，且使混合物升溫至室溫且使其反應15h。添加水(10mL)及醚(10mL)，且分離各層。用醚(2*30mL)洗滌水層。將經合 併之有機層乾燥(Na2 SO4 )，過濾，且在真空中濃縮。藉由矽膠管柱層析(10/0環己烷/乙酸乙酯至6/4)純化殘餘物，以得到呈無色油狀物之6-(((三氟甲基)磺醯基)氧基)-5-氮雜螺[2.5]辛-6-烯-5-甲酸苯甲酯(10 )。A solution of benzyl 6-oxy-5-azaspiro[2.5]octane-5-carboxylate ( 9 ) (200 mg, 0.83 mmol) in dry THF (4.8 mL) was cooled to -78 °C. 1M LiHMDS solution (1.04 mL of a 1M solution in THF, 1.04 mmol) was added over 5 min, and the mixture was stirred for 70 min. Distilled HMPA (288 μL, 1.66 mmol) was added and the solution was stirred for an additional 30 min, then a solution of PhNTf 2 (370 mg, 1.04 mmol) in dry THF (0.5 mL) was added and the mixture was allowed to warm to room temperature and allow The reaction was carried out for 15h. Water (10 mL) and ether (10 mL) were added, and the layers were separated. The aqueous layer was washed with ether (2*30 mL). The combined organic layers were dried ( Na2SO4 ) , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10/0 cyclohexane/ethyl acetate to 6/4) to give 6-(((trifluoromethyl)sulfonyl)oxy as a colorless oil yl)-5-azaspiro[2.5]oct-6-ene-5-carboxylic acid benzyl ( 10 ).

1 H NMR(CDCl3 ,400MHz)δ 7.40-7.32(m,5H),5.38(d,J =3.8Hz,1H),5.22(s,2H),3.47(s,2H),2.16(d,J =3.8Hz,2H),0.62-0.56(m,2H),0.44-0.40(m,2H)。 1 H NMR (CDCl 3 , 400MHz) δ 7.40-7.32(m, 5H), 5.38(d, J =3.8Hz, 1H), 5.22(s, 2H), 3.47(s, 2H), 2.16(d, J =3.8Hz, 2H), 0.62-0.56(m, 2H), 0.44-0.40(m, 2H).

步驟10：6-(4-氟苯基)-5-氮雜螺[2.5]辛6-烯-5-甲酸苯甲酯之合成Step 10: Synthesis of benzyl 6-(4-fluorophenyl)-5-azaspiro[2.5]oct6-ene-5-carboxylate

在氮氣氣氛下，向-(((三氟甲基)磺醯基)氧基)-5-氮雜螺[2.5]辛-6-烯-5-甲酸酯(140mg，0.36mmol)於THF(6mL)中之溶液中添加(Ph3 P)2 PdCl2 (13mg，17.9μmol)、(4-氟苯基)硼酸(65mg，0.46mmol)及2M Na2 CO3 水溶液(3.58mL)。在40℃下，將混合物攪拌16h。然後添加水(10mL)且將混合物用乙醚萃取且乾燥(Na2 SO4 )。藉由矽膠管柱層析(10/0環己烷/乙酸乙酯至1/9)純化殘餘物，以得到呈無色油狀物之6-(4-氟苯基)-5-氮雜螺[2.5]辛-6-烯-5-甲酸苯甲酯(11 )(60mg，50%)。To -(((trifluoromethyl)sulfonyl)oxy)-5-azaspiro[2.5]oct-6-ene-5-carboxylate (140 mg, 0.36 mmol) in THF under nitrogen atmosphere To the solution in (6 mL) was added (Ph3P) 2PdCl2 ( 13 mg , 17.9 μmol), (4-fluorophenyl)boronic acid (65 mg, 0.46 mmol) and 2M aqueous Na2CO3 ( 3.58 mL). The mixture was stirred for 16 h at 40 °C. Water (10 mL) was then added and the mixture was extracted with ether and dried ( Na2SO4 ) . The residue was purified by silica gel column chromatography (10/0 cyclohexane/ethyl acetate to 1/9) to give 6-(4-fluorophenyl)-5-azaspiro as a colorless oil [2.5] Benzyl oct-6-ene-5-carboxylate ( 11 ) (60 mg, 50%).

1 H NMR(CDCl3 ,400MHz)δ 7.47-7.15(m,7H),6.93(d,J =8.6Hz,2H),5.40(d,J =3.7Hz,1H),4.94(s,2H),3.57(s,2H),2.19(d,J =3.7Hz,2H),0.66-0.59(m,2H),0.45-0.40(m,2H)。 1 H NMR(CDCl 3 , 400MHz)δ 7.47-7.15(m, 7H), 6.93(d, J =8.6Hz, 2H), 5.40(d, J =3.7Hz, 1H), 4.94(s, 2H), 3.57(s, 2H), 2.19(d, J = 3.7Hz, 2H), 0.66-0.59(m, 2H), 0.45-0.40(m, 2H).

步驟11：6-(4-氟苯基)-5-氮雜螺[2.5]辛烷之合成Step 11: Synthesis of 6-(4-Fluorophenyl)-5-azaspiro[2.5]octane

將於炭上之Pd(OH)2 (10%，6mg)添加到6-(4-氟苯基)-5-氮雜螺[2.5]辛-6-烯-5-甲酸酯(11 )(60mg，0.18mmol)之(2,2,2)-三氟乙醇(1.2mL)溶液中。將溶液在室溫、H2 atm(1atm)下攪拌(16h)。透過針筒過濾器過濾反應混合物。將濾液用(2,2,2)-三氟乙醇洗滌。蒸發揮發物，以得到呈無色油狀物之6-(4-氟苯基)-5-氮雜螺[2.5]辛烷(35mg，96%)。Pd(OH) 2 (10%, 6 mg) on charcoal was added to 6-(4-fluorophenyl)-5-azaspiro[2.5]oct-6-ene-5-carboxylate ( 11 ) (60 mg, 0.18 mmol) in (2,2,2)-trifluoroethanol (1.2 mL). The solution was stirred (16h) at room temperature under H2 atm (1 atm). The reaction mixture was filtered through a syringe filter. The filtrate was washed with (2,2,2)-trifluoroethanol. The volatiles were evaporated to give 6-(4-fluorophenyl)-5-azaspiro[2.5]octane (35 mg, 96%) as a colorless oil.

1 H NMR(CDCl3 ,400MHz)δ 7.34(dd,J =5.6,8.7Hz,7H),7.00(d,J =8.7Hz,2H),3.64(dd,J =2.6,11.3Hz,1H),3.24(dd,J =1.1 12.3Hz,1H),2.25(dd,J =2.1,12.3 Hz,1H),2.05-1.98(m,1H),1.89-1.81(m,1H),1.75-1.64(m,1H),1.12-1.03(m,1H),0.53-0.45(m,1H),0.40-0.30(m,3H)。 1 H NMR (CDCl 3 , 400MHz) δ 7.34 (dd, J =5.6, 8.7Hz, 7H), 7.00 (d, J =8.7Hz, 2H), 3.64 (dd, J =2.6, 11.3Hz, 1H), 3.24(dd, J =1.1 12.3Hz, 1H), 2.25(dd, J =2.1, 12.3 Hz, 1H), 2.05-1.98(m, 1H), 1.89-1.81(m, 1H), 1.75-1.64(m , 1H), 1.12-1.03 (m, 1H), 0.53-0.45 (m, 1H), 0.40-0.30 (m, 3H).

3WW.1-甲基-6-(5-甲基-2-哌啶基)-3,4-二氫喹啉-2-酮 3WW. 1-methyl-6-(5-methyl-2-piperidinyl)-3,4-dihydroquinolin-2-one

步驟1：1-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫喹啉-2-酮之合成Step 1: 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydroquinoline Synthesis of Lin-2-ones

Figure 110128222-A0202-12-0671-746
Figure 110128222-A0202-12-0671-746

將6-溴-1-甲基-3,4-二氫喹啉-2-酮(5.18g，21.57mmol)、雙(頻哪醇)二硼(6.57g，25.89mmol)及乙酸鉀(6.35g，64.72mmol，4.05mL)於二噁烷(50mL)中之混合物用氬氣除氣10min。接著添加Pd(dppf)Cl2* DCM(880.93mg，1.08mmol)且將反應混合物在90℃下攪拌12h。將反應混合物冷卻至室溫且過濾，然後蒸發。將粗產物用己烷：mtbe(8：2)之混合物處理，且使其經歷急驟管柱層析(溶析液氯仿)。獲得1-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫喹啉-2-酮(4.6g，16.02mmol，74.25%產率)。Combine 6-bromo-1-methyl-3,4-dihydroquinolin-2-one (5.18 g, 21.57 mmol), bis(pinacol)diboron (6.57 g, 25.89 mmol) and potassium acetate (6.35 g g, 64.72 mmol, 4.05 mL) in dioxane (50 mL) was degassed with argon for 10 min. Then Pd(dppf)Cl2 * DCM (880.93 mg, 1.08 mmol) was added and the reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature and filtered, then evaporated. The crude product was treated with a mixture of hexane:mtbe (8:2) and subjected to flash column chromatography (eluent chloroform). 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydroquinoline- 2-keto (4.6 g, 16.02 mmol, 74.25% yield).

LCMS(ESI)：[M+H]+ m/z：計算值288.2；實測值288.2；Rt=1.321min。LCMS (ESI): [M+H] + m/z: calculated 288.2; found 288.2; Rt=1.321 min.

步驟2：3-甲基-6-(1-甲基-2-側氧基-3,4-二氫喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: 3-Methyl-6-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid Synthesis of tertiary butyl ester

Figure 110128222-A0202-12-0671-747
Figure 110128222-A0202-12-0671-747

將1-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫喹啉-2-酮(4.2g，14.63mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.07g，20.48mmol)、碳酸鈉(4.65g，43.88mmol，1.84mL) 及Pd(dppf)Cl2* DCM(1.19g，1.46mmol)混合於H2 O(20mL)及二噁烷(60mL)中，且用氬氣吹掃且在75℃下攪拌12h。將反應混合物用水稀釋且將所需產物用DCM萃取，經Na2 SO4 乾燥且在真空中濃縮。獲得3-甲基-6-(1-甲基-2-側氧基-3,4-二氫喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8g，粗品)。1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydroquinoline- 2-One (4.2 g, 14.63 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.07 g, 20.48 mmol), sodium carbonate (4.65 g, 43.88 mmol, 1.84 mL) and Pd(dppf)Cl2 * DCM (1.19 g, 1.46 mmol) were mixed in H2O (20 mL) and dioxane (60 mL) , and purged with argon and stirred at 75 °C for 12 h. The reaction mixture was diluted with water and the desired product was extracted with DCM, dried over Na2SO4 and concentrated in vacuo. Obtained 3-methyl-6-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid third Butyl ester (8 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值357.2；實測值357.4；Rt=1.437min。LCMS (ESI): [M+H] + m/z: calculated 357.2; found 357.4; Rt=1.437 min.

步驟3：1-甲基-6-(3-甲基2,3,4,5-四氫吡啶-6-基)-3,4-二氫喹啉-2-酮之合成Step 3: Synthesis of 1-methyl-6-(3-methyl 2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydroquinolin-2-one

Figure 110128222-A0202-12-0672-749
Figure 110128222-A0202-12-0672-749

將3-甲基-6-(1-甲基-2-側氧基-3,4-二氫喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8g，11.22mmol)溶解於CF3 COOH(10g，11.22mmol)中且在20℃下攪拌1h。然後，將反應混合物濃縮，用NaHCO3 水溶液處理且用DCM萃取，然後蒸發，以得到1-甲基-6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫喹啉-2-酮(4g，粗品)。3-methyl-6-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid third Butyl ester (8 g, 11.22 mmol) was dissolved in CF3COOH (10 g, 11.22 mmol) and stirred at 20 °C for 1 h. Then, the reaction mixture was concentrated, treated with aqueous NaHCO 3 and extracted with DCM, then evaporated to give 1-methyl-6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) )-3,4-dihydroquinolin-2-one (4 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值257.2；實測值257.2；Rt=0.674min。LCMS (ESI): [M+H] + m/z: calculated 257.2; found 257.2; Rt=0.674 min.

步驟4：1-甲基-6-(5-甲基-2-哌啶基)-3,4-二氫喹啉-2-酮之合成Step 4: Synthesis of 1-methyl-6-(5-methyl-2-piperidinyl)-3,4-dihydroquinolin-2-one

Figure 110128222-A0202-12-0672-748
Figure 110128222-A0202-12-0672-748

將1-甲基-6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫喹啉-2-酮(4g，7.33mmol)溶解於甲醇(40mL)中且添加硼氫化鈉(554.92mg，14.67mmol，518.62uL)。1h之後，將反應混合物濃縮，用NaHCO3 水溶液處理且用DCM萃取。將有 機相蒸發，以得到1-甲基-6-(5-甲基-2-哌啶基)-3,4-二氫喹啉-2-酮(2.9g，粗品)。Dissolve 1-methyl-6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydroquinolin-2-one (4 g, 7.33 mmol) In methanol (40 mL) and sodium borohydride (554.92 mg, 14.67 mmol, 518.62 uL) was added. After 1 h, the reaction mixture was concentrated, treated with aqueous NaHCO3 and extracted with DCM. The organic phase was evaporated to give 1-methyl-6-(5-methyl-2-piperidinyl)-3,4-dihydroquinolin-2-one (2.9 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值259.2；實測值259.2；Rt=0.717min。LCMS (ESI): [M+H] + m/z: calculated 259.2; found 259.2; Rt=0.717 min.

3XX.外消旋-6-((2R,5S)-5-甲基哌啶-2-基)咪唑并[1,5-a]吡啶 3XX. Racemic-6-((2R,5S)-5-methylpiperidin-2-yl)imidazo[1,5-a]pyridine

步驟1：6-(咪唑并[1,5-a]吡啶-6-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(imidazo[1,5-a]pyridin-6-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-0673-750
Figure 110128222-A0202-12-0673-750

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(100mg，289.57umol)、6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)咪唑并[1,5-a ]吡啶(70.68mg，289.57umol)及碳酸鈉(92.08mg，868.72umol，36.39uL)添加到1,4-二噁烷(3mL)及水(1mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，然後在氬氣下添加Pd(dppf)Cl2 *DCM(11.81mg，14.48umol)。將反應混合物在80℃下攪拌16h，然後用水處理且將所需產物用DCM萃取，然後蒸發。獲得6-咪唑并[1,5-a ]吡啶-6-基-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(150mg，粗品)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (100 mg, 289.57 umol), 6-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)imidazo[ 1,5-a ]pyridine (70.68mg, 289.57umol) and sodium carbonate ( 92.08 mg, 868.72 umol, 36.39 uL) was added to a mixture of 1,4-dioxane (3 mL) and water (1 mL). The resulting mixture was evacuated and backfilled with argon, then Pd(dppf)Cl2*DCM (11.81 mg , 14.48 umol) was added under argon. The reaction mixture was stirred at 80 °C for 16 h, then treated with water and the desired product was extracted with DCM and evaporated. 6-imidazo[ 1,5-a ]pyridin-6-yl-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (150 mg, crude) was obtained.

LCMS(ESI)：[M]+ m/z：計算值313.2；實測值314.2；Rt=1.044min。LCMS (ESI): [M] + m/z: calculated 313.2; found 314.2; Rt=1.044 min.

步驟2：6-(5-甲基-3,4,5,6-四氫吡啶-2-基)咪唑并[1,5-a]吡啶之合成Step 2: Synthesis of 6-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)imidazo[1,5-a]pyridine

Figure 110128222-A0202-12-0673-751
Figure 110128222-A0202-12-0673-751

將6-咪唑并[1,5-a ]吡啶-6-基-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3g，9.57mmol)溶解於TFA(20mL)中且在25℃下攪拌1h。在真空中濃縮反應混合物，將粗產物溶解於NaHCO3 水溶液中且用DCM(50ml)萃取。將有機相用水洗滌，經Na2 SO4 乾燥且蒸發，以得到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)咪唑并[1,5-a ]吡啶(3g，粗品)。6-imidazo[ 1,5-a ]pyridin-6-yl-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3 g, 9.57 mmol) was dissolved in TFA (20 mL) and stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo, the crude product was dissolved in aqueous NaHCO3 and extracted with DCM (50ml). The organic phase was washed with water, dried over Na 2 SO 4 and evaporated to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)imidazo[ 1,5-a ] Pyridine (3 g, crude).

LCMS(ESI)：[M]+ m/z：計算值213.2；實測值214.2；Rt=0.520min。LCMS (ESI): [M] + m/z: calculated 213.2; found 214.2; Rt=0.520 min.

步驟3：外消旋-6-((2R,5S)-5-甲基哌啶-2-基)咪唑并[1,5-a]吡啶之合成Step 3: Synthesis of Racemic-6-((2R,5S)-5-methylpiperidin-2-yl)imidazo[1,5-a]pyridine

Figure 110128222-A0202-12-0674-752
Figure 110128222-A0202-12-0674-752

將來自前一階段之粗品6-(3-甲基-2,3,4,5-四氫吡啶-6-基)咪唑并[1,5-a ]吡啶(3g，14.07mmol)溶解於甲醇(40mL)中，然後添加硼氫化鈉(800.00mg，21.15mmol，747.66uL)。將反應混合物攪拌隔夜然後蒸發。將粗產物溶解於DCM(100ml)中，用水洗滌兩次，經Na2 SO4 乾燥，然後在真空中濃縮，以得到6-[(2R,5S )-5-甲基-2-哌啶基]咪唑并[1,5-a ]吡啶(2.25g，粗品)。The crude 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)imidazo[ 1,5-a ]pyridine (3 g, 14.07 mmol) from the previous stage was dissolved in methanol ( 40 mL), then sodium borohydride (800.00 mg, 21.15 mmol, 747.66 uL) was added. The reaction mixture was stirred overnight and then evaporated. The crude product was dissolved in DCM (100 ml), washed twice with water, dried over Na2SO4 , and concentrated in vacuo to give 6-[( 2R,5S )-5-methyl-2-piperidinyl ]imidazo[ 1,5-a ]pyridine (2.25 g, crude).

LCMS(ESI)：[M]+ m/z：計算值215.2；實測值216.2；Rt=0.465min。LCMS (ESI): [M] + m/z: calculated 215.2; found 216.2; Rt=0.465 min.

3YY.外消旋-5-((2R,5S)-5-甲基哌啶-2-基)-1H-噻吩并[2,3-c]吡唑 3YY. Racemic-5-((2R,5S)-5-methylpiperidin-2-yl)-1H-thieno[2,3-c]pyrazole

步驟1：1-(四氫-2H-哌喃-2-基)-1H-噻吩并[2,3-c]吡唑-5-甲酸之合成Step 1: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid

Figure 110128222-A0202-12-0674-753
Figure 110128222-A0202-12-0674-753

將1H -噻吩并[2,3-c]吡唑-5-甲酸(5g，29.73mmol)懸浮於3,4-二氫-2H -哌喃(25.01g，297.31mmol，27.01mL)中，隨後添加甲苯磺酸(255.99mg，1.49mmol)。劇烈攪拌0.5h之後，溶解所有固體，將澄清溶液蒸發至乾且將粗殘餘物溶解於50% KOH水溶液中。將所獲得之乳狀懸浮液用DCM(30mL)洗滌五次且 用MTBE(30mL)洗滌2次。將澄清淡黃色溶液用10% NaHSO4 水溶液酸化至pH=2且用DCM(30mL)萃取2次。蒸發經合併之有機溶劑，得到呈位置異構物之混合物形式之1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-甲酸(7.2g，28.54mmol，95.99%產率)。 1H -thieno[2,3-c]pyrazole-5-carboxylic acid (5 g, 29.73 mmol) was suspended in 3,4-dihydro- 2H -pyran (25.01 g, 297.31 mmol, 27.01 mL), followed by Toluenesulfonic acid (255.99 mg, 1.49 mmol) was added. After vigorous stirring for 0.5 h, all solids were dissolved, the clear solution was evaporated to dryness and the crude residue was dissolved in 50% aqueous KOH. The milky suspension obtained was washed five times with DCM (30 mL) and twice with MTBE (30 mL). The clear pale yellow solution was acidified to pH=2 with 10% aqueous NaHSO 4 and extracted twice with DCM (30 mL). The combined organic solvents were evaporated to give 1-tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazole-5-carboxylic acid (7.2 g, 28.54 mmol, 95.99 g) as a mixture of positional isomers %Yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.95(m,6H),3.86(m,2H),5.56(m,1H),7.68(s,1H),8.28(s,1H),13.25(bds,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.95(m, 6H), 3.86(m, 2H), 5.56(m, 1H), 7.68(s, 1H), 8.28(s, 1H), 13.25 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值252.2；實測值253.2；Rt=1.089min。LCMS (ESI): [M] + m/z: calculated 252.2; found 253.2; Rt=1.089 min.

步驟2：(1H-咪唑-1-基)(1-(四氫-2H-哌喃-2-基)-1H-噻吩并[2,3-c]吡唑-5-基)甲酮之合成Step 2: (1H-imidazol-1-yl)(1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[2,3-c]pyrazol-5-yl)methanone synthesis

Figure 110128222-A0202-12-0675-754
Figure 110128222-A0202-12-0675-754

將1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-甲酸(7.2g，28.54mmol)溶解於DCM(100mL)中，隨後一次性添加CDI(6.94g，42.81mmol)。反應完成之後(藉由氣態副產物之最終逸出且藉由H-NMR推測)，將混合物用DCM(100mL)稀釋且用0.1M HCl水溶液洗滌(三次)。在減壓下蒸發有機溶劑，得到咪唑-1-基-(1-四氫哌喃-2-基噻吩并[2,3-c]吡唑-5-基)甲酮(5.8g，19.18mmol，67.22%產率)，其立即用於下一步驟。1-Tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazole-5-carboxylic acid (7.2 g, 28.54 mmol) was dissolved in DCM (100 mL) followed by CDI (6.94 g, 42.81 mmol). After the reaction was complete (by eventual evolution of gaseous by-products and presumed by H-NMR), the mixture was diluted with DCM (100 mL) and washed with 0.1 M aqueous HCl (three times). The organic solvent was evaporated under reduced pressure to give imidazol-1-yl-(1-tetrahydropyran-2-ylthieno[2,3-c]pyrazol-5-yl)methanone (5.8 g, 19.18 mmol) , 67.22% yield), which was used immediately in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.95(m,6H),3.82(m,1H),4.08(m,1H),5.62(m,1H),7.19(s,1H),7.69(s,1H),7.82(s,1H),8.12(s,1H),8.32(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.95(m, 6H), 3.82(m, 1H), 4.08(m, 1H), 5.62(m, 1H), 7.19(s, 1H), 7.69(s, 1H), 7.82(s, 1H), 8.12(s, 1H), 8.32(s, 1H).

步驟3：5-甲基-2-側氧基-3-(1-(四氫-2H-哌喃-2-基)-1H-噻吩并[2,3-c]吡唑-5-羰基)哌啶-1-甲酸第三丁酯之合成Step 3: 5-Methyl-2-oxo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[2,3-c]pyrazole-5-carbonyl ) Synthesis of tert-butyl piperidine-1-carboxylate

Figure 110128222-A0202-12-0675-755
Figure 110128222-A0202-12-0675-755

將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(4.50g，21.10mmol)溶解於THF(40mL)中且在Ar下冷卻至-78℃，隨後逐滴添加六甲基二矽氮烷鋰(1.03M，22.35mL)。再攪拌10min之後，添加咪唑-1-基-(1-四氫哌喃-2-基噻吩并[2,3-c]吡唑-5-基)甲酮(5.8g，19.18mmol)於THF(40mL)中之溶液且將反應混合物升溫至室溫。反應完成之後，將混合物倒入飽和NH4 Cl水溶液中且用EtOAc(100mL)萃取三次。蒸發有機溶劑且用CC(OK.Interchim；220g SiO2 ，石油醚/乙酸乙酯，其中乙酸乙酯為10~75%，流速=100mL/min，Rv=7.7 CV)純化，產生呈異構物之混合物形式之5-甲基-2-側氧基-3-(1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-羰基)哌啶-1-甲酸第三丁酯(4.5g，10.05mmol，52.42%產率)。將單獨級分合併且用於下一步驟。3-Butyl 5-methyl-2-oxypiperidine-1-carboxylate (4.50 g, 21.10 mmol) was dissolved in THF (40 mL) and cooled to -78 °C under Ar, followed by dropwise addition of six Lithium methyldisilazane (1.03M, 22.35 mL). After stirring for an additional 10 min, imidazol-1-yl-(1-tetrahydropyran-2-ylthieno[2,3-c]pyrazol-5-yl)methanone (5.8 g, 19.18 mmol) in THF was added (40 mL) and the reaction mixture was warmed to room temperature. After the reaction was complete, the mixture was poured into saturated aqueous NH4Cl and extracted three times with EtOAc (100 mL). The organic solvent was evaporated and purified with CC (OK. Interchim; 220 g SiO2 , petroleum ether/ethyl acetate with 10-75% ethyl acetate, flow rate = 100 mL/min, Rv = 7.7 CV) to give isomers 5-Methyl-2-oxo-3-(1-tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazole-5-carbonyl)piperidine-1-carboxylic acid as a mixture of Tertiary butyl ester (4.5 g, 10.05 mmol, 52.42% yield). The individual fractions were combined and used in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.08(d,3H),1.53(s,9H),1.62(m,4H),2.15(m,6H),3.23(m,1H),3.85(m,2H),4.39(m,1H),5.55(m,1H),7.86(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.08(d, 3H), 1.53(s, 9H), 1.62(m, 4H), 2.15(m, 6H), 3.23(m, 1H), 3.85( m, 2H), 4.39 (m, 1H), 5.55 (m, 1H), 7.86 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值347.2；實測值348.2；Rt=1.384min。LCMS (ESI): [M-Boc] + m/z: calculated 347.2; found 348.2; Rt=1.384 min.

步驟4：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-1H-噻吩并[2,3-c]吡唑之合成Step 4: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1H-thieno[2,3-c]pyrazole

Figure 110128222-A0202-12-0676-756
Figure 110128222-A0202-12-0676-756

將5-甲基-2-側氧基-3-(1-四氫哌喃-2-基噻吩并[2,3-c ]吡唑-5-羰基)哌啶-1-甲酸第三丁酯(4.5g，10.05mmol)溶解於乙酸(50mL)中且加熱至回流。逐滴添加HCl(10M，10.05mL)(小心！觀察到劇烈泡沫形成！)。氣體逸出停止之後，將混合物蒸發至乾，溶解於H2 O(50mL)中且用10% K2 CO3 水溶液鹼化至pH=10；將所獲得之不透明溶液用DCM(150mL)萃取，將其經Na2 SO4 乾燥且在減壓下蒸發，以得到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -噻吩并[2,3-c ]吡唑(1.6 g，7.30mmol，72.56%產率)。5-Methyl-2-oxo-3-(1-tetrahydropyran-2-ylthieno[ 2,3-c ]pyrazole-5-carbonyl)piperidine-1-carboxylic acid tertiary butyl The ester (4.5 g, 10.05 mmol) was dissolved in acetic acid (50 mL) and heated to reflux. HCl (10 M, 10.05 mL) was added dropwise (be careful! Vigorous foam formation was observed!). After gas evolution ceased, the mixture was evaporated to dryness, dissolved in H2O (50 mL) and basified to pH= 10 with 10 % aqueous K2CO3; the resulting opaque solution was extracted with DCM (150 mL), It was dried over Na 2 SO 4 and evaporated under reduced pressure to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H- thieno [ 2,3 -c ]pyrazole (1.6 g, 7.30 mmol, 72.56% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.02(d,3H),1.86(m,1H),1.95(m,2H),2.48(m,1H),2.86(m,1H),3.26(m,1H),4.02(m,1H),7.42(m,1H),7.82(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.86(m,1H), 1.95(m,2H), 2.48(m,1H), 2.86(m,1H), 3.26( m, 1H), 4.02 (m, 1H), 7.42 (m, 1H), 7.82 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值219.2；實測值220.2；Rt=0.802min。LCMS (ESI): [M] + m/z: calculated 219.2; found 220.2; Rt=0.802 min.

步驟5：外消旋-5-((2R,5S)-5-甲基哌啶-2-基)-1H-噻吩并[2,3-c]吡唑之合成Step 5: Synthesis of Racemic-5-((2R,5S)-5-methylpiperidin-2-yl)-1H-thieno[2,3-c]pyrazole

Figure 110128222-A0202-12-0677-757
Figure 110128222-A0202-12-0677-757

將5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -噻吩并[2,3-c ]吡唑(1.6g，7.30mmol)溶解於MeOH(20mL)中且冷卻至0℃。將硼氫化鈉(552.00mg，14.59mmol，515.89uL)分批添加到所獲得之混合物中且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH=2，用MTBE洗滌(2*10mL)，用10% NaOH水溶液鹼化至pH=10且用DCM(50mL)萃取。蒸發溶劑，得到純的5-[(2S,5R )-5-甲基-2-哌啶基]-2H -噻吩并[2,3-c ]吡唑(1.3g，5.87mmol，80.51%產率)。5-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H- thieno [ 2,3-c ]pyrazole (1.6 g, 7.30 mmol) was dissolved in MeOH ( 20 mL) and cooled to 0 °C. Sodium borohydride (552.00 mg, 14.59 mmol, 515.89 uL) was added portionwise to the resulting mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl, washed with MTBE (2*10 mL), basified with 10% aqueous NaOH to pH=10 and extracted with DCM (50 mL). The solvent was evaporated to give pure 5-[( 2S,5R )-5-methyl-2-piperidinyl] -2H -thieno[ 2,3-c ]pyrazole (1.3 g, 5.87 mmol, 80.51% yield Rate).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.98(d,3H),1.56(m,2H),1.68(m,2H),1.92(m,1H),2.02(m,1H),2.44(m,1H),3.20(m,1H),3.86(m,1H),6.83(s,1H),7.61(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.56(m,2H), 1.68(m,2H), 1.92(m,1H), 2.02(m,1H), 2.44( m, 1H), 3.20 (m, 1H), 3.86 (m, 1H), 6.83 (s, 1H), 7.61 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值221.2；實測值222.2；Rt=0.711min。LCMS (ESI): [M] + m/z: calculated 221.2; found 222.2; Rt=0.711 min.

3ZZ. N,N -二甲基-2-(3-((5S )-5-甲基哌啶-2-基)苯氧基)乙胺 3ZZ. N,N -dimethyl-2-(3-(( 5S )-5-methylpiperidin-2-yl)phenoxy)ethanamine

步驟1：(S)-6-(3-(2-(二甲胺基)乙氧基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: (S)-6-(3-(2-(Dimethylamino)ethoxy)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid 3rd Synthesis of Butyl Ester

Figure 110128222-A0202-12-0678-758
Figure 110128222-A0202-12-0678-758

將(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(8g，23.17mmol)、N,N -二甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]乙胺(5.62g，19.30mmol)及碳酸鈉(4.09g，38.61mmol，1.62mL)混合於二噁烷(45mL)及水(15mL)之混合物中。將所得混合物抽真空且用氬氣回填三次.將Pd(dppf)Cl2 *DCM(788.26mg，965.25μmol)添加到先前混合物中且將所得混合物在90℃下加熱隔夜。冷卻所得混合物且用水(100ml)稀釋。將所得混合物用EtOAc(2*100ml)萃取且將經合併之有機層用鹽水(60ml)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。將殘餘物(10.8g粗產物)與殘餘物(200mg粗產物)合併且藉由管柱層析純化，以獲得(3S )-6-[3-[2-(二甲胺基)乙氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.5g，12.48mmol，64.66%產率)。( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (8 g, 23.17 mmol), N ,N -dimethyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]ethanamine (5.62 g, 19.30 mmol) and sodium carbonate (4.09 g, 38.61 mmol, 1.62 mL) were combined in a mixture of dioxane (45 mL) and water (15 mL). The resulting mixture was evacuated and backfilled with argon three times. Pd(dppf)Cl2*DCM ( 788.26 mg, 965.25 μmol) was added to the previous mixture and the resulting mixture was heated at 90°C overnight. The resulting mixture was cooled and diluted with water (100 ml). The resulting mixture was extracted with EtOAc (2*100ml) and the combined organic layers were washed with brine (60ml), dried over Na2SO4 , filtered and concentrated in vacuo. The residue (10.8 g crude product) was combined with the residue (200 mg crude product) and purified by column chromatography to obtain ( 3S )-6-[3-[2-(dimethylamino)ethoxy ]Phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4.5 g, 12.48 mmol, 64.66% yield).

LCMS(ESI)：[M]+ m/z：計算值360.2；實測值361.2；Rt=1.077min。LCMS (ESI): [M] + m/z: calculated 360.2; found 361.2; Rt=1.077 min.

步驟2：(S)-N,N-二甲基-2-(3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯氧基)乙胺之合成Step 2: Synthesis of (S)-N,N-dimethyl-2-(3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenoxy)ethanamine

Figure 110128222-A0202-12-0678-759
Figure 110128222-A0202-12-0678-759

將(3S )-6-[3-[2-(二甲胺基)乙氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.5g，12.48mmol)溶解於DCM(18mL)中且向其中添加TFA(18mL)。攪拌 所得混合物1h。將反應混合物小心倒入NaHCO3 水溶液(20g於100ml水中)且將所得混合物用DCM(2*50ml)萃取。將經合併之有機層經硫酸鈉乾燥，過濾，且在真空中濃縮，以獲得N,N -二甲基-2-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]乙胺(2.36g，9.04mmol，72.46%產率)。( 3S )-6-[3-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4.5 g, 12.48 mmol) was dissolved in DCM (18 mL) and TFA (18 mL) was added to it. The resulting mixture was stirred for 1 h. The reaction mixture was poured carefully into aqueous NaHCO3 (20 g in 100 ml water) and the resulting mixture was extracted with DCM (2*50 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to obtain N,N -dimethyl-2-[3-[( 3S )-3-methyl-2,3,4, 5-Tetrahydropyridin-6-yl]phenoxy]ethanamine (2.36 g, 9.04 mmol, 72.46% yield).

LCMS(ESI)：[M]+ m/z：計算值260.2；實測值261.2；Rt=0.245min。LCMS (ESI): [M] + m/z: calculated 260.2; found 261.2; Rt=0.245min.

步驟3：N,N-二甲基-2-(3-((5S)-5-甲基哌啶-2-基)苯氧基)乙胺之合成Step 3: Synthesis of N,N-dimethyl-2-(3-((5S)-5-methylpiperidin-2-yl)phenoxy)ethanamine

Figure 110128222-A0202-12-0679-760
Figure 110128222-A0202-12-0679-760

將N,N -二甲基-2-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]乙胺(2.36g，9.06mmol)溶解於MeOH(45mL)中且分批添加硼氫化鈉(685.82mg，18.l3mmol，638.57μL)。將所得混合物攪拌隔夜。將水(20ml)添加到反應混合物中且在真空中濃縮所得混合物。將殘餘物用水(30ml)稀釋且將所得混合物用DCM(2*50ml)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾，且在真空中濃縮，以獲得N,N -二甲基-2-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]乙胺(2.02g，7.70mmol，84.94%產率)。 N,N -dimethyl-2-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenoxy]ethanamine (2.36 g, 9.06 mmol) was dissolved in MeOH (45 mL) and sodium borohydride (685.82 mg, 18.13 mmol, 638.57 μL) was added portionwise. The resulting mixture was stirred overnight. Water (20 ml) was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water (30ml) and the resulting mixture was extracted with DCM (2*50ml). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo to obtain N,N -dimethyl-2-[3-[( 2R,5S )-5-methyl-2- Piperidinyl]phenoxy]ethylamine (2.02 g, 7.70 mmol, 84.94% yield).

LCMS(ESI)：[M]+ m/z：計算值262.2；實測值263.2；Rt=0.498min。LCMS (ESI): [M] + m/z: calculated 262.2; found 263.2; Rt=0.498 min.

3AAA.5-((2R,5S)-5-甲基哌啶-2-基)-2-(2-(吡咯啶-1-基)乙基)苯并[d]噻唑 3AAA. 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(2-(pyrrolidin-1-yl)ethyl)benzo[d]thiazole

Figure 110128222-A0202-12-0680-761
Figure 110128222-A0202-12-0680-761

步驟1：5-氯-2-(2-(吡咯啶-1-基)乙基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(2-(pyrrolidin-1-yl)ethyl)benzo[d]thiazole

Figure 110128222-A0202-12-0680-762
Figure 110128222-A0202-12-0680-762

藉由一般程序方案J步驟1A製備。產率：4.3g(51.46%)。Prepared by General Procedure J, Step 1A. Yield: 4.3 g (51.46%).

CC條件： 藉由矽膠使用MTBE/MeOH作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using MTBE/MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值266.2；實測值267.2；Rt=1.014min。LCMS (ESI): [M] + m/z: calculated 266.2; found 267.2; Rt=1.014 min.

步驟2：2-(2-(吡咯啶-1-基)乙基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(2-(pyrrolidin-1-yl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Synthesis of 2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-0680-763
Figure 110128222-A0202-12-0680-763

將乙酸鉀(3.16g，32.23mmol，2.01mL)添加到5-氯-2-(2-吡咯啶-1-基乙基)-1,3-苯并噻唑(4.30g，16.12mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(4.50g，17.73mmol)於二 噁烷(50mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加參(二苯亞甲基丙酮)二鈀(0)(737.96mg，805.88umol)及XPhos(1.54g，3.22mmol)。在90℃、惰性氣氛下將所得混合物攪拌18h。然後添加40%吡咯啶水溶液(0.5當量)且將反應混合物在60℃下再攪拌12h。然後，將其冷卻，用EtOAc(200mL)稀釋且用Na2 CO3 (50mL，飽和水溶液)洗滌。將有機層經Na2 SO4 乾燥，在減壓下濃縮且藉由矽膠急驟層析，以0至100% CHCl3 -MeCN-MeOH梯度溶析來純化殘餘物，以得到產物2-(2-吡咯啶-1-基乙基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(2.2g，6.14mmol，38.10%產率)。Potassium acetate (3.16 g, 32.23 mmol, 2.01 mL) was added to 5-chloro-2-(2-pyrrolidin-1-ylethyl)-1,3-benzothiazole (4.30 g, 16.12 mmol) and 4 ,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3, A solution of 2-dioxaborolane (4.50 g, 17.73 mmol) in dioxane (50 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, under a stream of argon, paras(dibenzylideneacetone)dipalladium(0) (737.96 mg, 805.88 umol) and XPhos (1.54 g, 3.22 mmol) were added. The resulting mixture was stirred at 90 °C under an inert atmosphere for 18 h. Then 40% aqueous pyrrolidine (0.5 equiv.) was added and the reaction mixture was stirred at 60 °C for a further 12 h. It was then cooled, diluted with EtOAc ( 200 mL) and washed with Na2CO3 (50 mL, saturated aqueous solution). The organic layer was dried over Na2SO4 , concentrated under reduced pressure and the residue was purified by silica gel flash chromatography with a gradient of 0 to 100% CHCl3 -MeCN-MeOH to give the product 2-(2- Pyrrolidin-1-ylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzene Thiazole (2.2 g, 6.14 mmol, 38.10% yield).

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=1.001min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=1.001 min.

步驟3：(S)-3-甲基-6-(2-(2-(吡咯啶-1-基)乙基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(2-(pyrrolidin-1-yl)ethyl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine -1(2H)-Synthesis of tert-butyl formate

Figure 110128222-A0202-12-0681-764
Figure 110128222-A0202-12-0681-764

藉由一般程序方案J步驟3製備。產率：3g粗品。Prepared by General Procedure J, Step 3. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值427.2；實測值428.2；Rt=1.251min。LCMS (ESI): [M] + m/z: calculated 427.2; found 428.2; Rt=1.251 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(2-(吡咯啶-1-基)乙基)苯并[d]噻唑之合成Step 4: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(2-(pyrrolidin-1-yl)ethyl)benzo Synthesis of [d]thiazole

Figure 110128222-A0202-12-0682-765
Figure 110128222-A0202-12-0682-765

藉由一般程序方案J步驟4製備。產率：1.2g粗品。Prepared by General Procedure J, Step 4. Yield: 1.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.681min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.681 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(2-(吡咯啶-1-基)乙基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(2-(pyrrolidin-1-yl)ethyl)benzo[d]thiazole

Figure 110128222-A0202-12-0682-766
Figure 110128222-A0202-12-0682-766

藉由一般程序方案J步驟5製備。產率：1g粗品。Prepared by General Procedure J, Step 5. Yield: 1 g crude.

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.720min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.720 min.

3BBB.((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺 3BBB. ((2R,5S)-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)- 2-Pendant oxyacetamide

Figure 110128222-A0202-12-0682-767
Figure 110128222-A0202-12-0682-767

步驟1：5-溴-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-0683-770
Figure 110128222-A0202-12-0683-770

藉由一般程序方案J步驟1A製備。產率：14g(92.88%)。Prepared by General Procedure J, Step 1A. Yield: 14 g (92.88%).

LCMS(ESI)：[M]+ m/z：計算值311.2；實測值312.2；Rt=0.742min。LCMS (ESI): [M] + m/z: calculated 311.2; found 312.2; Rt=0.742 min.

步驟2：2-(1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)benzo[d]thiazole

Figure 110128222-A0202-12-0683-769
Figure 110128222-A0202-12-0683-769

藉由一般程序方案J步驟2製備。產率：8.5g(92.29%)。Prepared by General Procedure J, Step 2. Yield: 8.5 g (92.29%).

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=0.978min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=0.978 min.

步驟3：(S)-3-甲基-6-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

Figure 110128222-A0202-12-0683-768
Figure 110128222-A0202-12-0683-768

藉由一般程序方案J步驟3製備。產率：15g粗品。Prepared by General Procedure J, Step 3. Yield: 15 g crude.

LCMS(ESI)：[M]+ m/z：計算值427.2；實測值428.2；Rt=1.274min。LCMS (ESI): [M] + m/z: calculated 427.2; found 428.2; Rt=1.274 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 4: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d ]Synthesis of thiazole

Figure 110128222-A0202-12-0684-771
Figure 110128222-A0202-12-0684-771

藉由一般程序方案J步驟4製備。產率：6g(94.96%)。Prepared by General Procedure J, Step 4. Yield: 6 g (94.96%).

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.670min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.670 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-0684-772
Figure 110128222-A0202-12-0684-772

藉由一般程序方案J步驟5製備。產率：4g(66.26%)。Prepared by General Procedure J, Step 5. Yield: 4 g (66.26%).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.703min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.703 min.

步驟6：2-((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 6: 2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1- Synthesis of )-2-side oxyacetamide

Figure 110128222-A0202-12-0685-557
Figure 110128222-A0202-12-0685-557

在25℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(1.04g，5.46mmol)緩慢添加到2-(1-甲基-4-哌啶基)-5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑(1.5g，4.55mmol)及TEA(921.30mg，9.10mmol，1.27mL)於無水THF(50mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌0.5h，然後在25℃下將氣態氨鼓泡通過反應混合物達0.5h。過濾所得氯化銨沉澱且丟棄，在真空中濃縮濾液，以得到呈黃色固體之粗品2-[(2R,5S )-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(1.6g，3.99mmol，87.75%產率)，其直接用於下一步驟中。2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (1.04 g, 5.46 mmol) was slowly added to 2-(1-methyl-4-piperidinyl) at 25°C -5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzothiazole (1.5 g, 4.55 mmol) and TEA (921.30 mg, 9.10 mmol, 1.27 mL) in anhydrous in a stirred solution in THF (50 mL). The resulting mixture was stirred at 25°C for 0.5h, then gaseous ammonia was bubbled through the reaction mixture at 25°C for 0.5h. The resulting ammonium chloride precipitate was filtered and discarded, and the filtrate was concentrated in vacuo to give crude 2-[( 2R,5S )-5-methyl-2-[2-(1-methyl-4-piperidine as a yellow solid Peridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (1.6 g, 3.99 mmol, 87.75% yield), which was used directly in the following in one step.

LCMS(ESI)：[M]+ m/z：計算值400.2；實測值401.2；Rt=0.867min。LCMS (ESI): [M] + m/z: calculated 400.2; found 401.2; Rt=0.867 min.

2-((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)- 2-Pendant oxyacetamide

Figure 110128222-A0202-12-0685-558
Figure 110128222-A0202-12-0685-558

步驟1：5-溴-2-(1-甲基哌啶-4-基)苯并[d]噻唑)之合成Step 1: Synthesis of 5-bromo-2-(1-methylpiperidin-4-yl)benzo[d]thiazole)

Figure 110128222-A0202-12-0686-559
Figure 110128222-A0202-12-0686-559

藉由一般程序方案J步驟1A製備。產率：14g(92.88%)。Prepared by General Procedure J, Step 1A. Yield: 14 g (92.88%).

LCMS(ESI)：[M]+ m/z：計算值311.2；實測值312.2；Rt=0.742min。LCMS (ESI): [M] + m/z: calculated 311.2; found 312.2; Rt=0.742 min.

步驟2：2-(1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)benzo[d]thiazole

Figure 110128222-A0202-12-0686-560
Figure 110128222-A0202-12-0686-560

藉由一般程序方案J步驟2製備。產率：8.5g(92.29%)。Prepared by General Procedure J, Step 2. Yield: 8.5 g (92.29%).

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=0.978min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=0.978 min.

步驟3：(S)-3-甲基-6-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

Figure 110128222-A0202-12-0686-561
Figure 110128222-A0202-12-0686-561

藉由一般程序方案J步驟3製備。產率：15g粗品。Prepared by General Procedure J, Step 3. Yield: 15 g crude.

LCMS(ESI)：[M]+ m/z：計算值427.2；實測值428.2；Rt=1.274min。LCMS (ESI): [M] + m/z: calculated 427.2; found 428.2; Rt=1.274 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 4: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d ]Synthesis of thiazole

Figure 110128222-A0202-12-0687-562
Figure 110128222-A0202-12-0687-562

藉由一般程序方案J步驟4製備。產率：6g(94.96%)。Prepared by General Procedure J, Step 4. Yield: 6 g (94.96%).

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.670min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.670 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-0687-563
Figure 110128222-A0202-12-0687-563

藉由一般程序方案J步驟5製備。產率：4g(66.26%)。Prepared by General Procedure J, Step 5. Yield: 4 g (66.26%).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.703min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.703 min.

步驟6：2-((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 6: 2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1- Synthesis of )-2-side oxyacetamide

1-甲基-4-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)哌嗪1-Methyl-4-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)piperazine

步驟1：(2R,5S)-5-甲基-2-(3-(4-甲基哌嗪-1-基)苯基)哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,5S)-5-methyl-2-(3-(4-methylpiperazin-1-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-0688-564
Figure 110128222-A0202-12-0688-564

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(1.03g，2.91mmol)、1-甲基哌嗪(291.20mg，2.91mmol，322.48μL)、4,5-雙( 二苯基膦基)-9,9-二甲基二苯并哌喃(168.22mg，290.73μmol)及第三丁醇鈉(419.09mg，4.36mmol)一起混合於二噁烷(15mL)中，且將所得混合物抽真空且用氬氣回填三次。將參 (二苯亞甲基丙酮)二鈀(0)(133.11mg，145.36μmol)添加到先前的混合物中，且將所得混合物在100℃下(油浴)加熱隔夜。冷卻反應混合物且用水(50ml)稀釋。將所得混合物用EtOAc(3*50ml)萃取。將經合併之有機層用鹽水(2*50ml)洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酸第三丁酯(1.1g，粗品)。Combine ( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.03 g, 2.91 mmol), 1-methylpiperazine (291.20 mg, 2.91 mmol, 322.48 μL), 4,5 -bis( diphenylphosphino)-9,9-dimethyldibenzopyran (168.22 mg, 290.73 μmol) and sodium tert-butoxide (419.09 mg, 4.36 mmol) ) were mixed together in dioxane (15 mL), and the resulting mixture was evacuated and backfilled with argon three times. Ps(dibenzylideneacetone)dipalladium(0) (133.11 mg, 145.36 μmol) was added to the previous mixture, and the resulting mixture was heated at 100° C. (oil bath) overnight. The reaction mixture was cooled and diluted with water (50 ml). The resulting mixture was extracted with EtOAc (3*50ml). The combined organic layers were washed with brine (2*50ml), dried over Na2SO4 , filtered and evaporated to obtain ( 2R,5S )-5-methyl-2-[3-(4-methylpiperidine) Azin-1-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.1 g, crude).

LCMS(ESI)：[M]+ m/z：計算值373.2；實測值374.2；Rt=0.991min。LCMS (ESI): [M] + m/z: calculated 373.2; found 374.2; Rt=0.991 min.

步驟2：1-甲基-4-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)哌嗪之合成Step 2: Synthesis of 1-methyl-4-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)piperazine

Figure 110128222-A0202-12-0688-565
Figure 110128222-A0202-12-0688-565

將(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酸第三丁酯(1.1g，2.94mmol)溶解於DCM(15mL)中，然後添加二噁烷/HCl(2.94mmol，5mL)且將其在室溫下攪拌16h。藉由過濾收集不溶性材料，將濾餅用額外量之MTBE洗滌且風乾，以得到1-甲基-4-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]哌嗪(750mg，2.42mmol，82.19%產率，HCl)。( 2R,5S )-5-methyl-2-[3-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.94 mmol) was dissolved In DCM (15 mL), then dioxane/HCl (2.94 mmol, 5 mL) was added and it was stirred at room temperature for 16 h. The insoluble material was collected by filtration, the filter cake was washed with additional amount of MTBE and air dried to give 1-methyl-4-[3-[( 2R,5S )-5-methyl-2-piperidinyl]benzene yl]piperazine (750 mg, 2.42 mmol, 82.19% yield, HCl).

LCMS(ESI)：[M]+ m/z：計算值273.2；實測值274.2；Rt=0.675min。LCMS (ESI): [M] + m/z: calculated 273.2; found 274.2; Rt=0.675 min.

4. 經由用親核劑對哌啶酮進行開環來合成4. Synthesis via ring opening of piperidone with a nucleophile

Figure 110128222-A0202-12-0689-566
Figure 110128222-A0202-12-0689-566

在一些實施例中，可藉由親核加成到2-哌啶酮來製備二級胺。親核加成/開環可使用格任亞試劑(例如 R6 MgBr)來完成。親核加成反應可在諸如但不限於THF、Et2 O、TMEDA、DME及MTBE或其混合物之溶劑中進行。在一些實施例中，透過包含R6 Br、MgI2 及THF之條件完成親核加成。In some embodiments, secondary amines can be prepared by nucleophilic addition to 2-piperidone. Nucleophilic addition/ring opening can be accomplished using a Grignard reagent such as R6MgBr . Nucleophilic addition reactions can be carried out in solvents such as, but not limited to, THF, Et2O , TMEDA, DME, and MTBE, or mixtures thereof. In some embodiments, the nucleophilic addition is accomplished by conditions comprising R6Br , MgI2 , and THF.

在一些實施例中，二級胺經歷去保護、環化及還原之序列，以製備經取代之哌啶。用於移除保護基(PG)(例如， MoM或Boc)之條件為熟悉此項技術者已知的。用於移除保護基-PG(例如， -Boc)之條件可採用例如酸性條件(例如， 水/二噁烷、於質子性溶劑(例如，甲醇 )中之鹽酸、於非質子性溶劑(例如， 二噁烷)中之鹽酸、於非質子性溶劑(例如，二氯甲烷、 氯仿等)中之TFA)。在一些實施例中，去保護步驟採用於二噁烷中之HCl(4.0M)。在一些實施例中，去保護步驟採用於DCM中之HCl(4.0M)。In some embodiments, the secondary amine undergoes a sequence of deprotection, cyclization, and reduction to prepare substituted piperidines. Conditions for removing protecting groups (PG) ( eg, MoM or Boc) are known to those skilled in the art. Conditions for removing the protecting group -PG ( e.g., -Boc) can employ, for example, acidic conditions ( e.g., water/dioxane, hydrochloric acid in a protic solvent ( e.g., methanol ), in an aprotic solvent ( e.g. , , hydrochloric acid in dioxane), TFA) in an aprotic solvent ( eg, dichloromethane, chloroform, etc.). In some embodiments, the deprotection step employs HCl (4.0 M) in dioxane. In some embodiments, the deprotection step employs HCl (4.0 M) in DCM.

在一些實施例中，在將式I-5化合物去保護時可經歷自發環化以形成環狀亞胺。環狀亞胺之還原可使用還原劑諸如氫化物還原劑(例如， NaBH4 或LiAlH4 )、矽還原劑(例如， Cl3 SiH)或在存在催化劑(例如 Ir催化劑、Ru催化劑、Pd催化劑(例如， Pd/C、Pd(OAc)2 ))之情況下的H2 還原來完成。在一些實施例中，可使用包含於MeOH中之NaBH4 之條件完成還原。在一些實施例中，可使用包含於MeOH及H2 O中之NaBH4 之條件完成還原。在一些實施例中，去保護、環化及還原發生於單一合成步驟中。在一些實施例中，可使用包含NaBH4 、TFA、MeOH及H2 O之條件完成去保護/環化/還原。In some embodiments, compounds of formula 1-5 may undergo spontaneous cyclization upon deprotection to form cyclic imines. Cyclic imines can be reduced using reducing agents such as hydride reducing agents ( eg, NaBH 4 or LiAlH 4 ), silicon reducing agents ( eg, Cl 3 SiH), or in the presence of catalysts ( eg , Ir catalysts, Ru catalysts, Pd catalysts ( For example, H 2 reduction in the case of Pd/C, Pd(OAc) 2 )) is accomplished. In some embodiments, the reduction can be accomplished using conditions comprising NaBH in MeOH. In some embodiments, reduction can be accomplished using conditions comprising NaBH 4 in MeOH and H 2 O. In some embodiments, deprotection, cyclization, and reduction occur in a single synthetic step. In some embodiments, deprotection/cyclization/reduction can be accomplished using conditions comprising NaBH4 , TFA, MeOH, and H2O .

4A. (2R,5S)-2-(4-氟苯基 )-5-甲基哌啶之合成 4A. Synthesis of (2R,5S)-2-(4- fluorophenyl )-5-methylpiperidine

Figure 110128222-A0202-12-0690-567
Figure 110128222-A0202-12-0690-567

步驟1：N-[(2S)-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of N-[(2S)-5-(4-fluorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

在氬氣氣氛下，向裝備有磁性攪拌棒之乾燥的2頸圓底燒瓶中裝入鎂(1.44g，59.08mmol)。添加無水THF(125mL)及1-溴-4-氟苯(10.34g，59.08mmol，6.50mL)。將碘(107.11mg，421.99μmol)添加到經攪拌之溶液中，且輕微加熱所得反應混合物，直到其保持自身回流。當回流平息時，施加外部加熱以再保持回流1小時。向裝備有溫度計及磁性攪拌棒之單獨乾燥的3頸圓底燒瓶中裝入(S )-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(9g，42.20mmol)。在氬氣氣氛下添加無水THF(125mL)且將溶液冷卻至-78℃。在1小時期間將新鮮製備之格任亞試劑逐滴添加到所得混合物中，使內部溫度保持低於-70℃。使所得反應混合物升溫至室溫，用飽和NH4 Cl溶液淬滅且用DCM(3 x 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得呈淡黃色油狀物之產物N -[(2S )-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(13.2g，粗品)，其不經任何進一步純化即用於下一步反應。Under an argon atmosphere, a dry 2-neck round bottom flask equipped with a magnetic stir bar was charged with magnesium (1.44 g, 59.08 mmol). Anhydrous THF (125 mL) and 1-bromo-4-fluorobenzene (10.34 g, 59.08 mmol, 6.50 mL) were added. Iodine (107.11 mg, 421.99 μmol) was added to the stirred solution, and the resulting reaction mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. To a separate dry 3-neck round bottom flask equipped with a thermometer and magnetic stir bar was charged ( S )-tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (9 g, 42.20 mmol) . Anhydrous THF (125 mL) was added under an argon atmosphere and the solution was cooled to -78 °C. Freshly prepared Grignard reagent was added dropwise to the resulting mixture during 1 hour keeping the internal temperature below -70°C. The resulting reaction mixture was warmed to room temperature, quenched with saturated NH4Cl solution and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the product N -[( 2S )-5-(4-fluorophenyl)-2 as a pale yellow oil - tert -butyl methyl-5-pentyloxypentyl]carbamate (13.2 g, crude), which was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值309.2；實測值210.2；Rt=1.386min。LCMS (ESI): [M+Boc] + m/z: calculated 309.2; found 210.2; Rt=1.386 min.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.93(m,3H),1.42(s,9H),1.54-1.79(m,4H),2.90-3.10(m,3H),4.66(brs,1H),7.08(m,2H),7.97(m,2H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.93 (m, 3H), 1.42 (s, 9H), 1.54-1.79 (m, 4H), 2.90-3.10 (m, 3H), 4.66 (brs, 1H), 7.08 (m, 2H), 7.97 (m, 2H).

步驟2：(2R,5S)-2-(4-氟苯基)-5-甲基哌啶之合成Step 2: Synthesis of (2R,5S)-2-(4-fluorophenyl)-5-methylpiperidine

將N -[(2S )-5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(13.2g，42.67mmol)溶解於三氟乙酸(19.46g，170.67mmol，13.15mL)中且將所得反 應混合物攪拌1小時。1小時之後，將50% NaOH水溶液添加到反應混合物中，直到pH=13-14。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機相經MgSO4 乾燥且在減壓下濃縮。將所獲得之殘餘物溶解於甲醇(125mL)及水(25mL)中。向其中分批添加硼氫化鈉(1.61g，42.67mmol)。將所得反應混合物在氬氣氣氛、21℃下攪拌16小時。16小時之後，將反應混合物用1-2M HCl酸化，直到pH為1-3且攪拌30分鐘。然後，添加50% NaOH水溶液，直到pH=13-14。將所得混合物用DCM(4 x 100mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈淡黃色固體之(2R ,5S )-2-(4-氟苯基)-5-甲基哌啶(6.6g，34.15mmol，80.04%產率)。粗產物不經任何進一步純化即用於下一步反應。Dissolve tert-butyl N -[( 2S )-5-(4-fluorophenyl)-2-methyl-5-oxypentyl] carbamate (13.2 g, 42.67 mmol) in trifluoroacetic acid (19.46 g, 170.67 mmol, 13.15 mL) and the resulting reaction mixture was stirred for 1 hour. After 1 hour, 50% aqueous NaOH was added to the reaction mixture until pH=13-14. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The obtained residue was dissolved in methanol (125 mL) and water (25 mL). To this was added sodium borohydride (1.61 g, 42.67 mmol) portionwise. The resulting reaction mixture was stirred under an argon atmosphere at 21 °C for 16 hours. After 16 hours, the reaction mixture was acidified with 1-2M HCl until pH 1-3 and stirred for 30 minutes. Then, 50% aqueous NaOH was added until pH=13-14. The resulting mixture was extracted with DCM (4 x 100 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to obtain ( 2R , 5S )-2-(4-fluorophenyl)-5-methylpiperidine as a pale yellow solid (6.6 g, 34.15 mmol, 80.04% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值193.2；實測值194.2；Rt=0.704min。LCMS (ESI): [M+H] + m/z: calculated 193.2; found 194.2; Rt=0.704 min.

1 H NMR(CDCl3 ,500MHz)：δ(ppm)0.88(m,3H),1.14(m,1H),1.51(m,1H),1.64(m,2H),1.764(m,1H),1.87(m,1H),2.41(t,0.9H),2.87(d,0.1H，順式雜質)，2.97(d,0.1H，順式雜質)3.14(d,0.9H),3.52(d,0.9H),3.60(m,0.1H，順式雜質)，6.99(m,2H),7.32(m,2H)。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 0.88 (m, 3H), 1.14 (m, 1H), 1.51 (m, 1H), 1.64 (m, 2H), 1.764 (m, 1H), 1.87 (m, 1H), 2.41 (t, 0.9H), 2.87 (d, 0.1H, cis impurity), 2.97 (d, 0.1H, cis impurity) 3.14 (d, 0.9H), 3.52 (d, 0.9 H), 3.60 (m, 0.1H, cis impurity), 6.99 (m, 2H), 7.32 (m, 2H).

4B. 2-(4-氟苯基)-5-甲基哌啶之合成4B. Synthesis of 2-(4-fluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0691-568
Figure 110128222-A0202-12-0691-568

步驟1：(5-(4-氟苯基)-2-甲基-5-側氧基戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (5-(4-fluorophenyl)-2-methyl-5-oxypentyl)carbamate

在攪拌之情況下，在Ar下，向乾燥的2頸燒瓶中添加鎂(1.04g，42.86mmol，598.65μL)、無水THF(50mL)及1-溴-4-氟苯(5g，28.57mmol，3.14mL)。添加碘(72.52mg，285.72μmol)且輕微加熱混合物，直到其自身保持回流。當回流平息時，施加外部加熱以使回流再保持1小時。將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(6.09g，28.57mmol)添加到具有溫度計之乾燥的3頸圓底燒瓶中。在攪 拌之情況下，在Ar下，添加無水THF(50mL)且將溶液冷卻至-78℃。在1小時內將格任亞試劑添加到t -boc-內醯胺中，使內部溫度保持低於-70℃。使溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3x50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N -[5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(6.7g，粗品)且其不經進一步純化即用於下一步驟。With stirring, to a dry 2-neck flask under Ar was added magnesium (1.04 g, 42.86 mmol, 598.65 μL), anhydrous THF (50 mL) and 1-bromo-4-fluorobenzene (5 g, 28.57 mmol, 3.14mL). Iodine (72.52 mg, 285.72 μmol) was added and the mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. To a dry 3-neck round bottom flask with a thermometer was added tert-butyl 5-methyl-2-pentoxypiperidine-1-carboxylate (6.09 g, 28.57 mmol). With stirring, dry THF (50 mL) was added under Ar and the solution was cooled to -78 °C. The Grignard reagent was added to the t -boc-lactamide over 1 hour, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3x50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-Butyl N- [5-(4-fluorophenyl)-2-methyl-5-oxypentyl] carbamate (6.7 g, crude) was obtained as a pale yellow oil which was not treated with Further purification was used in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.95(d,3H),1.44(s,9H),1.82(m,3H),3.05(m,4H),4.71(bds,1H),7.13(d,2H),7.99(d,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.95(d, 3H), 1.44(s, 9H), 1.82(m, 3H), 3.05(m, 4H), 4.71(bds, 1H), 7.13( d, 2H), 7.99 (d, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值209.2；實測值210.2；Rt=1.508min。LCMS (ESI): [M-Boc] + m/z: calculated 209.2; found 210.2; Rt=1.508 min.

步驟2：2-(4-氟苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(4-Fluorophenyl)-5-methylpiperidine

將N -[5-(4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(6.7g，21.66mmol)於三氟乙酸(12.35g，108.28mmol，8.34mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4 x 20mL且將有機層合併，以MgSO4 乾燥且蒸發。將產物溶解於甲醇(50mL)/水(10mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(819.32mg，21.66mmol，765.72μL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發，以得到呈無色油狀物之2-(4-氟苯基)-5-甲基哌啶(1.4g，7.24mmol，33.45%產率)。 N- [5-(4-Fluorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert- butyl ester (6.7 g, 21.66 mmol) in trifluoroacetic acid (12.35 g, 108.28 mmol) , 8.34 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a methanol (50 mL)/water (10 mL) mixture and added to the flask followed by sodium borohydride (819.32 mg, 21.66 mmol, 765.72 μL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM (4 x 100 mL), the organic layers were combined, dried over Na 2 SO 4 , filtered and evaporated to give 2-( as a colorless oil 4-Fluorophenyl)-5-methylpiperidine (1.4 g, 7.24 mmol, 33.45% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.86(d,3H),1.13(m,1H),1.50(m,1H),1.62(m,1H),1.82(m,3H),2.38(t,1H),3.09(d,1H),3.51(d,1H),6.96(d,2H),7.30(d,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.86(d,3H), 1.13(m,1H), 1.50(m,1H), 1.62(m,1H), 1.82(m,3H), 2.38( t, 1H), 3.09 (d, 1H), 3.51 (d, 1H), 6.96 (d, 2H), 7.30 (d, 2H).

LCMS(ESI)：[M]+ m/z：計算值193.3；實測值194.2；Rt=1.985min。LCMS (ESI): [M] + m/z: calculated 193.3; found 194.2; Rt=1.985 min.

4C. 5-甲基-2-(間甲苯基)哌啶之合成4C. Synthesis of 5-methyl-2-(m-tolyl) piperidine

Figure 110128222-A0202-12-0693-569
Figure 110128222-A0202-12-0693-569

步驟1：5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate

向5-甲基哌啶-2-酮(1g，8.84mmol)及4-二甲胺基吡啶(10.80mg，88.37μmol)於CH3 CN(20mL)中之經攪拌之溶液中添加二碳酸二-第三丁酯(1.93g，8.84mmol，2.03mL)。將所得反應混合物在室溫下攪拌12小時。完成之後，將反應混合物在減壓下濃縮，以獲得5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(1.5g，7.03mmol，79.59%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 5-methylpiperidin-2-one (1 g, 8.84 mmol) and 4-dimethylaminopyridine (10.80 mg, 88.37 μmol) in CH3CN (20 mL) was added dicarbonate - tert-butyl ester (1.93 g, 8.84 mmol, 2.03 mL). The resulting reaction mixture was stirred at room temperature for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain 3-butyl 5-methyl-2-pendoxopiperidine-1-carboxylate (1.5 g, 7.03 mmol, 79.59% yield). The crude product was used in the next reaction without any further purification.

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.93(d,3H),1.43(m,10H),1.83(m,2H),2.38(m,2H),3.08(m,1H),3.66(m,1H) 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.93 (d, 3H), 1.43 (m, 10H), 1.83 (m, 2H), 2.38 (m, 2H), 3.08 (m, 1H) ,3.66(m,1H)

步驟2：N-[2-甲基-5-(間甲苯基)-5-側氧基戊基]胺甲酸第三丁酯之合成Step 2: Synthesis of 3-butyl N-[2-methyl-5-(m-tolyl)-5-oxypentyl]carbamate

在氬氣氣氛下，向裝備有磁性攪拌棒之乾燥的2頸圓底燒瓶(100mL)中裝入鎂(170.94mg，7.03mmol)。添加無水THF(20mL)及1-溴-3-甲基-苯(1.20g，7.03mmol)。將碘(7.85mg，70.33μmol)添加到經攪拌之溶液中，且輕微加熱所得反應混合物，直到其保持自身回流。當回流平息時，施加外部加熱以再保持回流1小時。向裝備有溫度計及磁性攪拌棒之單獨乾燥的3頸圓底燒瓶(100mL)中裝入5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2.14g，7.03mmol)。在氬氣氣氛下添加無水THF(20mL)且將溶液冷卻至-78℃。在30分鐘期間將新鮮製備之格任亞試劑逐滴添加到所得混合物中，使內部溫度保持低於-70℃。使所得反應混合物 升溫至室溫且在同一溫度下攪拌1小時。1小時之後，將反應混合物用飽和NH4 Cl溶液淬滅且用EtOAc(2 * 40mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得產物N -[2-甲基-5-(間甲苯基 )-5-側氧基戊基]胺甲酸第三丁 酯(1.5g，粗品)，其不經任何進一步純化即用於下一步反應。Under an argon atmosphere, a dry 2-neck round bottom flask (100 mL) equipped with a magnetic stir bar was charged with magnesium (170.94 mg, 7.03 mmol). Anhydrous THF (20 mL) and 1-bromo-3-methyl-benzene (1.20 g, 7.03 mmol) were added. Iodine (7.85 mg, 70.33 μmol) was added to the stirred solution, and the resulting reaction mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. A separate dry 3-neck round bottom flask (100 mL) equipped with a thermometer and magnetic stir bar was charged with tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (2.14 g, 7.03 mmol) . Anhydrous THF (20 mL) was added under an argon atmosphere and the solution was cooled to -78 °C. Freshly prepared Grignard reagent was added dropwise to the resulting mixture during 30 minutes, keeping the internal temperature below -70°C. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 1 hour. After 1 hour, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2*40 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain the product N- [2-methyl-5-( m-tolyl )-5-oxypentyl]carbamic acid The third butyl ester (1.5 g, crude) was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值305.2；實測值206.2；Rt=1.517min。LCMS (ESI): [M+Boc] + m/z: calculated 305.2; found 206.2; Rt=1.517 min.

步驟3：5-甲基-2-(間甲苯基)哌啶之合成Step 3: Synthesis of 5-methyl-2-(m-tolyl)piperidine

將N -[2-甲基-5-(間甲苯基 )-5-側氧基戊基]胺甲酸第三丁 酯(3.19g，4.91mmol)溶解於三氟乙酸(5.60g，49.11mmol，3.78mL)中且將所得反應混合物攪拌1小時。1小時之後，將50% NaOH水溶液添加到反應混合物中，直到pH=11-12。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。將所獲得之殘餘物溶解於甲醇(20mL)中且在0℃下分批添加硼氫化鈉(185.81mg，4.91mmol)。將所得反應混合物在20℃下攪拌1小時。1小時之後，將反應混合物在減壓下濃縮且將所獲得之殘餘物用50% NaOH水溶液稀釋。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以獲得5-甲基-2-(間甲苯基 )哌啶(0.2g，1.06mmol，21.51%產率)。粗產物不經任何進一步純化即用於下一步反應。 N- [2-Methyl-5-( m-tolyl )-5-oxypentyl]carbamic acid tert- butyl ester (3.19 g, 4.91 mmol) was dissolved in trifluoroacetic acid (5.60 g, 49.11 mmol, 3.78 mL) and the resulting reaction mixture was stirred for 1 hour. After 1 hour, 50% aqueous NaOH was added to the reaction mixture until pH=11-12. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in methanol (20 mL) and sodium borohydride (185.81 mg, 4.91 mmol) was added portionwise at 0 °C. The resulting reaction mixture was stirred at 20°C for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure and the obtained residue was diluted with 50% aqueous NaOH. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 5-methyl-2-( m-tolyl )piperidine (0.2 g, 1.06 mmol, 21.51% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值189.2；實測值190.2；Rt=0.838min。LCMS (ESI): [M+H] + m/z: calculated 189.2; found 190.2; Rt=0.838 min.

4D. 2-(3-氯苯基)-5-甲基哌啶之合成4D. Synthesis of 2-(3-chlorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0694-570
Figure 110128222-A0202-12-0694-570

步驟1：5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate

在21℃下，向5-甲基哌啶-2-酮(5g，44.19mmol)、三乙胺(4.47g，44.19mmol，6.16mL)及DMAP(539.83mg，4.42mmol)於DCM中之溶液中分批添加碳酸第三丁氧基羰基第三丁酯(9.64g，44.19mmol，10.14mL)。將所得溶液用10% HCl水溶液及鹽水洗滌，經Na2 SO4 乾燥且蒸發至乾，以得到呈橙色油狀物之5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(7.7g，36.10mmol，81.71%產率)。To a solution of 5-methylpiperidin-2-one (5 g, 44.19 mmol), triethylamine (4.47 g, 44.19 mmol, 6.16 mL) and DMAP (539.83 mg, 4.42 mmol) in DCM at 21 °C 3-Butoxycarbonyl 3-butyl carbonate (9.64 g, 44.19 mmol, 10.14 mL) was added portionwise. The resulting solution was washed with 10% aq. HCl and brine, dried over Na 2 SO 4 and evaporated to dryness to give tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate as an orange oil Ester (7.7 g, 36.10 mmol, 81.71% yield).

1 H NMR(500MHz,DMSO-d6 )δ(ppm)0.94(d,3H),1.42(s,10H),1.76(m,1H),1.92(m,1H),2.38(m,2H),3.07(t,1H),3.65(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ(ppm) 0.94(d, 3H), 1.42(s, 10H), 1.76(m, 1H), 1.92(m, 1H), 2.38(m, 2H), 3.07 (t, 1H), 3.65 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值213.1；實測值214.2；Rt=1.227min。LCMS (ESI): [M+H] + m/z: calculated 213.1; found 214.2; Rt=1.227 min.

步驟2：N-[5-(3-氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 2: Synthesis of N-[5-(3-chlorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

在攪拌之情況下，在Ar下，向乾燥的2頸燒瓶中添加鎂(253.90mg，10.45mmol，145.92μL)、無水THF(25mL)及5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2.23g，10.45mmol)，添加碘(13.36mg，104.46μmol)。輕微加熱混合物，直到其自身保持回流。當回流平息時，施加外部加熱以使回流再保持1小時。將1-溴-3-氯苯(2g，10.45mmol，1.23mL)添加到具有溫度計之乾燥的3頸圓底燒瓶中。在攪拌之情況下，在Ar下，添加無水THF(25mL)且將溶液冷卻至-78℃。在1小時內將格任亞試劑添加到t-Boc-內醯胺中，使內部溫度保持低於-70℃。使溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3* 50mL，且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N-[5-(3-氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(3.3g，粗品)且其不經進一步純化即用於下一步驟。With stirring, to a dry 2-neck flask under Ar was added magnesium (253.90 mg, 10.45 mmol, 145.92 μL), anhydrous THF (25 mL) and 5-methyl-2-oxopiperidine-1 - tert-butyl formate (2.23 g, 10.45 mmol), iodine (13.36 mg, 104.46 μmol) was added. The mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. 1-Bromo-3-chlorobenzene (2 g, 10.45 mmol, 1.23 mL) was added to a dry 3 neck round bottom flask with thermometer. With stirring, dry THF (25 mL) was added under Ar and the solution was cooled to -78 °C. The Grignard reagent was added to the t-Boc-lactamide over 1 hour, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3 * 50 mL, and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-butyl N-[5-(3-chlorophenyl)-2-methyl-5-oxypentyl]carbamate (3.3 g, crude) was obtained as a pale yellow oil and was not treated with Further purification was used in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.01(d,3H),1.49(m,10H),2.43(m,2H),3.07(m,2H),3.77(m,3H),7.27(m,4H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.01(d, 3H), 1.49(m, 10H), 2.43(m, 2H), 3.07(m, 2H), 3.77(m, 3H), 7.27( m, 4H).

LCMS(ESI)：[M+H]+ m/z：計算值325.2；實測值326.2；Rt=1.24min。LCMS (ESI): [M+H] + m/z: calculated 325.2; found 326.2; Rt=1.24 min.

步驟3：6-(3-氯苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-(3-chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將N-[5-(3-氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(3.3g，10.13mmol)於三氟乙酸(1.15g，10.13mmol，780.29μL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4* 20mL且將有機層合併，以MgSO4 乾燥且蒸發。獲得呈淡黃色油狀物之6-(3-氯苯基)-3-甲基-2,3,4,5-四氫吡啶(1.5g，粗品)，其不經進一步純化即用於下一步驟。N-[5-(3-Chlorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester (3.3 g, 10.13 mmol) in trifluoroacetic acid (1.15 g, 10.13 mmol) , 780.29 μL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 * 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. 6-(3-Chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (1.5 g, crude) was obtained as a pale yellow oil, which was used in the next step without further purification one step.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.21(d,3H),1.79(m,3H),2.84(m,2H),3.23(m,2H),7.25(s,1H),7.27(m,3H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.21(d,3H), 1.79(m,3H), 2.84(m,2H), 3.23(m,2H), 7.25(s,1H), 7.27( m, 3H).

LCMS(ESI)：[M+H]+ m/z：計算值207.2；實測值208.2；Rt=0.858min。LCMS (ESI): [M+H] + m/z: calculated 207.2; found 208.2; Rt=0.858 min.

步驟4：2-(3-氯苯基)-5-甲基哌啶之合成Step 4: Synthesis of 2-(3-Chlorophenyl)-5-methylpiperidine

將6-(3-氯苯基)-3-甲基-2,3,4,5-四氫吡啶(1.5g，7.22mmol)溶解於MeOH(25mL)/水(5mL)之混合物中且添加到燒瓶中，隨後添加硼氫化鈉(273.23mg，7.22mmol，255.35μL)。將混合物在Ar下攪拌隔夜。將反應混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH水溶液，直到pH為13-14且將產物用DCM(4* 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發，以得到呈淡黃色油狀物之2-(3-氯苯基)-5-甲基哌啶(0.9g，粗品)。6-(3-Chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (1.5 g, 7.22 mmol) was dissolved in a mixture of MeOH (25 mL)/water (5 mL) and added To the flask, sodium borohydride (273.23 mg, 7.22 mmol, 255.35 μL) was then added. The mixture was stirred under Ar overnight. The reaction mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. Aqueous NaOH was then added until pH was 13-14 and the product was extracted with DCM ( 4 * 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated to give 2- as a pale yellow oil (3-Chlorophenyl)-5-methylpiperidine (0.9 g, crude).

1 H NMR(400MHz,CDCl3 )δ 1.02(d,3H),1.89(m,4H),2.91(t,2H),3.27(m,2H),3.68(m,1H),7.25(m,3H),7.27(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.02(d,3H), 1.89(m,4H), 2.91(t,2H), 3.27(m,2H), 3.68(m,1H), 7.25(m,3H) ), 7.27(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值209.2；實測值210.2；Rt=0.869min。LCMS (ESI): [M+H] + m/z: calculated 209.2; found 210.2; Rt=0.869 min.

4E. 2-甲基-4-(5-甲基-2-哌啶基)吡啶之合成4E. Synthesis of 2-methyl-4-(5-methyl-2-piperidinyl)pyridine

Figure 110128222-A0202-12-0696-572
Figure 110128222-A0202-12-0696-572

步驟1：N-[2-甲基-5-(2-甲基-4-吡啶基)-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of N-[2-methyl-5-(2-methyl-4-pyridyl)-5-oxypentyl]carbamic acid tert-butyl ester

在-78℃、氬氣氣氛下，向4-溴-2-甲基吡啶(2g，11.63mmol，1.38mL)於THF(20mL)中之經攪拌之溶液中添加正丁基鋰 (2.5M於己烷中，819.21mg，12.79mmol，5.11mL)。將所得溶液在同一溫度下攪拌30分鐘。30分鐘之後，在-78℃下將所得溶液添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2.48g，11.63mmol)於THF(20mL)中之經攪拌之溶液中。使所得反應混合物升溫至室溫且在同一溫度下攪拌12小時。12小時之後，將反應混合物用飽和NH4 Cl水溶液淬滅且用EtOAc(2 x 100mL)萃取。將經合併之有機相用鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得N -[2-甲基-5-(2-甲基-4-吡啶基)-5-側氧基戊基]胺甲酸第三丁 酯(5g，粗品)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 4-bromo-2-methylpyridine (2 g, 11.63 mmol, 1.38 mL) in THF (20 mL) at -78 °C under argon atmosphere was added n-butyllithium (2.5 M in in hexane, 819.21 mg, 12.79 mmol, 5.11 mL). The resulting solution was stirred at the same temperature for 30 minutes. After 30 minutes, the resulting solution was added to tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (2.48 g, 11.63 mmol) in THF (20 mL) with stirring at -78 °C in the solution. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain N- [2-methyl-5-(2-methyl-4-pyridinyl)-5-side 3-butyl oxypentyl]carbamate (5 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值306.2；實測值251.2(t -Bu裂解之產物質量)；Rt=1.215min。LCMS (ESI): [M+Boc] + m/z: calculated 306.2; found 251.2 ( t -Bu cleavage product mass); Rt=1.215 min.

步驟2：2-甲基-4-(5-甲基-2-哌啶基)吡啶之合成Step 2: Synthesis of 2-methyl-4-(5-methyl-2-piperidinyl)pyridine

將N -[2-甲基-5-(2-甲基-4-吡啶基)-5-側氧基戊基]胺甲酸第三丁 酯(5g，16.32mmol)溶解於三氟乙酸(18.61g，163.19mmol，12.57mL)中且在室溫下將所得反應混合物攪拌1小時。1小時之後，將50% NaOH水溶液添加到反應混合物中，直到pH=11-12。將所得混合物用DCM(4 x 40mL)萃取。將經合併之有機相經Na2 SO4 乾燥且蒸發至乾。將所獲得之殘餘物溶解於MeOH(100mL)中且分批添加硼氫化鈉(617.37mg，16.32mmol)。將所得混合物在20℃下攪拌12小時。12小時之後，將反應混合物濃縮且將所獲得之殘餘物用50% NaOH水溶液稀釋。將所得混合物用DCM(4 x 40mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由HPLC純化所獲得之殘餘物，以獲得2-甲基-4-(5-甲基-2-哌啶基)吡啶(0.187g，982.74μmol，6.02%產率)。 N- [2-Methyl-5-(2-methyl-4-pyridyl)-5-oxypentyl]carbamic acid tert- butyl ester (5 g, 16.32 mmol) was dissolved in trifluoroacetic acid (18.6 l g, 163.19 mmol, 12.57 mL) and the resulting reaction mixture was stirred at room temperature for 1 hour. After 1 hour, 50% aqueous NaOH was added to the reaction mixture until pH=11-12. The resulting mixture was extracted with DCM (4 x 40 mL). The combined organic phases were dried over Na2SO4 and evaporated to dryness. The obtained residue was dissolved in MeOH (100 mL) and sodium borohydride (617.37 mg, 16.32 mmol) was added portionwise. The resulting mixture was stirred at 20°C for 12 hours. After 12 hours, the reaction mixture was concentrated and the obtained residue was diluted with 50% aqueous NaOH. The resulting mixture was extracted with DCM (4 x 40 mL). The combined organic phases were dried over Na2SO4 , filtered and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 2-methyl-4-(5-methyl-2-piperidinyl)pyridine (0.187 g, 982.74 μmol, 6.02% yield).

LCMS(ESI)：[M+H]+ m/z：計算值190.2；實測值191.2；Rt=0.756min。LCMS (ESI): [M+H] + m/z: calculated 190.2; found 191.2; Rt=0.756 min.

4F. 5-甲基-2-(對甲苯基 )哌啶之合成4F. Synthesis of 5-methyl-2-( p-tolyl ) piperidine

Figure 110128222-A0202-12-0698-573
Figure 110128222-A0202-12-0698-573

步驟1：N-[2-甲基-5-側氧基-5-(對甲苯基)戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-[2-methyl-5-oxy-5-(p-tolyl)pentyl]carbamate

在氬氣氣氛下，向裝備有磁性攪拌棒之乾燥的2頸圓底燒瓶(100mL)中裝入鎂(284.21mg，11.69mmol)。添加無水THF(25mL)及1-溴-4-甲基-苯(2g，11.69mmol，1.42mL)。將碘(29.68mg，116.94μmol)添加到經攪拌之溶液中，且輕微加熱所得反應混合物，直到其保持自身回流。當回流平息時，施加外部加熱以再保持回流1小時。向裝備有溫度計及磁性攪拌棒之單獨乾燥的3頸圓底燒瓶(100mL)中裝入5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2.49g，11.69mmol)。在氬氣氣氛下添加無水THF(25mL)且將溶液冷卻至-78℃。在1小時期間將新鮮製備之格任亞試劑逐滴添加到所得混合物中，使內部溫度保持低於-70℃。使所得反應混合物升溫至室溫且將反應混合物用飽和NH4 Cl溶液淬滅且用DCM(3 x 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得呈淺黃色油狀物之產物N -[2-甲基-5-側氧基-5-(對甲苯基 )戊基]胺甲酸第三丁 酯(3.2g，粗品)，其不經任何進一步純化即用於下一步反應Under an argon atmosphere, a dry 2-neck round bottom flask (100 mL) equipped with a magnetic stir bar was charged with magnesium (284.21 mg, 11.69 mmol). Anhydrous THF (25 mL) and 1-bromo-4-methyl-benzene (2 g, 11.69 mmol, 1.42 mL) were added. Iodine (29.68 mg, 116.94 μmol) was added to the stirred solution, and the resulting reaction mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. A separate dry 3-neck round bottom flask (100 mL) equipped with a thermometer and magnetic stir bar was charged with tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (2.49 g, 11.69 mmol) . Anhydrous THF (25 mL) was added under an argon atmosphere and the solution was cooled to -78 °C. Freshly prepared Grignard reagent was added dropwise to the resulting mixture during 1 hour keeping the internal temperature below -70°C. The resulting reaction mixture was warmed to room temperature and the reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain the product N- [2-methyl-5-oxy-5-( p-toluene) as a pale yellow oil tert - butyl )pentyl]carbamate (3.2 g, crude), which was used in the next reaction without any further purification

LCMS(ESI)：[M+Boc]+ m/z：計算值305.2；實測值206.2；Rt=1.345min。LCMS (ESI): [M+Boc] + m/z: calculated 305.2; found 206.2; Rt=1.345 min.

步驟2：3-甲基-6-(對甲苯基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 3-methyl-6-(p-tolyl)-2,3,4,5-tetrahydropyridine

將N -[2-甲基-5-側氧基-5-(對甲苯基 )戊基]胺甲酸第三丁 酯(3.2g，10.48mmol)溶解於三氟乙酸(7.40g，64.90mmol，5mL)中。將所得反應混合物攪拌1小時。在完成之後，將50% NaOH水溶液添加到反應混合物中，直到pH=13-14。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機相經MgSO4 乾燥且在減壓下濃縮，以獲得呈淡黃色油狀物之3-甲基-6-(對甲苯基 )-2,3,4,5-四氫吡啶(1.5 g，粗品)。粗產物不經任何進一步純化即用於下一步反應。Dissolve tert-butyl N- [2-methyl-5-oxy-5-( p-tolyl )pentyl] carbamate (3.2 g, 10.48 mmol) in trifluoroacetic acid (7.40 g, 64.90 mmol, 5mL). The resulting reaction mixture was stirred for 1 hour. After completion, 50% aqueous NaOH was added to the reaction mixture until pH=13-14. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic phases were dried over MgSO 4 and concentrated under reduced pressure to obtain 3-methyl-6-( p-tolyl )-2,3,4,5-tetrahydropyridine as a pale yellow oil (1.5 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值187.2；實測值188.2；Rt=0.867min。LCMS (ESI): [M+H] + m/z: calculated 187.2; found 188.2; Rt=0.867 min.

步驟3：5-甲基-2-(對甲苯基)哌啶之合成Step 3: Synthesis of 5-methyl-2-(p-tolyl)piperidine

將3-甲基-6-(對甲苯基 )-2,3,4,5-四氫吡啶(1.5g，8.01mmol)溶解於MeOH(25mL)及水(5mL)中。在0℃下分批添加硼氫化鈉(303.04mg，8.01mmol)。將所得反應混合物在氬氣氣氛下攪拌隔夜。完成之後，將反應混合物用1-2M HCl酸化，直到pH=1-3且將其攪拌30分鐘。30分鐘之後，將50% NaOH水溶液添加到所得混合物中，直到pH=13-14且用DCM(4 x 100mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下蒸發，以獲得呈淡黃色油狀物之5-甲基-2-(對甲苯基 )哌啶(1g，粗品)。粗產物不經任何進一步純化即用於下一步反應。3-Methyl-6-( p-tolyl )-2,3,4,5-tetrahydropyridine (1.5 g, 8.01 mmol) was dissolved in MeOH (25 mL) and water (5 mL). Sodium borohydride (303.04 mg, 8.01 mmol) was added portionwise at 0°C. The resulting reaction mixture was stirred under an argon atmosphere overnight. After completion, the reaction mixture was acidified with 1-2M HCl until pH=1-3 and it was stirred for 30 minutes. After 30 minutes, 50% aqueous NaOH was added to the resulting mixture until pH=13-14 and extracted with DCM (4 x 100 mL). The combined organic layers were dried over Na2SO4 , filtered and evaporated under reduced pressure to give 5-methyl-2-( p-tolyl )piperidine (1 g, crude) as a pale yellow oil. The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值189.2；實測值190.2；Rt=0.919min。LCMS (ESI): [M+H] + m/z: calculated 189.2; found 190.2; Rt=0.919 min.

4G. 2-(3-氟苯基)-5-甲基哌啶之合成4G. Synthesis of 2-(3-fluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0699-574
Figure 110128222-A0202-12-0699-574

步驟1：N-[5-(3-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-[5-(3-fluorophenyl)-2-methyl-5-oxypentyl]carbamate

在攪拌之情況下，在Ar下，向乾燥的2頸燒瓶中添加鎂(854.71mg，35.17mmol，491.22μL)、無水THF(25mL)及1-溴-3-氟苯(6.15g，35.17mmol，3.92mL)，添加碘(297.52mg，1.17mmol)且輕微加熱混合物，直到其本身保持回流。當回流平息時，施加外部加熱以再保持回流1小時。將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(5g，23.44mmol)添加到具有溫度計之乾燥的3頸圓底燒瓶中。在攪拌之情況下，在Ar下，添加無水THF(25mL)且將溶液冷卻至-78℃。在1小時內將格任亞試劑添加到t-Boc-內醯胺中，使內部溫度保持低於-70℃。使溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3x 50mL且將有機層合併， 經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N-[5-(3-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(8.5g，粗品)且其不經進一步純化即用於下一步驟。To a dry 2-neck flask under Ar was added magnesium (854.71 mg, 35.17 mmol, 491.22 μL), anhydrous THF (25 mL) and 1-bromo-3-fluorobenzene (6.15 g, 35.17 mmol) with stirring under Ar , 3.92 mL), iodine (297.52 mg, 1.17 mmol) was added and the mixture was heated slightly until it kept refluxing by itself. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. To a dry 3-neck round-bottom flask with thermometer was added tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (5 g, 23.44 mmol). With stirring, dry THF (25 mL) was added under Ar and the solution was cooled to -78 °C. The Grignard reagent was added to the t-Boc-lactamide over 1 hour, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted 3 x 50 mL with DCM and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-Butyl N-[5-(3-fluorophenyl)-2-methyl-5-oxypentyl]carbamate (8.5 g, crude) was obtained as a pale yellow oil and was not treated with Further purification was used in the next step.

1 H NMR(400MHz,CDCl3 )δ 0.94(d,3H),1.41(s,9H),1.72(m,3H),3.01(m,4H),7.24(m,2H),7.42(m,1H),7.60(d,1H),7.71(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.94(d,3H), 1.41(s,9H), 1.72(m,3H), 3.01(m,4H), 7.24(m,2H), 7.42(m,1H) ), 7.60(d, 1H), 7.71(d, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值209.2；實測值210.2；Rt=1.467min。LCMS (ESI): [M-Boc] + m/z: calculated 209.2; found 210.2; Rt=1.467 min.

步驟2：2-(3-氟苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(3-Fluorophenyl)-5-methylpiperidine

將N-[5-(3-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(8.5g，27.47mmol)於三氟乙酸(15.66g，137.37mmol，10.58mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4 x 20mL且將有機層合併，以MgSO4乾燥且蒸發。將產物溶解於MeOH(40mL)/水(10mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(1.04g，27.47mmol，971.44μL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發，以得到呈淡黃色油狀物之2-(3-氟苯基)-5-甲基哌啶(2.3g，11.90mmol，43.32%產率)。tert-butyl N-[5-(3-fluorophenyl)-2-methyl-5-oxypentyl]carbamate (8.5 g, 27.47 mmol) in trifluoroacetic acid (15.66 g, 137.37 mmol) , 10.58 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a MeOH (40 mL)/water (10 mL) mixture and added to the flask followed by sodium borohydride (1.04 g, 27.47 mmol, 971.44 μL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 x 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated to give 2- as a pale yellow oil (3-Fluorophenyl)-5-methylpiperidine (2.3 g, 11.90 mmol, 43.32% yield).

1 H NMR(500MHz,CDCl3 )δ 0.90(d,3H),1.49(m,1H),1.65(m,1H),1.87(m,4H),3.16(m,1H),3.54(m,1H),6.93(m,1H),7.13(m,2H),7.27(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.90(d,3H), 1.49(m,1H), 1.65(m,1H), 1.87(m,4H), 3.16(m,1H), 3.54(m,1H) ), 6.93 (m, 1H), 7.13 (m, 2H), 7.27 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值193.2；實測值194.2；Rt=0.878min。LCMS (ESI): [M+H] + m/z: calculated 193.2; found 194.2; Rt=0.878 min.

4H. 5-甲基-2-(噻吩-2-基)哌啶之合成4H. Synthesis of 5-methyl-2-(thiophen-2-yl)piperidine

Figure 110128222-A0202-12-0700-575
Figure 110128222-A0202-12-0700-575

步驟1：(2-甲基-5-側氧基-5-(噻吩-2-基)戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (2-methyl-5-oxy-5-(thiophen-2-yl)pentyl)carbamate

在攪拌之情況下，在Ar下，向乾燥的2頸燒瓶中添加鎂(854.72mg，35.17mmol，491.22μL)、無水THF(50mL)及2-溴噻吩(5.73g，35.17mmol，3.41mL)。添加碘(29.99mg，234.44μmol)且輕微加熱混合物，直到其自身保持回流。當回流平息時，施加外部加熱以使回流再保持1小時。將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(5g，23.44mmol)添加到具有溫度計之乾燥的3頸圓底燒瓶中。在攪拌之情況下，在Ar下，添加無水THF(50mL)且將溶液冷卻至-78℃。在1小時內將格任亞試劑添加到boc-內醯胺中，使內部溫度保持低於-70℃。使溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3x50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N -[2-甲基-5-側氧基-5-(2-噻吩基)戊基]胺甲酸第三丁 酯(5.1g，粗品)且其不經進一步純化即用於下一步驟。With stirring, to a dry 2-neck flask under Ar was added magnesium (854.72 mg, 35.17 mmol, 491.22 μL), anhydrous THF (50 mL) and 2-bromothiophene (5.73 g, 35.17 mmol, 3.41 mL) . Iodine (29.99 mg, 234.44 μmol) was added and the mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. To a dry 3-neck round-bottom flask with thermometer was added tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (5 g, 23.44 mmol). With stirring, dry THF (50 mL) was added under Ar and the solution was cooled to -78 °C. The Grignard reagent was added to the boc-lactamide over 1 hour, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3x50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-Butyl N- [2-methyl-5-pendoxyloxy-5-(2-thienyl)pentyl] carbamate (5.1 g, crude) was obtained as a pale yellow oil and was not used further Purification was used in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.94(d,3H),1.43(s,9H),1.56(m,1H),1.69(m,1H),1.81(m,1H),2.94(m,2H),3.06(m,2H),4.69(m,1H),7.12(t,1H),7.62(d,1H),7.74(d,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.94(d, 3H), 1.43(s, 9H), 1.56(m, 1H), 1.69(m, 1H), 1.81(m, 1H), 2.94( m, 2H), 3.06 (m, 2H), 4.69 (m, 1H), 7.12 (t, 1H), 7.62 (d, 1H), 7.74 (d, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值197.4；實測值198.2；Rt=1.421min。LCMS (ESI): [M-Boc] + m/z: calculated 197.4; found 198.2; Rt=1.421 min.

步驟2：5-甲基-2-(噻吩-2-基)哌啶之合成Step 2: Synthesis of 5-methyl-2-(thiophen-2-yl)piperidine

將N -[2-甲基-5-側氧基-5-(2-噻吩基)戊基]胺甲酸第三丁 酯(5.1g，17.15mmol)於三氟乙酸(9.78g，85.74mmol，6.61mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4x20mL且將有機層合併，以MgSO4 乾燥且蒸發。將產物溶解於MeOH(40mL)/水(10mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(648.75mg，17.15mmol，606.31μL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4x100mL)萃取，將有機層合併，用Na2 SO4 乾燥，過濾且蒸發，以得到呈 淡黃色油狀物之5-甲基-2-(2-噻吩基)哌啶(2.24g，12.36mmol，72.05%產率)。3-butyl N- [2-methyl-5-oxy-5-(2-thienyl)pentyl] carbamate (5.1 g, 17.15 mmol) in trifluoroacetic acid (9.78 g, 85.74 mmol, 6.61 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4x20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a MeOH (40 mL)/water (10 mL) mixture and added to the flask followed by sodium borohydride (648.75 mg, 17.15 mmol, 606.31 μL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM (4x100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated to give 5 -methyl as a pale yellow oil -2-(2-Thienyl)piperidine (2.24 g, 12.36 mmol, 72.05% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.85(d,3H),1.16(m,1H),1.62(m,3H),1.84(d,1H),1.94(d,1H),2.39(t,1H),3.09(d,1H),3.85(d,1H),6.91(m,2H),7.16(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.85(d,3H), 1.16(m,1H), 1.62(m,3H), 1.84(d,1H), 1.94(d,1H), 2.39( t, 1H), 3.09 (d, 1H), 3.85 (d, 1H), 6.91 (m, 2H), 7.16 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值181.3；實測值182.2；Rt=1.579min。LCMS (ESI): [M] + m/z: calculated 181.3; found 182.2; Rt=1.579 min.

4I. 外消旋-(1S,4S,5R)-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛烷之合成4I. Synthesis of racemic-(1S,4S,5R)-4-(2-thienyl)-3-azabicyclo[3.2.1]octane

Figure 110128222-A0202-12-0702-576
Figure 110128222-A0202-12-0702-576

步驟1：4-側氧基-3-氮雜雙環[3.2.1]辛烷-3-甲酸第三丁酯之合成Step 1: Synthesis of 4-Pendant Oxy-3-azabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester

向3-氮雜雙環[3.2.1]辛-4-酮(2.00g，15.98mmol)於CH3 CN(50mL)中之經攪拌之溶液中添加二碳酸二-第三丁酯(3.84g，17.58mmol，4.03mL)及DMAP(97.60mg，798.93μmol)。將所得反應混合物在25℃下攪拌12小時。12小時之後，在減壓下濃縮反應混合物。將水(50mL)添加到殘餘物中且用DCM(2*40mL)萃取。將經合併之有機層用鹽水(50mL)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得呈黃色固體之4-側氧基-3-氮雜雙環[3.2.1]辛烷-3-甲酸第三丁酯(3.45g，15.31mmol，95.84%產率)。To a stirred solution of 3-azabicyclo[3.2.1]octan-4-one (2.00 g, 15.98 mmol) in CH3CN (50 mL) was added di-tert-butyl dicarbonate (3.84 g, 17.58 mmol, 4.03 mL) and DMAP (97.60 mg, 798.93 μmol). The resulting reaction mixture was stirred at 25°C for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the residue and extracted with DCM (2*40 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 and evaporated in vacuo to give 4-pentoxy-3-azabicyclo[3.2.1]octane- as a yellow solid 3-Butyl 3-carboxylate (3.45 g, 15.31 mmol, 95.84% yield).

1 H NMR(CDCl3 ,500MHz)：δ(ppm)1.51(s,9H),1.63(m,2H),1.91(m,3H),2.00(m,1H),2.56(s,1H),2.85(s,1H),3.39(d,1H),3.55(d,1H)。LCMS(ESI)：[M+H]+ m/z：計算值225.2；實測值170.2(t -Bu裂解之產物質量)；Rt=1.053min。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 1.51 (s, 9H), 1.63 (m, 2H), 1.91 (m, 3H), 2.00 (m, 1H), 2.56 (s, 1H), 2.85 (s, 1H), 3.39 (d, 1H), 3.55 (d, 1H). LCMS (ESI): [M+H] + m/z: calculated 225.2; found 170.2 ( t -Bu cleavage product mass); Rt=1.053 min.

步驟2：N-[[3-(噻吩-2-羰基)環戊基]甲基]胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-[[3-(thiophene-2-carbonyl)cyclopentyl]methyl]carbamate

在氬氣氣氛下，向裝備有磁性攪拌棒之乾燥的2頸圓底燒瓶(100mL)中裝入鎂(372.21mg，15.31mmol)。添加無水THF(50mL)及2-溴噻吩(2.50g，15.31 mmol，1.49mL)。將碘(19.59mg，153.14μmol)添加到經攪拌之溶液中，且輕微加熱所得反應混合物，直到其保持自身回流。當回流平息時，施加外部加熱以再保持回流1小時。向裝備有溫度計及磁性攪拌棒之單獨乾燥的3頸圓底燒瓶(250mL)中裝入4-側氧基-3-氮雜雙環[3.2.1]辛烷-3-甲酸第三丁酯(3.45g，15.31mmol)。在氬氣氣氛下添加無水THF(50mL)且將溶液冷卻至-78℃。在30分鐘期間將新鮮製備之格任亞試劑逐滴添加到所得混合物中，使內部溫度保持低於-70℃。使所得反應混合物升溫至室溫且在同一溫度下攪拌1小時。1小時之後，將反應混合物用飽和NH4 Cl溶液淬滅且用DCM(2 * 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得呈淺黃色油狀物之產物N -[[3-(噻吩-2-羰基)環戊基]甲基]胺甲酸第三丁 酯(4.2g，13.57mmol，88.64%產率)，其不經任何進一步純化即用於下一步反應。Under an argon atmosphere, a dry 2-neck round bottom flask (100 mL) equipped with a magnetic stir bar was charged with magnesium (372.21 mg, 15.31 mmol). Anhydrous THF (50 mL) and 2-bromothiophene (2.50 g, 15.31 mmol, 1.49 mL) were added. Iodine (19.59 mg, 153.14 μmol) was added to the stirred solution, and the resulting reaction mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. To a separate dry 3-neck round bottom flask (250 mL) equipped with a thermometer and magnetic stir bar was charged 3-butyl 4-oxy-3-azabicyclo[3.2.1]octane-3-carboxylate ( 3.45 g, 15.31 mmol). Anhydrous THF (50 mL) was added under an argon atmosphere and the solution was cooled to -78 °C. Freshly prepared Grignard reagent was added dropwise to the resulting mixture during 30 minutes, keeping the internal temperature below -70°C. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 1 hour. After 1 hour, the reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM (2*50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the product N -[[3-(thiophene-2-carbonyl)cyclopentyl]methyl as a pale yellow oil ] tert -butyl carbamate (4.2 g, 13.57 mmol, 88.64% yield), which was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值309.2；實測值210.2；Rt=1.454min。LCMS (ESI): [M+Boc] + m/z: calculated 309.2; found 210.2; Rt=1.454 min.

步驟3：4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-烯之合成Step 3: Synthesis of 4-(2-thienyl)-3-azabicyclo[3.2.1]oct-3-ene

將N-[[3-(噻吩-2-羰基)環戊基]甲基]胺甲酸第三丁 酯(4.20g，13.57mmol)溶解於三氟乙酸(15g，131.55mmol，10.14mL)中。將所得反應混合物在25℃下攪拌12小時。12小時之後，將反應混合物在減壓下濃縮且將所獲得之殘餘物溶解於冰冷水中。添加5N NaOH溶液水溶液，直到pH=9且用DCM(3*50mL)萃取。將有機層用鹽水(50mL)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得呈紅色油狀物之4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-烯(2.3g，12.02mmol，88.58%產率)。粗產物不經任何進一步純化即用於下一步反應。3- butyl N-[[3-(thiophene-2-carbonyl)cyclopentyl]methyl]carbamate (4.20 g, 13.57 mmol) was dissolved in trifluoroacetic acid (15 g, 131.55 mmol, 10.14 mL). The resulting reaction mixture was stirred at 25°C for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in ice-cold water. Aqueous 5N NaOH solution was added until pH=9 and extracted with DCM (3*50 mL). The organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and evaporated in vacuo to give 4-(2-thienyl)-3-azabicyclo[3.2.1]octane as a red oil -3-ene (2.3 g, 12.02 mmol, 88.58% yield). The crude product was used in the next reaction without any further purification.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.62(s,2H),1.88(m,4H),2.29(s,1H),3.18(s,1H),3.65(d,1H),3.92(d,1H),7.01(t,1H),7.32(m,2H)。LCMS(ESI)：[M+H]+ m/z：計算值191.1；實測值192.0；Rt=0.724min。 1 H NMR (CDCl 3 , 400MHz): δ(ppm) 1.62(s, 2H), 1.88(m, 4H), 2.29(s, 1H), 3.18(s, 1H), 3.65(d, 1H), 3.92 (d, 1H), 7.01 (t, 1H), 7.32 (m, 2H). LCMS (ESI): [M+H] + m/z: calculated 191.1; found 192.0; Rt=0.724 min.

步驟4：外消旋-(1S,4S,5R)-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛烷之合成Step 4: Synthesis of Racemic-(1S,4S,5R)-4-(2-thienyl)-3-azabicyclo[3.2.1]octane

在0℃下，向4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-烯(2.30g，12.02mmol)於MeOH(50mL)中之經攪拌之溶液中分批添加硼氫化鈉(909.76mg，24.05mmol)。將所得混合物在25℃下攪拌2小時。2小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用水(50mL)稀釋且用DCM(2*50mL)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得粗產物。將MTBE(30mL)添加到粗產物中且過濾懸浮液。在真空中蒸發濾液，以獲得呈紅色油狀物之外消旋 -(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛烷(1.9g，9.83mmol，81.75%產率)。To a stirred solution of 4-(2-thienyl)-3-azabicyclo[3.2.1]oct-3-ene (2.30 g, 12.02 mmol) in MeOH (50 mL) at 0° C. Sodium borohydride (909.76 mg, 24.05 mmol) was added in batches. The resulting mixture was stirred at 25°C for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (50 mL) and extracted with DCM (2*50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to obtain crude product. MTBE (30 mL) was added to the crude product and the suspension was filtered. The filtrate was evaporated in vacuo to give rac- ( 1S , 4S , 5R )-4-(2-thienyl)-3-azabicyclo[3.2.1]octane as a red oil (1.9 g, 9.83 mmol, 81.75% yield).

1 H NMR(CDCl3 ,500MHz)：δ(ppm)1.49(m,1H),1.68(m,5H),2.14(s,1H),2.31(s,1H),2.82(dd,1H),2.95(d,1H),4.13(s,1H),6.91(d,1H),6.97(m,1H),7.18(d,1H)。LCMS(ESI)：[M+H]+ m/z：計算值193.1；實測值194.2；Rt=0.780min。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 1.49 (m, 1H), 1.68 (m, 5H), 2.14 (s, 1H), 2.31 (s, 1H), 2.82 (dd, 1H), 2.95 (d, 1H), 4.13 (s, 1H), 6.91 (d, 1H), 6.97 (m, 1H), 7.18 (d, 1H). LCMS (ESI): [M+H] + m/z: calculated 193.1; found 194.2; Rt=0.780 min.

4J. 外消旋-(1R,4R,5S)-4-苯基-3-氮雜雙環[3.2.1]辛烷之合成4J. Synthesis of racemic-(1R,4R,5S)-4-phenyl-3-azabicyclo[3.2.1]octane

Figure 110128222-A0202-12-0704-577
Figure 110128222-A0202-12-0704-577

步驟1在中間物4I之合成中給出之4-側氧基-3-氮雜雙環[3.2.1]辛烷-3-甲酸第三丁酯之製備。Step 1 Preparation of 4-pendant oxy-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester given in the synthesis of intermediate 4I.

步驟2：N-[(3-苯甲醯基環戊基)甲基]胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-[(3-benzylcyclopentyl)methyl]carbamate

向裝備有溫度計及磁性攪拌棒之乾燥的3頸圓底燒瓶(250mL)中裝入4-側氧基-3-氮雜雙環[3.2.1]辛烷-3-甲酸第三丁酯(4.5g，19.97mmol)。在氬氣氣氛下添加無水THF(80mL)且將所得溶液冷卻至-78℃。逐滴添加格任亞試劑苯基溴化鎂(1M於THF中，20.12g，19.97mmol，20.12mL)，使內部溫度保持低於-70 ℃。使所得反應混合物升溫至室溫且在同一溫度下攪拌1小時。1小時之後，將反應混合物用飽和NH4 Cl溶液淬滅且用DCM(2 * 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以得到呈淺黃色油狀物之N -[(3-苯甲醯基環戊基)甲基]胺甲酸第三丁 酯(5.5g，18.13mmol，90.76%產率)。粗產物不經任何進一步純化即用於下一步。A dry 3-neck round bottom flask (250 mL) equipped with a thermometer and magnetic stir bar was charged with 3-butyl 4-oxy-3-azabicyclo[3.2.1]octane-3-carboxylate (4.5 g, 19.97 mmol). Anhydrous THF (80 mL) was added under an argon atmosphere and the resulting solution was cooled to -78 °C. The Grignard reagent phenylmagnesium bromide (1 M in THF, 20.12 g, 19.97 mmol, 20.12 mL) was added dropwise keeping the internal temperature below -70 °C. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 1 hour. After 1 hour, the reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM (2*50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give N -[(3-benzylcyclopentyl)methyl]carbamic acid third as a pale yellow oil Butyl ester (5.5 g, 18.13 mmol, 90.76% yield). The crude product was used in the next step without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值303.2；實測值204.2；Rt=1.388min。LCMS (ESI): [M+Boc] + m/z: calculated 303.2; found 204.2; Rt=1.388 min.

步驟3：4-苯基-3-氮雜雙環[3.2.1]辛-3-烯之合成Step 3: Synthesis of 4-phenyl-3-azabicyclo[3.2.1]oct-3-ene

將N -[(3-苯甲醯基環戊基)甲基]胺甲酸第三丁 酯(5.5g，18.13mmol)溶解於三氟乙酸(2.07g，18.13mmol，1.40mL)中。將所得混合物在25℃下攪拌2小時。2小時之後，將反應混合物在減壓下濃縮且將所獲得之殘餘物溶解於冰冷水中。將pH用5N NaOH水溶液調節至9且用DCM(3*50mL)萃取。將經合併之有機層用鹽水(50mL)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得呈黃色油狀物之4-苯基-3-氮雜雙環[3.2.1]辛-3-烯(2.5g，13.49mmol，74.44%產率)。此產物不經任何進一步純化即用於下一步驟反應。3-Butyl N -[(3- benzylcyclopentyl )methyl]carbamate (5.5 g, 18.13 mmol) was dissolved in trifluoroacetic acid (2.07 g, 18.13 mmol, 1.40 mL). The resulting mixture was stirred at 25°C for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in ice-cold water. The pH was adjusted to 9 with 5N aqueous NaOH and extracted with DCM (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 and evaporated in vacuo to give 4-phenyl-3-azabicyclo[3.2.1]octane- as a yellow oil 3-ene (2.5 g, 13.49 mmol, 74.44% yield). This product was used in the next step reaction without any further purification.

1 H NMR(CDCl3 ,500MHz)：δ(ppm)1.67(m,2H),1.84(d,1H),1.98(m,3H),2.33(m,1H),3.24(m,1H),3.74(d,1H),3.99(dd,1H),7.39(m,3H),7.77(m,2H)。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 1.67 (m, 2H), 1.84 (d, 1H), 1.98 (m, 3H), 2.33 (m, 1H), 3.24 (m, 1H), 3.74 (d, 1H), 3.99 (dd, 1H), 7.39 (m, 3H), 7.77 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值185.1；實測值186.2；Rt=0.709min。LCMS (ESI): [M+H] + m/z: calculated 185.1; found 186.2; Rt=0.709 min.

步驟4：外消旋-(1R,4R,5S)-4-苯基-3-氮雜雙環[3.2.1]辛烷之合成Step 4: Synthesis of Racemic-(1R,4R,5S)-4-phenyl-3-azabicyclo[3.2.1]octane

在0℃下，向4-苯基-3-氮雜雙環[3.2.1]辛-3-烯(2.5g，13.49mmol)於MeOH(40mL)中之經攪拌之溶液中分批添加硼氫化鈉(1.02g，26.99mmol)。將所得反應混合物在25℃下攪拌2小時。2小時之後，將反應混合物在減壓下濃縮。將所獲得之殘餘物用水(50mL)稀釋且用DCM(2 * 50mL)萃取。將經合併之有機相用鹽水洗滌，經Na2 SO4 乾燥，過濾且在真空中蒸發，以獲得粗產物。將MTBE(30mL)添加到粗產物中且過濾懸浮液。在真空中蒸發濾液，以獲得呈淡黃色固 體之外消旋 -(1R ,4R ,5S )-4-苯基-3-氮雜雙環[3.2.1]辛烷(2.1g，11.21mmol，83.10%產率)。藉由2D NMR確認結構。To a stirred solution of 4-phenyl-3-azabicyclo[3.2.1]oct-3-ene (2.5 g, 13.49 mmol) in MeOH (40 mL) at 0 °C was added hydroboration portionwise Sodium (1.02 g, 26.99 mmol). The resulting reaction mixture was stirred at 25°C for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (50 mL) and extracted with DCM (2*50 mL). The combined organic phases were washed with brine, dried over Na2SO4 , filtered and evaporated in vacuo to obtain crude product. MTBE (30 mL) was added to the crude product and the suspension was filtered. The filtrate was evaporated in vacuo to give rac- ( 1R , 4R , 5S )-4-phenyl-3-azabicyclo[3.2.1]octane (2.1 g, 11.21 g) as a pale yellow solid mmol, 83.10% yield). The structure was confirmed by 2D NMR.

1 H NMR(CDCl3 ,500MHz)：δ(ppm)1.32(m,2H),1.66(m,3H),1.73(m,2H),2.17(s,1H),2.21(t,1H),2.89(dd,1H),2.96(d,1H),3.91(s,1H),7.23(t,1H),7.33(t,2H),7.40(d,2H)。LCMS(ESI)：[M+H]+ m/z：計算值187.2；實測值188.2；Rt=0.832min。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 1.32 (m, 2H), 1.66 (m, 3H), 1.73 (m, 2H), 2.17 (s, 1H), 2.21 (t, 1H), 2.89 (dd, 1H), 2.96 (d, 1H), 3.91 (s, 1H), 7.23 (t, 1H), 7.33 (t, 2H), 7.40 (d, 2H). LCMS (ESI): [M+H] + m/z: calculated 187.2; found 188.2; Rt=0.832 min.

4K. (2R,6R)-2-甲基-6-苯基哌啶及2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸甲酯之合成4K. (2R,6R)-2-methyl-6-phenylpiperidine and 2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxygen Synthesis of methyl ethyl acetate

Figure 110128222-A0202-12-0706-1189
Figure 110128222-A0202-12-0706-1189

步驟1：2-甲基-6-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 2-methyl-6-oxypiperidine-1-carboxylic acid tert-butyl ester

在21℃下，向6-甲基哌啶-2-酮(7.3g，64.51mmol)及DMAP(394.07mg，3.23mmol)於DCM(150mL)中之混合物中分批添加二碳酸二-第三丁酯(14.78g，67.74mmol，15.55mL)。將所獲得之混合物攪拌1h。然後，將所得溶液用10% HCl水溶液及鹽水洗滌，經Na2 SO4 乾燥且蒸發至乾，以得到呈黃色油狀物之2-甲基-6-側氧基哌啶-1-甲酸第三丁酯(13g，粗品，94.47%產率)。1 H NMR(400MHz,CDCl3 )δ 1.25(d,3H),1.50(s,9H),1.65(m,2H),1.89(m,2H),2.46(m,2H),4.26(m,1H)。LCMS(ESI)：[M-Boc]+ m/z：計算值113.1；實測值114.2；Rt=0.765min。To a mixture of 6-methylpiperidin-2-one (7.3 g, 64.51 mmol) and DMAP (394.07 mg, 3.23 mmol) in DCM (150 mL) at 21 °C was added bis-tertiary dicarbonate portionwise Butyl ester (14.78 g, 67.74 mmol, 15.55 mL). The obtained mixture was stirred for 1 h. The resulting solution was then washed with 10% aq. HCl and brine, dried over Na 2 SO 4 and evaporated to dryness to give 2-methyl-6-oxypiperidine-1-carboxylic acid as a yellow oil Tributyl ester (13 g, crude, 94.47% yield). 1 H NMR (400MHz, CDCl 3 )δ 1.25(d,3H), 1.50(s,9H), 1.65(m,2H), 1.89(m,2H), 2.46(m,2H), 4.26(m,1H) ). LCMS (ESI): [M-Boc] + m/z: calculated 113.1; found 114.2; Rt=0.765 min.

步驟2：N-(1-甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-(1-methyl-5-oxy-5-phenylpentyl)carbamate

在1小時內，在-78℃下，將苯基溴化鎂(132.62g，109.72mmol，135.33 mL)分批添加到2-甲基-6-側氧基哌啶-1-甲酸第三丁酯(13g，60.95mmol)於THF(20mL)中之溶液中，使內部溫度保持低於-70℃。將所得溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3* 50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N-(1-甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯(16.2g，55.60mmol，91.21%產率)且其不經進一步純化即用於下一步驟。1 H NMR(500MHz,CDCl3 )δ 1.14(d,3H),1.53(s,9H),1.80(m,4H),3.01(m,2H),3.70(m,2H),7.45(m,2H),7.56(m,1H),7.96(d,2H)。LCMS(ESI)：[M-Boc]+ m/z：計算值191.2；實測值192.2；Rt=1.492min。Phenylmagnesium bromide (132.62 g, 109.72 mmol, 135.33 mL) was added portionwise to tert-butyl 2-methyl-6-pendoxopiperidine-1-carboxylic acid at -78°C over 1 hour A solution of the ester (13 g, 60.95 mmol) in THF (20 mL) keeping the internal temperature below -70 °C. The resulting solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3 * 50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-Butyl N-(1-methyl-5-oxy-5-phenylpentyl)carbamate (16.2 g, 55.60 mmol, 91.21% yield) was obtained as a pale yellow oil and it was not It was used in the next step after further purification. 1 H NMR (500MHz, CDCl 3 )δ 1.14(d,3H), 1.53(s,9H), 1.80(m,4H), 3.01(m,2H), 3.70(m,2H), 7.45(m,2H) ), 7.56(m, 1H), 7.96(d, 2H). LCMS (ESI): [M-Boc] + m/z: calculated 191.2; found 192.2; Rt=1.492 min.

步驟3：(2R,6R)-2-甲基-6-苯基哌啶之合成Step 3: Synthesis of (2R,6R)-2-methyl-6-phenylpiperidine

將N-(1-甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯(16.2g，55.60mmol)於三氟乙酸(31.70g，277.98mmol，21.42mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4* 20mL且將有機層合併，以MgSO4 乾燥且蒸發。將產物溶解於水(10mL)/MeOH(50mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(2.10g，55.60mmol，1.97mL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4* 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發。藉由CC(Companion combiflash；120g SiO2 ；氯仿/乙腈，其中乙腈為0至18%，流速=85mL/min，Rv=5-8cv.)純化殘餘物，以得到呈淡黃色油狀物之(2R,6R)-2-甲基-6-苯基哌啶(2.4g，13.69mmol，24.63%產率)。1 H NMR(500MHz,CDCl3 )δ 1.11(d,3H),1.12(m,1H),1.50(m,2H),1.64(m,2H),1.76(m,1H),1.88(m,1H),2.82(m,1H),3.66(m,1H),7.23(m,2H),7.31(m,1H),7.39(m,2H)。LCMS(ESI)：[M+H]+ m/z：計算值175.1；實測值176.2；Rt=0.660min。3-butyl N-(1-methyl-5-oxy-5-phenylpentyl)carbamate (16.2 g, 55.60 mmol) in trifluoroacetic acid (31.70 g, 277.98 mmol, 21.42 mL) Stir for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 * 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a mixture of water (10 mL)/MeOH (50 mL) and added to the flask followed by sodium borohydride (2.10 g, 55.60 mmol, 1.97 mL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 * 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated. The residue was purified by CC (Companion combiflash; 120 g SiO 2 ; chloroform/acetonitrile with 0 to 18% acetonitrile, flow rate=85 mL/min, Rv=5-8 cv.) to give ( 2R,6R)-2-methyl-6-phenylpiperidine (2.4 g, 13.69 mmol, 24.63% yield). 1 H NMR (500MHz, CDCl 3 )δ 1.11(d,3H), 1.12(m,1H), 1.50(m,2H), 1.64(m,2H), 1.76(m,1H), 1.88(m,1H) ), 2.82 (m, 1H), 3.66 (m, 1H), 7.23 (m, 2H), 7.31 (m, 1H), 7.39 (m, 2H). LCMS (ESI): [M+H] + m/z: calculated 175.1; found 176.2; Rt=0.660 min.

步驟4：2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸甲酯之合成Step 4: Synthesis of methyl 2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxoacetate

在0℃下，向(2R,6R)-2-甲基-6-苯基哌啶(0.5g，2.85mmol)及三乙胺(346.40mg，3.42mmol，477.14μL)於DCM(25mL)中之溶液中添加2-氯-2-側氧基乙酸甲酯(384.43mg，3.14mmol)。在室溫下攪拌1h之後，將所得混合物過濾且蒸發至乾，以得到呈黃色固體之2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸甲酯(0.74g，2.83mmol，99.27%產率)，其不經進一步純化即用於下一步驟。To (2R,6R)-2-methyl-6-phenylpiperidine (0.5 g, 2.85 mmol) and triethylamine (346.40 mg, 3.42 mmol, 477.14 μL) in DCM (25 mL) at 0 °C To this solution was added methyl 2-chloro-2-oxoacetate (384.43 mg, 3.14 mmol). After stirring at room temperature for 1 h, the resulting mixture was filtered and evaporated to dryness to give 2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2 as a yellow solid - Methyl pendant oxyacetate (0.74 g, 2.83 mmol, 99.27% yield), which was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 0.83(m,3H),1.62(m,2H),1.88(m,2H),2.56(m,1H),3.86(m,1H),3.92(s,3H),4.87(m,1H),5.90(m,1H),7.37(m,5H)。LCMS(ESI)：[M+H]+ m/z：計算值261.1；實測值262.2；Rt=1.374min。 1 H NMR (500MHz, CDCl 3 )δ 0.83(m, 3H), 1.62(m, 2H), 1.88(m, 2H), 2.56(m, 1H), 3.86(m, 1H), 3.92(s, 3H) ), 4.87 (m, 1H), 5.90 (m, 1H), 7.37 (m, 5H). LCMS (ESI): [M+H] + m/z: calculated 261.1; found 262.2; Rt=1.374 min.

4L.N,N-二甲基-3-(哌啶-2-基)苯胺之合成 4L. Synthesis of N,N-dimethyl-3-(piperidin-2-yl)aniline

Figure 110128222-A0202-12-0708-579
Figure 110128222-A0202-12-0708-579

步驟1：3-溴-N,N-二甲基苯胺之合成Step 1: Synthesis of 3-bromo-N,N-dimethylaniline

將碘甲烷(3.63g，25.58mmol，1.59mL)添加到3-溴苯胺(2g，11.63mmol，1.27mL)、碳酸鉀顆粒(3.54g，25.58mmol，1.54mL)及DMF(10mL)之混合物中且將所得混合物在75℃下加熱12h。將混合物倒入NaHCO3 水溶液且用乙酸乙酯萃取。將有機層用鹽水洗滌，經硫酸鈉乾燥且在真空中濃縮，以獲得3-溴-N,N -二甲基苯胺(2g，10.00mmol，85.98%產率)。Iodomethane (3.63 g, 25.58 mmol, 1.59 mL) was added to a mixture of 3-bromoaniline (2 g, 11.63 mmol, 1.27 mL), potassium carbonate particles (3.54 g, 25.58 mmol, 1.54 mL) and DMF (10 mL) And the resulting mixture was heated at 75 °C for 12 h. The mixture was poured into aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to obtain 3-bromo- N,N -dimethylaniline (2 g, 10.00 mmol, 85.98% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)2.96(s,6H),6.60(d,1H),6.79(d,1H),6.81(s,1H),7.06(t,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 2.96 (s, 6H), 6.60 (d, 1H), 6.79 (d, 1H), 6.81 (s, 1H), 7.06 (t, 1H).

LCMS(ESI)：[M]+ m/z：計算值200.1；實測值201.2；Rt=1.486min。LCMS (ESI): [M] + m/z: calculated 200.1; found 201.2; Rt=1.486 min.

步驟2：(5-(3-(二甲胺基)苯基)-5-側氧基戊基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl (5-(3-(dimethylamino)phenyl)-5-oxypentyl)carbamate

在氬氣氣氛下，將3-溴-N,N -二甲基苯胺(2g，10.00mmol)添加到THF(20mL)及Mg(242.96mg，10.00mmol，139.63μL)之混合物中。向其中添加碘(2.54mg，10.00μmol)且將所得混合物加熱至回流達1h。在-78℃下，將所得混合物冷卻至室溫且逐滴添加2-側氧基哌啶-1-甲酸第三丁酯(1.99g，10.00mmol)於THF(20mL)中之溶液中。使所得混合物升溫至室溫，然後倒入NH4 Cl水溶液中。將所得混合物用EtOAc(2x40ml)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以獲得N -[5-[3-(二甲胺基)苯基]-5-側氧基戊基]胺甲酸第三丁 酯(1.8g，粗品)，其不經純化即用於下一步驟。Under argon atmosphere, 3-bromo- N,N -dimethylaniline (2 g, 10.00 mmol) was added to a mixture of THF (20 mL) and Mg (242.96 mg, 10.00 mmol, 139.63 μL). To this was added iodine (2.54 mg, 10.00 μmol) and the resulting mixture was heated to reflux for 1 h. The resulting mixture was cooled to room temperature at -78°C and a solution of tert-butyl 2-pentoxypiperidine-1-carboxylate (1.99 g, 10.00 mmol) in THF (20 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and then poured into aqueous NH4Cl . The resulting mixture was extracted with EtOAc (2x40ml). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated to give N- [5-[3-(dimethylamino)phenyl]-5-oxypentyl]carbamic acid The tertiary butyl ester (1.8 g, crude) was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.19(m,2H),1.42(s,9H),1.97(m,2H),2.92(s,6H),2.98(m,4H),6.68(m,2H),7.21(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.19(m, 2H), 1.42(s, 9H), 1.97(m, 2H), 2.92(s, 6H), 2.98(m, 4H), 6.68 (m, 2H), 7.21 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值320.4；實測值321.2；Rt=1.470min。LCMS (ESI): [M] + m/z: calculated 320.4; found 321.2; Rt=1.470 min.

步驟3：N,N-二甲基-3-(哌啶-2-基)苯胺之合成Step 3: Synthesis of N,N-dimethyl-3-(piperidin-2-yl)aniline

將N -[5-[3-(二甲胺基)苯基]-5-側氧基戊基]胺甲酸第三丁 酯(1.8g，5.62mmol)溶解於三氟乙酸(12.81g，112.35mmol，8.66mL)中且將所得混合物攪拌1h。向其中添加50% NaOH水溶液，直到pH 11-12。將所得混合物用DCM(4x40ml)萃取，將經合併之有機層蒸發至乾。將殘餘物再溶解於MeOH(15mL)中且添加硼氫化鈉(212.53mg，5.62mmol，198.62μL)。將所得混合物在20℃下攪拌12h且蒸發。將50% NaOH水溶液添加到殘餘物中。將所得混合物用DCM(4x40ml)萃取，將經合併之有機層蒸發至乾，以獲得N,N -二甲基-3-(2-哌啶基)苯胺(0.4g，粗品)，其不經純化即用於下一步驟。 N- [5-[3-(dimethylamino)phenyl]-5-oxypentyl]carbamic acid tert- butyl ester (1.8 g, 5.62 mmol) was dissolved in trifluoroacetic acid (12.81 g, 112.35 g mmol, 8.66 mL) and the resulting mixture was stirred for 1 h. To this was added 50% aqueous NaOH until pH 11-12. The resulting mixture was extracted with DCM (4x40ml) and the combined organic layers were evaporated to dryness. The residue was redissolved in MeOH (15 mL) and sodium borohydride (212.53 mg, 5.62 mmol, 198.62 μL) was added. The resulting mixture was stirred at 20 °C for 12 h and evaporated. Aqueous 50% NaOH was added to the residue. The resulting mixture was extracted with DCM (4x40ml) and the combined organic layers were evaporated to dryness to give N,N -dimethyl-3-(2-piperidinyl)aniline (0.4g, crude) which was not treated with Purification was used in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.32(m,3H),1.53(m,1H),1.66(m,1H),1.78(m,1H),2.67(m,1H),2.86(s,6H),3.04(m,1H),3.44(m,1H),6.68(m,2H),7.21(m,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.32(m, 3H), 1.53(m, 1H), 1.66(m, 1H), 1.78(m, 1H), 2.67(m, 1H), 2.86(s, 6H), 3.04(m, 1H), 3.44(m, 1H), 6.68(m, 2H), 7.21(m, 2H).

LCMS(ESI)：[M]+ m/z：計算值204.3；實測值205.2；Rt=0.744min。LCMS (ESI): [M] + m/z: calculated 204.3; found 205.2; Rt=0.744 min.

4M. 5,5-二甲基-2-苯基哌啶之合成4M. Synthesis of 5,5-dimethyl-2-phenylpiperidine

Figure 110128222-A0202-12-0710-581
Figure 110128222-A0202-12-0710-581

步驟1：5,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 5,5-dimethyl-2-oxypiperidine-1-carboxylate

向5,5-二甲基哌啶-2-酮(1g，7.86mmol)及4-二甲胺基吡啶(9.61mg，78.63μmol)於CH3 CN(20mL)中之經攪拌之溶液中添加二碳酸二-第三丁酯(1.89g，8.65mmol，1.98mL)。將所得反應混合物在20℃下攪拌12小時。12小時之後，將反應混合物在減壓下濃縮，以獲得5,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯(1.5g，6.60mmol，83.93%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 5,5-dimethylpiperidin-2-one (1 g, 7.86 mmol) and 4-dimethylaminopyridine (9.61 mg, 78.63 μmol) in CH3CN (20 mL) was added Di-tert-butyl dicarbonate (1.89 g, 8.65 mmol, 1.98 mL). The resulting reaction mixture was stirred at 20°C for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure to obtain tert-butyl 5,5-dimethyl-2-oxypiperidine-1-carboxylate (1.5 g, 6.60 mmol, 83.93% yield) . The crude product was used in the next reaction without any further purification.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.03(s,6H),1.50(s,9H),1.57(t,2H),2.46(t,2H),3.35(s,2H)。LCMS(ESI)：[M+H]+ m/z：計算值227.2；實測值172.2(t -Bu裂解之產物質量)；Rt=1.314min。 1 H NMR (CDCl 3 , 400 MHz): δ (ppm) 1.03 (s, 6H), 1.50 (s, 9H), 1.57 (t, 2H), 2.46 (t, 2H), 3.35 (s, 2H). LCMS (ESI): [M+H] + m/z: calculated 227.2; found 172.2 ( t -Bu cleavage product mass); Rt=1.314 min.

步驟2：N-(2,2-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-(2,2-dimethyl-5-oxy-5-phenylpentyl)carbamate

在-78℃，氬氣氣氛下向5,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯(1.5g，6.60mmol)於THF(20mL)中之經攪拌之溶液中逐滴添加苯基溴化鎂(1M於THF中，1.20g，6.60mmol，6.6mL)。使所得反應混合物升溫至室溫且在同一溫度下攪拌12小時。12小時之後，將反應混合物用飽和NH4 Cl水溶液淬滅且用EtOAc(2 x 50mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在真空中蒸發，以獲得N -(2,2-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(1.3g，4.26mmol，64.50%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 5,5-dimethyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.60 mmol) in THF (20 mL) at -78 °C under argon atmosphere Phenylmagnesium bromide (1 M in THF, 1.20 g, 6.60 mmol, 6.6 mL) was added dropwise to the solution. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and evaporated in vacuo to obtain N- (2,2-dimethyl-5-oxy-5-phenylpentyl)carbamic acid tertiary Butyl ester (1.3 g, 4.26 mmol, 64.50% yield). The crude product was used in the next reaction without any further purification.

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)0.82(s,6H),1.35(s,9H),1.47(m,2H),2.81 (d,2H),2.97(t,2H),3.30(brs,1H),7.51(t,2H),7.62(m,1H),7.96(d,2H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 0.82 (s, 6H), 1.35 (s, 9H), 1.47 (m, 2H), 2.81 (d, 2H), 2.97 (t, 2H) , 3.30 (brs, 1H), 7.51 (t, 2H), 7.62 (m, 1H), 7.96 (d, 2H).

LCMS(ESI)：[M+Boc]+ m/z：計算值305.2；實測值206.2；Rt=1.541min。LCMS (ESI): [M+Boc] + m/z: calculated 305.2; found 206.2; Rt=1.541 min.

步驟3：5,5-二甲基-2-苯基哌啶之合成Step 3: Synthesis of 5,5-Dimethyl-2-phenylpiperidine

將N -(2,2-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(1.3g，4.26mmol)溶解於三氟乙酸(4.85g，42.57mmol，3.28mL)中且將所得反應混合物在室溫下攪拌1小時。1小時之後，將50%NaOH水溶液添加到反應混合物中，直到pH=11-12。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且蒸發至乾。將所獲得之殘餘物溶解於MeOH(20mL)中且分批添加硼氫化鈉(161.04mg，4.26mmol)。將所得混合物在20℃下攪拌1小時。1小時之後，將反應混合物濃縮且將所獲得之殘餘物用50% NaOH水溶液稀釋。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得5,5-二甲基-2-苯基哌啶(0.1g，528.27μmol，12.41%產率)。粗產物不經任何進一步純化即用於下一步反應。3-butyl N- (2,2-dimethyl-5-oxy-5-phenylpentyl) carbamate (1.3 g, 4.26 mmol) was dissolved in trifluoroacetic acid (4.85 g, 42.57 mmol, 3.28 mL) and the resulting reaction mixture was stirred at room temperature for 1 hour. After 1 hour, 50% aqueous NaOH was added to the reaction mixture until pH=11-12. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic phases were dried over Na2SO4 and evaporated to dryness. The obtained residue was dissolved in MeOH (20 mL) and sodium borohydride (161.04 mg, 4.26 mmol) was added portionwise. The resulting mixture was stirred at 20°C for 1 hour. After 1 hour, the reaction mixture was concentrated and the obtained residue was diluted with 50% aqueous NaOH. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain 5,5-dimethyl-2-phenylpiperidine (0.1 g, 528.27 μmol, 12.41% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值189.2；實測值190.2；Rt=0.817min。LCMS (ESI): [M+H] + m/z: calculated 189.2; found 190.2; Rt=0.817 min.

4N. 3,5-二甲基-6-苯基-2,3,4,5-四氫吡啶之合成4N. Synthesis of 3,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine

Figure 110128222-A0202-12-0711-582
Figure 110128222-A0202-12-0711-582

步驟1：3,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 3,5-dimethyl-2-oxypiperidine-1-carboxylate

將二碳酸二-第三丁酯(20.59g，94.35mmol，21.65mL)添加到3,5-二甲基哌啶-2-酮(10g，78.63mmol)及4-二甲胺基吡啶(480.29mg，3.93mmol)於THF(100mL)中之溶液中。將所得混合物在40℃下攪拌3h。然後，添加水(10ml)。當CO2 逸出停止時，將混合物用MTBE(100ml)稀釋且用2% NaHSO4 (80ml)及鹽水(100ml)連續洗滌。然後，將其經Na2 SO4 乾燥且在減壓下蒸發，得到3,5-二甲 基-2-側氧基哌啶-1-甲酸第三丁酯(17.15g，75.45mmol，95.96%產率)。Di-tert-butyl dicarbonate (20.59 g, 94.35 mmol, 21.65 mL) was added to 3,5-dimethylpiperidin-2-one (10 g, 78.63 mmol) and 4-dimethylaminopyridine (480.29 mg, 3.93 mmol) in THF (100 mL). The resulting mixture was stirred at 40 °C for 3 h. Then, water (10 ml) was added. When CO2 evolution ceased, the mixture was diluted with MTBE (100ml) and washed successively with 2% NaHSO4 (80ml) and brine (100ml). Then, it was dried over Na 2 SO 4 and evaporated under reduced pressure to give 3,5-dimethyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (17.15 g, 75.45 mmol, 95.96% Yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.01(d,3H),1.20(d,3H),1.52(s,9H),1.64(m,1H),1.98(m,1H),2.04(m,1H),2.48(m,1H),3.18(m,1H),3.85(m,1H)。GCMS：[M]： 計算值227.2；實測值227.2；Rt=7.992min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.01(d,3H), 1.20(d,3H), 1.52(s,9H), 1.64(m,1H), 1.98(m,1H), 2.04( m, 1H), 2.48 (m, 1H), 3.18 (m, 1H), 3.85 (m, 1H). GCMS: [M] : Calculated value 227.2; Measured value 227.2; Rt=7.992min.

步驟2：(2,4-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl (2,4-dimethyl-5-oxy-5-phenylpentyl)carbamate

在氬氣下，將溴(苯基)鎂(100.32g，83.00mmol，102.37mL)逐滴添加到冷卻至-75℃之3,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯(17.15g，75.45mmol)於THF(150mL)中之溶液中。添加完成之後，移除冷卻浴且將混合物緩慢升溫至20℃。然後，添加飽和NH4 Cl(60ml)及MTBE(150ml)。將有機層分離且用水(100ml)及鹽水(100ml)連續洗滌，經Na2 SO4 乾燥且在減壓下濃縮，得到N -(2,4-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(20.7g，67.78mmol，89.83%產率)。Under argon, bromo(phenyl)magnesium (100.32 g, 83.00 mmol, 102.37 mL) was added dropwise to 3,5-dimethyl-2-oxypiperidine-1- , cooled to -75°C A solution of tert-butyl formate (17.15 g, 75.45 mmol) in THF (150 mL). After the addition was complete, the cooling bath was removed and the mixture was slowly warmed to 20°C. Then, saturated NH4Cl (60ml) and MTBE (150ml) were added. The organic layer was separated and washed successively with water (100 ml) and brine (100 ml), dried over Na 2 SO 4 and concentrated under reduced pressure to give N- (2,4-dimethyl-5-pentoxy-5- 3 -butyl phenylpentyl)carbamate (20.7 g, 67.78 mmol, 89.83% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.87(d,3H),0.95(m,1H),1.22(d,3H),1.49(s,9H),1.61(m,1H),1.77(m,1H),1.96(m,1H),3.02(m,1H),3.53(m,1H),4.64(m,1H),7.48(t,2H),7.57(t,1H),7.97(d,2H)。L CMS(ESI)：[M-Boc]+ m/z：計算值205.2；實測值206.2；Rt=1.479min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.87(d, 3H), 0.95(m, 1H), 1.22(d, 3H), 1.49(s, 9H), 1.61(m, 1H), 1.77( m, 1H), 1.96(m, 1H), 3.02(m, 1H), 3.53(m, 1H), 4.64(m, 1H), 7.48(t, 2H), 7.57(t, 1H), 7.97(d , 2H). L CMS (ESI): [M-Boc] + m/z: calculated 205.2; found 206.2; Rt=1.479 min.

步驟3：3,5-二甲基-6-苯基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 3,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine

將三氟乙酸(77.28g，677.78mmol，52.22mL)添加到N -(2,4-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(20.7g，67.78mmol)於DCM(50mL)中之溶液中。將所得混合物在20℃下攪拌2h。然後，在減壓下移除溶劑且將殘餘物分配於5% NaOH水溶液(150ml)與DCM(250ml)之間。將DCM層分離，經Na2 SO4 乾燥且在真空中蒸發，得到3,5-二甲基-6-苯基-2,3,4,5-四氫吡啶(12.1g，64.61mmol，95.33%產率)。Trifluoroacetic acid (77.28 g, 677.78 mmol, 52.22 mL) was added to tert-butyl N- (2,4-dimethyl-5-oxy-5-phenylpentyl) carbamate (20.7 g, 67.78 mmol) in DCM (50 mL). The resulting mixture was stirred at 20 °C for 2 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 5% aqueous NaOH (150ml) and DCM (250ml). The DCM layer was separated, dried over Na2SO4 and evaporated in vacuo to give 3,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine (12.1 g, 64.61 mmol, 95.33 g %Yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.94(d,3H),1.11(d,3H),1.59(m,1H),1.74(m, 1H),1.94(m,1H),3.12(m,1H),3.25(m,1H),3.99(m,1H),7.37(t,2H),7.52(t,1H),7.87(d,2H)。LCMS(ESI)：[M]+ m/z：計算值187.2；實測值188.2；Rt=0.863min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.94(d, 3H), 1.11(d, 3H), 1.59(m, 1H), 1.74(m, 1H), 1.94(m, 1H), 3.12( m, 1H), 3.25 (m, 1H), 3.99 (m, 1H), 7.37 (t, 2H), 7.52 (t, 1H), 7.87 (d, 2H). LCMS (ESI): [M] + m/z: calculated 187.2; found 188.2; Rt=0.863 min.

步驟4：3,5-二甲基-2-苯基哌啶之合成Step 4: Synthesis of 3,5-Dimethyl-2-phenylpiperidine

在15分鐘期間將硼氫化鈉(4.89g，129.22mmol，4.57mL)分批添加到3,5-二甲基-6-苯基-2,3,4,5-四氫吡啶(12.1g，64.61mmol)於甲醇(150mL)中之溶液中。將所得溶液在20℃下攪拌1h。然後，在減壓下移除溶劑且將殘餘物分配於水(100ml)與MTBE(200ml)之間。將有機層分離，經Na2 SO4 乾燥且在真空中蒸發，得到3,5-二甲基-2-苯基哌啶(11.2g，59.17mmol，91.58%產率)。所獲得之材料不經純化即用於下面的步驟。藉由管柱層析(80g SiO2 ，己烷-MTBE)純化殘餘物(10.5g)，得到1.9g 85%具有經驗證之組態之單一異構物級分。Sodium borohydride (4.89 g, 129.22 mmol, 4.57 mL) was added portionwise over 15 minutes to 3,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine (12.1 g, 64.61 mmol) in methanol (150 mL). The resulting solution was stirred at 20 °C for 1 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (100ml) and MTBE (200ml). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to give 3,5-dimethyl-2-phenylpiperidine (11.2 g, 59.17 mmol, 91.58% yield). The material obtained was used in the next step without purification. The residue (10.5 g) was purified by column chromatography (80 g SiO2 , hexane-MTBE) to give 1.9 g of a single isomer fraction of 85% with the verified configuration.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.76(d,3H),0.87(d,3H),1.25(m,1H),1.45(m,1H),1.75(m,1H),1.88(m,1H),2.03(m,1H),2.39(t,1H),3.18(d,1H),3.86(m,1H),7.30(m,5H)。LCMS(ESI)：[M]+ m/z：計算值189.3；實測值190.2；Rt=0.913min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.76(d,3H), 0.87(d,3H), 1.25(m,1H), 1.45(m,1H), 1.75(m,1H), 1.88( m, 1H), 2.03 (m, 1H), 2.39 (t, 1H), 3.18 (d, 1H), 3.86 (m, 1H), 7.30 (m, 5H). LCMS (ESI): [M] + m/z: calculated 189.3; found 190.2; Rt=0.913 min.

4O. 2-(苯并噻吩-3-基)哌啶之合成4O. Synthesis of 2-(benzothiophen-3-yl)piperidine

Figure 110128222-A0202-12-0713-583
Figure 110128222-A0202-12-0713-583

步驟1：6-(苯并噻吩-3-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(benzothiophen-3-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9g，27.17mmol)、苯并噻吩-3-基硼酸(4.84g，27.17mmol)及碳酸鈉(8.64g，81.50mmol，3.41mL)於二噁烷(100mL)及水(20mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物 (1.11g，1.36mmol)。將所得混合物除氣，用Ar再填充且在60℃下攪拌12h。過濾出沉澱，用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於150ml水中且用EtOAc(2* 100ml)萃取。將經合併之有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(9g)。藉由梯度層析(SiO2 ，己烷-MTBE)純化粗產物，以獲得6-(苯并噻吩-3-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.0g，15.85mmol，58.35%產率)。Combine 6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9 g, 27.17 mmol), benzothiophen-3-ylboronic acid (4.84 g, 27.17 mmol) and a suspension of sodium carbonate (8.64 g, 81.50 mmol, 3.41 mL) in dioxane (100 mL) and water (20 mL) degassed and refilled three times with Ar. To this solution was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1.11 g, 1.36 mmol). The resulting mixture was degassed, refilled with Ar and stirred at 60 °C for 12 h. The precipitate was filtered off and washed with dioxane (50 ml). The solvent was evaporated in vacuo and the residue was dissolved in 150 ml of water and extracted with EtOAc (2 * 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (9 g). The crude product was purified by gradient chromatography ( SiO2 , hexane-MTBE) to obtain tert-butyl 6-(benzothiophen-3-yl)-3,4-dihydro-2H-pyridine-1-carboxylate (5.0 g, 15.85 mmol, 58.35% yield).

1 H NMR(500MHz,DMSO-d6 )δ 077(s,9H),1.90(m,2H),2.30(m,2H),3.76(m,2H),5.35(m,1H),7.32(m,3H),7.69(d,1H),7.85(d,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 077(s, 9H), 1.90(m, 2H), 2.30(m, 2H), 3.76(m, 2H), 5.35(m, 1H), 7.32(m , 3H), 7.69(d, 1H), 7.85(d, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值259.0；實測值260.0；Rt=1.711min。LCMS (ESI): [M-tBu] + m/z: calculated 259.0; found 260.0; Rt=1.711 min.

步驟2：6-(苯并噻吩-3-基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(benzothiophen-3-yl)-2,3,4,5-tetrahydropyridine

將6-(苯并噻吩-3-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5g，15.85mmol)溶解於三氟乙酸(18.07g，158.51mmol，12.21mL)中。將所得混合物在25℃下攪拌2h(直至氣體逸出結束)。將溶液之pH用10% NaOH溶液調節至8且用DCM(3* 70ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得6-(苯并噻吩-3-基)-2,3,4,5-四氫吡啶(3g，13.93mmol，87.90%產率)。6-(benzothiophen-3-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 g, 15.85 mmol) was dissolved in trifluoroacetic acid (18.07 g, 158.51 mmol, 12.21 mmol) mL). The resulting mixture was stirred at 25°C for 2 h (until gas evolution was complete). The pH of the solution was adjusted to 8 with 10% NaOH solution and extracted with DCM (3 * 70ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated in vacuo to obtain 6-(benzothiophen-3-yl)-2,3,4,5-tetrahydropyridine (3 g, 13.93 mmol, 87.90% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.60(m,2H),1.76(m,2H),2.66(m,2H),3.79(m,2H),7.36(m,2H),7.95(m,1H),8.15(s,1H),8.82(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.60(m, 2H), 1.76(m, 2H), 2.66(m, 2H), 3.79(m, 2H), 7.36(m, 2H), 7.95(m , 1H), 8.15(s, 1H), 8.82(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值215.1；實測值216.0；Rt=0.866min。LCMS (ESI): [M+H] + m/z: calculated 215.1; found 216.0; Rt=0.866 min.

步驟3：2-(苯并噻吩-3-基)哌啶之合成Step 3: Synthesis of 2-(benzothiophen-3-yl)piperidine

在0℃下，向6-(苯并噻吩-3-基)-2,3,4,5-四氫吡啶(3g，13.93mmol)於MeOH(60mL)中之溶液中分批添加硼氫化鈉(1.05g，27.87mmol，985.29μL)。將所得混合物在周圍溫度下攪拌2h且蒸發。將殘餘物溶解於水(50ml)中且用DCM(3* 50ml)萃取。將經合併之有機層用鹽水(2* 40ml)洗滌，經Na2 SO4 乾燥且 在真空中蒸發，以獲得2-(苯并噻吩-3-基)哌啶(2.8g，12.88mmol，92.47%產率)。To a solution of 6-(benzothiophen-3-yl)-2,3,4,5-tetrahydropyridine (3 g, 13.93 mmol) in MeOH (60 mL) at 0 °C was added sodium borohydride portionwise (1.05 g, 27.87 mmol, 985.29 μL). The resulting mixture was stirred at ambient temperature for 2 h and evaporated. The residue was dissolved in water (50ml) and extracted with DCM (3 * 50ml). The combined organic layers were washed with brine (2 * 40ml), dried over Na2SO4 and evaporated in vacuo to give 2-(benzothiophen-3-yl)piperidine (2.8g, 12.88mmol, 92.47 g %Yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.45(m,4H),1.85(m,2H),2.33(m,1H),2.71(m,1H),3.06(m,1H),3.95(m,1H),7.35(m,2H),7.50(s,1H),7.95(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.45(m, 4H), 1.85(m, 2H), 2.33(m, 1H), 2.71(m, 1H), 3.06(m, 1H), 3.95(m , 1H), 7.35 (m, 2H), 7.50 (s, 1H), 7.95 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值217.1；實測值218.2；Rt=0.854min。LCMS (ESI): [M+H] + m/z: calculated 217.1; found 218.2; Rt=0.854 min.

4P. 5-甲基-2-(萘-2-基)哌啶之合成4P. Synthesis of 5-methyl-2-(naphthalen-2-yl)piperidine

Figure 110128222-A0202-12-0715-585
Figure 110128222-A0202-12-0715-585

步驟1：(2-甲基-5-(萘-2-基)-5-側氧基戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (2-methyl-5-(naphthalen-2-yl)-5-oxypentyl)carbamate

在氬氣氣氛下，將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(3g，14.07mmol)添加到THF(50mL)及鎂(341.89mg，14.07mmol，196.49μL)之混合物中。向其中添加碘(17.85mg，70.33μmol)且將所得混合物加熱至回流達1h。在-78℃下，將所得混合物冷卻至室溫且逐滴添加到2-溴萘(2.91g，14.07mmol)於THF(50mL)中之溶液中。使所得混合物升溫至室溫且倒入NH4 Cl水溶液中。將所得混合物用EtOAc(2x40ml)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以獲得N -[2-甲基-5-(2-萘基)-5-側氧基戊基]胺甲酸第三丁 酯(5g，粗品)，其不經純化即用於下一步驟。Under argon atmosphere, tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (3 g, 14.07 mmol) was added to THF (50 mL) and magnesium (341.89 mg, 14.07 mmol, 196.49 μL) ) in the mixture. To this was added iodine (17.85 mg, 70.33 μmol) and the resulting mixture was heated to reflux for 1 h. The resulting mixture was cooled to room temperature and added dropwise to a solution of 2-bromonaphthalene (2.91 g, 14.07 mmol) in THF (50 mL) at -78 °C. The resulting mixture was warmed to room temperature and poured into aqueous NH4Cl . The resulting mixture was extracted with EtOAc (2x40ml). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated to give N- [2-methyl-5-(2-naphthyl)-5-oxypentyl]carbamic acid No. Tributyl ester (5 g, crude) was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.44(s,9H),1.78(m,3H),2.89(m,2H),3.15(m,3H),7.51(m,2H),7.89(m,2H),7.99(m,2H),8.69(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.86(d,3H), 1.44(s,9H), 1.78(m,3H), 2.89(m,2H), 3.15(m,3H), 7.51 (m, 2H), 7.89 (m, 2H), 7.99 (m, 2H), 8.69 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值241.2；實測值242.2；Rt=1.524min。LCMS (ESI): [M-Boc] + m/z: calculated 241.2; found 242.2; Rt=1.524 min.

步驟2：5-甲基-2-(萘-2-基)哌啶之合成 將N -[2-甲基-5-(2-萘基)-5-側氧基戊基]胺 甲酸第三丁 酯(5g，14.64mmol)溶解於三氟乙酸(16.70g，146.44mmol，11.28mL)中且將所得混合物攪拌1h。向其中添加50% NaOH水溶液，直至pH 11-12。將所得混合物用DCM(4x40ml)萃取。將經合併之有機層蒸發至乾。將殘餘物再溶解於MeOH(50mL)中且添加硼氫化鈉(554.01mg，14.64mmol，517.77μL)。將所得混合物在20℃下攪拌12h且蒸發。將50% NaOH水溶液添加到殘餘物中。將所得混合物用DCM(4x40ml)萃取，將經合併之有機層蒸發至乾，以獲得5-甲基-2-(2-萘基)哌啶(0.5g，2.22mmol，15.15%產率)，其不經純化即用於下一步驟。 Step 2: Synthesis of 5-methyl-2-(naphthalen-2-yl)piperidine N- [2-methyl-5-(2-naphthyl)-5- oxypentyl ]carbamic acid Tributyl ester (5 g, 14.64 mmol) was dissolved in trifluoroacetic acid (16.70 g, 146.44 mmol, 11.28 mL) and the resulting mixture was stirred for 1 h. To this was added 50% aqueous NaOH until pH 11-12. The resulting mixture was extracted with DCM (4x40ml). The combined organic layers were evaporated to dryness. The residue was redissolved in MeOH (50 mL) and sodium borohydride (554.01 mg, 14.64 mmol, 517.77 μL) was added. The resulting mixture was stirred at 20 °C for 12 h and evaporated. Aqueous 50% NaOH was added to the residue. The resulting mixture was extracted with DCM (4x40ml) and the combined organic layers were evaporated to dryness to give 5-methyl-2-(2-naphthyl)piperidine (0.5g, 2.22mmol, 15.15% yield), It was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.15(m,1H),1.41(m,1H),1.62(m,1H),1.75(m,2H),2.31(t,1H),2.40(m,1H),3.05(d,1H),3.62(d,1H),7.51(m,3H),7.91(m,4H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.86(d,3H), 1.15(m,1H), 1.41(m,1H), 1.62(m,1H), 1.75(m,2H), 2.31(t,1H), 2.40(m,1H), 3.05(d,1H), 3.62(d,1H), 7.51(m,3H), 7.91(m,4H).

LCMS(ESI)：[M]+ m/z：計算值225.3；實測值226.2；Rt=1.473min。LCMS (ESI): [M] + m/z: calculated 225.3; found 226.2; Rt=1.473 min.

4Q.外消旋 -2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺及外消旋 -2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺之合成4Q. Racemic -2-[( 2R , 3R , 6S )-2,3-dimethyl-6-phenyl-1-piperidinyl] -N- (5-methyl-3- Pyridyl)-2-oxyacetamide and rac -2-[( 2S , 3R , 6S )-2,3-dimethyl-6-phenyl-1-piperidinyl] Synthesis of -N-(5-methyl-3-pyridyl)-2-oxoacetamide

Figure 110128222-A0202-12-0716-586
Figure 110128222-A0202-12-0716-586

步驟1：2,3-二甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 2,3-dimethylpiperidine-1-carboxylate

向2,3-二甲基哌啶(5g，44.17mmol)於CH2 Cl2 (50mL)中之經攪拌之溶液中逐滴添加二碳酸二-第三丁酯(10.12g，46.38mmol，10.64mL)。將所得反應混合物在20℃下攪拌12小時。12小時之後，將所得反應混合物在減壓下濃縮， 以獲得2,3-二甲基哌啶-1-甲酸第三丁酯(9.2g，43.13mmol，97.64%產率)。To a stirred solution of 2,3-dimethylpiperidine (5 g, 44.17 mmol) in CH 2 Cl 2 (50 mL) was added di-tert-butyl dicarbonate (10.12 g, 46.38 mmol, 10.64 mmol) dropwise mL). The resulting reaction mixture was stirred at 20°C for 12 hours. After 12 hours, the resulting reaction mixture was concentrated under reduced pressure to obtain 3-butyl 2,3-dimethylpiperidine-1-carboxylate (9.2 g, 43.13 mmol, 97.64% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.81(dd,1H),0.96(m,3H),1.13(dd,2H),1.27(m,2H),1.41(s,9H),1.66(m,3H),2.75(m,1H),3.93(m,2H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.81 (dd, 1H), 0.96 (m, 3H), 1.13 (dd, 2H), 1.27 (m, 2H), 1.41 (s, 9H), 1.66 (m, 3H), 2.75 (m, 1H), 3.93 (m, 2H).

LCMS(ESI)：[M+Boc]+ m/z：計算值213.2；實測值158.2(t -Bu裂解之產物質量)；Rt=1.509min。LCMS (ESI): [M+Boc] + m/z: calculated 213.2; found 158.2 ( t -Bu cleavage product mass); Rt=1.509 min.

步驟2：2,3-二甲基-6-側氧基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-butyl 2,3-dimethyl-6-oxypiperidine-1-carboxylate

將2,3-二甲基哌啶-1-甲酸第三丁酯(8.2g，38.44mmol)於EtOAc(80mL)中之溶液添加到過碘酸鈉(32.89g，153.76mmol)於水(80mL)中之經攪拌之溶液中。將氯化釕(III)單水合物(43.33mg，192.20μmol)添加到反應混合物中且將所得雙相混合物在20℃下攪拌12小時。12小時之後，過濾反應混合物。將濾餅用EtOAc(2 x 15mL)洗滌。將濾液用鹽水洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以獲得2,3-二甲基-6-側氧基哌啶-1-甲酸第三丁酯(8.25g，粗品)。粗產物不經任何進一步純化即用於下一步反應。A solution of tert-butyl 2,3-dimethylpiperidine-1-carboxylate (8.2 g, 38.44 mmol) in EtOAc (80 mL) was added to sodium periodate (32.89 g, 153.76 mmol) in water (80 mL) ) in a stirred solution. Ruthenium(III) chloride monohydrate (43.33 mg, 192.20 μmol) was added to the reaction mixture and the resulting biphasic mixture was stirred at 20° C. for 12 hours. After 12 hours, the reaction mixture was filtered. The filter cake was washed with EtOAc (2 x 15 mL). The filtrate was washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain tert-butyl 2,3-dimethyl-6-oxypiperidine-1-carboxylate (8.25 g, crude) . The crude product was used in the next reaction without any further purification.

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)0.93(d,1.4H),1.00(d,1.6H),1.06(d,1.4H),1.19(d,1.6H),1.43(m,9H),1.60(m,1H),1.85(m,2H),2.35(m,2H),3.70(m,0.5H),4.00(m,0.5H)。 1 H NMR (DMSO- d 6 , 400MHz): δ(ppm) 0.93(d, 1.4H), 1.00(d, 1.6H), 1.06(d, 1.4H), 1.19(d, 1.6H), 1.43( m, 9H), 1.60 (m, 1H), 1.85 (m, 2H), 2.35 (m, 2H), 3.70 (m, 0.5H), 4.00 (m, 0.5H).

LCMS(ESI)：[M+Boc]+ m/z：計算值227.2；實測值172.2(t -Bu裂解之產物質量)；Rt=1.312min。LCMS (ESI): [M+Boc] + m/z: calculated 227.2; found 172.2 ( t -Bu cleavage product mass); Rt=1.312 min.

步驟3：N-(1,2-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl N-(1,2-dimethyl-5-oxy-5-phenylpentyl)carbamate

在-78℃、氬氣氣氛下，向2,3-二甲基-6-側氧基哌啶-1-甲酸第三丁酯(9g，39.60mmol)於THF(100mL)中之經攪拌之溶液中逐滴添加苯基溴化鎂(1M於THF中，7.18g，39.60mmol，39.6mL)。使所得反應混合物升溫至室溫且在同一溫度下攪拌12小時。12小時之後，將反應混合物用飽和NH4 Cl水溶液淬滅且用EtOAc(2 x 150mL)萃取。將經合併之有機相用鹽水洗滌，經Na2 SO4 乾燥且在 真空中蒸發，以獲得N -(1,2-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(10g，32.74mmol，82.69%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 2,3-dimethyl-6-oxypiperidine-1-carboxylic acid tert-butyl ester (9 g, 39.60 mmol) in THF (100 mL) at -78 °C under argon atmosphere Phenylmagnesium bromide (1 M in THF, 7.18 g, 39.60 mmol, 39.6 mL) was added dropwise to the solution. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to obtain N- (1,2-dimethyl-5-pentoxy-5-phenylpentyl)carbamic acid Tertiary butyl ester (10 g, 32.74 mmol, 82.69% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值305.2；實測值206.2；Rt=1.542min。LCMS (ESI): [M+Boc] + m/z: calculated 305.2; found 206.2; Rt=1.542 min.

步驟4：2,3-二甲基-6-苯基哌啶之合成Step 4: Synthesis of 2,3-Dimethyl-6-phenylpiperidine

將N -(1,2-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(10g，32.74mmol)溶解於三氟乙酸(18.67g，163.71mmol，12.61mL)中且將所得反應混合物攪拌1小時。1小時之後，將50%NaOH水溶液添加到反應混合物中，直到pH=11-12。將所得混合物用DCM(4 x 40mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。將所獲得之殘餘物溶解於MeOH(100mL)中在0℃下分批添加硼氫化鈉(1.24g，32.74mmol)。將所得混合物在20℃下攪拌1小時。1小時之後，將反應混合物在減壓下濃縮且將所獲得之殘餘物用50%NaOH水溶液稀釋。將所得混合物用DCM(4 x 40mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以獲得2,3-二甲基-6-苯基哌啶(3g，15.85mmol，48.40%產率)。粗產物不經任何進一步純化即用於下一步反應。Dissolve tert-butyl N- (1,2-dimethyl-5-oxy-5-phenylpentyl) carbamate (10 g, 32.74 mmol) in trifluoroacetic acid (18.67 g, 163.71 mmol, 12.61 g mL) and the resulting reaction mixture was stirred for 1 hour. After 1 hour, 50% aqueous NaOH was added to the reaction mixture until pH=11-12. The resulting mixture was extracted with DCM (4 x 40 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in MeOH (100 mL) and sodium borohydride (1.24 g, 32.74 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at 20°C for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure and the obtained residue was diluted with 50% aqueous NaOH. The resulting mixture was extracted with DCM (4 x 40 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 2,3-dimethyl-6-phenylpiperidine (3 g, 15.85 mmol, 48.40% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值189.2；實測值190.2；Rt=0.854min。LCMS (ESI): [M+H] + m/z: calculated 189.2; found 190.2; Rt=0.854 min.

4R. 3-(5-甲基-2-哌啶基)吡啶之合成4R. Synthesis of 3-(5-methyl-2-piperidinyl)pyridine

Figure 110128222-A0202-12-0718-587
Figure 110128222-A0202-12-0718-587

步驟1：N-[2-甲基-5-側氧基-5-(3-吡啶基)戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-[2-methyl-5-oxo-5-(3-pyridyl)pentyl]carbamate

在-78℃、氬氣氣氛下，向3-溴吡啶(10g，63.29mmol，6.17mL)於 Et2 O(100mL)中之經攪拌之溶液中逐滴添加正丁基鋰 (2.5M於己烷中，24.05g，63.29mmol，25.3mL)。將所得混合物攪拌1小時(溶液1 )。在氬氣氣氛下，向裝備有磁性攪拌棒及溫度計之單獨乾燥的3頸圓底燒瓶裝入5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(11.25g，52.74mmol)及無水Et2 O(100mL)。將溶液冷卻至-78℃且在1小時期間逐滴添加溶液1 ，將內部溫度保持低於-70℃。使所得反應混合物升溫至室溫且用飽和NH4 Cl溶液淬滅。將水層用DCM(3 x 50mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得呈淡黃色油狀物之N -[2-甲基-5-側氧基-5-(3-吡啶基)戊基]胺甲酸第三丁 酯(12.5g，42.75mmol，81.06%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 3-bromopyridine (10 g, 63.29 mmol, 6.17 mL) in Et2O (100 mL) was added n-butyllithium (2.5 M in hexane) dropwise at -78 °C under argon atmosphere alkane, 24.05 g, 63.29 mmol, 25.3 mL). The resulting mixture was stirred for 1 hour ( solution 1 ). Under an argon atmosphere, a separate dry 3-neck round bottom flask equipped with a magnetic stir bar and thermometer was charged with tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (11.25 g, 52.74 g mmol) and anhydrous Et2O (100 mL). The solution was cooled to -78°C and solution 1 was added dropwise during 1 hour, keeping the internal temperature below -70°C. The resulting reaction mixture was warmed to room temperature and quenched with saturated NH4Cl solution. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain N- [2-methyl- 5-Pendoxo-5-(3-pyridyl)pentyl]carbamic acid tert -butyl ester (12.5 g, 42.75 mmol, 81.06% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值292.2；實測值237.2(t -Bu裂解之產物質量)；Rt=1.174min。LCMS (ESI): [M+Boc] + m/z: calculated 292.2; found 237.2 ( t -Bu cleavage product mass); Rt=1.174 min.

步驟2：3-(5-甲基-2-哌啶基)吡啶之合成Step 2: Synthesis of 3-(5-methyl-2-piperidinyl)pyridine

將N -[2-甲基-5-側氧基-5-(3-吡啶基)戊基]胺甲酸第三丁 酯(12.5g，42.75mmol)於三氟乙酸(24.37g，213.77mmol，16.47mL)攪拌1小時。藉由TLC確認反應完成。將50% w/v NaOH溶液添加到混合物，直到pH為13-14。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機層經MgSO4 乾燥且在減壓下濃縮。將所獲得之粗產物溶解於MeOH(125mL)中且在0℃下分批添加硼氫化鈉(1.62g，42.75mmol)。將所得反應混合物攪拌隔夜。然後將反應混合物用1-2M HCl酸化，直到pH為1-3且再攪拌30分鐘。30分鐘之後，添加NaOH溶液，直到pH為13-14且將所得混合物用DCM(4 x 100mL)萃取。將合併之有機層經由Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由管柱層析(Combiflash；120g SiO2 ，溶析液：於MTBE中之0-30%甲醇+2% TEA；流速=85mL/min，Rv=7.8CV)純化所獲得之殘餘物，以得到呈淡黃色油狀物之3-(5-甲基-2-哌啶基)吡啶(1.5g，8.51mmol，19.91%產率)。3-butyl N- [2-methyl-5-oxy-5-(3-pyridyl)pentyl] carbamate (12.5 g, 42.75 mmol) in trifluoroacetic acid (24.37 g, 213.77 mmol, 16.47 mL) and stirred for 1 hour. The completion of the reaction was confirmed by TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The obtained crude product was dissolved in MeOH (125 mL) and sodium borohydride (1.62 g, 42.75 mmol) was added portionwise at 0 °C. The resulting reaction mixture was stirred overnight. The reaction mixture was then acidified with 1-2M HCl until pH 1-3 and stirred for an additional 30 minutes. After 30 minutes, NaOH solution was added until the pH was 13-14 and the resulting mixture was extracted with DCM (4 x 100 mL). The combined organic layers were dried over Na2SO4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (Combiflash; 120 g SiO 2 , eluent: 0-30% methanol + 2% TEA in MTBE; flow rate = 85 mL/min, Rv = 7.8 CV) to give 3-(5-Methyl-2-piperidinyl)pyridine (1.5 g, 8.51 mmol, 19.91% yield) was obtained as a pale yellow oil.

LCMS(ESI)：[M+H]+ m/z：計算值176.2；實測值177.2；Rt=0.537min。LCMS (ESI): [M+H] + m/z: calculated 176.2; found 177.2; Rt=0.537 min.

4S. 2-(3-氯苯基)-5-甲基哌啶之合成4S. Synthesis of 2-(3-chlorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0720-588
Figure 110128222-A0202-12-0720-588

步驟1：N-[5-(3-氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of N-[5-(3-chlorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

在攪拌之情況下，在Ar下，向乾燥的2頸燒瓶中添加鎂(1.27g，52.23mmol，729.75μL)、無水THF(25mL)及5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(7.43g，34.82mmol)。添加碘(88.38mg，348.21μmol)且輕微加熱混合物，直到其本身保持回流。當回流平息時，施加外部加熱以使回流再保持1小時。將1-溴-3-氯苯(10g，52.23mmol，6.13mL)添加到具有溫度計之乾燥的3頸圓底燒瓶中。在攪拌之情況下，在Ar下，添加無水THF(25mL)且將溶液冷卻至-78℃。在1小時內將格任亞試劑添加到t-Boc-內醯胺中，使內部溫度保持低於-70℃。使溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3 x 50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N-[5-(3-氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(10.9g，粗品)且其不經進一步純化即用於下一步驟。To a dry 2-neck flask under Ar, with stirring, were added magnesium (1.27 g, 52.23 mmol, 729.75 μL), anhydrous THF (25 mL) and 5-methyl-2-oxopiperidine-1 - tert-butyl formate (7.43 g, 34.82 mmol). Iodine (88.38 mg, 348.21 μmol) was added and the mixture was heated slightly until it kept refluxing by itself. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. 1-Bromo-3-chlorobenzene (10 g, 52.23 mmol, 6.13 mL) was added to a dry 3-neck round bottom flask with thermometer. With stirring, dry THF (25 mL) was added under Ar and the solution was cooled to -78 °C. The Grignard reagent was added to the t-Boc-lactamide over 1 hour, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3 x 50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-Butyl N-[5-(3-chlorophenyl)-2-methyl-5-oxypentyl]carbamate (10.9 g, crude) was obtained as a pale yellow oil and was not treated with Further purification was used in the next step.

1 H NMR(400MHz,CDCl3 )δ 0.93(d,3H),1.42(m,9H),1.50-1.60(m,1H),1.65-1.77(m,2H),2.97-3.05(m,4H),4.66(brs,1H),7.38(t,1H),7.50(d,1H),7.79(d,1H),7.90(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 0.93 (d, 3H), 1.42 (m, 9H), 1.50-1.60 (m, 1H), 1.65-1.77 (m, 2H), 2.97-3.05 (m, 4H) , 4.66(brs, 1H), 7.38(t, 1H), 7.50(d, 1H), 7.79(d, 1H), 7.90(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值325.2；實測值326.2；Rt=1.601min。LCMS (ESI): [M+H]+ m/z: calculated 325.2; found 326.2; Rt=1.601 min.

步驟2：2-(3-氯苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(3-Chlorophenyl)-5-methylpiperidine

將N-[5-(3-氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(10.9g，33.45mmol)於三氟乙酸(13.35g，117.09mmol，9.02mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物 用DCM萃取4 x 20mL且將有機層合併，以MgSO4乾燥且蒸發。將產物溶解於水(15mL)/MeOH(150mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(1.27g，33.45mmol，1.18mL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發，以得到呈淡黃色油狀物之2-(3-氯苯基)-5-甲基哌啶(6.05g，28.85mmol，86.24%產率)。N-[5-(3-Chlorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester (10.9 g, 33.45 mmol) in trifluoroacetic acid (13.35 g, 117.09 mmol) , 9.02 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a mixture of water (15 mL)/MeOH (150 mL) and added to the flask followed by sodium borohydride (1.27 g, 33.45 mmol, 1.18 mL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 x 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated to give 2- as a pale yellow oil (3-Chlorophenyl)-5-methylpiperidine (6.05 g, 28.85 mmol, 86.24% yield).

1 H NMR(400MHz,CDCl3 )δ 0.88-1.12(m,3H),1.12(m,1H),1.48-1.83(m,5H),2.37(t,1H),3.10(d,1H),3.60(d,1H),7.20(brs,3H),7.35(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 0.88-1.12(m, 3H), 1.12(m, 1H), 1.48-1.83(m, 5H), 2.37(t, 1H), 3.10(d, 1H), 3.60 (d, 1H), 7.20 (brs, 3H), 7.35 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值209.1；實測值210.2；Rt=0.590min。LCMS (ESI): [M+H] + m/z: calculated 209.1; found 210.2; Rt=0.590 min.

4T. 4,5-二甲基-2-苯基哌啶之合成4T. Synthesis of 4,5-dimethyl-2-phenylpiperidine

Figure 110128222-A0202-12-0721-589
Figure 110128222-A0202-12-0721-589

步驟1：4,5-二甲基-1H-吡啶-2-酮之合成Step 1: Synthesis of 4,5-Dimethyl-1H-pyridin-2-one

向硫酸(2.41g，24.56mmol)於水(8mL)中之經攪拌之溶液中添加4,5-二甲基吡啶-2-胺(1g，8.19mmol)。將所得溶液冷卻至0℃且在0℃下使用加料漏斗逐滴添加亞硝酸鈉(1.69g，24.56mmol，780.78μL)於水(7mL)中之溶液。將反應混合物升溫至室溫且在室溫下再攪拌30min。然後，將所得混合物用DCM(2* 30ml)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾出，且蒸發，以得到4,5-二甲基-1H-吡啶-2-酮(0.561g，4.56mmol，55.65%產率)，其不經進一步純化即用於下一步驟。To a stirred solution of sulfuric acid (2.41 g, 24.56 mmol) in water (8 mL) was added 4,5-lutidine-2-amine (1 g, 8.19 mmol). The resulting solution was cooled to 0 °C and a solution of sodium nitrite (1.69 g, 24.56 mmol, 780.78 μL) in water (7 mL) was added dropwise at 0 °C using an addition funnel. The reaction mixture was warmed to room temperature and stirred for an additional 30 min at room temperature. Then, the resulting mixture was extracted with DCM (2 * 30ml). The combined organic layers were dried over Na 2 SO 4 , filtered off, and evaporated to give 4,5-dimethyl-lH-pyridin-2-one (0.561 g, 4.56 mmol, 55.65% yield) which was Used in the next step without further purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.91(s,3H),2.05(s,3H),6.13(s,1H),7.05(s,1H),11.14(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.91(s,3H), 2.05(s,3H), 6.13(s,1H), 7.05(s,1H), 11.14(s,1H).

LCMS(ESI)：[M+H]+ m/z：計算值123.2；實測值124.2；Rt=1.688min。LCMS (ESI): [M+H] + m/z: calculated 123.2; found 124.2; Rt=1.688 min.

步驟2：4,5-二甲基哌啶-2-酮之合成Step 2: Synthesis of 4,5-Dimethylpiperidin-2-one

將4,5-二甲基-1H-吡啶-2-酮(0.561g，4.56mmol)溶解於MeOH(5mL)及AcOH(1mL)中且添加Pd/C JM A402028-10(0.06g，4.56mmol)。將所得混合物在50℃下用H2 (50atm)氫化60h。透過矽藻土過濾反應混合物且在45℃下在真空中濃縮濾液。將殘餘物溶解於DCM(25ml)中且用NaHCO3 水溶液洗滌。將有機層經Na2 SO4 乾燥，過濾出，且在40℃下在真空中濃縮，以得到4,5-二甲基哌啶-2-酮(0.45g，3.54mmol，77.67%產率)。4,5-Dimethyl-1H-pyridin-2-one (0.561 g, 4.56 mmol) was dissolved in MeOH (5 mL) and AcOH (1 mL) and Pd/C JM A402028-10 (0.06 g, 4.56 mmol) was added ). The resulting mixture was hydrogenated with H2 (50 atm) at 50 °C for 60 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo at 45°C. The residue was dissolved in DCM (25ml) and washed with aqueous NaHCO3 . The organic layer was dried over Na 2 SO 4 , filtered off, and concentrated in vacuo at 40 °C to give 4,5-dimethylpiperidin-2-one (0.45 g, 3.54 mmol, 77.67% yield) .

1 H NMR(500MHz,CDCl3 )δ 0.96(s,6H),1.59(m,1H),2.16(m,2H),2.43(m,1H),2.95(m,1H),3.30(m,1H),6.00(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.96(s, 6H), 1.59(m, 1H), 2.16(m, 2H), 2.43(m, 1H), 2.95(m, 1H), 3.30(m, 1H) ), 6.00 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值127.2；實測值129.2；Rt=0.467min。LCMS (ESI): [M+2H] + m/z: calculated 127.2; found 129.2; Rt=0.467 min.

步驟3：4,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 3-butyl 4,5-dimethyl-2-oxypiperidine-1-carboxylate

將4,5-二甲基哌啶-2-酮(0.45g，3.54mmol)、二碳酸二-第三丁酯(888.03mg，4.07mmol，933.78μL)及DMAP(43.23mg，353.82μmol)溶解於MeCN(10mL)中。將反應混合物在80℃下攪拌12h。將所得混合物在真空中濃縮。將殘餘物溶解於DCM中且用NaHSO4 水溶液洗滌。將有機相經Na2 SO4 乾燥，過濾出，且在真空中蒸發，以得到4,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯(0.656g，2.89mmol，81.57%產率)。4,5-Dimethylpiperidin-2-one (0.45 g, 3.54 mmol), di-tert-butyl dicarbonate (888.03 mg, 4.07 mmol, 933.78 μL) and DMAP (43.23 mg, 353.82 μmol) were dissolved in MeCN (10 mL). The reaction mixture was stirred at 80 °C for 12 h. The resulting mixture was concentrated in vacuo. The residue was dissolved in DCM and washed with aq. NaHSO4 . The organic phase was dried over Na 2 SO 4 , filtered off, and evaporated in vacuo to give tert-butyl 4,5-dimethyl-2-oxypiperidine-1-carboxylate (0.656 g, 2.89 mmol). , 81.57% yield).

1 H NMR(400MHz,CDCl3 )δ 0.92(m,6H),1.50(m,9H),1.60(m,1H),2.12(m,2H),2.53(m,1H),3.10(m,1H),3.75(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.92(m, 6H), 1.50(m, 9H), 1.60(m, 1H), 2.12(m, 2H), 2.53(m, 1H), 3.10(m, 1H) ), 3.75(m, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值171.2；實測值172.2；Rt=3.31min。LCMS (ESI): [M-tBu] + m/z: calculated 171.2; found 172.2; Rt=3.31 min.

步驟4：N-(2,3-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯之合成(Step 4: Synthesis of tert-butyl N-(2,3-dimethyl-5-oxy-5-phenylpentyl)carbamate (

在-40℃、氬氣氣氛下，將溴(苯基)鎂(601.77mg，3.32mmol)逐滴添加到4,5-二甲基-2-側氧基哌啶-1-甲酸第三丁酯(0.656g，2.89mmol)於THF(15 mL)中之溶液中。添加完成之後，將所得混合物在-40℃下攪拌30min，然後使其升溫至室溫且攪拌12h。將飽和氯化銨水溶液添加到反應混合物中且將所得混合物攪拌15min。將有機層分離且將水層用EtOAc(3* 30ml)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾出，且蒸發，以得到N-(2,3-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯(648mg，2.12mmol，73.52%產率)，其不經進一步純化即用於下一步驟。Under argon atmosphere, bromo(phenyl)magnesium (601.77 mg, 3.32 mmol) was added dropwise to tert-butyl 4,5-dimethyl-2-oxypiperidine-1-carboxylic acid at -40°C A solution of ester (0.656 g, 2.89 mmol) in THF (15 mL). After the addition was complete, the resulting mixture was stirred at -40 °C for 30 min, then allowed to warm to room temperature and stirred for 12 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was stirred for 15 min. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 * 30ml). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered off, and evaporated to give N-(2,3-dimethyl-5-pentoxy-5-phenylpentyl)amine 3-Butyl formate (648 mg, 2.12 mmol, 73.52% yield) was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 0.96(m,6H),1.44(s,9H),1.71(m,1H),2.33(m,1H),2.85(m,1H),3.13(m,3H),4.74(m,1H),7.46(m,2H),7.56(dd,1H),7.97(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ 0.96(m, 6H), 1.44(s, 9H), 1.71(m, 1H), 2.33(m, 1H), 2.85(m, 1H), 3.13(m, 3H) ), 4.74 (m, 1H), 7.46 (m, 2H), 7.56 (dd, 1H), 7.97 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值205.2；實測值206.4；Rt=4.039min。LCMS (ESI): [M-Boc] + m/z: calculated 205.2; found 206.4; Rt=4.039 min.

步驟5：3,4-二甲基-6-苯基-2,3,4,5-四氫吡啶之合成Step 5: Synthesis of 3,4-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine

將N-(2,3-二甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯(0.648g，2.12mmol)溶解於DCM(6mL)中且逐滴添加TFA(6mL)。將反應混合物在20℃下攪拌隔夜。然後，小心添加飽和碳酸鉀水溶液且將混合物攪拌30min。將混合物用DCM稀釋。將水層用DCM(2* 25ml)洗滌，將有機相經Na2 SO4 乾燥，過濾出，且在40℃下在真空中濃縮，以得到3,4-二甲基-6-苯基-2,3,4,5-四氫吡啶(0.388g，2.07mmol，97.64%產率)，其不經進一步純化即用於下一步驟。3-butyl N-(2,3-Dimethyl-5-oxy-5-phenylpentyl)carbamate (0.648 g, 2.12 mmol) was dissolved in DCM (6 mL) and TFA was added dropwise (6 mL). The reaction mixture was stirred at 20°C overnight. Then, saturated aqueous potassium carbonate solution was carefully added and the mixture was stirred for 30 min. The mixture was diluted with DCM. The aqueous layer was washed with DCM (2 * 25ml), the organic phase was dried over Na2SO4 , filtered off, and concentrated in vacuo at 40°C to give 3,4-dimethyl-6-phenyl- 2,3,4,5-Tetrahydropyridine (0.388 g, 2.07 mmol, 97.64% yield) was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 0.90(d,3H),0.94(m,3H),0.98(m,1H),1.06(m,1H),1.87(m,1H),2.84(m,1H),3.31(m,1H),4.03(m,1H),7.37(s,3H),7.77(s,2H)。 1 H NMR (500MHz, CDCl 3 )δ 0.90(d,3H), 0.94(m,3H), 0.98(m,1H), 1.06(m,1H), 1.87(m,1H), 2.84(m,1H) ), 3.31(m, 1H), 4.03(m, 1H), 7.37(s, 3H), 7.77(s, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值187.2；實測值188.2；Rt=1.490min。LCMS (ESI): [M+H] + m/z: calculated 187.2; found 188.2; Rt=1.490 min.

步驟6：4,5-二甲基-2-苯基哌啶之合成Step 6: Synthesis of 4,5-Dimethyl-2-phenylpiperidine

將3,4-二甲基-6-苯基-2,3,4,5-四氫吡啶(0.388g，2.07mmol)溶解於MeOH(5mL)中且在用冷水冷卻之情況下分批添加硼氫化鈉(627.04mg，16.57mmol，586.02μL)。將反應混合物加熱至室溫且攪拌12h。然後，添加NH4 Cl(水溶液)且將甲醇蒸發，將水層用DCM(3* 30ml)萃取且將經合併之有機層經Na2 SO4 乾燥。過濾出懸浮液且在45℃下在真空下蒸發，以得到4,5-二甲基-2-苯基哌啶(0.23g，1.22mmol，58.65%產率)，其不經進一步純化即用於下一步驟。4,5-二甲基-2-苯基哌啶(0.23g，1.22mmol，58.65%產率)。3,4-Dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine (0.388 g, 2.07 mmol) was dissolved in MeOH (5 mL) and added portionwise with cooling with cold water Sodium borohydride (627.04 mg, 16.57 mmol, 586.02 μL). The reaction mixture was warmed to room temperature and stirred for 12 h. Then, NH4Cl (aq) was added and the methanol was evaporated, the aqueous layer was extracted with DCM (3 * 30ml) and the combined organic layers were dried over Na2SO4 . The suspension was filtered off and evaporated under vacuum at 45°C to give 4,5-dimethyl-2-phenylpiperidine (0.23 g, 1.22 mmol, 58.65% yield) which was used without further purification in the next step. 4,5-Dimethyl-2-phenylpiperidine (0.23 g, 1.22 mmol, 58.65% yield).

1 H NMR(400MHz,CDCl3 )δ 0.89(m,6H),1.24(m,2H),1.76(m,2H),2.43(m,1H),2.98(m,1H),3.10(m,1H),3.61(m,1H),7.31(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ 0.89 (m, 6H), 1.24 (m, 2H), 1.76 (m, 2H), 2.43 (m, 1H), 2.98 (m, 1H), 3.10 (m, 1H) ), 3.61 (m, 1H), 7.31 (m, 5H).

LCMS(ESI)：[M+H]+ m/z：計算值189.2；實測值190.4；Rt=2.024min。LCMS (ESI): [M+H] + m/z: calculated 189.2; found 190.4; Rt=2.024 min.

4U. 2-[4-(二氟甲基)苯基]-5-甲基哌啶之合成4U. Synthesis of 2-[4-(difluoromethyl)phenyl]-5-methylpiperidine

Figure 110128222-A0202-12-0724-590
Figure 110128222-A0202-12-0724-590

步驟1：N-[5-[4-(二氟甲基)苯基]-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of N-[5-[4-(difluoromethyl)phenyl]-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

在-78℃下，在30min時段內，向1-溴-4-(二氟甲基)苯(4.6g，22.22mmol)於THF(25mL)中之溶液中逐滴添加正丁基鋰(6.19g，22.22mmol，8.93mL，23%純度)。將反應物質在-78℃下攪拌1h且在同一溫度下添加5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(4.74g，22.22mmol)且將反應物在-78℃下再攪拌1h。完成之後，使反應混合物升高至0℃且用飽和氯化銨溶液處理並用乙酸乙酯萃取。將有機層經無水硫酸鈉乾燥，過濾且在減壓下濃縮，以得到N-[5-[4-(二氟甲基)苯基]-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(7.2g，21.09mmol，94.91%產率)，其不經進一步純化即用於下一步驟。To a solution of 1-bromo-4-(difluoromethyl)benzene (4.6 g, 22.22 mmol) in THF (25 mL) was added n-butyllithium (6.19 g) dropwise at -78 °C over a period of 30 min g, 22.22 mmol, 8.93 mL, 23% purity). The reaction mass was stirred at -78°C for 1 h and tert-butyl 5-methyl-2-pendoxopiperidine-1-carboxylate (4.74 g, 22.22 mmol) was added at the same temperature and the reaction mass was heated at -78 Stir at °C for another 1 h. After completion, the reaction mixture was raised to 0°C and treated with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-[5-[4-(difluoromethyl)phenyl]-2-methyl-5-pentoxypentyl] 3-Butyl carbamate (7.2 g, 21.09 mmol, 94.91% yield) was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d6 )δ 0.94(m,3H),1.43(m,9H),1.69(m,2H),2.35(m,2H),3.04(m,2H),4.71(m,2H),7.50(m,2H),7.59(m,2H),8.04(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.94(m, 3H), 1.43(m, 9H), 1.69(m, 2H), 2.35(m, 2H), 3.04(m, 2H), 4.71(m , 2H), 7.50 (m, 2H), 7.59 (m, 2H), 8.04 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值241.2；實測值242.2；Rt=1.564min。LCMS (ESI): [M-Boc] + m/z: calculated 241.2; found 242.2; Rt=1.564 min.

步驟2：2-[4-(二氟甲基)苯基]-5-甲基哌啶之合成Step 2: Synthesis of 2-[4-(difluoromethyl)phenyl]-5-methylpiperidine

將N-[5-[4-(二氟甲基)苯基]-2-甲基-5-側氧基戊基]胺甲酸第三丁酯 (8.8g，25.78mmol)於三氟乙酸(14.70g，128.88mmol，9.93mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4 x 20mL且將有機層合併，以MgSO4乾燥且蒸發。將產物溶解於MeOH(50mL)/水(50mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(975.20mg，25.78mmol，911.40μL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發。藉由CC(Companion combiflash，120g SiO2 ，乙腈/甲醇，其中甲醇為0~5%，流速=85mL/min，Rv=4CV)純化殘餘物，以得到呈淡黃色油狀物之2-[4-(二氟甲基)苯基]-5-甲基哌啶(0.63g，2.80mmol，10.85%產率)。N-[5-[4-(difluoromethyl)phenyl]-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester (8.8 g, 25.78 mmol) in trifluoroacetic acid ( 14.70 g, 128.88 mmol, 9.93 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a MeOH (50 mL)/water (50 mL) mixture and added to the flask followed by sodium borohydride (975.20 mg, 25.78 mmol, 911.40 μL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 x 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated. The residue was purified by CC (Companion combiflash, 120 g SiO 2 , acetonitrile/methanol with 0-5% methanol, flow rate=85 mL/min, Rv=4CV) to give 2-[4 as pale yellow oil -(Difluoromethyl)phenyl]-5-methylpiperidine (0.63 g, 2.80 mmol, 10.85% yield).

1 H NMR(500MHz,CDCl3 )δ 0.92(d,3H),1.17(m,1H),1.84(m,5H),2.43(m,1H),3.16(m,1H),3.62(m,1H),7.47(s,4H)。 1 H NMR (500MHz, CDCl 3 )δ 0.92(d,3H), 1.17(m,1H), 1.84(m,5H), 2.43(m,1H), 3.16(m,1H), 3.62(m,1H) ), 7.47(s, 4H).

LCMS(ESI)：[M+H]+ m/z：計算值225.2；實測值226.2；Rt=0.890min。LCMS (ESI): [M+H] + m/z: calculated 225.2; found 226.2; Rt=0.890 min.

4V.5-甲基-2-苯基哌啶 之合成4V. Synthesis of 5-methyl-2-phenylpiperidine

Figure 110128222-A0202-12-0725-591
Figure 110128222-A0202-12-0725-591

步驟1：(2-甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (2-methyl-5-oxy-5-phenylpentyl)carbamate

在攪拌之情況下，向乾燥的2頸燒瓶中添加THF(300mL)及5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(30g，140.66mmol)且將溶液冷卻至-78℃。在1小時內將苯基溴化鎂(255.04g，211.00mmol，260.25mL)試劑添加到t -boc-內醯胺中，將內部溫度保持低於-70℃。將溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3 x 50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N -(2-甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(41g，粗品)且其不經進一步純化即用於下一步驟。With stirring, to a dry 2-neck flask was added THF (300 mL) and tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (30 g, 140.66 mmol) and the solution was cooled to -78°C. Phenylmagnesium bromide (255.04 g, 211.00 mmol, 260.25 mL) reagent was added to t -boc-lactam over 1 hour, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3 x 50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-Butyl N- (2-methyl-5-oxy-5-phenylpentyl)carbamate (41 g, crude) was obtained as a pale yellow oil and used in the next step without further purification one step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.96(d,3H),1.45(s,9H),1.68(m,1H),1.72(m,1H),1.85(m,1H),3.05(m,4H),4.71(m,1H),7.45(t,2H),7.55(t,1H),7.96(d,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.96(d, 3H), 1.45(s, 9H), 1.68(m, 1H), 1.72(m, 1H), 1.85(m, 1H), 3.05( m, 4H), 4.71 (m, 1H), 7.45 (t, 2H), 7.55 (t, 1H), 7.96 (d, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值191.2；實測值192.2；Rt=1.486min。LCMS (ESI): [M-Boc] + m/z: calculated 191.2; found 192.2; Rt=1.486 min.

步驟2：5-甲基-2-苯基哌啶之合成Step 2: Synthesis of 5-methyl-2-phenylpiperidine

將N -(2-甲基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(41g，140.71mmol)於三氟乙酸(80.22g，703.54mmol，54.20mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4 x 20mL且將有機層合併，以MgSO4 乾燥且蒸發。將產物溶解於MeOH(500mL)/水(100mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(5.32g，140.71mmol，4.98mL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，用Na2 SO4 乾燥，過濾且蒸發，以得到呈淡黃色油狀物之5-甲基-2-苯基哌啶(21.2g，粗品)。Stir tert-butyl N- (2-methyl-5-oxy-5-phenylpentyl) carbamate (41 g, 140.71 mmol) in trifluoroacetic acid (80.22 g, 703.54 mmol, 54.20 mL) 1h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a MeOH (500 mL)/water (100 mL) mixture and added to the flask followed by sodium borohydride (5.32 g, 140.71 mmol, 4.98 mL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 x 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated to give 5- as a pale yellow oil Methyl-2-phenylpiperidine (21.2 g, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.87(d,3H),1.14(m,1H),1.56(m,2H),1.81(m,3H),2.40(t,1H),3.11(d,1H),3.53(d,1H),7.29(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.87(d,3H), 1.14(m,1H), 1.56(m,2H), 1.81(m,3H), 2.40(t,1H), 3.11( d, 1H), 3.53 (d, 1H), 7.29 (m, 5H).

LCMS(ESI)：[M+1]m/z：計算值175.2；實測值176.2；Rt=0.779min。LCMS (ESI): [M+1] m/z: calculated 175.2; found 176.2; Rt=0.779 min.

4W. 2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙酸之合成4W. Synthesis of 2-(5-methyl-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-2-side oxyacetic acid

Figure 110128222-A0202-12-0726-592
Figure 110128222-A0202-12-0726-592

步驟1：(2-甲基-5-側氧基-5-(4-(三氟甲基)苯基)戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (2-methyl-5-oxy-5-(4-(trifluoromethyl)phenyl)pentyl)carbamate

在攪拌之情況下，在Ar下，向乾燥的2頸燒瓶中添加鎂(1.08g，44.44mmol，620.80μL)、無水THF(50mL)及1-溴-4-(三氟甲基)苯(10g，44.44mmol，6.21mL)。添加碘(433.85mg，1.71mmol)且輕微加熱混合物，直到其自身保持回流。當回流平息時，施加外部加熱以再保持回流1h。將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(7.29g，34.19mmol)添加到具有溫度計之乾燥的3頸圓底燒瓶中。在攪拌之情況下，在Ar下，添加無水THF(50mL)且將溶液冷卻至-78℃。在1h內將格任亞試劑添加到t -boc-內醯胺中，使內部溫度保持低於-70℃。使溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3x50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈淡黃色油狀物之N -[2-甲基-5-側氧基-5-[4-(三氟甲基)苯基]戊基]胺甲酸第三丁 酯(13g，粗品)且其不經進一步純化即用於下一步驟。With stirring, to a dry 2-neck flask under Ar was added magnesium (1.08 g, 44.44 mmol, 620.80 μL), anhydrous THF (50 mL) and 1-bromo-4-(trifluoromethyl)benzene ( 10 g, 44.44 mmol, 6.21 mL). Iodine (433.85 mg, 1.71 mmol) was added and the mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heating was applied to maintain the reflux for an additional 1 h. To a dry 3-neck round bottom flask with thermometer was added tert-butyl 5-methyl-2-pentoxypiperidine-1-carboxylate (7.29 g, 34.19 mmol). With stirring, dry THF (50 mL) was added under Ar and the solution was cooled to -78 °C. The Grignard reagent was added to the t -boc-lactamide over 1 h, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3x50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. tert-butyl N- [2-methyl-5-oxy-5-[4-(trifluoromethyl)phenyl]pentyl] carbamate was obtained as a pale yellow oil (13 g, crude) and it was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.93(d,3H),1.43(s,9H),1.80(m,3H),3.05(m,3H),4.12(m,1H),5.12(m,1H),7.71(m,2H),8.05(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.93(d, 3H), 1.43(s, 9H), 1.80(m, 3H), 3.05(m, 3H), 4.12(m, 1H), 5.12( m, 1H), 7.71 (m, 2H), 8.05 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值259.2；實測值260.2；Rt=1.605min。LCMS (ESI): [M-Boc] + m/z: calculated 259.2; found 260.2; Rt=1.605 min.

步驟2：5-甲基-2-(4-(三氟甲基)苯基)哌啶之合成Step 2: Synthesis of 5-methyl-2-(4-(trifluoromethyl)phenyl)piperidine

將N-[2-甲基-5-側氧基-5-[4-(三氟甲基)苯基]戊基]胺甲酸第三丁 酯(13g，36.17mmol)於三氟乙酸(20.62g，180.87mmol，13.93mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4 x 20mL且將有機層合併，以MgSO4 乾燥且蒸發。將產物溶解於水(50mL)/MeOH(125mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(1.37g，36.17mmol，1.28mL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發。藉由CC(Interchim，120g SiO2 ，己烷/MTBE，其中MTBE為15~55%，流速=85ml/min， RV=5,5CV.)純化殘餘物，以得到呈淡黃色油狀物之5-甲基-2-[4-(三氟甲基)苯基]哌啶(3.4g，13.98mmol，38.64%產率)。N-[2-Methyl-5-oxy-5-[4-(trifluoromethyl)phenyl]pentyl] carbamate (13 g, 36.17 mmol) was dissolved in trifluoroacetic acid (20.62 mmol) g, 180.87 mmol, 13.93 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a mixture of water (50 mL)/MeOH (125 mL) and added to the flask followed by sodium borohydride (1.37 g, 36.17 mmol, 1.28 mL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 x 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated. The residue was purified by CC (Interchim, 120 g SiO 2 , hexane/MTBE with 15-55% MTBE, flow rate=85 ml/min, RV=5, 5CV.) to give 5 as a pale yellow oil - Methyl-2-[4-(trifluoromethyl)phenyl]piperidine (3.4 g, 13.98 mmol, 38.64% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.91(d,3H),1.16(m,1H),1.79(m,5H),2.43(m,1H),3.15(m,1H),3.70(m,1H),7.48(m,2H),7.58(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.91(d,3H), 1.16(m,1H), 1.79(m,5H), 2.43(m,1H), 3.15(m,1H), 3.70( m, 1H), 7.48 (m, 2H), 7.58 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值243.2；實測值244.2；Rt=1.082min。LCMS (ESI): [M] + m/z: calculated 243.2; found 244.2; Rt=1.082 min.

步驟3：2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 3: Compound of 2-(5-methyl-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester synthesis

在-10℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(783.11mg，4.11mmol)逐滴添加到5-甲基-2-[4-(三氟甲基)苯基]哌啶(1g，4.11mmol)及TEA(415.96mg，4.11mmol，572.95μL)於THF(20mL)中之溶液中。將所得混合物升溫至室溫且攪拌12h。過濾出所得沉澱。蒸發濾液，以獲得2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.3g，3.27mmol，79.60%產率)，其不經純化即用於下一步驟。2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (783.11 mg, 4.11 mmol) was added dropwise to 5-methyl-2-[4-(trifluoroethyl) at -10°C Fluoromethyl)phenyl]piperidine (1 g, 4.11 mmol) and TEA (415.96 mg, 4.11 mmol, 572.95 μL) in THF (20 mL). The resulting mixture was warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered off. The filtrate was evaporated to obtain 2,2,2-trifluoroethyl 2-[5-methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetic acid Ester (1.3 g, 3.27 mmol, 79.60% yield), which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.48(m,1H),1.56(m,2H),1.98(m,1H),2.12(m,2H),3.21(m,1H),3.98(m,1H),5.12(s,2H),7.48(m,2H),7.78(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.48(m,1H), 1.56(m,2H), 1.98(m,1H), 2.12(m,2H), 3.21 (m, 1H), 3.98 (m, 1H), 5.12 (s, 2H), 7.48 (m, 2H), 7.78 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值397.2；實測值398.2；Rt=1.600min。LCMS (ESI): [M] + m/z: calculated 397.2; found 398.2; Rt=1.600 min.

步驟4：2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙酸之合成Step 4: Synthesis of 2-(5-methyl-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoacetic acid

將98%氫氧化鋰單水合物(137.30mg，3.27mmol，90.93μL)添加到2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.3g，3.27mmol)於THF(20mL)及水(2mL)中之溶液中，且將所得混合物在20℃下攪拌12h。將所得混合物蒸發至乾，以獲得2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸(0.9g，2.79mmol，85.36%產率，Li+ )，其不經純化即用於下一步驟。98% Lithium hydroxide monohydrate (137.30 mg, 3.27 mmol, 90.93 μL) was added to 2-[5-methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl] - A solution of 2,2,2-trifluoroethyl 2-pendoxoacetic acid (1.3 g, 3.27 mmol) in THF (20 mL) and water (2 mL), and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was evaporated to dryness to obtain 2-[5-methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-pendoxoacetic acid (0.9 g, 2.79 g mmol, 85.36% yield, Li + ), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.36(m,1H),1.52(m,1H),1.86(m,1H),2.12(m,2H),2.38(m,1H),2.98(m,1H),3.76(m,1H),5.36(m,1H),7.48(m,1H),7.68(m,3H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.36(m,1H), 1.52(m,1H), 1.86(m,1H), 2.12(m,2H), 2.38(m,1H), 2.98(m,1H), 3.76(m,1H), 5.36(m,1H), 7.48(m,1H), 7.68(m,3H).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=1.384min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=1.384 min.

4X. 2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙酸之合成4X. Synthesis of 2-(5-methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoacetic acid

Figure 110128222-A0202-12-0729-596
Figure 110128222-A0202-12-0729-596

步驟1：(2-甲基-5-側氧基-5-(3-(三氟甲基)苯基)戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (2-methyl-5-oxy-5-(3-(trifluoromethyl)phenyl)pentyl)carbamate

在氬氣氣氛下，將1-溴-3-(三氟甲基)苯(10g，44.44mmol，6.21mL)添加到THF(100mL)及Mg(1.19g，48.89mmol，682.88μL)之混合物中。向其中添加碘(112.80mg，444.43μmol)且將所得混合物加熱至回流達1h。在-78℃下，將所得混合物冷卻至室溫且逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(9.48g，44.44mmol)於THF(100mL)中之溶液中。使所得混合物升溫至室溫然後倒入NH4 Cl水溶液中。將所得混合物用EtOAc(2x40ml)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以獲得N -[2-甲基-5-側氧基-5-[3-(三氟甲基)苯基]戊基]胺甲酸第三丁 酯(10g，27.83mmol，62.61%產率)，其不經純化即用於下一步驟。1-Bromo-3-(trifluoromethyl)benzene (10 g, 44.44 mmol, 6.21 mL) was added to a mixture of THF (100 mL) and Mg (1.19 g, 48.89 mmol, 682.88 μL) under argon atmosphere . To this was added iodine (112.80 mg, 444.43 μmol) and the resulting mixture was heated to reflux for 1 h. The resulting mixture was cooled to room temperature and added dropwise to tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (9.48 g, 44.44 mmol) in THF (100 mL) at -78 °C in the solution. The resulting mixture was allowed to warm to room temperature and poured into aqueous NH4Cl . The resulting mixture was extracted with EtOAc (2x40ml). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated to give N- [2-methyl-5-oxy-5-[3-(trifluoromethyl)phenyl] 3 -Butyl pentyl]carbamate (10 g, 27.83 mmol, 62.61% yield) was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.42(s,9H),1.62(m,1H),1.78(m,1H),2.06(m,1H),2.82(m,1H),3.12(m,2H),3.78(m,1H),5.55(m,1H),7.57(m,4H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.86(d, 3H), 1.42(s, 9H), 1.62(m, 1H), 1.78(m, 1H), 2.06(m, 1H), 2.82 (m, 1H), 3.12 (m, 2H), 3.78 (m, 1H), 5.55 (m, 1H), 7.57 (m, 4H).

LCMS(ESI)：[M-Boc]+ m/z：計算值259.2；實測值260.2；Rt=1.585min。LCMS (ESI): [M-Boc] + m/z: calculated 259.2; found 260.2; Rt=1.585 min.

步驟2：5-甲基-2-(3-(三氟甲基)苯基)哌啶之合成Step 2: Synthesis of 5-methyl-2-(3-(trifluoromethyl)phenyl)piperidine

將N -[2-甲基-5-側氧基-5-[3-(三氟甲基)苯基]戊基]胺甲酸第三丁 酯(10g，27.83mmol)溶解於TFA(31.73g，278.26mmol，21.44mL)中且將所得混合物攪拌1h。向其中添加50%NaOH水溶液，直至pH 11-12。將所得混合物用DCM(4x40 l)萃取，將經合併之有機層蒸發至乾。將殘餘物溶解於MeOH(50mL)中且添加硼氫化鈉(1.05g，27.83mmol，983.84μL)。將所得混合物在20℃下攪拌12h且蒸發。將50%NaOH水溶液添加到殘餘物中。將所得混合物用DCM(4x40ml)萃取，將經合併之有機層蒸發至乾，以獲得5-甲基-2-[3-(三氟甲基)苯基]哌啶(2g，8.22mmol，29.55%產率)，其不經純化即用於下一步驟。Dissolve tert-butyl N- [2-methyl-5-oxy-5-[3-(trifluoromethyl)phenyl]pentyl] carbamate (10 g, 27.83 mmol) in TFA (31.73 g) , 278.26 mmol, 21.44 mL) and the resulting mixture was stirred for 1 h. To this was added 50% aqueous NaOH until pH 11-12. The resulting mixture was extracted with DCM (4x40 1) and the combined organic layers were evaporated to dryness. The residue was dissolved in MeOH (50 mL) and sodium borohydride (1.05 g, 27.83 mmol, 983.84 μL) was added. The resulting mixture was stirred at 20 °C for 12 h and evaporated. Aqueous 50% NaOH was added to the residue. The resulting mixture was extracted with DCM (4x40 ml) and the combined organic layers were evaporated to dryness to give 5-methyl-2-[3-(trifluoromethyl)phenyl]piperidine (2 g, 8.22 mmol, 29.55 g % yield), which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.12(m,1H),1.26(m,1H),1.52(m,1H),1.78(m,2H),2.24(t,1H),2.98(d,1H),3.56(d,1H),7.53(m,2H),7.68(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.86(d,3H), 1.12(m,1H), 1.26(m,1H), 1.52(m,1H), 1.78(m,2H), 2.24(t, 1H), 2.98(d, 1H), 3.56(d, 1H), 7.53(m, 2H), 7.68(m, 2H).

LCMS(ESI)：[M]+ m/z：計算值243.2；實測值244.2；Rt=0.969min。LCMS (ESI): [M] + m/z: calculated 243.2; found 244.2; Rt=0.969 min.

步驟3：2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 3: Compound of 2,2,2-trifluoroethyl 2-(5-methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoacetic acid synthesis

在-10℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(783.11mg，4.11mmol)逐滴添加到5-甲基-2-[3-(三氟甲基)苯基]哌啶(1g，4.11mmol)及TEA(415.96mg，4.11mmol，572.95μL)於THF(20mL)中之溶液中。將所得混合物升溫至室溫且攪拌12h。過濾出所得沉澱。蒸發濾液，以獲得2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.3g，3.27mmol，79.60%產率)，其不經純化即用於下一步驟。2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (783.11 mg, 4.11 mmol) was added dropwise to 5-methyl-2-[3-(trifluoroethyl) at -10°C Fluoromethyl)phenyl]piperidine (1 g, 4.11 mmol) and TEA (415.96 mg, 4.11 mmol, 572.95 μL) in THF (20 mL). The resulting mixture was warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered off. The filtrate was evaporated to obtain 2,2,2-trifluoroethyl 2-[5-methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetic acid Ester (1.3 g, 3.27 mmol, 79.60% yield), which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.48(m,1H),1.68(m,1H),1.98(m,1H),2.12(m,2H),3.36(m,3H),5.52(s,2H),7.68(m,4H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.48(m,1H), 1.68(m,1H), 1.98(m,1H), 2.12(m,2H), 3.36 (m, 3H), 5.52 (s, 2H), 7.68 (m, 4H).

LCMS(ESI)：[M]+ m/z：計算值397.2；實測值398.2；Rt=1.502min。LCMS (ESI): [M] + m/z: calculated 397.2; found 398.2; Rt=1.502 min.

步驟4：2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙酸之合成Step 4: Synthesis of 2-(5-methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoacetic acid

將98%氫氧化鋰單水合物(137.30mg，3.27mmol，90.93μL)添加到2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.3,3.27mmol)於水(2mL)及THF(20mL)中之溶液中且將所得混合物在20℃下攪拌12h。將所得混合物蒸發至乾，以獲得2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸(0.9，2.79mmol，85.36%產率，Li+ )，其不經純化即用於下一步驟。98% Lithium hydroxide monohydrate (137.30 mg, 3.27 mmol, 90.93 μL) was added to 2-[5-methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl] - A solution of 2,2,2-trifluoroethyl 2-pendoxoacetic acid (1.3, 3.27 mmol) in water (2 mL) and THF (20 mL) and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was evaporated to dryness to obtain 2-[5-methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-pendoxoacetic acid (0.9, 2.79 mmol , 85.36% yield, Li + ), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.48(m,2H),2.12(m,2H),2.48(m,1H),3.02(m,1H),3.36(m,2H),5.25(m,1H),7.56(m,4H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.48(m,2H), 2.12(m,2H), 2.48(m,1H), 3.02(m,1H), 3.36 (m, 2H), 5.25 (m, 1H), 7.56 (m, 4H).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=1.165min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=1.165 min.

4Y. 2-異丙基-5-甲基哌啶之合成4Y. Synthesis of 2-isopropyl-5-methylpiperidine

Figure 110128222-A0202-12-0731-597
Figure 110128222-A0202-12-0731-597

步驟1：N-(2,5-二甲基-4-側氧基己基)胺甲酸第三丁酯之合成Step 1: Synthesis of 3-butyl N-(2,5-dimethyl-4-oxyhexyl)carbamate

向鎂(2.56g，105.22mmol，1.47mL)於THF(100mL)中之懸浮液中添加2-溴丙烷(12.94g，105.22mmol)。將反應混合物攪拌45分鐘，以得到灰色溶液。在-78℃下，將新鮮製備之格任亞試劑逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(20.4g，95.65mmol)於THF(200mL)中之經預冷卻之懸浮液中。將反應混合物在-78℃下攪拌1小時。1小時之後，使反應混合物升溫至室溫且攪拌12小時。12小時之後，將反應物用MTBE(500mL)稀釋且用100mL飽和氯化銨水溶液緩慢淬滅。將有機相用飽和碳酸氫鈉溶液(2 x 200mL)洗滌。將經合併之水性級分用MTBE反萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析純化粗產物，以獲得呈淡黃色液體之N -(2,5-二甲基-4-側氧基己基)胺甲酸第三丁 酯(6.79g，27.91mmol，29.18%產率)。To a suspension of magnesium (2.56 g, 105.22 mmol, 1.47 mL) in THF (100 mL) was added 2-bromopropane (12.94 g, 105.22 mmol). The reaction mixture was stirred for 45 minutes to obtain a grey solution. Freshly prepared Grignard reagent was added dropwise to tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (20.4 g, 95.65 mmol) in THF (200 mL) at -78 °C in the pre-cooled suspension. The reaction mixture was stirred at -78°C for 1 hour. After 1 hour, the reaction mixture was warmed to room temperature and stirred for 12 hours. After 12 hours, the reaction was diluted with MTBE (500 mL) and slowly quenched with 100 mL of saturated aqueous ammonium chloride. The organic phase was washed with saturated sodium bicarbonate solution (2 x 200 mL). The combined aqueous fractions were back extracted with MTBE. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 3-butyl N- (2,5-dimethyl-4-oxyhexyl) carbamate (6.79 g, 27.91 mmol, 29.18%) as a pale yellow liquid Yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.88(m,3H),1.07(m,6H),1.42(m,10H),1.62 (m,3H),2.46(m,2H),2.58(m,1H),2.97(m,2H),4.63(brs,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.88 (m, 3H), 1.07 (m, 6H), 1.42 (m, 10H), 1.62 (m, 3H), 2.46 (m, 2H), 2.58 (m, 1H), 2.97 (m, 2H), 4.63 (brs, 1H).

步驟2：6-異丙基-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-isopropyl-3-methyl-2,3,4,5-tetrahydropyridine

將N -(2,5-二甲基-4-側氧基己基)胺甲酸第三丁 酯(6.79g，27.91mmol)於TFA(30mL)及DCM(30mL)之溶液在25℃下攪拌12小時。12小時之後，添加飽和硫酸鈉水溶液(50mL)，然後將其用DCM(2 x 50mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得呈淡黃色油狀物之6-異丙基-3-甲基-2,3,4,5-四氫吡啶(3.6g，25.86mmol，92.65%產率)。粗產物不經任何進一步純化即用於下一步反應。A solution of tert-butyl N- (2,5-dimethyl-4-oxyhexyl) carbamate (6.79 g, 27.91 mmol) in TFA (30 mL) and DCM (30 mL) was stirred at 25 °C for 12 Hour. After 12 hours, saturated aqueous sodium sulfate (50 mL) was added, which was then extracted with DCM (2 x 50 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 6-isopropyl-3-methyl-2,3,4,5-tetrakis as a pale yellow oil Hydropyridine (3.6 g, 25.86 mmol, 92.65% yield). The crude product was used in the next reaction without any further purification.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.88(m,3H),1.19(m,6H),1.40(m,1H),1.53(m,1H),1.72(m,1H),2.07(m,2H),2.21(m,1H),2.98(m,1H),3.65(d,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.88 (m, 3H), 1.19 (m, 6H), 1.40 (m, 1H), 1.53 (m, 1H), 1.72 (m, 1H), 2.07 (m, 2H), 2.21 (m, 1H), 2.98 (m, 1H), 3.65 (d, 1H).

步驟3：2-異丙基-5-甲基哌啶之合成Step 3: Synthesis of 2-isopropyl-5-methylpiperidine

將硼氫化鈉(1.96g，51.71mmol)分批添加到6-異丙基-3-甲基-2,3,4,5-四氫吡啶(3.6g，25.86mmol)於甲醇(72mL)中之溶液中。將混合物在室溫下攪拌12小時。12小時之後，添加水(50mL)且將所得混合物用EtOAc(2 x 50mL)萃取。將經合併之有機相經硫酸鈉乾燥，過濾。添加於二噁烷中之HCl(50mL)且將所得溶液在減壓下濃縮，以獲得呈黃色油狀物之2-異丙基-5-甲基哌啶(4g，粗品，鹽酸鹽)。粗產物不經任何進一步純化即用於下一步反應。Sodium borohydride (1.96 g, 51.71 mmol) was added portionwise to 6-isopropyl-3-methyl-2,3,4,5-tetrahydropyridine (3.6 g, 25.86 mmol) in methanol (72 mL) in the solution. The mixture was stirred at room temperature for 12 hours. After 12 hours, water (50 mL) was added and the resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over sodium sulfate and filtered. HCl in dioxane (50 mL) was added and the resulting solution was concentrated under reduced pressure to give 2-isopropyl-5-methylpiperidine (4 g, crude, hydrochloride) as a yellow oil . The crude product was used in the next reaction without any further purification.

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)0.93(m,9H),1.08(m,1H),1.34(m,1H),1.84(m,4H),2.45(m,1H),2.68(m,1H),3.07(m,1H),8.90(brs,2H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 0.93 (m, 9H), 1.08 (m, 1H), 1.34 (m, 1H), 1.84 (m, 4H), 2.45 (m, 1H) , 2.68 (m, 1H), 3.07 (m, 1H), 8.90 (brs, 2H).

4Z. 2-(4-第三丁基 環己基)-5-甲基哌啶之合成4Z. Synthesis of 2-(4-tert -butylcyclohexyl )-5-methylpiperidine

Figure 110128222-A0202-12-0733-598
Figure 110128222-A0202-12-0733-598

步驟1：6-(4-第三丁基環己烯-1-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(4-tert-butylcyclohexen-1-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7.19g，20.82mmol)、2-(4-第三丁基 環己烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(5g，18.92mmol))及碳酸鈉(6.02g，56.77mmol)於1,4-二噁烷(90mL)及水(30mL)中之正攪拌溶液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 (772.71mg，946.22μmol)。將反應混合物在氬氣、80℃下攪拌14小時。14小時之後，將反應混合物冷卻且過濾。將濾餅用1.4-二噁烷(2 x 20mL)洗滌且丟棄。在真空中蒸發濾液且藉由管柱層析純化殘餘物，以得到呈無色油狀物之6-(4-第三丁基 環己烯-1-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.10g，9.30mmol，49.12%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7.19 g, 20.82 mmol), 2-( 4- tert-butylcyclohexen -1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5g, 18.92mmol)) and carbonic acid A stirring solution of sodium (6.02 g, 56.77 mmol) in 1,4-dioxane (90 mL) and water (30 mL) was purged with argon. Then, Pd(dppf)Cl 2 (772.71 mg, 946.22 μmol) was added under argon. The reaction mixture was stirred under argon at 80°C for 14 hours. After 14 hours, the reaction mixture was cooled and filtered. The filter cake was washed with 1.4-dioxane (2 x 20 mL) and discarded. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 6-(4-tert -butylcyclohexen -1-yl)-3-methyl-3,4 as a colorless oil - Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.10 g, 9.30 mmol, 49.12% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值333.3；實測值278.2(t -Bu裂解之產物質量)；Rt=1.903min。LCMS (ESI): [M+Boc] + m/z: calculated 333.3; found 278.2 ( t -Bu cleavage product mass); Rt=1.903 min.

步驟2：Step 2: 6-(4-第三丁基環己烯-1-基)-3-甲基-2,3,4,5-四氫吡啶之合成Synthesis of 6-(4-tert-butylcyclohexen-1-yl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(4-第三丁基 環己烯-1-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.1g，9.30mmol)溶解於三氟乙酸(30g，263.10mmol，20.27mL)中。將所得反應混合物在25℃下攪拌3小時。3小時之後，將反應混合物冷卻至0℃且逐滴 添加20% NaOH水溶液。將所得懸浮液用二氯甲烷(2 x 100mL)萃取。將經合併之有機相用水(100mL)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以得到呈無色油狀物之6-(4-第三丁基 環己烯-1-基)-3-甲基-2,3,4,5-四氫吡啶(2.1g，9.00mmol，96.80%產率)。粗產物不經任何進一步純化即用於下一步反應。6-(4-tert -butylcyclohexen -1-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.1 g, 9.30 mmol) Dissolve in trifluoroacetic acid (30 g, 263.10 mmol, 20.27 mL). The resulting reaction mixture was stirred at 25°C for 3 hours. After 3 hours, the reaction mixture was cooled to 0 °C and 20% aqueous NaOH was added dropwise. The resulting suspension was extracted with dichloromethane (2 x 100 mL). The combined organic phases were washed with water (100 mL), dried over Na 2 SO 4 and evaporated under reduced pressure to give 6-(4-tert -butylcyclohexen -1-yl) as a colorless oil -3-Methyl-2,3,4,5-tetrahydropyridine (2.1 g, 9.00 mmol, 96.80% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值233.2；實測值234.2；Rt=1.045min。LCMS (ESI): [M+H] + m/z: calculated 233.2; found 234.2; Rt=1.045 min.

步驟3：2-(4-第三丁基環己烯-1-基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(4-tert-butylcyclohexen-1-yl)-5-methylpiperidine

在0℃下，向6-(4-第三丁基 環己烯-1-基)-3-甲基-2,3,4,5-四氫吡啶(2.1g，9.00mmol)於MeOH(30mL)中之經攪拌之溶液中分批添加硼氫化鈉(1.02g，26.99mmol，954.42μL)。將所得反應混合物在25℃下攪拌4小時。4小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用水(80mL)稀釋且用DCM(2 x 100mL)萃取。將經合併之有機相用鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以得到呈無色油狀物之2-(4-第三丁基 環己烯-1-基)-5-甲基哌啶(2g，8.50mmol，94.42%產率)。粗產物不經任何進一步純化即用於下一步反應。To 6-(4-tert -butylcyclohexen -1-yl)-3-methyl-2,3,4,5-tetrahydropyridine (2.1 g, 9.00 mmol) in MeOH ( To the stirred solution in 30 mL) was added sodium borohydride (1.02 g, 26.99 mmol, 954.42 μL) portionwise. The resulting reaction mixture was stirred at 25°C for 4 hours. After 4 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (80 mL) and extracted with DCM (2 x 100 mL). The combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 2-(4-tert -butylcyclohexen -1-yl)-5 as a colorless oil - Methylpiperidine (2 g, 8.50 mmol, 94.42% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值235.2；實測值236.2；Rt=1.222min。LCMS (ESI): [M+H] + m/z: calculated 235.2; found 236.2; Rt=1.222 min.

步驟4：2-(4-第三丁基環己基)-5-甲基哌啶之合成Step 4: Synthesis of 2-(4-tert-butylcyclohexyl)-5-methylpiperidine

將2-(4-第三丁基 環己烯-1-基)-5-甲基哌啶(2g，8.50mmol)於甲醇(50mL)中之溶液在鈀(10%於碳上)(0.2g)上在氫氣氣氛、25℃下氫化72小時。完成之後，將反應混合物過濾，將濾餅用甲醇洗滌且在減壓下濃縮濾液，以得到呈淡黃色膠狀物之2-(4-第三丁基 環己基)-5-甲基哌啶(1.5g，6.32mmol，74.36%產率)。粗產物不經任何進一步純化即用於下一步反應。A solution of 2-(4-tert -butylcyclohexen -1-yl)-5-methylpiperidine (2 g, 8.50 mmol) in methanol (50 mL) in palladium (10% on carbon) (0.2 g) was hydrogenated at 25° C. for 72 hours under a hydrogen atmosphere. After completion, the reaction mixture was filtered, the filter cake was washed with methanol and the filtrate was concentrated under reduced pressure to give 2-(4-tert -butylcyclohexyl )-5-methylpiperidine as a pale yellow gum (1.5 g, 6.32 mmol, 74.36% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值237.3；實測值238.2；Rt=1.267min。LCMS (ESI): [M+H] + m/z: calculated 237.3; found 238.2; Rt=1.267 min.

4AA . 2-環丁基-5-甲基哌啶之合成 4AA . Synthesis of 2-cyclobutyl-5-methylpiperidine

Figure 110128222-A0202-12-0735-599
Figure 110128222-A0202-12-0735-599

步驟1：N-(4-環丁基-2-甲基-4-側氧基丁基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-(4-cyclobutyl-2-methyl-4-oxybutyl)carbamate

向鎂(3.13g，128.94mmol，1.80mL)於THF(200mL)中之懸浮液中添加環丁基溴(17.41g，128.94mmol)。將反應混合物攪拌45分鐘，以得到灰色溶液。在-78℃下，將新鮮製備之格任亞試劑逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(25g，117.22mmol)於THF(100mL)中之經預冷卻之懸浮液中。將反應混合物在-78℃下攪拌1小時。1小時之後，使反應混合物升溫至室溫且攪拌12小時。12小時之後，將反應物用MTBE(500mL)稀釋且用100mL飽和氯化銨水溶液緩慢淬滅。將有機相用飽和碳酸氫鈉溶液(2 x 200mL)洗滌。將經合併之水性級分用MTBE反萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析純化粗產物，以獲得呈無色液體之N -(4-環丁基-2-甲基-4-側氧基丁基)胺甲酸第三丁 酯(3.9g，15.27mmol，13.03%產率)。To a suspension of magnesium (3.13 g, 128.94 mmol, 1.80 mL) in THF (200 mL) was added cyclobutyl bromide (17.41 g, 128.94 mmol). The reaction mixture was stirred for 45 minutes to obtain a grey solution. Freshly prepared Grignard reagent was added dropwise to tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (25 g, 117.22 mmol) in THF (100 mL) at -78 °C in the pre-cooled suspension. The reaction mixture was stirred at -78°C for 1 hour. After 1 hour, the reaction mixture was warmed to room temperature and stirred for 12 hours. After 12 hours, the reaction was diluted with MTBE (500 mL) and slowly quenched with 100 mL of saturated aqueous ammonium chloride. The organic phase was washed with saturated sodium bicarbonate solution (2 x 200 mL). The combined aqueous fractions were back extracted with MTBE. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain tert-butyl N- (4-cyclobutyl-2-methyl-4-oxybutyl) carbamate (3.9 g, 15.27 mmol) as a colorless liquid , 13.03% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.85(m,3H),1.42(m,10H),1.59(m,3H),1.86(m,2H),2.16(m,4H),2.34(m,2H),2.98(m,2H),3.23(m,1H),4.61(brs,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.85 (m, 3H), 1.42 (m, 10H), 1.59 (m, 3H), 1.86 (m, 2H), 2.16 (m, 4H), 2.34 (m, 2H), 2.98 (m, 2H), 3.23 (m, 1H), 4.61 (brs, 1H).

步驟2：6-環丁基-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-cyclobutyl-3-methyl-2,3,4,5-tetrahydropyridine

將N -(4-環丁基-2-甲基-4-側氧基丁基)胺甲酸第三丁 酯(3.9g，15.27mmol)於TFA(20mL)及DCM(20mL)中之溶液在25℃下攪拌12小時。12小時之後，添加飽和硫酸鈉水溶液(50mL)，然後將其用DCM(2 x 50mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得呈淡黃色油狀物之6-環丁基-3-甲基-2,3,4,5-四氫吡啶(2.6g，粗品)。粗產物不經任何進一步純化即用於下一步反應。A solution of tert-butyl N- (4-cyclobutyl-2-methyl-4-oxybutyl) carbamate (3.9 g, 15.27 mmol) in TFA (20 mL) and DCM (20 mL) was Stir at 25°C for 12 hours. After 12 hours, saturated aqueous sodium sulfate (50 mL) was added, which was then extracted with DCM (2 x 50 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 6-cyclobutyl-3-methyl-2,3,4,5-tetrakis as a pale yellow oil Hydropyridine (2.6 g, crude). The crude product was used in the next reaction without any further purification.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.89(m,3H),1.19(m,1H),1.54(m,1H),1.72 (m,2H),1.88(m,1H),2.09(m,6H),2.96(m,2H),3.72(d,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.89 (m, 3H), 1.19 (m, 1H), 1.54 (m, 1H), 1.72 (m, 2H), 1.88 (m, 1H), 2.09 (m, 6H), 2.96 (m, 2H), 3.72 (d, 1H).

步驟3：2-環丁基-5-甲基哌啶之合成Step 3: Synthesis of 2-cyclobutyl-5-methylpiperidine

將硼氫化鈉(1.30g，34.38mmol，1.22mL)分批添加到6-環丁基-3-甲基-2,3,4,5-四氫吡啶(2.6g，17.19mmol)於甲醇(30mL)中之溶液中。將混合物在室溫下攪拌12小時。12小時之後，添加水(50mL)且將所得混合物用EtOAc(2 x 50mL)萃取。將經合併之有機相經硫酸鈉乾燥，過濾且在減壓下濃縮，以獲得呈淡黃色液體之2-環丁基-5-甲基哌啶(1.56g，粗品)。粗產物不經任何進一步純化即用於下一步反應。Sodium borohydride (1.30 g, 34.38 mmol, 1.22 mL) was added portionwise to 6-cyclobutyl-3-methyl-2,3,4,5-tetrahydropyridine (2.6 g, 17.19 mmol) in methanol ( 30 mL) in the solution. The mixture was stirred at room temperature for 12 hours. After 12 hours, water (50 mL) was added and the resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-cyclobutyl-5-methylpiperidine (1.56 g, crude) as a pale yellow liquid. The crude product was used in the next reaction without any further purification.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.81(m,3H),0.92(m,2H),1.43(m,2H),1.68(m,7H),1.92(m,4H),2.17(m,4H),2.98(d,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.81 (m, 3H), 0.92 (m, 2H), 1.43 (m, 2H), 1.68 (m, 7H), 1.92 (m, 4H), 2.17 (m, 4H), 2.98 (d, 1H).

4BB.外消旋 -3-氯-5-((2R,5S )-5-甲基哌啶-2-基)吡啶之合成4BB. Synthesis of racemic -3-chloro-5-(( 2R,5S )-5-methylpiperidin-2-yl)pyridine

Figure 110128222-A0202-12-0736-601
Figure 110128222-A0202-12-0736-601

步驟1：(5-(5-氯吡啶-3-基)-2-甲基-5-側氧基戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (5-(5-chloropyridin-3-yl)-2-methyl-5-oxypentyl)carbamate

將3-溴-5-氯吡啶(5g，25.98mmol)溶解於THF(30mL)中且在Ar下冷卻至-78℃。逐滴添加異丙基氯化鎂氯化鋰(1.3M，9.70mL)，保持溫度接近-78℃。在添加試劑之後，使反應混合物升溫至室溫且在同一溫度下攪拌3h，隨後緩慢添加5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(5.54g，25.98mmol)於EtOAc(50mL)中之溶液且使反應混合物緩慢升溫至室溫。反應完成之後，將混合物倒入10% NH4 Cl水溶液中且用EtOAc(30mL)萃取三次。蒸發經合併之有機溶劑且藉由CC(OK.Interchim，330g SiO2，石油醚/MTBE，其中MTBE為10~100%，流速=135mL/min，Rv=11-12CV)純化，得到N -[5-(5-氯-3-吡啶基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(4.5g，13.77mmol，52.99%產率)。3-Bromo-5-chloropyridine (5 g, 25.98 mmol) was dissolved in THF (30 mL) and cooled to -78 °C under Ar. Lithium isopropylmagnesium chloride (1.3M, 9.70 mL) was added dropwise maintaining the temperature near -78°C. After the addition of the reagents, the reaction mixture was allowed to warm to room temperature and stirred at the same temperature for 3 h, followed by the slow addition of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (5.54 g, 25.98 mmol) solution in EtOAc (50 mL) and the reaction mixture was slowly warmed to room temperature. After the reaction was completed, the mixture was poured into 10% aqueous NH4Cl and extracted three times with EtOAc (30 mL). The combined organic solvents were evaporated and purified by CC (OK.Interchim, 330g SiO2, petroleum ether/MTBE, where MTBE was 10-100%, flow rate=135mL/min, Rv=11-12CV) to give N- [5 -(5-Chloro-3-pyridyl)-2-methyl-5-oxypentyl]carbamic acid tert- butyl ester (4.5 g, 13.77 mmol, 52.99% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.98(d,3H),1.42(s,9H),1.77(m,3H),3.02(m,4H),4.67(m,1H),8.17(s,1H),8.71(s,1H),9.00(s,1H)。LCMS(ESI)：[M-Boc]+ m/z：計算值226.2；實測值227.2；Rt=1.316min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.98(d, 3H), 1.42(s, 9H), 1.77(m, 3H), 3.02(m, 4H), 4.67(m, 1H), 8.17( s, 1H), 8.71 (s, 1H), 9.00 (s, 1H). LCMS (ESI): [M-Boc] + m/z: calculated 226.2; found 227.2; Rt=1.316 min.

步驟2：5'-氯-5-甲基-3,4,5,6-四氫-2,3'-聯吡啶之合成Step 2: Synthesis of 5'-chloro-5-methyl-3,4,5,6-tetrahydro-2,3'-bipyridine

將N -[5-(5-氯-3-吡啶基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(4.5g，13.77mmol)溶解於DCM(40mL)中，隨後添加TFA(3.14g，27.54mmol，2.12mL)且攪拌3h。反應完成(氣體逸出停止)之後，將混合物用50% NaOH水溶液鹼化至pH=14。分離各層，且另外用DCM(3*20mL)萃取上層。將經合併之有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到3-氯-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(2.5g，11.98mmol，87.00%產率)，其不經純化即用於下一步驟。3-Butyl N- [5-(5-chloro-3-pyridyl)-2-methyl-5-oxypentyl] carbamate (4.5 g, 13.77 mmol) was dissolved in DCM (40 mL) , then TFA (3.14 g, 27.54 mmol, 2.12 mL) was added and stirred for 3 h. After the reaction was complete (gas evolution ceased), the mixture was basified to pH=14 with 50% aqueous NaOH. The layers were separated and the upper layer was additionally extracted with DCM (3*20 mL). The combined organic layers were dried over Na 2 SO 4 and evaporated under reduced pressure to give 3-chloro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine (2.5 g, 11.98 mmol, 87.00% yield), which was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值208.2；實測值209.2；Rt=0.493min。LCMS (ESI): [M] + m/z: calculated 208.2; found 209.2; Rt=0.493 min.

步驟3：外消旋-3-氯-5-((2R,5S)-5-甲基哌啶-2-基)吡啶之合成Step 3: Synthesis of racemic-3-chloro-5-((2R,5S)-5-methylpiperidin-2-yl)pyridine

將3-氯-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(2.5g，11.98mmol)溶解於MeOH(5mL)中且冷卻至0℃。將硼氫化鈉(906.44mg，23.96mmol，847.14μL)分批添加到所獲得之混合物中且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH=2，用MTBE洗滌(2*10mL)，用10% NaOH水溶液鹼化至pH=10且用DCM(20mL)萃取。蒸發溶劑，得到純的3-氯-5-[(2R,5S )-5-甲基-2-哌啶基]吡啶(2.2g，10.44mmol，87.16%產率)。3-Chloro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine (2.5 g, 11.98 mmol) was dissolved in MeOH (5 mL) and cooled to 0 °C. Sodium borohydride (906.44 mg, 23.96 mmol, 847.14 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl, washed with MTBE (2*10 mL), basified with 10% aqueous NaOH to pH=10 and extracted with DCM (20 mL). The solvent was evaporated to give pure 3-chloro-5-[( 2R,5S )-5-methyl-2-piperidinyl]pyridine (2.2 g, 10.44 mmol, 87.16% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.12(m,1H),1.78(m,5H),2.42(m,1H),3.12(m,1H),3.61(m,1H),7.72(s,1H),8.48(s,2H)。LCMS(ESI)：[M]+ m/z：計算值210.2；實測值211.2；Rt=0.631min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.12(m,1H), 1.78(m,5H), 2.42(m,1H), 3.12(m,1H), 3.61 (m, 1H), 7.72 (s, 1H), 8.48 (s, 2H). LCMS (ESI): [M] + m/z: calculated 210.2; found 211.2; Rt=0.631 min.

4CC. 2-(3,5-二氯苯基)-5-甲基哌啶之合成4CC. Synthesis of 2-(3,5-dichlorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0738-602
Figure 110128222-A0202-12-0738-602

步驟1. N-[5-(3,5-二氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1. Synthesis of N-[5-(3,5-dichlorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(241.77mg，1.16mmol)及5-(5-甲基-2-哌啶基)-1H-吡唑并[4,3-b]吡啶(0.25g，1.16mmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(439.51mg，1.16mmol)，隨後添加TEA(116.97mg，1.16mmol，161.11μL)，且在周圍溫度下攪拌12h。在真空中蒸發反應混合物且藉由製備型(25-45% 1-6min水-甲醇(NH3 0.1%)，流速30ml/min)純化所獲得之0.48g粗產物，以得到產物5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.14g，343.62μmol，29.73%產率)。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (241.77 mg, 1.16 mmol) and 5-(5-methyl-2-piperidinyl)- 1H-Pyrazolo[4,3-b]pyridine (0.25 g, 1.16 mmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (439.51 mg, 1.16 mmol) was added followed by TEA (116.97 mg, 1.16 mmol, 161.11 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and the obtained 0.48 g of crude product was purified by preparative (25-45% 1-6 min water-methanol ( NH3 0.1%), flow rate 30 ml/min) to give the product 5-[[ 2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2-pendoxetylacetone yl]amino]pyridine-3-carboxamide (0.14 g, 343.62 μmol, 29.73% yield).

1 H NMR(400MHz,CDCl3 )δ 0.92(m,3H),1.42(s,13H),1.67-1.82(m,2H),2.95(m,2H),4.68(m,1H),7.21(m,1H),7.82(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ 0.92(m, 3H), 1.42(s, 13H), 1.67-1.82(m, 2H), 2.95(m, 2H), 4.68(m, 1H), 7.21(m , 1H), 7.82 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值360.0；實測值360.2；Rt=1.683min。LCMS (ESI): [M] + m/z: calculated 360.0; found 360.2; Rt=1.683 min.

步驟2. 2-(3,5-二氯苯基)-5-甲基哌啶之合成Step 2. Synthesis of 2-(3,5-dichlorophenyl)-5-methylpiperidine

將N-[5-(3,5-二氯苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(12g，33.31mmol)於三氟乙酸(18.99g，166.54mmol，12.83mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4 x 20mL且將有機層合併，以MgSO4乾燥且蒸發。將產物溶解於水(25mL)/MeOH(150mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(1.26g，33.31mmol，1.18mL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發。藉由 CC(Interchim，120g SiO2，己烷/MTBE，其中MTBE為0~100%，流速=85ml/min，RV=6,9CV.)純化殘餘物，以得到呈淡黃色油狀物之2-(3,5-二氯苯基)-5-甲基哌啶(2.9g，11.88mmol，35.66%產率)。N-[5-(3,5-Dichlorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester (12 g, 33.31 mmol) in trifluoroacetic acid (18.99 g, 166.54 mmol, 12.83 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a mixture of water (25 mL)/MeOH (150 mL) and added to the flask followed by sodium borohydride (1.26 g, 33.31 mmol, 1.18 mL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 x 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated. The residue was purified by CC (Interchim, 120 g SiO2, hexane/MTBE, where MTBE was 0-100%, flow rate=85 ml/min, RV=6, 9CV.) to give 2- as a pale yellow oil (3,5-Dichlorophenyl)-5-methylpiperidine (2.9 g, 11.88 mmol, 35.66% yield).

1 H NMR(400MHz,CDCl3 )δ 0.88(d,3H),1.13(m,1H),1.45(dd,1H),1.63(m,2H),1.77(d,1H),1.85(d,1H),2.38(dd,1H),3.11(d,1H),3.60(d,1H),7.21(s,1H),7.26(s,2H)。 1 H NMR (400MHz, CDCl 3 )δ 0.88(d,3H), 1.13(m,1H), 1.45(dd,1H), 1.63(m,2H), 1.77(d,1H), 1.85(d,1H) ), 2.38(dd, 1H), 3.11(d, 1H), 3.60(d, 1H), 7.21(s, 1H), 7.26(s, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值243.0；實測值244.2；Rt=0.978min。LCMS (ESI): [M+1] + m/z: calculated 243.0; found 244.2; Rt=0.978 min.

4DD. 2-甲基-5-[(2R,5S)-5-甲基-2-哌啶基]吡啶之合成4DD. Synthesis of 2-methyl-5-[(2R,5S)-5-methyl-2-piperidinyl]pyridine

Figure 110128222-A0202-12-0739-604
Figure 110128222-A0202-12-0739-604

步驟1：N-[2-甲基-5-(6-甲基-3-吡啶基)-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of N-[2-methyl-5-(6-methyl-3-pyridyl)-5-oxypentyl]carbamic acid tert-butyl ester

將5-溴-2-甲基吡啶(3g，17.44mmol)溶解於THF(30mL)中且在Ar下冷卻至-78℃。逐滴添加丁基鋰(2.5M，7.67mL)，保持溫度為約-78℃。添加試劑之後，將反應混合物在同一溫度下攪拌0.5h，隨後緩慢添加5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(3.72g，17.44mmol)於THF(10mL)中之溶液且使反應混合物緩慢升溫至室溫。反應完成之後，將混合物倒入10% NH4 Cl水溶液中且用EtOAc(50mL)萃取三次。蒸發經合併之有機溶劑，得到粗品N-[2-甲基-5-(6-甲基-3-吡啶基)-5-側氧基戊基]胺甲酸第三丁酯(7g，粗品)，其不經純化即用於下一步驟。5-Bromo-2-methylpyridine (3 g, 17.44 mmol) was dissolved in THF (30 mL) and cooled to -78 °C under Ar. Butyllithium (2.5M, 7.67 mL) was added dropwise maintaining the temperature at about -78°C. After addition of the reagents, the reaction mixture was stirred at the same temperature for 0.5 h, followed by the slow addition of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (3.72 g, 17.44 mmol) in THF (10 mL) solution in and the reaction mixture was slowly warmed to room temperature. After the reaction was completed, the mixture was poured into 10% aqueous NH4Cl and extracted three times with EtOAc (50 mL). The combined organic solvents were evaporated to give crude tert-butyl N-[2-methyl-5-(6-methyl-3-pyridyl)-5-oxypentyl]carbamate (7 g, crude) , which was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ 1.02(m,3H),1.24(s,9H),1.46(m,2H),1.86(m,2H),2.59(m,3H),2.67(m,3H),4.72(m,1H),7.24(s,1H),8.09(s,1H),9.02(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.02 (m, 3H), 1.24 (s, 9H), 1.46 (m, 2H), 1.86 (m, 2H), 2.59 (m, 3H), 2.67 (m, 3H) ), 4.72(m, 1H), 7.24(s, 1H), 8.09(s, 1H), 9.02(s, 1H).

步驟2：2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶之合成Step 2: Synthesis of 2-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine

將N-[2-甲基-5-(6-甲基-3-吡啶基)-5-側氧基戊基]胺甲酸第三丁酯(7 g，22.85mmol)溶解於DCM(30mL)中，隨後添加TFA(5.21g，45.69mmol，3.52mL)且攪拌3h。反應完成(氣體逸出停止)之後，將混合物用50% NaOH水溶液鹼化至pH 14。分離各層，且另外用DCM(3*20mL)萃取上層。將經合併之有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(3.5g，粗品)。3-butyl N-[2-methyl-5-(6-methyl-3-pyridinyl)-5-oxypentyl]carbamate (7 g, 22.85 mmol) was dissolved in DCM (30 mL) In, TFA (5.21 g, 45.69 mmol, 3.52 mL) was then added and stirred for 3 h. After the reaction was complete (gas evolution ceased), the mixture was basified to pH 14 with 50% aqueous NaOH. The layers were separated and the upper layer was additionally extracted with DCM (3*20 mL). The combined organic layers were dried over Na 2 SO 4 and evaporated under reduced pressure to give 2-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) Pyridine (3.5 g, crude).

1 H NMR(400MHz,CDCl3 )δ 1.04(m,3H),1.21(m,2H),1.91(m,2H),3.71(m,3H),3.21(m,2H),4.01(m,1H),7.12(s,1H),7.98(s,1H),8.78(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.04 (m, 3H), 1.21 (m, 2H), 1.91 (m, 2H), 3.71 (m, 3H), 3.21 (m, 2H), 4.01 (m, 1H) ), 7.12(s, 1H), 7.98(s, 1H), 8.78(s, 1H).

步驟3：2-甲基-5-[(2R,5S)-5-甲基-2-哌啶基]吡啶之合成Step 3: Synthesis of 2-methyl-5-[(2R,5S)-5-methyl-2-piperidinyl]pyridine

將2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(2.92g，15.51mmol)溶解於甲醇(20mL)中且冷卻至0℃。將硼氫化鈉(1.17g，31.02mmol，1.10mL)分批添加到所獲得之混合物且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH 2，用MTBE洗滌(2*10mL)，用10% NaOH水溶液鹼化至pH 10且用DCM(40mL)萃取。蒸發溶劑且藉由矽膠管柱層析(Companion；120g SiO2 ；MtBE/甲醇，其中甲醇為0至20%，流速=85ml/min，Rv=10-11cv.)純化，產生純的2-甲基-5-[(2R,5S)-5-甲基-2-哌啶基]吡啶(0.7g，3.68mmol，23.72%產率)。2-Methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine (2.92 g, 15.51 mmol) was dissolved in methanol (20 mL) and cooled to 0 °C . Sodium borohydride (1.17 g, 31.02 mmol, 1.10 mL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH 2 with 10% aqueous HCl, washed with MTBE (2*10 mL), basified to pH 10 with 10% aqueous NaOH and extracted with DCM (40 mL). The solvent was evaporated and purified by silica gel column chromatography (Companion; 120 g SiO2 ; MtBE/methanol with 0 to 20% methanol, flow rate=85 ml/min, Rv=10-11 cv.) to yield pure 2-methanone yl-5-[(2R,5S)-5-methyl-2-piperidinyl]pyridine (0.7 g, 3.68 mmol, 23.72% yield).

1 H NMR(500MHz,CDCl3 )δ 0.94(m,3H),1.07(m,1H),1.72(m,5H),2.41(m,1H),2.55(s,3H),3.05(m,1H),3.55(m,1H),7.03(s,1H),7.56(s,1H),8.41(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.94(m, 3H), 1.07(m, 1H), 1.72(m, 5H), 2.41(m, 1H), 2.55(s, 3H), 3.05(m, 1H) ), 3.55(m, 1H), 7.03(s, 1H), 7.56(s, 1H), 8.41(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值190.2；實測值191.2；Rt=0.458min。LCMS (ESI): [M+H] + m/z: calculated 190.2; found 191.2; Rt=0.458 min.

4EE.外消旋 -(2S ,4R )-4-乙基-2-苯基哌啶之合成 4EE . Synthesis of racemic- ( 2S ,4R)-4-ethyl-2-phenylpiperidine

Figure 110128222-A0202-12-0740-605
Figure 110128222-A0202-12-0740-605

步驟1：4-乙基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 4-ethyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

向4-乙基哌啶-2-酮(5g，39.31mmol)於DCM(1000mL)中之經攪拌之 溶液中添加DMAP(48.03mg，393.13μmol)。將所得反應混合物加熱至回流。在48小時內逐滴添加二碳酸二-第三丁酯(17.16g，78.63mmol，18.04mL)。完成之後，將反應混合物在減壓下濃縮，以得到4-乙基-2-側氧基哌啶-1-甲酸第三丁酯(10g，粗品)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 4-ethylpiperidin-2-one (5 g, 39.31 mmol) in DCM (1000 mL) To the solution was added DMAP (48.03 mg, 393.13 μmol). The resulting reaction mixture was heated to reflux. Di-tert-butyl dicarbonate (17.16 g, 78.63 mmol, 18.04 mL) was added dropwise over 48 hours. After completion, the reaction mixture was concentrated under reduced pressure to give 3-butyl 4-ethyl-2-pendoxopiperidine-1-carboxylate (10 g, crude). The crude product was used in the next reaction without any further purification.

步驟2：N-[6-側氧基-6-(2-噻吩基)己基]胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-[6-oxy-6-(2-thienyl)hexyl]carbamate

在-78℃、氬氣氣氛下，向4-乙基-2-側氧基哌啶-1-甲酸第三丁酯(5g，22.00mmol)於THF(50mL)中之經攪拌之溶液中逐滴添加苯基氯化鎂(1M於THF中，3.99g，22.00mmol，22mL)。使反應混合物緩慢升溫至室溫。完成之後，將反應混合物用飽和NH4 Cl水溶液淬滅且用EtOAc(3 x 100mL)萃取。將經合併之有機相用鹽水(3 x 30mL)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以得到N -(3-乙基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(2.5g，8.19mmol，37.21%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 4-ethyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (5 g, 22.00 mmol) in THF (50 mL) at -78 °C under argon Phenylmagnesium chloride (1M in THF, 3.99 g, 22.00 mmol, 22 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over Na 2 SO 4 and evaporated under reduced pressure to give N- (3-ethyl-5-oxy-5-phenylpentyl ) tert -butyl carbamate (2.5 g, 8.19 mmol, 37.21% yield). The crude product was used in the next reaction without any further purification.

步驟3：4-乙基-6-苯基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 4-ethyl-6-phenyl-2,3,4,5-tetrahydropyridine

向N -(3-乙基-5-側氧基-5-苯基戊基)胺甲酸第三丁 酯(2.5g，8.19mmol)於DCM(20mL)中之經攪拌之溶液中添加TFA(1.87g，16.37mmol，1.26mL)。將所得反應混合物在室溫下攪拌3小時。完成之後，將反應混合物用50% NaOH水溶液鹼化至pH=14。將所得懸浮液用DCM(3 x 20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以得到4-乙基-6-苯基-2,3,4,5-四氫吡啶(1.4g，7.48mmol，91.32%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of tert-butyl N- (3-ethyl-5-oxy-5-phenylpentyl) carbamate (2.5 g, 8.19 mmol) in DCM (20 mL) was added TFA ( 1.87 g, 16.37 mmol, 1.26 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was basified to pH=14 with 50% aqueous NaOH. The resulting suspension was extracted with DCM (3 x 20 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to give 4-ethyl-6-phenyl-2,3,4,5-tetrahydropyridine (1.4 g, 7.48 mmol, 91.32 g %Yield). The crude product was used in the next reaction without any further purification.

步驟4：外消旋-(2S,4R)-4-乙基-2-苯基哌啶之合成Step 4: Synthesis of Racemic-(2S,4R)-4-ethyl-2-phenylpiperidine

在0℃下，將硼氫化鈉(282.80mg，7.48mmol，264.30μL)分批添加到4-乙基-6-苯基-2,3,4,5-四氫吡啶(1.4g，7.48mmol)於MeOH及H2 O中之經攪拌之溶液中。將所得反應混合物在室溫下攪拌隔夜。完成之後，將反應混合物用10% HCl水溶液酸化至pH=2，用MTBE(2 x 10mL)洗滌。將水層用10% NaOH 水溶液鹼化至pH=10且用DCM萃取。將有機層經Na2 SO4 乾燥且在減壓下濃縮，以獲得外消旋 -(2S ,4R )-4-乙基-2-苯基哌啶(0.8g，4.23mmol，56.53%產率)。Sodium borohydride (282.80 mg, 7.48 mmol, 264.30 μL) was added portionwise to 4-ethyl-6-phenyl-2,3,4,5-tetrahydropyridine (1.4 g, 7.48 mmol) at 0 °C ) in a stirred solution in MeOH and H2O . The resulting reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was acidified to pH=2 with 10% aqueous HCl, washed with MTBE (2 x 10 mL). The aqueous layer was basified with 10% aq. NaOH to pH=10 and extracted with DCM. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain rac- (2S,4R)-4-ethyl-2-phenylpiperidine (0.8 g, 4.23 mmol, 56.53 %) Yield).

5. 由吡啶合成5. Synthesis from Pyridine

5A. 2-(3,4-二甲基苯基)-5-甲基哌啶之合成5A. Synthesis of 2-(3,4-dimethylphenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0742-606
Figure 110128222-A0202-12-0742-606

步驟1：2-(3,4-二甲基苯基)-5-甲基吡啶之合成Step 1: Synthesis of 2-(3,4-Dimethylphenyl)-5-methylpyridine

向2-溴-5-甲基吡啶(1g，5.81mmol)及(3,4-二甲基苯基)硼酸(1.05g，6.98mmol)於二噁烷(20mL)中之經攪拌之溶液中添加碳酸銫(7.58g，23.25mmol)。將所得懸浮液用氬氣除氣。添加99.8%(基於金屬)肆(三苯基膦)鈀(0)(335.87mg，290.66μmol)。將反應混合物在65℃下攪拌隔夜。完成之後，過濾反應混合物且在真空中蒸發濾液，以得到油狀殘餘物。藉由反相HPLC(49%，水-乙腈，0.5-8.5min；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFire 100*19mm，5um)純化殘餘物，以得到2-(3,4-二甲基苯基)-5-甲基吡啶(0.78g，3.95mmol，68.02%產率)。To a stirred solution of 2-bromo-5-methylpyridine (1 g, 5.81 mmol) and (3,4-dimethylphenyl)boronic acid (1.05 g, 6.98 mmol) in dioxane (20 mL) Cesium carbonate (7.58 g, 23.25 mmol) was added. The resulting suspension was degassed with argon. 99.8% (metal based) tetra(triphenylphosphine)palladium(0) (335.87 mg, 290.66 μmol) was added. The reaction mixture was stirred at 65°C overnight. After completion, the reaction mixture was filtered and the filtrate was evaporated in vacuo to give an oily residue. The residue was purified by reverse phase HPLC (49%, water-acetonitrile, 0.5-8.5 min; flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile; column: SunFire 100*19 mm, 5 um) to give 2 -(3,4-Dimethylphenyl)-5-methylpyridine (0.78 g, 3.95 mmol, 68.02% yield).

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)2.25(s,3H),2.29(s,3H),2.30(s,3H),7.21(d,1H),7.64(dd,1H),7.77(m,2H),7.85(s,1H),8.46(s,1H)。 1 H NMR (DMSO- d 6 , 400MHz): δ(ppm) 2.25(s,3H), 2.29(s,3H), 2.30(s,3H), 7.21(d,1H), 7.64(dd,1H) , 7.77(m, 2H), 7.85(s, 1H), 8.46(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值197.2；實測值198.2；Rt=2.588min。LCMS (ESI): [M+H] + m/z: calculated 197.2; found 198.2; Rt=2.588 min.

步驟2：2-(3,4-二甲基苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(3,4-Dimethylphenyl)-5-methylpiperidine

將2-(3,4-二甲基苯基)-5-甲基吡啶(0.78g，3.95mmol)於MeOH(20mL)中之溶液在5% Pd(OH)2 /C(488.01mg，3.95mmol)上在100atm H2 壓力、50℃下氫化18小時。完成之後，過濾反應混合物，將殘餘物用MeOH(10mL)洗滌 且在減壓下濃縮濾液，以獲得2-(3,4-二甲基苯基)-5-甲基哌啶(0.7g，3.44mmol，87.07%產率)。粗產物不經任何進一步純化即用於下一步反應。A solution of 2-(3,4-dimethylphenyl)-5-methylpyridine (0.78 g, 3.95 mmol) in MeOH (20 mL) in 5% Pd(OH) 2 /C (488.01 mg, 3.95 mmol) at 100 atm H2 pressure at 50 °C for 18 h. After completion, the reaction mixture was filtered, the residue was washed with MeOH (10 mL) and the filtrate was concentrated under reduced pressure to obtain 2-(3,4-dimethylphenyl)-5-methylpiperidine (0.7 g, 3.44 mmol, 87.07% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值203.2；實測值204.2；Rt=0.901minLCMS(ESI): [M+H] + m/z: Calculated 203.2; Measured 204.2; Rt=0.901min

5B. 1-(4-(3-(哌啶-2-基)苯基)哌啶-1-基)乙酮之合成5B. Synthesis of 1-(4-(3-(piperidin-2-yl)phenyl)piperidin-1-yl)ethanone

Figure 110128222-A0202-12-0743-607
Figure 110128222-A0202-12-0743-607

步驟1：1-(4-(3-溴苯基)哌啶-1-基)乙酮之合成Step 1: Synthesis of 1-(4-(3-bromophenyl)piperidin-1-yl)ethanone

在0℃下，向4-(3-溴苯基)哌啶(20g，72.31mmol，HCl)及三乙胺(18.29g，180.77mmol，25.20mL)於DCM(250mL)中之溶液中逐滴添加乙醯氯(6.81g，86.77mmol，5.28mL)。將所得混合物在25℃下攪拌12h且用水(70ml)稀釋。將有機層分離，用鹽水(3*50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得1-[4-(3-溴苯基)-1-哌啶基]乙酮(19.3g，68.40mmol，94.59%產率)。To a solution of 4-(3-bromophenyl)piperidine (20 g, 72.31 mmol, HCl) and triethylamine (18.29 g, 180.77 mmol, 25.20 mL) in DCM (250 mL) dropwise at 0 °C Acetyl chloride (6.81 g, 86.77 mmol, 5.28 mL) was added. The resulting mixture was stirred at 25°C for 12h and diluted with water (70ml). The organic layer was separated, washed with brine (3*50ml), dried over Na2SO4 and evaporated in vacuo to give 1-[4-(3-bromophenyl)-1-piperidinyl]ethanone ( 19.3 g, 68.40 mmol, 94.59% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.59(m,2H),1.88(m,2H),2.13(s,3H),2.59(t,1H),2.71(t,1H),3.15(t,1H),3.92(d,1H),4.78(d,1H),7.12(d,1H),7.18(t,1H),7.34(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.59(m, 2H), 1.88(m, 2H), 2.13(s, 3H), 2.59(t, 1H), 2.71(t, 1H), 3.15( t, 1H), 3.92 (d, 1H), 4.78 (d, 1H), 7.12 (d, 1H), 7.18 (t, 1H), 7.34 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值282.2；實測值283.2；Rt=1.277min。LCMS (ESI): [M] + m/z: calculated 282.2; found 283.2; Rt=1.277 min.

步驟2：1-(4-(3-(吡啶-2-基)苯基)哌啶-1-基)乙酮之合成Step 2: Synthesis of 1-(4-(3-(pyridin-2-yl)phenyl)piperidin-1-yl)ethanone

將1-[4-(3-溴苯基)-1-哌啶基]乙酮(8g，28.35mmol)、三丁基(2-吡啶基)甲錫烷(11.48g，31.19mmol，10.07mL)及99.8%(基於金屬)肆(三苯基膦)鈀(0)(Pd 9% min)(1.64g，1.42mmol)於甲苯(150mL)中之溶液在在Ar氣氛、100℃下加熱18h。在真空中蒸發溶劑且藉由梯度層析(DCM-ACN)純化殘餘物，以獲 得1-[4-[3-(2-吡啶基)苯基]-1-哌啶基]乙酮(7.3g，26.04mmol，91.84%產率)Combine 1-[4-(3-bromophenyl)-1-piperidinyl]ethanone (8 g, 28.35 mmol), tributyl(2-pyridyl)stannane (11.48 g, 31.19 mmol, 10.07 mL) ) and 99.8% (metal based) tetrakis(triphenylphosphine)palladium(0) (Pd 9% min) (1.64 g, 1.42 mmol) in toluene (150 mL) was heated at 100 °C for 18 h under Ar atmosphere . The solvent was evaporated in vacuo and the residue was purified by gradient chromatography (DCM-ACN) to obtain Obtained 1-[4-[3-(2-pyridyl)phenyl]-1-piperidinyl]ethanone (7.3 g, 26.04 mmol, 91.84% yield)

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.51(m,1H),1.67(m,1H),1.83(m,2H),2.03(s,3H),2.62(t,1H),2.86(t,1H),3.14(t,1H),3.92(d,1H),4.55(d,1H),7.32(m,2H),7.41(m,1H),7.86(m,2H),7.95(m,2H),8.65(d,1H)。LCMS(ESI)：[M]+ m/z：計算值280.4；實測值281.2；Rt=0.949min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.51(m, 1H), 1.67(m, 1H), 1.83(m, 2H), 2.03(s, 3H), 2.62(t, 1H), 2.86(t,1H),3.14(t,1H),3.92(d,1H),4.55(d,1H),7.32(m,2H),7.41(m,1H),7.86(m,2H),7.95 (m, 2H), 8.65 (d, 1H). LCMS (ESI): [M] + m/z: calculated 280.4; found 281.2; Rt=0.949 min.

步驟3：1-(4-(3-(哌啶-2-基)苯基)哌啶-1-基)乙酮之合成Step 3: Synthesis of 1-(4-(3-(piperidin-2-yl)phenyl)piperidin-1-yl)ethanone

將1-[4-[3-(2-吡啶基)苯基]-1-哌啶基]乙酮(7.3g，26.04mmol)溶解於MeOH(350mL)中且添加無水5%鉑/碳(1.02g，5.21mmol)。將反應混合物在100℃下在高壓容器中在50atm H2 壓力下加熱96h。過濾出催化劑，用MeOH洗滌且蒸發溶劑，將殘餘物乾燥，以得到1-[4-[3-(2-哌啶基)苯基]-1-哌啶基]乙酮(6g，20.95mmol，80.46%產率)。1-[4-[3-(2-Pyridinyl)phenyl]-1-piperidinyl]ethanone (7.3 g, 26.04 mmol) was dissolved in MeOH (350 mL) and anhydrous 5% platinum on carbon ( 1.02 g, 5.21 mmol). The reaction mixture was heated at 100 °C in a high pressure vessel under 50 atm H2 pressure for 96 h. The catalyst was filtered off, washed with MeOH and the solvent was evaporated, the residue was dried to give 1-[4-[3-(2-piperidinyl)phenyl]-1-piperidinyl]ethanone (6 g, 20.95 mmol , 80.46% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.47(m,1H),1.62(m,2H),1.83(m,6H),2.02(s,3H),2.61(t,1H),2.74(t,1H),2.98(t,1H),3.15(t,1H),3.26(d,1H),3.91(d,1H),4.15(bds,1H),4.52(d,1H),7.24(m,1H),7.32(m,2H),7.41(m,1H),7.52(s,1H),9.41(bds,1H)。LCMS(ESI)：[M]+ m/z：計算值286.4；實測值287.2；Rt=0.786min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.47(m,1H), 1.62(m,2H), 1.83(m,6H), 2.02(s,3H), 2.61(t,1H), 2.74(t,1H),2.98(t,1H),3.15(t,1H),3.26(d,1H),3.91(d,1H),4.15(bds,1H),4.52(d,1H),7.24 (m, 1H), 7.32 (m, 2H), 7.41 (m, 1H), 7.52 (s, 1H), 9.41 (bds, 1H). LCMS (ESI): [M] + m/z: calculated 286.4; found 287.2; Rt=0.786 min.

5C. 3-(5-甲基-2-哌啶基)苯胺之合成5C. Synthesis of 3-(5-methyl-2-piperidinyl)aniline

Figure 110128222-A0202-12-0744-608
Figure 110128222-A0202-12-0744-608

步驟1：5-甲基-2-(3-硝基苯基)吡啶之合成Step 1: Synthesis of 5-methyl-2-(3-nitrophenyl)pyridine

將(3-硝基苯基)硼酸(10.19g，61.04mmol)及2-溴-5-甲基吡啶(10g，58.13mmol)溶解於二噁烷(50mL)及H2 O(1mL)中，隨後添加碳酸鈉(24.65g，232.53mmol，9.74mL)。將所得懸浮液徹底除氣且添加99.8%(基於金屬)肆(三苯 基膦)鈀(0)(Pd 9% min)(1.34g，1.16mmol)。將反應混合物在75℃下攪拌隔夜。反應完成(如藉由LCMS顯示)之後，過濾反應混合物且在真空中濃縮，以得到油狀殘餘物，其藉由急驟層析(OK.第1次運行：Companion combiflash，330g SiO2 ，石油醚/乙酸乙酯，其中乙酸乙酯為0~25%，流速100mL/min，Rv=8CV；第2次運行：Companion combiflash，120g SiO2 ，氯仿/乙腈，其中乙腈為0~5%，流速85mL/min，Rv=5CV)進行純化，以得到5-甲基-2-(3-硝基苯基)吡啶(3.8g，17.74mmol，30.51%產率)。(3-Nitrophenyl)boronic acid (10.19 g, 61.04 mmol) and 2-bromo-5-methylpyridine (10 g, 58.13 mmol) were dissolved in dioxane (50 mL) and H2O (1 mL), Sodium carbonate (24.65 g, 232.53 mmol, 9.74 mL) was then added. The resulting suspension was thoroughly degassed and 99.8% (metal based) tetrakis(triphenylphosphine)palladium(0) (Pd 9% min) (1.34 g, 1.16 mmol) was added. The reaction mixture was stirred at 75°C overnight. After the reaction was complete (as shown by LCMS), the reaction mixture was filtered and concentrated in vacuo to give an oily residue which was purified by flash chromatography (OK. 1st run: Companion combiflash, 330 g SiO2 , petroleum ether /ethyl acetate, wherein ethyl acetate is 0~25%, flow rate 100mL/min, Rv=8CV; 2nd run: Companion combiflash, 120g SiO 2 , chloroform/acetonitrile, wherein acetonitrile is 0~5%, flow rate 85mL /min, Rv=5CV) was purified to give 5-methyl-2-(3-nitrophenyl)pyridine (3.8 g, 17.74 mmol, 30.51% yield).

1 H NMR(500MHz,DMSO-d6 )δ 2.31(s,3H),7.62(m,2H),7.91(m,1H),8.12(m,1H),8.32(m,1H),8.45(d,1H),9.82(t,1H) 1 H NMR (500MHz, DMSO-d 6 )δ 2.31(s, 3H), 7.62(m, 2H), 7.91(m, 1H), 8.12(m, 1H), 8.32(m, 1H), 8.45(d ,1H),9.82(t,1H)

LCMS(ESI)：[M+H]+ m/z：計算值214.1；實測值215.0；Rt=1.416min。LCMS (ESI): [M+H] + m/z: calculated 214.1; found 215.0; Rt=1.416 min.

步驟2：3-(5-甲基-2-哌啶基)苯胺之合成Step 2: Synthesis of 3-(5-methyl-2-piperidinyl)aniline

將5-甲基-2-(3-硝基苯基)吡啶(2.1g，9.80mmol)添加到5%氫氧化鈀/碳(1.21g)於EtOH(20mL)中之懸浮液中。將混合物在高壓釜中在80℃(100atm)下氫化168h。反應完成之後，過濾固體且將有機溶劑蒸發。藉由HPLC(1-20% 0.5-6.5min；水-乙腈+TFA；流速30mL/min；(裝載泵4mL/min-水)；目標質量190；管柱SunFire 100* 19mm 5um)純化所獲得之粗殘餘物，以得到3-(5-甲基-2-哌啶基)苯胺(1.2g，5.29mmol，53.99%產率，HCl)。5-Methyl-2-(3-nitrophenyl)pyridine (2.1 g, 9.80 mmol) was added to a suspension of 5% palladium hydroxide on carbon (1.21 g) in EtOH (20 mL). The mixture was hydrogenated in an autoclave at 80 °C (100 atm) for 168 h. After the reaction was complete, the solid was filtered and the organic solvent was evaporated. Purified by HPLC (1-20% 0.5-6.5min; water-acetonitrile+TFA; flow rate 30mL/min; (loading pump 4mL/min-water); target mass 190; column SunFire 100 * 19mm 5um) Crude residue to give 3-(5-methyl-2-piperidinyl)aniline (1.2 g, 5.29 mmol, 53.99% yield, HCl).

1 H NMR(400MHz,DMSO-d6 )δ 0.95(m,3H),1.38(m,1H),1.81(m,4H),2.08(m,1H),2.71(m,1H),3.20(m,1H),4.01(m,1H),6.78(m,3H),7.18(dd,1H),8.87(m,1H),9.08(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.95(m, 3H), 1.38(m, 1H), 1.81(m, 4H), 2.08(m, 1H), 2.71(m, 1H), 3.20(m , 1H), 4.01 (m, 1H), 6.78 (m, 3H), 7.18 (dd, 1H), 8.87 (m, 1H), 9.08 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值190.1；實測值191.4；Rt=1.497min。LCMS (ESI): [M+H] + m/z: calculated 190.1; found 191.4; Rt=1.497 min.

5D. 2-(3-甲氧基苯基)-5-甲基哌啶之合成5D. Synthesis of 2-(3-methoxyphenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0746-609
Figure 110128222-A0202-12-0746-609

步驟1：2-(3-甲氧基苯基)-5-甲基吡啶之合成Step 1: Synthesis of 2-(3-methoxyphenyl)-5-methylpyridine

將2-溴-5-甲基吡啶(3g，17.44mmol)及(3-甲氧基苯基)硼酸(3.18g，20.93mmol)溶解於二噁烷(40mL)及水(4mL)中。向其中添加碳酸銫(14.21g，43.60mmol)。然後，添加肆(三苯基磷烷)鈀(0)(87.20μmol)且將反應燒瓶快速抽真空且用氬氣再填充。將所得混合物在65℃下攪拌12h。此後，將其冷卻且蒸發。將殘餘物分配於EtOAc(100ml)與水(100ml)之間。收集有機相，將其經Na2 SO4 乾燥且蒸發。使殘餘物經歷管柱層析以獲得2-(3-甲氧基苯基)-5-甲基吡啶(2g，10.04mmol，57.56%產率)。2-Bromo-5-methylpyridine (3 g, 17.44 mmol) and (3-methoxyphenyl)boronic acid (3.18 g, 20.93 mmol) were dissolved in dioxane (40 mL) and water (4 mL). To this was added cesium carbonate (14.21 g, 43.60 mmol). Then, tetrakis(triphenylphosphine)palladium(0) (87.20 μmol) was added and the reaction flask was quickly evacuated and refilled with argon. The resulting mixture was stirred at 65 °C for 12 h. After that, it was cooled and evaporated. The residue was partitioned between EtOAc (100ml) and water (100ml). The organic phase was collected, dried over Na2SO4 and evaporated. The residue was subjected to column chromatography to obtain 2-(3-methoxyphenyl)-5-methylpyridine (2 g, 10.04 mmol, 57.56% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)3.32(s,3H),3.82(s,3H),6.96(m,1H),7.37(m,1H),7.61(m,2H),7.66(m,1H),7.87(m,1H),8.49(s,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 3.32(s,3H), 3.82(s,3H), 6.96(m,1H), 7.37(m,1H), 7.61(m,2H), 7.66 (m, 1H), 7.87 (m, 1H), 8.49 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值199.2；實測值200.2；Rt=1.024min。LCMS (ESI): [M] + m/z: calculated 199.2; found 200.2; Rt=1.024 min.

步驟2：2-(3-甲氧基苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(3-Methoxyphenyl)-5-methylpiperidine

將乾燥的487型鈀(10%於碳上)(106.82mg，1.00mmol)添加到2-(3-甲氧基苯基)-5-甲基吡啶(2g，10.04mmol)於MeOH(20mL)中之溶液中且將所得混合物在50atm壓力及80℃下氫化72h。在起始材料消耗(H-NMR對照)之後，將所得混合物冷卻至室溫，過濾。將濾液蒸發至乾，以獲得2-(3-甲氧基苯基)-5-甲基哌啶(1.3g，6.33mmol，63.09%產率)。Dry palladium Form 487 (10% on carbon) (106.82 mg, 1.00 mmol) was added to 2-(3-methoxyphenyl)-5-methylpyridine (2 g, 10.04 mmol) in MeOH (20 mL) in solution and the resulting mixture was hydrogenated at 50 atm pressure and 80 °C for 72 h. After consumption of starting material (H-NMR control), the resulting mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness to obtain 2-(3-methoxyphenyl)-5-methylpiperidine (1.3 g, 6.33 mmol, 63.09% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.82(d,3H),1.12(m,1H),1.36(m,1H),1.51(m,1H),1.72(m,2H),2.23(t,1H),2.96(d,1H),3.22(m,1H),3.41(d,1H),3.72(s,3H),6.76(d,1H),6.89(m,2H),7.19(t,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.82(d, 3H), 1.12(m, 1H), 1.36(m, 1H), 1.51(m, 1H), 1.72(m, 2H), 2.23(t, 1H), 2.96(d, 1H), 3.22(m, 1H), 3.41(d, 1H), 3.72(s, 3H), 6.76(d, 1H), 6.89(m, 2H), 7.19 (t, 1H).

LCMS(ESI)：[M]+ m/z：計算值205.3；實測值206.2；Rt=0.833min。LCMS (ESI): [M] + m/z: calculated 205.3; found 206.2; Rt=0.833 min.

5E. N-甲基-6-(5-甲基-2-哌啶基)吡啶-3-胺之合成5E. Synthesis of N-methyl-6-(5-methyl-2-piperidinyl)pyridin-3-amine

Figure 110128222-A0202-12-0747-610
Figure 110128222-A0202-12-0747-610

步驟1A. 3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1A. 3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro- Synthesis of 2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.5g，10.14mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.86g，15.20mmol)及99%無水碳酸鉀(2.80g，20.27mmol，1.22mL)一起混合於二噁烷(60mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加雙(三苯基膦)氯化鈀(II)(355.69mg，506.76μmol)及三苯基膦(265.83mg，1.01mmol)。將反應混合物在氬氣、90℃下攪拌12h，然後冷卻且在真空中蒸發，將其倒入水(150ml)中且用EtOAc(2x80ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下4.3g粗產物，4.3g粗產物藉由矽膠管柱層析使用己烷/MTBE梯度(10-100% EtOAc)進行純化，以得到產物3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.2g，6.81mmol，67.15%產率)3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.5 g, 10.14 mmol) and 4,4, 5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-di Oxaborolane (3.86 g, 15.20 mmol) and 99% anhydrous potassium carbonate (2.80 g, 20.27 mmol, 1.22 mL) were mixed together in dioxane (60 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times, followed by the addition of bis(triphenylphosphine)palladium(II) chloride (355.69 mg, 506.76 μmol) and triphenylphosphine ( 265.83 mg, 1.01 mmol). The reaction mixture was stirred under argon at 90°C for 12h, then cooled and evaporated in vacuo, poured into water (150ml) and extracted with EtOAc (2x80ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 4.3g of crude product which was subjected to silica gel column chromatography using a hexane/MTBE gradient ( 10-100% EtOAc) to give the product 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl )-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.2 g, 6.81 mmol, 67.15% yield)

1 H NMR(500MHz,CDCl3 )δ(ppm)0.90(d,3H),1.25(s,12H),1.50(s,9H),1.50-1.75(m,2H),2.15(m,1H),2.75(t,1H),3.56(d,1H),5.22(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.90(d, 3H), 1.25(s, 12H), 1.50(s, 9H), 1.50-1.75(m, 2H), 2.15(m, 1H), 2.75(t, 1H), 3.56(d, 1H), 5.22(s, 1H).

步驟1.N-(6-溴-3-吡啶基)-N-甲基-胺甲酸第三丁酯之合成Step 1. Synthesis of N-(6-bromo-3-pyridyl)-N-methyl-carbamic acid tert-butyl ester

將6-溴-N-甲基吡啶-3-胺(8g，42.77mmol)及DMAP(104.51mg， 855.45μmol)溶解於THF(40mL)中且逐滴添加二碳酸二-第三丁酯(28.00g，128.32mmol，29.45mL)。將反應混合物在80℃下攪拌48h。在真空中蒸發所得混合物，將其倒入NaHCO3 (濃)水溶液(50ml)中且用EtOAc(2x30ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到N-(6-溴-3-吡啶基)-N-甲基-胺甲酸第三丁酯(10g，34.82mmol，81.42%產率)6-Bromo-N-methylpyridin-3-amine (8 g, 42.77 mmol) and DMAP (104.51 mg, 855.45 μmol) were dissolved in THF (40 mL) and di-tert-butyl dicarbonate (28.00 g, 128.32 mmol, 29.45 mL). The reaction mixture was stirred at 80 °C for 48 h. The resulting mixture was evaporated in vacuo, poured into aqueous NaHCO3 (cone) (50ml) and extracted with EtOAc (2x30ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to give tert-butyl N-(6-bromo-3-pyridyl)-N-methyl-carbamic acid Ester (10 g, 34.82 mmol, 81.42% yield)

1 H NMR(500MHz,CDCl3 )δ(ppm)1.46(s,9H),3.27(s,3H),7.25(s,1H),7.41(d,1H),7.49(m,1H),8.29(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.46(s, 9H), 3.27(s, 3H), 7.25(s, 1H), 7.41(d, 1H), 7.49(m, 1H), 8.29( s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值287.2；實測值289.0；Rt=1.276min。LCMS (ESI): [M-Boc] + m/z: calculated 287.2; found 289.0; Rt=1.276 min.

步驟2. 6-[5-[第三丁氧基羰基(甲基)胺基]-2-吡啶基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2. 6-[5-[Third-butoxycarbonyl(methyl)amino]-2-pyridyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid third Synthesis of Butyl Ester

將3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.37g，13.52mmol)及N-(6-溴-3-吡啶基)-N-甲基-胺甲酸第三丁酯(2.59g，9.01mmol)一起混合於t-BuOH(100mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加於t-BuOH(100mL)中之乙酸鈀(II)(202.35mg，901.31μmol)及CM-Phos(727.42mg，1.80mmol)。將反應混合物在氬氣、115℃下攪拌17h，然後冷卻且在真空中蒸發，將其倒入水(150ml)中且用EtOAc(2x50ml)萃取。將經合併之有機萃取物用水(2*10ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下3.6g粗產物，3.6g粗產物藉由矽膠管柱層析使用己烷/MTBE梯度(10-100% MTBE)進行純化且藉由製備型(70-70-80% 0-1-6min H2 O/MeOH/0.1%NH4OH，流速：30ml/min靶目標量)純化1.1g所獲得之粗產物，以得到產物6-[5-[第三丁氧基羰基(甲基)胺基]-2-吡啶基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.022g，54.52μmol，6.05e-1%產率)及粗級分17mg，藉由LCMS為66.23%。3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-2H- Combine tert-butyl pyridine-1-carboxylate (4.37 g, 13.52 mmol) and N-(6-bromo-3-pyridyl)-N-methyl-carbamic acid tert-butyl ester (2.59 g, 9.01 mmol) together in t-BuOH (100 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then palladium(II) acetate (202.35 mg, 901.31 μmol) and CM-Phos ( 727.42 mg, 1.80 mmol). The reaction mixture was stirred under argon at 115°C for 17h, then cooled and evaporated in vacuo, poured into water (150ml) and extracted with EtOAc (2x50ml). The combined organic extracts were washed with water (2*10ml), dried over sodium sulfate and evaporated in vacuo to leave 3.6g of crude product which was subjected to silica gel column chromatography using a hexane/MTBE gradient ( 10-100% MTBE) and 1.1 g obtained by preparative (70-70-80% 0-1-6 min H2O /MeOH/0.1% NH4OH, flow rate: 30 ml/min target amount) crude product to give the product 6-[5-[tert-butoxycarbonyl(methyl)amino]-2-pyridyl]-3-methyl-3,4-dihydro-2H-pyridine-1- 3-Butyl formate (0.022 g, 54.52 μmol, 6.05e-1% yield) and crude fraction 17 mg, 66.23% by LCMS.

LCMS(ESI)：[M+1]+ m/z：計算值403.3；實測值404.4；Rt=3.854min。LCMS (ESI): [M+1] + m/z: calculated 403.3; found 404.4; Rt=3.854 min.

步驟4. N-甲基-6-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-3-胺之合成Step 4. Synthesis of N-methyl-6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridin-3-amine

將6-[5-[第三丁氧基羰基(甲基)胺基]-2-吡啶基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.017g，42.13μmol)於DCM(2mL)及三氟乙酸(2g，17.54mmol，1.35mL)中之溶液在0℃下攪拌5h，然後在真空中蒸發。將碎冰(10g)添加到殘餘物中且用10%碳酸氫鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*10mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到N-甲基-6-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-3-胺(0.011g，粗品)。6-[5-[Third-butoxycarbonyl(methyl)amino]-2-pyridyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.017 g, 42.13 μmol) in DCM (2 mL) and trifluoroacetic acid (2 g, 17.54 mmol, 1.35 mL) was stirred at 0 °C for 5 h, then evaporated in vacuo. Crushed ice (10 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (2*10 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N-methyl-6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine- 3-amine (0.011 g, crude).

LCMS(ESI)：[M+1]+ m/z：計算值203.3；實測值204.1；Rt=0.853min。LCMS (ESI): [M+1] + m/z: calculated 203.3; found 204.1; Rt=0.853 min.

步驟5. N-甲基-6-(5-甲基-2-哌啶基)吡啶-3-胺之合成Step 5. Synthesis of N-methyl-6-(5-methyl-2-piperidinyl)pyridin-3-amine

在0℃下，將硼氫化鈉(4.09mg，108.22μmol，3.83μL)一次性添加到N-甲基-6-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-3-胺(0.011g，54.11μmol)於MeOH中之經攪拌之溶液中。將所得混合物在0℃下攪拌5h，然後在真空中蒸發。將殘餘物用水(10mL)稀釋且用二氯甲烷(2*10mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到N-甲基-6-(5-甲基-2-哌啶基)吡啶-3-胺(0.009g，43.84μmol，81.01%產率)。Sodium borohydride (4.09 mg, 108.22 μmol, 3.83 μL) was added in one portion to N-methyl-6-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0 °C yl)pyridin-3-amine (0.011 g, 54.11 μmol) in a stirred solution of MeOH. The resulting mixture was stirred at 0 °C for 5 h, then evaporated in vacuo. The residue was diluted with water (10 mL) and extracted with dichloromethane (2*10 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N-methyl-6-(5-methyl-2-piperidinyl)pyridin-3-amine (0.009 g, 43.84 μmol, 81.01% yield).

LCMS(ESI)：[M+1]+ m/z：計算值205.3；實測值206.2；Rt=0.527min。LCMS (ESI): [M+1] + m/z: calculated 205.3; found 206.2; Rt=0.527 min.

5F. 4-甲基-2-苯基哌啶之合成 5F. Synthesis of 4-methyl-2-phenylpiperidine

Figure 110128222-A0202-12-0749-611
Figure 110128222-A0202-12-0749-611

步驟1：4-甲基-2-苯基吡啶之合成Step 1: Synthesis of 4-methyl-2-phenylpyridine

將2-溴-4-甲基吡啶(5g，29.07mmol，3.23mL)及苯基硼酸(4.25g，34.88mmol)於THF(100mL)及水(10mL)中之正攪拌懸浮液用氬氣吹掃10分鐘。10分鐘之後，在氬氣下添加Pd(PPh3 )4 (1.68g，1.45mmol)及Cs2 CO3 (23.68g，72.66mmol)。將反應混合物在氬氣、65℃下攪拌12小時。12小時之後，將反應混合物 冷卻至室溫且濃縮。將所獲得之殘餘物分配於EtOAc(100mL)與水(100mL)之間。將有機層經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析純化粗產物，以獲得4-甲基-2-苯基吡啶(1.5g，8.86mmol，30.50%產率)。A stirring suspension of 2-bromo-4-methylpyridine (5 g, 29.07 mmol, 3.23 mL) and phenylboronic acid (4.25 g, 34.88 mmol) in THF (100 mL) and water (10 mL) was purged with argon Sweep for 10 minutes. After 10 minutes, Pd( PPh3 ) 4 (1.68 g, 1.45 mmol) and Cs2CO3 ( 23.68 g, 72.66 mmol) were added under argon. The reaction mixture was stirred under argon at 65°C for 12 hours. After 12 hours, the reaction mixture was cooled to room temperature and concentrated. The obtained residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 4-methyl-2-phenylpyridine (1.5 g, 8.86 mmol, 30.50% yield).

LCMS(ESI)：[M+H]+ m/z：計算值169.1；實測值170.2；Rt=0.675min。LCMS (ESI): [M+H] + m/z: calculated 169.1; found 170.2; Rt=0.675 min.

步驟2：4-甲基-2-苯基哌啶之合成Step 2: Synthesis of 4-methyl-2-phenylpiperidine

將4-甲基-2-苯基吡啶於AcOH(30mL)中之溶液在Noblyst P2058，5% Pt上在50atm壓力、50℃下氫化48小時。完成之後，過濾反應混合物且將濾液在減壓下蒸發，以獲得4-甲基-2-苯基哌啶(0.8g，4.56mmol)。粗產物不經任何進一步純化即用於下一步反應。A solution of 4-methyl-2-phenylpyridine in AcOH (30 mL) was hydrogenated over Noblyst P2058, 5% Pt at 50 atm pressure, 50 °C for 48 h. After completion, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to obtain 4-methyl-2-phenylpiperidine (0.8 g, 4.56 mmol). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值175.2；實測值176.2；Rt=0.702min。LCMS (ESI): [M+H] + m/z: calculated 175.2; found 176.2; Rt=0.702 min.

6. 硼酸酯與哌啶三氟甲烷磺酸乙烯酯之偶合6. Coupling of boronate esters with vinyl piperidine trifluoromethanesulfonate

Figure 110128222-A0202-12-0750-612
Figure 110128222-A0202-12-0750-612

在一些實施例中，可透過鹼性烯醇鹽形成、隨後用三氟甲烷磺酸酯來源淬滅來製備三氟甲烷磺酸乙烯酯。在一些實施例中，可透過使用強鹼(例如，有機鋰鹼，例如n -BuLi、t -BuLi、二異丙基醯胺化鋰(LDA)、雙(三甲基矽基)醯胺化鋰(LiHMDS)；氫化物鹼，例如NaH或KH)來進行三氟甲烷磺酸化。在一些實施例中，三氟甲烷磺酸酯來源為N-苯基三氟甲磺醯胺或Tf2 O。在一些實施例 中，可透過使哌啶酮暴露於在THF中之LiHMDS，隨後用苯基三氟甲磺醯胺淬滅來完成三氟甲烷磺酸化。In some embodiments, vinyl trifluoromethanesulfonate can be prepared via basic enolate formation followed by quenching with a trifluoromethanesulfonate source. In some embodiments, this can be achieved by using strong bases (eg, organolithium bases such as n -BuLi, t -BuLi, lithium diisopropylamide (LDA), bis(trimethylsilyl)amide Lithium (LiHMDS); a hydride base such as NaH or KH) for trifluoromethanesulfonation. In some embodiments, the triflate source is N-phenyltrifluoromethanesulfonamide or Tf2O . In some embodiments, trifluoromethanesulfonation can be accomplished by exposing piperidone to LiHMDS in THF, followed by quenching with phenyl trifluoromethanesulfonamide.

在一些實施例中，可透過使三氟甲烷磺酸乙烯酯與合適交叉偶合配偶體交叉偶合來製備經取代之四氫吡啶。在一些實施例中，合適的交叉偶合配偶體包括但不限於含硼交叉偶合配偶體，例如R6 B(OH)2 、R6 Bpin。在一些實施例中，交叉偶合可藉由金屬催化劑(例如Pd催化劑)來促成。在一些實施例中，Pd催化劑為Pd(dppf)2 ．DCM、Pd(PPh3 )4 、Pd(dppf)Cl2 ．DCM、PdCl2 (PPh3 )2 或Pd(OAc)2 。在一些實施例中，交叉偶合反應可透過利用包含Pd(dppf)Cl2 ．DCM、Na2 CO3 、二噁烷及水之條件來完成。在一些實施例中，交叉偶合反應可透過利用包含PdCl2 (PPh3 )2 、Na2 CO3 、二噁烷及水之條件來完成。In some embodiments, substituted tetrahydropyridines can be prepared by cross-coupling vinyl trifluoromethanesulfonate with a suitable cross-coupling partner. In some embodiments, suitable cross-coupling partners include, but are not limited to, boron-containing cross-coupling partners, eg, R 6 B(OH) 2 , R 6 Bpin. In some embodiments, cross-coupling can be facilitated by metal catalysts, such as Pd catalysts. In some embodiments, the Pd catalyst is Pd(dppf) 2 . DCM, Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 . DCM, PdCl 2 (PPh 3 ) 2 or Pd(OAc) 2 . In some embodiments, the cross-coupling reaction can be achieved by utilizing Pd(dppf)Cl 2 . was completed with DCM, Na2CO3 , dioxane and water. In some embodiments, the cross-coupling reaction can be accomplished by utilizing conditions comprising PdCl 2 (PPh 3 ) 2 , Na 2 CO 3 , dioxane, and water.

用於移除保護基(PG)(例如， MoM或Boc)之條件為熟悉此項技術者已知的。用於移除保護基-PG(例如， -Boc)之條件可採用例如酸性條件(例如， 水/二噁烷、於質子性溶劑(例如，甲醇 )中之鹽酸、於非質子性溶劑(例如， 二噁烷)中之鹽酸、於非質子性溶劑(例如，二氯甲烷 、氯仿等)中之TFA)。在一些實施例中，去保護步驟採用於二噁烷中之HCl(4.0M)。在一些實施例中，去保護步驟採用於DCM中之HCl(4.0M)。在一些實施例中，去保護步驟採用於DCM中之TFA。Conditions for removing protecting groups (PG) ( eg, MoM or Boc) are known to those skilled in the art. Conditions for removing the protecting group -PG ( eg, -Boc) can employ, for example, acidic conditions ( eg, water/dioxane, hydrochloric acid in a protic solvent ( eg, methanol ), in an aprotic solvent ( eg , , hydrochloric acid in dioxane), TFA) in an aprotic solvent ( eg, dichloromethane , chloroform, etc.). In some embodiments, the deprotection step employs HCl (4.0 M) in dioxane. In some embodiments, the deprotection step employs HCl (4.0 M) in DCM. In some embodiments, the deprotection step employs TFA in DCM.

環狀亞胺之還原可使用還原劑諸如氫化物還原劑(例如， NaBH4 或LiAlH4 )、矽還原劑(例如， Cl3 SiH)或在存在催化劑(例如 Ir催化劑、Ru催化劑、Pd催化劑(例如， Pd/C、Pd(OAc)2 ))之情況下的H2 還原來完成。在一些實施例中，可使用包含於MeOH中之NaBH4 之條件完成還原。在一些實施例中，可使用包含於MeOH及H2 O中之NaBH4 之條件完成還原。在一些實施例中，去保護、環化及還原發生於單一合成步驟中。在一些實施例中，可使用包含NaBH4 、TFA、MeOH及H2 O之條件完成去保護/環化/還原。Cyclic imines can be reduced using reducing agents such as hydride reducing agents ( eg, NaBH 4 or LiAlH 4 ), silicon reducing agents ( eg, Cl 3 SiH), or in the presence of catalysts ( eg , Ir catalysts, Ru catalysts, Pd catalysts ( For example, H 2 reduction in the case of Pd/C, Pd(OAc) 2 )) is accomplished. In some embodiments, the reduction can be accomplished using conditions comprising NaBH in MeOH. In some embodiments, reduction can be accomplished using conditions comprising NaBH 4 in MeOH and H 2 O. In some embodiments, deprotection, cyclization, and reduction occur in a single synthetic step. In some embodiments, deprotection/cyclization/reduction can be accomplished using conditions comprising NaBH4 , TFA, MeOH, and H2O .

6A. 1-(4-(3-(5-甲基哌啶-2-基)苯基)哌啶-1-基)乙酮之合成6A. Synthesis of 1-(4-(3-(5-methylpiperidin-2-yl)phenyl)piperidin-1-yl)ethanone

Figure 110128222-A0202-12-0752-613
Figure 110128222-A0202-12-0752-613

步驟1：1-(4-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)哌啶-1-基)乙酮之合成Step 1: 1-(4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)piperidine-1 -Synthesis of ethyl ketone

在Ar氣氛下，向1-[4-(3-溴苯基)-1-哌啶基]乙酮(9.1g，32.25mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-聯-1,3,2-二氧雜硼雜環戊烷(9.01g，35.47mmol)及乙酸鉀(7.91g，80.62mmol，5.04mL)於二噁烷(100mL)中之溶液中添加[1,1'-雙( 二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(1.32g，1.61mmol)。將所得混合物在80℃下加熱12h且冷卻至室溫。過濾沉澱且在真空中蒸發溶劑。將殘餘物溶解於DCM(100ml)中，將所得溶液用鹽水(2*50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發溶劑以獲得粗產物(17g)。藉由梯度層析(CHCl3 -CH3 CN)純化粗產物，以得到1-[4-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-1-哌啶基]乙酮(10.2g，30.98mmol，96.06%產率)。To 1-[4-(3-bromophenyl)-1-piperidinyl]ethanone (9.1 g, 32.25 mmol), 4,4,4',4',5,5,5 under Ar atmosphere ',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane (9.01 g, 35.47 mmol) and potassium acetate (7.91 g, 80.62 mmol, 5.04 mL) To a solution in dioxane (100 mL) was added a complex of [1,1'- bis( diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1.32 g, 1.61 mmol) . The resulting mixture was heated at 80 °C for 12 h and cooled to room temperature. The precipitate was filtered and the solvent was evaporated in vacuo. The residue was dissolved in DCM (100ml), the resulting solution was washed with brine (2*50ml), dried over Na2SO4 and the solvent was evaporated in vacuo to obtain crude product (17g). The crude product was purified by gradient chromatography ( CHCl3 - CH3CN ) to give 1-[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborole Heterocyclopentan-2-yl)phenyl]-1-piperidinyl]ethanone (10.2 g, 30.98 mmol, 96.06% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.32(s,12H),1.65(m,2H),1.88(m,2H),2.11(s,3H),2.59(t,1H),2.73(t,1H),3.13(t,1H),3.91(d,1H),4.76(d,1H),7.29(m,2H),7.62(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.32(s, 12H), 1.65(m, 2H), 1.88(m, 2H), 2.11(s, 3H), 2.59(t, 1H), 2.73( t, 1H), 3.13 (t, 1H), 3.91 (d, 1H), 4.76 (d, 1H), 7.29 (m, 2H), 7.62 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=1.553min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=1.553 min.

步驟2：6-(3-(1-乙醯基哌啶-4-基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 2: Synthesis of 6-(3-(1-Acetylpiperidin-4-yl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將1-[4-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-1-哌啶基]乙酮(6g，18.22mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(6.29g，18.22mmol)及碳酸鈉(5.79g，54.67mmol，2.29mL)於二噁烷(30mL)及水(120mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加[1,1'-雙( 二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(744.11mg，911.19μmol)。將所得混合物除氣，用Ar再填充且在80℃下攪拌24h。過濾出沉澱，用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於水150ml中且用DCM(2*100ml)萃取。將經合併之有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(10g)。藉由梯度層析(CHCl3 -ACN)純化粗產物，以獲得6-[3-(1-乙醯基-4-哌啶基)苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.8g，9.53mmol，52.32%產率)。1-[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-1-piperidinyl ] ethyl ketone (6 g, 18.22 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (6.29 g , 18.22 mmol) and sodium carbonate (5.79 g, 54.67 mmol, 2.29 mL) in dioxane (30 mL) and water (120 mL) were degassed and refilled three times with Ar. To this solution was added a complex of [1,1'- bis( diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (744.11 mg, 911.19 [mu]mol). The resulting mixture was degassed, refilled with Ar and stirred at 80 °C for 24 h. The precipitate was filtered off and washed with dioxane (50 ml). The solvent was evaporated in vacuo and the residue was dissolved in water 150ml and extracted with DCM (2*100ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (10 g). The crude product was purified by gradient chromatography ( CHCl3 -ACN) to obtain 6-[3-(1-acetyl-4-piperidinyl)phenyl]-3-methyl-3,4-dihydro - 2H -Pyridine-1-carboxylic acid tert-butyl ester (3.8 g, 9.53 mmol, 52.32% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.03(m,11H),1.61(m,3H),1.85(m,3H),1.98(m,1H),2.12(s,3H),2.38(m,1H),2.59(t,1H),2.69(t,1H),2.96(t,1H),3.13(t,1H),3.90(d,1H),4.05(d,1H),4.76(d,1H),5.25(m,1H),7.02(d,1H),7.10(m,2H),7.21(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.03(m, 11H), 1.61(m, 3H), 1.85(m, 3H), 1.98(m, 1H), 2.12(s, 3H), 2.38( m, 1H), 2.59(t, 1H), 2.69(t, 1H), 2.96(t, 1H), 3.13(t, 1H), 3.90(d, 1H), 4.05(d, 1H), 4.76(d , 1H), 5.25 (m, 1H), 7.02 (d, 1H), 7.10 (m, 2H), 7.21 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值298.4；實測值299.2；Rt=1.624min。LCMS (ESI): [M-Boc] + m/z: calculated 298.4; found 299.2; Rt=1.624 min.

步驟3：1-(4-(3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)哌啶-1-基)乙酮之合成Step 3: Synthesis of 1-(4-(3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)piperidin-1-yl)ethanone

將6-[3-(1-乙醯基-4-哌啶基)苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.8g，9.53mmol)溶解於三氟乙酸(22.20g，194.70mmol，15mL)中。將所得混合物在25℃下攪拌1h(直至氣體逸出結束)且在真空中移除溶劑。將所獲得之殘餘物用水稀釋。將溶液之pH用10% NaOH溶液調節至8且用DCM(3*70ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得1-[4-[3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]-1-哌啶基]乙酮(2.8g，9.38mmol，98.40%產率)。此化合物不經純化即用於下一步驟。6-[3-(1-Acetyl-4-piperidinyl)phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.8 g, 9.53 mmol) was dissolved in trifluoroacetic acid (22.20 g, 194.70 mmol, 15 mL). The resulting mixture was stirred at 25°C for 1 h (until gas evolution was over) and the solvent was removed in vacuo. The obtained residue was diluted with water. The pH of the solution was adjusted to 8 with 10% NaOH solution and extracted with DCM (3*70ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated in vacuo to obtain 1-[4-[3-(3-methyl-2,3,4,5-tetrakis Hydropyridin-6-yl)phenyl]-1-piperidinyl]ethanone (2.8 g, 9.38 mmol, 98.40% yield). This compound was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.97(d,3H),1.37(m,1H),1.64(m,3H),1.88(m,3H),2.11(s,3H),2.58(m,2H),2.74(m,2H),3.13(m,1H),3.24(m,1H),3.95(m,2H),4.75(d,1H),7.18(m,1H),7.30(m,1H),7.54(m,1H),7.65(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.97(d,3H), 1.37(m,1H), 1.64(m,3H), 1.88(m,3H), 2.11(s,3H), 2.58( m, 2H), 2.74(m, 2H), 3.13(m, 1H), 3.24(m, 1H), 3.95(m, 2H), 4.75(d, 1H), 7.18(m, 1H), 7.30(m , 1H), 7.54 (m, 1H), 7.65 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值298.2；實測值299.2；Rt=0.812min。LCMS (ESI): [M] + m/z: calculated 298.2; found 299.2; Rt=0.812 min.

步驟4：1-(4-(3-(5-甲基哌啶-2-基)苯基)哌啶-1-基)乙酮之合成Step 4: Synthesis of 1-(4-(3-(5-methylpiperidin-2-yl)phenyl)piperidin-1-yl)ethanone

在0℃下，向1-[4-[3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]-1-哌啶基]乙酮(2.8g，9.38mmol)於MeOH(50mL)中之溶液中分批添加硼氫化鈉(532.46mg，14.07mmol，497.62μL)。將所得混合物在25℃下攪拌1h且在真空中蒸發溶劑，將殘餘物溶解於水(50ml)且用DCM(3*50ml)萃取。將經合併之有機萃取物用鹽水(2*50ml)洗滌，經Na2 SO4 乾燥且蒸發，以得到1-[4-[3-(5-甲基-2-哌啶基)苯基]-1-哌啶基]乙酮(2.3g，粗品)。此化合物不經純化即用於下一步驟。To 1-[4-[3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenyl]-1-piperidinyl]ethanone (2.8 g, 9.38 mmol) in MeOH (50 mL) was added portionwise sodium borohydride (532.46 mg, 14.07 mmol, 497.62 μL). The resulting mixture was stirred at 25°C for 1 h and the solvent was evaporated in vacuo, the residue was dissolved in water (50ml) and extracted with DCM (3*50ml). The combined organic extracts were washed with brine (2*50ml), dried over Na2SO4 and evaporated to give 1-[ 4- [3-(5-methyl-2-piperidinyl)phenyl] -1-Piperidinyl]ethanone (2.3 g, crude). This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.82(d,3H),1.08(m,1H),1.42(m,3H),1.58(m,2H),1.74(m,3H),2.02(s,3H),2.24(t,1H),2.59(t,1H),2.72(t,1H),2.99(d,1H),3.10(t,1H),3.43(m,2H),3.91(d,1H),4.51(d,1H),7.01(d,1H),7.20(m,3H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.82(d,3H), 1.08(m,1H), 1.42(m,3H), 1.58(m,2H), 1.74(m,3H), 2.02(s, 3H), 2.24(t, 1H), 2.59(t, 1H), 2.72(t, 1H), 2.99(d, 1H), 3.10(t, 1H), 3.43(m, 2H), 3.91 (d, 1H), 4.51 (d, 1H), 7.01 (d, 1H), 7.20 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值300.2；實測值301.2；Rt=0.975min。LCMS (ESI): [M] + m/z: calculated 300.2; found 301.2; Rt=0.975 min.

6B. N-甲基-3-(2-哌啶基)苯胺之合成6B. Synthesis of N-methyl-3-(2-piperidinyl)aniline

Figure 110128222-A0202-12-0754-614
Figure 110128222-A0202-12-0754-614

步驟1：6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-[3-(methylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5g，15.09mmol)及N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯胺(4.07 g，15.09mmol，HCl)溶解於二噁烷(50mL)中。將反應混合物徹底除氣，隨後後續添加碳酸銫(4.92g，15.09mmol)、H2 O(5mL)及肆(三苯基膦)鈀(0)(17.44g，15.09mmol)。然後，將所得反應混合物在回流下攪拌隔夜。在反應完成(藉由反應混合物之LCMS推斷)之後，將有機溶劑發且將粗混合物分配於EtOAc(50mL)與H2 O(15mL)之間。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到粗品6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.5g，粗品)。所獲得之產物無需純化即用於下一步驟。6-(Trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 g, 15.09 mmol) and N-methyl-3-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)aniline (4.07 g, 15.09 mmol, HCl) was dissolved in dioxane (50 mL). The reaction mixture was thoroughly degassed, followed by the subsequent addition of cesium carbonate (4.92 g, 15.09 mmol), H2O (5 mL) and tetrakis(triphenylphosphine)palladium(0) (17.44 g, 15.09 mmol). Then, the resulting reaction mixture was stirred at reflux overnight. After completion of the reaction (inferred by LCMS of the reaction mixture), the organic solvent was evaporated and the crude mixture was partitioned between EtOAc (50 mL) and H2O (15 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give crude 6-[3-(methylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl Ester (5.5 g, crude). The obtained product was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ 1.11(s,9H),1.85(m,2H),2.25(m,2H),2.81(s,3H),3.69(m,2H),5.33(m,1H),6.49(d,1H),6.54(s,1H),6.65(d,1H),7.08(dd,1H)，未觀察到NH。 1 H NMR (500MHz, CDCl 3 )δ 1.11(s, 9H), 1.85(m, 2H), 2.25(m, 2H), 2.81(s, 3H), 3.69(m, 2H), 5.33(m, 1H) ), 6.49(d, 1H), 6.54(s, 1H), 6.65(d, 1H), 7.08(dd, 1H), no NH was observed.

LCMS(ESI)：[M-t -Bu]+ m/z：計算值232.1；實測值233.2；Rt=1.297min。LCMS (ESI): [M- t -Bu] + m/z: calculated 232.1; found 233.2; Rt=1.297 min.

步驟2：N-甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺之合成Step 2: Synthesis of N-methyl-3-(2,3,4,5-tetrahydropyridin-6-yl)aniline

將6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2g，4.85mmol)溶解於DCM，隨後添加TFA(1.11g，9.71mmol，748.03μL)。將反應混合物攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且將有機溶劑蒸發，以得到N-甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺(1.2g，粗品)，其不經純化即用於下一步驟。6-[3-(Methylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2 g, 4.85 mmol) was dissolved in DCM followed by the addition of TFA (1.11 g, 9.71 mmol, 748.03 μL). The reaction mixture was stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH solution, and the organic solvent was evaporated to obtain N-methyl-3-(2,3,4,5-tetrahydropyridin-6-yl)aniline (1.2 g, crude product), which was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ 1.65(m,2H),1.84(m,2H),2.61(m,1H),2.79(s,3H),3.43(m,2H),3.87(m,2H),6.59(m,1H),7.18(m,2H),7.21(m,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.65 (m, 2H), 1.84 (m, 2H), 2.61 (m, 1H), 2.79 (s, 3H), 3.43 (m, 2H), 3.87 (m, 2H) ), 6.59 (m, 1H), 7.18 (m, 2H), 7.21 (m, 1H).

步驟3：N-甲基-3-(2-哌啶基)苯胺之合成Step 3: Synthesis of N-methyl-3-(2-piperidinyl)aniline

將N-甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺(1.2g，6.37mmol)及N-甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺(1.2g，6.37mmol)溶解於MeOH(20mL)及H2 O(20mL)中。將所得混合物冷卻至25℃且一次性添加硼氫化鈉(482.28mg，12.75mmol，450.73μL)。然後，將反應混合物再攪拌隔夜。反應完成之後，將混合物 用10% HCl水溶液酸化至pH 2。將所獲得之混合物用MTBE(2* 10mL)洗滌，用10% NaOH水溶液鹼化至pH 10且用DCM(50mL)萃取。蒸發溶劑，得到純的N-甲基-3-(2-哌啶基)苯胺(0.9g，4.73mmol，74.21%產率)。N-methyl-3-(2,3,4,5-tetrahydropyridin-6-yl)aniline (1.2 g, 6.37 mmol) and N-methyl-3-(2,3,4,5- Tetrahydropyridin-6-yl)aniline (1.2 g, 6.37 mmol) was dissolved in MeOH (20 mL) and H2O (20 mL). The resulting mixture was cooled to 25°C and sodium borohydride (482.28 mg, 12.75 mmol, 450.73 μL) was added in one portion. Then, the reaction mixture was stirred for an additional overnight. After the reaction was completed, the mixture was acidified to pH 2 with 10% aqueous HCl. The obtained mixture was washed with MTBE (2 * 10 mL), basified to pH 10 with 10% aq. NaOH and extracted with DCM (50 mL). The solvent was evaporated to give pure N-methyl-3-(2-piperidinyl)aniline (0.9 g, 4.73 mmol, 74.21% yield).

1 H NMR(400MHz,CDCl3 )δ 1.74(m,8H),2.82(m,4H),3.12(m,1H),3.51(m,1H),6.47(d,1H),6.65(s,1H),6.68(d,1H),7.11(dd,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.74(m, 8H), 2.82(m, 4H), 3.12(m, 1H), 3.51(m, 1H), 6.47(d, 1H), 6.65(s, 1H) ), 6.68(d, 1H), 7.11(dd, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值190.1；實測值191.2；Rt=0.539min。LCMS (ESI): [M+H] + m/z: calculated 190.1; found 191.2; Rt=0.539 min.

6C. N,N-二甲基-3-(2-哌啶基)苯胺之合成6C. Synthesis of N,N-dimethyl-3-(2-piperidinyl)aniline

Figure 110128222-A0202-12-0756-615
Figure 110128222-A0202-12-0756-615

步驟1與中間物6B相同。Step 1 is the same as Intermediate 6B.

步驟2：6-[3-(二甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-[3-(dimethylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.5g，5.20mmol)溶解於DMF(10mL)中。將所得混合物冷卻至0℃且添加於礦物油中之60%氫化鈉(油分散物)分散物(119.58mg，5.20mmol)，隨後添加碘甲烷(738.28mg，5.20mmol，323.81μL)。攪拌18h之後，將混合物倒入濃NH4 Cl水溶液(30mL)且用EtOAc(50mL)萃取。蒸發有機溶劑得到粗品6-[3-(二甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.1g，3.64mmol，69.93%產率)，其不經純化即用於下一步驟。6-[3-(Methylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 5.20 mmol) was dissolved in DMF (10 mL). The resulting mixture was cooled to 0°C and a 60% dispersion of sodium hydride (oil dispersion) in mineral oil (119.58 mg, 5.20 mmol) was added followed by methyl iodide (738.28 mg, 5.20 mmol, 323.81 μL). After stirring for 18 h, the mixture was poured into concentrated aqueous NH4Cl (30 mL) and extracted with EtOAc (50 mL). Evaporation of the organic solvent gave crude 6-[3-(dimethylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.1 g, 3.64 mmol, 69.93% yield) , which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值302.1；實測值303.2；Rt=1.256min。LCMS (ESI): [M+H] + m/z: calculated 302.1; found 303.2; Rt=1.256 min.

步驟3：N,N-二甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺之合成Step 3: Synthesis of N,N-dimethyl-3-(2,3,4,5-tetrahydropyridin-6-yl)aniline

將6-[3-(二甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.1g， 3.64mmol)溶解於DCM(10mL)，隨後添加TFA(2.07g，18.19mmol，1.40mL)且攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且將有機溶劑蒸發，以得到N,N-二甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺(0.7g，3.46mmol，95.13%產率)，其不經純化即用於下一步驟。6-[3-(Dimethylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.1 g, 3.64 mmol) was dissolved in DCM (10 mL), then TFA (2.07 g, 18.19 mmol, 1.40 mL) was added and stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH, and the organic solvent was evaporated to obtain N,N-dimethyl-3-(2,3,4,5-tetrahydropyridin-6-yl)aniline ( 0.7 g, 3.46 mmol, 95.13% yield), which was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ 1.80(m,2H),1.84(m,2H),2.62(m,2H),2.98(s,6H),3.83(m,2H),7.07(s,1H),7.20(m,3H) 1 H NMR (500MHz, CDCl 3 ) δ 1.80(m, 2H), 1.84(m, 2H), 2.62(m, 2H), 2.98(s, 6H), 3.83(m, 2H), 7.07(s, 1H ),7.20(m,3H)

步驟4：N,N-二甲基-3-(2-哌啶基)苯胺之合成Step 4: Synthesis of N,N-dimethyl-3-(2-piperidinyl)aniline

將N,N-二甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺(0.7g，3.46mmol)溶解於MeOH(10mL)及H2 O(2mL)且冷卻至0℃。將硼氫化鈉(392.74mg，10.38mmol，367.04μL)分批添加到所獲得之混合物中且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH 2，用MTBE(2* 10mL)洗滌，用10% NaOH水溶液鹼化至pH 10且用DCM(20mL)萃取。蒸發溶劑，得到純的N,N-二甲基-3-(2-哌啶基)苯胺(0.5g，2.45mmol，70.72%產率)。N,N-Dimethyl-3-(2,3,4,5-tetrahydropyridin-6-yl)aniline (0.7 g, 3.46 mmol) was dissolved in MeOH (10 mL) and H2O ( 2 mL) and Cool to 0°C. Sodium borohydride (392.74 mg, 10.38 mmol, 367.04 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH 2 with 10% aqueous HCl, washed with MTBE (2 * 10 mL), basified to pH 10 with 10% aqueous NaOH and extracted with DCM (20 mL). The solvent was evaporated to give pure N,N-dimethyl-3-(2-piperidinyl)aniline (0.5 g, 2.45 mmol, 70.72% yield).

1 H NMR(500MHz,CDCl3 )δ 1.82(m,4H),2.61(m,2H),2.2.90(s,6H),3.42(m,2H),3.61(m,1H),3.84(m,1H),6.69(m,1H),6.72(m,1H),6.81(m,1H),7.30(m,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.82 (m, 4H), 2.61 (m, 2H), 2.2.90 (s, 6H), 3.42 (m, 2H), 3.61 (m, 1H), 3.84 (m , 1H), 6.69 (m, 1H), 6.72 (m, 1H), 6.81 (m, 1H), 7.30 (m, 1H).

6D. N-甲基-3-(5-甲基-2-哌啶基)苯胺之合成6D. Synthesis of N-methyl-3-(5-methyl-2-piperidinyl)aniline

Figure 110128222-A0202-12-0757-616
Figure 110128222-A0202-12-0757-616

步驟1：3-甲基-6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-[3-(methylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁 酯(5，14.48mmol)及N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯胺(3.38g，12.52mmol，HCl)溶解於二噁烷(50mL)中且將反應混合物徹底除氣，隨後後續添加碳酸銫(4.72g，14.48mmol)、H2 O(5mL)及肆(三苯基膦)鈀(0)(16.73g，14.48mmol)。將所獲得之反應混合物在回流下攪拌隔夜。在反應完成(藉由反應混合物之LCMS推測)之後，將有機溶劑蒸發且將粗混合物分配於EtOAc(50mL)與H2 O(30mL)之間。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到粗品3-甲基-6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.5g，粗品)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5, 14.48 mmol) and N-methyl- 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)aniline (3.38 g, 12.52 mmol, HCl) was dissolved in dioxane ( 50 mL) and the reaction mixture was thoroughly degassed, followed by the subsequent addition of cesium carbonate (4.72 g, 14.48 mmol), H2O (5 mL) and tetrakis(triphenylphosphine)palladium(0) (16.73 g, 14.48 mmol). The obtained reaction mixture was stirred at reflux overnight. After completion of the reaction (presumed by LCMS of the reaction mixture), the organic solvent was evaporated and the crude mixture was partitioned between EtOAc (50 mL) and H2O (30 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give crude 3-methyl-6-[3-(methylamino)phenyl]-3,4-dihydro-2H-pyridine-1 - tert-butyl formate (5.5 g, crude), which was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ 0.98(d,3H),1.15(s,9H),1.79(m,1H),1.97(m,2H),2.38(m,1H),2.84(s,3H),2.96(m,1H),4.06(m,1H),5.30(m,1H),6.49(d,1H),6.54(s,1H),6.66(d,1H),7.08(dd,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.98(d,3H), 1.15(s,9H), 1.79(m,1H), 1.97(m,2H), 2.38(m,1H), 2.84(s,3H) ), 2.96(m, 1H), 4.06(m, 1H), 5.30(m, 1H), 6.49(d, 1H), 6.54(s, 1H), 6.66(d, 1H), 7.08(dd, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值302.2；實測值303.2；Rt=1.406min。LCMS (ESI): [M+H] + m/z: calculated 302.2; found 303.2; Rt=1.406 min.

步驟2：N-甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯胺之合成Step 2: Synthesis of N-methyl-3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)aniline

將3-甲基-6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2，6.61mmol)溶解於DCM(30mL)中，隨後添加TFA(500.41mg，4.39mmol，338.12μL)且攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且將有機溶劑蒸發，以得到N-甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯胺(1.5g，粗品)，其不經純化即用於下一步驟。3-Methyl-6-[3-(methylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2, 6.61 mmol) was dissolved in DCM (30 mL) , then TFA (500.41 mg, 4.39 mmol, 338.12 μL) was added and stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH solution, and the organic solvent was evaporated to obtain N-methyl-3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) Aniline (1.5 g, crude) was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ 1.02(m,3H),1.42(m,1H),1.73(m,1H),1.87(m,1H),2.52(m,1H),2.73(m,1H),2.89(s,3H),3.20(m,1H),4.01(m,1H),6.64(d,1H),7.05(d,1H),7.08(s,1H),7.19(dd,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.02(m,3H), 1.42(m,1H), 1.73(m,1H), 1.87(m,1H), 2.52(m,1H), 2.73(m,1H) ), 2.89(s, 3H), 3.20(m, 1H), 4.01(m, 1H), 6.64(d, 1H), 7.05(d, 1H), 7.08(s, 1H), 7.19(dd, 1H) .

步驟3：N-甲基-3-(5-甲基-2-哌啶基)苯胺之合成Step 3: Synthesis of N-methyl-3-(5-methyl-2-piperidinyl)aniline

將N-甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯胺(1.34g，6.61mmol)溶解於MeOH(25.00mL)及H2 O(5.00mL)且冷卻至0℃。將硼氫化鈉(500.15mg， 13.22mmol，467.43μL)分批添加到所獲得之混合物且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH 2，用水稀釋，用MTBE(2* 10mL)洗滌，用10% NaOH水溶液鹼化至pH 10且用DCM(30.00mL)萃取。蒸發溶劑，得到純的N-甲基-3-(5-甲基-2-哌啶基)苯胺(0.92g，4.50mmol，68.12%產率)。N-methyl-3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)aniline (1.34 g, 6.61 mmol) was dissolved in MeOH (25.00 mL) and H2O ( 5.00 mL) and cooled to 0 °C. Sodium borohydride (500.15 mg, 13.22 mmol, 467.43 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH 2 with 10% aq. HCl, diluted with water, washed with MTBE (2 * 10 mL), basified to pH 10 with 10% aq. NaOH and extracted with DCM (30.00 mL). The solvent was evaporated to give pure N-methyl-3-(5-methyl-2-piperidinyl)aniline (0.92 g, 4.50 mmol, 68.12% yield).

1 H NMR(400MHz,CDCl3 )δ 0.89(m,3H),1.52(m,6H),2.41(m,1H),2.81(s,3H),3.10(m,1H),3.48(m,1H),3.71(m,1H),6.47(d,1H),6.68(m,2H),7.11(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.89(m,3H), 1.52(m,6H), 2.41(m,1H), 2.81(s,3H), 3.10(m,1H), 3.48(m,1H) ), 3.71(m, 1H), 6.47(d, 1H), 6.68(m, 2H), 7.11(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值204.2；實測值205.2；Rt=0.579min。LCMS (ESI): [M+H] + m/z: calculated 204.2; found 205.2; Rt=0.579 min.

6E. N,N-二甲基-3-(5-甲基-2-哌啶基)苯胺之合成6E. Synthesis of N,N-dimethyl-3-(5-methyl-2-piperidinyl)aniline

Figure 110128222-A0202-12-0759-617
Figure 110128222-A0202-12-0759-617

步驟1與中間物6D相同。Step 1 is the same as Intermediate 6D.

步驟2：6-[3-(二甲胺基)苯基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-[3-(dimethylamino)phenyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-[3-(甲胺基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.5g，4.96mmol)溶解於dmf(10mL)中且冷卻至0℃，隨後添加於礦物油中之60%氫化鈉(油分散物)分散物(114.03mg，4.96mmol)及碘甲烷(704.04mg，4.96mmol，308.79μL)。攪拌18h之後，將混合物倒入濃NH4 Cl水溶液(30mL)且用EtOAc(20mL)萃取。蒸發有機溶劑，得到粗品6-[3-(二甲胺基)苯基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.3g，4.11mmol，82.83%產率)，其不經純化即用於下一步驟。3-Methyl-6-[3-(methylamino)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 4.96 mmol) was dissolved in dmf (10 mL) ) and cooled to 0°C, then a 60% dispersion of sodium hydride (oil dispersion) in mineral oil (114.03 mg, 4.96 mmol) and iodomethane (704.04 mg, 4.96 mmol, 308.79 μL) were added. After stirring for 18 h, the mixture was poured into concentrated aqueous NH4Cl (30 mL) and extracted with EtOAc (20 mL). The organic solvent was evaporated to give crude 6-[3-(dimethylamino)phenyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.3 g, 4.11 mmol , 82.83% yield), which was used in the next step without purification.

LCMS(ESI)：[M-t -Bu]+ m/z：計算值260.2；實測值260.2；Rt=1.572min。LCMS (ESI): [M- t -Bu] + m/z: calculated 260.2; found 260.2; Rt=1.572 min.

步驟3：N,N-二甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯胺之合成Step 3: Synthesis of N,N-dimethyl-3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)aniline

將6-[3-(二甲胺基)苯基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.3g，4.11mmol)溶解於DCM(10mL)，隨後添加TFA(468.43mg，4.11mmol，316.51μL)且攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且將有機溶劑蒸發，以得到N,N-二甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯胺(0.75g，3.47mmol，84.39%產率)，其不經純化即用於下一步驟。6-[3-(Dimethylamino)phenyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.3 g, 4.11 mmol) was dissolved in DCM ( 10 mL), then TFA (468.43 mg, 4.11 mmol, 316.51 μL) was added and stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH solution, and the organic solvent was evaporated to obtain N,N-dimethyl-3-(3-methyl-2,3,4,5-tetrahydropyridine-6 -yl)aniline (0.75 g, 3.47 mmol, 84.39% yield), which was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ 1.08(d,3H),1.74(m,2H),1.88(m,1H),2.62(m,1H),2.98(m,6H),3.21(m,1H),4.01(m,1H),7.07(s,1H),7.20(m,3H)。 1 H NMR (500MHz, CDCl 3 )δ 1.08(d,3H), 1.74(m,2H), 1.88(m,1H), 2.62(m,1H), 2.98(m,6H), 3.21(m,1H) ), 4.01(m, 1H), 7.07(s, 1H), 7.20(m, 3H).

步驟4：N,N-二甲基-3-(5-甲基-2-哌啶基)苯胺之合成Step 4: Synthesis of N,N-dimethyl-3-(5-methyl-2-piperidinyl)aniline

將N,N-二甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯胺(0.75g，3.47mmol)溶解於MeOH(10mL)及H2 O(2mL)中且冷卻至0℃。將硼氫化鈉(131.17mg，3.47mmol，122.59μL)分批添加到所獲得之混合物且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH 2，用MTBE(2* 10mL)洗滌，用10% NaOH水溶液鹼化至pH 10且用DCM(20mL)萃取。蒸發溶劑，得到純的N,N-二甲基-3-(5-甲基-2-哌啶基)苯胺(0.55g，2.52mmol，72.66%產率)。N,N-Dimethyl-3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)aniline (0.75 g, 3.47 mmol) was dissolved in MeOH (10 mL) and H2 O (2 mL) and cooled to 0 °C. Sodium borohydride (131.17 mg, 3.47 mmol, 122.59 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH 2 with 10% aqueous HCl, washed with MTBE (2 * 10 mL), basified to pH 10 with 10% aqueous NaOH and extracted with DCM (20 mL). The solvent was evaporated to give pure N,N-dimethyl-3-(5-methyl-2-piperidinyl)aniline (0.55 g, 2.52 mmol, 72.66% yield).

1 H NMR(500MHz,CDCl3 )δ 0.91(m,3H),1.62(m,2H),1.82(m,2H),2.38(m,1H),2.85(s,6H),3.14(m,1H),3.52(m,1H),6.63(m,1H),6.71(m,1H),6.78(s,1H),7.18(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.91(m,3H), 1.62(m,2H), 1.82(m,2H), 2.38(m,1H), 2.85(s,6H), 3.14(m,1H) ), 3.52(m, 1H), 6.63(m, 1H), 6.71(m, 1H), 6.78(s, 1H), 7.18(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值218.2；實測值219.2；Rt=0.823min。LCMS (ESI): [M+H] + m/z: calculated 218.2; found 219.2; Rt=0.823 min.

6F. 4-(5-甲基-2-哌啶基)苯胺之合成6F. Synthesis of 4-(5-methyl-2-piperidinyl)aniline

Figure 110128222-A0202-12-0761-618
Figure 110128222-A0202-12-0761-618

步驟1：3-甲基-6-(4-硝基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(4-nitrophenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(10.3g，29.83mmol)及4,4,5,5-四甲基-2-(4-硝基苯基)-1,3,2-二氧雜硼雜環戊烷(7.43g，29.83mmol)溶解於二噁烷(50mL)中。將反應混合物徹底除氣，隨後添加碳酸銫(48.59g，149.13mmol，1.01mL)、H2 O(10mL)及Pd(PPh3 )4 (3.45g，2.98mmol)。將所獲得之反應混合物在回流下攪拌隔夜。在反應完成(藉由反應混合物之HNMR推斷)之後，將有機溶劑發且將粗混合物分配於EtOAc(250mL)與H2 O(200mL)之間。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到3-甲基-6-(4-硝基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(10g，粗品)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (10.3 g, 29.83 mmol) and 4,4, 5,5-Tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (7.43 g, 29.83 mmol) was dissolved in dioxane (50 mL). The reaction mixture was thoroughly degassed, followed by the addition of cesium carbonate (48.59 g, 149.13 mmol, 1.01 mL), H2O (10 mL) and Pd( PPh3 ) 4 (3.45 g, 2.98 mmol). The obtained reaction mixture was stirred at reflux overnight. After completion of the reaction (inferred by HNMR of the reaction mixture), the organic solvent was evaporated and the crude mixture was partitioned between EtOAc (250 mL) and H2O (200 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give 3-methyl-6-(4-nitrophenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid third Butyl ester (10 g, crude) was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ 1.37(m,11H),2.03(m,3H),2.45(m,1H),3.00(m,1H),4.04(m,1H),5.45(s,1H),7.43(m,2H),8.14(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ 1.37(m,11H), 2.03(m,3H), 2.45(m,1H), 3.00(m,1H), 4.04(m,1H), 5.45(s,1H) ), 7.43 (m, 2H), 8.14 (m, 2H).

步驟2：3-甲基-6-(4-硝基苯基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 3-methyl-6-(4-nitrophenyl)-2,3,4,5-tetrahydropyridine

將3-甲基-6-(4-硝基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(10g，25.13mmol)溶解於DCM(30mL)中。將所得混合物攪拌5min，隨後添加TFA(14.33g，125.64mmol，9.68mL)。然後，將反應混合物攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且將有機溶劑蒸發，以得到3-甲基-6-(4-硝基苯基)-2,3,4,5-四氫吡啶(7g，粗品)，其不經純化即用於下一步驟。3-Methyl-6-(4-nitrophenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (10 g, 25.13 mmol) was dissolved in DCM (30 mL). The resulting mixture was stirred for 5 min before TFA (14.33 g, 125.64 mmol, 9.68 mL) was added. Then, the reaction mixture was stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH, and the organic solvent was evaporated to obtain 3-methyl-6-(4-nitrophenyl)-2,3,4,5-tetrahydropyridine (7 g , crude), which was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ 1.01(d,3H),1.31(m,1H),1.62(m,1H),1.92(m,1H), 2.52(m,1H),2.78(m,1H),3.25(m,1H),4.04(m,1H),7.94(m,2H),8.20(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ 1.01(d,3H), 1.31(m,1H), 1.62(m,1H), 1.92(m,1H), 2.52(m,1H), 2.78(m,1H) ), 3.25(m, 1H), 4.04(m, 1H), 7.94(m, 2H), 8.20(m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值218.1；實測值219.2；Rt=0.789minLCMS(ESI): [M+H] + m/z: Calculated 218.1; Found 219.2; Rt=0.789min

步驟3：4-(5-甲基-2-哌啶基)苯胺之合成Step 3: Synthesis of 4-(5-methyl-2-piperidinyl)aniline

將3-甲基-6-(4-硝基苯基)-2,3,4,5-四氫吡啶(7g，25.66mmol)溶解於MeOH(20mL)及H2 O(5mL)之混合物中。將所得混合物冷卻至0℃，隨後分批添加硼氫化鈉(3.88g，102.63mmol，3.63mL)。將反應混合物攪拌隔夜。反應完成之後，將混合物用10% HCl水溶液酸化至pH 2，用水稀釋，用MTBE(2* 10mL)洗滌，用10% NaOH水溶液鹼化至pH 10且用DCM(50mL)萃取。將有機層在減壓下蒸發，以得到純的4-(5-甲基-2-哌啶基)苯胺(5.1g，粗品)。3-Methyl-6-(4-nitrophenyl)-2,3,4,5-tetrahydropyridine (7 g, 25.66 mmol) was dissolved in a mixture of MeOH (20 mL) and H2O (5 mL) . The resulting mixture was cooled to 0°C, then sodium borohydride (3.88 g, 102.63 mmol, 3.63 mL) was added portionwise. The reaction mixture was stirred overnight. After completion of the reaction, the mixture was acidified to pH 2 with 10% aq. HCl, diluted with water, washed with MTBE (2 * 10 mL), basified to pH 10 with 10% aq. NaOH and extracted with DCM (50 mL). The organic layer was evaporated under reduced pressure to give pure 4-(5-methyl-2-piperidinyl)aniline (5.1 g, crude).

1 H NMR(400MHz,CDCl3 )δ 0.75(d,3H),1.05(m,1H),1.23(m,2H),1.42(m,1H),1.73(m,1H),1.94(m,1H),2.38(m,1H),3.07(m,1H),3.40(m,1H),3.57(m,2H),6.61(d,2H),7.12(d,2H)。 1 H NMR (400MHz, CDCl 3 )δ 0.75(d,3H), 1.05(m,1H), 1.23(m,2H), 1.42(m,1H), 1.73(m,1H), 1.94(m,1H) ), 2.38(m, 1H), 3.07(m, 1H), 3.40(m, 1H), 3.57(m, 2H), 6.61(d, 2H), 7.12(d, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值190.1；實測值191.2；Rt=0.413min。LCMS (ESI): [M+H] + m/z: calculated 190.1; found 191.2; Rt=0.413 min.

6G. -(5-甲基-3,4,5,6-四氫吡啶-2-基)苯酚之合成6G. Synthesis of -(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenol

Figure 110128222-A0202-12-0762-620
Figure 110128222-A0202-12-0762-620

步驟1：6-(3-羥基苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3-hydroxyphenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7g，20.27mmol)、(3-羥基苯基)硼酸(3.63g，26.35mmol)及碳酸鈉(6.45g，60.81mmol，2.55mL)添加到1,4-二噁烷(90mL)及水(30mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 DCM(661.62mg，810.81μmol)。將反應混合物在氬氣、70℃下攪拌12h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用己烷/MTBE梯度(0-100% MTBE)純化殘餘 物，以得到呈白色固體之6-(3-羥基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.7g，9.33mmol，46.03%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7 g, 20.27 mmol), (3-hydroxybenzene yl)boronic acid (3.63 g, 26.35 mmol) and sodium carbonate (6.45 g, 60.81 mmol, 2.55 mL) were added to a mixture of 1,4-dioxane (90 mL) and water (30 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf) Cl2DCM (661.62 mg, 810.81 μmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 12 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) to give 6-(3-hydroxyphenyl)-3- as a white solid Methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2.7 g, 9.33 mmol, 46.03% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.00(d,3H),1.12(s,9H),1.87(m,1H),2.02(m,1H),2.41(m,1H),2.98(t,1H),4.03(d,1H),5.33(m,1H),5.78(bds,1H),6.75(m,2H),6.88(d,1H),7.15(t,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.00(d, 3H), 1.12(s, 9H), 1.87(m, 1H), 2.02(m, 1H), 2.41(m, 1H), 2.98( t, 1H), 4.03 (d, 1H), 5.33 (m, 1H), 5.78 (bds, 1H), 6.75 (m, 2H), 6.88 (d, 1H), 7.15 (t, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值189.2；實測值190.2；Rt=1.473min。LCMS (ESI): [M-Boc] + m/z: calculated 189.2; found 190.2; Rt=1.473 min.

步驟2：3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯酚之合成Step 2: Synthesis of 3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenol

將6-(3-羥基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0.5g，1.73mmol)溶解於三氟乙酸(3.75g，32.89mmol，2.53mL)中。將所得溶液在25℃下攪拌1h，然後在真空中蒸發，以得到呈黃色膠狀物之粗品3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(1.1g，粗品)，其直接用於下一步驟中。6-(3-Hydroxyphenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (0.5 g, 1.73 mmol) was dissolved in trifluoroacetic acid (3.75 g, 32.89 mmol, 2.53 mL). The resulting solution was stirred at 25°C for 1 h, then evaporated in vacuo to give crude 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol as a yellow gum (1.1 g, crude), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.18(d,3H),1.68(m,1H),2.12(m,2H),3.15(m,1H),3.38(m,2H),4.01(m,1H),7.25(m,2H),7.41(m,2H),12.45(bds,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.18(d,3H), 1.68(m,1H), 2.12(m,2H), 3.15(m,1H), 3.38(m,2H), 4.01( m, 1H), 7.25 (m, 2H), 7.41 (m, 2H), 12.45 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值189.2；實測值190.2；Rt=0.788min。LCMS (ESI): [M] + m/z: calculated 189.2; found 190.2; Rt=0.788 min.

步驟3：3-(5-甲基哌啶-2-基)苯酚之合成Step 3: Synthesis of 3-(5-methylpiperidin-2-yl)phenol

在0℃下，在1h內，將硼氫化鈉(1.76g，46.50mmol，1.64mL)分批添加到3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(1.1g，5.81mmol)於甲醇(30mL)中之經攪拌之溶液中。使所得混合物升溫且在25℃下攪拌12h，然後在真空中蒸發。將殘餘物用氯仿(50ml)稀釋，攪拌0.1h且過濾。將濾餅另外用氯仿(2*10ml)洗滌且丟棄。將經合併之濾液在真空中蒸發，以得到呈黃色固體之粗品3-(5-甲基-2-哌啶基)苯酚(0.47g，2.46mmol，42.28%產率)，其直接用於下一步驟中。Sodium borohydride (1.76 g, 46.50 mmol, 1.64 mL) was added portionwise to 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) at 0 °C over 1 h ) phenol (1.1 g, 5.81 mmol) in a stirred solution of methanol (30 mL). The resulting mixture was warmed and stirred at 25 °C for 12 h, then evaporated in vacuo. The residue was diluted with chloroform (50 ml), stirred for 0.1 h and filtered. The filter cake was additionally washed with chloroform (2*10ml) and discarded. The combined filtrates were evaporated in vacuo to give crude 3-(5-methyl-2-piperidinyl)phenol (0.47 g, 2.46 mmol, 42.28% yield) as a yellow solid, which was used directly in the following in one step.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.98(d,3H),1.05(m,1H),1.69(m,3H),2.34(m,1H),3.30(m,2H),3.44(m,3H),6.64(m,3H),7.07(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.05(m,1H), 1.69(m,3H), 2.34(m,1H), 3.30(m,2H), 3.44( m, 3H), 6.64 (m, 3H), 7.07 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值191.2；實測值192.2；Rt=0.708min。LCMS (ESI): [M] + m/z: calculated 191.2; found 192.2; Rt=0.708 min.

6H. 4-(5-甲基哌啶-2-基)苯酚及乙酸外消旋 -4-((2R,5S )-5-甲基哌啶-2-基)苯酯之合成6H. Synthesis of 4-(5-methylpiperidin-2-yl)phenol and acetic acid racemic -4-(( 2R,5S )-5-methylpiperidin-2-yl)phenyl ester

Figure 110128222-A0202-12-0764-621
Figure 110128222-A0202-12-0764-621

步驟1：6-(4-羥基苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(4-hydroxyphenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(32g，92.66mmol)、(4-羥基苯基)硼酸(15.98g，115.83mmol)及碳酸鈉(29.46g，277.99mmol，11.65mL)添加到1,4-二噁烷(360mL)及水(120mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 DCM(3.02g，3.71mmol)。將反應混合物在氬氣、90℃下攪拌18h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用己烷/乙酸乙酯梯度(0-100%乙酸乙酯)純化殘餘物，以得到呈白色固體之6-(4-羥基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(12g，41.47mmol，44.75%產率)，其直接用於下一步驟中。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (32 g, 92.66 mmol), (4-hydroxybenzene base) boronic acid (15.98 g, 115.83 mmol) and sodium carbonate (29.46 g, 277.99 mmol, 11.65 mL) were added to a mixture of 1,4-dioxane (360 mL) and water (120 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf) Cl2DCM (3.02 g, 3.71 mmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 18 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/ethyl acetate gradient (0-100% ethyl acetate) to give 6-(4-hydroxyphenyl as a white solid) )-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (12 g, 41.47 mmol, 44.75% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.99(d,3H),1.12(s,9H),1.99(m,1H),2.00(m,1H),2.36(d,1H),2.96(t,1H),4.06(d,1H),5.22(m,1H),6.77(m,2H),7.15(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.99(d,3H), 1.12(s,9H), 1.99(m,1H), 2.00(m,1H), 2.36(d,1H), 2.96( t, 1H), 4.06 (d, 1H), 5.22 (m, 1H), 6.77 (m, 2H), 7.15 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值189.2；實測值190.2；Rt=1.395minLCMS(ESI): [M-Boc] + m/z: Calculated 189.2; Found 190.2; Rt=1.395min

步驟2：4-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯酚之合成Step 2: Synthesis of 4-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenol

將6-(4-羥基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(12g， 41.47mmol)溶解於三氟乙酸(141.85g，1.24mol，95.85mL)中。將所得溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(100g)添加到殘餘物中且用10%碳酸鈉水溶液將pH調節至9。將所得混合物用二氯甲烷(2*300ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈米色固體之4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(8.5g，粗品)，其直接用於下一步驟中。6-(4-Hydroxyphenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (12 g, 41.47 mmol) was dissolved in trifluoroacetic acid (141.85 g, 1.24 g mol, 95.85 mL). The resulting solution was stirred at 25°C for 1 h, then evaporated in vacuo. Crushed ice (100 g) was added to the residue and the pH was adjusted to 9 with 10% aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (2*300ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (8.5 oz) as a beige solid g, crude), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.98(d,3H),1.32(m,1H),1.67(m,1H),1.83(m,1H),2.56(m,1H),2.74(m,1H),3.11(m,1H),3.80(m,1H),6.50(m,2H),7.42(m,2H),10.89(bds,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.32(m,1H), 1.67(m,1H), 1.83(m,1H), 2.56(m,1H), 2.74( m, 1H), 3.11 (m, 1H), 3.80 (m, 1H), 6.50 (m, 2H), 7.42 (m, 2H), 10.89 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值189.2；實測值190.2；Rt=0.730min。LCMS (ESI): [M] + m/z: calculated 189.2; found 190.2; Rt=0.730 min.

步驟3：4-(5-甲基哌啶-2-基)苯酚之合成Step 3: Synthesis of 4-(5-methylpiperidin-2-yl)phenol

在0℃下，將硼氫化鈉(2g，52.87mmol，1.87mL)一次性添加到4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(8.5g，44.91mmol)於甲醇(100mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物溶解於甲醇(150ml)中且添加於二噁烷中之4.0M氯化氫溶液(117.81g，449.13mmol，112.20mL，13.9%純度)。在真空中蒸發所得混濁溶液，將殘餘物用THF(150ml)稀釋且攪拌0.5h。過濾沉澱，用THF(2*50ml)洗滌且在真空中乾燥，以得到呈淡黃色固體之經氯化鈉(大約3g)污染之70%純度粗品4-(5-甲基-2-哌啶基)苯酚(10.5g，粗品，HCl)，其直接用於下一步驟中。Sodium borohydride (2 g, 52.87 mmol, 1.87 mL) was added in one portion to 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (8.5 g at 0 °C) , 44.91 mmol) in a stirred solution of methanol (100 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was dissolved in methanol (150 ml) and a 4.0M solution of hydrogen chloride in dioxane (117.81 g, 449.13 mmol, 112.20 mL, 13.9% purity) was added. The resulting cloudy solution was evaporated in vacuo and the residue was diluted with THF (150ml) and stirred for 0.5h. The precipitate was filtered, washed with THF (2*50ml) and dried in vacuo to give 70% pure crude 4-(5-methyl-2-piperidine) contaminated with sodium chloride (approximately 3g) as a pale yellow solid yl)phenol (10.5 g, crude, HCl), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.92(d,3H),1.28(m,1H),1.95(m,3H),2.11(m,1H),2.65(m,1H),3.12(m,1H),3.99(m,1H),6.81(m,2H),7.40(m,2H),9.30(m,1H),9.70(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.92(d, 3H), 1.28(m, 1H), 1.95(m, 3H), 2.11(m, 1H), 2.65(m, 1H), 3.12 (m, 1H), 3.99 (m, 1H), 6.81 (m, 2H), 7.40 (m, 2H), 9.30 (m, 1H), 9.70 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值191.2；實測值192.2；Rt=0.732min。LCMS (ESI): [M] + m/z: calculated 191.2; found 192.2; Rt=0.732 min.

步驟4：外消旋-(2R,5S)-2-(4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of racemic-(2R,5S)-2-(4-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將4-[(2S,5R )-5-甲基-2-哌啶基]苯酚(2g，10.46mmol)及TEA(3.17g， 31.37mmol，4.37mL)溶解於THF(30mL)中。將溶液攪拌15min，之後逐滴添加二碳酸二-第三丁酯(2.51g，11.50mmol，2.64mL)。此後，將反應混合物在室溫下攪拌隔夜，然後將其用EtOAc稀釋，用NaHSO4 (水溶液)、鹽水洗滌，經Na2 SO4 乾燥，過濾且在真空下蒸發，以得到(2S,5R )-2-(4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯(2.86g，9.82mmol，93.87%產率)，其不經進一步純化即用於下一步驟。4-[( 2S,5R )-5-methyl-2-piperidinyl]phenol (2 g, 10.46 mmol) and TEA (3.17 g, 31.37 mmol, 4.37 mL) were dissolved in THF (30 mL). The solution was stirred for 15 min before di-tert-butyl dicarbonate (2.51 g, 11.50 mmol, 2.64 mL) was added dropwise. After this time, the reaction mixture was stirred at room temperature overnight, then it was diluted with EtOAc, washed with NaHSO4 (aq), brine, dried over Na2SO4 , filtered and evaporated in vacuo to give ( 2S,5R ) - 2-(4-Hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2.86 g, 9.82 mmol, 93.87% yield), which was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.00(d,3H),1.28(m,2H),1.49(s,9H),1.78(m,2H),2.07(m,2H),2.97(m,1H),3.71(m,1H),5.24(m,1H),6.78(d,2H),7.05(d,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.00(d, 3H), 1.28(m, 2H), 1.49(s, 9H), 1.78(m, 2H), 2.07(m, 2H), 2.97( m, 1H), 3.71 (m, 1H), 5.24 (m, 1H), 6.78 (d, 2H), 7.05 (d, 2H).

步驟5：外消旋-(2R,5S)-2-(4-乙醯氧基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of racemic-(2R,5S)-2-(4-acetoxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2S,5R )-2-(4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯(2.86g，9.82mmol)及乙醯氯(847.54mg，10.80mmol，657.01μL)TEA(2.98g，29.45mmol，4.10mL)溶解於無水DCM(36mL)中且冷卻至0℃。逐滴添加乙醯氯(847.54mg，10.80mmol，657.01μL)，然後使反應混合物升溫至室溫且攪拌隔夜，然後用NaHSO4 (水溶液)、NaHCO3 (水溶液)及鹽水洗滌。將有機相經Na2 SO4 乾燥，過濾且在真空下蒸發，以得到(2S,5R )-2-(4-乙醯氧基苯基)-5-甲基哌啶-1-甲酸第三丁酯(3.11g，9.33mmol，95.03%產率)，其不經進一步純化即用於下一步驟。 (2S,5R )-2-(4-乙醯氧基苯基)-5-甲基哌啶-1-甲酸第三丁酯(3.11g，9.33mmol，95.03%產率)。Combine ( 2S,5R )-2-(4-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2.86 g, 9.82 mmol) and acetyl chloride (847.54 mg, 10.80 mmol, 657.01 g) μL) TEA (2.98 g, 29.45 mmol, 4.10 mL) was dissolved in dry DCM (36 mL) and cooled to 0 °C. Acetyl chloride (847.54 mg, 10.80 mmol, 657.01 μL) was added dropwise, then the reaction mixture was warmed to room temperature and stirred overnight, then washed with NaHSO4 (aq), NaHCO3 (aq) and brine. The organic phase was dried over Na 2 SO 4 , filtered and evaporated in vacuo to give ( 2S,5R )-2-(4-acetoxyphenyl)-5-methylpiperidine-1-carboxylic acid third Butyl ester (3.11 g, 9.33 mmol, 95.03% yield) was used in the next step without further purification. ( 2S,5R )-2-(4-Acetyloxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (3.11 g, 9.33 mmol, 95.03% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.04(d,3H),1.31(m,1H),1.53(s,9H),1.80(m,2H),2.12(m,2H),2.29(s,3H),2.99(m,1H),3.73(m,1H),5.31(m,1H),7.05(d,2H),7.23(d,2H) 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.04(d, 3H), 1.31(m, 1H), 1.53(s, 9H), 1.80(m, 2H), 2.12(m, 2H), 2.29( s, 3H), 2.99(m, 1H), 3.73(m, 1H), 5.31(m, 1H), 7.05(d, 2H), 7.23(d, 2H)

步驟6：乙酸外消旋-4-((2R,5S)-5-甲基哌啶-2-基)苯酯之合成Step 6: Synthesis of Acetic Acid Racemic-4-((2R,5S)-5-methylpiperidin-2-yl)phenyl Ester

將(2S,5R )-2-(4-乙醯氧基苯基)-5-甲基哌啶-1-甲酸第三丁酯(3.11g，9.33mmol)溶解於於二噁烷中之4.0M氯化氫溶液(6.80g，186.55mmol，8.50mL) 中且在20℃下攪拌3h。在真空下濃縮反應混合物，以得到乙酸[4-[(2S,5R )-5-甲基-2-哌啶基]苯]酯(2.38g，8.82mmol，94.51%產率，HCl)，其不經進一步純化即用於下一步驟。( 2S,5R )-2-(4-Acetyloxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (3.11 g, 9.33 mmol) was dissolved in 4.0 mol in dioxane M hydrogen chloride solution (6.80 g, 186.55 mmol, 8.50 mL) and stirred at 20 °C for 3 h. The reaction mixture was concentrated under vacuum to give [4-[( 2S,5R )-5-methyl-2-piperidinyl]phenyl] acetate (2.38 g, 8.82 mmol, 94.51% yield, HCl) as Used in the next step without further purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.90(d,3H),1.27(m,1H),2.05(m,3H),2.22(s,3H),2.63(m,2H),3.17(m,1H),3.96(m,1H),7.16(d,2H),7.62(d,2H),9.26(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.90(d, 3H), 1.27(m, 1H), 2.05(m, 3H), 2.22(s, 3H), 2.63(m, 2H), 3.17 (m, 1H), 3.96 (m, 1H), 7.16 (d, 2H), 7.62 (d, 2H), 9.26 (m, 1H).

6I.5-(5-甲基哌啶-2-基)-1H-吲哚 之合成6I. Synthesis of 5-(5-methylpiperidin-2-yl)-1H-indole

Figure 110128222-A0202-12-0767-622
Figure 110128222-A0202-12-0767-622

步驟1：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吲哚之合成Step 1: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-indole

將乙酸鉀(15.02g，153.03mmol，9.57mL)添加到5-溴-1H -吲哚(15g，76.51mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(22.34g，87.99mmol)於二噁烷(400mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加Pd(dppf)Cl2 *DCM(3.12g，3.83mmol)。在90℃、惰性氣氛下將所得混合物攪拌28h。然後，將其冷卻，用MTBE(700mL)稀釋且過濾。在減壓下濃縮濾液且藉由矽膠急驟層析以0至100% MTBE-己烷梯度溶析來純化殘餘物，以得到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H -吲哚(7.2g，29.62mmol，38.71%產率)。Potassium acetate (15.02 g, 153.03 mmol, 9.57 mL) was added to 5-bromo- 1H -indole (15 g, 76.51 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (22.34g, 87.99mmol) in dioxaborolane in oxane (400 mL). The reaction flask was evacuated and refilled with argon 3 times. Then Pd(dppf)Cl2*DCM (3.12 g , 3.83 mmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 28 h. It was then cooled, diluted with MTBE (700 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography with a gradient of 0 to 100% MTBE-hexane to give 5-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborol-2- yl )-1H-indole (7.2 g, 29.62 mmol, 38.71% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.35(s,12H),6.55(d,1H),7.17(s,1H),7.36(d,1H),7.63(d,1H),8.17(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.35(s, 12H), 6.55(d, 1H), 7.17(s, 1H), 7.36(d, 1H), 7.63(d, 1H), 8.17( m, 2H).

GCMS：計算值243.2；實測值243.2；Rt=11.341min。GCMS: Calculated 243.2; Found 243.2; Rt=11.341 min.

步驟2：6-(1H-吲哚-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 2: Synthesis of 6-(1H-indol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

在80℃、氬氣氣氛下，將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.73g，13.70mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H -吲哚(4.16g，17.12mmol)、環戊基(二苯基)磷烷；二氯甲烷；二氯鈀；鐵(559.27mg，684.84μmol)及碳酸鈉(4.36g，41.09mmol，1.72mL)於二噁烷(75mL)及水(25mL)中之混合物攪拌28h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(100mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析以0至100% MTBE-己烷梯度溶析來純化殘餘物，以得到6-(1H -吲哚-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.2g，3.84mmol，28.04%產率)。At 80°C under argon atmosphere, 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4.73 g , 13.70 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2- yl )-1H-indole (4.16 g, 17.12 mmol) ), cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; iron (559.27 mg, 684.84 μmol) and sodium carbonate (4.36 g, 41.09 mmol, 1.72 mL) in dioxane (75 mL) and The mixture in water (25 mL) was stirred for 28 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (100 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography with a gradient of 0 to 100% MTBE-hexane to give 6-( lH -indol-5-yl)-3-methyl- 3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.2 g, 3.84 mmol, 28.04% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.87(s,9H),0.97(m,2H),1.24(m,2H),1.85(m,2H),2.38(m,1H),3.02(m,1H),3.92(d,1H),5.20(m,1H),6.37(m,1H),6.99(d,1H),7.29(d,1H),7.38(m,1H),10.97(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.87(s, 9H), 0.97(m, 2H), 1.24(m, 2H), 1.85(m, 2H), 2.38(m, 1H), 3.02(m, 1H), 3.92(d, 1H), 5.20(m, 1H), 6.37(m, 1H), 6.99(d, 1H), 7.29(d, 1H), 7.38(m, 1H), 10.97 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值212.2；實測值213.2；Rt=1.591min。LCMS (ESI): [M-Boc] + m/z: calculated 212.2; found 213.2; Rt=1.591 min.

步驟3：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-1H-吲哚之合成Step 3: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1H-indole

將6-(1H -吲哚-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.2g，3.84mmol)於TFA(7.01g，61.46mmol，4.73mL)中之溶液在20℃下攪拌1h，然後在真空中蒸發。將碎冰(10g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -吲哚(0.8g，粗品)，其直接用於下一步驟中。Dissolve 6-( 1H -indol-5-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.2 g, 3.84 mmol) in TFA (7.01 g, The solution in 61.46 mmol, 4.73 mL) was stirred at 20 °C for 1 h, then evaporated in vacuo. Crushed ice (10 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6- yl )-1H- as a yellow solid Indole (0.8 g, crude) was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(m,3H),1.17(m,2H),1.98(m,2H),3.04(m,1H),3.22(m,2H),3.87(m,1H),6.58(m,1H),7.32(m,1H),7.46(m,1H),8.24(m,1H),11.05(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.96(m, 3H), 1.17(m, 2H), 1.98(m, 2H), 3.04(m, 1H), 3.22(m, 2H), 3.87 (m, 1H), 6.58 (m, 1H), 7.32 (m, 1H), 7.46 (m, 1H), 8.24 (m, 1H), 11.05 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值212.2；實測值213.2；Rt=0.940minLCMS(ESI): [M] + m/z: Calculated 212.2; Measured 213.2; Rt=0.940min

步驟4：5-(5-甲基哌啶-2-基)-1H-吲哚之合成Step 4: Synthesis of 5-(5-Methylpiperidin-2-yl)-1H-indole

在0℃下，將硼氫化鈉(285.12mg，7.54mmol，266.47μL)一次性添加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -吲哚(0.8g，3.77mmol)於MeOH(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(10mL)稀釋且用二氯甲烷(2*20mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之5-(5-甲基-2-哌啶基)-1H -吲哚(0.8g，粗品)，其直接用於下一步驟中。At 0 °C, sodium borohydride (285.12 mg, 7.54 mmol, 266.47 μL) was added in one portion to 5-(3-methyl-2,3,4,5-tetrahydropyridin-6- yl )-1H- Indole (0.8 g, 3.77 mmol) in a stirred solution of MeOH (20 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (10 mL) and extracted with dichloromethane (2*20 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl) -1H -indole (0.8 g, crude) as a yellow solid used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.79(d,3H),1.06(m,1H),1.34(m,2H),1.74(m,2H),2.25(m,1H),2.98(m,1H),3.29(m,1H),5.28(m,1H),6.30(m,1H),723(m,4H),10.90(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.79(d,3H), 1.06(m,1H), 1.34(m,2H), 1.74(m,2H), 2.25(m,1H), 2.98(m,1H), 3.29(m,1H), 5.28(m,1H), 6.30(m,1H), 723(m,4H), 10.90(m,1H).

LCMS(ESI)：[M]+ m/z：計算值214.2；實測值215.2；Rt=0.950min。LCMS (ESI): [M] + m/z: calculated 214.2; found 215.2; Rt=0.950 min.

6J. 5-(5-甲基哌啶-2-基)-1H -苯并[d ]咪唑之合成6J. Synthesis of 5-(5-methylpiperidin-2- yl )-1H-benzo[ d ]imidazole

Figure 110128222-A0202-12-0769-623
Figure 110128222-A0202-12-0769-623

步驟1：6-(1H-苯并[d]咪唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(1H-benzo[d]imidazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4g，11.58mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H -苯并咪唑(4.06g，14.48mmol，HCl)、Pd(dppf)Cl2 *DCM(472.95mg，579.15μmol)及碳酸鈉(4.91g，46.33mmol，1.94mL)於二噁烷(75mL)及水(25mL)中之混合物在80℃、氬氣氣氛下攪拌48h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(100mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析以0至100% MeCN-CHCl3 梯度溶析來純化殘餘物，以得到6-(1H -苯并咪唑-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.5g，4.79mmol，41.32%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4 g, 11.58 mmol), 5-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2- yl )-1H-benzimidazole (4.06g, 14.48mmol, HCl), Pd(dppf)Cl 2 * A mixture of DCM (472.95 mg, 579.15 μmol) and sodium carbonate (4.91 g, 46.33 mmol, 1.94 mL) in dioxane (75 mL) and water (25 mL) was stirred at 80 °C under argon atmosphere for 48 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (100 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography with a gradient of 0 to 100% MeCN - CHCl to give 6-( 1H -benzimidazol-5-yl)-3-methyl -3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 4.79 mmol, 41.32% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.03(d,3H),1.25(s,9H),1.86(m,1H),2.04(m, 1H),2.44(d,1H),3.06(t,1H),4.11(d,1H),5.35(s,1H),7.25(m,1H),7.58(m,3H),8.01(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.03(d, 3H), 1.25(s, 9H), 1.86(m, 1H), 2.04(m, 1H), 2.44(d, 1H), 3.06( t, 1H), 4.11 (d, 1H), 5.35 (s, 1H), 7.25 (m, 1H), 7.58 (m, 3H), 8.01 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值313.2；實測值314.2；Rt=1.015min。LCMS (ESI): [M] + m/z: calculated 313.2; found 314.2; Rt=1.015 min.

步驟2：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-1H-苯并[d]咪唑之合成Step 2: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1H-benzo[d]imidazole

將6-(1H -苯并咪唑-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.50g，4.79mmol)於TFA(8.73g，76.58mmol，5.90mL)中之溶液在20℃下攪拌1h，然後在真空中蒸發。將碎冰(10g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至8。將所得混合物用EtOAc(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色膠狀物之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -苯并咪唑(1g，粗品)，其直接用於下一步驟中。6-( 1H -benzimidazol-5-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.50 g, 4.79 mmol) was dissolved in TFA (8.73 g) , 76.58 mmol, 5.90 mL) was stirred at 20 °C for 1 h and then evaporated in vacuo. Crushed ice (10 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with EtOAc (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)- as a brown gum 1H -benzimidazole (1 g, crude) was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.37(m,1H),1.71(m,1H),1.88(m,1H),2.75(m,1H),2.99(m,1H),3.23(m,1H),3.93(m,1H),7.55(m,1H),7.77(m,1H),8.05(m,1H),8.28(m,1H),12.56(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.37(m,1H), 1.71(m,1H), 1.88(m,1H), 2.75(m,1H), 2.99(m,1H),3.23(m,1H),3.93(m,1H),7.55(m,1H),7.77(m,1H),8.05(m,1H),8.28(m,1H),12.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值213.2；實測值214.2；Rt=0.693min。LCMS (ESI): [M] + m/z: calculated 213.2; found 214.2; Rt=0.693 min.

步驟3：5-(5-甲基哌啶-2-基)-1H-苯并[d]咪唑之合成Step 3: Synthesis of 5-(5-methylpiperidin-2-yl)-1H-benzo[d]imidazole

在0℃下，將硼氫化鈉(266.08mg，7.03mmol，248.67μL)一次性添加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -苯并咪唑(1.00g，4.69mmol)於MeOH(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(10mL)稀釋且用二氯甲烷(2*20mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之5-(5-甲基-2-哌啶基)-1H -苯并咪唑(0.82g，粗品)，其直接用於下一步驟中。At 0 °C, sodium borohydride (266.08 mg, 7.03 mmol, 248.67 μL) was added in one portion to 5-(3-methyl-2,3,4,5-tetrahydropyridin-6- yl )-1H- In a stirred solution of benzimidazole (1.00 g, 4.69 mmol) in MeOH (20 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (10 mL) and extracted with dichloromethane (2*20 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl) -1H -benzimidazole (0.82 g, crude) as a brown solid, It is used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.84(m,3H),1.11(m,1H),1.53(m,2H),1.79(m,2H),2.31(m,1H),3.02(m,1H),3.56(m,1H),7.17(m,1H),7.49(m,3H),8.13(m,1H),12.36(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.84(m, 3H), 1.11(m, 1H), 1.53(m, 2H), 1.79(m, 2H), 2.31(m, 1H), 3.02 (m, 1H), 3.56 (m, 1H), 7.17 (m, 1H), 7.49 (m, 3H), 8.13 (m, 1H), 12.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值215.2；實測值216.2；Rt=0.627min。LCMS (ESI): [M] + m/z: calculated 215.2; found 216.2; Rt=0.627 min.

6K. 5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑之合成6K. Synthesis of 5-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole

Figure 110128222-A0202-12-0771-624
Figure 110128222-A0202-12-0771-624

步驟1：6-(1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(1H-Indazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吲唑(3g，12.29mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.24g，12.29mmol)、碳酸鈉(5.21g，49.16mmol，2.06mL)及四丁基溴化銨(198.10mg，614.51μmol)於二噁烷(60mL)及水(12mL)中之混合物除氣且用Ar再填充三次。向此溶液中添加Pd(dppf)Cl2* DCM(501.83mg，614.51μmol)。將所得混合物除氣，用Ar再填充且在95℃下攪拌72h。過濾出沉澱，用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於150ml水中且用EtOAc(2* 100ml)萃取。將經合併之有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(7g)。藉由梯度層析(SiO2 ，CHCl3 -MeOH)純化粗產物，以獲得6-(1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.5g，4.79mmol，38.94%產率)。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-indazole (3 g, 12.29 mmol), 3-methyl tert-butyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylate (4.24 g, 12.29 mmol), sodium carbonate (5.21 g, 49.16 mmol) , 2.06 mL) and tetrabutylammonium bromide (198.10 mg, 614.51 μmol) in dioxane (60 mL) and water (12 mL) was degassed and refilled three times with Ar. To this solution was added Pd(dppf)Cl2 * DCM (501.83 mg, 614.51 μmol). The resulting mixture was degassed, refilled with Ar and stirred at 95 °C for 72 h. The precipitate was filtered off and washed with dioxane (50ml). The solvent was evaporated in vacuo and the residue was dissolved in 150 ml of water and extracted with EtOAc (2 * 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (7 g). The crude product was purified by gradient chromatography ( SiO2 , CHCl3 -MeOH) to obtain 6-(1H-indazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1 - tert-butyl formate (1.5 g, 4.79 mmol, 38.94% yield).

1 H NMR(500MHz,DMSO-d6 )：δ(ppm)0.96(s,9H),0.97(d,3H),1.85(m,2H),2.40(m,1H),3.02(m,1H),3.91(m,1H),5.29(s,1H),7.24(d,1H),7.44(d,1H),7.58(s,1H),8.01(s,1H)，未觀察到NH。 1 H NMR (500MHz, DMSO-d 6 ): δ(ppm) 0.96(s, 9H), 0.97(d, 3H), 1.85(m, 2H), 2.40(m, 1H), 3.02(m, 1H) , 3.91(m, 1H), 5.29(s, 1H), 7.24(d, 1H), 7.44(d, 1H), 7.58(s, 1H), 8.01(s, 1H), no NH was observed.

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值314.2；Rt=1.321min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 314.2; Rt=1.321 min.

步驟2：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 2: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

將6-(1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.5g，4.79mmol)溶解於三氟乙酸(14.80g，129.80mmol，10mL)中。將所得混合物 在25℃下攪拌2h(直至氣體逸出結束)且在真空中蒸發溶劑。將溶液之pH用10% NaHCO3 水溶液調節至8且用DCM(3* 70ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(0.8g，3.75mmol，78.37%產率)。此化合物不經純化即用於下一步驟。6-(1H-Indazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 4.79 mmol) was dissolved in trifluoroacetic acid ( 14.80 g, 129.80 mmol, 10 mL). The resulting mixture was stirred at 25 °C for 2 h (until gas evolution was over) and the solvent was evaporated in vacuo. The pH of the solution was adjusted to 8 with 10% aqueous NaHCO3 and extracted with DCM (3 * 70ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl )-1H-indazole (0.8 g, 3.75 mmol, 78.37% yield). This compound was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )：δ(ppm)1.00(d,3H),1.42(m,1H),1.74(m,1H),1.95(m,1H),2.67(m,1H),2.86(m,1H),3.29(m,1H),4.05(m,1H),7.40(d,1H),7.96(d,1H),8.08(s,2H),10.73(m,1H)。 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 1.00 (d, 3H), 1.42 (m, 1H), 1.74 (m, 1H), 1.95 (m, 1H), 2.67 (m, 1H), 2.86 (m, 1H), 3.29 (m, 1H), 4.05 (m, 1H), 7.40 (d, 1H), 7.96 (d, 1H), 8.08 (s, 2H), 10.73 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值213.2；實測值214.2；Rt=0.727min。LCMS (ESI): [M+H] + m/z: calculated 213.2; found 214.2; Rt=0.727 min.

步驟3：5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑之合成Step 3: Synthesis of 5-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole

在0℃下，向5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(0.8g，3.75mmol)於MeOH(20mL)中之溶液中分批添加硼氫化鈉(283.82mg，7.50mmol，265.25μL)。將所得混合物在25℃下攪拌3h且在真空中蒸發溶劑，將殘餘物溶解於水(30ml)中且用EtOAc(3* 30ml)萃取。將經合併之有機萃取物用鹽水(2* 50ml)洗滌，經Na2 SO4 乾燥且蒸發，以得到5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(0.73g，3.39mmol，90.40%產率)。此化合物不經純化即用於下一步驟。To a solution of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole (0.8 g, 3.75 mmol) in MeOH (20 mL) at 0 °C Sodium borohydride (283.82 mg, 7.50 mmol, 265.25 μL) was added portionwise. The resulting mixture was stirred at 25°C for 3h and the solvent was evaporated in vacuo, the residue was dissolved in water (30ml) and extracted with EtOAc (3 * 30ml). The combined organic extracts were washed with brine (2 * 50ml), dried over Na2SO4 and evaporated to give 5 -[(2S,5R)-5-methyl-2-piperidinyl]-1H- Indazole (0.73 g, 3.39 mmol, 90.40% yield). This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )：δ(ppm)0.80(d,3H),1.07(m,2H),1.35(m,1H),1.49(m,1H),1.73(m,2H),2.25(m,1H),2.96(m,1H),3.50(m,1H),7.31(d,1H),7.39(d,1H),7.64(s,1H),7.95(s,1H),12.89(m,1H)。 1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) 0.80 (d, 3H), 1.07 (m, 2H), 1.35 (m, 1H), 1.49 (m, 1H), 1.73 (m, 2H) ,2.25(m,1H),2.96(m,1H),3.50(m,1H),7.31(d,1H),7.39(d,1H),7.64(s,1H),7.95(s,1H), 12.89 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值215.1；實測值216.2；Rt=0.645min。LCMS (ESI): [M+H] + m/z: calculated 215.1; found 216.2; Rt=0.645 min.

6L. 5-(2-哌啶基)-1H-吲唑之合成6L. Synthesis of 5-(2-piperidinyl)-1H-indazole

Figure 110128222-A0202-12-0773-626
Figure 110128222-A0202-12-0773-626

步驟1：5-溴吲唑-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-butyl 5-bromoindazole-1-carboxylate

在0℃下，向5-溴-1H-吲唑(20.5g，104.04mmol)於乙腈(300mL)中之經攪拌之溶液中添加三乙胺(10.53g，104.04mmol，14.50mL)、二碳酸二-第三丁酯(34.06g，156.07mmol，35.82mL)及DMAP(1.27g，10.40mmol)。將所得反應混合物在25℃下攪拌16h。16小時之後，將反應混合物在減壓下濃縮，以獲得呈深橙色膠狀物之粗產物。藉由管柱層析(0-100%於己烷中之MTBE)純化粗產物，以獲得呈淡橙色液體之產物5-溴吲唑-1-甲酸第三丁酯(30.0g，100.96mmol，97.04%產率)。To a stirred solution of 5-bromo-1H-indazole (20.5 g, 104.04 mmol) in acetonitrile (300 mL) at 0 °C was added triethylamine (10.53 g, 104.04 mmol, 14.50 mL), dicarbonic acid Di-tert-butyl ester (34.06 g, 156.07 mmol, 35.82 mL) and DMAP (1.27 g, 10.40 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. After 16 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude product as a dark orange gum. The crude product was purified by column chromatography (0-100% MTBE in hexanes) to give the product tert-butyl 5-bromoindazole-1-carboxylate (30.0 g, 100.96 mmol, 5-bromoindazole-1-carboxylate) as a pale orange liquid. 97.04% yield).

1 H NMR(CDCl3 ,400MHz)：δ 1.69(s,9H),7.60(d,1H),7.85(s,1H),8.08(m,2H)。 1 H NMR (CDCl 3 , 400 MHz): δ 1.69 (s, 9H), 7.60 (d, 1H), 7.85 (s, 1H), 8.08 (m, 2H).

步驟2：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯之合成Step 2: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid tert-butyl ester

向5-溴吲唑-1-甲酸第三丁酯(30g，100.96mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-聯-1,3,2-二氧雜硼雜環戊烷(28.20g，111.06mmol)及乙酸鉀(19.82g，201.92mmol，12.62mL)於二噁烷(700mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(4.12g，5.05mmol)，將所得混合物在90℃下攪拌48h，冷卻，過濾，在真空中蒸發。藉由梯度層析(己烷-EA)純化殘餘物(50g)，以得到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯(29g，84.25mmol，83.45%產率)。To 3-butyl 5-bromoindazole-1-carboxylate (30 g, 100.96 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- A suspension of bi-1,3,2-dioxaborolane (28.20 g, 111.06 mmol) and potassium acetate (19.82 g, 201.92 mmol, 12.62 mL) in dioxane (700 mL) was degassed and Fill three more times with Ar. To this solution was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (4.12 g, 5.05 mmol), and the resulting mixture was heated at 90°C It was stirred for 48 h, cooled, filtered and evaporated in vacuo. The residue (50 g) was purified by gradient chromatography (hexane-EA) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)indazole-1-carboxylic acid tert-butyl ester (29 g, 84.25 mmol, 83.45% yield).

1 H NMR(CDCl3 ,400MHz)：δ 1.35(m,12H),1.71(s,9H),7.92(d,1H),8.14(m,1H),8.21(s,1H)。 1 H NMR (CDCl 3 , 400 MHz): δ 1.35 (m, 12H), 1.71 (s, 9H), 7.92 (d, 1H), 8.14 (m, 1H), 8.21 (s, 1H).

步驟3：5-(1-第三丁氧基羰基-3,4-二氫-2H-吡啶-6-基)吲唑-1-甲酸第三丁酯之合成Step 3: Synthesis of 5-(1-tert-butoxycarbonyl-3,4-dihydro-2H-pyridin-6-yl)indazole-1-carboxylic acid tert-butyl ester

在氮氣、室溫下，向6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.00g，5.55mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯(2.12g，5.55mmol)及碳酸鈉(1.77g，16.66mmol，697.99μL)於二噁烷(24mL)及水(8mL)中之經攪拌之溶液中添加Pd(dppf)Cl2‧DCM(226.77mg，277.69μmol)。在90℃、氮氣下將所得反應混合物攪拌16h。16小時之後，使反應混合物冷卻至室溫且透過矽膠墊過濾。用乙酸乙酯(100mL)洗滌矽膠墊。在減壓下濃縮濾液以獲得深棕色粗產物。藉由矽膠管柱層析(0-100%於己烷中之MTBE)純化粗產物，以得到呈灰白色固體之產物5-(1-第三丁氧基羰基-3,4-二氫-2H-吡啶-6-基)吲唑-1-甲酸第三丁酯(550mg，1.38mmol，24.79%產率)。To 6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.00 g, 5.55 mmol), 5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid tert-butyl ester (2.12 g, 5.55 mmol) and To a stirred solution of sodium carbonate (1.77 g, 16.66 mmol, 697.99 μL) in dioxane (24 mL) and water (8 mL) was added Pd(dppf)Cl2·DCM (226.77 mg, 277.69 μmol). The resulting reaction mixture was stirred at 90 °C under nitrogen for 16 h. After 16 hours, the reaction mixture was cooled to room temperature and filtered through a pad of silica gel. The silica pad was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to obtain dark brown crude product. The crude product was purified by silica gel column chromatography (0-100% MTBE in hexanes) to give the product 5-(1-tert-butoxycarbonyl-3,4-dihydro-2H as an off-white solid - Pyridin-6-yl)indazole-1-carboxylic acid tert-butyl ester (550 mg, 1.38 mmol, 24.79% yield).

1 H NMR(500MHz,CDCl3 )δ 0.99(s,9H),1.22(s,9H),1.87(m,2H),2.27(m,2H),5.33(s,1H),7.35(s,1H),7.40(s,1H),7.66(s,1H),8.04(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.99(s, 9H), 1.22(s, 9H), 1.87(m, 2H), 2.27(m, 2H), 5.33(s, 1H), 7.35(s, 1H) ), 7.40(s, 1H), 7.66(s, 1H), 8.04(s, 1H).

LCMS(ESI)：[M-Boc+H]+ m/z：計算值300.0；實測值300；Rt=1.369min。LCMS (ESI): [M-Boc+H] + m/z: calculated 300.0; found 300; Rt=1.369 min.

步驟4：5-(2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 4: Synthesis of 5-(2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

將於三氟乙酸(3.03g，26.53mmol，2.04mL)中之5-(1-第三丁氧基羰基-3,4-二氫-2H-吡啶-6-基)吲唑-1-甲酸第三丁酯(0.53g，1.33mmol)在25℃下攪拌1h。1小時之後，在減壓下濃縮反應混合物，以獲得淡橙色膠狀粗產物。將水(10mL)添加到粗產物中且將水相用10% NaOH溶液鹼化，直至pH=10。將所獲得之懸浮液用二氯甲烷(3 x 20mL)萃取。將經合併之有機相用水(10mL)洗滌，經硫酸鈉乾燥，過濾且在減壓下濃縮，以獲得呈灰白色固體之粗產物5-(2,3,4,5-四氫吡啶-6-基)-1H-吲唑(300mg，粗品)。將粗產物用於下一步驟反應中。5-(1-Third-butoxycarbonyl-3,4-dihydro-2H-pyridin-6-yl)indazole-1-carboxylic acid in trifluoroacetic acid (3.03 g, 26.53 mmol, 2.04 mL) The tert-butyl ester (0.53 g, 1.33 mmol) was stirred at 25 °C for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure to obtain the crude product as a pale orange gum. Water (10 mL) was added to the crude product and the aqueous phase was basified with 10% NaOH solution until pH=10. The obtained suspension was extracted with dichloromethane (3 x 20 mL). The combined organic phases were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 5-(2,3,4,5-tetrahydropyridine-6- as an off-white solid) yl)-1H-indazole (300 mg, crude). The crude product was used in the next step reaction.

1 H NMR(500MHz,CDCl3 )δ 1.69(m,2H),1.87(m,2H),2.74(m,2H),3.88(m,2H),7.42(d,1H),7.99(d,1H),8.10(s,2H),10.71(brs,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.69 (m, 2H), 1.87 (m, 2H), 2.74 (m, 2H), 3.88 (m, 2H), 7.42 (d, 1H), 7.99 (d, 1H) ), 8.10(s, 2H), 10.71(brs, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值199.1；實測值200.2；Rt=0.644min。LCMS (ESI): [M+H] + m/z: calculated 199.1; found 200.2; Rt=0.644 min.

步驟5：5-(2-哌啶基)-1H-吲唑之合成Step 5: Synthesis of 5-(2-piperidinyl)-1H-indazole

在25℃下向5-(2,3,4,5-四氫吡啶-6-基)-1H-吲唑(300mg，1.51mmol)於甲醇(8mL)中之經攪拌之溶液中添加硼氫化鈉(85.44mg，2.26mmol，79.85μL)。將所得反應混合物在同一溫度下攪拌1h。1小時之後，將反應混合物在減壓下濃縮且將粗產物用水(20mL)淬滅。將所獲得之混合物用二氯甲烷(3 x 30mL)萃取，用水(20mL)洗滌，經硫酸鈉乾燥，過濾且在減壓下濃縮，以獲得呈灰白色固體之粗產物5-(2-哌啶基)-1H-吲唑(200mg，粗品)。將粗產物用於下一步驟反應中。To a stirred solution of 5-(2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole (300 mg, 1.51 mmol) in methanol (8 mL) was added hydroboration at 25 °C Sodium (85.44 mg, 2.26 mmol, 79.85 μL). The resulting reaction mixture was stirred at the same temperature for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure and the crude product was quenched with water (20 mL). The obtained mixture was extracted with dichloromethane (3 x 30 mL), washed with water (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 5-(2-piperidine as an off-white solid) yl)-1H-indazole (200 mg, crude). The crude product was used in the next step reaction.

1 H NMR(DMSO,400MHz)：δ 1.33-1.43(m,3H),1.55(m,1H),1.68(m,1H),1.71(m,1H),2.27(m,1H),2.64(m,1H),3.04(m,1H),3.60(m,1H),7.34(d,1H),7.43(d,1H),7.67(s,1H),7.98(s,1H)。 1 H NMR (DMSO, 400MHz): δ 1.33-1.43 (m, 3H), 1.55 (m, 1H), 1.68 (m, 1H), 1.71 (m, 1H), 2.27 (m, 1H), 2.64 (m , 1H), 3.04(m, 1H), 3.60(m, 1H), 7.34(d, 1H), 7.43(d, 1H), 7.67(s, 1H), 7.98(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值201.2；實測值202.2；Rt=0.668min。LCMS (ESI): [M+H] + m/z: calculated 201.2; found 202.2; Rt=0.668 min.

6M. 2-甲基-4-(5-甲基-2-哌啶基)苯酚之合成6M. Synthesis of 2-methyl-4-(5-methyl-2-piperidinyl)phenol

Figure 110128222-A0202-12-0775-628
Figure 110128222-A0202-12-0775-628

步驟1：2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚之合成Step 1: Synthesis of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol

將4-溴-2-甲基-苯酚(18.8g，100.52mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(30.63g，120.62mmol)及KOAc(29.59g，301.55mmol，18.85mL)於1,4-二噁烷(400mL)中之正攪拌溶液用氬氣吹掃10分鐘。10分鐘之後，在氬氣下添加Pd(dppf)Cl2 ‧CH2 Cl2 (1.5g，1.84mmol)。將反應混合物在氬氣、100℃下攪拌16小時。然後將反應混合物冷卻至室溫，過濾且在減壓下濃縮濾液。藉由急驟層析(SiO2 ，溶析液：CHCl3 ： 乙腈)純化所獲得之粗產物，以得到呈白色固體之2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(11.4g，48.70mmol，48.45%產率)。4-Bromo-2-methyl-phenol (18.8 g, 100.52 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane-2-yl)-1,3,2-dioxaborolane (30.63 g, 120.62 mmol) and KOAc (29.59 g, 301.55 mmol, 18.85 mL) were dissolved in A stirring solution in 1,4-dioxane (400 mL) was purged with argon for 10 minutes. After 10 minutes, Pd(dppf)Cl2 - CH2Cl2 ( 1.5 g, 1.84 mmol) was added under argon. The reaction mixture was stirred under argon at 100°C for 16 hours. The reaction mixture was then cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography ( SiO2 , eluent: CHCl3 :acetonitrile) to give 2-methyl-4-(4,4,5,5-tetramethyl) as a white solid -1,3,2-Dioxaborol-2-yl)phenol (11.4 g, 48.70 mmol, 48.45% yield).

LCMS(ESI)：[M+H]+ m/z：計算值234.2；實測值235.4；Rt=1.386minLCMS(ESI): [M+H] + m/z: Calculated 234.2; Found 235.4; Rt=1.386min

步驟2：6-(4-羥基-3-甲基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(4-hydroxy-3-methylphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.54g，10.25mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(3g，12.82mmol)及碳酸鈉(3.26g，30.76mmol，1.29mL)於1,4-二噁烷(15mL)及水(5mL)中之正攪拌溶液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 ‧CH2 Cl2 (418.29mg，512.60μmol)。將反應混合物在氬氣、75℃下攪拌16小時。16小時之後，使反應混合物冷卻至室溫且過濾。將濾餅用1,4-二噁烷(10mL)洗滌且丟棄。將濾液用水洗滌且用DCM萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析(SiO2 ；溶析液：於己烷中之MTBE)純化所獲得之粗產物，以得到6-(4-羥基-3-甲基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2g，粗品)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.54 g, 10.25 mmol), 2-methyl yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol (3 g, 12.82 mmol) and sodium carbonate (3.26 g, A stirring solution of 30.76 mmol, 1.29 mL) in 1,4-dioxane (15 mL) and water (5 mL) was purged with argon. Then, Pd(dppf)Cl 2 ·CH 2 Cl 2 (418.29 mg, 512.60 μmol) was added under argon. The reaction mixture was stirred under argon at 75°C for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with 1,4-dioxane (10 mL) and discarded. The filtrate was washed with water and extracted with DCM. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product obtained was purified by column chromatography ( SiO2 ; eluent: MTBE in hexanes) to give 6-(4-hydroxy-3-methylphenyl)-3-methyl- 3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值303.2；實測值304.2；Rt=1.498min。LCMS (ESI): [M+H] + m/z: calculated 303.2; found 304.2; Rt=1.498 min.

步驟3：2-甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚之合成Step 3: Synthesis of 2-methyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol

將6-(4-羥基-3-甲基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2g，粗品)溶解於三氟乙酸(29.60g，259.60mmol，20mL)中且在室溫下攪拌16小時。16小時之後，將反應混合物在減壓下濃縮，以得到深棕色油狀物。將所獲得之粗產物用MTBE處理，用水洗滌且在真空中濃縮，以得到2-甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(2.4g，粗品)。粗產物不經任何進一步純化即用於下一步反應。6-(4-Hydroxy-3-methylphenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2 g, crude) was dissolved in trifluoroacetic acid (29.60 g, 259.60 mmol, 20 mL) and stirred at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated under reduced pressure to give a dark brown oil. The crude product obtained was treated with MTBE, washed with water and concentrated in vacuo to give 2-methyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (2.4g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值203.2；實測值204.2；Rt=0.680min。LCMS (ESI): [M+H] + m/z: calculated 203.2; found 204.2; Rt=0.680 min.

步驟4：2-甲基-4-(5-甲基-2-哌啶基)苯酚之合成Step 4: Synthesis of 2-methyl-4-(5-methyl-2-piperidinyl)phenol

在0℃下，將硼氫化鈉(446.66mg，11.81mmol)分批添加到2-甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(2.4g，11.81mmol)於甲醇(20mL)中之經攪拌之溶液中。將反應混合物在室溫下攪拌1小時。1小時之後，將反應混合物在減壓下濃縮，將殘餘物用水稀釋且用DCM(2 x 25mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在真空中蒸發。藉由反相HPLC(溶析液：40-70% CH3 CN+甲酸/H2 O；流速：30mL/min；裝載泵：4mL，CH3 CN；管柱：SunFire 100 x 19mm，5μM)純化粗產物，以獲得2-甲基-4-(5-甲基-2-哌啶基)苯酚(0.21g，1.02mmol，8.66%產率)。Sodium borohydride (446.66 mg, 11.81 mmol) was added portionwise to 2-methyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol at 0 °C (2.4 g, 11.81 mmol) in a stirred solution in methanol (20 mL). The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water and extracted with DCM (2 x 25 mL). The combined organic phases were dried over Na2SO4 and evaporated in vacuo. The crude was purified by reverse phase HPLC (eluent: 40-70% CH3CN + formic acid/ H2O ; flow rate: 30 mL/min; loading pump: 4 mL, CH3CN ; column: SunFire 100 x 19 mm, 5 μM) product to obtain 2-methyl-4-(5-methyl-2-piperidinyl)phenol (0.21 g, 1.02 mmol, 8.66% yield).

LCMS(ESI)：[M+H]+ m/z：計算值205.2；實測值206.4；Rt=1.881min。LCMS (ESI): [M+H] + m/z: calculated 205.2; found 206.4; Rt=1.881 min.

6N.5-(5-甲基-2-哌啶基)吲哚啉-2-酮 之合成6N. The synthesis of 5-(5-methyl-2-piperidinyl) indolin-2-one

Figure 110128222-A0202-12-0777-629
Figure 110128222-A0202-12-0777-629

步驟1：3-甲基-6-(2-側氧基吲哚啉-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(2-oxyindolin-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(10g，28.96mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲哚啉-2-酮(8.25g，31.85mmol)及碳酸鈉(6.14g，57.91mmol)於1,4-二噁烷(90mL)及水(30mL)中之正攪拌懸浮液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 (1.18g，1.45mmol)。將反應混合物在氬氣、75℃下攪拌18小時。18小時之後，將反應混合物冷卻且過濾。在真空中蒸發濾液且將殘餘物用水(100mL)及MTBE(150mL)稀釋。分離兩層。將水層用MTBE(100mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮。將殘餘物用MTBE(3 x 50mL)洗滌且在真空下乾燥，以獲 得呈棕色固體之3-甲基-6-(2-側氧基吲哚啉-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7.84g，粗品)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (10 g, 28.96 mmol), 5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indolin-2-one (8.25g, 31.85mmol) and sodium carbonate (6.14g , 57.91 mmol) in 1,4-dioxane (90 mL) and water (30 mL) were stirred with argon purged. Then, Pd(dppf)Cl2 (1.18 g , 1.45 mmol) was added under argon. The reaction mixture was stirred under argon at 75°C for 18 hours. After 18 hours, the reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo and the residue was diluted with water (100 mL) and MTBE (150 mL). Separate the two layers. The aqueous layer was extracted with MTBE (100 mL). The combined organic layers were dried over Na2SO4 , filtered and concentrated under reduced pressure. The residue was washed with MTBE (3 x 50 mL) and dried under vacuum to obtain 3-methyl-6-(2-oxyindolin-5-yl)-3,4-di as a brown solid Hydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7.84 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值328.2；實測值329.2；Rt=1.336min。LCMS (ESI): [M+H] + m/z: calculated 328.2; found 329.2; Rt=1.336 min.

步驟2：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮之合成Step 2: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)indolin-2-one

在0℃下，向3-甲基-6-(2-側氧基吲哚啉-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7.84g，23.86mmol)於DCM(40mL)中之經攪拌之溶液中逐滴添加CF3 CO2 H(20mL)。將所得反應混合物在0℃下攪拌1小時。1小時之後，將反應混合物小心倒入K2 CO3 溶液中且用DCM(2 x 75mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮(5.54g，粗品)。粗產物不經任何進一步純化即用於下一步反應。To 3-methyl-6-(2-oxyindolin-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7.84 g) at 0 °C , 23.86 mmol) in DCM (40 mL) was added dropwise to a stirred solution of CF3CO2H ( 20 mL). The resulting reaction mixture was stirred at 0°C for 1 hour. After 1 hour, the reaction mixture was carefully poured into K2CO3 solution and extracted with DCM ( 2 x 75 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)indoline -2-one (5.54 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值228.2；實測值229.2；Rt=0.727min。LCMS (ESI): [M+H] + m/z: calculated 228.2; found 229.2; Rt=0.727 min.

步驟3：5-(5-甲基-2-哌啶基)吲哚啉-2-酮之合成Step 3: Synthesis of 5-(5-methyl-2-piperidinyl)indolin-2-one

在0℃下，將硼氫化鈉(2.75g，72.80mmol)分批添加5-(3-甲基-2,3,4,5-四氫吡哌-6-基)吲哚啉-2-酮(5.54g，24.27mmol)於MeOH(120mL)中之經攪拌之溶液中。將反應混合物在20℃下攪拌18小時。18小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用水(100mL)稀釋。將所得混合物用DCM(3 x 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮。將所獲得之殘餘物溶解於DCM(50mL)中且用NaHSO4 水溶液萃取。將水層用DCM(3 x 50mL)洗滌，然後用K2 CO3 鹼化。將所得混合物再一次用DCM(3 x 50mL)萃取。將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得5-(5-甲基-2-啶啶基)吲哚啉-2-酮(2.5g，10.86mmol，44.73%產率)。Sodium borohydride (2.75 g, 72.80 mmol) was added portionwise 5-(3-methyl-2,3,4,5-tetrahydropiper-6-yl)indoline-2- at 0 °C Ketone (5.54 g, 24.27 mmol) in a stirred solution of MeOH (120 mL). The reaction mixture was stirred at 20°C for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (100 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4 , filtered and concentrated under reduced pressure. The obtained residue was dissolved in DCM (50 mL) and extracted with aq. NaHSO 4 . The aqueous layer was washed with DCM ( 3 x 50 mL), then basified with K2CO3. The resulting mixture was extracted again with DCM (3 x 50 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 5-(5-methyl-2-pyridinyl)indolin-2-one (2.5 g, 10.86 mmol) , 44.73% yield).

LCMS(ESI)：[M+H]+ m/z：計算值230.1；實測值231.2；Rt=0.664min。LCMS (ESI): [M+H] + m/z: calculated 230.1; found 231.2; Rt=0.664 min.

6O. 6-[(2R,5S)-5-甲基-2-哌啶基]-1,2,3,4-四氫喹啉之合成6O. Synthesis of 6-[(2R,5S)-5-methyl-2-piperidinyl]-1,2,3,4-tetrahydroquinoline

Figure 110128222-A0202-12-0779-630
Figure 110128222-A0202-12-0779-630

步驟1：6-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)-3,4-二氫-2H-喹啉-1-甲酸第三丁酯之合成Step 1: 6-(1-Third-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)-3,4-dihydro-2H-quinoline-1- Synthesis of tert-butyl formate

將6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-喹啉-1-甲酸第三丁酯(2.24g，6.23mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.79g，5.20mmol)、碳酸鈉(1.65g，15.59mmol，653.00μL)及Pd(dppf)Cl2 DCM(169.74mg，207.83μmol)添加到1,4-二噁烷(15mL)及水(5mL)之混合物中。在惰性氣氛、75℃下，將反應混合物攪拌12h，然後冷卻至室溫且過濾。將濾餅用二噁烷洗滌且丟棄。在真空中蒸發濾液且藉由管柱層析純化殘餘物，以得到6-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)-3,4-二氫-2H-喹啉-1-甲酸第三丁酯(0.9g，2.10mmol，40.42%產率)。6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-2H-quinoline-1- 3-butyl formate (2.24 g, 6.23 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid 3-butyl ester (1.79 g, 5.20 mmol), sodium carbonate (1.65 g, 15.59 mmol, 653.00 μL) and Pd(dppf)Cl 2 DCM (169.74 mg, 207.83 μmol) were added to 1,4-dioxane (15 mL) and water ( 5mL) of the mixture. The reaction mixture was stirred under an inert atmosphere at 75 °C for 12 h, then cooled to room temperature and filtered. The filter cake was washed with dioxane and discarded. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 6-(1-tert-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl) - 3,4-Dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.9 g, 2.10 mmol, 40.42% yield).

LCMS(ESI)：[M+H]+ m/z：計算值428.2；實測值429.2；Rt=1.835min。LCMS (ESI): [M+H] + m/z: calculated 428.2; found 429.2; Rt=1.835 min.

步驟2：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,2,3,4-四氫喹啉之合成Step 2: Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,2,3,4-tetrahydroquinoline

將6-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)-3,4-二氫-2H-喹啉-1-甲酸第三丁酯(0.9g，2.10mmol)溶解於TFA(2.96g，25.96mmol，2mL)及DCM(2mL)之混合物中且將其在24℃下攪拌0.5h。反應完成之後，在真空中蒸發反應混合物。將殘餘物溶解於DCM(5mL)中且用水(3* 5mL)洗滌。將有機 層經Na2 SO4 乾燥且在真空中蒸發，以得到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,2,3,4-四氫喹啉(0.38g，1.66mmol，79.25%產率)。6-(1-Third-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid Tributyl ester (0.9 g, 2.10 mmol) was dissolved in a mixture of TFA (2.96 g, 25.96 mmol, 2 mL) and DCM (2 mL) and it was stirred at 24 °C for 0.5 h. After the reaction was complete, the reaction mixture was evaporated in vacuo. The residue was dissolved in DCM (5 mL) and washed with water (3 * 5 mL). The organic layer was dried over Na 2 SO 4 and evaporated in vacuo to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,2,3,4- Tetrahydroquinoline (0.38 g, 1.66 mmol, 79.25% yield).

LCMS(ESI)：[M+H]+ m/z：計算值228.2；實測值229.2；Rt=0.878min。LCMS (ESI): [M+H] + m/z: calculated 228.2; found 229.2; Rt=0.878 min.

步驟3：6-[(2R,5S)-5-甲基-2-哌啶基]-1,2,3,4-四氫喹啉之合成Step 3: Synthesis of 6-[(2R,5S)-5-methyl-2-piperidinyl]-1,2,3,4-tetrahydroquinoline

將6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,2,3,4-四氫喹啉(0.38g，1.66mmol)溶解於甲醇(2mL)中且在攪拌之情況下一次性添加硼氫化鈉(75.56mg，2.00mmol，70.61μL)。12h之後，將反應混合物蒸發。將殘餘物溶解於DCM(5mL)中且用水(2* 5mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到6-[(2R,5S)-5-甲基-2-哌啶基]-1,2,3,4-四氫喹啉(0.2g，粗品)，其不經純化即用於下一步驟。6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,2,3,4-tetrahydroquinoline (0.38 g, 1.66 mmol) was dissolved in methanol (2 mL) ) and with stirring sodium borohydride (75.56 mg, 2.00 mmol, 70.61 μL) was added in one portion. After 12 h, the reaction mixture was evaporated. The residue was dissolved in DCM (5 mL) and washed with water (2 * 5 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give 6-[(2R,5S)-5-methyl-2-piperidinyl]-1,2,3,4-tetrahydroquinoline phenoline (0.2 g, crude), which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值230.2；實測值231.2；Rt=0.73min。LCMS (ESI): [M+H] + m/z: calculated 230.2; found 231.2; Rt=0.73 min.

6P. 6-(5-甲基-2-哌啶基)-3,4-二氫-1H-喹啉-2-酮之合成6P. Synthesis of 6-(5-methyl-2-piperidinyl)-3,4-dihydro-1H-quinolin-2-one

Figure 110128222-A0202-12-0780-632
Figure 110128222-A0202-12-0780-632

步驟1：3-甲基-6-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: 3-Methyl-6-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid 3rd Synthesis of Butyl Ester

將6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-1H-喹啉-2-酮(2.5g，9.15mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.63g，7.63mmol)、碳酸鈉(2.43g，22.88mmol，958.62μL)及Pd(dppf)Cl2 DCM(249.18mg，305.10μmol)添加到1,4-二噁烷(15mL)及水(5mL)之混合物中。在惰性氣氛、75℃下，將反應混合物攪拌12h，然後冷卻至室溫且 過濾。將濾餅用二噁烷洗滌且丟棄。在真空中蒸發濾液且藉由管柱層析純化殘餘物，以得到3-甲基-6-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1g，2.92mmol，38.29%產率)。6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-1H-quinoline-2- Ketone (2.5 g, 9.15 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.63 g, 7.63 mmol), sodium carbonate (2.43 g, 22.88 mmol, 958.62 μL) and Pd(dppf) Cl2DCM (249.18 mg, 305.10 μmol) were added to a mixture of 1,4-dioxane (15 mL) and water (5 mL) middle. The reaction mixture was stirred under an inert atmosphere at 75 °C for 12 h, then cooled to room temperature and filtered. The filter cake was washed with dioxane and discarded. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 3-methyl-6-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-3 , 3-butyl 4-dihydro-2H-pyridine-1-carboxylate (1 g, 2.92 mmol, 38.29% yield).

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值343.2；Rt=1.405min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 343.2; Rt=1.405 min.

步驟2：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-1H-喹啉-2-酮之合成Step 2: Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro-1H-quinolin-2-one

將3-甲基-6-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1g，2.92mmol)溶解於TFA(4.12g，36.10mmol，2.78mL)及DCM(2mL)之混合物中且在24℃下攪拌0.5h。反應完成之後，在真空中蒸發反應混合物。將殘餘物溶解於DCM(25mL)中且用水(3* 5mL)洗滌。將有機層經Na2 SO4 乾燥且在真空中蒸發，以得到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-1H-喹啉-2-酮(0.67g，粗品)。3-methyl-6-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1 g, 2.92 mmol) was dissolved in a mixture of TFA (4.12 g, 36.10 mmol, 2.78 mL) and DCM (2 mL) and stirred at 24 °C for 0.5 h. After the reaction was complete, the reaction mixture was evaporated in vacuo. The residue was dissolved in DCM (25 mL) and washed with water (3 * 5 mL). The organic layer was dried over Na 2 SO 4 and evaporated in vacuo to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro-1H -quinolin-2-one (0.67 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值242.2；實測值243.2；Rt=0.751min。LCMS (ESI): [M+H] + m/z: calculated 242.2; found 243.2; Rt=0.751 min.

步驟3：6-(5-甲基-2-哌啶基)-3,4-二氫-1H-喹啉-2-酮之合成Step 3: Synthesis of 6-(5-Methyl-2-piperidinyl)-3,4-dihydro-1H-quinolin-2-one

將6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-1H-喹啉-2-酮(0.7g，2.89mmol)溶解於甲醇(8mL)中且在攪拌之情況下一次性添加硼氫化鈉(131.14mg，3.47mmol，122.56μL)。12h之後，將反應混合物蒸發。將殘餘物溶解於HCl/二噁烷溶液中且蒸發，以得到6-(5-甲基-2-哌啶基)-3,4-二氫-1H-喹啉-2-酮(0.9g，粗品，HCl)，其不經純化即用於下一步驟。6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro-1H-quinolin-2-one (0.7 g, 2.89 mmol) was dissolved in To methanol (8 mL) was added sodium borohydride (131.14 mg, 3.47 mmol, 122.56 μL) in one portion with stirring. After 12 h, the reaction mixture was evaporated. The residue was dissolved in HCl/dioxane solution and evaporated to give 6-(5-methyl-2-piperidinyl)-3,4-dihydro-1H-quinolin-2-one (0.9 g , crude, HCl), which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值230.2；實測值231.2；Rt=0.730min。LCMS (ESI): [M+H] + m/z: calculated 230.2; found 231.2; Rt=0.730 min.

6Q. 5-(5-甲基哌啶-2-基)吡啶-2-胺6Q. 5-(5-methylpiperidin-2-yl)pyridin-2-amine

Figure 110128222-A0202-12-0782-633
Figure 110128222-A0202-12-0782-633

步驟1：6-(6-胺基-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(6-amino-3-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，11.58mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-2-胺(2.55g，11.58mmol)及碳酸鈉(2.46g，23.17mmol，970.50μL)一起混合於二噁烷(48mL)及水(16mL)之混合物中。將所得混合物抽真空且用氬氣回填三次，且向其中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(945.91mg，1.16mmol)。將反應混合物在90℃下加熱18h。將反應混合物冷卻至室溫且用水(100mL)稀釋。將所得混合物用EtOAc(3* 150mL)萃取且將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由管柱層析(SiO2 ，以己烷-MTBE-MeOH為流動相)純化殘餘物，以獲得6-(6-胺基-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.98g，6.83mmol，58.95%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4 g, 11.58 mmol), 5-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-amine (2.55g, 11.58mmol) and sodium carbonate (2.46g, 23.17mmol) , 970.50 μL) were mixed together in a mixture of dioxane (48 mL) and water (16 mL). The resulting mixture was evacuated and backfilled with argon three times, and to it was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (945.91 mg) , 1.16 mmol). The reaction mixture was heated at 90 °C for 18 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 * 150 mL) and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography (SiO 2 with hexane-MTBE-MeOH as mobile phase) to obtain 6-(6-amino-3-pyridyl)-3-methyl-3,4- Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.98 g, 6.83 mmol, 58.95% yield).

1 H NMR(500MHz,CDCl3 )δ 1.02(d,3H),1.18(s,9H),1.81(m,1H),1.86(m,1H),2.36(m,1H),2.97(t,1H),4.07(m,1H),4.47(m,2H),5.21(s,1H),6.46(d,1H),7.37(d,1H),8.02(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.02(d,3H), 1.18(s,9H), 1.81(m,1H), 1.86(m,1H), 2.36(m,1H), 2.97(t,1H) ), 4.07(m, 1H), 4.47(m, 2H), 5.21(s, 1H), 6.46(d, 1H), 7.37(d, 1H), 8.02(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值289.2；實測值290.2；Rt=0.957min。LCMS (ESI): [M+H] + m/z: calculated 289.2; found 290.2; Rt=0.957 min.

步驟2：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-2-胺之合成Step 2: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridin-2-amine

將6-(6-胺基-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.98g，6.84mmol)溶解於DCM(10mL)中且添加CF3 COOH(10mL)。攪拌所得 混合物1h。將反應混合物小心倒入K2 CO3 (20g)水溶液中且將所得混合物用DCM(2* 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾出且蒸發，以獲得5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-2-胺(1.28g，6.75mmol，98.69%產率)。6-(6-Amino-3-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.98 g, 6.84 mmol) was dissolved in DCM (10 mL) ) and added CF3COOH (10 mL). The resulting mixture was stirred for 1 h. The reaction mixture was poured carefully into aqueous K2CO3 ( 20 g) and the resulting mixture was extracted with DCM (2 * 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered off and evaporated to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridin-2-amine ( 1.28 g, 6.75 mmol, 98.69% yield).

1 H NMR(500MHz,CDCl3 )δ 1.00(d,3H),1.37(m,1H),1.71(m,1H),1.92(m,1H),2.55(m,1H),2.72(m,1H),3.22(m,1H),3.93(m,1H),4.60(s,2H),6.49(d,1H),7.98(d,1H),8.44(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.00(d,3H), 1.37(m,1H), 1.71(m,1H), 1.92(m,1H), 2.55(m,1H), 2.72(m,1H) ), 3.22(m, 1H), 3.93(m, 1H), 4.60(s, 2H), 6.49(d, 1H), 7.98(d, 1H), 8.44(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值189.2；實測值190.2；Rt=0.669min。LCMS (ESI): [M+H] + m/z: calculated 189.2; found 190.2; Rt=0.669 min.

步驟3：5-(5-甲基哌啶-2-基)吡啶-2-胺之合成Step 3: Synthesis of 5-(5-methylpiperidin-2-yl)pyridin-2-amine

將5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-2-胺(1.28g，6.76mmol)溶解於MeOH(25mL)中且分批添加硼氫化鈉(767.62mg，20.29mmol，717.40μL)。攪拌所得混合物18h。將反應混合物在減壓下濃縮且添加水(20mL)。將所得漿液用DCM(2* 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾出且蒸發，以獲得C11 H17 N3 (1.23g，6.43mmol，95.08%產率)。5-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridin-2-amine (1.28 g, 6.76 mmol) was dissolved in MeOH (25 mL) and hydroboration was added portionwise Sodium (767.62 mg, 20.29 mmol, 717.40 μL). The resulting mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and water (20 mL) was added. The resulting slurry was extracted with DCM (2 * 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered off and evaporated to obtain C 11 H 17 N 3 (1.23 g, 6.43 mmol, 95.08% yield).

1 H NMR(400MHz,CDCl3 )δ 0.86(d,3H),1.09(m,1H),1.61(m,5H),2.36(t,1H),3.07(m,1H),3.40(m,1H),4.33(s,2H),6.46(d,1H),7.44(d,1H),7.99(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.86(d,3H), 1.09(m,1H), 1.61(m,5H), 2.36(t,1H), 3.07(m,1H), 3.40(m,1H) ), 4.33(s, 2H), 6.46(d, 1H), 7.44(d, 1H), 7.99(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值191.2；實測值192.2；Rt=0.299min。LCMS (ESI): [M+H] + m/z: calculated 191.2; found 192.2; Rt=0.299 min.

6R. N-甲基-5-(5-甲基-2-哌啶基)吡啶-2-胺之合成6R. Synthesis of N-methyl-5-(5-methyl-2-piperidinyl)pyridin-2-amine

Figure 110128222-A0202-12-0783-634
Figure 110128222-A0202-12-0783-634

步驟1：3-甲基-6-[6-(甲胺基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合Step 1: Combination of 3-methyl-6-[6-(methylamino)-3-pyridyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 成to make

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.95g，5.64mmol)、N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-2-胺(1.68g，6.21mmol，HCl)及碳酸鈉(1.79g，16.93mmol，709.44μL)一起混合於二噁烷(24mL)及水(8mL)之混合物中。將所得混合物抽真空且用氬氣回填三次，且向其中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(460.97mg，564.48μmol)。將反應混合物在90℃下加熱18h。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.95 g, 5.64 mmol), N-methyl -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-amine (1.68 g, 6.21 mmol, HCl) and Sodium carbonate (1.79 g, 16.93 mmol, 709.44 μL) was mixed together in a mixture of dioxane (24 mL) and water (8 mL). The resulting mixture was evacuated and backfilled with argon three times, and to it was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (460.97 mg) , 564.48 μmol). The reaction mixture was heated at 90 °C for 18 h.

將反應混合物冷卻至室溫且用水(50mL)稀釋。將所得混合物用EtOAc(3* 100mL)萃取且將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由管柱層析(SiO2 ，以己烷-MTBE為流動相)純化殘餘物，以獲得3-甲基-6-[6-(甲胺基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.28g，4.22mmol，74.68%產率)。The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 * 100 mL) and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography ( SiO2 with hexane-MTBE as mobile phase) to obtain 3-methyl-6-[6-(methylamino)-3-pyridinyl]-3,4 - Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.28 g, 4.22 mmol, 74.68% yield).

1 H NMR(500MHz,CDCl3 )δ 1.02(d,3H),1.18(s,9H),1.82(m,1H),2.01(m,1H),2.37(m,1H),2.93(d,3H),2.97(m,1H),4.07(m,1H),4.62(m,1H),5.20(m,1H),6.37(d,1H),7.41(d,1H),8.05(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.02(d,3H), 1.18(s,9H), 1.82(m,1H), 2.01(m,1H), 2.37(m,1H), 2.93(d,3H) ), 2.97(m, 1H), 4.07(m, 1H), 4.62(m, 1H), 5.20(m, 1H), 6.37(d, 1H), 7.41(d, 1H), 8.05(s, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值303.2；實測值304.2；Rt=0.988min。LCMS (ESI): [M+H] + m/z: calculated 303.2; found 304.2; Rt=0.988 min.

步驟2：N-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-2-胺之合成Step 2: Synthesis of N-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridin-2-amine

將3-甲基-6-[6-(甲胺基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.28g，4.22mmol)溶解於DCM(6.5mL)中且添加CF3 COOH(6.5mL)。攪拌所得混合物1h。將反應混合物倒入K2 CO3 (12g)水溶液中且將所得混合物用DCM(2* 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾出且蒸發，以獲得N-甲基-5-(3-甲基-2,3,4,5-四氫吡哌-6-基)吡啶-2-胺(0.883g，粗品)。3-Methyl-6-[6-(methylamino)-3-pyridinyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.28 g, 4.22 mmol) was dissolved in DCM (6.5 mL) and CF3COOH (6.5 mL) was added. The resulting mixture was stirred for 1 h. The reaction mixture was poured into aqueous K2CO3 ( 12 g) and the resulting mixture was extracted with DCM (2 * 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered off and evaporated to obtain N-methyl-5-(3-methyl-2,3,4,5-tetrahydropiper-6-yl) Pyridin-2-amine (0.883 g, crude).

1 H NMR(500MHz,CDCl3 )δ 0.99(d,3H),1.38(m,1H),1.72(m,1H),1.92(m,2H),2.53(m,1H),2.73(m,1H),2.97(d,3H),3.21(m,1H),4.76(m,1H),6.39(d,1H),8.00 (d,1H),8.46(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.99(d,3H), 1.38(m,1H), 1.72(m,1H), 1.92(m,2H), 2.53(m,1H), 2.73(m,1H) ), 2.97(d, 3H), 3.21(m, 1H), 4.76(m, 1H), 6.39(d, 1H), 8.00(d, 1H), 8.46(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值203.2；實測值204.2；Rt=0.785min。LCMS (ESI): [M+H] + m/z: calculated 203.2; found 204.2; Rt=0.785 min.

步驟3：N-甲基-5-(5-甲基-2-哌啶基)吡啶-2-胺之合成Step 3: Synthesis of N-methyl-5-(5-methyl-2-piperidinyl)pyridin-2-amine

將N-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-2-胺(0.883g，4.34mmol)溶解於MeOH(15mL)中且分批添加硼氫化鈉(493.00mg，13.03mmol，460.75μL)。攪拌所得混合物18h。將反應混合物在減壓下濃縮且將水(10mL)添加到殘餘物中。將所得漿液用DCM(2* 40mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得N-甲基-5-(5-甲基-2-哌啶基)吡啶-2-胺(0.957g，粗品)。N-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridin-2-amine (0.883 g, 4.34 mmol) was dissolved in MeOH (15 mL) and Sodium borohydride (493.00 mg, 13.03 mmol, 460.75 μL) was added portionwise. The resulting mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added to the residue. The resulting slurry was extracted with DCM (2 * 40 mL) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to obtain N-methyl-5-(5-methyl-2-piperidinyl) Pyridin-2-amine (0.957 g, crude).

1 H NMR(400MHz,CDCl3 )δ 0.86(d,3H),1.10(m,1H),1.62(m,4H),2.38(m,1H),2.88(m,4H),3.07(m,1H),3.39(m,1H),4.44(m,1H),6.33(d,1H),7.49(d,1H),8.00(s,1H). 1 H NMR (400MHz, CDCl 3 )δ 0.86(d,3H), 1.10(m,1H), 1.62(m,4H), 2.38(m,1H), 2.88(m,4H), 3.07(m,1H) ), 3.39(m, 1H), 4.44(m, 1H), 6.33(d, 1H), 7.49(d, 1H), 8.00(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值205.2；實測值206.2；Rt=0.448min。LCMS (ESI): [M+H] + m/z: calculated 205.2; found 206.2; Rt=0.448 min.

6S. (2S,5R)-2-(苯并噻吩-5-基)-5-甲基哌啶之合成6S. Synthesis of (2S,5R)-2-(benzothiophen-5-yl)-5-methylpiperidine

Figure 110128222-A0202-12-0785-635
Figure 110128222-A0202-12-0785-635

步驟1：6-(苯并噻吩-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(benzothiophen-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將2-(苯并噻吩-5-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(5.3g，20.37mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.74g，22.41mmol)及碳酸鈉(6.48g，61.12mmol，2.56mL)於二噁烷(60mL)及水(20mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(831.83mg，1.02mmol)。將所得混合物除氣，用Ar再填充且在65℃下攪拌12h。過濾出沉澱，將其用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於150ml水中且用EtOAc(2*100ml)萃取。將經合併之有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產 物(7.5g)。藉由梯度層析(己烷-MTBE)純化粗產物，以獲得6-(苯并噻吩-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.lg，12.44mmol，61.09%產率)。2-(benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.3 g, 20.37 mmol), 3-methyl tert-butyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylate (7.74g, 22.41mmol) and sodium carbonate (6.48g, 61.12mmol) , 2.56 mL) in dioxane (60 mL) and water (20 mL) was degassed and refilled three times with Ar. To this solution was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (831.83 mg, 1.02 mmol). The resulting mixture was degassed, refilled with Ar and stirred at 65 °C for 12 h. The precipitate was filtered off and washed with dioxane (50ml). The solvent was evaporated in vacuo and the residue was dissolved in 150 ml of water and extracted with EtOAc (2*100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (7.5 g). The crude product was purified by gradient chromatography (hexane-MTBE) to obtain 6-(benzothiophen-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid third Butyl ester (4.1 g, 12.44 mmol, 61.09% yield).

1 H NMR(CDCl3 ,400MHz)：δ 0.885(s,9H),0.929(m,3H),1.838(m,2H),2.33(m,1H),3.00(m,1H),3.86(d,1H),5.34(m,1H),7.21(m,1H),7.38(m,1H),7.68(m,2H),7.88(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ 0.885 (s, 9H), 0.929 (m, 3H), 1.838 (m, 2H), 2.33 (m, 1H), 3.00 (m, 1H), 3.86 (d, 1H), 5.34 (m, 1H), 7.21 (m, 1H), 7.38 (m, 1H), 7.68 (m, 2H), 7.88 (m, 1H).

LCMS(ESI)：[M-Boc+1]+ m/z：計算值329.2；實測值231.0；Rt=1.774min。LCMS (ESI): [M-Boc+1] + m/z: calculated 329.2; found 231.0; Rt=1.774 min.

步驟2：6-(苯并噻吩-5-基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(benzothiophen-5-yl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(苯并噻吩-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.1g，12.44mmol)溶解於三氟乙酸(29.60g，259.60mmol，20mL)中。將所得混合物在25℃下攪拌1h(直至氣體逸出結束)。將溶液之pH用10% NaOH溶液調節至8且用DCM(3*70ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得6-(苯并噻吩-5-基)-3-甲基-2,3,4,5-四氫吡啶(2.5g，10.90mmol，87.59%產率)。Dissolve 6-(benzothiophen-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.1 g, 12.44 mmol) in trifluoroacetic acid (29.60 g g, 259.60 mmol, 20 mL). The resulting mixture was stirred at 25°C for 1 h (until gas evolution ended). The pH of the solution was adjusted to 8 with 10% NaOH solution and extracted with DCM (3*70ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated in vacuo to give 6-(benzothiophen-5-yl)-3-methyl-2,3,4, 5-Tetrahydropyridine (2.5 g, 10.90 mmol, 87.59% yield).

1 H NMR(CDCl3 ,500MHz)：δ 1.03(d,3H),1.44(m,1H),1.75(m,1H),1.96(m,1H),2.67(m,1H),2.88(dd,1H),3.29(dd,1H),4.03(d,1H),7.36(d,1H)m 7.45(d,1H),7.86(m,2H),8.21(s,1H)。 1 H NMR (CDCl 3 , 500MHz): δ 1.03 (d, 3H), 1.44 (m, 1H), 1.75 (m, 1H), 1.96 (m, 1H), 2.67 (m, 1H), 2.88 (dd, 1H), 3.29(dd, 1H), 4.03(d, 1H), 7.36(d, 1H) m 7.45(d, 1H), 7.86(m, 2H), 8.21(s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值229.2；實測值230.0；Rt=0.923min。LCMS (ESI): [M+1] + m/z: calculated 229.2; found 230.0; Rt=0.923 min.

步驟3：(2S,5R)-2-(苯并噻吩-5-基)-5-甲基哌啶之合成Step 3: Synthesis of (2S,5R)-2-(benzothiophen-5-yl)-5-methylpiperidine

在0℃下，向6-(苯并噻吩-5-基)-3-甲基-2,3,4,5-四氫吡啶(2.5g，10.90mmol)於MeOH(50mL)中之溶液中分批添加硼氫化鈉(824.81mg，21.80mmol，770.85μL)。將所得混合物在25℃下攪拌2h在真空中蒸發溶劑，將殘餘物溶解於水(30ml)中且用DCM(3*30ml)萃取。將經合併之有機萃取物用鹽水(2*50ml)洗滌，經Na2 SO4 乾燥且蒸發，以得到外消旋-(2S,5R)-2-(苯并噻吩-5-基)-5-甲基哌啶(2.1g，9.08mmol，83.27%產率)。To a solution of 6-(benzothiophen-5-yl)-3-methyl-2,3,4,5-tetrahydropyridine (2.5 g, 10.90 mmol) in MeOH (50 mL) at 0 °C Sodium borohydride (824.81 mg, 21.80 mmol, 770.85 μL) was added portionwise. The resulting mixture was stirred at 25°C for 2h, the solvent was evaporated in vacuo, the residue was dissolved in water (30ml) and extracted with DCM (3*30ml). The combined organic extracts were washed with brine (2*50ml), dried over Na2SO4 and evaporated to give rac-(2S,5R)-2-(benzothiophen-5-yl)-5 - Methylpiperidine (2.1 g, 9.08 mmol, 83.27% yield).

1 H NMR(DMSO,400MHz)：δ 0.82(d,3H),1.07(m,1H),1.36(dd,1H),1.51(m,1H),1.68-1.72(m,2H),2.25(dd,1H),2.97(d,1H),3.25(brs,1H),3.54(d,1H),7.33-7.37(m,2H),7.66(d,1H),7.81-7.85(m,2H)。 1 H NMR (DMSO, 400MHz): δ 0.82 (d, 3H), 1.07 (m, 1H), 1.36 (dd, 1H), 1.51 (m, 1H), 1.68-1.72 (m, 2H), 2.25 (dd , 1H), 2.97(d, 1H), 3.25(brs, 1H), 3.54(d, 1H), 7.33-7.37(m, 2H), 7.66(d, 1H), 7.81-7.85(m, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值231.1；實測值232.0；Rt=0.790min。LCMS (ESI): [M+1] + m/z: calculated 231.1; found 232.0; Rt=0.790 min.

6T. 2-甲基-5-(5-甲基哌啶-2-基)苯并[d]噻唑之合成6T. Synthesis of 2-methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-0787-636
Figure 110128222-A0202-12-0787-636

步驟1：5-溴-2-甲基苯并[d ]噻唑之合成Step 1: Synthesis of 5-bromo-2-methylbenzo[ d ]thiazole

將2-胺基-4-溴-苯硫醇(19g，93.10mmol)及4-甲基苯磺酸水合物(106.25mg，558.58μmol，85.69μL)溶解於原乙酸三甲酯(38.03g，316.53mmol，3.49mL)中。將所得溶液在100℃下再攪拌6h。然後直接濃縮混合物，以得到所要產物5-溴-2-甲基-1,3-苯并噻唑(20g，87.68mmol，94.18%產率)。2-Amino-4-bromo-benzenethiol (19 g, 93.10 mmol) and 4-methylbenzenesulfonic acid hydrate (106.25 mg, 558.58 μmol, 85.69 μL) were dissolved in trimethyl orthoacetate (38.03 g, 316.53 mmol, 3.49 mL). The resulting solution was stirred at 100 °C for an additional 6 h. The mixture was then directly concentrated to give the desired product 5-bromo-2-methyl-1,3-benzothiazole (20 g, 87.68 mmol, 94.18% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)2.79(s,3H),7.55(d,1H),8.00(d,1H),8.11(s,1H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 2.79 (s, 3H), 7.55 (d, 1H), 8.00 (d, 1H), 8.11 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值228.2；實測值229.2；Rt=1.267min。LCMS (ESI): [M] + m/z: calculated 228.2; found 229.2; Rt=1.267 min.

步驟2：2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d]thiazole

將乙酸鉀(18.93g，192.89mmol，12.06mL)添加到5-溴-2-甲基-1,3-苯并噻唑(22g，96.45mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(28.16g，110.91mmol)於DMSO(200mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加 PddppfCl2 *DCM(3.94g，4.82mmol)。在90℃、惰性氣氛下將所得混合物攪拌28h。然後，將其冷卻，用EA(400mL)稀釋且用水(2x200mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟層析，以0-100%己烷-EA梯度溶析來純化殘餘物，以得到2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(22g，79.95mmol，82.90%產率)。Potassium acetate (18.93 g, 192.89 mmol, 12.06 mL) was added to 5-bromo-2-methyl-1,3-benzothiazole (22 g, 96.45 mmol) and 4,4,5,5-tetramethyl- 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane ( 28.16 g, 110.91 mmol) in DMSO (200 mL). The reaction flask was evacuated and refilled with argon 3 times. Then PddppfCl2 *DCM (3.94 g, 4.82 mmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 28 h. It was then cooled, diluted with EA (400 mL) and washed with water (2 x 200 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a 0-100% hexane-EA gradient to give 2-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)-1,3-benzothiazole (22 g, 79.95 mmol, 82.90% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.35(s,12H),2.81(s,3H),7.78(m,2H),8.36(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.35 (s, 12H), 2.81 (s, 3H), 7.78 (m, 2H), 8.36 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值275.2；實測值276.2；Rt=1.531min。LCMS (ESI): [M] + m/z: calculated 275.2; found 276.2; Rt=1.531 min.

步驟3：3-甲基-6-(2-甲基苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: Synthesis of 3-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(16.73g，48.45mmol)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(16g，58.15mmol)、[1,1'-雙( 二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(1.98g，2.42mmol)及碳酸鈉(15.41g，145.36mmol，6.09mL)於二噁烷(300mL)及水(100mL)之混合物在80℃、氬氣氣氛下攪拌18h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(500mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析，以0至100% MTBE-己烷梯度溶析來純化殘餘物，以得到3-甲基-6-(2-甲基-1,3-苯并噻唑-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(12g，34.84mmol，71.89%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (16.73 g, 48.45 mmol), 2-methyl -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazole (16 g, 58.15 mmol), [1,1'- Bis( diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (1.98 g, 2.42 mmol) and sodium carbonate (15.41 g, 145.36 mmol, 6.09 mL) were dissolved in A mixture of dioxane (300 mL) and water (100 mL) was stirred at 80 °C under argon atmosphere for 18 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (500 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography with a gradient of 0 to 100% MTBE-hexane to give 3-methyl-6-(2-methyl-1,3- Benzothiazol-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (12 g, 34.84 mmol, 71.89% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.01(s,12H),1.85(m,1H),2.02(m,1H),2.43(m,1H),2.80(s,3H),3.01(t,1H),4.10(d,1H),5.36(m,1H),7.29(d,1H),7.69(d,1H),7.86(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.01(s, 12H), 1.85(m, 1H), 2.02(m, 1H), 2.43(m, 1H), 2.80(s, 3H), 3.01( t, 1H), 4.10 (d, 1H), 5.36 (m, 1H), 7.29 (d, 1H), 7.69 (d, 1H), 7.86 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=1.654min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=1.654 min.

步驟4：2-甲基-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: Synthesis of 2-methyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole

將3-甲基-6-(2-甲基-1,3-苯并噻唑-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(12.51g，36.31mmol)於TFA(66.25g，581.04mmol，44.76mL)中之溶液在20℃下攪拌1h，然後在真空中蒸發。將碎冰(50g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*100mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(8.8g，36.01mmol，99.17%產率)，其直接用於下一步驟中。3-Methyl-6-(2-methyl-1,3-benzothiazol-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (12.51 g, 36.31 g mmol) in TFA (66.25 g, 581.04 mmol, 44.76 mL) was stirred at 20 °C for 1 h, then evaporated in vacuo. Crushed ice (50 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate (2*100 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a yellow solid yl)-1,3-benzothiazole (8.8 g, 36.01 mmol, 99.17% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.92(d,3H),1.33(m,1H),1.63(m,1H),1.86(m,1H),2.48(m,1H),2.81(s,3H),3.19(m,1H),3.92(m,1H),7.88(d,1H),7.97(d,1H),8.23(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.92(d,3H), 1.33(m,1H), 1.63(m,1H), 1.86(m,1H), 2.48(m,1H), 2.81(s, 3H), 3.19(m, 1H), 3.92(m, 1H), 7.88(d, 1H), 7.97(d, 1H), 8.23(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值244.2；實測值245.2；Rt=0.871min。LCMS (ESI): [M] + m/z: calculated 244.2; found 245.2; Rt=0.871 min.

步驟5：2-甲基-5-(5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 2-methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazole

在0℃下，將硼氫化鈉(2.04g，54.02mmol，1.91mL)一次性添加到2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(8.8g，36.01mmol)於MeOH(200mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(150mL)稀釋且用二氯甲烷(2*150mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之2-甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(8g，32.47mmol，90.17%產率)，其直接用於下一步驟中。Sodium borohydride (2.04 g, 54.02 mmol, 1.91 mL) was added in one portion to 2-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0 °C yl)-1,3-benzothiazole (8.8 g, 36.01 mmol) in a stirred solution of MeOH (200 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (150 mL) and extracted with dichloromethane (2*150 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-methyl-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole as a yellow solid (8 g, 32.47 mmol, 90.17% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.83(d,3H),1.34(m,1H),1.36(m,1H),1.52(m,1H),1.75(m,2H),2.26(m,1H),2.38(m,1H),2.75(s,3H),3.01(m,1H),3.55(m,1H),7.38(d,1H),7.83(s,1H),7.89(d,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.83(d,3H), 1.34(m,1H), 1.36(m,1H), 1.52(m,1H), 1.75(m,2H), 2.26(m, 1H), 2.38(m, 1H), 2.75(s, 3H), 3.01(m, 1H), 3.55(m, 1H), 7.38(d, 1H), 7.83(s, 1H), 7.89 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值246.2；實測值247.2；Rt=0.696min。LCMS (ESI): [M] + m/z: calculated 246.2; found 247.2; Rt=0.696 min.

6U. 2-(3,4-二氟苯基)-5-甲基哌啶之合成6U. Synthesis of 2-(3,4-difluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0790-637
Figure 110128222-A0202-12-0790-637

步驟1：6-(3,4-二氟苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3,4-difluorophenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5g，14.48mmol)、(3,4-二氟苯基)硼酸(2.29g，14.48mmol)及碳酸鈉(4.60g，43.44mmol，1.82mL)添加到二噁烷(45mL)及水(15mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)2 Cl2 *DCM(723.93μmol)。將反應混合物在氬氣、70℃下攪拌14h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之6-(3,4-二氟苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4g，12.93mmol，89.31%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (5 g, 14.48 mmol), (3,4- Difluorophenyl)boronic acid (2.29 g, 14.48 mmol) and sodium carbonate (4.60 g, 43.44 mmol, 1.82 mL) were added to a mixture of dioxane (45 mL) and water (15 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)2Cl2*DCM ( 723.93 μmol ) was added under argon. The reaction mixture was stirred under argon at 70 °C for 14 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 6-(3,4-difluorophenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester as a brown oil (4 g, 12.93 mmol, 89.31% yield), which was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ(ppm) 1 H NMR (400MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M-Boc]+ m/z：計算值209.2；實測值210.2；Rt=0.683min。LCMS (ESI): [M-Boc] + m/z: calculated 209.2; found 210.2; Rt=0.683 min.

步驟2：6-(3,4-二氟苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3,4-difluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(3,4-二氟苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4g，12.93mmol)於三氟乙酸(29.49g，258.61mmol，19.92mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用DCM(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之6-(3,4-二氟苯基)-3-甲基-2,3,4,5-四氫吡啶(2g，9.56mmol，73.92%產率)，其直接用於下一步驟中。6-(3,4-Difluorophenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4 g, 12.93 mmol) in trifluoroacetic acid (29.49 g) , 258.61 mmol, 19.92 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with DCM (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 6-(3,4-difluorophenyl)-3-methyl-2,3,4,5-tetrakis as a brown solid Hydropyridine (2 g, 9.56 mmol, 73.92% yield) was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值209.2；實測值210.2；Rt=0.671min。LCMS (ESI): [M] + m/z: calculated 209.2; found 210.2; Rt=0.671 min.

步驟3：2-(3,4-二氟苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(3,4-difluorophenyl)-5-methylpiperidine

在0℃下，將硼氫化鈉(723.26mg，19.12mmol，675.94μL)一次性添加到6-(3,4-二氟苯基)-3-甲基-2,3,4,5-四氫吡啶(2g，9.56mmol)於MeOH(50mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用DCM(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷CC，以得到2-(3,4-二氟苯基)-5-甲基哌啶(0.528g，2.50mmol，26.15%產率)。Sodium borohydride (723.26 mg, 19.12 mmol, 675.94 μL) was added in one portion to 6-(3,4-difluorophenyl)-3-methyl-2,3,4,5-tetrakis at 0 °C Hydropyridine (2 g, 9.56 mmol) in a stirred solution of MeOH (50 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with DCM (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The obtained oil was subjected to CC to give 2-(3,4-difluorophenyl)-5-methylpiperidine (0.528 g, 2.50 mmol, 26.15% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.24(m,1H),1.86(m,3H),2.08(m,1H),2.48(m,1H),2.58(m,1H),3.18(m,1H),7.48(m,2H),7.84(s,1H),9.61(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.86(d,3H), 1.24(m,1H), 1.86(m,3H), 2.08(m,1H), 2.48(m,1H), 2.58(m,1H), 3.18(m,1H), 7.48(m,2H), 7.84(s,1H), 9.61(m,1H).

LCMS(ESI)：[M]+ m/z：計算值211.2；實測值212.2；Rt=0.969min。LCMS (ESI): [M] + m/z: calculated 211.2; found 212.2; Rt=0.969 min.

6V. 5-甲基-2-(3,4,5-三氟苯基)哌啶之合成6V. Synthesis of 5-methyl-2-(3,4,5-trifluorophenyl)piperidine

Figure 110128222-A0202-12-0791-638
Figure 110128222-A0202-12-0791-638

步驟1：3-甲基-6-(3,4,5-三氟苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(3,4,5-trifluorophenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5g，14.48mmol)、(3,4,5-三氟苯基)硼酸(2.55g，14.48mmol)及碳酸鈉(4.60g，43.44mmol，1.82mL)添加到二噁烷(45mL)及水(15mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)2 Cl2 *DCM(723.94μmol)。將反應混合物在氬氣、70℃下攪拌12h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之3-甲基-6-(3,4,5-三氟苯基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.5g，13.75mmol，94.95%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (5 g, 14.48 mmol), (3,4, 5-Trifluorophenyl)boronic acid (2.55 g, 14.48 mmol) and sodium carbonate (4.60 g, 43.44 mmol, 1.82 mL) were added to a mixture of dioxane (45 mL) and water (15 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)2Cl2*DCM ( 723.94 μmol ) was added under argon. The reaction mixture was stirred under argon at 70 °C for 12 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 3-methyl-6-(3,4,5-trifluorophenyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid as a brown oil Butyl ester (4.5 g, 13.75 mmol, 94.95% yield) was used in the next step without purification.

LCMS(ESI)：[M-Boc]+ m/z：計算值227.2；實測值228.2；Rt=1.586min。LCMS (ESI): [M-Boc] + m/z: calculated 227.2; found 228.2; Rt=1.586 min.

步驟2：3-甲基-6-(3,4,5-三氟苯基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 3-methyl-6-(3,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyridine

將3-甲基-6-(3,4,5-三氟苯基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.5g，13.75mmol)於三氟乙酸(31.35g，274.94mmol，21.18mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用DCM(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之3-甲基-6-(3,4,5-三氟苯基)-2,3,4,5-四氫吡啶(2.5g，11.00mmol，80.03%產率)，其直接用於下一步驟中。3-Methyl-6-(3,4,5-trifluorophenyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4.5 g, 13.75 mmol) in trifluoroacetic acid The solution in (31.35 g, 274.94 mmol, 21.18 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with DCM (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 3-methyl-6-(3,4,5-trifluorophenyl)-2,3,4,5 as a brown solid - Tetrahydropyridine (2.5 g, 11.00 mmol, 80.03% yield), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值227.2；實測值228.2；Rt=0.887min。LCMS (ESI): [M] + m/z: calculated 227.2; found 228.2; Rt=0.887min.

步驟3：5-甲基-2-(3,4,5-三氟苯基)哌啶之合成Step 3: Synthesis of 5-methyl-2-(3,4,5-trifluorophenyl)piperidine

在0℃下，將硼氫化鈉(832.49mg，22.00mmol，778.03μL)一次性添加到3-甲基-6-(3,4,5-三氟苯基)-2,3,4,5-四氫吡啶(2.5g，11.00mmol)於MeOH(50mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷CC，以得到5-甲基-2-(3,4,5-三氟苯基)哌啶(0.45g，1.96mmol，17.84%產率)。Sodium borohydride (832.49 mg, 22.00 mmol, 778.03 μL) was added in one portion to 3-methyl-6-(3,4,5-trifluorophenyl)-2,3,4,5 at 0 °C - Tetrahydropyridine (2.5 g, 11.00 mmol) in a stirred solution of MeOH (50 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The obtained oil was subjected to CC to give 5-methyl-2-(3,4,5-trifluorophenyl)piperidine (0.45 g, 1.96 mmol, 17.84% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.86(d,3H),1.12(m,1H),1.28(m,1H),1.46(m,1H),1.63(m,1H),1.82(m,2H),2.36(m,1H),3.18(m,1H),3.48(m,1H),7.02(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.86(d,3H), 1.12(m,1H), 1.28(m,1H), 1.46(m,1H), 1.63(m,1H), 1.82( m, 2H), 2.36 (m, 1H), 3.18 (m, 1H), 3.48 (m, 1H), 7.02 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值229.2；實測值230.2；Rt=0.773min。LCMS (ESI): [M] + m/z: calculated 229.2; found 230.2; Rt=0.773 min.

6W. 4-(5-甲基哌啶-2-基)環己醇之合成6W. Synthesis of 4-(5-methylpiperidin-2-yl)cyclohexanol

Figure 110128222-A0202-12-0792-639
Figure 110128222-A0202-12-0792-639

步驟1：3-甲基-6-(1,4-二氧雜螺[4.5]癸-7-烯-8-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: 3-Methyl-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl Synthesis of Esters

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7.22g，18.82mmol)、2-(1,4-二氧雜螺[4.5 ]癸-7-烯 -8-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(5.01g，18.82mmol)及碳酸鈉(5.98g，56.45mmol)添加到二噁烷(120mL)及水(40mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 (688.40mg，940.83μmol)。將反應混合物在氬氣、90℃下攪拌16h，然後冷卻且過濾。將濾餅用乙酸乙酯(200ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析使用己烷/MTBE梯度(0-100% MTBE)純化殘餘物，以得到呈淡黃色膠狀物之6-(1,4-二氧雜螺[4.5 ]癸-7-烯- 8-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.00g，5.96mmol，31.69%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7.22 g, 18.82 mmol), 2-(1 ,4-dioxaspiro[ 4.5 ] dec-7-en -8-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.01 g , 18.82 mmol) and sodium carbonate (5.98 g, 56.45 mmol) were added to a mixture of dioxane (120 mL) and water (40 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2 ( 688.40 mg, 940.83 μmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 16 h, then cooled and filtered. The filter cake was washed with ethyl acetate (200 ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) to give 6-(1,4-dioxa as a pale yellow gum Spiro[ 4.5 ] dec-7-en- 8-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2.00 g, 5.96 mmol, 31.69% yield) .

1 H NMR(500MHz,CDCl3 )δ(ppm)0.96(d,3H),1.48(s,9H),1.68(m,1H),1.82(m,2H),1.96(m,1H),2.26(m,2H),2.38(m,3H),2.76(m,1H),3.82(m,1H),3.96(d,4H),5.21(m,1H),5.68(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.96(d, 3H), 1.48(s, 9H), 1.68(m, 1H), 1.82(m, 2H), 1.96(m, 1H), 2.26( m, 2H), 2.38 (m, 3H), 2.76 (m, 1H), 3.82 (m, 1H), 3.96 (d, 4H), 5.21 (m, 1H), 5.68 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值235.2；實測值236.2；Rt=1.392min。LCMS (ESI): [M-Boc] + m/z: calculated 235.2; found 236.2; Rt=1.392 min.

步驟2：4-(5-甲基-3,4,5,6-四氫吡啶-2-基)環己-3-烯酮之合成Step 2: Synthesis of 4-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)cyclohex-3-enone

在25℃下，將三氟乙酸(40.79g，357.74mmol，27.56mL)添加到6-(1,4-二氧雜螺[4.5 ]癸-7-烯 -8-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.2g，3.58mmol)中。將所得反應混合物在25℃下攪拌18h，然後在真空中蒸發，以得到呈橙色膠狀物之粗品4-(3-甲基-2,3,4,5-四氫吡啶-6-基)環己-3-烯-1-酮(3g，粗品)，其直接用於下一步驟中。Trifluoroacetic acid (40.79 g, 357.74 mmol, 27.56 mL) was added to 6-(1,4-dioxaspiro[ 4.5 ] dec-7-en -8-yl)-3-methyl at 25°C - 3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.2 g, 3.58 mmol). The resulting reaction mixture was stirred at 25 °C for 18 h, then evaporated in vacuo to give crude 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) as an orange gum Cyclohex-3-en-1-one (3 g, crude), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.08(d,3H),1.56(m,1H),2.12(m,2H),2.62(m,2H),2.89(m,2H),3.32(m,3H),4.02(m,1H),4.66(m,2H),7.27(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.08(d,3H), 1.56(m,1H), 2.12(m,2H), 2.62(m,2H), 2.89(m,2H), 3.32( m, 3H), 4.02 (m, 1H), 4.66 (m, 2H), 7.27 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值191.2；實測值192.2；Rt=1.648min。LCMS (ESI): [M] + m/z: calculated 191.2; found 192.2; Rt=1.648 min.

步驟3：4-(5-甲基哌啶-2-基)環己-3-烯醇之合成Step 3: Synthesis of 4-(5-methylpiperidin-2-yl)cyclohex-3-enol

在0.2h內將硼氫化鈉(2.5g，66.09mmol，2.34mL)分批添加到4-(3-甲基-2,3,4,5-四氫吡啶-6-基)環己-3-烯-1-酮(3g，15.68mmol)於DME(100mL)中之經攪拌之溶液中。將反應混合物在0℃下攪拌2h，然後在0℃下緩慢添加MeOH(50mL)以淬滅反應物(起泡！)。使所得混合物升溫至25℃，攪拌0.5h，然後在真空中蒸發。將殘餘物用水(50ml)稀釋且用10%氫氧化鈉水溶液將pH調節至10。將所得混濁溶液用二氯甲烷(2*70ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈淡黃色膠狀物之粗品4-(5-甲基-2-哌啶基)環己-3-烯-1-醇(0.65g，3.33mmol，21.22%產率)，其直接用於下一步驟中。Sodium borohydride (2.5 g, 66.09 mmol, 2.34 mL) was added portionwise to 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)cyclohexyl-3 over 0.2 h -en-1-one (3 g, 15.68 mmol) in a stirred solution of DME (100 mL). The reaction mixture was stirred at 0 °C for 2 h, then MeOH (50 mL) was added slowly at 0 °C to quench the reaction (foaming!). The resulting mixture was warmed to 25 °C, stirred for 0.5 h, then evaporated in vacuo. The residue was diluted with water (50 ml) and the pH was adjusted to 10 with 10% aqueous sodium hydroxide solution. The resulting cloudy solution was extracted with dichloromethane (2*70ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give crude 4-(5-methyl-2-piperidinyl)cyclohex-3-ene-1- as a pale yellow gum Alcohol (0.65 g, 3.33 mmol, 21.22% yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.96(d,3H),1.22(m,1H),1.96(m,8H),2.36(m,3H),2.86(m,1H),3.42(m,1H),3.52(m,1H),3.85(m,1H),3.96(m,1H),5.57(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.96(d,3H), 1.22(m,1H), 1.96(m,8H), 2.36(m,3H), 2.86(m,1H), 3.42( m, 1H), 3.52 (m, 1H), 3.85 (m, 1H), 3.96 (m, 1H), 5.57 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值195.2；實測值196.2；Rt=0.598min。LCMS (ESI): [M] + m/z: calculated 195.2; found 196.2; Rt=0.598 min.

步驟4：4-(5-甲基哌啶-2-基)環己醇之合成Step 4: Synthesis of 4-(5-methylpiperidin-2-yl)cyclohexanol

將4-(5-甲基-2-哌啶基)環己-3-烯-1-醇(0.65g，3.33mmol)及鈀(10%於碳上)(0.5g，3.33mmol)於MeOH(40mL)中之混合物在氫氣氣氛、45℃下攪拌12h。過濾出催化劑，在真空中蒸發濾液，以得到呈淡黃色膠狀物之4-(5-甲基-2-哌啶基)環己醇(0.4g，2.03mmol，60.91%產率)，其直接用於下一步驟中。4-(5-Methyl-2-piperidinyl)cyclohex-3-en-1-ol (0.65 g, 3.33 mmol) and palladium (10% on carbon) (0.5 g, 3.33 mmol) in MeOH The mixture in (40 mL) was stirred at 45 °C for 12 h under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 4-(5-methyl-2-piperidinyl)cyclohexanol (0.4 g, 2.03 mmol, 60.91% yield) as a pale yellow gum used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.86(d,3H),1.12(m,2H),1.36(m,2H),1.54(m,5H),1.86(m,4H),2.08(m,2H),2.28(m,2H),3.12(m,1H),3.55(m,1H),4.02(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.86(d, 3H), 1.12(m, 2H), 1.36(m, 2H), 1.54(m, 5H), 1.86(m, 4H), 2.08( m, 2H), 2.28 (m, 2H), 3.12 (m, 1H), 3.55 (m, 1H), 4.02 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值197.2；實測值198.2；Rt=0.719min。LCMS (ESI): [M] + m/z: calculated 197.2; found 198.2; Rt=0.719 min.

6X. 5-(5-甲基-2-哌啶基)-1H-吡唑并[3,4-b]吡啶之合成6X. Synthesis of 5-(5-methyl-2-piperidinyl)-1H-pyrazolo[3,4-b]pyridine

Figure 110128222-A0202-12-0795-640
Figure 110128222-A0202-12-0795-640

步驟1：5-溴吡唑并[3,4-b]吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 5-bromopyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester

在0℃下，將二碳酸二-第三丁酯(8.99g，41.21mmol，9.46mL)逐滴添加到5-溴-1H-吡唑并[3,4-b]吡啶(8g，40.40mmol)及DMAP(49.36mg，404.00μmol)於DCM(80mL)中之經攪拌懸浮液中。將所得混合物在室溫下攪拌12h，然後在真空中蒸發，倒入到水(100ml)中且用DCM(2x50ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物5-溴吡唑并[3,4-b]吡啶-1-甲酸第三丁酯(9.3g，31.19mmol，77.21%產率)。Di-tert-butyl dicarbonate (8.99 g, 41.21 mmol, 9.46 mL) was added dropwise to 5-bromo-1H-pyrazolo[3,4-b]pyridine (8 g, 40.40 mmol) at 0 °C ) and DMAP (49.36 mg, 404.00 μmol) in a stirred suspension of DCM (80 mL). The resulting mixture was stirred at room temperature for 12h, then evaporated in vacuo, poured into water (100ml) and extracted with DCM (2x50ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo to give the product 3-butyl 5-bromopyrazolo[3,4-b]pyridine-1-carboxylate (9.3 g, 31.19 mmol, 77.21% yield).

1 H NMR(CDCl3 ,500MHz)：1.73(s,9H),8.13(s,1H),8.23(s,1H),8.78(s,1H)。 1 H NMR (CDCl 3 , 500 MHz): 1.73 (s, 9H), 8.13 (s, 1H), 8.23 (s, 1H), 8.78 (s, 1H).

LCMS(ESI)：[M-Boc+H]+ m/z：計算值298.1；實測值200.0；Rt=1.243min。LCMS (ESI): [M-Boc+H] + m/z: calculated 298.1; found 200.0; Rt=1.243 min.

步驟2：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑并[3,4-b]吡啶-1-甲酸第三丁酯(P1)及5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡唑并[3,4-b]吡啶(P2)之合成Step 2: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyrazolo[3,4-b]pyridine-1 -Third-butyl formate (P1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazolo Synthesis of [3,4-b]pyridine (P2)

將5-溴吡唑并[3,4-b]吡啶-1-甲酸第三丁酯(9.3g，31.19mmol)及 4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(7.92g，31.19mmol)一起混合於二噁烷(100mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(1.14g，1.56mmol)。將反應混合物在氬氣、100℃下攪拌8h，然後冷卻且在真空中蒸發，將其倒入水(150ml)中且用EtOAc(2x80ml)萃取。將經合併之有機萃取物用水洗滌(2*40ml)，經硫酸鈉乾燥且在真空中蒸發，留下13g粗產物，13g粗產物藉由矽膠管柱層析，使用己烷/MTBE梯度(10-100% MTBE)溶析進行純化，以得到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑并[3,4-b]吡啶-1-甲酸第三丁酯(2.5g，7.24mmol，23.22%產率)及5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡唑并[3,4-b]吡啶(2g，8.16mmol，26.16%產率)。5-Bromopyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (9.3 g, 31.19 mmol) and 4,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3 , 2-dioxaborolane (7.92 g, 31.19 mmol) were mixed together in dioxane (100 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.14 g) was added under argon , 1.56 mmol). The reaction mixture was stirred under argon at 100°C for 8h, then cooled and evaporated in vacuo, poured into water (150ml) and extracted with EtOAc (2x80ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 13g of crude product which was chromatographed on a silica gel column using a hexane/MTBE gradient (10 -100% MTBE) elution to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazolo[ 3,4-b]pyridine-1-carboxylic acid tert-butyl ester (2.5 g, 7.24 mmol, 23.22% yield) and 5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborol-2-yl)-lH-pyrazolo[3,4-b]pyridine (2 g, 8.16 mmol, 26.16% yield).

P1-1： 1 H NMR(CDCl3 ,500MHz)：1.36(s,12H),1.73(s,9H),8.15(s,1H),8.51(s,1H),9.07(s,1H)。 P1-1: 1 H NMR (CDCl 3 , 500 MHz): 1.36 (s, 12H), 1.73 (s, 9H), 8.15 (s, 1H), 8.51 (s, 1H), 9.07 (s, 1H).

LCMS(ESI)：[M-Boc+H]+ m/z：計算值345.2；實測值246.2；Rt=0.940min。LCMS (ESI): [M-Boc+H] + m/z: calculated 345.2; found 246.2; Rt=0.940 min.

P1-2： 1 H NMR(CDCl3 ,500MHz)：1.32(s,12H),8.13(s,1H),8.61(s,1H),8.95(s,1H)，未觀察到NH。 P1-2: 1 H NMR (CDCl 3 , 500 MHz): 1.32 (s, 12H), 8.13 (s, 1H), 8.61 (s, 1H), 8.95 (s, 1H), no NH was observed.

LCMS(ESI)：[M+H]+ m/z：計算值245.1；實測值246.2；Rt=0.555min。LCMS (ESI): [M+H]+ m/z: calculated 245.1; found 246.2; Rt=0.555min.

步驟3：5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)吡唑并[3,4-b]吡啶-1-甲酸第三丁酯之合成Step 3: 5-(1-Third-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)pyrazolo[3,4-b]pyridine-1-carboxylic acid Synthesis of tertiary butyl ester

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑并[3,4-b]吡啶-1-甲酸第三丁酯(4g，11.59mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.00g，11.59mmol)一起混合於水(8mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(8mL)中之碳酸鈉(2.46g，23.17mmol，970.88μL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯 鈀(II)與二氯甲烷之複合物(473.14mg，579.37μmol)。將反應混合物在氬氣、80℃下攪拌12h，然後冷卻且在真空中蒸發，將其倒入水(120ml)中且用EtOAc(2x60ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下3.6g粗產物，3.6g粗產物藉由矽膠管柱層析，使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到產物5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)吡唑并[3,4-b]吡啶-1-甲酸第三丁酯(2.4g，5.79mmol，49.97%產率)。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (4 g, 11.59 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.00 g, 11.59 mmol) were mixed together in water (8 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (2.46 g, 23.17 mmol, 970.88 μL) in water (8 mL) and [1,1′-bis() were added under argon Diphenylphosphino)ferrocene]dichloro Palladium(II) complex with dichloromethane (473.14 mg, 579.37 [mu]mol). The reaction mixture was stirred under argon at 80°C for 12h, then cooled and evaporated in vacuo, poured into water (120ml) and extracted with EtOAc (2x60ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 3.6g of crude product which was subjected to silica gel column chromatography using a hexane/MTBE gradient (10-100% MTBE) to give the product 5-(1-tert-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)pyrazolo[3 ,4-b]pyridine-1-carboxylic acid tert-butyl ester (2.4 g, 5.79 mmol, 49.97% yield).

1 H NMR(DMSO,400MHz)：1.04(s,9H),1.91(m,6H),3.05(m,1H),4.07(m,1H),5.33(m,1H),7.97(s,1H),8.05(s,1H),8.57(s,1H),11.78(s,1H)(僅一個Boc基團存在於結構中) 1 H NMR (DMSO, 400MHz): 1.04(s, 9H), 1.91(m, 6H), 3.05(m, 1H), 4.07(m, 1H), 5.33(m, 1H), 7.97(s, 1H) , 8.05(s, 1H), 8.57(s, 1H), 11.78(s, 1H) (only one Boc group is present in the structure)

LCMS(ESI)：[M-Boc+H]+ m/z：計算值414.5；實測值315.2；Rt=1.367min。LCMS (ESI): [M-Boc+H] + m/z: calculated 414.5; found 315.2; Rt=1.367 min.

步驟4：5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-1H-吡唑并[3,4-b]吡啶之合成Step 4: Synthesis of 5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-1H-pyrazolo[3,4-b]pyridine

將3-甲基-6-(1H-吡唑并[3,4-b]吡啶-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.4g，7.63mmol)於TFA(26.11g，229.02mmol，17.64mL)中之溶液在0℃下攪拌1h，然後在真空中蒸發。將碎冰(20g)添加到殘餘物中且用10%碳酸氫鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-1H-吡唑并[3,4-b]吡啶(1.3g，6.07mmol，79.48%產率)，其直接用於下一步驟中。3-Methyl-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.4 g, A solution of 7.63 mmol) in TFA (26.11 g, 229.02 mmol, 17.64 mL) was stirred at 0 °C for 1 h, then evaporated in vacuo. Crushed ice (20 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-1H- as a yellow solid Pyrazolo[3,4-b]pyridine (1.3 g, 6.07 mmol, 79.48% yield) was used directly in the next step.

1 H NMR(500MHz,CDCl3 )1.03(d,3H),1.46(m,1H),1.61(m,1H),1.77(m,1H),2.82(m,1H),2.86(m,1H),3.32(m,1H),4.07(m,1H),8.08(s,1H),8.47(s,1H),9.11(s,1H),11.35(m,1H)。 1 H NMR (500MHz, CDCl 3 ) 1.03(d,3H), 1.46(m,1H), 1.61(m,1H), 1.77(m,1H), 2.82(m,1H), 2.86(m,1H) , 3.32(m, 1H), 4.07(m, 1H), 8.08(s, 1H), 8.47(s, 1H), 9.11(s, 1H), 11.35(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值214.27；實測值215.2；Rt=0.722min。LCMS (ESI): [M+H] + m/z: calculated 214.27; found 215.2; Rt=0.722 min.

步驟5：5-(5-甲基-2-哌啶基)-1H-吡唑并[3,4-b]吡啶之合成Step 5: Synthesis of 5-(5-Methyl-2-piperidinyl)-1H-pyrazolo[3,4-b]pyridine

在0℃下，將硼氫化鈉(344.31mg，9.10mmol，321.78μL)一次性添加到5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-1H-吡唑并[3,4-b]吡啶(1.3g，6.07mmol)於MeOH(25mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌2h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用二氯甲烷(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之5-(5-甲基-2-哌啶基)-1H-吡唑并[3,4-b]吡啶(1.2g，5.55mmol，91.45%產率)，其直接用於下一步驟中。At 0 °C, sodium borohydride (344.31 mg, 9.10 mmol, 321.78 μL) was added in one portion to 5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-1H- In a stirred solution of pyrazolo[3,4-b]pyridine (1.3 g, 6.07 mmol) in MeOH (25 mL). The resulting mixture was stirred at 0 °C for 2 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl)-1H-pyrazolo[3,4-b] as a brown solid Pyridine (1.2 g, 5.55 mmol, 91.45% yield) was used directly in the next step.

1 H NMR(500MHz,CDCl3 )1.08(d,3H),1.62(m,2H),1.73(m,2H),1.93(m,2H),2.48(t,1H),3.18(m,1H),3.76(m,1H),8.06(s,1H),8.15(s,1H),8.63(s,1H),11.78(m,1H)。 1 H NMR (500MHz, CDCl 3 ) 1.08(d,3H), 1.62(m,2H), 1.73(m,2H), 1.93(m,2H), 2.48(t,1H), 3.18(m,1H) , 3.76(m, 1H), 8.06(s, 1H), 8.15(s, 1H), 8.63(s, 1H), 11.78(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值216.2；實測值217.2；Rt=0.728min。LCMS (ESI): [M+H] + m/z: calculated 216.2; found 217.2; Rt=0.728 min.

6Y. 2-(3-氯-4-氟苯基)-5-甲基哌啶之合成6Y. Synthesis of 2-(3-chloro-4-fluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0798-641
Figure 110128222-A0202-12-0798-641

步驟1：N-[5-(3-氯-4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of N-[5-(3-chloro-4-fluorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

在攪拌之情況下，在Ar下，向乾燥的2頸燒瓶中添加鎂(1.16g，47.75mmol，666.93μL)、無水THF(75mL)及4-溴-2-氯-1-氟苯(10g，47.75mmol，5.78mL)。輕微加熱混合物，直到其自身保持回流。當回流平息時，施加外部加熱以再保持回流1小時。將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(7.83g，36.73mmol)添加到具有溫度計之乾燥的3頸圓底燒瓶中。在攪拌之情況下，在Ar下，添加無水THF(75mL)且將溶液冷卻至-78℃。在1小時內將格任亞試劑添加到t-Boc-內醯胺中，使內部溫度保持低於-70℃。使溶液升溫至室溫且添加飽和NH4 Cl。將水層用DCM萃取3 x 50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。 獲得呈淡黃色油狀物之N-[5-(3-氯-4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(13g，粗品)且其不經進一步純化即用於下一步驟。With stirring, to a dry 2-neck flask were added magnesium (1.16 g, 47.75 mmol, 666.93 μL), anhydrous THF (75 mL) and 4-bromo-2-chloro-1-fluorobenzene (10 g) under Ar , 47.75 mmol, 5.78 mL). The mixture was heated slightly until it kept refluxing on its own. When the reflux subsided, external heat was applied to maintain the reflux for an additional hour. To a dry 3-neck round-bottom flask with thermometer was added tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (7.83 g, 36.73 mmol). With stirring, dry THF (75 mL) was added under Ar and the solution was cooled to -78 °C. The Grignard reagent was added to the t-Boc-lactamide over 1 hour, keeping the internal temperature below -70°C. The solution was warmed to room temperature and saturated NH4Cl was added. The aqueous layer was extracted with DCM 3 x 50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. 3-Butyl N-[5-(3-chloro-4-fluorophenyl)-2-methyl-5-oxypentyl]carbamate (13 g, crude) was obtained as a pale yellow oil and It was used in the next step without further purification.

1 H NMR(CDCl3 ,500MHz)：δ 0.95(d,3H),1.44(s,9H),1.71-1.80(m,4H),2.98(t,2H),4.02(t,1H),4.68(brs,1H),7.20(t,1H),7.87(dd,1H),8.03(d,1H)。 1 H NMR (CDCl 3 , 500MHz): δ 0.95 (d, 3H), 1.44 (s, 9H), 1.71-1.80 (m, 4H), 2.98 (t, 2H), 4.02 (t, 1H), 4.68 ( brs, 1H), 7.20 (t, 1H), 7.87 (dd, 1H), 8.03 (d, 1H).

LCMS(ESI)：[M+Na]+ m/z：計算值343.2；實測值366.2；Rt=1.622min。LCMS (ESI): [M+Na] + m/z: calculated 343.2; found 366.2; Rt=1.622 min.

步驟2：2-(3-氯-4-氟苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(3-Chloro-4-fluorophenyl)-5-methylpiperidine

將N-[5-(3-氯-4-氟苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(13g，37.81mmol)於三氟乙酸(17.25g，151.24mmol，11.65mL)中攪拌1h。使用TLC檢查反應進展。將50% w/v NaOH溶液添加到混合物中，直到pH為13-14。將產物用DCM萃取4 x 20mL且將有機層合併，以MgSO4乾燥且蒸發。將產物溶解於水(25mL)/MeOH(150mL)混合物中且添加到燒瓶中，隨後添加硼氫化鈉(1.43g，37.81mmol，1.34mL)。將混合物在Ar下攪拌隔夜。將混合物用1-2M HCl酸化，直到pH為1-3且靜置30分鐘。然後添加NaOH溶液，直到pH為13-14且將產物用DCM(4 x 100mL)萃取，將有機層合併，以Na2 SO4 乾燥，過濾且蒸發。藉由CC(Companion combiflash；120g SiO2 ；氯仿/乙腈，其中乙腈為0至17%，流速=85ml/min，Rv=7-11cv.)純化殘餘物，以得到呈淡黃色油狀物之2-(3-氯-4-氟苯基)-5-甲基哌啶(2.2g，9.66mmol，25.55%產率)。N-[5-(3-Chloro-4-fluorophenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester (13 g, 37.81 mmol) in trifluoroacetic acid (17.25 g) , 151.24 mmol, 11.65 mL) and stirred for 1 h. The progress of the reaction was checked using TLC. 50% w/v NaOH solution was added to the mixture until the pH was 13-14. The product was extracted with DCM 4 x 20 mL and the organic layers were combined, dried over MgSO4 and evaporated. The product was dissolved in a mixture of water (25 mL)/MeOH (150 mL) and added to the flask followed by sodium borohydride (1.43 g, 37.81 mmol, 1.34 mL). The mixture was stirred under Ar overnight. The mixture was acidified with 1-2M HCl until pH 1-3 and left to stand for 30 minutes. NaOH solution was then added until pH was 13-14 and the product was extracted with DCM ( 4 x 100 mL), the organic layers were combined, dried over Na2SO4 , filtered and evaporated. The residue was purified by CC (Companion combiflash; 120 g SiO2 ; chloroform/acetonitrile with 0 to 17% acetonitrile, flow rate=85 ml/min, Rv=7-11 cv.) to give 2 as a pale yellow oil -(3-Chloro-4-fluorophenyl)-5-methylpiperidine (2.2 g, 9.66 mmol, 25.55% yield).

1 H NMR(CDCl3 ,400MHz)：δ 0.86(d,3H),1.12(m,1H),1.42(m,1H),1.61-1.84(m,4H),2.37(t,1H),3.10(d,1H),3.48(d,1H),7.04(t,1H),7.18(dd,1H),7.42(d,1H)LCMS(ESI)：[M+H]+ m/z：計算值227.1；實測值228.2；Rt=0.895min。 1 H NMR (CDCl 3 , 400MHz): δ 0.86 (d, 3H), 1.12 (m, 1H), 1.42 (m, 1H), 1.61-1.84 (m, 4H), 2.37 (t, 1H), 3.10 ( d,1H), 3.48(d,1H), 7.04(t,1H), 7.18(dd,1H), 7.42(d,1H) LCMS(ESI): [M+H] + m/z: calcd. 227.1 ; Measured value 228.2; Rt=0.895min.

6Z. 2-(3,4-二氯苯基)-5-甲基哌啶之合成6Z. Synthesis of 2-(3,4-dichlorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0799-642
Figure 110128222-A0202-12-0799-642

步驟1：6-(3,4-二氯苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3,4-dichlorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5g，14.48mmol)、(3,4-二氯苯基)硼酸(2.76g，14.48mmol)及碳酸鈉(4.60g，43.44mmol，1.82mL)添加到二噁烷(45mL)及水(15mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)2Cl2*DCM(723.93μmol)。將反應混合物在氬氣、70℃下攪拌15h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之6-(3,4-二氯苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.5g，13.15mmol，90.81%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 g, 14.48 mmol), (3,4- Dichlorophenyl)boronic acid (2.76 g, 14.48 mmol) and sodium carbonate (4.60 g, 43.44 mmol, 1.82 mL) were added to a mixture of dioxane (45 mL) and water (15 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)2Cl2*DCM (723.93 μmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 15 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 6-(3,4-dichlorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a brown oil (4.5 g, 13.15 mmol, 90.81% yield), which was used in the next step without purification.

步驟2：6-(3,4-二氯苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3,4-dichlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(3,4-二氯苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.5g，13.15mmol)於三氟乙酸(29.98g，262.96mmol，20.26mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之6-(3,4-二氯苯基)-3-甲基-2,3,4,5-四氫吡啶(3g，12.39mmol，94.23%產率)，其直接用於下一步驟中。Dissolve 6-(3,4-dichlorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.5 g, 13.15 mmol) in trifluoroacetic acid (29.98 g g, 262.96 mmol, 20.26 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 6-(3,4-dichlorophenyl)-3-methyl-2,3,4,5-tetrakis as a brown solid Hydropyridine (3 g, 12.39 mmol, 94.23% yield) was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值241.1；實測值242.2；Rt=0.793min。LCMS (ESI): [M+H] + m/z: calculated 241.1; found 242.2; Rt=0.793 min.

步驟3：2-(3,4-二氯苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(3,4-Dichlorophenyl)-5-methylpiperidine

在0℃下，將硼氫化鈉(937.44mg，24.78mmol，876.11μL)一次性添加到6-(3,4-二氯苯基)-3-甲基-2,3,4,5-四氫吡啶(3g，12.39mmol)於MeOH(50mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷HPLC(2-10min 50-70% ACN+HCL/H2 O 30ml/min(裝載泵4ml ACN+HCL管柱：SunFire 100*19mm，5 微米)，以得到2-(3,4-二氯苯基)-5-甲基哌啶(1.43g，5.86mmol，47.27%產率)。Sodium borohydride (937.44 mg, 24.78 mmol, 876.11 μL) was added in one portion to 6-(3,4-dichlorophenyl)-3-methyl-2,3,4,5-tetrakis at 0 °C Hydropyridine (3 g, 12.39 mmol) in a stirred solution of MeOH (50 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The oil obtained was subjected to HPLC (2-10min 50-70% ACN+HCL/ H2O 30ml/min (load pump 4ml ACN+HCL column: SunFire 100*19mm, 5 microns) to give 2- (3,4-Dichlorophenyl)-5-methylpiperidine (1.43 g, 5.86 mmol, 47.27% yield).

1 H NMR(DMSO,400MHz)：0.88(d,3H),1.22(m,1H),1.85(m,2H),2.05(m,1H),2.67(m,1H),4.22(m,1H),7.52(d,1H),7.69(d,1H),8.02(s,1H),9.62(m,1H)。 1 H NMR (DMSO, 400MHz): 0.88(d,3H), 1.22(m,1H), 1.85(m,2H), 2.05(m,1H), 2.67(m,1H), 4.22(m,1H) , 7.52(d, 1H), 7.69(d, 1H), 8.02(s, 1H), 9.62(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值243.1；實測值244.2；Rt=2.063min。LCMS (ESI): [M+H] + m/z: calculated 243.1; found 244.2; Rt=2.063 min.

6AA. 2-(3-氯-4-甲基苯基)-5-甲基哌啶之合成6AA. Synthesis of 2-(3-chloro-4-methylphenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0801-643
Figure 110128222-A0202-12-0801-643

步驟1：6-(3-氯-4-甲基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3-Chloro-4-methylphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5g，14.48mmol)、(3-氯-4-甲基苯基)硼酸(2.47g，14.48mmol)及碳酸鈉(4.60g，43.44mmol，1.82mL)添加到二噁烷(45mL)及水(15mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)2 Cl2* DCM(723.93μmol)。將反應混合物在氬氣、70℃下攪拌15h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之6-(3-氯-4-甲基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，12.43mmol，85.84%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 g, 14.48 mmol), (3-chloro- 4-Methylphenyl)boronic acid (2.47 g, 14.48 mmol) and sodium carbonate (4.60 g, 43.44 mmol, 1.82 mL) were added to a mixture of dioxane (45 mL) and water (15 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)2Cl2 * DCM ( 723.93 μmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 15 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 6-(3-chloro-4-methylphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid as a brown oil Butyl ester (4 g, 12.43 mmol, 85.84% yield) was used in the next step without purification.

LCMS(ESI)：[M-tBu]+ m/z：計算值265.1；實測值266.2；Rt=1.827min。LCMS (ESI): [M-tBu] + m/z: calculated 265.1; found 266.2; Rt=1.827 min.

步驟2：6-(3-氯-4-甲基苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3-Chloro-4-methylphenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(3-氯-4-甲基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，12.43mmol)於三氟乙酸(28.34g，248.57mmol，19.15mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2* 30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之6-(3-氯-4-甲基苯基)-3-甲基-2,3,4,5-四氫吡啶(2g，9.02mmol，72.58%產率)，其直接用於下一步 驟中。Dissolve 6-(3-chloro-4-methylphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4 g, 12.43 mmol) in trifluoroacetic acid ( The solution in 28.34 g, 248.57 mmol, 19.15 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2 * 30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 6-(3-chloro-4-methylphenyl)-3-methyl-2,3,4,5 as a brown solid - Tetrahydropyridine (2 g, 9.02 mmol, 72.58% yield), which was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值221.1；實測值222.0；Rt=0.999min。LCMS (ESI): [M+H] + m/z: calculated 221.1; found 222.0; Rt=0.999 min.

步驟3：2-(3-氯-4-甲基苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(3-Chloro-4-methylphenyl)-5-methylpiperidine

在0℃下，將硼氫化鈉(682.51mg，18.04mmol，637.86μL)一次性添加到6-(3-氯-4-甲基苯基)-3-甲基-2,3,4,5-四氫吡啶(2g，9.02mmol)於MeOH(50mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2* 40ml)萃取。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。使所獲得之油狀物經歷HPLC(Waters SunFire C18 19*100mm 5mkm管柱，以己烷-MeOH 50-50為流動相，流速12mL/min)，以得到2-(3-氯-4-甲基苯基)-5-甲基哌啶(513.6mg，2.30mmol，25.45%產率)。Sodium borohydride (682.51 mg, 18.04 mmol, 637.86 μL) was added in one portion to 6-(3-chloro-4-methylphenyl)-3-methyl-2,3,4,5 at 0 °C - Tetrahydropyridine (2 g, 9.02 mmol) in a stirred solution of MeOH (50 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2 * 40ml). The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The oil obtained was subjected to HPLC (Waters SunFire C18 19*100mm 5mkm column with hexane-MeOH 50-50 as mobile phase, flow rate 12mL/min) to give 2-(3-chloro-4-methan). phenyl)-5-methylpiperidine (513.6 mg, 2.30 mmol, 25.45% yield).

LCMS(ESI)：[M+H]+ m/z：計算值223.1；實測值224.4；Rt=2.606min。LCMS (ESI): [M+H] + m/z: calculated 223.1; found 224.4; Rt=2.606 min.

6BB. 4-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑之合成6BB. Synthesis of 4-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole

Figure 110128222-A0202-12-0802-644
Figure 110128222-A0202-12-0802-644

步驟1：6-(1H-吲唑-4-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(1H-Indazol-4-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鈉(7.82g，73.74mmol，3.09mL)添加到3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.34g，27.04mmol)及4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吲唑(6g，24.58mmol)於二噁烷(90mL)及水(30mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2*DCM(1.00g，1.23mmol)。在90℃、惰性氣氛下將所得混合物攪拌14h。將反應混合物蒸發，以得到粗產物(25g)，其藉由梯度管柱層析進行純化，以得到6-(1H-吲唑-4-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.2g，13.40mmol，54.52%產率)。Sodium carbonate (7.82 g, 73.74 mmol, 3.09 mL) was added to 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid third Butyl ester (9.34 g, 27.04 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-indazole ( 6 g, 24.58 mmol) in dioxane (90 mL) and water (30 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, Pd(dppf)Cl2*DCM (1.00 g, 1.23 mmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 14 h. The reaction mixture was evaporated to give crude product (25 g) which was purified by gradient column chromatography to give 6-(1H-indazol-4-yl)-3-methyl-3,4-dihydro -2H-pyridine-1-carboxylic acid tert-butyl ester (4.2 g, 13.40 mmol, 54.52% yield).

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值314.2；Rt=1.337min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 314.2; Rt=1.337 min.

步驟2：4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 2: Synthesis of 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

向6-(1H-吲唑-4-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2g，6.38mmol)中添加三氟乙酸(7.28g，63.82mmol，4.92mL)且將反應混合物在25℃下攪拌1h。蒸發TFA。將殘餘物用氯仿稀釋且蒸發至乾，以得到4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(0.9g，4.22mmol，66.12%產率)。To 6-(1H-indazol-4-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2 g, 6.38 mmol) was added trifluoroacetic acid (7.28 g g, 63.82 mmol, 4.92 mL) and the reaction mixture was stirred at 25 °C for 1 h. Evaporate TFA. The residue was diluted with chloroform and evaporated to dryness to give 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole (0.9 g, 4.22 mmol, 66.12 g %Yield).

1 H NMR(CDCl3 ,400MHz)：1.53(d,3H),1.73(m,1H),2.22(m,2H),3.45(m,1H),3.49(m,2H),4.14(m,1H),7.58(d,1H),7.65(dd,1H),7.90(d,1H),8.35(s,1H),12.55(s,1H)。 1 H NMR (CDCl 3 , 400MHz): 1.53(d,3H), 1.73(m,1H), 2.22(m,1H), 3.45(m,1H), 3.49(m,2H), 4.14(m,1H) ), 7.58(d, 1H), 7.65(dd, 1H), 7.90(d, 1H), 8.35(s, 1H), 12.55(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值213.2；實測值214.2；Rt=0.608min。LCMS (ESI): [M+H] + m/z: calculated 213.2; found 214.2; Rt=0.608 min.

步驟3：4-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑之合成Step 3: Synthesis of 4-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole

向4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(0.9g，4.22mmol)於MeOH(10mL)中之經預冷卻(0℃)之溶液中分批添加硼氫化鈉(191.56mg，5.06mmol，179.03μL)。然後將反應混合物在25℃下攪拌1h。蒸發MeOH，將殘餘物溶解於MeOH(5ml)中且添加二噁烷*HCl(5ml)。將混合物攪拌15min。蒸發溶劑，以得到粗品固體產物，將其用THF(2*10ml)洗滌，在真空中乾燥，以得到4-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(1.7g，粗品，HCl)。To a precooled (0 °C) solution of 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole (0.9 g, 4.22 mmol) in MeOH (10 mL) ) was added portionwise sodium borohydride (191.56 mg, 5.06 mmol, 179.03 μL). The reaction mixture was then stirred at 25°C for 1 h. MeOH was evaporated, the residue was dissolved in MeOH (5ml) and dioxane*HCl (5ml) was added. The mixture was stirred for 15 min. The solvent was evaporated to give crude solid product which was washed with THF (2*10ml) and dried in vacuo to give 4-[(2S,5R)-5-methyl-2-piperidinyl]-1H- Indazole (1.7 g, crude, HCl).

LCMS(ESI)：[M+H]+ m/z：計算值215.2；實測值216.0；Rt=0.773min。LCMS (ESI): [M+H] + m/z: calculated 215.2; found 216.0; Rt=0.773 min.

6CC. 6-(5-甲基哌啶-2-基)異吲哚啉-1-酮之合成6CC. The synthesis of 6-(5-methylpiperidin-2-yl)isoindolin-1-one

Figure 110128222-A0202-12-0803-645
Figure 110128222-A0202-12-0803-645

步驟1：3-甲基-6-(3-側氧基異吲哚啉-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(3-oxyisoindolin-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(10.00g，28.96mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異吲哚啉-1-酮(7.50g，28.96mmol)及碳酸鈉(9.21g，86.87mmol，3.64mL)添加到二噁烷(90mL)及水(30mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 DCM(1.18g，1.45mmol)。將反應混合物在氬氣、70℃下攪拌12h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之3-甲基-6-(3-側氧基異吲哚啉-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(9g，27.41mmol，94.64%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (10.00 g, 28.96 mmol), 6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)isoindolin-1-one (7.50g, 28.96mmol) and sodium carbonate (9.21 g, 86.87 mmol, 3.64 mL) was added to a mixture of dioxane (90 mL) and water (30 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf) Cl2DCM (1.18 g, 1.45 mmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 12 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 3-methyl-6-(3-oxyisoindolin-5-yl)-3,4-dihydro- 2H -pyridine-1- as a brown oil 3-Butyl formate (9 g, 27.41 mmol, 94.64% yield) was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.12(s,9H),1.42(m,1H),1.96(m,2H),2.48(m,1H),3.06(m,1H),3.54(s,2H),5.38(m,1H),7.49(m,2H),8.51(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.12(s,9H), 1.42(m,1H), 1.96(m,2H), 2.48(m,1H), 3.06 (m, 1H), 3.54 (s, 2H), 5.38 (m, 1H), 7.49 (m, 2H), 8.51 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值228.2；實測值229.2；Rt=1.375min。LCMS (ESI): [M-Boc] + m/z: calculated 228.2; found 229.2; Rt=1.375 min.

步驟2：6-(5-甲基-3,4,5,6-四氫吡啶-2-基)異吲哚啉-1-酮之合成Step 2: Synthesis of 6-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)isoindolin-1-one

將3-甲基-6-(3-側氧基異吲哚啉-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(9g，27.41mmol)於TFA(31.25g，274.05mmol，21.11mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用DCM(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異吲哚啉-1-酮(6g，26.28mmol，95.90%產率)，其直接用於下一步驟中。3-Methyl-6-(3-oxyisoindolin-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (9 g, 27.41 mmol) in TFA The solution in (31.25 g, 274.05 mmol, 21.11 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with DCM (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)iso as a brown oil Indolin-1-one (6 g, 26.28 mmol, 95.90% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.97(d,3H),1.31(m,1H),1.72(m,1H),1.89(m,1H),2.72(m,1H),2.96(m,1H),3.33(m,2H),3.92(m,1H),4.42(s,2H),6.98(d,1H),7.12(d,1H),8.07(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.97(d,3H), 1.31(m,1H), 1.72(m,1H), 1.89(m,1H), 2.72(m,1H), 2.96(m,1H), 3.33(m,2H), 3.92(m,1H), 4.42(s,2H), 6.98(d,1H), 7.12(d,1H), 8.07(s,1H).

LCMS(ESI)：[M]+ m/z：計算值228.2；實測值229.2；Rt=0.514min。LCMS (ESI): [M] + m/z: calculated 228.2; found 229.2; Rt=0.514 min.

步驟3：6-(5-甲基哌啶-2-基)異吲哚啉-1-酮之合成Step 3: Synthesis of 6-(5-Methylpiperidin-2-yl)isoindolin-1-one

在0℃下，將硼氫化鈉(1.99g，52.56mmol，1.86mL)分批添加到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異吲哚啉-1-酮(6g，26.28mmol)於MeOH(60mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後將溶液升溫至室溫。10h之後，將其在真空中蒸發。向殘餘物中添加水(20ml)且過濾。所獲得之呈灰色固體之6-(5-甲基-2-哌啶基)異吲哚啉-1-酮(1g，4.34mmol，16.52%產率)不經純化即用於下一步驟中。Sodium borohydride (1.99 g, 52.56 mmol, 1.86 mL) was added portionwise to 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)isoindole at 0 °C A stirred solution of olin-1-one (6 g, 26.28 mmol) in MeOH (60 mL). The resulting mixture was stirred at 0 °C for 1 h, then the solution was warmed to room temperature. After 10 h, it was evaporated in vacuo. To the residue was added water (20 ml) and filtered. The obtained 6-(5-methyl-2-piperidinyl)isoindolin-1-one (1 g, 4.34 mmol, 16.52% yield) as a grey solid was used in the next step without purification .

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.12(m,1H),1.32(m,1H),1.56(m,1H),1.74(m,2H),2.22(m,1H),2.38(m,1H),3.01(m,1H),3.58(m,1H),4.38(s,2H),7.48(d,1H),7.55(d,1H),7.67(s,1H),8.49(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.86(d,3H), 1.12(m,1H), 1.32(m,1H), 1.56(m,1H), 1.74(m,2H), 2.22(m, 1H), 2.38(m, 1H), 3.01(m, 1H), 3.58(m, 1H), 4.38(s, 2H), 7.48(d, 1H), 7.55(d, 1H), 7.67 (s, 1H), 8.49 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值230.2；實測值231.2；Rt=0.761min。LCMS (ESI): [M] + m/z: calculated 230.2; found 231.2; Rt=0.761 min.

6DD. 外消旋-(2R,5S)-2-(3-氯-5-(三氟甲基)苯基)-5-甲基哌啶之合成6DD. Synthesis of racemic-(2R,5S)-2-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0805-646
Figure 110128222-A0202-12-0805-646

步驟1：2-(3-氯-5-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊現之合成Step 1: Synthesis of 2-(3-Chloro-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

將1-溴-3-氯-5-(三氟甲基)苯(19.9g，76.70mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(29.22g，115.05mmol)及KOAc(22.58g，230.10mmol，14.38mL)於二噁烷(300mL)中之混合物用氬氣除氣10min。接著添加Pd(dppf)Cl2 *DCM(1g，1.22mmol)且將反應混合物加熱至90℃達16h。將反應混合物冷卻至室溫，過濾且在減壓下濃縮。將殘餘物用己烷處理，透過SiO2 薄層過濾且蒸發至乾。藉由SiO2 急驟層析(己烷：CHCl3 )純化粗產物，以得到2-[3-氯-5-(三氟甲基)苯基]-4,4,5,5-四甲基-1,3,2-二 氧雜硼雜環戊烷(8.1g，26.43mmol，34.45%產率)。1-Bromo-3-chloro-5-(trifluoromethyl)benzene (19.9 g, 76.70 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl) Methyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (29.22 g, 115.05 mmol) and KOAc (22.58 g, A mixture of 230.10 mmol, 14.38 mL) in dioxane (300 mL) was degassed with argon for 10 min. Then Pd(dppf)Cl2*DCM ( 1 g, 1.22 mmol) was added and the reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was treated with hexane, filtered through a thin layer of SiO2 and evaporated to dryness. The crude product was purified by flash chromatography on SiO2 (hexane: CHCl3 ) to give 2-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl - 1,3,2-Dioxaborolane (8.1 g, 26.43 mmol, 34.45% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.12(s,12H),7.92(m,3H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 1.12 (s, 12H), 7.92 (m, 3H).

GCMS：計算值306.2；實測值306.2；Rt=7.597min。GCMS: Calculated 306.2; Found 306.2; Rt=7.597min.

步驟2：6-(3-氯-5-(三氟甲基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 2: Synthesis of 6-(3-chloro-5-(trifluoromethyl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(6.76g，19.57mmol)、2-[3-氯-5-(三氟甲基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(7.5g，24.47mmol)及碳酸鈉(6.22g，58.72mmol，2.46mL)添加到1,4-二噁烷(22.5mL)及水(7.5mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，然後在氬氣下添加Pd(dppf)Cl2 *DCM(798.65mg，978.74μmol)。將反應混合物在75℃下攪拌16h，然後用水處理且將所需產物用DCM萃取，然後蒸發。 獲得6-[3-氯-5-(三氟甲基)苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7g，粗品)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (6.76 g, 19.57 mmol), 2-[3 -Chloro-5-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.5g, 24.47mmol) and carbonic acid Sodium (6.22 g, 58.72 mmol, 2.46 mL) was added to a mixture of 1,4-dioxane (22.5 mL) and water (7.5 mL). The resulting mixture was evacuated, then backfilled with argon, then Pd(dppf)Cl2*DCM ( 798.65 mg, 978.74 μmol) was added under argon. The reaction mixture was stirred at 75 °C for 16 h, then treated with water and the desired product was extracted with DCM and evaporated. 6-[3-Chloro-5-(trifluoromethyl)phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7 g, crude) was obtained.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.93(d,3H),1.01(s,9H),1.36(m,1H),1.81(m,1H),2.36(m,1H),3.05(m,1H),3.87(m,1H),5.58(m,1H),7.47(s,1H),7.59(s,1H),7.72(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.93(d,3H), 1.01(s,9H), 1.36(m,1H), 1.81(m,1H), 2.36(m,1H), 3.05(m, 1H), 3.87(m, 1H), 5.58(m, 1H), 7.47(s, 1H), 7.59(s, 1H), 7.72(s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值275.2；實測值276.2；Rt=1.752min。LCMS (ESI): [M-Boc] + m/z: calculated 275.2; found 276.2; Rt=1.752 min.

步驟3：6-(3-氯-5-(三氟甲基)苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-(3-Chloro-5-(trifluoromethyl)phenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-[3-氯-5-(三氟甲基)苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7g，18.63mmol)(來自前一階段之粗產物)溶解於99%三氟乙酸(22.20g，194.70mmol，15mL)中且攪拌1h，然後蒸發至乾，以得到6-[3-氯-5-(三氟甲基)苯基]-3-甲基-2,3,4,5-四氫吡啶(10g，粗品)。6-[3-Chloro-5-(trifluoromethyl)phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7 g, 18.63 mmol) ( The crude product from the previous stage) was dissolved in 99% trifluoroacetic acid (22.20 g, 194.70 mmol, 15 mL) and stirred for 1 h, then evaporated to dryness to give 6-[3-chloro-5-(trifluoromethyl) )phenyl]-3-methyl-2,3,4,5-tetrahydropyridine (10 g, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.06(d,3H),1.53(m,1H),1.98(m,2H),3.36(m,3H),3.95(m,1H),8.25(m,3H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.06(d,3H), 1.53(m,1H), 1.98(m,2H), 3.36(m,3H), 3.95(m,1H), 8.25 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值275.2；實測值276.2；Rt=0.958min。LCMS (ESI): [M] + m/z: calculated 275.2; found 276.2; Rt=0.958 min.

步驟4：外消旋-(2R,5S)-2-(3-氯-5-(三氟甲基)苯基)-5-甲基哌啶之合成Step 4: Synthesis of racemic-(2R,5S)-2-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpiperidine

將6-[3-氯-5-(三氟甲基)苯基]-3-甲基-2,3,4,5-四氫吡啶(10g，36.27mmol)溶解於甲醇(20mL)中，然後添加硼氫化鈉(2.5g，66.08mmol，2.34mL)。劇烈攪拌1h(pH>7)之後，蒸發溶劑，將粗產物用水處理，然後用DCM(2*75ml)萃取且在真空中濃縮。藉由矽膠急驟層析(CHCl3 ：MeOH，梯度)純化粗產物。獲得(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基哌啶(1g，3.60mmol，9.93%產率)。6-[3-Chloro-5-(trifluoromethyl)phenyl]-3-methyl-2,3,4,5-tetrahydropyridine (10 g, 36.27 mmol) was dissolved in methanol (20 mL), Then sodium borohydride (2.5 g, 66.08 mmol, 2.34 mL) was added. After vigorous stirring for 1 h (pH>7), the solvent was evaporated and the crude product was treated with water, then extracted with DCM (2*75 ml) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography ( CHCl3 :MeOH, gradient). ( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methylpiperidine (1 g, 3.60 mmol, 9.93% yield) was obtained.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.88(d,3H),1.12(m,1H),1.32(m,1H),1.55(m,1H),1.81(m,2H),2.28(t,1H),3.02(d,1H),3.57(d,1H),7.53(s,1H),7.61(s,1H),7.66(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.88(d,3H), 1.12(m,1H), 1.32(m,1H), 1.55(m,1H), 1.81(m,2H), 2.28(t, 1H), 3.02(d, 1H), 3.57(d, 1H), 7.53(s, 1H), 7.61(s, 1H), 7.66(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值277.2；實測值278.2；Rt=0.929min。LCMS (ESI): [M] + m/z: calculated 277.2; found 278.2; Rt=0.929 min.

6EE.2-(3-氯-5-氟苯基)-5-甲基哌啶 之合成6EE. Synthesis of 2-(3-chloro-5-fluorophenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0807-647
Figure 110128222-A0202-12-0807-647

步驟1：6-(3-氯-5-氟苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3-chloro-5-fluorophenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將(3-氯-5-氟苯基)硼酸(3g，17.21mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5.94g，17.21mmol)溶解於二噁烷(30mL)中且將反應混合物徹底除氣，隨後後續添加碳酸銫(22.42g，68.82mmol)及肆(三苯基膦)鈀(0)(198.82mg，172.05μmol)。將所獲得之反應混合物在回流下攪拌隔夜；反應完成之後，在減壓下蒸發有機溶劑，且將粗混合物分配於EtOAc與H2 O之間。將水層另外用EtOAc萃取兩次；將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以得到6-(3-氯-5-氟苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7g，粗品)，其不經純化即用於下一步驟。Combine (3-chloro-5-fluorophenyl)boronic acid (3 g, 17.21 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine- 3-Butyl 1-carboxylate (5.94 g, 17.21 mmol) was dissolved in dioxane (30 mL) and the reaction mixture was thoroughly degassed, followed by the subsequent addition of cesium carbonate (22.42 g, 68.82 mmol) and tetrakis(triphenylphosphine) ) palladium(0) (198.82 mg, 172.05 μmol). The resulting reaction mixture was stirred at reflux overnight; after completion of the reaction, the organic solvent was evaporated under reduced pressure, and the crude mixture was partitioned between EtOAc and H2O . The aqueous layer was extracted two more times with EtOAc; the combined organic layers were washed with brine, dried over Na2SO4 and evaporated to give 6-(3-chloro-5-fluorophenyl)-3-methyl- 3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7 g, crude) was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.96(d,3H),1.25(s,9H),1.95(m,2H),2.38(m,1H),2.93(t,1H),4.01(d,1H),5.32(m,1H),6.88(s,2H),7.05(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.96(d, 3H), 1.25(s, 9H), 1.95(m, 2H), 2.38(m, 1H), 2.93(t, 1H), 4.01( d, 1H), 5.32 (m, 1H), 6.88 (s, 2H), 7.05 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值325.2；實測值326.2；Rt=1.815min。LCMS (ESI): [M] + m/z: calculated 325.2; found 326.2; Rt=1.815 min.

步驟2：6-(3-氯-5-氟苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3-Chloro-5-fluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(3-氯-5-氟苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7g，17.19mmol)溶解於DCM(50mL)中，隨後添加TFA(9.80g，85.94mmol，6.62mL)且攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且蒸發有機溶劑，以得到6-(3-氯-5-氟苯基)-3-甲基-2,3,4,5-四氫吡啶(3.5g，15.51mmol，90.22%產率)，其不經純化即用於下一步驟。6-(3-Chloro-5-fluorophenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7 g, 17.19 mmol) was dissolved in DCM (50 mL) , then TFA (9.80 g, 85.94 mmol, 6.62 mL) was added and stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH, and the organic solvent was evaporated to obtain 6-(3-chloro-5-fluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (3.5 g, 15.51 mmol, 90.22% yield), which was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.96(d,3H),1.36(m,1H),1.68(m,1H),1.91(m,1H),2.50(m,1H),2.68(m,1H),3.24(m,1H),3.96(m,1H),7.08(s,1H),7.38(s,1H),7.54(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.96(d,3H), 1.36(m,1H), 1.68(m,1H), 1.91(m,1H), 2.50(m,1H), 2.68( m, 1H), 3.24 (m, 1H), 3.96 (m, 1H), 7.08 (s, 1H), 7.38 (s, 1H), 7.54 (s, 1H).

步驟3：2-(3-氯-5-氟苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(3-Chloro-5-fluorophenyl)-5-methylpiperidine

將6-(3-氯-5-氟苯基)-3-甲基-2,3,4,5-四氫吡啶(3.5g，15.51mmol)溶解於MeOH(20mL)且冷卻至0℃。將硼氫化鈉(1.17g，31.02mmol，1.10mL)分批添加到所獲得之混合物且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH=2，用MTBE洗滌(2*10mL)，用10% NaOH水溶液鹼化至pH=10且用DCM(40mL)萃取。蒸發溶劑，得到純的(2R,5S )-2-(3-氯-5-氟苯基)-5-甲基哌啶。6-(3-Chloro-5-fluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (3.5 g, 15.51 mmol) was dissolved in MeOH (20 mL) and cooled to 0 °C. Sodium borohydride (1.17 g, 31.02 mmol, 1.10 mL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl, washed with MTBE (2*10 mL), basified with 10% aqueous NaOH to pH=10 and extracted with DCM (40 mL). The solvent was evaporated to give pure ( 2R,5S )-2-(3-chloro-5-fluorophenyl)-5-methylpiperidine.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.12(m,1H),1.48(m,1H),1.86(m,4H),2.39(m,1H),3.12(m,1H),3.52(m,1H),6.95(s,1H),7.00(s,1H),7.16(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d,3H), 1.12(m,1H), 1.48(m,1H), 1.86(m,4H), 2.39(m,1H), 3.12( m, 1H), 3.52 (m, 1H), 6.95 (s, 1H), 7.00 (s, 1H), 7.16 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值227.2；實測值228.2；Rt=0.752min。LCMS (ESI): [M] + m/z: calculated 227.2; found 228.2; Rt=0.752 min.

6FF. 2-(3-氯-4-(三氟甲基)苯基)-5-甲基哌啶之合成6FF. Synthesis of 2-(3-chloro-4-(trifluoromethyl)phenyl)-5-methylpiperidine

Figure 110128222-A0202-12-0809-648
Figure 110128222-A0202-12-0809-648

步驟1：6-(3-氯-4-(三氟甲基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3-chloro-4-(trifluoromethyl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將2-[3-氯-4-(三氟甲基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(9g，29.36mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(8.11g，23.49mmol)、碳酸鈉(9.34g，88.09mmol，3.69mL)及Pd(dppf)Cl2 DCM(23.98g，29.36mmol)添加到1,4-二噁烷(100mL)及水(50mL)之混合物中且將反應混合物在氬氣氣氛、80℃下攪拌15h。冷卻之後，將反應混合物用水稀釋且用DCM萃取。將將有機層分離，經Na2 SO4 乾燥，在減壓下濃縮且提交至急驟層析(以己烷-MTBE為溶析液混合物)，以得到6-[3-氯-4-(三氟甲基)苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5g，粗品)，其不具有高雜質，但不經另外純化即用於下一步驟。2-[3-Chloro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9 g, 29.36 g mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (8.11 g, 23.49 mmol), sodium carbonate (9.34 g, 88.09 mmol, 3.69 mL) and Pd(dppf) Cl2DCM (23.98 g, 29.36 mmol) were added to a mixture of 1,4-dioxane (100 mL) and water (50 mL) and the reaction mixture was placed in The mixture was stirred at 80 °C for 15 h in an argon atmosphere. After cooling, the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried over Na 2 SO 4 , concentrated under reduced pressure and submitted to flash chromatography (hexane-MTBE as eluent mixture) to give 6-[3-chloro-4-(tris Fluoromethyl)phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (5 g, crude) with no high impurities but used without additional purification in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.12(s,9H),1.98(m,2H),2.41(m,1H),3.02(m,1H),3.98(m,1H),5.42(m,1H),7.38(m,2H),7.76(d,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.98(d, 3H), 1.12(s, 9H), 1.98(m, 2H), 2.41(m, 1H), 3.02(m, 1H), 3.98 (m, 1H), 5.42 (m, 1H), 7.38 (m, 2H), 7.76 (d, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值275.2；實測值276.2；Rt=1.826min。LCMS (ESI): [M-Boc] + m/z: calculated 275.2; found 276.2; Rt=1.826 min.

步驟2：6-(3-氯-4-(三氟甲基)苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3-Chloro-4-(trifluoromethyl)phenyl)-3-methyl-2,3,4,5-tetrahydropyridine

在室溫下，向粗品6-[3-氯-4-(三氟甲基)苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2g，5.32mmol)於DCM(5mL)中之經攪拌之溶液中添加TFA(7.40g，64.90mmol，5mL)。將所得反應混合物在室溫下攪拌0.5h。完成之後，將反應混合物在減壓下濃縮且將殘餘物用NaOH溶液處理且用DCM萃取。將經合併之有機相用水、鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得粗品6-[3-氯-4-(三氟甲基)苯基]-3-甲基-2,3,4,5-四氫吡啶(1.4g，粗品)，其不經純化即直接 用於下一步驟。To crude 6-[3-chloro-4-(trifluoromethyl)phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester ( To a stirred solution of 2 g, 5.32 mmol) in DCM (5 mL) was added TFA (7.40 g, 64.90 mmol, 5 mL). The resulting reaction mixture was stirred at room temperature for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was treated with NaOH solution and extracted with DCM. The combined organic phases were washed with water, brine, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain crude 6-[3-chloro-4-(trifluoromethyl)phenyl]-3-methyl - 2,3,4,5-Tetrahydropyridine (1.4 g, crude), which was used directly in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值275.2；實測值276.2；Rt=0.953min。LCMS (ESI): [M] + m/z: calculated 275.2; found 276.2; Rt=0.953 min.

步驟3：2-(3-氯-4-(三氟甲基)苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(3-Chloro-4-(trifluoromethyl)phenyl)-5-methylpiperidine

在室溫下，向6-[3-氯-4-(三氟甲基)苯基]-3-甲基-2,3,4,5-四氫吡啶(1.4g，4.72mmol)於MeOH(15mL)中之經攪拌之溶液中分3批添加硼氫化鈉(232.27mg，6.14mmol，217.07μL)。將所得反應混合物在室溫下攪拌12h，然後在減壓下濃縮。將殘餘物溶解於DCM(15mL)中，用水洗滌，經Na2 SO4 乾燥且在旋轉蒸發儀上濃縮，以得到2-[3-氯-4-(三氟甲基)苯基]-5-甲基哌啶(1.8g，粗品)，其不經純化即用於後續步驟。To 6-[3-chloro-4-(trifluoromethyl)phenyl]-3-methyl-2,3,4,5-tetrahydropyridine (1.4 g, 4.72 mmol) in MeOH at room temperature To the stirred solution in (15 mL) was added sodium borohydride (232.27 mg, 6.14 mmol, 217.07 μL) in 3 portions. The resulting reaction mixture was stirred at room temperature for 12 h, then concentrated under reduced pressure. The residue was dissolved in DCM (15 mL), washed with water, dried over Na 2 SO 4 and concentrated on a rotary evaporator to give 2-[3-chloro-4-(trifluoromethyl)phenyl]-5 - Methylpiperidine (1.8 g, crude), which was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值277.2；實測值278.2；Rt=0.748min。LCMS (ESI): [M] + m/z: calculated 277.2; found 278.2; Rt=0.748 min.

6GG.外消旋 -3-((2R,5S)-5-甲基哌啶-2-基)苯磺醯胺之合成6GG. Synthesis of racemic -3-((2R,5S)-5-methylpiperidin-2-yl)benzenesulfonamide

Figure 110128222-A0202-12-0810-649
Figure 110128222-A0202-12-0810-649

步驟1：3-甲基-6-(3-胺磺醯基苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(3-aminosulfonylphenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將碳酸鈉(1.87g，17.66mmol，739.77μL)添加到3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯磺醯胺(2g，7.06mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.56g，7.42mmol)於二噁烷(20mL)及水(7.5mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2 dppf*DCM(230.73mg，282.53μmol)。在90℃、惰性氣氛下將所得混合物攪拌15h。然後，將其在減壓下濃縮且將殘餘物用乙酸乙酯(50ml)萃取。透過短矽膠墊過濾所獲得之溶液且在減壓下蒸發，得到3-甲基-6-(3-胺磺醯基苯基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.58g，粗品)。Sodium carbonate (1.87 g, 17.66 mmol, 739.77 μL) was added to 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene Sulfonamide (2 g, 7.06 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2.56 g , 7.42 mmol) in dioxane (20 mL) and water (7.5 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl 2 dppf*DCM (230.73 mg, 282.53 μmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 15 h. Then, it was concentrated under reduced pressure and the residue was extracted with ethyl acetate (50 ml). The resulting solution was filtered through a short pad of silica gel and evaporated under reduced pressure to give 3-methyl-6-(3-aminosulfonylphenyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid Tributyl ester (4.58 g, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.91(d,3H),1.44(s,9H),1.87(m,2H),2.42 (m,1H),3.04(m,1H),3.88(m,1H),5.40(m,1H),7.34(m,2H),7.58(m,2H),7.68(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.91(d,3H), 1.44(s,9H), 1.87(m,2H), 2.42(m,1H), 3.04(m,1H), 3.88 (m, 1H), 5.40 (m, 1H), 7.34 (m, 2H), 7.58 (m, 2H), 7.68 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值252.4；實測值253.2；Rt=1.354min。LCMS (ESI): [M-Boc] + m/z: calculated 252.4; found 253.2; Rt=1.354 min.

步驟2：3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯磺醯胺之合成Step 2: Synthesis of 3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzenesulfonamide

將三氟乙酸(22.20g，194.70mmol，15mL)添加到3-甲基-6-(3-胺磺醯基苯基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.58g，12.99mmol)於DCM(30mL)中之溶液中。將所得混合物在20℃下攪拌2h。然後，在減壓下移除揮發物且將殘餘物用水(40ml)稀釋。透過棉絨墊過濾出不溶性焦油。將濾液用20% K2 CO3 水溶液鹼化至pH

Figure 110128222-A0202-12-0811-676
10-11。過濾出經沉澱之白色固體且將其乾燥，得到3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯磺醯胺(968mg，3.84mmol，29.52%產率)。Trifluoroacetic acid (22.20 g, 194.70 mmol, 15 mL) was added to 3-methyl-6-(3-sulfamonophenyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl A solution of ester (4.58 g, 12.99 mmol) in DCM (30 mL). The resulting mixture was stirred at 20 °C for 2 h. Then, the volatiles were removed under reduced pressure and the residue was diluted with water (40 ml). The insoluble tar was filtered through a cotton wool pad. The filtrate was basified to pH with 20 % aqueous K2CO3
Figure 110128222-A0202-12-0811-676
10-11. The precipitated white solid was filtered off and dried to give 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)benzenesulfonamide (968 mg, 3.84 mmol, 29.52% yield). Rate).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.95(d,3H),1.34(m,1H),1.65(m,1H),1.88(m,1H),2.58(m,1H),2.79(m,1H),3.22(m,1H),3.94(m,1H),7.36(m,2H),7.58(t,1H),7.83(d,1H),7.96(d,1H),8.31(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.95(d,3H), 1.34(m,1H), 1.65(m,1H), 1.88(m,1H), 2.58(m,1H), 2.79(m, 1H), 3.22(m, 1H), 3.94(m, 1H), 7.36(m, 2H), 7.58(t, 1H), 7.83(d, 1H), 7.96(d, 1H), 8.31 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值252.4；實測值253.2；Rt=0.593min。LCMS (ESI): [M] + m/z: calculated 252.4; found 253.2; Rt=0.593 min.

步驟3：外消旋-3-((2R,5S)-5-甲基哌啶-2-基)苯磺醯胺之合成Step 3: Synthesis of Racemic-3-((2R,5S)-5-methylpiperidin-2-yl)benzenesulfonamide

在15分鐘內將硼氫化鈉(217.69mg，5.75mmol，203.44μL)一次性添加到3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯磺醯胺(968mg，3.84mmol)於MeOH(20mL)中之溶液中。將所得溶液在20℃下攪拌1h。然後，在減壓下移除溶劑且將殘餘物分配於水(20ml)與乙酸乙酯(40ml)之間。將有機層分離，經Na2 SO4 乾燥且在真空中蒸發，得到3-[(2S,5R )-5-甲基-2-哌啶基]苯磺醯胺(980mg，粗品)。Sodium borohydride (217.69 mg, 5.75 mmol, 203.44 μL) was added to 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)benzenesulfonamide in one portion over 15 minutes (968 mg, 3.84 mmol) in MeOH (20 mL). The resulting solution was stirred at 20 °C for 1 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (20ml) and ethyl acetate (40ml). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to give 3-[( 2S,5R )-5-methyl-2-piperidinyl]benzenesulfonamide (980 mg, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.85(d,3H),1.12(m,2H),1.31(m,1H),1.53(m,1H),1.77(m,2H),2.26(m,1H),3.01(m,1H),3.54(t,1H),7.30(m,2H),7.47(t,1H),7.54(d,1H),7.66(d,1H),7.85(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.85(d, 3H), 1.12(m, 2H), 1.31(m, 1H), 1.53(m, 1H), 1.77(m, 2H), 2.26(m, 1H), 3.01(m, 1H), 3.54(t, 1H), 7.30(m, 2H), 7.47(t, 1H), 7.54(d, 1H), 7.66(d, 1H), 7.85 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值254.4；實測值255.2；Rt=0.766min。LCMS (ESI): [M] + m/z: calculated 254.4; found 255.2; Rt=0.766 min.

6HH.外消旋 -(2R,5S )-5-甲基-2-(3-(甲基磺醯基)苯基)哌啶之合成6HH. Synthesis of racemic- (2R, 5S )-5-methyl-2-(3-(methylsulfonyl)phenyl)piperidine

Figure 110128222-A0202-12-0812-650
Figure 110128222-A0202-12-0812-650

步驟1：3-甲基-6-(3-(甲基磺醯基)苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(3-(methylsulfonyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(18g，52.12mmol)、4,4,5,5-四甲基-2-(3-甲基磺醯基苯基)-1,3,2-二氧雜硼雜環戊烷(15g，53.16mmol)及碳酸鈉(17g，160.39mmol，6.72mL)添加到1,4-二噁烷(270mL)及水(90mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(2.13g，2.61mmol)。將反應混合物在氬氣、90℃下攪拌18h，然後冷卻且過濾。將濾餅用二噁烷(2*50ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用氯仿/乙酸乙酯梯度(0-100%乙酸乙酯)純化殘餘物，以得到呈黃色膠狀物之3-甲基-6-(3-甲基磺醯基苯基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(8.5g，24.18mmol，46.40%產率)，其直接用於下一步驟中。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (18 g, 52.12 mmol), 4,4,5 , 5-tetramethyl-2-(3-methylsulfonylphenyl)-1,3,2-dioxaborolane (15g, 53.16mmol) and sodium carbonate (17g, 160.39mmol, 6.72 mL) was added to a mixture of 1,4-dioxane (270 mL) and water (90 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM (2.13 g , 2.61 mmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 18 h, then cooled and filtered. The filter cake was washed with dioxane (2*50ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a chloroform/ethyl acetate gradient (0-100% ethyl acetate) to give 3-methyl-6- as a yellow gum (3-Methylsulfonylphenyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (8.5 g, 24.18 mmol, 46.40% yield), which was used directly in the next step middle.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.03(m,1H),1.09(s,9H),1.89(d,1H),2.04(m,2H),2.44(d,1H),3.02(s,3H),4.12(m,1H),7.49(t,1H),7.57(d,1H),7.80(d,1H),7.86(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.03(m,1H), 1.09(s,9H), 1.89(d,1H), 2.04(m,2H), 2.44( d, 1H), 3.02 (s, 3H), 4.12 (m, 1H), 7.49 (t, 1H), 7.57 (d, 1H), 7.80 (d, 1H), 7.86 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值251.4；實測值252.2；Rt=1.360min。LCMS (ESI): [M-Boc] + m/z: calculated 251.4; found 252.2; Rt=1.360 min.

步驟2：3-甲基-6-(3-(甲基磺醯基)苯基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 3-methyl-6-(3-(methylsulfonyl)phenyl)-2,3,4,5-tetrahydropyridine

將3-甲基-6-(3-甲基磺醯基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3g，8.54mmol)於三氟乙酸(29.20g，256.08mmol，19.73mL)中之溶液在25℃下攪拌1h。1小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用冰冷水(50mL)稀釋且用10% NaOH水溶液中和，直至pH=10。將所得混合物用二氯甲 烷(2x50mL)萃取。將經合併之有機相經硫酸鈉乾燥且在減壓下濃縮，以得到呈淡黃色膠狀物之3-甲基-6-(3-甲基磺醯基苯基)-2,3,4,5-四氫吡啶(2g，7.96mmol，93.22%產率)。Dissolve 3-methyl-6-(3-methylsulfonylphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3 g, 8.54 mmol) in trifluoroacetic acid (29.20 mmol) g, 256.08 mmol, 19.73 mL) was stirred at 25 °C for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ice-cold water (50 mL) and neutralized with 10% aqueous NaOH until pH=10. The resulting mixture was treated with dichloromethane alkane (2 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 3-methyl-6-(3-methylsulfonylphenyl)-2,3,4 as a pale yellow gum , 5-tetrahydropyridine (2 g, 7.96 mmol, 93.22% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.46(m,1H),1.72(m,1H),1.94(m,1H),2.59(m,1H),2.79(m,1H),3.06(s,3H),3.27(m,1H),4.04(d,1H),7.58(t,1H),7.93(d,1H),8.05(d,1H),8.32(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.46(m,1H), 1.72(m,1H), 1.94(m,1H), 2.59(m,1H), 2.79( m, 1H), 3.06(s, 3H), 3.27(m, 1H), 4.04(d, 1H), 7.58(t, 1H), 7.93(d, 1H), 8.05(d, 1H), 8.32(s , 1H).

LCMS(ESI)：[M]+ m/z：計算值251.4；實測值252.2；Rt=0.584min。LCMS (ESI): [M] + m/z: calculated 251.4; found 252.2; Rt=0.584 min.

步驟3：外消旋-(2R,5S)-5-甲基-2-(3-(甲基磺醯基)苯基)哌啶之合成Step 3: Synthesis of Racemic-(2R,5S)-5-methyl-2-(3-(methylsulfonyl)phenyl)piperidine

在0℃下，向3-甲基-6-(3-甲基磺醯基苯基)-2,3,4,5-四氫吡啶(2g，7.96mmol)於MeOH(50mL)中之經攪拌之溶液中分批添加硼氫化鈉(0.9g，23.79mmol，841.12μL)。將所得反應混合物在0℃下攪拌1h，然後使其升溫至25℃且攪拌12h，且在減壓下濃縮。將殘餘物用水(50mL)稀釋且用二氯甲烷(2 x 50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空下濃縮，以獲得呈淡黃色固體之粗產物(2R,5S )-5-甲基-2-(3-甲基磺醯基苯基)哌啶(1.8g，7.10mmol，89.28%產率)，其直接用於下一步驟中。To 3-methyl-6-(3-methylsulfonylphenyl)-2,3,4,5-tetrahydropyridine (2 g, 7.96 mmol) in MeOH (50 mL) at 0 °C To the stirred solution was added sodium borohydride (0.9 g, 23.79 mmol, 841.12 [mu]L) portionwise. The resulting reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to 25 °C and stirred for 12 h, and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the crude product ( 2R,5S )-5-methyl-2-(3-methylsulfonylphenyl) as a pale yellow solid Piperidine (1.8 g, 7.10 mmol, 89.28% yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.98(d,3H),1.07(m,1H),1.87(m,5H),2.39(m,1H),3.06(s,3H),3.17(d,1H),3.67(d,1H),7.53(t,1H),7.68(d,1H),7.82(d,1H),7.95(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.07(m,1H), 1.87(m,5H), 2.39(m,1H), 3.06(s,3H), 3.17( d, 1H), 3.67 (d, 1H), 7.53 (t, 1H), 7.68 (d, 1H), 7.82 (d, 1H), 7.95 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值253.4；實測值254.2；Rt=0.626min。LCMS (ESI): [M] + m/z: calculated 253.4; found 254.2; Rt=0.626 min.

6II. 外消旋-N -甲基-3-((2R,5S )-5-甲基哌啶-2-基)苯磺醯胺之合成6II. Synthesis of racemic- N -methyl-3-(( 2R,5S )-5-methylpiperidin-2-yl)benzenesulfonamide

Figure 110128222-A0202-12-0814-651
Figure 110128222-A0202-12-0814-651

步驟1：N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯磺醯胺之合成Step 1: Synthesis of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzenesulfonamide

將40% w/w甲胺水溶液(2.71g，34.95mmol，3.02mL，40%純度)添加到3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯磺醯基氟(2g，6.99mmol)於二噁烷(10mL)中之溶液中。將所得混合物在20℃下攪拌15h。然後，在減壓下移除揮發物且將殘餘物用水(15ml)稀釋。藉由過濾收集所得白色沉澱且乾燥，得到N -甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯磺醯胺(1.75g，5.89mmol，84.25%產率)。Aqueous 40% w/w methylamine solution (2.71 g, 34.95 mmol, 3.02 mL, 40% purity) was added to 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborole) A solution of cyclopentan-2-yl)benzenesulfonyl fluoride (2 g, 6.99 mmol) in dioxane (10 mL). The resulting mixture was stirred at 20 °C for 15 h. Then, the volatiles were removed under reduced pressure and the residue was diluted with water (15 ml). The resulting white precipitate was collected by filtration and dried to give N -methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) Besylate (1.75 g, 5.89 mmol, 84.25% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.32(s,12H),2.62(d,3H),4.48(m,1H),7.51(t,1H),7.91(d,1H),7.96(d,1H),8.25(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.32(s, 12H), 2.62(d, 3H), 4.48(m, 1H), 7.51(t, 1H), 7.91(d, 1H), 7.96(d, 1H), 8.25(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值297.4；實測值298.2；Rt=1.323min。LCMS (ESI): [M] + m/z: calculated 297.4; found 298.2; Rt=1.323 min.

步驟2：3-甲基-6-(3-(N-甲基胺磺醯基)苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 2: Synthesis of 3-methyl-6-(3-(N-methylaminosulfonyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將碳酸鈉(1.56g，14.72mmol，616.74μL)添加到N -甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯磺醯胺(1.75g，5.89mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.14g，6.18mmol)於二噁烷(17mL)及水(6.5mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2 dppf*DCM(192.36mg，235.55μmol)。在90℃、惰性氣氛下將所得混合物攪拌15h。然後，將其在減壓下濃縮且將殘餘物用乙酸乙酯 (50ml)萃取。透過短矽膠墊過濾所獲得之溶液且在減壓下蒸發，得到3-甲基-6-[3-(甲基胺磺醯基)苯基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.98g，粗品)。Sodium carbonate (1.56 g, 14.72 mmol, 616.74 μL) was added to N -methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzenesulfonamide (1.75 g, 5.89 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid A solution of tributyl ester (2.14 g, 6.18 mmol) in dioxane (17 mL) and water (6.5 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl 2 dppf*DCM (192.36 mg, 235.55 μmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 15 h. Then, it was concentrated under reduced pressure and the residue was extracted with ethyl acetate (50 ml). The resulting solution was filtered through a short pad of silica gel and evaporated under reduced pressure to give 3-methyl-6-[3-(methylaminosulfonyl)phenyl]-3,4-dihydro- 2H -pyridine- 3-Butyl 1-carboxylate (3.98 g, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.89(d,3H),1.01(s,9H),1.36(m,2H),1.91(m,1H),2.38(d,3H),3.07(m,1H),3.56(m,2H),3.92(m,1H),7.53(m,2H),7.64(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.89(d,3H), 1.01(s,9H), 1.36(m,2H), 1.91(m,1H), 2.38(d,3H), 3.07 (m, 1H), 3.56 (m, 2H), 3.92 (m, 1H), 7.53 (m, 2H), 7.64 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值266.4；實測值267.2；Rt=1.302min。LCMS (ESI): [M-Boc] + m/z: calculated 266.4; found 267.2; Rt=1.302 min.

步驟3：N-甲基-3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯磺醯胺之合成Step 3: Synthesis of N-methyl-3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzenesulfonamide

將三氟乙酸(22.20g，194.70mmol，15mL)添加到3-甲基-6-[3-(甲基胺磺醯基)苯基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.97g，10.83mmol)於DCM(20mL)中之溶液中。將所得混合物在20℃下攪拌2h。然後，在減壓下移除揮發物且將殘餘物用水(40ml)稀釋。透過棉絨墊過濾出不溶性焦油。將濾液用20% K2 CO3 水溶液鹼化至pH

Figure 110128222-A0202-12-0815-677
10-11且用乙酸乙酯(2x25ml)萃取。將經合併之有機層經Na2 SO4 乾燥且在減壓下濃縮，得到N -甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯磺醯胺(1.34g，5.03mmol，46.44%產率)。Trifluoroacetic acid (22.20 g, 194.70 mmol, 15 mL) was added to 3-methyl-6-[3-(methylaminosulfonyl)phenyl]-3,4-dihydro- 2H -pyridine-1- A solution of tert-butyl formate (3.97 g, 10.83 mmol) in DCM (20 mL). The resulting mixture was stirred at 20 °C for 2 h. Then, the volatiles were removed under reduced pressure and the residue was diluted with water (40 ml). The insoluble tar was filtered through a cotton wool pad. The filtrate was basified to pH with 20 % aqueous K2CO3
Figure 110128222-A0202-12-0815-677
10-11 and extracted with ethyl acetate (2x25ml). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to give N -methyl-3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)benzene Sulfonamide (1.34 g, 5.03 mmol, 46.44% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.92(d,3H),1.31(m,1H),1.53(m,1H),1.96(m,1H),2.38(d,3H),2.56(m,1H),2.78(m,1H),3.20(m,1H),3.88(m,1H),7.45(m,1H),7.61(t,1H),7.78(d,1H),7.99(d,1H),8.23(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.92(d,3H), 1.31(m,1H), 1.53(m,1H), 1.96(m,1H), 2.38(d,3H), 2.56(m, 1H), 2.78(m, 1H), 3.20(m, 1H), 3.88(m, 1H), 7.45(m, 1H), 7.61(t, 1H), 7.78(d, 1H), 7.99 (d, 1H), 8.23 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值266.4；實測值267.2；Rt=0.693min。LCMS (ESI): [M] + m/z: calculated 266.4; found 267.2; Rt=0.693 min.

步驟4：外消旋-N-甲基-3-((2R,5S)-5-甲基哌啶-2-基)苯磺醯胺之合成Step 4: Synthesis of Racemic-N-methyl-3-((2R,5S)-5-methylpiperidin-2-yl)benzenesulfonamide

在15分鐘內將硼氫化鈉(285.49mg，7.55mmol，266.82μL)分批添加到N -甲基-3-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯磺醯胺(1.34g，5.03mmol)於MeOH(20mL)中之溶液中。將所得溶液在20℃下攪拌1h。然後，在減壓下移除溶劑且將殘餘物分配於水(20ml)與乙酸乙酯(40ml)之間。將有機層分離，經Na2 SO4 乾燥且在真空中蒸發，得到N -甲基-3-[(2S,5R )-5-甲基-2-哌啶基]苯磺醯胺(1.07g， 3.99mmol，79.25%產率)。Sodium borohydride (285.49 mg, 7.55 mmol, 266.82 μL) was added portionwise to N -methyl-3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl over 15 minutes) ) in a solution of benzenesulfonamide (1.34 g, 5.03 mmol) in MeOH (20 mL). The resulting solution was stirred at 20 °C for 1 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (20ml) and ethyl acetate (40ml). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to give N -methyl-3-[( 2S,5R )-5-methyl-2-piperidinyl]benzenesulfonamide (1.07 g) , 3.99 mmol, 79.25% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.85(d,3H),1.17(m,2H),1.32(m,1H),1.52(m,1H),1.77(m,2H),2.26(m,1H),2.38(d,3H),3.01(m,1H),3.55(t,1H),7.39(m,1H),7.49(t,1H),7.61(m,2H),7.79(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.85(d, 3H), 1.17(m, 2H), 1.32(m, 1H), 1.52(m, 1H), 1.77(m, 2H), 2.26(m, 1H), 2.38(d, 3H), 3.01(m, 1H), 3.55(t, 1H), 7.39(m, 1H), 7.49(t, 1H), 7.61(m, 2H), 7.79 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值268.4；實測值269.2；Rt=0.848min。LCMS (ESI): [M] + m/z: calculated 268.4; found 269.2; Rt=0.848 min.

6JJ.N -甲基-5-(5-甲基哌啶-2-基)苯并[d ]噻唑-2-胺之合成6JJ. Synthesis of N -methyl-5-(5-methylpiperidin-2-yl)benzo[ d ]thiazol-2-amine

Figure 110128222-A0202-12-0816-653
Figure 110128222-A0202-12-0816-653

步驟1：N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-胺之合成Step 1: N-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d]thiazole-2 -Synthesis of amines

將乙酸鉀(8.88g，90.49mmol，5.66mL)添加到5-溴-N -甲基-1,3-苯并噻唑-2-胺(11g，45.24mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(13.21g，52.03mmol)於二噁烷(150mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加Pd(dppf)Cl2 *DCM(1.85g，2.26mmol)。在100℃、惰性氣氛下將所得混合物攪拌28h。然後，將其冷卻，用二噁烷(700mL)稀釋且過濾。在減壓下濃縮濾液且藉由矽膠急驟層析，使用0至100% MTBE-氯仿梯度溶析來純化殘餘物，以得到N -甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-胺(3.5g，12.06mmol，26.66%產率)。Potassium acetate (8.88 g, 90.49 mmol, 5.66 mL) was added to 5-bromo- N -methyl-1,3-benzothiazol-2-amine (11 g, 45.24 mmol) and 4,4,5,5- Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A solution of cyclopentane (13.21 g, 52.03 mmol) in dioxane (150 mL). The reaction flask was evacuated and refilled with argon 3 times. Then Pd(dppf)Cl2*DCM (1.85 g , 2.26 mmol) was added under argon flow. The resulting mixture was stirred at 100 °C under an inert atmosphere for 28 h. It was then cooled, diluted with dioxane (700 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% MTBE-chloroform gradient to give N -methyl-5-(4,4,5,5-tetramethyl) (3.5 g, 12.06 mmol, 26.66% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.29(s,12H),2.96(d,3H),7.32(d,1H),7.58(d,1H),7.65(s,1H),7.89(bds,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.29(s, 12H), 2.96(d, 3H), 7.32(d, 1H), 7.58(d, 1H), 7.65(s, 1H), 7.89 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值290.2；實測值291.2；Rt=1.201min。LCMS (ESI): [M] + m/z: calculated 290.2; found 291.2; Rt=1.201 min.

步驟2：3-甲基-6-(2-(甲胺基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁Step 2: 3-Methyl-6-(2-(methylamino)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl 酯之合成Synthesis of Esters

將6-二苯氧基磷醯氧基-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.76g，9.09mmol)、N -甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-胺(2.9g，9.99mmol)、環戊基(二苯基)磷烷；二氯甲烷；二氯鈀；鐵(370.96mg，454.25μmol)及碳酸鈉(2.89g，27.26mmol，1.14mL)於二噁烷(45mL)及水(15mL)中之混合物在90℃、氬氣氣氛下攪拌24h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(300mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析，以0至100% MTBE-己烷梯度溶析來純化殘餘物，以得到3-甲基-6-[2-(甲胺基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.5g，4.17mmol，45.93%產率)。6-Diphenoxyphosphoryloxy-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4.76 g, 9.09 mmol), N -methyl-5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazol-2-amine (2.9 g, 9.99 mmol ), cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; iron (370.96 mg, 454.25 μmol) and sodium carbonate (2.89 g, 27.26 mmol, 1.14 mL) in dioxane (45 mL) and The mixture in water (15 mL) was stirred at 90 °C under argon atmosphere for 24 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (300 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography with a gradient of 0 to 100% MTBE-hexane to give 3-methyl-6-[2-(methylamino)-1 , 3-Benzothiazol-5-yl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 4.17 mmol, 45.93% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.02(s,9H),1.12(d,3H),1.78(m,1H),1.94(m,1H),2.32(m,1H),2.96(d,3H),3.11(m,1H),3.91(d,1H),5.22(m,1H),6.88(d,1H),7.18(s,1H),7.42(d,1H),7.76(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.02(s, 9H), 1.12(d, 3H), 1.78(m, 1H), 1.94(m, 1H), 2.32(m, 1H), 2.96(d,3H),3.11(m,1H),3.91(d,1H),5.22(m,1H),6.88(d,1H),7.18(s,1H),7.42(d,1H),7.76 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值359.2；實測值360.2；Rt=1.341min。LCMS (ESI): [M] + m/z: calculated 359.2; found 360.2; Rt=1.341 min.

步驟3：N-甲基-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-胺之合成Step 3: Synthesis of N-methyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-amine

將3-甲基-6-[2-(甲胺基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2g，5.56mmol)於TFA(10.15g，89.02mmol，6.86mL)中之溶液在20℃下攪拌1h，然後在真空中蒸發。將碎冰(20g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色膠狀物之N -甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑-2-胺(1.5g，粗品)，其直接用於下一步驟中。3-Methyl-6-[2-(methylamino)-1,3-benzothiazol-5-yl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2 g , 5.56 mmol) in TFA (10.15 g, 89.02 mmol, 6.86 mL) was stirred at 20 °C for 1 h, then evaporated in vacuo. Crushed ice (20 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N -methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine- as a yellow gum) 6-yl)-1,3-benzothiazol-2-amine (1.5 g, crude), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.94(d,3H),1.32(m,1H),1.62(m,1H),1.85(m,1H),2.49(m,1H),2.74(m,1H),2.94(d,3H),3.33(m,1H),4.02(m,1H),7.52(d, 1H),7.64(d,1H),7.77(s,1H),7.96(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.94(d,3H), 1.32(m,1H), 1.62(m,1H), 1.85(m,1H), 2.49(m,1H), 2.74(m, 1H), 2.94(d, 3H), 3.33(m, 1H), 4.02(m, 1H), 7.52(d, 1H), 7.64(d, 1H), 7.77(s, 1H), 7.96 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值259.2；實測值260.2；Rt=0.803min。LCMS (ESI): [M] + m/z: calculated 259.2; found 260.2; Rt=0.803 min.

步驟4：N-甲基-5-(5-甲基哌啶-2-基)苯并[d]噻唑-2-胺之合成Step 4: Synthesis of N-methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazol-2-amine

在0℃下，將硼氫化鈉(328.17mg，8.67mmol，306.70μL)一次性添加到N -甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑-2-胺(1.5g，5.78mmol)於MeOH(40mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用DCM(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之N -甲基-5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(1.5g，5.74mmol，99.23%產率)，其直接用於下一步驟中。Sodium borohydride (328.17 mg, 8.67 mmol, 306.70 μL) was added in one portion to N -methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0 °C yl)-1,3-benzothiazol-2-amine (1.5 g, 5.78 mmol) in a stirred solution of MeOH (40 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with DCM (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N -methyl-5-[( 2R,5S )-5-methyl-2-piperidinyl]-1 as a yellow solid , 3-benzothiazol-2-amine (1.5 g, 5.74 mmol, 99.23% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.84(d,3H),1.07(m,2H),1.34(m,1H),1.51(m,1H),1.70(m,2H),2.26(m,1H),2.91(d,3H),3.00(m,1H),3.47(d,1H),7.00(d,1H),7.36(s,1H),7.54(d,1H),7.85(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.84(d,3H), 1.07(m,2H), 1.34(m,1H), 1.51(m,1H), 1.70(m,2H), 2.26(m, 1H), 2.91(d, 3H), 3.00(m, 1H), 3.47(d, 1H), 7.00(d, 1H), 7.36(s, 1H), 7.54(d, 1H), 7.85 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值261.2；實測值262.2；Rt=0.787min。LCMS (ESI): [M] + m/z: calculated 261.2; found 262.2; Rt=0.787 min.

6KK. 5-(5-甲基-2-哌啶基)-1,3-苯并噻唑之合成6KK. Synthesis of 5-(5-methyl-2-piperidinyl)-1,3-benzothiazole

Figure 110128222-A0202-12-0818-654
Figure 110128222-A0202-12-0818-654

步驟1：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑之合成Step 1: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole

將乙酸鉀(13.75g，140.13mmol，8.76mL)添加到5-溴-1,3-苯并噻唑(15g，70.07mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(20.46g，80.58mmol)於DMSO(100mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2DPPF*CH2Cl2(2.86g，3.50mmol)。在90℃、惰性氣氛下將所得混合物攪拌28h。然後，將其冷卻，用MTBE(100mL)稀釋且用水(2x40mL)洗滌。將有機 層經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟層析，以0至100% CHCl3 -EA梯度溶析來純化殘餘物，以得到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(8.6g，32.93mmol，47.00%產率)。Potassium acetate (13.75 g, 140.13 mmol, 8.76 mL) was added to 5-bromo-1,3-benzothiazole (15 g, 70.07 mmol) and 4,4,5,5-tetramethyl-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (20.46 g, 80.58 mmol ) in DMSO (100 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl2DPPF*CH2Cl2 (2.86 g, 3.50 mmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 28 h. It was then cooled, diluted with MTBE (100 mL) and washed with water (2 x 40 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a gradient of 0 to 100% CHCl3 -EA to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxa Borolin-2-yl)-1,3-benzothiazole (8.6 g, 32.93 mmol, 47.00% yield).

1 H NMR(CDCl3 ,400MHz)：δ 1.36(s,12H),7.82(d,1H),7.94(d,1H),8.57(s,1H),8.98(s,1H) 1 H NMR (CDCl 3 , 400MHz): δ 1.36(s,12H), 7.82(d,1H), 7.94(d,1H), 8.57(s,1H), 8.98(s,1H)

LCMS(ESI)：[M+H]+ m/z：計算值261.1；實測值261.2；Rt=1.375min。LCMS (ESI): [M+H] + m/z: calculated 261.1; found 261.2; Rt=1.375 min.

步驟2：6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(1,3-benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.72g，22.36mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(7.3g，27.95mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(913.12mg，1.12mmol)及碳酸鈉(7.11g，67.09mmol，2.81mL)於二噁烷(120mL)及水(40mL)中之混合物在80℃、氬氣氣氛下攪拌18h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(500mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析，以0至100% MTBE-己烷梯度溶析來純化殘餘物，以得到6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.9g，17.85mmol，79.84%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.72 g, 22.36 mmol), 5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazole (7.3g, 27.95mmol), [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (913.12 mg, 1.12 mmol) and sodium carbonate (7.11 g, 67.09 mmol, 2.81 mL) in dioxane A mixture of alkane (120 mL) and water (40 mL) was stirred at 80 °C under argon atmosphere for 18 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (500 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography with a 0 to 100% MTBE-hexane gradient to give 6-(1,3-benzothiazol-5-yl)-3 - Methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.9 g, 17.85 mmol, 79.84% yield).

1 H NMR(DMSO-d6,500MHz)：δ 0.95-1.03(m,12H),1.86(m,1H),1.90(s,1H),2.50(m,1H),3.0(t,1H),3.97(d,1H),5.41(s,1H),7.37(d,1H),7.78(s,1H),7.99(d,1H),9.27(s,1H)。 1 H NMR (DMSO-d6, 500MHz): δ 0.95-1.03(m, 12H), 1.86(m, 1H), 1.90(s, 1H), 2.50(m, 1H), 3.0(t, 1H), 3.97 (d, 1H), 5.41 (s, 1H), 7.37 (d, 1H), 7.78 (s, 1H), 7.99 (d, 1H), 9.27 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值330.2；實測值331.2；Rt=1.435min。LCMS (ESI): [M+H] + m/z: calculated 330.2; found 331.2; Rt=1.435 min.

步驟3：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑之合成Step 3: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole

將6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.9g，17.85mmol)於TFA(32.57g，285.68mmol，22.01mL)中之溶液在20℃下攪拌1h，然後在真空中蒸發。將碎冰(10g)添加到殘餘物中且用10%氫氧化鈉水 溶液將pH調節至8。將所得混合物用乙酸乙酯(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(4.1g，17.80mmol，99.70%產率)，其直接用於下一步驟中。6-(1,3-Benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.9 g, 17.85 mmol) was dissolved in TFA ( The solution in 32.57 g, 285.68 mmol, 22.01 mL) was stirred at 20 °C for 1 h, then evaporated in vacuo. Crushed ice (10 g) was added to the residue and washed with 10% aqueous sodium hydroxide The pH of the solution was adjusted to 8. The resulting mixture was extracted with ethyl acetate (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1 as a yellow solid, 3-benzothiazole (4.1 g, 17.80 mmol, 99.70% yield) was used directly in the next step.

1 H NMR(DMSO-d6,500MHz)：δ 0.95(m,3H),1.35(m,1H),1.65(m,1H),1.89(m,1H),2.67(m,1H),2.87(d,1H),3.19(t,1H),3.95(d,1H),8.02(d,1H),8.14(d,1H),8.43(s,1H),9.41(s,1H)。 1 H NMR (DMSO-d6, 500MHz): δ 0.95(m, 3H), 1.35(m, 1H), 1.65(m, 1H), 1.89(m, 1H), 2.67(m, 1H), 2.87(d , 1H), 3.19(t, 1H), 3.95(d, 1H), 8.02(d, 1H), 8.14(d, 1H), 8.43(s, 1H), 9.41(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值230.1；實測值231.2；Rt=0.828min。LCMS (ESI): [M+H] + m/z: calculated 230.1; found 231.2; Rt=0.828 min.

步驟4：5-(5-甲基-2-哌啶基)-1,3-苯并噻唑之合成Step 4: Synthesis of 5-(5-Methyl-2-piperidinyl)-1,3-benzothiazole

在0℃下，將硼氫化鈉(1.01g，26.70mmol，944.02μL)一次性添加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(4.1g，17.80mmol)於甲醇(90mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(50mL)稀釋且用二氯甲烷(2*75mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色油狀物之5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(4.1g，17.65mmol，99.13%產率)，其直接用於下一步驟中。Sodium borohydride (1.01 g, 26.70 mmol, 944.02 μL) was added in one portion to 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1 at 0 °C, In a stirred solution of 3-benzothiazole (4.1 g, 17.80 mmol) in methanol (90 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (50 mL) and extracted with dichloromethane (2*75 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (4.1 g) as a yellow oil , 17.65 mmol, 99.13% yield), which was used directly in the next step.

1 H NMR(DMSO-d6,400MHz)：δ 0.82(d,3H),1.05(m,1H),1.34(m,1H),1.52(m,1H),1.75(m,2H),2.26(t,1H),3.00(d,1H),3.61(d,1H),7.46(d,1H),8.03(m,2H),9.31(s,1H)。 1 H NMR (DMSO-d6, 400MHz): δ 0.82(d,3H), 1.05(m,1H), 1.34(m,1H), 1.52(m,1H), 1.75(m,2H), 2.26(t , 1H), 3.00 (d, 1H), 3.61 (d, 1H), 7.46 (d, 1H), 8.03 (m, 2H), 9.31 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值232.1；實測值233.0；Rt=0.691min。LCMS (ESI): [M+H] + m/z: calculated 232.1; found 233.0; Rt=0.691 min.

6LL. 5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成6LL. Synthesis of 5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole

Figure 110128222-A0202-12-0821-655
Figure 110128222-A0202-12-0821-655

步驟1. (3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1. Synthesis of (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

在氬氣下，將雙(三甲基矽基)醯胺化鋰(102.00g，121.91mmol，113.33mL，20%純度)(1.08M於THF/乙苯中)逐滴添加到冷卻至-78℃之(5S)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(20g，93.78mmol)於THF(200mL)中之溶液中達0.5h。將所得溶液在-78℃下攪拌1.5h，然後一次性添加1,1,1-三氟-N-苯基-N-(三氟甲基磺醯基)甲磺醯胺(41.88g，117.22mmol)。使反應混合物緩慢升溫(不移除冷卻浴！)至25℃且攪拌12h，然後用水(50ml)及MTBE(250ml)稀釋。將有機層分離，另外用MTBE(50ml)萃取水層。將經合併之有機萃取物用10%氫氧化鈉水溶液(3*15ml)洗滌，經碳酸鉀乾燥，且在真空中濃縮。將殘餘物用己烷/MTBE混合物稀釋(3/1,200mL，重複8次)且攪拌0.5h。將所得混濁溶液自油狀殘餘物傾析，透過短矽膠墊(40ml無水矽膠)過濾且在真空中蒸發，以得到呈淡黃色油狀物之粗品(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(32g，92.66mmol，98.81%產率)，其直接用於下一步驟中。Under argon, lithium bis(trimethylsilyl)amide (102.00 g, 121.91 mmol, 113.33 mL, 20% purity) (1.08 M in THF/ethylbenzene) was added dropwise to a cooled to -78 A solution of (5S)-tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (20 g, 93.78 mmol) in THF (200 mL) at °C for 0.5 h. The resulting solution was stirred at -78 °C for 1.5 h, then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (41.88 g, 117.22 g) was added in one portion mmol). The reaction mixture was slowly warmed (without removing the cooling bath!) to 25°C and stirred for 12h, then diluted with water (50ml) and MTBE (250ml). The organic layer was separated and the aqueous layer was additionally extracted with MTBE (50 ml). The combined organic extracts were washed with 10% aqueous sodium hydroxide solution (3*15ml), dried over potassium carbonate and concentrated in vacuo. The residue was diluted with a hexane/MTBE mixture (3/1, 200 mL, repeated 8 times) and stirred for 0.5 h. The resulting cloudy solution was decanted from the oily residue, filtered through a short pad of silica gel (40 ml of anhydrous silica) and evaporated in vacuo to give crude (3S)-3-methyl-6-( Trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (32 g, 92.66 mmol, 98.81% yield) was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.99(d,1H),1.49(s,9H),1.80-1.90(m,2H),2.40(m,1H),2.99(dd,1H),3.88(d,1H),5.25(t,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.99(d, 1H), 1.49(s, 9H), 1.80-1.90(m, 2H), 2.40(m, 1H), 2.99(dd, 1H), 3.88(d, 1H), 5.25(t, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值345.0；實測值290.0；Rt=1.710min。LCMS (ESI): [M-tBu] + m/z: calculated 345.0; found 290.0; Rt=1.710 min.

步驟2. (3S)-6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之Step 2. (3S)-6-(1,3-benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 合成synthesis

將(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(32g，83.40mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(23.96g，91.74mmol)、環戊基(二苯基)磷烷；二氯甲烷；二氯鈀；鐵(3.41g，4.17mmol)及碳酸鈉(26.52g，250.19mmol，10.48mL)於二噁烷(525mL)及水(175mL)中之混合物在90℃、氬氣氣氛下攪拌18h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(300mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析，使用0至100%己烷-MTBE梯度溶析來純化殘餘物，以得到(3S)-6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(14g，42.37mmol，50.80%產率)。Combine (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (32 g, 83.40 mmol), 5 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazole (23.96 g, 91.74 mmol), cyclo Amyl(diphenyl)phosphine; dichloromethane; dichloropalladium; iron (3.41 g, 4.17 mmol) and sodium carbonate (26.52 g, 250.19 mmol, 10.48 mL) in dioxane (525 mL) and water (175 mL) ) was stirred at 90 °C under argon atmosphere for 18 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (300 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% hexane-MTBE gradient to give (3S)-6-(1,3-benzothiazole-5- yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (14 g, 42.37 mmol, 50.80% yield).

1 H NMR(CDCl3 ,500MHz)：δ 1.03(s,9H),1.35(m,1H),1.92(m,1H),2.05(m,1H),2.42(m,1H),3.03(t,1H),4.13(d,1H),5.42(s,1H),7.26(d,1H),7.42(d,1H),8.07(s,1H),8.98(s,1H)。 1 H NMR (CDCl 3 , 500MHz): δ 1.03 (s, 9H), 1.35 (m, 1H), 1.92 (m, 1H), 2.05 (m, 1H), 2.42 (m, 1H), 3.03 (t, 1H), 4.13(d, 1H), 5.42(s, 1H), 7.26(d, 1H), 7.42(d, 1H), 8.07(s, 1H), 8.98(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值330.1；實測值331.2；Rt=1.596min。LCMS (ESI): [M+H] + m/z: calculated 330.1; found 331.2; Rt=1.596 min.

步驟3. 5-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑之合成Step 3. Synthesis of 5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole

將(3S)-6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(14.35g，43.43mmol)於TFA(79.22g，694.82mmol，53.53mL)中之溶液在20℃下攪拌1h，然後在真空中蒸發。將碎冰(70g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*100mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之5-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑(10g，43.42mmol，99.98%產率)，其直接用於下一步驟中。(3S)-6-(1,3-benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (14.35 g, 43.43 mmol ) in TFA (79.22 g, 694.82 mmol, 53.53 mL) was stirred at 20 °C for 1 h, then evaporated in vacuo. Crushed ice (70 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate (2*100 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl as a yellow solid ]-1,3-benzothiazole (10 g, 43.42 mmol, 99.98% yield), which was used directly in the next step.

1 H NMR(DMSO-d6,500MHz)：δ 0.95(m,3H),1.35(m,1H),1.65(m,1H),1.89(m,1H),2.67(m,1H),2.87(d,1H),3.19(t,1H),3.95(d,1H),8.02(d,1H),8.14(d,1H), 8.43(s,1H),9.41(s,1H)。 1 H NMR (DMSO-d6, 500MHz): δ 0.95(m, 3H), 1.35(m, 1H), 1.65(m, 1H), 1.89(m, 1H), 2.67(m, 1H), 2.87(d , 1H), 3.19(t, 1H), 3.95(d, 1H), 8.02(d, 1H), 8.14(d, 1H), 8.43(s, 1H), 9.41(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值230.1；實測值231.2；Rt=0.828min。LCMS (ESI): [M+H] + m/z: calculated 230.1; found 231.2; Rt=0.828 min.

步驟4. 5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 4. Synthesis of 5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole

在0℃下，將硼氫化鈉(2.46g，65.12mmol，2.30mL)一次性添加到5-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑(10.00g，43.42mmol)於甲醇(200mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(100mL)稀釋且用二氯甲烷(2*80mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色油狀物之5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(10g，43.04mmol，99.13%產率)，其直接用於下一步驟中。Sodium borohydride (2.46 g, 65.12 mmol, 2.30 mL) was added in one portion to 5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl at 0 °C ]-1,3-benzothiazole (10.00 g, 43.42 mmol) in a stirred solution of methanol (200 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (100 mL) and extracted with dichloromethane (2*80 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3- as a yellow oil Benzothiazole (10 g, 43.04 mmol, 99.13% yield) was used directly in the next step.

1 H NMR(DMSO-d6,400MHz)：δ 0.91(d,3H),1.18(m,1H),1.30-1.60(m,6H),2.47(t,1H),3.17(d,1H),3.73(d,1H),7.52(d,1H),7.88(d,1H),8.12(s,1H),8.98(s,1H)。 1 H NMR (DMSO-d6, 400MHz): δ 0.91(d,3H), 1.18(m,1H), 1.30-1.60(m,6H), 2.47(t,1H), 3.17(d,1H), 3.73 (d, 1H), 7.52 (d, 1H), 7.88 (d, 1H), 8.12 (s, 1H), 8.98 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值232.1；實測值233.0；Rt=0.691min。LCMS (ESI): [M+H] + m/z: calculated 232.1; found 233.0; Rt=0.691 min.

6MM. 2-(4,4-二氟環己基)哌啶之合成6MM. Synthesis of 2-(4,4-difluorocyclohexyl)piperidine

Figure 110128222-A0202-12-0823-656
Figure 110128222-A0202-12-0823-656

步驟1：6-(4,4-二氟環己烯-1-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(4,4-difluorocyclohexen-1-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(8g，24.15mmol)、2-(4,4-二氟環己烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(6.48g，26.56mmol)及碳酸鈉(5.12g，48.29mmol，2.02mL)於1,4-二噁烷(75mL)及水(25mL)中之正攪拌溶液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 (985.95mg，1.21mmol)。將反應混合物在氬氣、75℃下攪拌18小時。18小時之後，將反應混合物過濾。將濾餅用1.4-二噁烷(2 x 25mL)洗滌且丟棄。在真空中蒸發濾 液且將殘餘物溶解於水(100mL)及MTBE(150mL)之混合物中。分離有機層。將水層用MTBE(100mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下蒸發。藉由管柱層析純化殘餘物以獲得呈黃色油狀物之6-(4,4-二氟環己烯-1-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.40g，11.36mmol，47.04%產率)。6-(Trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (8 g, 24.15 mmol), 2-(4,4-difluoro Cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.48g, 26.56mmol) and sodium carbonate (5.12g, 48.29g) mmol, 2.02 mL) in 1,4-dioxane (75 mL) and water (25 mL) under stirring with argon purged. Then, Pd(dppf)Cl2 ( 985.95 mg, 1.21 mmol) was added under argon. The reaction mixture was stirred under argon at 75°C for 18 hours. After 18 hours, the reaction mixture was filtered. The filter cake was washed with 1.4-dioxane (2 x 25 mL) and discarded. The filtrate was evaporated in vacuo and the residue was dissolved in a mixture of water (100 mL) and MTBE (150 mL). The organic layer was separated. The aqueous layer was extracted with MTBE (100 mL). The combined organic layers were dried over Na2SO4 , filtered and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 6-(4,4-difluorocyclohexen-1-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid as a yellow oil Tertiary butyl ester (3.40 g, 11.36 mmol, 47.04% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值299.2；實測值244.0(t -Bu裂解之產物質量)；Rt=1.668min。LCMS (ESI): [M+Boc] + m/z: calculated 299.2; found 244.0 ( t -Bu cleavage product mass); Rt=1.668 min.

步驟2：2-(4,4-二氟環己基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-butyl 2-(4,4-difluorocyclohexyl)piperidine-1-carboxylate

將6-(4,4-二氟環己烯-1-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.40g，11.36mmol)於甲醇(120mL)中之溶液在487型鈀(10%於碳上)(483.48mg，4.54mmol)上在氫氣氣氛(30atm)、室溫下氫化48小時。完成之後，過濾反應混合物且在減壓下蒸發濾液，以得到呈淡黃色膠狀物之2-(4,4-二氟環己基)哌啶-1-甲酸第三丁酯(2.83g，9.33mmol，82.13%產率)。粗產物直接用於下一步驟。6-(4,4-Difluorocyclohexen-1-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.40 g, 11.36 mmol) in methanol (120 mL) The solution was hydrogenated over palladium Form 487 (10% on carbon) (483.48 mg, 4.54 mmol) under a hydrogen atmosphere (30 atm) at room temperature for 48 hours. After completion, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give tert-butyl 2-(4,4-difluorocyclohexyl)piperidine-1-carboxylate (2.83 g, 9.33 g) as a pale yellow gum mmol, 82.13% yield). The crude product was used directly in the next step.

GCMS：m/z：計算值303.2；實測值246.1；Rt=9.752minGCMS: m/z: Calculated 303.2; Measured 246.1; Rt=9.752min

步驟3：2-(4,4-二氟環己基)哌啶之合成Step 3: Synthesis of 2-(4,4-Difluorocyclohexyl)piperidine

向2-(4,4-二氟環己基)哌啶-1-甲酸第三丁酯(2.83g，9.33mmol)於MTBE(50mL)中之經攪拌之溶液中添加於二噁烷中之4.0M HCl(1.36g，37.31mmol，1.70mL)。將所得反應混合物在室溫下攪拌隔夜。然後在減壓下濃縮反應混合物。LCMS指示反應無進展。將殘餘物溶解於MeOH(15mL)中且添加於二噁烷中之4.0M HCl(15mL)。將所得反應混合物攪拌2小時，然後在減壓下濃縮，以獲得呈紅色膠狀物之2-(4,4-二氟環己基)哌啶(2.6g，粗品，HCl)。粗產物不經任何進一步純化即用於下一步反應。To a stirred solution of 3-butyl 2-(4,4-difluorocyclohexyl)piperidine-1-carboxylate (2.83 g, 9.33 mmol) in MTBE (50 mL) was added 4.0 mol in dioxane M HCl (1.36 g, 37.31 mmol, 1.70 mL). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. LCMS indicated no progress of the reaction. The residue was dissolved in MeOH (15 mL) and 4.0 M HCl in dioxane (15 mL) was added. The resulting reaction mixture was stirred for 2 hours, then concentrated under reduced pressure to give 2-(4,4-difluorocyclohexyl)piperidine (2.6 g, crude, HCl) as a red gum. The crude product was used in the next reaction without any further purification.

6NN. 2-(苯并噻吩-3-基)-5-甲基哌啶之合成6NN. Synthesis of 2-(benzothiophen-3-yl)-5-methylpiperidine

Figure 110128222-A0202-12-0825-657
Figure 110128222-A0202-12-0825-657

步驟1：6-(苯并噻吩-3-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(benzothiophen-3-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8g，20.85mmol)、苯并噻吩-3-基硼酸(4.45g，25.02mmol)及碳酸鈉(7.29g，68.80mmol，2.88mL)添加到1,4-二噁烷(100mL)及水(30mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2* DCM(851.32mg，1.04mmol)。將反應混合物在氬氣、90℃下攪拌18h，然後冷卻且過濾。將濾餅用二噁烷(2* 30mL)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用己烷/MTBE梯度(0-100% MTBE)純化殘餘物，以得到呈紅色膠狀物之6-(苯并噻吩-3-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.2g，12.75mmol，61.14%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8 g, 20.85 mmol), benzothiophene-3 Boronic acid (4.45 g, 25.02 mmol) and sodium carbonate (7.29 g, 68.80 mmol, 2.88 mL) were added to a mixture of 1,4-dioxane (100 mL) and water (30 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2 * DCM (851.32 mg, 1.04 mmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 18 h, then cooled and filtered. The filter cake was washed with dioxane (2 * 30 mL) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) to give 6-(benzothiophen-3-yl as a red gum )-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.2 g, 12.75 mmol, 61.14% yield).

1 H NMR(500MHz,CDCl3 )δ 0.87(s,9H),1.22(m,3H),1.90(m,1H),2.10(m,1H),2.44(m,1H),3.13(m,1H),4.19(m,1H),5.38(m,1H),7.22(s,1H),7.35(m,2H),7.80(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ 0.87(s, 9H), 1.22(m, 3H), 1.90(m, 1H), 2.10(m, 1H), 2.44(m, 1H), 3.13(m, 1H) ), 4.19(m, 1H), 5.38(m, 1H), 7.22(s, 1H), 7.35(m, 2H), 7.80(m, 2H).

LCMS(ESI)：[M-t -Bu]+ m/z：計算值273.0；實測值274.1；Rt=1.608min。LCMS (ESI): [M- t -Bu] + m/z: calculated 273.0; found 274.1; Rt=1.608 min.

步驟2：6-(苯并噻吩-3-基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(benzothiophen-3-yl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(苯并噻吩-3-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.20g，12.75mmol)於三氟乙酸(29.60g，259.60mmol，20mL)中之混合物在25℃下攪拌1h。1小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用冰冷水(50mL)稀釋且用10% NaOH水溶液中和，直至pH 10。將所得懸浮液用二氯甲烷(3* 30mL)萃取。將經合併之有機相用水(30mL)洗滌，經硫酸鈉乾燥，過濾且在減壓下濃縮，以獲得呈灰白色固體之產物6-(苯并噻吩-3-基)-3-甲基-2,3,4,5-四氫吡啶 (2.20g，9.59mmol，75.25%產率)。將粗產物用於下一步驟反應中。Dissolve 6-(benzothiophen-3-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.20 g, 12.75 mmol) in trifluoroacetic acid (29.60 g) , 259.60 mmol, 20 mL) was stirred at 25 °C for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ice-cold water (50 mL) and neutralized with 10% aqueous NaOH until pH 10. The resulting suspension was extracted with dichloromethane (3 * 30 mL). The combined organic phases were washed with water (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product 6-(benzothiophen-3-yl)-3-methyl-2 as an off-white solid , 3,4,5-tetrahydropyridine (2.20 g, 9.59 mmol, 75.25% yield). The crude product was used in the next step reaction.

1 H NMR(400MHz,CDCl3 )δ 1.04(m,3H),1.44(m,1H),1.79(m,1H),1.95(m,1H),2.68(m,1H),2.85(m,1H),3.36(m,1H),4.10(d,1H),7.40(m,2H),7.71(s,1H),7.84(d,1H),8.80(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.04(m,3H), 1.44(m,1H), 1.79(m,1H), 1.95(m,1H), 2.68(m,1H), 2.85(m,1H) ), 3.36(m, 1H), 4.10(d, 1H), 7.40(m, 2H), 7.71(s, 1H), 7.84(d, 1H), 8.80(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值229.1；實測值230.2；Rt=0.839min。LCMS (ESI): [M+H] + m/z: calculated 229.1; found 230.2; Rt=0.839 min.

步驟3：2-(苯并噻吩-3-基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(benzothiophen-3-yl)-5-methylpiperidine

在0℃下，向6-(苯并噻吩-3-基)-3-甲基-2,3,4,5-四氫吡啶(2.20g，9.59mmol)於甲醇(60mL)中之經攪拌之溶液中分批添加硼氫化鈉(544.38mg，14.39mmol)。將所得反應混合物在同一溫度下攪拌2h。然後，在減壓下濃縮反應混合物，以獲得紅色膠狀殘餘物。將所獲得之殘餘物用水(30mL)稀釋且用二氯甲烷(3* 30mL)萃取。將經合併之有機相用水(30mL)洗滌，經硫酸鈉乾燥，過濾且在真空下濃縮，以獲得呈紅色膠狀物之粗產物2-(苯并噻吩-3-基)-5-甲基哌啶(2.20g，粗品)。將粗產物用於下一步驟反應中。粗產物含有約10-11%順式雜質。To a stirred solution of 6-(benzothiophen-3-yl)-3-methyl-2,3,4,5-tetrahydropyridine (2.20 g, 9.59 mmol) in methanol (60 mL) at 0 °C To this solution was added sodium borohydride (544.38 mg, 14.39 mmol) portionwise. The resulting reaction mixture was stirred at the same temperature for 2 h. Then, the reaction mixture was concentrated under reduced pressure to obtain a red gummy residue. The obtained residue was diluted with water (30 mL) and extracted with dichloromethane (3 * 30 mL). The combined organic phases were washed with water (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford crude 2-(benzothiophen-3-yl)-5-methyl as a red gum Piperidine (2.20 g, crude). The crude product was used in the next step reaction. The crude product contains about 10-11% cis impurities.

1 H NMR(400MHz,CDCl3 )δ 0.94(m,3H),1.30(m,1H),1.69(m,2H),1.73(m,2H),2.01(m,1H),2.61(m,1H),3.21(m,1H),3.98(m,1H),7.36(m,3H),7.87(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ 0.94 (m, 3H), 1.30 (m, 1H), 1.69 (m, 2H), 1.73 (m, 2H), 2.01 (m, 1H), 2.61 (m, 1H) ), 3.21 (m, 1H), 3.98 (m, 1H), 7.36 (m, 3H), 7.87 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值231.1；實測值232.2；Rt=0.977minLCMS(ESI): [M+H] + m/z: Calculated 231.1; Found 232.2; Rt=0.977min

6OO. 3-(5-甲基-2-哌啶基)環己醇之合成600. The synthesis of 3-(5-methyl-2-piperidinyl) cyclohexanol

Figure 110128222-A0202-12-0826-658
Figure 110128222-A0202-12-0826-658

步驟1：3-甲基-6-(3-側氧基環己烯-1-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合Step 1: The combination of 3-methyl-6-(3-oxycyclohexen-1-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 成to make

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(16.5g，47.78mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-2-烯-1-酮(10.61g，47.78mmol)及碳酸鈉(15.19g，143.34mmol，6.00mL)添加到1,4-二噁烷(180mL)及水(60mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2* DCM(1.56g，1.91mmol)。將反應混合物在氬氣、90℃下攪拌18h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用己烷/MTBE梯度(5-100% MTBE)純化殘餘物，以得到呈淡黃色膠狀物之3-甲基-6-(3-側氧基環己烯-1-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9g，30.89mmol，64.64%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (16.5 g, 47.78 mmol), 3-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-2-en-1-one (10.61g, 47.78mmol) and sodium carbonate (15.19 g, 143.34 mmol, 6.00 mL) was added to a mixture of 1,4-dioxane (180 mL) and water (60 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2 * DCM (1.56 g, 1.91 mmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 18 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/MTBE gradient (5-100% MTBE) to give 3-methyl-6-(3-methyl-6-(3) as a pale yellow gum - Pendant oxycyclohexen-1-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9 g, 30.89 mmol, 64.64% yield).

1 H NMR(400MHz,CDCl3 )δ 0.99(d,3H),1.42(s,9H),1.80(m,1H),2.02(m,3H),2.39(m,2H),2.86(m,3H),2.89(m,1H),3.92(m,1H),5.51(m,1H),6.06(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.99(d,3H), 1.42(s,9H), 1.80(m,1H), 2.02(m,3H), 2.39(m,2H), 2.86(m,3H) ), 2.89(m, 1H), 3.92(m, 1H), 5.51(m, 1H), 6.06(s, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值235.2；實測值236.2；Rt=1.358min。LCMS (ESI): [M-tBu] + m/z: calculated 235.2; found 236.2; Rt=1.358 min.

步驟2：3-(3-甲基-2,3,4,5-四氫吡啶-6-基)環己-2-烯-1-酮之合成Step 2: Synthesis of 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)cyclohex-2-en-1-one

在25℃下，將三氟乙酸(150g，1.32mol，101.35mL)添加到3-甲基-6-(3-側氧基環己烯-1-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9g，30.89mmol)中。將所得反應混合物在25℃下攪拌1h，然後在真空中蒸發，以得到呈橙色膠狀物之粗品3-(3-甲基-2,3,4,5-四氫吡啶-6-基)環己-2-烯-1-酮(15g，粗品)，其直接用於下一步驟中。Trifluoroacetic acid (150 g, 1.32 mol, 101.35 mL) was added to 3-methyl-6-(3-oxycyclohexen-1-yl)-3,4-dihydro-2H at 25 °C - in tert-butyl pyridine-1-carboxylate (9 g, 30.89 mmol). The resulting reaction mixture was stirred at 25°C for 1 h, then evaporated in vacuo to give crude 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) as an orange gum Cyclohex-2-en-1-one (15 g, crude), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ 1.11(s,3H),1.56(m,1H),2.11(m,4H),3.16(m,4H),3.36(m,1H),3.38(m,1H),3.40(m,1H),4.01(m,1H),6.73(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.11(s,3H), 1.56(m,1H), 2.11(m,4H), 3.16(m,4H), 3.36(m,1H), 3.38(m,1H) ), 3.40(m, 1H), 4.01(m, 1H), 6.73(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值191.1；實測值192.2；Rt=0.535min。LCMS (ESI): [M+H] + m/z: calculated 191.1; found 192.2; Rt=0.535 min.

步驟3：3-(5-甲基-2-哌啶基)環己-2-烯-1-醇之合成Step 3: Synthesis of 3-(5-methyl-2-piperidinyl)cyclohex-2-en-1-ol

在0℃下，在0.2h內，將硼氫化鈉(6g，158.60mmol，5.61mL)分批添加到3-(3-甲基-2,3,4,5-四氫吡啶-6-基)環己-2-烯-1-酮(15g，78.42mmol)於DME(300mL)中之經攪拌之溶液中。將反應混合物在0℃下攪拌2h，然後在0℃下緩慢添加甲醇(100mL)以淬滅反應物(起泡！)。使所得混合物升溫至25℃，攪拌0.5h，然後在真空中蒸發。將殘餘物用水(200ml)稀釋且用10%氫氧化鈉水溶液將pH調節至10。將所得混濁溶液用二氯甲烷(2* 150ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。將殘餘物用100ml MTBE再蒸發，以得到呈淡黃色泡沫之粗品3-(5-甲基-2-哌啶基)環己-2-烯-1-醇(4.5g，23.04mmol，29.38%產率)，其直接用於下一步驟中。Sodium borohydride (6 g, 158.60 mmol, 5.61 mL) was added portionwise to 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) at 0 °C over 0.2 h ) in a stirred solution of cyclohex-2-en-1-one (15 g, 78.42 mmol) in DME (300 mL). The reaction mixture was stirred at 0 °C for 2 h, then methanol (100 mL) was slowly added at 0 °C to quench the reaction (foaming!). The resulting mixture was warmed to 25 °C, stirred for 0.5 h, then evaporated in vacuo. The residue was diluted with water (200 ml) and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting cloudy solution was extracted with dichloromethane (2 * 150ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was re-evaporated with 100 ml of MTBE to give crude 3-(5-methyl-2-piperidinyl)cyclohex-2-en-1-ol (4.5 g, 23.04 mmol, 29.38%) as a pale yellow foam yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ 0.91(m,3H),1.77(m,10H),1.79(m,1H),2.35(m,1H),3.29(m,1H),4.16(m,1H),5.71(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.91 (m, 3H), 1.77 (m, 10H), 1.79 (m, 1H), 2.35 (m, 1H), 3.29 (m, 1H), 4.16 (m, 1H) ), 5.71(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值195.2；實測值196.2；Rt=0.327min。LCMS (ESI): [M+H] + m/z: calculated 195.2; found 196.2; Rt=0.327 min.

步驟4：3-(5-甲基-2-哌啶基)環己醇之合成Step 4: Synthesis of 3-(5-methyl-2-piperidinyl)cyclohexanol

將3-(5-甲基-2-哌啶基)環己-2-烯-1-醇(4.5g，23.04mmol)及鈀(10%於碳上)(0.5g，23.04mmol)於甲醇(100mL)中之混合物在氫氣氣氛、42℃下攪拌48h。過濾出催化劑，在真空中蒸發濾液，以得到呈淡黃色膠狀物之3-(5-甲基-2-哌啶基)環己醇(4g，20.27mmol，87.98%產率)，其直接用於下一步驟中。3-(5-Methyl-2-piperidinyl)cyclohex-2-en-1-ol (4.5 g, 23.04 mmol) and palladium (10% on carbon) (0.5 g, 23.04 mmol) in methanol The mixture in (100 mL) was stirred under a hydrogen atmosphere at 42 °C for 48 h. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 3-(5-methyl-2-piperidinyl)cyclohexanol (4 g, 20.27 mmol, 87.98% yield) as a pale yellow gum which was directly used in the next step.

1 H NMR(400MHz,CDCl3 )δ 0.95(d,3H),1.14(m,6H),1.68(m,5H),1.93(m,2H),2.21(m,2H),3.01(m,1H),3.54(m,1H),4.08(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.95(d,3H), 1.14(m,6H), 1.68(m,5H), 1.93(m,2H), 2.21(m,2H), 3.01(m,1H) ), 3.54 (m, 1H), 4.08 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值197.2；實測值198.2；Rt=0.512min。LCMS (ESI): [M+H] + m/z: calculated 197.2; found 198.2; Rt=0.512 min.

6PP. 2-甲氧基-4-(5-甲基-2-哌啶基)吡啶之合成6PP. Synthesis of 2-methoxy-4-(5-methyl-2-piperidinyl)pyridine

Figure 110128222-A0202-12-0828-659
Figure 110128222-A0202-12-0828-659

步驟1：6-(2-甲氧基-4-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(2-Methoxy-4-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5g，14.48mmol)、(2-甲氧基-4-吡啶基)硼酸(2.21g，14.48mmol)及碳酸鈉(4.60g，43.44mmol，1.82mL)添加到水(15mL)及二噁烷(45mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)2Cl2*DCM(723.93μmol)。將反應混合物在氬氣、70℃下攪拌16h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之6-(2-甲氧基-4-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3g，9.86mmol，68.07%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 g, 14.48 mmol), (2-methoxy yl-4-pyridyl)boronic acid (2.21 g, 14.48 mmol) and sodium carbonate (4.60 g, 43.44 mmol, 1.82 mL) were added to a mixture of water (15 mL) and dioxane (45 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)2Cl2*DCM (723.93 μmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 16 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 6-(2-methoxy-4-pyridinyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid as a brown oil Butyl ester (3 g, 9.86 mmol, 68.07% yield) was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值304.2；實測值305.2；Rt=1.437min。LCMS (ESI): [M+H] + m/z: calculated 304.2; found 305.2; Rt=1.437 min.

步驟2：2-甲氧基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶之合成Step 2: Synthesis of 2-methoxy-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine

將6-(2-甲氧基-4-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3g，9.86mmol)於TFA(11.24g，98.56mmol，7.59mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之2-甲氧基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(2g，9.79mmol，99.34%產率)，其直接用於下一步驟中。Dissolve 6-(2-methoxy-4-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3 g, 9.86 mmol) in TFA (11.24 g) , 98.56 mmol, 7.59 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-methoxy-4-(3-methyl-2,3,4,5-tetrahydropyridine-6 as a brown solid -yl)pyridine (2 g, 9.79 mmol, 99.34% yield), which was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值206.2；實測值207.2；Rt=0.628min。LCMS (ESI): [M+H] + m/z: calculated 206.2; found 207.2; Rt=0.628 min.

步驟3：2-甲氧基-4-(5-甲基-2-哌啶基)吡啶之合成Step 3: Synthesis of 2-methoxy-4-(5-methyl-2-piperidinyl)pyridine

在0℃下，將硼氫化鈉(740.84mg，19.58mmol，692.38μL)一次性添加到2-甲氧基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(2g，9.79mmol)於MeOH(50mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌2h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷HPLC，以得到2-甲氧基 -4-(5-甲基-2-哌啶基)吡啶(720.2mg，3.49mmol，35、66%產率)。Sodium borohydride (740.84 mg, 19.58 mmol, 692.38 μL) was added in one portion to 2-methoxy-4-(3-methyl-2,3,4,5-tetrahydropyridine-6 at 0 °C -yl)pyridine (2 g, 9.79 mmol) in a stirred solution of MeOH (50 mL). The resulting mixture was stirred at 0 °C for 2 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The oil obtained was subjected to HPLC to give 2-methoxy -4-(5-Methyl-2-piperidinyl)pyridine (720.2 mg, 3.49 mmol, 35, 66% yield).

LCMS(ESI)：[M+H]+ m/z：計算值206.2；實測值207.4；Rt=1.697min。LCMS (ESI): [M+H] + m/z: calculated 206.2; found 207.4; Rt=1.697 min.

6QQ. 外消旋-3-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑之合成6QQ. Synthesis of racemic-3-methyl-5-(5-methyl-2-piperidinyl)-1H-indazole

Figure 110128222-A0202-12-0830-661
Figure 110128222-A0202-12-0830-661

步驟1：3-甲基-6-(3-甲基-1H-吲唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(3-methyl-1H-indazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.86g，28.55mmol)、C14 H19 BN2 O2 ．HCl(9.25g，31.40mmol，HCl)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(1.17g，1.43mmol)及碳酸鈉(9.08g，85.64mmol，3.59mL)於二噁烷(150mL)及水(50mL)中之混合物在90℃、氬氣氣氛下攪拌24h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(400mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析，使用0至100% CHCl3 -EtOAc梯度溶析來純化殘餘物，以得到3-甲基-6-(3-甲基-1H-吲唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(10g，粗品)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.86 g, 28.55 mmol), C 14 H 19 BN 2 O 2 . HCl (9.25 g, 31.40 mmol, HCl), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.17 g, 1.43 mmol) and A mixture of sodium carbonate (9.08 g, 85.64 mmol, 3.59 mL) in dioxane (150 mL) and water (50 mL) was stirred at 90 °C under argon atmosphere for 24 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (400 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% CHCl3 -EtOAc gradient to give 3-methyl-6-(3-methyl-lH-indazole -5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值327.2；實測值328.2；Rt=1.133min。LCMS (ESI): [M+H] + m/z: calculated 327.2; found 328.2; Rt=1.133 min.

步驟2：3-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 2: Synthesis of 3-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

將3-甲基-6-(3-甲基-1H-吲唑-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(10g，30.54mmol)於TFA(55.72g，488.67mmol，37.65mL)中之溶液在20℃下攪拌1h， 然後在真空中蒸發。將碎冰(10g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之3-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(8g，粗品)，其直接用於下一步驟中。3-Methyl-6-(3-methyl-1H-indazol-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (10 g, 30.54 mmol) in TFA The solution in (55.72 g, 488.67 mmol, 37.65 mL) was stirred at 20 °C for 1 h, It was then evaporated in vacuo. Crushed ice (10 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 3-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a yellow solid yl)-1H-indazole (8 g, crude), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d6 )δ 0.89(d,3H),1.26(m,2H),1.32(m,1H),1.46(m,1H),2.43(s,3H),2.67(m,1H),2.93(m,1H),3.72(m,1H),7.53(d,1H),7.90(d,1H),8.04(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.89(d,3H), 1.26(m,2H), 1.32(m,1H), 1.46(m,1H), 2.43(s,3H), 2.67(m , 1H), 2.93 (m, 1H), 3.72 (m, 1H), 7.53 (d, 1H), 7.90 (d, 1H), 8.04 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值227.2；實測值228.2；Rt=0.801min。LCMS (ESI): [M+H] + m/z: calculated 227.2; found 228.2; Rt=0.801 min.

步驟3：外消旋-3-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑之合成Step 3: Synthesis of racemic-3-methyl-5-(5-methyl-2-piperidinyl)-1H-indazole

在0℃下，將硼氫化鈉(2.00g，52.79mmol，1.87mL)一次性添加到3-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(8g，35.20mmol)於甲醇(200mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用二氯甲烷(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之外消旋-3-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑(4g，17.44mmol，49.56%產率)，其直接用於下一步驟中。Sodium borohydride (2.00 g, 52.79 mmol, 1.87 mL) was added in one portion to 3-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0 °C yl)-lH-indazole (8 g, 35.20 mmol) in a stirred solution of methanol (200 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give rac-3-methyl-5-(5-methyl-2-piperidinyl)-1H-indone as a brown solid azole (4 g, 17.44 mmol, 49.56% yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ 0.84(d,3H),1.07(m,2H),1.41(m,2H),1.77(m,1H),2.27(m,2H),2.45(s,3H),3.00(m,1H),3.53(m,1H),7.32(m,2H),7.61(s,1H),12.47(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.84(d,3H), 1.07(m,2H), 1.41(m,2H), 1.77(m,1H), 2.27(m,2H), 2.45(s,3H) ), 3.00(m, 1H), 3.53(m, 1H), 7.32(m, 2H), 7.61(s, 1H), 12.47(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值229.2；實測值230.2；Rt=0.830min。LCMS (ESI): [M+H] + m/z: calculated 229.2; found 230.2; Rt=0.830 min.

6RR. 7-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑之合成6RR. Synthesis of 7-methyl-5-(5-methyl-2-piperidinyl)-1H-indazole

Figure 110128222-A0202-12-0832-662
Figure 110128222-A0202-12-0832-662

步驟1：5-溴-7-甲基-吲唑-1-甲酸第三丁酯之合成Step 1: Synthesis of 5-bromo-7-methyl-indazole-1-carboxylic acid tert-butyl ester

在0℃下，將二碳酸二-第三丁酯(8.99g，41.21mmol，9.46mL)逐滴添加到5-溴-7-甲基-1H-吲唑(8.53g，40.40mmol)及DMAP(49.36mg，404.00μmol)於DCM(100mL)中之經攪拌之懸浮液中。將所得混合物在室溫下攪拌12h，然後在真空中蒸發，倒入到水(100ml)中且用DCM(2x50ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物5-溴-7-甲基-吲唑-1-甲酸第三丁酯(12g，38.56mmol，95.45%產率)。Di-tert-butyl dicarbonate (8.99 g, 41.21 mmol, 9.46 mL) was added dropwise to 5-bromo-7-methyl-1H-indazole (8.53 g, 40.40 mmol) and DMAP at 0 °C (49.36 mg, 404.00 μmol) in a stirred suspension in DCM (100 mL). The resulting mixture was stirred at room temperature for 12h, then evaporated in vacuo, poured into water (100ml) and extracted with DCM (2x50ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo to give the product tert-butyl 5-bromo-7-methyl-indazole-1-carboxylate (12g, 38.56 mmol, 95.45% yield).

1 H NMR(CDCl3 ,400MHz)：1.69(s,9H),2.59(s,3H),7.12(s,1H),7.60(s,1H),8.46(s,1H)。 1 H NMR (CDCl 3 , 400 MHz): 1.69 (s, 9H), 2.59 (s, 3H), 7.12 (s, 1H), 7.60 (s, 1H), 8.46 (s, 1H).

LCMS(ESI)：[M-Boc+H]+ m/z：計算值311.2；實測值211.0；Rt=1.487min。LCMS (ESI): [M-Boc+H] + m/z: calculated 311.2; found 211.0; Rt=1.487 min.

步驟2：7-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯之合成Step 2: 7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid 3rd Synthesis of Butyl Ester

將5-溴-7-甲基-吲唑-1-甲酸第三丁酯(10.3g，33.10mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(8.41g，33.10mmol)一起混合於二噁烷(150mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加[1,1'-雙(二苯基膦基)二茂鐵] 二氯鈀(II)(1.35g，1.66mmol)。將反應混合物在氬氣、100℃下攪拌17h，然後冷卻且在真空中蒸發，將其倒入水(150ml)中且用EtOAc(2x80ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下13g粗產物，13g粗產物藉由矽膠管柱層析使用己烷/EtOAc梯度(10-100% EtOAc)進行純化，以得到產物7-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯(4.3g，12.00mmol，36.26%產率)。5-Bromo-7-methyl-indazole-1-carboxylic acid tert-butyl ester (10.3 g, 33.10 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (8.41 g, 33.10 mmol) was mixed together in dioxaborolane oxane (150 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then [1,1'-bis(diphenylphosphino)ferrocene] was added under argon Dichloropalladium(II) (1.35 g, 1.66 mmol). The reaction mixture was stirred under argon at 100°C for 17h, then cooled and evaporated in vacuo, poured into water (150ml) and extracted with EtOAc (2x80ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 13g of crude product which was subjected to silica gel column chromatography using a hexane/EtOAc gradient (10- 100% EtOAc) to give the product 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indium 3-butyl oxazole-1-carboxylate (4.3 g, 12.00 mmol, 36.26% yield).

1 H NMR(CDCl3 ,500MHz)：1.34(s,12H),1.70(s,9H),2.60(s,3H),7.40(s,1H),8.01(s,1H),8.54(s,1H)。 1 H NMR (CDCl 3 , 500MHz): 1.34 (s, 12H), 1.70 (s, 9H), 2.60 (s, 3H), 7.40 (s, 1H), 8.01 (s, 1H), 8.54 (s, 1H) ).

LCMS(ESI)：[M-C4 H8 ]+ m/z：計算值358.2；實測值302.2；Rt=1.727min。LCMS (ESI): [MC 4 H 8 ] + m/z: calculated 358.2; found 302.2; Rt=1.727 min.

步驟3：5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)-7-甲基-吲唑-1-甲酸第三丁酯之合成Step 3: 5-(1-Third-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)-7-methyl-indazole-1-carboxylic acid tert-butyl Synthesis of Esters

將7-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯(4.3g，12.00mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.15g，12.00mmol)一起混合於水(1mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(1mL)中之碳酸鈉(1.27g，12.00mmol，502.85μL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(439.14mg，600.16μmol)。將反應混合物在氬氣、100℃下攪拌80h，然後冷卻且在真空中蒸發，將其倒入水(120ml)中且用EtOAc(2x90ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下8g粗產物，8g粗產物藉由矽膠管柱層析使用己烷/IPA梯度(10-100% IPA)進行純化，以得到產物5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)-7-甲基-吲唑-1-甲酸第三丁酯(3.4g，7.95mmol，66.25%產率)。7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid tert-butyl ester (4.3 g, 12.00 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.15 g, 12.00 mmol) in water (1 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (1.27 g, 12.00 mmol, 502.85 μL) in water (1 mL) and [1,1′-bis(1,1′-bis(1.1′-bis(1.1’-bis(1.1’-bis(1.27 g, 12.00 mmol, 502.85 μL) were then added under argon. Diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (439.14 mg, 600.16 [mu]mol). The reaction mixture was stirred under argon at 100°C for 80h, then cooled and evaporated in vacuo, poured into water (120ml) and extracted with EtOAc (2x90ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 8g of crude product which was subjected to silica gel column chromatography using a hexane/IPA gradient (10- 100% IPA) to give the product 5-(1-tert-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)-7-methyl-indazole - 3-butyl 1-carboxylate (3.4 g, 7.95 mmol, 66.25% yield).

LCMS(ESI)：[M+H-Boc]+ m/z：計算值427.5；實測值328.2；Rt=1.478min。LCMS (ESI): [M+H-Boc] + m/z: calculated 427.5; found 328.2; Rt=1.478 min.

步驟4：7-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 4: Synthesis of 7-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

將5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)-7-甲基吲唑-1-甲酸第三丁酯(3g，7.02mmol)於MeOH(30mL)及三氟乙酸(24.00g，210.51mmol，16.22mL)中之溶液在25℃下攪拌8h，然後在真空中蒸發。將碎冰(20g)添加到殘餘物中且用10%碳酸氫鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*60mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之7-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(1g，4.40mmol，62.70%產率)，其直接用於下一步驟中。5-(1-Third-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)-7-methylindazole-1-carboxylic acid tert-butyl ester (3 g , 7.02 mmol) in MeOH (30 mL) and trifluoroacetic acid (24.00 g, 210.51 mmol, 16.22 mL) was stirred at 25 °C for 8 h, then evaporated in vacuo. Crushed ice (20 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (2*60 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 7-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a yellow solid yl)-1H-indazole (1 g, 4.40 mmol, 62.70% yield), which was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值227.3；實測值228.2；Rt=1.207min。LCMS (ESI): [M+H] + m/z: calculated 227.3; found 228.2; Rt=1.207 min.

步驟5：7-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑之合成Step 5: Synthesis of 7-methyl-5-(5-methyl-2-piperidinyl)-1H-indazole

在0℃下，將硼氫化鈉(366.17mg，9.68mmol，342.21μL)一次性添加到7-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(1.1g，4.84mmol)於MeOH(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌4h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用二氯甲烷(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到7-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑(0.7g，3.05mmol，63.08%產率)。Sodium borohydride (366.17 mg, 9.68 mmol, 342.21 μL) was added in one portion to 7-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0 °C yl)-1H-indazole (1.1 g, 4.84 mmol) in a stirred solution of MeOH (20 mL). The resulting mixture was stirred at 0 °C for 4 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 7-methyl-5-(5-methyl-2-piperidinyl)-1H-indazole (0.7 g, 3.05 mmol, 63.08% yield).

LCMS(ESI)：[M+H]+ m/z：計算值229.3；實測值230.2；Rt=1.263min。LCMS (ESI): [M+H] + m/z: calculated 229.3; found 230.2; Rt=1.263 min.

6SS. 4-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成6SS. Synthesis of 4-fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

Figure 110128222-A0202-12-0834-663
Figure 110128222-A0202-12-0834-663

步驟1：5-溴-4-氟-1H-吲唑之合成Step 1: Synthesis of 5-bromo-4-fluoro-1H-indazole

將4-溴-3-氟-2-甲基苯胺(10g，49.01mmol)溶解於AcOH(200mL)中 且在室溫下分批添加亞硝酸鈉(4.06g，58.81mmol，1.87mL)。攪拌所得混合物18h。將反應混合物倒入水(500ml)中且將所形成之沉澱過濾，用水(2*200ml)洗滌。將沉澱溶解於DCM(400ml)中，經Na2 SO4 乾燥，過濾且蒸發，以獲得5-溴-4-氟-1H-吲唑(8.54g，39.71mmol，81.02%產率)。4-Bromo-3-fluoro-2-methylaniline (10 g, 49.01 mmol) was dissolved in AcOH (200 mL) and sodium nitrite (4.06 g, 58.81 mmol, 1.87 mL) was added portionwise at room temperature. The resulting mixture was stirred for 18 h. The reaction mixture was poured into water (500ml) and the formed precipitate was filtered, washed with water (2*200ml). The precipitate was dissolved in DCM ( 400 ml), dried over Na2SO4 , filtered and evaporated to give 5-bromo-4-fluoro-lH-indazole (8.54 g, 39.71 mmol, 81.02% yield).

LCMS(ESI)：[M+H]+ m/z：計算值213.9；實測值215.0；Rt=1.086min。LCMS (ESI): [M+H] + m/z: calculated 213.9; found 215.0; Rt=1.086 min.

步驟2：5-溴-4-氟-1-四氫哌喃-2-基-吲唑之合成Step 2: Synthesis of 5-bromo-4-fluoro-1-tetrahydropyran-2-yl-indazole

將5-溴-4-氟-1H-吲唑(8.54g，39.72mmol)及3,4-二氫-2H-哌喃(4.18g，49.65mmol，4.51mL)溶解於DCM(170mL)中且添加對甲苯磺酸單水合物(377.74mg，1.99mmol，304.63μL)。將反應混合物攪拌20h。將反應混合物倒入到NaHCO3 (濃)水溶液中且將有機層分離，經Na2 SO4 乾燥，過濾且蒸發，以獲得5-溴-4-氟-1-四氫哌喃-2-基-吲唑(11.76g，39.30mmol，98.95%產率)。5-Bromo-4-fluoro-1H-indazole (8.54 g, 39.72 mmol) and 3,4-dihydro-2H-pyran (4.18 g, 49.65 mmol, 4.51 mL) were dissolved in DCM (170 mL) and Add p-toluenesulfonic acid monohydrate (377.74 mg, 1.99 mmol, 304.63 μL). The reaction mixture was stirred for 20 h. The reaction mixture was poured into aqueous NaHCO 3 (cone) and the organic layer was separated, dried over Na 2 SO 4 , filtered and evaporated to give 5-bromo-4-fluoro-1-tetrahydropyran-2-yl -Indazole (11.76 g, 39.30 mmol, 98.95% yield).

1 H NMR(CDCl3 ,500MHz)：1.43(m,2H),1.53(m,1H),1.69(m,2H),1.96(m,1H),3.70(m,1H),3.81(m,1H),5.85(m,1H),7.56(m,2H),8.23(s,1H)。 1 H NMR (CDCl 3 , 500MHz): 1.43 (m, 2H), 1.53 (m, 1H), 1.69 (m, 2H), 1.96 (m, 1H), 3.70 (m, 1H), 3.81 (m, 1H) ), 5.85(m, 1H), 7.56(m, 2H), 8.23(s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值298.03；實測值300.8；Rt=1.244min。LCMS (ESI): [M+2H]+ m/z: calculated 298.03; found 300.8; Rt=1.244 min.

步驟3：4-氟-1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 3: 4-Fluoro-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of base)indazole

將5-溴-4-氟-1-四氫哌喃-2-基吲唑(11.25g，37.62mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(9.55g，37.62mmol)及乙酸鉀(7.38g，75.24mmol，4.70mL)一起混合於二噁烷(225mL)中，且將所得混合物抽真空且用氬氣回填三次。向其中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(1.54g，1.88mmol)且將反應混合物在100℃下加熱20h。冷卻反應混合物且過濾。在真空中濃縮濾液且藉由管柱層析純化，以獲得4-氟-1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑(9.22g，26.63mmol，70.79%產率)。5-Bromo-4-fluoro-1-tetrahydropyran-2-ylindazole (11.25 g, 37.62 mmol), 4,4,5,5-tetramethyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (9.55 g, 37.62 mmol) and potassium acetate (7.38 g, 75.24 mmol, 4.70 mL) were mixed together in dioxane (225 mL), and the resulting mixture was evacuated and backfilled with argon three times. To this was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.54 g, 1.88 mmol) and the reaction mixture was heated at 100 °C 20h. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo and purified by column chromatography to obtain 4-fluoro-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)indazole (9.22 g, 26.63 mmol, 70.79% yield).

1 H NMR(DMSO,500MHz)：1.31(s,12H),1.60(m,2H),1.74(m,1H),1.95(m,1H),2.04(m,1H),2.38(m,1H),3.72(m,1H),3.85(m,1H),5.81(m,1H),7.46(d,1H),7.55(d,1H),8.11(s,1H)。 1 H NMR (DMSO, 500MHz): 1.31(s, 12H), 1.60(m, 2H), 1.74(m, 1H), 1.95(m, 1H), 2.04(m, 1H), 2.38(m, 1H) , 3.72(m, 1H), 3.85(m, 1H), 5.81(m, 1H), 7.46(d, 1H), 7.55(d, 1H), 8.11(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值346.2；實測值347.0；Rt=1.505min。LCMS (ESI): [M+H] + m/z: calculated 346.2; found 347.0; Rt=1.505 min.

步驟4：6-(4-氟-1-四氫哌喃-2-基吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 4: 6-(4-Fluoro-1-tetrahydropyran-2-ylindazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl Synthesis of Esters

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.02g，14.55mmol)、4-氟-1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑(5.54g，16.00mmol)及碳酸鈉(3.08g，29.09mmol，1.22mL)一起混合於二噁烷(60mL)及水(20mL)之混合物中。將所得混合物抽真空且用氬氣回填三次，且向其中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(594.00mg，727.37μmol)。將反應混合物在90℃下加熱18h。冷卻反應混合物且用水(120ml)稀釋。將所得混合物用EtOAc(2*100ml)萃取且將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得6-(4-氟-1-四氫哌喃-2-基吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.92g，粗品)。Combine 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.02 g, 14.55 mmol), 4-fluoro- 1-Tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole (5.54g , 16.00 mmol) and sodium carbonate (3.08 g, 29.09 mmol, 1.22 mL) were mixed together in a mixture of dioxane (60 mL) and water (20 mL). The resulting mixture was evacuated and backfilled with argon three times, and to it was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (594.00 mg) , 727.37 μmol). The reaction mixture was heated at 90 °C for 18 h. The reaction mixture was cooled and diluted with water (120 ml). The resulting mixture was extracted with EtOAc (2*100ml) and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated to give 6-( 4 -fluoro-1-tetrahydropyran-2 -ylindazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.92 g, crude).

1 H NMR(400MHz,DMSO)0.92(m,12H),1.54(m,3H),1.94(m,2H),2.35(m,3H),3.03(m,1H),3.69(m,2H),3.85(m,2H),5.21(m,1H),5.82(m,1H),7.23(d,1H),7.45(d,1H),8.14(s,1H)。 1 H NMR (400MHz, DMSO) 0.92(m, 12H), 1.54(m, 3H), 1.94(m, 2H), 2.35(m, 3H), 3.03(m, 1H), 3.69(m, 2H), 3.85(m, 2H), 5.21(m, 1H), 5.82(m, 1H), 7.23(d, 1H), 7.45(d, 1H), 8.14(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值415.3；實測值416.2；Rt=1.745min。LCMS (ESI): [M+H] + m/z: calculated 415.3; found 416.2; Rt=1.745 min.

步驟5：4-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 5: Synthesis of 4-fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

將6-(4-氟-1-四氫哌喃-2-基吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.92g，19.06mmol)溶解於DCM(30mL)中且向其中添加CF3 COOH(30mL)。將反應混合物攪拌18h。將反應混合物蒸發至乾且將殘餘物用K2 CO3 水溶液鹼化。將所得混合物用DCM(3*50ml)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得4-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(6.75g，粗品)。6-(4-Fluoro-1-tetrahydropyran-2-ylindazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester ( 7.92 g, 19.06 mmol) was dissolved in DCM (30 mL) and CF3COOH (30 mL) was added to it. The reaction mixture was stirred for 18 h. The reaction mixture was evaporated to dryness and the residue was basified with aqueous K2CO3. The resulting mixture was extracted with DCM (3*50ml). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to give 4-fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H- Indazole (6.75 g, crude).

1 H NMR(500MHz,DMSO)0.94(d,3H),1.81(m,2H),2.70(m,2H),3.16(m,1H),3.87(m,2H),7.31(d,1H),7.67(d,1H),8.19(s,1H),13.42(s,1H)。 1 H NMR (500MHz, DMSO) 0.94(d,3H), 1.81(m,2H), 2.70(m,2H), 3.16(m,1H), 3.87(m,2H), 7.31(d,1H), 7.67(d, 1H), 8.19(s, 1H), 13.42(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值231.1；實測值232.2；Rt=0.482min。LCMS (ESI): [M+H] + m/z: calculated 231.1; found 232.2; Rt=0.482 min.

步驟6：4-氟-5-(5-甲基-2-哌啶基)-1H-吲唑之合成Step 6: Synthesis of 4-fluoro-5-(5-methyl-2-piperidinyl)-1H-indazole

將4-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(6.75g，29.19mmol)溶解於MeOH(50mL)中且分批添加硼氫化鈉(3.31g，87.56mmol，3.10mL)。將反應混合物攪拌18h。將反應混合物蒸發至乾。將殘餘物溶解於DCM(100ml)中且將所得混合物用NaHSO4 水溶液(2*50ml)萃取。將經合併之水層用DCM(3*100ml)洗滌，然後用K2 CO3 鹼化。將所得混合物用DCM(2*100ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得4-氟-5-(5-甲基-2-哌啶基)-1H-吲唑(2.13g，9.13mmol，31.28%產率)。4-Fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole (6.75 g, 29.19 mmol) was dissolved in MeOH (50 mL) and separated Sodium borohydride (3.31 g, 87.56 mmol, 3.10 mL) was added in batches. The reaction mixture was stirred for 18 h. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (100ml) and the resulting mixture was extracted with aq. NaHSO4 (2*50ml). The combined aqueous layers were washed with DCM ( 3 *100ml), then basified with K2CO3. The resulting mixture was extracted with DCM (2*100ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to give 4 -fluoro-5-(5-methyl-2-piperidinyl)- 1H-Indazole (2.13 g, 9.13 mmol, 31.28% yield).

1 H NMR(400MHz,DMSO)0.81(d,3H),1.12(m,2H),1.39(m,1H),1.51(m,1H),1.62(m,1H),1.77(m,1H),2.25(m,1H),2.97(m,1H),3.85(m,1H),7.26(d,1H),7.47(d,1H),8.06(s,1H),13.23(s,1H)。 1 H NMR (400MHz, DMSO) 0.81(d,3H), 1.12(m,2H), 1.39(m,1H), 1.51(m,1H), 1.62(m,1H), 1.77(m,1H), 2.25(m,1H), 2.97(m,1H), 3.85(m,1H), 7.26(d,1H), 7.47(d,1H), 8.06(s,1H), 13.23(s,1H).

LCMS(ESI)：[M+H]+ m/z：計算值233.2；實測值234.2；Rt=0.642min。LCMS (ESI): [M+H] + m/z: calculated 233.2; found 234.2; Rt=0.642 min.

6TT. 2-氟-5-[(2R,5S)-5-甲基-2-哌啶基]苯酚之合成6TT. Synthesis of 2-fluoro-5-[(2R,5S)-5-methyl-2-piperidinyl]phenol

Figure 110128222-A0202-12-0838-664
Figure 110128222-A0202-12-0838-664

步驟1：6-(4-氟-3-甲氧基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(4-fluoro-3-methoxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(20g，52.12mmol)、(4-氟-3-甲氧基苯基)硼酸(9.74g，57.34mmol)及碳酸鈉(18.23g，172.01mmol，7.21mL)添加到1,4-二噁烷(240mL)及水(80mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 DCM(2.13g，2.61mmol)。將反應混合物在氬氣、90℃下攪拌18h，然後冷卻且過濾。將濾餅用二噁烷(2*50ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用己烷/MTBE梯度(0-100% MTBE)進行第一次純化且使用己烷/氯仿梯度(5-100%氯仿)進行第二次純化來純化殘餘物兩次，以得到呈淡黃色膠狀物之6-(4-氟-3-甲氧基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(6.2g，19.29mmol，37.01%產率)。Combine 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (20 g, 52.12 mmol), (4-fluoro- 3-Methoxyphenyl)boronic acid (9.74 g, 57.34 mmol) and sodium carbonate (18.23 g, 172.01 mmol, 7.21 mL) were added to a mixture of 1,4-dioxane (240 mL) and water (80 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2 DCM (2.13 g, 2.61 mmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 18 h, then cooled and filtered. The filter cake was washed with dioxane (2*50ml) and discarded. The filtrate was evaporated in vacuo and purified by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) for the first time and a hexane/chloroform gradient (5-100% chloroform) for the second The residue was purified twice to give 6-(4-fluoro-3-methoxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine- 3-Butyl 1-carboxylate (6.2 g, 19.29 mmol, 37.01% yield).

1 H NMR(CDCl3 ,400MHz)：0.92(d,3H),1.10(s,9H),1.81(m,1H),2.01(m,1H),2.41(m,1H),2.99(m,1H),3.87(s,3H),4.07(m,1H),5.28(s,1H),6.84(m,1H),6.89(d,1H),7.00(dd,1H)。 1 H NMR (CDCl 3 , 400MHz): 0.92 (d, 3H), 1.10 (s, 9H), 1.81 (m, 1H), 2.01 (m, 1H), 2.41 (m, 1H), 2.99 (m, 1H) ), 3.87(s, 3H), 4.07(m, 1H), 5.28(s, 1H), 6.84(m, 1H), 6.89(d, 1H), 7.00(dd, 1H).

LCMS(ESI)：[M+Na]+ m/z：計算值321.4；實測值344.0；Rt=1.659min。LCMS (ESI): [M+Na] + m/z: calculated 321.4; found 344.0; Rt=1.659 min.

步驟2：6-(4-氟-3-甲氧基苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(4-Fluoro-3-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(4-氟-3-甲氧基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(6.2g，19.29mmol)於三氟乙酸(65.99g，578.74mmol，44.59mL)中之溶液在25℃下攪拌1h。1小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用冰冷水(50mL)稀釋且用10% NaOH水溶液中和，直至pH=10。用二氯甲烷(2 x 100mL)萃取所得混合物。將經合併之有機相用水(30mL)洗滌，經硫酸鈉乾燥，過濾且在減壓下濃縮，以獲得呈淡黃色膠狀物之產物6-(4-氟-3-甲氧基苯基)-3-甲基-2,3,4,5-四氫吡啶(3.5g，15.82mmol，81.99%產率)。6-(4-Fluoro-3-methoxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.2 g, 19.29 mmol) in trifluoro A solution in acetic acid (65.99 g, 578.74 mmol, 44.59 mL) was stirred at 25 °C for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ice-cold water (50 mL) and neutralized with 10% aqueous NaOH until pH=10. The resulting mixture was extracted with dichloromethane (2 x 100 mL). The combined organic phases were washed with water (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product 6-(4-fluoro-3-methoxyphenyl) as a pale yellow gum -3-Methyl-2,3,4,5-tetrahydropyridine (3.5 g, 15.82 mmol, 81.99% yield).

1 H NMR(CDCl3 ,500MHz)：1.10(d,1H),1.70(m,1H),1.92(m,1H),2.10(m,1H),2.55(m,1H),2.78(m,1H),3.25(m,1H),3.94(s,3H),4.01(m,1H),7.05(dd,1H),7.21(m,1H),7.56(d,1H)。 1 H NMR (CDCl 3 , 500MHz): 1.10(d,1H), 1.70(m,1H), 1.92(m,1H), 2.10(m,1H), 2.55(m,1H), 2.78(m,1H) ), 3.25(m, 1H), 3.94(s, 3H), 4.01(m, 1H), 7.05(dd, 1H), 7.21(m, 1H), 7.56(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值221.3；實測值222.0；Rt=0.699min。LCMS (ESI): [M+H] + m/z: calculated 221.3; found 222.0; Rt=0.699 min.

步驟3：(2R,5S)-2-(4-氟-3-甲氧基苯基)-5-甲基哌啶之合成Step 3: Synthesis of (2R,5S)-2-(4-fluoro-3-methoxyphenyl)-5-methylpiperidine

在0℃下，向6-(4-氟-3-甲氧基苯基)-3-甲基-2,3,4,5-四氫吡啶(3.5g，15.82mmol)於甲醇(60mL)中之經攪拌之溶液中分批添加硼氫化鈉(897.58mg，23.73mmol，838.86μL)。將所得反應混合物在0℃下攪拌1h，然後在減壓下濃縮。將殘餘物用水(50mL)稀釋且用二氯甲烷(2 x 100mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空下濃縮，以獲得呈淡黃色膠狀物之粗產物(2R,5S)-2-(4-氟-3-甲氧基苯基)-5-甲基哌啶(3.3g，14.78mmol，93.43%產率)，其直接用於下一步驟中。To 6-(4-fluoro-3-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydropyridine (3.5 g, 15.82 mmol) in methanol (60 mL) at 0 °C To the stirred solution was added sodium borohydride (897.58 mg, 23.73 mmol, 838.86 μL) portionwise. The resulting reaction mixture was stirred at 0 °C for 1 h, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the crude product (2R,5S)-2-(4-fluoro-3-methoxyphenyl)- as a pale yellow gum 5-Methylpiperidine (3.3 g, 14.78 mmol, 93.43% yield) was used directly in the next step.

1 H NMR(CDCl3 ,500MHz)：0.92(d,3H),1.14(m,1H),1.50(m,1H),1.77(m,4H),2.42(m,1H),3.13(m,1H),3.50(m,1H),3.90(s,3H),6.85(m,1H),7.00(m,2H)。 1 H NMR (CDCl 3 , 500MHz): 0.92(d,3H), 1.14(m,1H), 1.50(m,1H), 1.77(m,4H), 2.42(m,1H), 3.13(m,1H) ), 3.50(m, 1H), 3.90(s, 3H), 6.85(m, 1H), 7.00(m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值223.3；實測值224.2；Rt=0.687min。LCMS (ESI): [M+H] + m/z: calculated 223.3; found 224.2; Rt=0.687 min.

步驟4：2-氟-5-[(2R,5S)-5-甲基-2-哌啶基]苯酚之合成Step 4: Synthesis of 2-fluoro-5-[(2R,5S)-5-methyl-2-piperidinyl]phenol

使用回流冷凝器將(2R,5S)-2-(4-氟-3-甲氧基苯基)-5-甲基哌啶(1.60 g，7.17mmol)於48%氫溴酸(35g，432.57mmol，23.49mL)中之溶液在110℃下攪拌48h，然後冷卻且在真空中蒸發。將殘餘物另外在真空中(1mm.Hg)乾燥，以得到呈棕色固體之2-氟-5-[(2R,5S)-5-甲基-2-哌啶基]苯酚(2.2g，粗品，HBr)，其直接用於下一步驟中。(2R,5S)-2-(4-fluoro-3-methoxyphenyl)-5-methylpiperidine (1.60 g, 7.17 mmol) in 48% hydrobromic acid (35 g, 432.57 mmol, 23.49 mL) was stirred at 110 °C for 48 h, then cooled and evaporated in vacuo. The residue was additionally dried in vacuo (1 mm.Hg) to give 2-fluoro-5-[(2R,5S)-5-methyl-2-piperidinyl]phenol (2.2 g, crude) as a brown solid , HBr), which was used directly in the next step.

1 H NMR(500MHz,DMSO)0.92(d,3H),1.32(m,1H),1.90(m,4H),2.70(m,1H),3.23(m,1H),4.11(m,1H),6.95(m,1H),7.07(d,1H),7.21(dd,1H),9.00(m,2H),10.09(s,1H)。 1 H NMR (500MHz, DMSO) 0.92(d, 3H), 1.32(m, 1H), 1.90(m, 4H), 2.70(m, 1H), 3.23(m, 1H), 4.11(m, 1H), 6.95 (m, 1H), 7.07 (d, 1H), 7.21 (dd, 1H), 9.00 (m, 2H), 10.09 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值209.2；實測值210.2；Rt=0.783min。LCMS (ESI): [M+H] + m/z: calculated 209.2; found 210.2; Rt=0.783 min.

6UU. 5-(5-甲基-2-哌啶基)-1H-吲唑-3-胺之合成6UU. Synthesis of 5-(5-methyl-2-piperidinyl)-1H-indazol-3-amine

Figure 110128222-A0202-12-0840-665
Figure 110128222-A0202-12-0840-665

步驟1：6-(3-氰基-4-氟苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3-cyano-4-fluorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯甲腈(5g，20.24mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8.39g，24.28mmol)一起混合於水(5mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(5mL)中之碳酸鈉(4.29g，40.47mmol，1.70mL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(826.31mg，1.01mmol)。將反應混合物在氬氣、90℃下攪拌48h，然後冷卻且在真空中蒸發，將其倒入水(120ml)中且用EtOAc(2x60ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下6g粗產物，6 g粗產物藉由矽膠管柱層析，使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到產物6-(3-氰基-4-氟苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.7g，18.02mmol，89.03%產率)。2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzonitrile (5 g, 20.24 mmol) and 3 -Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.39 g, 24.28 mmol) was mixed with water (5 mL) middle. The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (4.29 g, 40.47 mmol, 1.70 mL) in water (5 mL) and [1,1'-bis() were added under argon. Diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (826.31 mg, 1.01 mmol). The reaction mixture was stirred under argon at 90°C for 48h, then cooled and evaporated in vacuo, poured into water (120ml) and extracted with EtOAc (2x60ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 6g of crude product, 6 g crude product was purified by silica gel column chromatography using a hexane/MTBE gradient (10-100% MTBE) to give the product 6-(3-cyano-4-fluorophenyl)-3-methyl- 3,4-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.7 g, 18.02 mmol, 89.03% yield).

LCMS(ESI)：[M+H]+ m/z：計算值316.4；實測值317.2；Rt=1.586min。LCMS (ESI): [M+H] + m/z: calculated 316.4; found 317.2; Rt=1.586 min.

步驟2：6-(3-胺基-1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(3-amino-1H-indazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

在100℃下，將於水中之35%水合肼溶液(22%肼)(2.56g，51.21mmol，2.49mL)一次性添加到6-(3-氰基-4-氟苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.7g，8.53mmol)於二噁烷(50mL)中之經攪拌之溶液中。將所得混合物在100℃下攪拌48h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用二氯甲烷(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到6-(3-胺基-1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2g，6.09mmol，71.36%產率)。A 35% solution of hydrazine hydrate in water (22% hydrazine) (2.56 g, 51.21 mmol, 2.49 mL) was added in one portion to 6-(3-cyano-4-fluorophenyl)-3- at 100 °C In a stirred solution of methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.7 g, 8.53 mmol) in dioxane (50 mL). The resulting mixture was stirred at 100 °C for 48 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 6-(3-amino-1H-indazol-5-yl)-3-methyl-3,4-dihydro-2H - tert-butyl pyridine-1-carboxylate (2 g, 6.09 mmol, 71.36% yield).

LCMS(ESI)：[M+H]+ m/z：計算值328.4；實測值329.2；Rt=1.262min。LCMS (ESI): [M+H] + m/z: calculated 328.4; found 329.2; Rt=1.262 min.

步驟3：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑-3-胺之合成Step 3: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazol-3-amine

將6-(3-胺基-1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.7g，2.13mmol)於DCM(10mL)及三氟乙酸(10g，87.70mmol，6.76mL)中之溶液在0℃下攪拌5h，然後在真空中蒸發。將碎冰(30g)添加到殘餘物中且用10%碳酸氫鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑-3-胺(0.3g，1.31mmol，61.65%產率)。6-(3-Amino-1H-indazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.7 g, 2.13 mmol) was added to A solution in DCM (10 mL) and trifluoroacetic acid (10 g, 87.70 mmol, 6.76 mL) was stirred at 0 °C for 5 h, then evaporated in vacuo. Crushed ice (30 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazol-3 - Amine (0.3 g, 1.31 mmol, 61.65% yield).

LCMS(ESI)：[M+H]+ m/z：計算值228.3；實測值229.2；Rt=0.528min。LCMS (ESI): [M+H] + m/z: calculated 228.3; found 229.2; Rt=0.528 min.

步驟4：5-(5-甲基-2-哌啶基)-1H-吲唑-3-胺之合成Step 4: Synthesis of 5-(5-Methyl-2-piperidinyl)-1H-indazol-3-amine

在0℃下，將硼氫化鈉(139.20mg，3.68mmol，130.10μL)一次性添 加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑-3-胺(0.42g，1.84mmol)於MeOH(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌6h，然後在真空中蒸發。將殘餘物用水(30mL)稀釋且用二氯甲烷(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到5-(5-甲基-2-哌啶基)-1H-吲唑-3-胺(0.34g，1.48mmol，80.24%產率)。Sodium borohydride (139.20 mg, 3.68 mmol, 130.10 μL) was added in one portion at 0 °C Addition of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazol-3-amine (0.42 g, 1.84 mmol) in MeOH (20 mL) in the stirred solution. The resulting mixture was stirred at 0 °C for 6 h, then evaporated in vacuo. The residue was diluted with water (30 mL) and extracted with dichloromethane (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl)-1H-indazol-3-amine (0.34 g, 1.48 mmol, 80.24 g %Yield).

LCMS(ESI)：[M+H]+ m/z：計算值230.3；實測值231.0；Rt=0.776min。LCMS (ESI): [M+H] + m/z: calculated 230.3; found 231.0; Rt=0.776 min.

6VV. (2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)哌啶之合成6VV. Synthesis of (2R,5S)-5-methyl-2-(4-methylsulfonylphenyl)piperidine

Figure 110128222-A0202-12-0842-666
Figure 110128222-A0202-12-0842-666

步驟1：3-甲基-6-(4-甲基磺醯基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(4-methylsulfonylphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(20g，57.91mmol)、(4-甲基磺醯基苯基)硼酸(15.8g，78.99mmol)及碳酸鈉(24.55g，231.66mmol，9.70mL)添加到1,4-二噁烷(350mL)及水(110mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 DCM(2.36g，2.90mmol)。將反應混合物在氬氣、90℃下攪拌18h，然後冷卻且過濾。將濾餅用二噁烷(2*50ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析使用氯仿/乙酸乙酯梯度(0-100%乙酸乙酯)純化殘餘物，以得到呈米色固體之3-甲基-6-(4-甲基磺醯基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(11.3g，32.15mmol，55.52%產率)，其直接用於下一步驟中。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (20 g, 57.91 mmol), (4-methyl) Sulfonylphenyl)boronic acid (15.8 g, 78.99 mmol) and sodium carbonate (24.55 g, 231.66 mmol, 9.70 mL) were added to a mixture of 1,4-dioxane (350 mL) and water (110 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2 DCM (2.36 g, 2.90 mmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 18 h, then cooled and filtered. The filter cake was washed with dioxane (2*50ml) and discarded. The filtrate was evaporated in vacuo, and the residue was purified by silica gel column chromatography using a chloroform/ethyl acetate gradient (0-100% ethyl acetate) to give 3-methyl-6-(4-methyl) as a beige solid Methylsulfonylphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.3 g, 32.15 mmol, 55.52% yield), which was used directly in the next step.

1 H NMR(CDCl3 ,400MHz)：0.92(d,3H),1.18(m,9H),1.93(m,1H),2.02(m,1H),2.46(m,1H),3.05(m,4H),4.05(m,1H),5.44(s,1H),7.49(d,2H),7.87(d,2H)。 1 H NMR (CDCl 3 , 400MHz): 0.92 (d, 3H), 1.18 (m, 9H), 1.93 (m, 1H), 2.02 (m, 1H), 2.46 (m, 1H), 3.05 (m, 4H) ), 4.05(m, 1H), 5.44(s, 1H), 7.49(d, 2H), 7.87(d, 2H).

LCMS(ESI)：[M+Na]+ m/z：計算值351.5；實測值374.2；Rt=1.345min。LCMS (ESI): [M+Na] + m/z: calculated 351.5; found 374.2; Rt=1.345 min.

步驟2：3-甲基-6-(4-甲基磺醯基苯基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 3-methyl-6-(4-methylsulfonylphenyl)-2,3,4,5-tetrahydropyridine

將3-甲基-6-(4-甲基磺醯基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3g，8.54mmol)於三氟乙酸(29.20g，256.08mmol，19.73mL)中之溶液在25℃下攪拌1h。1小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用冰冷水(50mL)稀釋且用10% NaOH水溶液中和，直至pH 10。用二氯甲烷(2 x 50mL)萃取所得混合物。將經合併之有機相經乾燥硫酸鈉且在減壓下濃縮，以得到呈白色固體之3-甲基-6-(4-甲基磺醯基苯基)-2,3,4,5-四氫吡啶(2.05g，8.16mmol，95.55%產率)。3-Methyl-6-(4-methylsulfonylphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3 g, 8.54 mmol) in trifluoroacetic acid (29.20 g, 256.08 mmol, 19.73 mL) was stirred at 25 °C for 1 h. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ice-cold water (50 mL) and neutralized with 10% aqueous NaOH until pH 10. The resulting mixture was extracted with dichloromethane (2 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 3-methyl-6-(4-methylsulfonylphenyl)-2,3,4,5- as a white solid Tetrahydropyridine (2.05 g, 8.16 mmol, 95.55% yield).

1 H NMR(CDCl3 ,500MHz)：1.01(d,3H),1.42(m,1H),1.62(m,1H),1.97(m,1H),2.60(m,1H),2.75(m,1H),2.80(s,3H),3.30(m,1H),4.08(m,1H),7.95(m,4H)。 1 H NMR (CDCl 3 , 500MHz): 1.01 (d, 3H), 1.42 (m, 1H), 1.62 (m, 1H), 1.97 (m, 1H), 2.60 (m, 1H), 2.75 (m, 1H) ), 2.80(s, 3H), 3.30(m, 1H), 4.08(m, 1H), 7.95(m, 4H).

LCMS(ESI)：[M+H]+ m/z：計算值251.3；實測值252.0；Rt=0.746min。LCMS (ESI): [M+H] + m/z: calculated 251.3; found 252.0; Rt=0.746 min.

步驟3：(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)哌啶之合成Step 3: Synthesis of (2R,5S)-5-methyl-2-(4-methylsulfonylphenyl)piperidine

在0℃下，向3-甲基-6-(4-甲基磺醯基苯基)-2,3,4,5-四氫吡啶(2.05g，8.16mmol)於甲醇(50mL)中之經攪拌之懸浮液中分批添加硼氫化鈉(900mg，23.79mmol，841.12μL)。將所得反應混合物在0℃下攪拌1h，然後使其升溫至25℃且攪拌12h，然後在減壓下濃縮。將殘餘物用水(50mL)稀釋且用二氯甲烷(2 x 50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空下濃縮，以獲得呈白色固體之粗產物(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)哌啶(1.9g，7.50mmol，91.95%產率)，其直接用於下一步驟中。To 3-methyl-6-(4-methylsulfonylphenyl)-2,3,4,5-tetrahydropyridine (2.05 g, 8.16 mmol) in methanol (50 mL) at 0 °C Sodium borohydride (900 mg, 23.79 mmol, 841.12 μL) was added portionwise to the stirred suspension. The resulting reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to 25 °C and stirred for 12 h, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude (2R,5S)-5-methyl-2-(4-methylsulfonylphenyl)piperidine as a white solid pyridine (1.9 g, 7.50 mmol, 91.95% yield), which was used directly in the next step.

1 H NMR(CDCl3 ,400MHz)：1.01(d,3H),1.42(m,1H),1.62(m,1H),1.87(m,2H),1.90(m,2H),2.40(m,1H),3.05(s,3H),3.15(m,1H),3.66(m,1H),7.58(d,2H),7.88(d,2H)。 1 H NMR (CDCl 3 , 400MHz): 1.01 (d, 3H), 1.42 (m, 1H), 1.62 (m, 1H), 1.87 (m, 2H), 1.90 (m, 2H), 2.40 (m, 1H) ), 3.05(s, 3H), 3.15(m, 1H), 3.66(m, 1H), 7.58(d, 2H), 7.88(d, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值253.4；實測值254.0；Rt=0.610min。LCMS (ESI): [M+H] + m/z: calculated 253.4; found 254.0; Rt=0.610 min.

6WW. 6-[(2S,5R)-5-甲基-2-哌啶基]噻唑并[5,4-b]吡啶之合成6WW. Synthesis of 6-[(2S,5R)-5-methyl-2-piperidinyl]thiazolo[5,4-b]pyridine

Figure 110128222-A0202-12-0844-667
Figure 110128222-A0202-12-0844-667

步驟1：6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)噻唑并[5,4-b]吡啶之合成Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)thiazolo[5,4-b]pyridine

將6-溴噻唑并[5,4-b]吡啶(3g，13.95mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(5.31g，20.92mmol)及CH3COOK(4.11g，41.85mmol，2.62mL)於二噁烷(10mL)中之混合物用氬氣除氣10min。接著添加(dppf)PdCl2*CH2Cl2(1.14g，1.39mmol)且將反應混合物加熱至90℃達16h。將反應混合物冷卻至室溫，過濾且在減壓下濃縮。藉由SiO2急驟層析(梯度CHCl3 ：乙腈)純化粗產物，以得到6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)噻唑并[5,4-b]吡啶(2.6g，9.92mmol，71.11%產率)。6-Bromothiazolo[5,4-b]pyridine (3 g, 13.95 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (5.31 g, 20.92 mmol) and CH3COOK (4.11 g, 41.85 mmol, 2.62 mL) ) in dioxane (10 mL) was degassed with argon for 10 min. Then (dppf)PdCl2*CH2Cl2 (1.14 g, 1.39 mmol) was added and the reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The crude product was purified by SiO2 flash chromatography (gradient CHCl3 :acetonitrile) to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)thiazolo[5,4-b]pyridine (2.6 g, 9.92 mmol, 71.11% yield).

LCMS(ESI)：[M-4Me]+ m/z：計算值180.2；實測值181.2；Rt=0.698min。LCMS (ESI): [M-4Me] + m/z: calculated 180.2; found 181.2; Rt=0.698 min.

步驟2：3-甲基-6-噻唑并[5,4-b]吡啶-6-基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-methyl-6-thiazolo[5,4-b]pyridin-6-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.54g，7.35mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)噻唑并[5,4-b]吡啶(2.41g，9.19mmol)及碳酸鈉(2.34g，22.06mmol，924.02μL)添加到1,4-二噁烷(30mL)及水(10mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，然後在氬氣下添加Pd(dppf)Cl2 DCM(299.97mg，367.61μmol)。將反應混合物在氬氣、75℃下攪拌16h，然後用水處理且將所需產物用DCM萃取，然後 蒸發。藉由SiO2急驟層析(梯度MTBE：甲醇)純化粗產物，以得到3-甲基-6-噻唑并[5,4-b]吡啶-6-基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.55g，4.68mmol，63.61%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.54 g, 7.35 mmol), 6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)thiazolo[5,4-b]pyridine (2.41g, 9.19mmol) and sodium carbonate (2.34 g, 22.06 mmol, 924.02 μL) was added to a mixture of 1,4-dioxane (30 mL) and water (10 mL). The resulting mixture was evacuated and backfilled with argon, then Pd(dppf)Cl2 DCM (299.97 mg, 367.61 μmol) was added under argon. The reaction mixture was stirred under argon at 75 °C for 16 h, then treated with water and the desired product was extracted with DCM, then evaporation. The crude product was purified by SiO2 flash chromatography (gradient MTBE: methanol) to give 3-methyl-6-thiazolo[5,4-b]pyridin-6-yl-3,4-dihydro-2H-pyridine - 3-Butyl 1-carboxylate (1.55 g, 4.68 mmol, 63.61% yield).

1 H NMR(DMSO-d6,500MHz)：0.96(s,11H),1.85(m,2H),3.10(m,2H),3.90(m,2H),5.56(s,1H),8.23(s,1H),8.56(s,1H),9.52(s,1H)。 1 H NMR (DMSO-d6, 500MHz): 0.96(s, 11H), 1.85(m, 2H), 3.10(m, 2H), 3.90(m, 2H), 5.56(s, 1H), 8.23(s, 1H), 8.56(s, 1H), 9.52(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值331.2；實測值332.2；Rt=1.493min。LCMS (ESI): [M+H] + m/z: calculated 331.2; found 332.2; Rt=1.493 min.

步驟3：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)噻唑并[5,4-b]吡啶之合成Step 3: Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)thiazolo[5,4-b]pyridine

將3-甲基-6-噻唑并[5,4-b]吡啶-6-基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.55g，4.68mmol)溶解於99%三氟乙酸(22.20g，194.70mmol，15mL)中且攪拌1h。將反應混合物蒸發至乾，將殘餘物溶解於40ml DCM中，用飽和NaHCO3 溶液洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)噻唑并[5,4-b]吡啶(0.8g，3.46mmol，73.95%產率)。3-Methyl-6-thiazolo[5,4-b]pyridin-6-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.55 g, 4.68 mmol) was dissolved in 99% trifluoroacetic acid (22.20 g, 194.70 mmol, 15 mL) and stirred for 1 h. The reaction mixture was evaporated to dryness, the residue was dissolved in 40 ml DCM, washed with saturated NaHCO 3 solution, dried over Na 2 SO 4 and concentrated in vacuo to give 6-(3-methyl-2,3,4 ,5-tetrahydropyridin-6-yl)thiazolo[5,4-b]pyridine (0.8 g, 3.46 mmol, 73.95% yield).

1 H NMR(CDCl3 ,400MHz)：1.01(d,3H),1.44(m,1H),1.75(m,1H),1.97(m,1H),2.68(m,1H),2.87(m,1H),3.29(m,1H),4.06(m,1H),8.65(s,1H),9.11(s,2H)。 1 H NMR (CDCl 3 , 400MHz): 1.01(d,3H), 1.44(m,1H), 1.75(m,1H), 1.97(m,1H), 2.68(m,1H), 2.87(m,1H) ), 3.29(m, 1H), 4.06(m, 1H), 8.65(s, 1H), 9.11(s, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值231.1；實測值232.2；Rt=0.582min。LCMS (ESI): [M+H] + m/z: calculated 231.1; found 232.2; Rt=0.582 min.

步驟4：6-[(2S,5R)-5-甲基-2-哌啶基]噻唑并[5,4-b]吡啶之合成Step 4: Synthesis of 6-[(2S,5R)-5-methyl-2-piperidinyl]thiazolo[5,4-b]pyridine

將6-(3-甲基-2,3,4,5-四氫吡啶-6-基)噻唑并[5,4-b]吡啶(0.8g，3.46mmol)溶解於甲醇(20mL)中且分若干批添加硼氫化鈉(196.26mg，5.19mmol，183.42μL)。1h之後，將反應混合物在真空中濃縮，然後溶解於DCM中，用水洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到6-[(2S,5R)-5-甲基-2-哌啶基]噻唑并[5,4-b]吡啶(0.65g，2.79mmol，80.55%產率)。6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)thiazolo[5,4-b]pyridine (0.8 g, 3.46 mmol) was dissolved in methanol (20 mL) and Sodium borohydride (196.26 mg, 5.19 mmol, 183.42 μL) was added in several portions. After 1 h, the reaction mixture was concentrated in vacuo, then dissolved in DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to give 6-[(2S,5R)-5-methyl-2- Piperidinyl]thiazolo[5,4-b]pyridine (0.65 g, 2.79 mmol, 80.55% yield).

1 H NMR(500MHz,DMSO)0.93(d,3H),1.18(m,1H),1.59(m,1H),1.62(m,1H),1.90(m,3H),2.47(m,1H),3.19(m,1H),3.77(m,1H),8.39(s,1H),8.69(s,1H),9.10(s,1H)。 1 H NMR (500MHz, DMSO) 0.93(d, 3H), 1.18(m, 1H), 1.59(m, 1H), 1.62(m, 1H), 1.90(m, 3H), 2.47(m, 1H), 3.19(m, 1H), 3.77(m, 1H), 8.39(s, 1H), 8.69(s, 1H), 9.10(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值233.1；實測值234.2；Rt=0.561min。LCMS (ESI): [M+H] + m/z: calculated 233.1; found 234.2; Rt=0.561 min.

6XX. 外消旋-6-(5-甲基-2-哌啶基)-1H-喹啉-2-酮之合成6XX. Synthesis of racemic-6-(5-methyl-2-piperidinyl)-1H-quinolin-2-one

Figure 110128222-A0202-12-0846-1190
Figure 110128222-A0202-12-0846-1190

步驟1：6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-喹啉-2-酮之合成Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-quinolin-2-one

將乙酸鉀(7.88g，80.34mmol，5.02mL)添加到6-溴-1H-喹啉-2-酮(9g，40.17mmol)於二噁烷(200mL)中之溶液中，隨後添加4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(10.20g，40.17mmol)及Pd(dppf)Cl2 *DCM(1.64g，2.01mmol)。將溶液在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋，過濾且蒸發。藉由管柱層析(己烷/MTBE)純化所得粗沉澱物，以獲得6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-喹啉-2-酮(10.54g，粗品)。Potassium acetate (7.88 g, 80.34 mmol, 5.02 mL) was added to a solution of 6-bromo-1H-quinolin-2-one (9 g, 40.17 mmol) in dioxane (200 mL) followed by 4,4 ,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2- Dioxaborolane (10.20 g, 40.17 mmol) and Pd(dppf)Cl2*DCM (1.64 g , 2.01 mmol). The solution was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc, filtered and evaporated. The resulting crude precipitate was purified by column chromatography (hexane/MTBE) to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-quinolin-2-one (10.54 g, crude).

1 H NMR(400MHz,DMSO-d6 )δ 1.30(s,12H),6.48(d,1H),7.27(d,1H),7.72(d,1H),7.97(s,1H),7.99(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.30(s, 12H), 6.48(d, 1H), 7.27(d, 1H), 7.72(d, 1H), 7.97(s, 1H), 7.99(d , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值271.2；實測值272.2；Rt=1.106min。LCMS (ESI): [M+H] + m/z: calculated 271.2; found 272.2; Rt=1.106 min.

步驟2：3-甲基-6-(2-側氧基-1H-喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-methyl-6-(2-oxy-1H-quinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

向碳酸鉀(7.65g，55.33mmol，3.34mL)、Pd(dppf)Cl2 *DCM(753.02mg，922.11μmol)於水(5mL)中之溶液中添加6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-喹啉-2-酮(5g，18.44mmol)於二噁烷(5mL)中之溶液，隨後添 加3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.01g，20.29mmol)及Pd(dppf)Cl2 *DCM(753.02mg，922.11μmol)。將所得混合物在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋且用水(2x40ml)洗滌。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得3-甲基-6-(2-側氧基-1H-喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8.3g，粗品)。To a solution of potassium carbonate (7.65 g, 55.33 mmol, 3.34 mL), Pd(dppf)Cl2*DCM ( 753.02 mg, 922.11 μmol) in water (5 mL) was added 6-(4,4,5,5- A solution of tetramethyl-1,3,2-dioxaborol-2-yl)-1H-quinolin-2-one (5 g, 18.44 mmol) in dioxane (5 mL) followed by Add 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.01 g, 20.29 mmol) and Pd (dppf) Cl2*DCM ( 753.02 mg, 922.11 [mu]mol). The resulting mixture was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc and washed with water (2x40ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 3-methyl-6-(2-oxy-1H-quinolin-6-yl)-3,4-dihydro-2H-pyridine-1 - tert-butyl formate (8.3 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值340.2；實測值341.2；Rt=1.239min。LCMS (ESI): [M+H] + m/z: calculated 340.2; found 341.2; Rt=1.239 min.

步驟3：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-喹啉-2-酮之合成Step 3: Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-quinolin-2-one

將3-甲基-6-(2-側氧基-1H-喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8.3g，24.38mmol)於TFA(40mL)中之溶液在25℃下攪拌13h。將飽和碳酸鉀水溶液添加到該溶液(50ml)中，然後用DCM(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾出且蒸發，以獲得6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-喹啉-2-酮(6.3g，粗品)。3-Methyl-6-(2-oxy-1H-quinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.3 g, 24.38 mmol) The solution in TFA (40 mL) was stirred at 25 °C for 13 h. Saturated aqueous potassium carbonate solution was added to the solution (50ml), then extracted with DCM (2x50ml). The organic phase was dried over sodium sulfate, filtered off and evaporated to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-quinolin-2-one (6.3 g, crude product).

LCMS(ESI)：[M+H]+ m/z：計算值240.2；實測值241.2；Rt=0.593min。LCMS (ESI): [M+H] + m/z: calculated 240.2; found 241.2; Rt=0.593 min.

步驟4：外消旋-6-(5-甲基-2-哌啶基)-1H-喹啉-2-酮之合成Step 4: Synthesis of racemic-6-(5-methyl-2-piperidinyl)-1H-quinolin-2-one

將硼氫化鈉(1.98g，52.43mmol，1.85mL)分批添加到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-喹啉-2-酮(6.3g，26.22mmol)於甲醇(100mL)中之溶液中。將混合物在室溫下攪拌12h。添加水(50ml)且將所得混合物用EtOAc(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發。藉由管柱層析純化所得粗產物，以獲得外消旋-6-(5-甲基-2-哌啶基)-1H-喹啉-2-酮(1.1g，4.54mmol，17.32%產率)。Sodium borohydride (1.98 g, 52.43 mmol, 1.85 mL) was added portionwise to 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-quinoline-2- A solution of ketone (6.3 g, 26.22 mmol) in methanol (100 mL). The mixture was stirred at room temperature for 12 h. Water (50ml) was added and the resulting mixture was extracted with EtOAc (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting crude product was purified by column chromatography to obtain rac-6-(5-methyl-2-piperidinyl)-1H-quinolin-2-one (1.1 g, 4.54 mmol, 17.32% yield). Rate).

1 H NMR(500MHz,DMSO-d6 )δ 0.89(d,3H),1.16(m,2H),1.63(m,2H),1.82(m,1H),2.38(m,1H),3.05(m,1H),3.63(m,2H),6.44(d,1H),7.24(d,1H),7.30(d,1H),7.58(s,1H),7.78(d,1H),11.64(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.89(d,3H), 1.16(m,2H), 1.63(m,2H), 1.82(m,1H), 2.38(m,1H), 3.05(m ,1H),3.63(m,2H),6.44(d,1H),7.24(d,1H),7.30(d,1H),7.58(s,1H),7.78(d,1H),11.64(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值242.2；實測值243.0；Rt=0.714min。LCMS (ESI): [M+H] + m/z: calculated 242.2; found 243.0; Rt=0.714 min.

6YY. 6-(5-甲基-2-哌啶基)異喹啉之合成6YY. Synthesis of 6-(5-methyl-2-piperidinyl)isoquinoline

Figure 110128222-A0202-12-0848-669
Figure 110128222-A0202-12-0848-669

步驟1：6-(6-異喹啉基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(6-isoquinolinyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異喹啉(5.3g，20.77mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.17g，20.77mmol)及碳酸鈉(2.20g，20.77mmol，870.32μL)一起混合於二噁烷(45mL)中且向其中添加H2 O(15mL)。將所得混合物抽真空且用氬氣回填三次。將Pd(dppf)Cl2 DCM(20.77mmol)添加到先前混合物中且將所得混合物在90℃下加熱18h。冷卻反應混合物且用水(150ml)稀釋。過濾所得混合物且用水(100ml)及EtOAc(200ml)沖洗。將濾液轉移至分液漏斗且分離有機層。將水層用EtOAc(2*200ml)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物，其藉由CC進行純化，以獲得6-(6-異喹啉基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.3g，16.34mmol，78.64%產率)。6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)isoquinoline (5.3 g, 20.77 mmol), 3-methyl -6-(Trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.17 g, 20.77 mmol) and sodium carbonate (2.20 g, 20.77 mmol, 870.32 μL) were mixed together in dioxane (45 mL) and H2O (15 mL) was added to it. The resulting mixture was evacuated and backfilled with argon three times. Pd(dppf)Cl2 DCM (20.77 mmol) was added to the previous mixture and the resulting mixture was heated at 90 °C for 18 h. The reaction mixture was cooled and diluted with water (150 ml). The resulting mixture was filtered and rinsed with water (100ml) and EtOAc (200ml). The filtrate was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with EtOAc (2*200ml). The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated to give crude product which was purified by CC to give 6-(6-isoquinolinyl)-3-methyl-3 , 3-butyl 4-dihydro-2H-pyridine-1-carboxylate (5.3 g, 16.34 mmol, 78.64% yield).

LCMS(ESI)：[M+H]+ m/z：計算值324.2；實測值325.4；Rt=1.189min。LCMS (ESI): [M+H] + m/z: calculated 324.2; found 325.4; Rt=1.189 min.

步驟2：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異喹啉之合成Step 2: Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)isoquinoline

將6-(6-異喹啉基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.3g，16.34mmol)及三氟乙酸(18.63g，163.37mmol，12.59mL)溶解於DCM(18mL)中且在室溫下攪拌1h，然後在真空中蒸發。將殘餘物溶解於Na2 CO3水溶液中且添加DCM。將有機相分離，用鹽水洗滌，乾燥且蒸發，以獲得6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異喹啉(2.3g，10.25mmol，62.77%產率)。Combine 6-(6-isoquinolinyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.3 g, 16.34 mmol) and trifluoroacetic acid (18.63 g, 163.37 mmol, 12.59 mL) was dissolved in DCM (18 mL) and stirred at room temperature for 1 h, then evaporated in vacuo. The residue was dissolved in aqueous Na2CO3 and DCM was added. The organic phase was separated, washed with brine, dried and evaporated to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)isoquinoline (2.3 g, 10.25 mmol, 62.77 g %Yield).

1 H NMR(400MHz,CDCl3 )δ 1.02(d,3H),1.43(m,1H),1.78(m,1H),1.97(m,1H),2.69(m,1H),2.88(m,1H),3.30(m,1H),4.06(m,1H),7.67(d,1H),7.95(d,1H),8.10(s,1H),8.12(d,1H),8.51(d,1H),9.23(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.02(d,3H), 1.43(m,1H), 1.78(m,1H), 1.97(m,1H), 2.69(m,1H), 2.88(m,1H) ), 3.30(m, 1H), 4.06(m, 1H), 7.67(d, 1H), 7.95(d, 1H), 8.10(s, 1H), 8.12(d, 1H), 8.51(d, 1H) , 9.23(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值224.2；實測值225.2；Rt=0.676min。LCMS (ESI): [M+H] + m/z: calculated 224.2; found 225.2; Rt=0.676 min.

步驟3：6-(5-甲基-2-哌啶基)異喹啉之合成Step 3: Synthesis of 6-(5-methyl-2-piperidinyl)isoquinoline

將6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異喹啉(2.3g，10.25mmol)溶解於甲醇(25mL)中且逐滴添加硼氫化鈉(775.88mg，20.51mmol，725.12μL)。將反應混合物在室溫下攪拌隔夜。將反應混合物蒸發至乾。將殘餘物溶解於DCM(150ml)中且將所得混合物用檸檬酸溶液(2*100mL)萃取。將經合併之水層用DCM(3*50mL)洗滌，然後用K2 CO3 鹼化。將所得混合物用DCM(2*200mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發。6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)isoquinoline (2.3 g, 10.25 mmol) was dissolved in methanol (25 mL) and sodium borohydride ( 775.88 mg, 20.51 mmol, 725.12 μL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (150 ml) and the resulting mixture was extracted with citric acid solution (2*100 mL). The combined aqueous layers were washed with DCM ( 3 *50 mL), then basified with K2CO3. The resulting mixture was extracted with DCM (2*200 mL) and the combined organic layers were dried over Na2SO4 , filtered and evaporated.

1 H NMR(400MHz,CDCl3 )δ 0.89(d,3H),1.18(m,2H),1.71(m,1H),1.88(m,2H),2.12(m,1H),2.45(m,1H),3.18(m,1H),3.73(m,1H),7.60(m,2H),7.81(s,1H),7.88(d,1H),8.46(d,1H),8.18(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.89(d,3H), 1.18(m,2H), 1.71(m,1H), 1.88(m,2H), 2.12(m,1H), 2.45(m,1H) ), 3.18(m, 1H), 3.73(m, 1H), 7.60(m, 2H), 7.81(s, 1H), 7.88(d, 1H), 8.46(d, 1H), 8.18(s, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值226.2；實測值227.2；Rt=0.607min。LCMS (ESI): [M+H] + m/z: calculated 226.2; found 227.2; Rt=0.607 min.

6ZZ.外消旋-(2R,5S) -1',5-二甲基-2,4'-聯哌啶之合成6ZZ. Synthesis of racemic-(2R,5S) -1',5-dimethyl-2,4'-bipiperidine

Figure 110128222-A0202-12-0849-670
Figure 110128222-A0202-12-0849-670

步驟1：1',5-二甲基-1',2',3',5,6,6'-六氫-[2,4'-聯吡啶]-1(4H)-甲酸第三丁酯之合成Step 1: 1',5-Dimethyl-1',2',3',5,6,6'-hexahydro-[2,4'-bipyridine]-1(4H)-carboxylate Synthesis of Esters

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(22.17g，54.56mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H -吡啶(14g，62.75mmol)、[1,1'-雙( 二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(2.23g，2.73mmol)及碳酸鈉(17.35g，163.69mmol，6.86mL)於二噁烷(225mL)及水(75mL)中之混合物在90℃、氬氣氣氛下攪拌28h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(500mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析，使用0至100% MeOH-MTBE梯度溶析來純化殘 餘物，以得到3-甲基-6-(1-甲基-3,6-二氫-2H -吡啶-4-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(6g，20.52mmol，37.61%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (22.17 g, 54.56 mmol), 1-methyl -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro- 2H -pyridine (14g, 62.75 g mmol), a complex of [1,1'- bis( diphenylphosphino)ferrocene]dichloropalladium(II) and DCM (2.23 g, 2.73 mmol) and sodium carbonate (17.35 g, 163.69 mmol, 6.86 g mL) in dioxane (225 mL) and water (75 mL) was stirred at 90 °C under argon atmosphere for 28 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (500 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% MeOH-MTBE gradient to give 3-methyl-6-(1-methyl-3,6-di Hydro- 2H -pyridin-4-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (6 g, 20.52 mmol, 37.61% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.85(d,3H),1.31(s,9H),1.73(m,2H),2.01(m,1H),2.10(m,2H),2.18(s,3H),2.46(m,2H),2.75(m,1H),2.83(m,2H),3.69(m,1H),5.09(m,1H),5.48(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.85(d, 3H), 1.31(s, 9H), 1.73(m, 2H), 2.01(m, 1H), 2.10(m, 2H), 2.18(s, 3H), 2.46(m, 2H), 2.75(m, 1H), 2.83(m, 2H), 3.69(m, 1H), 5.09(m, 1H), 5.48(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值292.2；實測值293.2；Rt=1.118min。LCMS (ESI): [M] + m/z: calculated 292.2; found 293.2; Rt=1.118 min.

步驟2：1',5-二甲基-1',2',3,3',4,5,6,6'-八氫-2,4'-聯吡啶之合成Step 2: Synthesis of 1',5-dimethyl-1',2',3,3',4,5,6,6'-octahydro-2,4'-bipyridine

將3-甲基-6-(1-甲基-3,6-二氫-2H -吡啶-4-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(6g，20.52mmol)於TFA(37.43g，328.30mmol，25.29mL)中之溶液在20℃下攪拌1h，然後在真空中蒸發。將碎冰(10g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用乙酸乙酯(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色固體之1-甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,6-二氫-2H -吡啶(3g，15.60mmol，76.03%產率)，其直接用於下一步驟中。3-Methyl-6-(1-methyl-3,6-dihydro- 2H -pyridin-4-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (6g , 20.52 mmol) in TFA (37.43 g, 328.30 mmol, 25.29 mL) was stirred at 20 °C for 1 h, then evaporated in vacuo. Crushed ice (10 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 1-methyl-4-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a brown solid yl)-3,6-dihydro- 2H -pyridine (3 g, 15.60 mmol, 76.03% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.85(d,3H),1.15(m,2H),1.71(m,2H),2.26(s,3H),2.37(m,2H),2.48(m,2H),2.94(m,3H),3.72(m,1H),3.90(m,1H),6.19(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.85(d,3H), 1.15(m,2H), 1.71(m,2H), 2.26(s,3H), 2.37(m,2H), 2.48 (m, 2H), 2.94 (m, 3H), 3.72 (m, 1H), 3.90 (m, 1H), 6.19 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值192.2；實測值193.2；Rt=0.198min。LCMS (ESI): [M] + m/z: calculated 192.2; found 193.2; Rt=0.198 min.

步驟3：外消旋-1-甲基-4-((2R,5S)-5-甲基哌啶-2-基)-1,2,3,6-四氫吡啶之合成Step 3: Synthesis of racemic-1-methyl-4-((2R,5S)-5-methylpiperidin-2-yl)-1,2,3,6-tetrahydropyridine

在0℃下，將硼氫化鈉(885.26mg，23.40mmol，827.34μL)一次性添加到1-甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,6-二氫-2H -吡啶(3g，15.60mmol)於MeOH(90mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(100mL)稀釋且用DCM(2*200mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色油狀物之1-甲基 -4-[(2R,5S )-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶(2.6g，13.38mmol，85.77%產率)，其直接用於下一步驟中。Sodium borohydride (885.26 mg, 23.40 mmol, 827.34 μL) was added in one portion to 1-methyl-4-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0 °C yl)-3,6-dihydro- 2H -pyridine (3 g, 15.60 mmol) in a stirred solution of MeOH (90 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (100 mL) and extracted with DCM (2*200 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 1-methyl-4-[( 2R,5S )-5-methyl-2-piperidinyl] as a yellow oil -3,6-Dihydro- 2H -pyridine (2.6 g, 13.38 mmol, 85.77% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.75(d,3H),1.06(m,4H),1.37(m,1H),1.54(m,1H),1.70(m,1H),2.09(m,3H),2.16(s,3H),2.36(m,2H),2.75(m,2H),2.86(m,1H),5.47(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.75(d,3H), 1.06(m,4H), 1.37(m,1H), 1.54(m,1H), 1.70(m,1H), 2.09(m, 3H), 2.16(s, 3H), 2.36(m, 2H), 2.75(m, 2H), 2.86(m, 1H), 5.47(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值194.2；實測值195.2；Rt=0.151min。LCMS (ESI): [M] + m/z: calculated 194.2; found 195.2; Rt=0.151 min.

步驟4：外消旋-(2R,5S)-1',5-二甲基-2,4'-聯哌啶之合成Step 4: Synthesis of Racemic-(2R,5S)-1',5-dimethyl-2,4'-bipiperidine

向1-甲基-4-[(2R,5S )-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶(2.60g，13.38mmol)於MeOH(300mL)中之溶液中添加鈀(10%於碳上)(1.42g，13.38mmol)。在氫氣氣氛(1bar)下進行反應且在45℃下劇烈攪拌。24h之後，藉由過濾移除催化劑，且在真空中濃縮濾液，以得到1-甲基-4-[(2R,5S )-5-甲基-2-哌啶基]哌啶(2.6g，13.24mmol，98.97%產率)。To 1-methyl-4-[( 2R,5S )-5-methyl-2-piperidinyl]-3,6-dihydro- 2H -pyridine (2.60 g, 13.38 mmol) in MeOH (300 mL) To this solution was added palladium (10% on carbon) (1.42 g, 13.38 mmol). The reaction was carried out under a hydrogen atmosphere (1 bar) with vigorous stirring at 45°C. After 24 h, the catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give 1-methyl-4-[( 2R,5S )-5-methyl-2-piperidinyl]piperidine (2.6 g, 13.24 mmol, 98.97% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.73(d,3H),0.78(m,1H),0.89(m,1H),1.15(m,3H),1.32(m,2H),1.71(m,7H),2.09(s,3H),2.27(m,1H),2.72(m,2H),2.86(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.73(d, 3H), 0.78(m, 1H), 0.89(m, 1H), 1.15(m, 3H), 1.32(m, 2H), 1.71 (m, 7H), 2.09 (s, 3H), 2.27 (m, 1H), 2.72 (m, 2H), 2.86 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值196.2；實測值197.2；Rt=0.112min。LCMS (ESI): [M] + m/z: calculated 196.2; found 197.2; Rt=0.112 min.

6AA.外消旋 -4-((2R,5S)-5-甲基哌啶-2-基)-5,6-二氫吡啶-1(2H )-甲酸苯甲酯之合成6AA. Synthesis of racemic -4-((2R,5S)-5-methylpiperidin-2-yl)-5,6-dihydropyridine-1( 2H )-benzyl carboxylate

Figure 110128222-A0202-12-0851-672
Figure 110128222-A0202-12-0851-672

步驟1：4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-5,6-二氫吡啶-1(2H)-甲酸苯甲酯之合成Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-5,6-dihydropyridine-1(2H) -Synthesis of benzyl formate

在10℃下，向4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2- 基)-1,2,3,6-四氫吡啶(36g，146.61mmol，HCl)及碳酸氫鈉(30.79g，366.53mmol，14.26mL)於THF(700mL)及水(350mL)中之溶液中逐滴添加氯甲酸苯甲酯(32.51g，190.59mmol)。將反應混合物在室溫下攪拌攪拌12h，且在真空中蒸發溶劑。將殘餘物用水(300mL)處理且用EtOAc(2x200mL)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到呈黃色固體之產物4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(45g，131.11mmol，89.43%產率)。At 10 °C, to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,6-tetra To a solution of hydropyridine (36 g, 146.61 mmol, HCl) and sodium bicarbonate (30.79 g, 366.53 mmol, 14.26 mL) in THF (700 mL) and water (350 mL) was added benzyl chloroformate (32.51 g, 190.59 mmol). The reaction mixture was stirred at room temperature for 12 h, and the solvent was evaporated in vacuo. The residue was treated with water (300 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the product 4-(4,4,5,5-tetramethyl-1,3,2- as a yellow solid Dioxaborol-2-yl)-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (45 g, 131.11 mmol, 89.43% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.15(s,12H),2.06(m,2H),3.36(m,2H),3.92(m,2H),5.04(s,2H),6.35(m,1H),7.32(m,5H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.15(s, 12H), 2.06(m, 2H), 3.36(m, 2H), 3.92(m, 2H), 5.04(s, 2H), 6.35 (m, 1H), 7.32 (m, 5H).

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=1.676min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=1.676 min.

步驟2：5-甲基-5,5',6,6'-四氫-[2,4'-聯吡啶]-1,1'(2'H,4H)-二甲酸1'-苯甲酯1-第三丁酯之合成Step 2: 5-Methyl-5,5',6,6'-tetrahydro-[2,4'-bipyridine]-1,1'(2'H,4H)-dicarboxylic acid 1'-benzyl Synthesis of ester 1-tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(30.79g，89.15mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(45g，111.44mmol)、[1,1'-雙( 二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(3.64g，4.46mmol)及碳酸鈉(28.35g，267.46mmol，11.20mL)於二噁烷(420mL)及水(140mL)中之混合物在90℃、氬氣氣氛下攪拌28h。冷卻至室溫之後，過濾出反應混合物。將濾餅用二噁烷(600mL)洗滌且丟棄。在減壓下濃縮濾液且藉由矽膠急驟層析，使用0至100% EtOAc-己烷梯度溶析來純化殘餘物，以得到6-(1-苯甲氧基羰基-3,6-二氫-2H -吡啶-4-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(9.1g，22.06mmol，24.74%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (30.79 g, 89.15 mmol), 4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (45g , 111.44 mmol), a complex of [1,1'- bis( diphenylphosphino)ferrocene]dichloropalladium(II) and DCM (3.64 g, 4.46 mmol) and sodium carbonate (28.35 g, 267.46 mmol) , 11.20 mL) in dioxane (420 mL) and water (140 mL) was stirred at 90 °C under argon atmosphere for 28 h. After cooling to room temperature, the reaction mixture was filtered off. The filter cake was washed with dioxane (600 mL) and discarded. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% EtOAc-hexane gradient to give 6-(1-benzyloxycarbonyl-3,6-dihydro - 2H -Pyridin-4-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (9.1 g, 22.06 mmol, 24.74% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.94(d,3H),1.26(m,2H),1.42(s,9H),1.71(m,1H),1.89(m,1H),2.27(m,2H),2.83(m,1H),3.70(m,2H),3.88(m,1H),4.03(m,2H),5.16(s,2H),5.67(m,1H),7.35(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.94(d, 3H), 1.26(m, 2H), 1.42(s, 9H), 1.71(m, 1H), 1.89(m, 1H), 2.27( m, 2H), 2.83(m, 1H), 3.70(m, 2H), 3.88(m, 1H), 4.03(m, 2H), 5.16(s, 2H), 5.67(m, 1H), 7.35(m , 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值312.2；實測值313.2；Rt=1.634min。LCMS (ESI): [M-Boc] + m/z: calculated 312.2; found 313.2; Rt=1.634 min.

步驟3：5-甲基-3,4,5,5',6,6'-六氫-[2,4'-聯吡啶]-1'(2'H)-甲酸苯甲酯之合成Step 3: Synthesis of benzyl 5-methyl-3,4,5,5',6,6'-hexahydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

在室溫下，將磷酸(21.38g，218.17mmol，12.58mL)小心添加到6-(1-苯甲氧基羰基-3,6-二氫-2H -吡啶-4-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(9g，21.82mmol)於DCM(100mL)中之溶液中。然後將反應混合物在室溫下攪拌12h。將碎冰(25g)添加到殘餘物中且將pH用5% Na2 CO3 水溶液調節至8。將所得混合物用DCM(2*150mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(7g，粗品)，其直接用於下一步驟中。Phosphoric acid (21.38 g, 218.17 mmol, 12.58 mL) was carefully added to 6-(1-benzyloxycarbonyl-3,6-dihydro- 2H -pyridin-4-yl)-3-methyl at room temperature A solution of tert-butyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid (9 g, 21.82 mmol) in DCM (100 mL). The reaction mixture was then stirred at room temperature for 12 h. Crushed ice (25 g) was added to the residue and the pH was adjusted to 8 with 5 % aqueous Na2CO3 . The resulting mixture was extracted with DCM (2*150 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)- as a brown oil 3,6-Dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (7 g, crude) was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.84(d,3H),1.29(m,5H),2.12(m,4H),2.86(m,2H),3.48(m,1H),4.12(m,2H),5.05(s,2H),7.29(m,5H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.84(d, 3H), 1.29(m, 5H), 2.12(m, 4H), 2.86(m, 2H), 3.48(m, 1H), 4.12 (m, 2H), 5.05 (s, 2H), 7.29 (m, 5H).

LCMS(ESI)：[M]+ m/z：計算值312.2；實測值313.2；Rt=1.039min。LCMS (ESI): [M] + m/z: calculated 312.2; found 313.2; Rt=1.039 min.

步驟4：外消旋-4-((2R,5S)-5-甲基哌啶-2-基)-5,6-二氫吡啶-1(2H)-甲酸苯甲酯之合成Step 4: Synthesis of rac-4-((2R,5S)-5-methylpiperidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

在0℃下，將硼氫化鈉(1.27g，33.61mmol，1.19mL)一次性添加到4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(7g，22.41mmol)於MeOH(150mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(150mL)稀釋且用DCM(2*200mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之4-[(2R,5S )-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(7g，粗品)，其直接用於下一步驟中。At 0 °C, sodium borohydride (1.27 g, 33.61 mmol, 1.19 mL) was added in one portion to 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3, Benzyl 6-dihydro- 2H -pyridine-1-carboxylate (7 g, 22.41 mmol) in a stirred solution of MeOH (150 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (150 mL) and extracted with DCM (2*200 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 4-[( 2R,5S )-5-methyl-2-piperidinyl]-3,6- as a brown oil Benzyl dihydro- 2H -pyridine-1-carboxylate (7 g, crude) was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.74(d,3H),0.96(m,1H),1.06(m,5H),1.56(m,2H),2.12(m,3H),2.86(m,2H),3.29(m,1H),4.12(m,1H),4.46(m,1H),5.04(s,2H),7.29(m,5H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.74(d,3H), 0.96(m,1H), 1.06(m,5H), 1.56(m,2H), 2.12(m,3H), 2.86(m, 2H), 3.29(m, 1H), 4.12(m, 1H), 4.46(m, 1H), 5.04(s, 2H), 7.29(m, 5H).

LCMS(ESI)：[M]+ m/z：計算值314.2；實測值315.2；Rt=1.076min。LCMS (ESI): [M] + m/z: calculated 314.2; found 315.2; Rt=1.076 min.

6BBB.外消旋 -3-((2R,5S)-5-甲基哌啶-2-基)-5,6-二氫吡啶-1(2H )-甲酸苯甲酯之合成6BBB. The synthesis of racemic -3-((2R,5S)-5-methylpiperidin-2-yl)-5,6-dihydropyridine-1( 2H )-carboxylate benzyl

Figure 110128222-A0202-12-0854-673
Figure 110128222-A0202-12-0854-673

步驟1：5-甲基-5,5',6,6'-四氫-[2,3'-聯吡啶]-1,1'(2'H,4H)-二甲酸1'-苯甲酯1-第三丁酯之合成Step 1: 5-Methyl-5,5',6,6'-tetrahydro-[2,3'-bipyridine]-1,1'(2'H,4H)-dicarboxylic acid 1'-benzyl Synthesis of ester 1-tert-butyl ester

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(12g，34.96mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(14.49g，41.96mmol)、碳酸鈉(11.12g，104.89mmol，4.39mL)於二噁烷(100mL)及水(30mL)中之溶液抽真空且用Ar再填充三次。向此混合物中添加[1,1'-雙( 二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(1.43g，1.75mmol)且將所得混合物在95℃下攪拌12h，冷卻，過濾且蒸發。將殘餘物溶解於水(200ml)中且用MTBE(3*200ml)萃取。將有機層用鹽水(150ml)洗滌，經Na2 SO4 乾燥，透過SiO2 薄層過濾且在真空中蒸發，以得到6-(1-苯甲氧基羰基-3,6-二氫-2H -吡啶-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(15g，粗品)。此化合物不經進一步純化即用於下一步驟。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro- 2H -pyridine-1-carboxylic acid Benzyl methyl ester (12 g, 34.96 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (14.49 g , 41.96 mmol), sodium carbonate (11.12 g, 104.89 mmol, 4.39 mL) in dioxane (100 mL) and water (30 mL) was evacuated and refilled three times with Ar. To this mixture was added [1,1'- bis( diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (1.43 g, 1.75 mmol) and the resulting mixture was stirred at 95 °C 12h, cooled, filtered and evaporated. The residue was dissolved in water (200ml) and extracted with MTBE (3*200ml). The organic layer was washed with brine (150 ml), dried over Na 2 SO 4 , filtered through a thin layer of SiO 2 and evaporated in vacuo to give 6-(1-benzyloxycarbonyl-3,6-dihydro- 2H -Pyridin-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (15 g, crude). This compound was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.93(d,3H),1.21(s,9H),2.16(m,4H),2.77(m,1H),3.48(m,3H),3.86(m,2H),4.06(m,1H),4.25(m,1H),5.11(s,2H),5.77(m,1H),7.32(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.93(d, 3H), 1.21(s, 9H), 2.16(m, 4H), 2.77(m, 1H), 3.48(m, 3H), 3.86( m, 2H), 4.06 (m, 1H), 4.25 (m, 1H), 5.11 (s, 2H), 5.77 (m, 1H), 7.32 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值312.2；實測值313.2；Rt=1.749min。LCMS (ESI): [M-Boc] + m/z: calculated 312.2; found 313.2; Rt=1.749 min.

步驟2：5-甲基-3,4,5,5',6,6'-六氫-[2,3'-聯吡啶]-1'(2'H)-甲酸苯甲酯之合成Step 2: Synthesis of benzyl 5-methyl-3,4,5,5',6,6'-hexahydro-[2,3'-bipyridine]-1'(2'H)-carboxylate

將6-(1-苯甲氧基羰基-3,6-二氫-2H -吡啶-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(15g，36.36mmol)於TFA(62.19g，545.43mmol，42.02mL) 中之溶液在25℃下攪拌2h且在真空中移除溶劑。將殘餘物溶解於水(150ml)中且將pH用NaOH溶液調節至8-9，用DCM(3*100)萃取。將有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且在真空中移除溶劑，以得到呈棕色膠狀物之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(11g，粗品)。此化合物不經進一步純化即用於下一步驟。6-(1-Benzyloxycarbonyl-3,6-dihydro- 2H -pyridin-5-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl A solution of the ester (15 g, 36.36 mmol) in TFA (62.19 g, 545.43 mmol, 42.02 mL) was stirred at 25 °C for 2 h and the solvent was removed in vacuo. The residue was dissolved in water (150 ml) and the pH was adjusted to 8-9 with NaOH solution, extracted with DCM (3*100). The organic layer was washed with brine (100 ml), dried over Na 2 SO 4 and the solvent was removed in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydro as a brown gum Pyridin-6-yl)-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (11 g, crude). This compound was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.23(m,2H),1.68(m,2H),1.96(m,2H),2.24(m,4H),2.78(m,1H),3.54(m,1H),4.25(m,1H),4.57(m,1H),5.15(s,2H),7.35(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d,3H), 1.23(m,2H), 1.68(m,2H), 1.96(m,2H), 2.24(m,4H), 2.78( m, 1H), 3.54 (m, 1H), 4.25 (m, 1H), 4.57 (m, 1H), 5.15 (s, 2H), 7.35 (m, 5H).

LCMS(ESI)：[M]+ m/z：計算值312.2；實測值313.2；Rt=0.901min。LCMS (ESI): [M] + m/z: calculated 312.2; found 313.2; Rt=0.901 min.

步驟3：外消旋-3-((2R,5S)-5-甲基哌啶-2-基)-5,6-二氫吡啶-1(2H)-甲酸苯甲酯之合成Step 3: Synthesis of rac-3-((2R,5S)-5-methylpiperidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

在0℃下，向5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(11g，35.21mmol)於MeOH(100mL)中之溶液中分批添加硼氫化鈉(2.00g，52.82mmol，1.87mL)。將所得混合物攪拌2h，且在真空中蒸發溶劑，且將殘餘物溶解於水(150ml)且用DCM(3*100ml)萃取，用鹽水(100ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以得到粗品5-[(2R,5S )-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(10g，粗品)。此化合物不經純化即用於下一步驟。Add 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl methyl ester (11 g) at 0 °C , 35.21 mmol) in MeOH (100 mL) was added portionwise sodium borohydride (2.00 g, 52.82 mmol, 1.87 mL). The resulting mixture was stirred for 2h, and the solvent was evaporated in vacuo, and the residue was dissolved in water (150ml) and extracted with DCM (3*100ml), washed with brine (100ml), dried over Na2SO4 and in vacuo Evaporated to give crude 5-[( 2R,5S )-5-methyl-2-piperidinyl]-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (10 g, crude). This compound was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.82(m,1H),0.98(d,3H),1.69(m,3H),1.95(m,1H),2.10(m,2H),2.62(m,2H),3.17(m,2H),3.54(m,1H),3.95(m,2H),4.55(m,1H),4.78(m,1H),5.12(s,2H),7.33(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.82(m, 1H), 0.98(d, 3H), 1.69(m, 3H), 1.95(m, 1H), 2.10(m, 2H), 2.62( m, 2H), 3.17(m, 2H), 3.54(m, 1H), 3.95(m, 2H), 4.55(m, 1H), 4.78(m, 1H), 5.12(s, 2H), 7.33(m , 5H).

LCMS(ESI)：[M]+ m/z：計算值314.2；實測值315.2；Rt=0.941min。LCMS (ESI): [M] + m/z: calculated 314.2; found 315.2; Rt=0.941 min.

6CCC. 7-(5-甲基哌啶-2-基)-3,4-二氫-2H -苯并[b ][1,4 ]噁嗪之合成6CCC. Synthesis of 7-(5-methylpiperidin-2-yl)-3,4-dihydro- 2H -benzo[ b ][ 1,4 ]oxazine

Figure 110128222-A0202-12-0856-674
Figure 110128222-A0202-12-0856-674

步驟1：7-溴-3,4-二氫-2H-苯并[b][1,4]噁嗪之合成Step 1: Synthesis of 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine

在氬氣下，向LAH(1.21g，31.85mmol)於THF(10mL)中之懸浮液中小心逐滴添加於THF(100mL)中之7-溴-4H -1,4-苯并噁嗪-3-酮(6.05g，26.54mmol)。將所得混合物在70℃下加熱12h。冷卻至室溫之後，逐滴添加1ml於水中之50% KOH溶液。過濾所得沉澱，用THF(2x5ml)洗滌且丟棄。將所獲得之溶劑合併，用硫酸鈉乾燥且蒸發，以獲得7-溴-3,4-二氫-2H -1,4-苯并噁嗪(5.9g，粗品)，其不經進一步純化即用於下一步驟。To a suspension of LAH (1.21 g, 31.85 mmol) in THF (10 mL) under argon was carefully added dropwise 7-bromo- 4H -1,4-benzoxazine- 3-keto (6.05 g, 26.54 mmol). The resulting mixture was heated at 70 °C for 12 h. After cooling to room temperature, 1 ml of a 50% KOH solution in water was added dropwise. The resulting precipitate was filtered, washed with THF (2x5ml) and discarded. The obtained solvents were combined, dried over sodium sulfate and evaporated to give 7-bromo-3,4-dihydro- 2H -1,4-benzoxazine (5.9 g, crude) which was used without further purification for the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)3.38(t,2H),4.22(t,2H),5.28(m,1H),6.46(d,1H),6.82(d,1H),6.89(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 3.38(t, 2H), 4.22(t, 2H), 5.28(m, 1H), 6.46(d, 1H), 6.82(d, 1H), 6.89( s, 1H).

GCMS：計算值214.2；實測值214.2；Rt=9.248min。GCMS: Calculated 214.2; Found 214.2; Rt=9.248min.

步驟2：7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-苯并[b][1,4]噁嗪之合成Step 2: 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-2H-benzo[ Synthesis of b][1,4]oxazine

將乙酸鉀(3.97g，40.46mmol，2.53mL)添加到7-溴-3,4-二氫-2H -1,4-苯并噁嗪(3.94g，18.39mmol)於二噁烷(40mL)中之溶液中，隨後添加雙( 頻哪醇)二硼(4.67g，18.39mmol)及Pd(dppf)Cl2 (672.76mg，919.44μmol)。將所得溶液在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋，過濾且蒸發。藉由管柱層析(己烷/MTBE)純化所得粗沉澱，以獲得7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H -1,4-苯并噁嗪(710mg，2.72mmol，14.79%產率)。Potassium acetate (3.97 g, 40.46 mmol, 2.53 mL) was added to 7-bromo-3,4-dihydro- 2H -1,4-benzoxazine (3.94 g, 18.39 mmol) in dioxane (40 mL) To this solution, bis( pinacol)diboron (4.67 g, 18.39 mmol) and Pd(dppf)Cl2 ( 672.76 mg, 919.44 μmol) were then added. The resulting solution was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc, filtered and evaporated. The resulting crude precipitate was purified by column chromatography (hexane/MTBE) to obtain 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3,4-dihydro- 2H -1,4-benzoxazine (710 mg, 2.72 mmol, 14.79% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.29(s,12),3.42(t,2H),4.20(t,2H),6.52(d,1H),7.21(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.29 (s, 12), 3.42 (t, 2H), 4.20 (t, 2H), 6.52 (d, 1H), 7.21 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值261.2；實測值262.2；Rt=1.369min。LCMS (ESI): [M] + m/z: calculated 261.2; found 262.2; Rt=1.369 min.

步驟3：6-(3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: 6-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-methyl-3,4-dihydropyridine-1(2H) -Synthesis of tert-butyl formate

向碳酸鉀(1.13g，8.16mmol，492.31μL)於水(10mL)中之溶液中添加7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H -1,4-苯并噁嗪(710mg，2.72mmol)於二噁烷(10mL)中之溶液，隨後添加3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.03g，2.99mmol)及Pd(dppf)Cl2 (99.48mg，135.95μmol)。將所得混合物在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋且用水(2x40ml)洗滌。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得6-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(900mg，粗品)。To a solution of potassium carbonate (1.13 g, 8.16 mmol, 492.31 μL) in water (10 mL) was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborole) Pentan-2-yl)-3,4-dihydro- 2H -1,4-benzoxazine (710 mg, 2.72 mmol) in dioxane (10 mL) followed by 3-methyl-6 -(Trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.03 g, 2.99 mmol) and Pd(dppf)Cl 2 (99.48 mg, 135.95 μmol). The resulting mixture was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc and washed with water (2x40ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 6-(3,4-dihydro- 2H -1,4-benzoxazin-7-yl)-3-methyl-3,4-di Hydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (900 mg, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.01(d,3H),1.17(m,3H),1.29(s,9H),1.81(m,1H),1.99(m,1H),2.38(m,1H),2.93(m,1H),3.43(m,2H),3.98(m,1H),4.24(m,1H),6.64(m,3H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.01(d, 3H), 1.17(m, 3H), 1.29(s, 9H), 1.81(m, 1H), 1.99(m, 1H), 2.38( m, 1H), 2.93 (m, 1H), 3.43 (m, 2H), 3.98 (m, 1H), 4.24 (m, 1H), 6.64 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值330.2；實測值331.2；Rt=1.394min。LCMS (ESI): [M] + m/z: calculated 330.2; found 331.2; Rt=1.394 min.

步驟4：7-(5-甲基-3,4,5,6-四氫吡啶-2-基)-3,4-二氫-2H-苯并[b][1,4]噁嗪之合成Step 4: 7-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine synthesis

將6-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.25g，3.78mmol)於TFA(5mL)及DCM(5mL)中之溶液在25℃下攪拌12h。將飽和碳酸鉀水溶液添加到該溶液(50ml)中，然後用DCM(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得7-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-2H -1,4-苯并噁嗪(882mg，粗品)。6-(3,4-Dihydro- 2H -1,4-benzoxazin-7-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.25 g, 3.78 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 25 °C for 12 h. Saturated aqueous potassium carbonate solution was added to the solution (50ml), then extracted with DCM (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 7-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro- 2H -1, 4-Benzoxazine (882 mg, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.94(d,3H),1.72(m,4H),2.49(m,1H),3.02(m,1H),3.22(m,1H),3.40(m,2H),3.89(m,1H),4.21(m,1H),6.58(m,2H),6.74(m,1H),6.98(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.94(d,3H), 1.72(m,4H), 2.49(m,1H), 3.02(m,1H), 3.22(m,1H), 3.40( m, 2H), 3.89 (m, 1H), 4.21 (m, 1H), 6.58 (m, 2H), 6.74 (m, 1H), 6.98 (m, 1H).

步驟5：7-(5-甲基哌啶-2-基)-3,4-二氫-2H-苯并[b][1,4]噁嗪之合成Step 5: Synthesis of 7-(5-Methylpiperidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

將硼氫化鈉(173.87mg，4.60mmol，162.49μL)分批添加到7-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-2H -1,4-苯并噁嗪(882mg，3.83mmol)於MeOH(10mL)中之溶液中。將混合物在室溫下攪拌2h。添加水(50ml)且將所得混合物用EtOAc(2x30ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得7-(5-甲基-2-哌啶基)-3,4-二氫-2H-1,4-苯并噁嗪(0.68g，粗品)。Sodium borohydride (173.87 mg, 4.60 mmol, 162.49 μL) was added portionwise to 7-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro- A solution of 2H -1,4-benzoxazine (882 mg, 3.83 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 2 h. Water (50ml) was added and the resulting mixture was extracted with EtOAc (2x30ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 7-(5-methyl-2-piperidinyl)-3,4-dihydro-2H-1,4-benzoxazine (0.68 g, Crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.84(d,3H),1.48(m,2H),1.76(m,5H),2.36(m,1H),3.09(m,1H),3.40(m,2H),4.22(m,2H),6.58(m,2H),6.75(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.84(d, 3H), 1.48(m, 2H), 1.76(m, 5H), 2.36(m, 1H), 3.09(m, 1H), 3.40( m, 2H), 4.22 (m, 2H), 6.58 (m, 2H), 6.75 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值232.2；實測值233.2；Rt=0.789min。LCMS (ESI): [M] + m/z: calculated 232.2; found 233.2; Rt=0.789 min.

6DDD.外消旋 -5-((2R,5S )-5-甲基哌啶-2-基)異吲哚啉-1-酮之合成6DDD. Synthesis of racemic -5-(( 2R,5S )-5-methylpiperidin-2-yl)isoindolin-1-one

Figure 110128222-A0202-12-0858-1
Figure 110128222-A0202-12-0858-1

步驟1：3-甲基-6-(1-側氧基異吲哚啉-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(1-oxyisoindolin-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異吲哚啉-1-酮(4g，15.44mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5.86g，16.98mmol)及碳酸鈉(3.27g，30.88mmol，1.29mL)一起混合於二噁烷(60mL)及水(20mL)之混合物中。將燒瓶抽真空且用氬氣回填三次，且向其中添加二氯(1,1'-雙( 二苯基磷烷基)二茂鐵)鈀(II)*DCM(630.12mg，771.88μmol)。將反應混合物在75℃下加熱12h。將反應混合物用EtOAc稀釋，將所形成之固體過濾出，用另外的EtOAc洗滌且在真空下乾燥，以得到3-甲基-6-(1-側氧基異吲哚啉-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.7g，11.27mmol，72.98%產率)，其不經進一步純化即用於下一步驟。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)isoindolin-1-one (4 g, 15.44 mmol), 3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (5.86 g, 16.98 mmol) and sodium carbonate (3.27 g , 30.88 mmol, 1.29 mL) were mixed together in a mixture of dioxane (60 mL) and water (20 mL). The flask was evacuated and backfilled with argon three times, and to it was added dichloro(1,1'- bis( diphenylphosphonyl)ferrocene)palladium(II)*DCM (630.12 mg, 771.88 μmol). The reaction mixture was heated at 75 °C for 12 h. The reaction mixture was diluted with EtOAc, the solid formed was filtered off, washed with additional EtOAc and dried under vacuum to give 3-methyl-6-(1-oxyisoindolin-5-yl) -3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.7 g, 11.27 mmol, 72.98% yield), which was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.98(s,12H),1.87(m,2H),2.41(m,1H),3.03(m,1H),3.88(m,1H),4.32(m,2H),5.43(m,1H),7.42(m,3H),8.46(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.98(s, 12H), 1.87(m, 2H), 2.41(m, 1H), 3.03(m, 1H), 3.88(m, 1H), 4.32 (m, 2H), 5.43 (m, 1H), 7.42 (m, 3H), 8.46 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值328.2；實測值329.2；Rt=3.610min。LCMS (ESI): [M] + m/z: calculated 328.2; found 329.2; Rt=3.610 min.

步驟2：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)異吲哚啉-1-酮之合成Step 2: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)isoindolin-1-one

將3-甲基-6-(1-側氧基異吲哚啉-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.67g，11.18mmol)溶解於DCM(11mL)及TFA(11mL)之混合物中，然後在室溫下攪拌1h。將反應混合物用20% NaOH水溶液中和，將所獲得之溶液用DCM稀釋，將有機相分離且將水層用額外DCM洗滌。將有機相經Na2 SO4 乾燥，過濾且在真空下濃縮，以得到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)異吲哚啉-1-酮(1.77g，7.73mmol，69.18%產率)，其不經進一步純化即用於下一步驟。Dissolve 3-methyl-6-(1-oxyisoindolin-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.67 g, 11.18 mmol) In a mixture of DCM (11 mL) and TFA (11 mL), then stirred at room temperature for 1 h. The reaction mixture was neutralized with 20% aqueous NaOH, the resulting solution was diluted with DCM, the organic phase was separated and the aqueous layer was washed with additional DCM. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)isoindoline-1- The ketone (1.77 g, 7.73 mmol, 69.18% yield) was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.03(d,3H),1.41(m,1H),1.75(m,2H),1.97(m,1H),2.65(m,1H),2.83(m,1H),3.31(m,1H),4.07(m,1H),4.46(m,1H),6.88(m,1H),7.88(m,3H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.03(d,3H), 1.41(m,1H), 1.75(m,2H), 1.97(m,1H), 2.65(m,1H), 2.83( m, 1H), 3.31 (m, 1H), 4.07 (m, 1H), 4.46 (m, 1H), 6.88 (m, 1H), 7.88 (m, 3H).

步驟3：外消旋-5-((2R,5S)-5-甲基哌啶-2-基)異吲哚啉-1-酮之合成Step 3: Synthesis of Racemic-5-((2R,5S)-5-methylpiperidin-2-yl)isoindolin-1-one

將5-(3-甲基-2,3,4,5-四氫吡啶-6-基)異吲哚啉-1-酮(1.77g，7.73mmol)溶解於MeOH(20mL)中且在使用冰水冷卻之情況下分批添加硼氫化鈉(877.50mg，23.19mmol，820.09μL)。將反應混合物加熱至室溫且攪拌12h。添加NH4 Cl(水溶液)且蒸發MeOH，將水層用DCM(3*30ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在45℃下在真空下蒸發，以得到5-[(2R,5S )-5-甲基-2-哌啶基]異吲哚啉-1-酮(1.24g，5.38mmol，69.64%產率)，其不經進一步純化即用於下一步驟。5-[(2R,5S )-5-甲基-2-哌啶基]異吲哚啉-1-酮(1.24g，5.38mmol，69.64%產率)。5-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)isoindolin-1-one (1.77 g, 7.73 mmol) was dissolved in MeOH (20 mL) and used Sodium borohydride (877.50 mg, 23.19 mmol, 820.09 μL) was added portionwise under ice-water cooling. The reaction mixture was warmed to room temperature and stirred for 12 h. NH4Cl (aq) was added and MeOH was evaporated, the aqueous layer was extracted with DCM (3*30ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated under vacuum at 45°C to give 5 -[( 2R,5S )-5-methyl-2-piperidinyl]isoindolin-1-one (1.24 g, 5.38 mmol, 69.64% yield), which was used in the next step without further purification step. 5-[( 2R,5S )-5-methyl-2-piperidinyl]isoindolin-1-one (1.24 g, 5.38 mmol, 69.64% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.89(d,3H),1.17(m,2H),1.85(m,4H),2.42(m,1H),3.15(m,1H),3.64(m,1H),4.40(m,2H),6.96(m,1H),7.50(m,2H),7.78(m, 1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.89(d,3H), 1.17(m,2H), 1.85(m,4H), 2.42(m,1H), 3.15(m,1H), 3.64( m, 1H), 4.40 (m, 2H), 6.96 (m, 1H), 7.50 (m, 2H), 7.78 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值230.2；實測值231.2；Rt=0.889min。LCMS (ESI): [M] + m/z: calculated 230.2; found 231.2; Rt=0.889 min.

6EEE. 5-(4-(5-甲基哌啶-2-基)苯基)噻唑之合成6EEE. Synthesis of 5-(4-(5-methylpiperidin-2-yl)phenyl)thiazole

Figure 110128222-A0202-12-0860-2
Figure 110128222-A0202-12-0860-2

步驟1：5-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)噻唑之合成Step 1: Synthesis of 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)thiazole

將乙酸鉀(11.44g，116.61mmol，7.29mL)添加到5-(4-溴苯基)噻唑(14g，58.30mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(16.29g，64.13mmol)於二噁烷(150mL)中之溶液中。將反應燒瓶抽真空且用Ar再填充3次。然後在氬氣流下添加Pd(dppf)Cl2 *DCM(2.38g，2.92mmol)。在90℃、惰性氣氛下將所得混合物攪拌14h。然後，將其冷卻，用EtOAc(400mL)稀釋且用水(2x200mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟層析，使用0至100%己烷-MTBE梯度溶析來純化殘餘物，以得到5-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]噻唑(10g，34.82mmol，59.72%產率)。Potassium acetate (11.44 g, 116.61 mmol, 7.29 mL) was added to 5-(4-bromophenyl)thiazole (14 g, 58.30 mmol) and 4,4,5,5-tetramethyl-2-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (16.29 g, 64.13 mmol) in dioxane (150 mL). The reaction flask was evacuated and refilled 3 times with Ar. Then Pd(dppf)Cl2*DCM (2.38 g , 2.92 mmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 14 h. It was then cooled, diluted with EtOAc (400 mL) and washed with water (2 x 200 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a 0 to 100% hexane-MTBE gradient to give 5-[4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)phenyl]thiazole (10 g, 34.82 mmol, 59.72% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.32(s,12H),7.58(d,2H),7.68(d,2H),8.12(s,1H),8.82(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.32 (s, 12H), 7.58 (d, 2H), 7.68 (d, 2H), 8.12 (s, 1H), 8.82 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值287.2；實測值288.2；Rt=1.546min。LCMS (ESI): [M] + m/z: calculated 287.2; found 288.2; Rt=1.546 min.

步驟2：3-甲基-6-(4-(噻唑-5-基)苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 2: Synthesis of 3-methyl-6-(4-(thiazol-5-yl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4.81g，13.93mmol)、5-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]噻唑(4g，13.93mmol)及碳酸鈉(4.43g，41.79mmol，1.75mL)添加到水(15mL)及二噁烷(45mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作 重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(568.72mg，696.42μmol)。將反應混合物在氬氣、70℃下攪拌14h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之3-甲基-6-(4-噻唑-5-基苯基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4g，11.22mmol，80.56%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4.81 g, 13.93 mmol), 5-[4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]thiazole (4 g, 13.93 mmol) and sodium carbonate (4.43 g, 41.79 mmol, 1.75 mL) was added to a mixture of water (15 mL) and dioxane (45 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM ( 568.72 mg, 696.42 μmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 14 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 3-methyl-6-(4-thiazol-5-ylphenyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl as a brown oil Ester (4 g, 11.22 mmol, 80.56% yield), which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.95(d,3H),1.06(s,9H),1.86(m,1H),2.46(m,1H),3.12(m,1H),3.26(m,1H),4.42(m,1H),5.72(m,1H),7.28(d,2H),7.67(d,2H),8.29(s,1H),9.06(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.95(d,3H), 1.06(s,9H), 1.86(m,1H), 2.46(m,1H), 3.12(m,1H), 3.26(m,1H), 4.42(m,1H), 5.72(m,1H), 7.28(d,2H), 7.67(d,2H), 8.29(s,1H), 9.06(s,1H).

LCMS(ESI)：[M]+ m/z：計算值356.2；實測值357.2；Rt=1.654min。LCMS (ESI): [M] + m/z: calculated 356.2; found 357.2; Rt=1.654 min.

步驟3：5-(4-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)噻唑之合成Step 3: Synthesis of 5-(4-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)thiazole

將3-甲基-6-(4-噻唑-5-基苯基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4g，11.22mmol)於TFA(19.19g，168.31mmol，12.97mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用DCM(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之5-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]噻唑(2.8g，10.92mmol，97.34%產率)，其直接用於下一步驟中。3-Methyl-6-(4-thiazol-5-ylphenyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (4 g, 11.22 mmol) in TFA (19.19 g, The solution in 168.31 mmol, 12.97 mL) was stirred at 25°C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with DCM (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-[4-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a brown oil yl)phenyl]thiazole (2.8 g, 10.92 mmol, 97.34% yield), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.89(d,3H),1.28(m,1H),1.58(m,1H),1.82(m,1H),2.71(m,1H),3.15(m,1H),3.86(m,1H),4.30(m,1H),7.41(d,2H),7.64(d,2H),8.32(s,1H),9.05(s,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.89(d,3H), 1.28(m,1H), 1.58(m,1H), 1.82(m,1H), 2.71(m,1H), 3.15(m, 1H), 3.86(m, 1H), 4.30(m, 1H), 7.41(d, 2H), 7.64(d, 2H), 8.32(s, 1H), 9.05(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值256.2；實測值257.2；Rt=0.945min。LCMS (ESI): [M] + m/z: calculated 256.2; found 257.2; Rt=0.945min.

步驟4：5-(4-(5-甲基哌啶-2-基)苯基)噻唑之合成Step 4: Synthesis of 5-(4-(5-methylpiperidin-2-yl)phenyl)thiazole

在0℃下，將硼氫化鈉(826.41mg，21.84mmol，772.34μL)一次性添加到5-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]噻唑(2.8g，10.92mmol)於MeOH(50mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌12h，然後在真空中 蒸發。將殘餘物用水(20ml)稀釋且用DCM(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以MeOH為溶析液混合物)，以得到5-[4-(5-甲基-2-哌啶基)苯基]噻唑(0.37g，1.43mmol，13.11%產率)。Sodium borohydride (826.41 mg, 21.84 mmol, 772.34 μL) was added in one portion to 5-[4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) at 0 °C Phenyl]thiazole (2.8 g, 10.92 mmol) in a stirred solution of MeOH (50 mL). The resulting mixture was stirred at 25 °C for 12 h, then in vacuo evaporation. The residue was diluted with water (20ml) and extracted with DCM (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The oil obtained was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with MeOH as eluent mixture) to give 5-[4-(5-methyl-2-piperidinyl)phenyl ]thiazole (0.37 g, 1.43 mmol, 13.11% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.81(d,3H),1.08(m,1H),1.22(m,1H),1.48(m,1H),1.71(m,2H),2.22(m,1H),2.96(m,1H),3.46(m,1H),4.36(m,1H),7.39(d,2H),7.54(d,2H),8.28(s,1H),9.05(s,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.81(d,3H), 1.08(m,1H), 1.22(m,1H), 1.48(m,1H), 1.71(m,2H), 2.22(m, 1H), 2.96(m, 1H), 3.46(m, 1H), 4.36(m, 1H), 7.39(d, 2H), 7.54(d, 2H), 8.28(s, 1H), 9.05 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值258.2；實測值259.2；Rt=1.410min。LCMS (ESI): [M] + m/z: calculated 258.2; found 259.2; Rt=1.410 min.

6FFF. 6-[(2S,5R)-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成6FFF. Synthesis of 6-[(2S,5R)-5-methyl-2-piperidinyl]-1,3-benzothiazole

Figure 110128222-A0202-12-0862-3
Figure 110128222-A0202-12-0862-3

步驟1. 6-(1,3-苯并噻唑-6-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1. Synthesis of 6-(1,3-benzothiazol-6-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鈉(4.06g，38.29mmol，1.60mL)添加到6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(5g，19.15mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.27g，21.06mmol)於二噁烷(60mL)及水(20mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加二氯(1,1'-雙(二苯基磷烷基)二茂鐵)鈀(II)*CH2Cl2(781.50mg，957.32μmol)。在90℃、惰性氣氛下將所得混合物攪拌12h。在減壓下移除溶劑且將殘餘物再溶解於EA中。透過短矽膠墊過濾出不溶性固體且在真空中濃縮濾液，得到6-(1,3-苯并噻唑-6-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(6.11g，18.49mmol，96.57%產率)。Sodium carbonate (4.06 g, 38.29 mmol, 1.60 mL) was added to 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)- 1,3-benzothiazole (5 g, 19.15 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl A solution of the ester (7.27 g, 21.06 mmol) in dioxane (60 mL) and water (20 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, dichloro(1,1'-bis(diphenylphosphonyl)ferrocene)palladium(II)*CH2Cl2 (781.50 mg, 957.32 μmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 12 h. The solvent was removed under reduced pressure and the residue was redissolved in EA. The insoluble solid was filtered through a short pad of silica gel and the filtrate was concentrated in vacuo to give 6-(1,3-benzothiazol-6-yl)-3-methyl-3,4-dihydro-2H-pyridine-1- 3-Butyl formate (6.11 g, 18.49 mmol, 96.57% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.99(m,13H),1.46(m,1H),1.85(m,1H),2.02(m,1H),2.40(m,1H),3.04(m,1H),4.07(m,1H),5.37(m,1H),7.46(d,1H),7.84(s, 1H),7.99(d,1H),8.92(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.99(m, 13H), 1.46(m, 1H), 1.85(m, 1H), 2.02(m, 1H), 2.40(m, 1H), 3.04( m, 1H), 4.07 (m, 1H), 5.37 (m, 1H), 7.46 (d, 1H), 7.84 (s, 1H), 7.99 (d, 1H), 8.92 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值330.2；實測值331.0；Rt=1.542min。LCMS (ESI): [M+1] + m/z: calculated 330.2; found 331.0; Rt=1.542 min.

步驟2. 6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑之合成Step 2. Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole

將6-(1,3-苯并噻唑-6-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(6.11g，18.49mmol)溶解於DCM(18mL)及TFA(18mL)之混合物中，然後在室溫下攪拌1h。將反應混合物用20% NaOH水溶液中和，將所獲得之溶液用DCM稀釋，將有機相分離且將水層用額外DCM洗滌。將有機相經Na2 SO4 乾燥，過濾且在真空下濃縮，以得到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(4.1g，17.80mmol，96.27%產率)，其不經進一步純化即用於下一步驟。6-(1,3-Benzothiazol-6-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.11 g, 18.49 mmol) was dissolved in DCM (18 mL) and TFA (18 mL), then stirred at room temperature for 1 h. The reaction mixture was neutralized with 20% aqueous NaOH, the resulting solution was diluted with DCM, the organic phase was separated and the aqueous layer was washed with additional DCM. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzo Thiazole (4.1 g, 17.80 mmol, 96.27% yield) was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.00(m,3H),1.42(m,1H),1.74(m,1H),1.96(m,1H),2.65(m,1H),2.84(m,1H),3.29(m,1H),4.02(d,1H),7.96(d,1H),8.10(d,1H),8.39(s,1H),9.01(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.00(m, 3H), 1.42(m, 1H), 1.74(m, 1H), 1.96(m, 1H), 2.65(m, 1H), 2.84( m, 1H), 3.29 (m, 1H), 4.02 (d, 1H), 7.96 (d, 1H), 8.10 (d, 1H), 8.39 (s, 1H), 9.01 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值230.1；實測值231.2；Rt=0.581min。LCMS (ESI): [M+1] + m/z: calculated 230.1; found 231.2; Rt=0.581 min.

步驟3. 6-[(2S,5R)-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 3. Synthesis of 6-[(2S,5R)-5-methyl-2-piperidinyl]-1,3-benzothiazole

將6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(4.1g，17.80mmol)溶解於甲醇(40mL)中且在使用冰水冷卻之情況下分批添加硼氫化鈉(2.02g，53.40mmol，1.89mL)。將反應混合物加熱至室溫且攪拌12h。添加NH4 Cl(水溶液)且蒸發甲醇，將水層用DCM(3*30ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空下在45℃下蒸發，以得到6-[(2S,5R)-5-甲基-2-哌啶基]-1,3-苯并噻唑(4g，17.22mmol，96.71%產率)，其不經進一步純化即用於下一步驟。6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole (4.1 g, 17.80 mmol) was dissolved in methanol (40 mL) and used Sodium borohydride (2.02 g, 53.40 mmol, 1.89 mL) was added portionwise under ice-water cooling. The reaction mixture was warmed to room temperature and stirred for 12 h. NH4Cl (aq) was added and methanol was evaporated, the aqueous layer was extracted with DCM (3*30ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated under vacuum at 45°C to give 6 -[(2S,5R)-5-methyl-2-piperidinyl]-1,3-benzothiazole (4 g, 17.22 mmol, 96.71% yield), which was used in the next step without further purification .

1 H NMR(400MHz,CDCl3 )δ(ppm)0.90(m,3H),1.16(m,2H),1.57-1.65(m,3H),1.85(m,2H),2.43(t,1H),3.15(d,1H),3.67(d,1H),7.49(d,1H),7.98(s,1H),8.02(d,1H),8.92(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.90(m, 3H), 1.16(m, 2H), 1.57-1.65(m, 3H), 1.85(m, 2H), 2.43(t, 1H), 3.15(d,1H), 3.67(d,1H), 7.49(d,1H), 7.98(s,1H), 8.02(d,1H), 8.92(s,1H).

LCMS(ESI)：[M+1]+ m/z：計算值232.1；實測值233.2；Rt=0.837min。LCMS (ESI): [M+1] + m/z: calculated 232.1; found 233.2; Rt=0.837 min.

6GGG.外消旋 -5-[(2S ,5R )-5-甲基-2-哌啶基]-1,3-二氫苯并咪唑-2-酮之合成 6GGG . Synthesis of racemic -5-[(2S, 5R )-5-methyl-2-piperidinyl]-1,3-dihydrobenzimidazol-2-one

Figure 110128222-A0202-12-0864-4
Figure 110128222-A0202-12-0864-4

步驟1：3-甲基-6-(2-側氧基-1,3-二氫苯并咪唑-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: 3-Methyl-6-(2-oxo-1,3-dihydrobenzimidazol-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester synthesis

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.98g，11.53mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-二氫苯并咪唑-2-酮(3g，11.53mmol)及碳酸鉀(4.78g，34.60mmol，2.09mL)於1,4-二噁烷(50mL)及水(50mL)中之正攪拌懸浮液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 (421.98mg，576.71μmol)。將反應混合物在氬氣、90℃下攪拌12小時。12小時之後，將反應混合物冷卻且過濾。在真空中蒸發濾液且將殘餘物用水(80mL)及EtOAc稀釋。分離兩層。將有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得呈黑色膠狀物之3-甲基-6-(2-側氧基-1,3-二氫苯并咪唑-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.01g，粗品)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.98 g, 11.53 mmol), 5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-dihydrobenzimidazol-2-one (3 g, 11.53 mmol ) and potassium carbonate (4.78 g, 34.60 mmol, 2.09 mL) in 1,4-dioxane (50 mL) and water (50 mL) were stirred with argon purged. Then, Pd(dppf)Cl 2 (421.98 mg, 576.71 μmol) was added under argon. The reaction mixture was stirred under argon at 90°C for 12 hours. After 12 hours, the reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo and the residue was diluted with water (80 mL) and EtOAc. Separate the two layers. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain 3-methyl-6-(2-oxy-1,3-dihydrobenzimidazole- as a black gum) 5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2.01 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值329.2；實測值330.2；Rt=1.231min。LCMS (ESI): [M+H] + m/z: calculated 329.2; found 330.2; Rt=1.231 min.

步驟2：5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-1,3-二氫苯并咪唑-2-酮之合成Step 2: Synthesis of 5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-1,3-dihydrobenzimidazol-2-one

在0℃下，向3-甲基-6-(2-側氧基-1,3-二氫苯并咪唑-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.8g，5.46mmol)於DCM(20mL)中之經攪拌之溶液中逐滴添加CF3 CO2 H(20mL)。將所得反應混合物在25℃下攪拌2小時。2小時之後，將反應混合物小心倒入到K2 CO3 溶液(50mL)中且用DCM(2 x 50mL)萃取。 將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-1,3-二氫苯并咪唑-2-酮(1.92g，粗品)。粗產物不經任何進一步純化即用於下一步反應。To 3-methyl-6-(2-oxo-1,3-dihydrobenzimidazol-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid at 0 °C To a stirred solution of tert-butyl ester (1.8 g, 5.46 mmol) in DCM (20 mL) was added CF3CO2H ( 20 mL) dropwise. The resulting reaction mixture was stirred at 25°C for 2 hours. After 2 hours, the reaction mixture was carefully poured into K2CO3 solution (50 mL) and extracted with DCM ( 2 x 50 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain 5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-1, 3-Dihydrobenzimidazol-2-one (1.92 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值229.1；實測值230.2；Rt=0.697min。LCMS (ESI): [M+H] + m/z: calculated 229.1; found 230.2; Rt=0.697 min.

步驟3：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-二氫苯并咪唑-2-酮之合成Step 3: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-dihydrobenzimidazol-2-one

將碳酸鉀(1.74g，12.56mmol)於水(40mL)中之溶液添加到5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-1,3-二氫苯并咪唑-2-酮(1.92g，8.37mmol)中。將所得混合物攪拌30分鐘，然後蒸發至乾。添加DCM(50mL)且過濾所得混合物。將所獲得之殘餘物用DCM洗滌且在真空下乾燥，以獲得呈棕色固體之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-二氫苯并咪唑-2-酮(1.8g，粗品)。A solution of potassium carbonate (1.74 g, 12.56 mmol) in water (40 mL) was added to 5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-1,3-di in hydrobenzimidazol-2-one (1.92 g, 8.37 mmol). The resulting mixture was stirred for 30 minutes and then evaporated to dryness. DCM (50 mL) was added and the resulting mixture was filtered. The obtained residue was washed with DCM and dried under vacuum to obtain 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3- as a brown solid Dihydrobenzimidazol-2-one (1.8 g, crude).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.92(s,3H),1.26(m,1H),1.60(m,1H),1.83(m,1H),2.70(m,1H),3.14(m,2H),3.82(m,1H),6.91(m,2H),7.41(m,2H)。 1 H NMR (DMSO- d 6 , 500MHz): δ(ppm) 0.92(s, 3H), 1.26(m, 1H), 1.60(m, 1H), 1.83(m, 1H), 2.70(m, 1H) , 3.14 (m, 2H), 3.82 (m, 1H), 6.91 (m, 2H), 7.41 (m, 2H).

步驟4：外消旋-5-[(2S,5R)-5-甲基-2-哌啶基]-1,3-二氫苯并咪唑-2-酮之合成Step 4: Synthesis of Racemic-5-[(2S,5R)-5-methyl-2-piperidinyl]-1,3-dihydrobenzimidazol-2-one

在0℃下，將硼氫化鈉(593.99mg，15.70mmol)分批添加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-二氫苯并咪唑-2-酮(1.8g，7.85mmol)於MeOH(20mL)中之經攪拌之溶液中。將反應混合物在20℃下攪拌3小時。3小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用水(50mL)稀釋。將所得混合物用EtOAc(2 x 50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由HPLC純化所獲得之殘餘物，以獲得呈白色固體之外消旋 -5-[(2S ,5R )-5-甲基-2-哌啶基]-1,3-二氫苯并咪唑-2-酮(50.4mg，217.91μmol，2.78%產率)。Sodium borohydride (593.99 mg, 15.70 mmol) was added portionwise to 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-di at 0 °C In a stirred solution of hydrobenzimidazol-2-one (1.8 g, 7.85 mmol) in MeOH (20 mL). The reaction mixture was stirred at 20°C for 3 hours. After 3 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4 , filtered and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain rac -5-[( 2S , 5R )-5-methyl-2-piperidinyl]-1,3-dihydrobenzo as a white solid Imidazol-2-one (50.4 mg, 217.91 μmol, 2.78% yield).

LCMS(ESI)：[M+H]+ m/z：計算值231.2；實測值232.2；Rt=0.754min。LCMS (ESI): [M+H] + m/z: calculated 231.2; found 232.2; Rt=0.754 min.

6HHH. N-[4-(5-甲基-2-哌啶基)環己基]乙醯胺之合成6HHH. Synthesis of N-[4-(5-methyl-2-piperidinyl)cyclohexyl]acetamide

Figure 110128222-A0202-12-0866-5
Figure 110128222-A0202-12-0866-5

步驟1：4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-胺之合成Step 1: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-3-en-1-amine

向N -[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-基]胺甲酸第三丁 酯(7.5g，23.20mmol)於DCM(50mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌12小時。12小時之後，將反應混合物在減壓下濃縮，以獲得呈白色固體之4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-胺(5.9g，22.73mmol，97.96%產率，鹽酸鹽)。To N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-3-en-1-yl]amine To a stirred solution of tert -butyl formate (7.5 g, 23.20 mmol) in DCM (50 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (8.00 g, 219.41 mmol, 10 mL). The resulting mixture was stirred at 25°C for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure to obtain 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 as a white solid -yl)cyclohex-3-en-1-amine (5.9 g, 22.73 mmol, 97.96% yield, hydrochloride).

LCMS(ESI)：[M+H]+ m/z：計算值223.2；實測值224.2；Rt=0.840min。LCMS (ESI): [M+H] + m/z: calculated 223.2; found 224.2; Rt=0.840 min.

步驟2：N-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-基]乙醯胺之合成Step 2: N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-3-en-1-yl ] Synthesis of Acetamide

在0℃下，向4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-胺(5.9g，22.73mmol，鹽酸鹽)及三乙胺(6.90g，68.19mmol，9.50mL)於DCM(100mL)中之經攪拌之懸浮液中逐滴添加乙醯氯(2.14g，27.27mmol，1.66mL)。將所得反應混合物在室溫下攪拌3小時。3小時之後，添加水(50mL)。分離兩層。將有機層用鹽水(2 x 40mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈白色固體之N -[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-基]乙醯胺(5.5g，20.74mmol，91.26%產率)。To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-3-en-1-amine at 0 °C To a stirred suspension of (5.9 g, 22.73 mmol, hydrochloride) and triethylamine (6.90 g, 68.19 mmol, 9.50 mL) in DCM (100 mL) was added acetyl chloride (2.14 g, 27.27 mmol) dropwise , 1.66mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After 3 hours, water (50 mL) was added. Separate the two layers. The organic layer was washed with brine (2 x 40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain N- [4-(4,4,5,5-tetramethyl-1 as a white solid ,3,2-dioxaborol-2-yl)cyclohex-3-en-1-yl]acetamide (5.5 g, 20.74 mmol, 91.26% yield).

LCMS(ESI)：[M+H]+ m/z：計算值265.2；實測值266.2；Rt=1.109min。LCMS (ESI): [M+H] + m/z: calculated 265.2; found 266.2; Rt=1.109 min.

步驟3：6-(4-乙醯胺基環己烯-1-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 6-(4-acetamidocyclohexen-1-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將N -[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-基]乙醯胺(5.5g，20.74mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7.16g，20.74mmol)及碳酸鈉(6.60g，62.23mmol，2.61mL)於二噁烷(100mL)及水(20mL)中之經攪拌之懸浮液用氬氣吹掃10分鐘。10分鐘之後，添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(846.96mg，1.04mmol)。將所得反應混合物在氬氣、55℃下攪拌12小時。12小時之後，使反應混合物冷卻至室溫且過濾。將濾餅用二噁烷(50mL)洗滌。在減壓下濃縮濾液。將水(150mL)添加到所獲得之殘餘物中且用EtOAc(2 x 100mL)萃取。將經合併之有機相用鹽水(100mL)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得粗產物(9g)，其藉由管柱層析進行純化，以獲得呈淡黃色固體之6-(4-乙醯胺基環己烯-1-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.4g，7.18mmol，34.60%產率)。 N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-3-en-1-yl]ethyl amide (5.5 g, 20.74 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7.16 g, 20.74 mmol) and a stirred suspension of sodium carbonate (6.60 g, 62.23 mmol, 2.61 mL) in dioxane (100 mL) and water (20 mL) were purged with argon for 10 min. After 10 minutes, a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (846.96 mg, 1.04 mmol) was added. The resulting reaction mixture was stirred under argon at 55°C for 12 hours. After 12 hours, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with dioxane (50 mL). The filtrate was concentrated under reduced pressure. Water (150 mL) was added to the obtained residue and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na 2 SO 4 and evaporated in vacuo to obtain crude product (9 g), which was purified by column chromatography to obtain as a pale yellow solid. 6-(4-Acetamidocyclohexen-1-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2.4 g, 7.18 mmol, 34.60 g %Yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值334.2；實測值279.4(t -Bu裂解之產物質量)；Rt=1.374min。LCMS (ESI): [M+Boc] + m/z: calculated 334.2; found 279.4 ( t -Bu cleavage product mass); Rt=1.374 min.

步驟4：2-(4-乙醯胺基環己基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of 2-(4-acetamidocyclohexyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將6-(4-乙醯胺基環己烯-1-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.4g，7.18mmol)於MeOH(60mL)中之溶液在乾燥的487型鈀(10%於碳上)(305.46mg，2.87mmol)上在氫氣氣氛、25℃下氫化120小時。120小時之後，過濾反應混合物且在減壓下濃縮濾液，以獲得呈白色固體之2-(4-乙醯胺基環己基)-5-甲基哌啶-1-甲酸第三丁酯(2.3g，6.80mmol，94.69%產率)。產物不經任何進一步純化即用於下一步反應。6-(4-Acetamidocyclohexen-1-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2.4 g, 7.18 mmol) A solution in MeOH (60 mL) was hydrogenated over dry palladium Form 487 (10% on carbon) (305.46 mg, 2.87 mmol) under a hydrogen atmosphere at 25 °C for 120 h. After 120 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain tert-butyl 2-(4-acetamidocyclohexyl)-5-methylpiperidine-1-carboxylate (2.3%) as a white solid. g, 6.80 mmol, 94.69% yield). The product was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值336.2；實測值337.2；Rt=1.346min。LCMS (ESI): [M+Boc] + m/z: calculated 336.2; found 337.2; Rt=1.346 min.

步驟5：N-[4-(5-甲基-2-哌啶基)環己基]乙醯胺之合成Step 5: Synthesis of N-[4-(5-methyl-2-piperidinyl)cyclohexyl]acetamide

將2-(4-乙醯胺基環己基)-5-甲基哌啶-1-甲酸第三丁酯(2.3g，6.80mmol)溶解於三氟乙酸(14.80g，129.80mmol，10mL)中且在25℃下攪拌2小時。2小時之後，將NaOH溶液添加到反應混合物中以調節pH=9，然後用DCM(3 x 30mL)萃取。將經合併之有機相用鹽水(40mL)洗滌，經Na2 SO4 乾燥且在真空中蒸發。將所獲得之粗產物溶解於MeOH(50mL)中，且將所得溶液在乾燥的487型鈀(10%於碳上)(144.63mg，1.36mmol)上在氫氣氣氛、25℃下再氫化24小時。然後過濾反應混合物且在真空中蒸發濾液，以得到呈白色固體之N -[4-(5-甲基-2-哌啶基)環己基]乙醯胺(0.9g，3.78mmol，55.57%產率)。2-(4-Acetamidocyclohexyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2.3 g, 6.80 mmol) was dissolved in trifluoroacetic acid (14.80 g, 129.80 mmol, 10 mL) And it stirred at 25 degreeC for 2 hours. After 2 hours, NaOH solution was added to the reaction mixture to adjust pH=9, then extracted with DCM (3 x 30 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4 and evaporated in vacuo. The obtained crude product was dissolved in MeOH (50 mL) and the resulting solution was hydrogenated over dry palladium Form 487 (10% on carbon) (144.63 mg, 1.36 mmol) under a hydrogen atmosphere at 25 °C for an additional 24 h . The reaction mixture was then filtered and the filtrate was evaporated in vacuo to give N- [4-(5-methyl-2-piperidinyl)cyclohexyl]acetamide (0.9 g, 3.78 mmol, 55.57% yield) as a white solid Rate).

GCMS：m/z：計算值238.2；實測值238.2；Rt=10.371min。GCMS: m/z: calculated 238.2; found 238.2; Rt=10.371 min.

6III. 外消旋 -2,6-二氟-4-[(2R ,5S )-5-甲基-2-哌啶基]苯酚之合成 6III . Synthesis of racemic -2,6-difluoro-4-[( 2R ,5S)-5-methyl-2-piperidinyl]phenol

Figure 110128222-A0202-12-0868-6
Figure 110128222-A0202-12-0868-6

步驟1：4-溴-2,6-二氟苯酚之合成Step 1: Synthesis of 4-bromo-2,6-difluorophenol

在0℃下，向2,6-二氟苯酚(10g，76.87mmol)於DMF(60mL)中之經攪拌之溶液中添加NBS(13.68g，76.87mmol，6.51mL)。將所得反應混合物在室溫下攪拌16小時。將所得反應混合物在真空中濃縮，將水添加到所獲得之殘餘物中且用乙酸乙酯萃取。將有機相經Na2 SO4 乾燥且在減壓下濃縮，以得到呈黃色固體之4-溴-2,6-二氟苯酚(13g，62.20mmol，80.92%產率)。To a stirred solution of 2,6-difluorophenol (10 g, 76.87 mmol) in DMF (60 mL) at 0 °C was added NBS (13.68 g, 76.87 mmol, 6.51 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated in vacuo, water was added to the obtained residue and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 4 -bromo-2,6-difluorophenol (13 g, 62.20 mmol, 80.92% yield) as a yellow solid.

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)7.32(s,2H),10.41(s,1H)。 1 H NMR (DMSO- d 6 , 400 MHz): δ (ppm) 7.32 (s, 2H), 10.41 (s, 1H).

步驟2：2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚之合成Step 2: Synthesis of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol

將4-溴-2,6-二氟苯酚(9g，43.06mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(12.03g，47.37mmol)及KOAc(16.91g，172.26mmol)於1,4-二噁烷(200mL)中之正攪拌溶液用氬氣吹掃10分鐘。10分鐘之後，在氬氣下添加Pd(dppf)Cl2 ‧CH2 Cl2 (1.78g，2.15mmol)。將反應混合物在氬氣、80℃下攪拌24小時。然後將反應混合物冷卻至室溫，透過矽藻土過濾且在減壓下濃縮濾液。藉由急驟層析純化所獲得之粗產物，以得到呈白色固體之2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(4g，15.62mmol，36.28%產率)。4-Bromo-2,6-difluorophenol (9 g, 43.06 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane-2-yl)-1,3,2-dioxaborolane (12.03 g, 47.37 mmol) and KOAc (16.91 g, 172.26 mmol) in 1,4 - A stirring solution in dioxane (200 mL) was purged with argon for 10 minutes. After 10 minutes, Pd(dppf)Cl2 - CH2Cl2 ( 1.78 g, 2.15 mmol) was added under argon. The reaction mixture was stirred under argon at 80°C for 24 hours. The reaction mixture was then cooled to room temperature, filtered through celite and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography to give 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborole as a white solid cyclopentan-2-yl)phenol (4 g, 15.62 mmol, 36.28% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)1.25(s,12H),7.20(s,2H),10.30(s,1H)。 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 1.25 (s, 12H), 7.20 (s, 2H), 10.30 (s, 1H).

步驟3：第三丁基-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-二甲基矽烷之合成Step 3: Tert-butyl-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) Synthesis of Phenoxy]-Dimethylsilane

在0℃下，向2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(2.88g，11.25mmol)及咪唑(1.44g，21.15mmol)於DMF(42mL)中之經攪拌之溶液中分批添加第三丁基 氯二甲基矽烷(2g，13.27mmol，2.47mL)。使反應混合物升溫至室溫且在同一溫度下攪拌18小時。18小時之後，將反應混合物在真空中濃縮且將所獲得之殘餘物分配於水(100mL)與DCM(100mL)之間。將有機層經Na2 SO4 乾燥且在減壓下濃縮，以得到第三丁基 -[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]二甲基矽烷(2.4g，粗品)。粗產物不經任何進一步純化即用於下一步反應。To 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol (2.88 g, 11.25 mmol) and imidazole (1.44 g, 21.15 mmol) in DMF (42 mL) was added portionwise tert- butylchlorodimethylsilane (2 g, 13.27 mmol, 2.47 mL). The reaction mixture was warmed to room temperature and stirred at the same temperature for 18 hours. After 18 hours, the reaction mixture was concentrated in vacuo and the obtained residue was partitioned between water (100 mL) and DCM (100 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give tert-butyl- [2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)phenoxy]dimethylsilane (2.4 g, crude). The crude product was used in the next reaction without any further purification.

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.16(s,6H),0.96(s,9H),1.27(s,12H),7.24(s,2H)。 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.16 (s, 6H), 0.96 (s, 9H), 1.27 (s, 12H), 7.24 (s, 2H).

步驟4：6-(3,5-二氟-4-羥基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合Step 4: The combination of 6-(3,5-difluoro-4-hydroxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 成to make

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(2.01g，5.83mmol)、第三丁基 -[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]二甲基矽烷(2.4g，6.48mmol)及碳酸鈉(2.06g，19.44mmol)於1,4-二噁烷(20mL)及水(10mL)中之正攪拌溶液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 ‧CH2 Cl2 (267.90mg，324.05μmol)。將反應混合物在氬氣、75℃下攪拌14小時。14小時之後，將反應混合物用水稀釋且用DCM萃取。將有機層經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析(SiO2 ，溶析液：0-100%甲醇中之CHCl3 )純化所獲得之粗材料，以得到6-(3,5-二氟-4-羥基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.15g，3.53mmol，54.54%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (2.01 g, 5.83 mmol), tert -butyl yl- [2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]dimethyl A stirring solution of siloxane (2.4 g, 6.48 mmol) and sodium carbonate (2.06 g, 19.44 mmol) in 1,4-dioxane (20 mL) and water (10 mL) was purged with argon. Then, Pd(dppf)Cl 2 ·CH 2 Cl 2 (267.90 mg, 324.05 μmol) was added under argon. The reaction mixture was stirred under argon at 75°C for 14 hours. After 14 hours, the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude material obtained was purified by column chromatography ( SiO2 , eluent: 0-100% CHCl3 in methanol) to give 6-(3,5-difluoro-4-hydroxyphenyl)- 3-Methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.15 g, 3.53 mmol, 54.54% yield).

步驟5：2,6-二氟-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚之合成Step 5: Synthesis of 2,6-difluoro-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol

將TFA(2.98g，26.14mmol，2mL)添加到6-(3,5-二氟-4-羥基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0.65g，2.00mmol)於DCM(2mL)中之經攪拌之溶液中。將所得反應混合物攪拌30分鐘然後在真空中濃縮，以得到呈棕色油狀物之2,6-二氟-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(0.2g，粗品)。粗產物不經任何進一步純化即直接用於下一步反應。TFA (2.98 g, 26.14 mmol, 2 mL) was added to 6-(3,5-difluoro-4-hydroxyphenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid In a stirred solution of tert-butyl ester (0.65 g, 2.00 mmol) in DCM (2 mL). The resulting reaction mixture was stirred for 30 minutes then concentrated in vacuo to give 2,6-difluoro-4-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a brown oil yl)phenol (0.2 g, crude). The crude product was used directly in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值225.1；實測值226.2；Rt=0.741min。LCMS (ESI): [M+H] + m/z: calculated 225.1; found 226.2; Rt=0.741 min.

步驟6：外消旋-2,6-二氟-4-[(2R,5S)-5-甲基-2-哌啶基]苯酚之合成Step 6: Synthesis of Racemic-2,6-difluoro-4-[(2R,5S)-5-methyl-2-piperidinyl]phenol

將硼氫化鈉(24.02mg，634.90μmol)一次性添加到2,6-二氟-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(0.2g，488.38μmol)於甲醇(4mL)中之經攪拌之溶液中。將反應混合物在室溫下攪拌14小時。14小時之後，將反應混合物在減壓下濃縮，藉由反相HPLC純化(溶析液：2-10min，80-95%水-MeOH+NH3 ；流速：30mL/min；裝載泵：4mL/min，MeOH+NH3 ；管柱：TRIART C18，100 x 20mm，5μM)純化殘餘物，以獲得外消旋 -2,6-二氟-4-[(2R ,5S )-5-甲基-2-哌啶基]苯酚(0.05 g，220.02μmol，45.05%產率)。Sodium borohydride (24.02 mg, 634.90 μmol) was added in one portion to 2,6-difluoro-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (0.2 g , 488.38 μmol) in a stirred solution of methanol (4 mL). The reaction mixture was stirred at room temperature for 14 hours. After 14 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC (eluent: 2-10 min, 80-95% water-MeOH+ NH3 ; flow rate: 30 mL/min; loading pump: 4 mL/min min, MeOH+ NH3 ; column: TRIART C18, 100 x 20 mm, 5 μM) The residue was purified to obtain rac -2,6-difluoro-4-[( 2R ,5S)-5- methan yl-2-piperidinyl]phenol (0.05 g, 220.02 μmol, 45.05% yield).

LCMS(ESI)：[M+H]+ m/z：計算值227.1；實測值228.2；Rt=0.849min。LCMS (ESI): [M+H] + m/z: calculated 227.1; found 228.2; Rt=0.849 min.

6JJJ. 外消旋-2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]噻唑之合成6JJJ. Synthesis of racemic-2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]thiazole

Figure 110128222-A0202-12-0871-7
Figure 110128222-A0202-12-0871-7

步驟1：2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]噻唑之合成Step 1: Synthesis of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]thiazole

將2-(4-溴苯基)噻唑(10g，41.65mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(11.32g，44.56mmol)、乙酸鉀(16.35g，166.58mmol，10.41mL)及Pd(dppf)Cl2 DCM(1.70g，2.08mmol)混合於1,4-二噁烷(300mL)中且將混合物在80℃下攪拌17h。冷卻之後，將反應混合物用水稀釋且用DCM萃取若干次。將經合併之萃取物在減壓下濃縮且將殘餘物提交至急驟管柱層析，以得到2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]噻唑(10g，34.82mmol，83.61%產率)。2-(4-Bromophenyl)thiazole (10 g, 41.65 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2 -dioxaborol-2-yl)-1,3,2-dioxaborolane (11.32 g, 44.56 mmol), potassium acetate (16.35 g, 166.58 mmol, 10.41 mL) and Pd(dppf)Cl2 DCM (1.70 g, 2.08 mmol) was mixed in 1,4-dioxane (300 mL) and the mixture was stirred at 80 °C for 17 h. After cooling, the reaction mixture was diluted with water and extracted several times with DCM. The combined extracts were concentrated under reduced pressure and the residue was submitted to flash column chromatography to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborol-2-yl)phenyl]thiazole (10 g, 34.82 mmol, 83.61% yield).

層析資料：120g SiO2 ，CHCl3 -MeCN 0~100%，流速=100mL/min，cv=7Chromatography data: 120g SiO 2 , CHCl 3 -MeCN 0~100%, flow rate=100mL/min, cv=7

LCMS(ESI)：[M+H]+ m/z：計算值287.2；實測值288.2；Rt=1.585min。LCMS (ESI): [M+H] + m/z: calculated 287.2; found 288.2; Rt=1.585 min.

步驟2：3-甲基-6-(4-噻唑-2-基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-methyl-6-(4-thiazol-2-ylphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]噻唑(9g，31.34mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8.66g，25.07mmol)、Pd(dppf)Cl2 DCM(1.02g，1.25mmol)及碳酸鈉(9.96g， 94.02mmol，3.94mL)添加到1,4-二噁烷(105mL)及水(35mL)之混合物中且將所得混合物在80℃下攪拌15h。冷卻之後，將反應混合物用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。將殘餘物提交至急驟管柱層析，以得到3-甲基-6-(4-噻唑-2-基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.5g，15.43mmol，49.23%產率)。2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]thiazole (9 g, 31.34 mmol), 3 - Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.66 g, 25.07 mmol), Pd(dppf)Cl2 DCM (1.02 g, 1.25 mmol) and sodium carbonate (9.96 g, 94.02 mmol, 3.94 mL) were added to a mixture of 1,4-dioxane (105 mL) and water (35 mL) and the resulting mixture was stirred at 80 °C for 15 h . After cooling, the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was submitted to flash column chromatography to give 3-methyl-6-(4-thiazol-2-ylphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.5 g, 15.43 mmol, 49.23% yield).

層析資料：Companion combiflash；120g SiO2 ，HEX-MTBE 0~100%，流速=85mL/min，cv=7Chromatography data: Companion combiflash; 120g SiO 2 , HEX-MTBE 0~100%, flow rate=85mL/min, cv=7

LCMS(ESI)：[M+H]+ m/z：計算值356.2；實測值357.2；Rt=1.673min。LCMS (ESI): [M+H] + m/z: calculated 356.2; found 357.2; Rt=1.673 min.

步驟3：2-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]噻唑之合成Step 3: Synthesis of 2-[4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenyl]thiazole

在室溫下，向3-甲基-6-(4-噻唑-2-基苯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.5g，15.43mmol)於DCM(15mL)中之經攪拌之溶液中添加TFA(10g，87.70mmol，6.76mL)。將所得反應混合物在室溫下攪拌0.5h。將反應混合物在減壓下濃縮，用NaOH水溶液處理且用DCM萃取。將有機層經Na2 SO4 乾燥且在減壓下濃縮，以得到2-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]噻唑(3.9g，粗品)，其不經純化即直接用於下一步驟。To 3-methyl-6-(4-thiazol-2-ylphenyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.5 g, 15.43 mmol) at room temperature To a stirred solution in DCM (15 mL) was added TFA (10 g, 87.70 mmol, 6.76 mL). The resulting reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure, treated with aqueous NaOH and extracted with DCM. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give 2-[4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenyl]thiazole ( 3.9 g, crude), which was used directly in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值256.2；實測值257.0；Rt=0.961min。LCMS (ESI): [M+H] + m/z: calculated 256.2; found 257.0; Rt=0.961 min.

步驟4：外消旋-2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]噻唑之合成Step 4: Synthesis of Racemic-2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]thiazole

將2-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]噻唑(3.9g，15.21mmol)溶解於甲醇(50mL)中且一次性添加硼氫化鈉(805.75mg，21.30mmol，753.04μL)。將反應混合物在25℃下攪拌16h，然後在減壓下濃縮。將殘餘物溶解於DCM中，用NaOH水溶液、鹽水洗滌且在旋轉蒸發儀上濃縮，以得到2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]噻唑(2g，粗品)，其不經進一步純化即用於下面的步驟。2-[4-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)phenyl]thiazole (3.9 g, 15.21 mmol) was dissolved in methanol (50 mL) and added in one portion Sodium borohydride (805.75 mg, 21.30 mmol, 753.04 μL). The reaction mixture was stirred at 25 °C for 16 h, then concentrated under reduced pressure. The residue was dissolved in DCM, washed with aqueous NaOH, brine and concentrated on a rotary evaporator to give 2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl] Thiazole (2 g, crude) was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值258.2；實測值259.2；Rt=0.874min。LCMS (ESI): [M+H] + m/z: calculated 258.2; found 259.2; Rt=0.874 min.

6KKK. 外消旋-5-(5-甲基-2-哌啶基)-2-(三氟甲基)-1,3-苯并噻唑之合成6KKK. Synthesis of racemic-5-(5-methyl-2-piperidinyl)-2-(trifluoromethyl)-1,3-benzothiazole

Figure 110128222-A0202-12-0873-8
Figure 110128222-A0202-12-0873-8

步驟1：5-溴-2-(三氟甲基)-1,3-苯并噻唑之合成Step 1: Synthesis of 5-bromo-2-(trifluoromethyl)-1,3-benzothiazole

在80℃下，將2-胺基-4-溴-苯硫醇(9.5g，46.55mmol)一次性添加到三氟乙酸(70g，613.93mmol，47.30mL)之經攪拌之溶液中。將所得混合物在80℃下攪拌17h，然後在真空中蒸發。將殘餘物用水(200mL)稀釋且用EtOAc(2*90mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到5-溴-2-(三氟甲基)-1,3-苯并噻唑(9g，31.91mmol，68.54%產率)。2-Amino-4-bromo-benzenethiol (9.5 g, 46.55 mmol) was added in one portion to a stirred solution of trifluoroacetic acid (70 g, 613.93 mmol, 47.30 mL) at 80 °C. The resulting mixture was stirred at 80 °C for 17 h, then evaporated in vacuo. The residue was diluted with water (200 mL) and extracted with EtOAc (2*90 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-bromo-2-(trifluoromethyl)-1,3-benzothiazole (9 g, 31.91 mmol, 68.54% yield) .

1 H NMR(400MHz,CDCl3 )δ 7.66(d,1H),7.84(d,1H),8.35(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, 1H), 7.84 (d, 1H), 8.35 (s, 1H).

步驟2：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-(三氟甲基)-1,3-苯并噻唑之合成Step 2: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-2-(trifluoromethyl)-1,3 -Synthesis of benzothiazole

將乙酸鉀(6.26g，63.81mmol，3.99mL)添加到5-溴-2-(三氟甲基)-1,3-苯并噻唑(9g，31.91mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(9.72g，38.29mmol)於二噁烷(250mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2*DCM(1.30g，1.60mmol)。在100℃、惰性氣氛下將所得混合物攪拌15h。然後，將其冷卻，用MTBE(600mL)稀釋且過濾。在減壓下濃縮濾液，留下14.5g粗產物，14.5g粗產物藉由矽膠管柱層析，使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到產物5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-(三氟甲基)-1,3-苯并噻唑(7.5g，22.79mmol，71.42%產率)。Potassium acetate (6.26 g, 63.81 mmol, 3.99 mL) was added to 5-bromo-2-(trifluoromethyl)-1,3-benzothiazole (9 g, 31.91 mmol) and 4,4,5,5- Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A solution of cyclopentane (9.72 g, 38.29 mmol) in dioxane (250 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, Pd(dppf)Cl2*DCM (1.30 g, 1.60 mmol) was added under argon flow. The resulting mixture was stirred at 100 °C for 15 h under an inert atmosphere. It was then cooled, diluted with MTBE (600 mL) and filtered. The filtrate was concentrated under reduced pressure to leave 14.5 g of crude product, which was purified by silica gel column chromatography using a hexane/MTBE gradient (10-100% MTBE) to give the product 5-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-2-(trifluoromethyl)-1,3-benzothiazole (7.5 g, 22.79 mmol, 71.42% yield).

1 H NMR(500MHz,DMSO-d6 )δ 1.38(s,12H),7.96(m,2H),8.67(s,1H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 1.38 (s, 12H), 7.96 (m, 2H), 8.67 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值329.0；實測值330.0；Rt=1.609min。LCMS (ESI): [M+H] + m/z: calculated 329.0; found 330.0; Rt=1.609 min.

步驟3：3-甲基-6-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: 3-Methyl-6-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl Synthesis of Esters

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-(三氟甲基)-1,3-苯并噻唑(4.52g，13.73mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.69g，16.48mmol)一起混合於水(2mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(2mL)中之碳酸鈉(2.91g，27.47mmol，1.15mL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(502.41mg，686.63μmol)。將反應混合物在氬氣、100℃下攪拌14h，然後冷卻且在真空中蒸發，將其倒入水(120ml)中且用EtOAc(2x90ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下8g粗產物，8g粗產物藉由矽膠管柱層析，使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到產物3-甲基-6-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，10.04mmol，73.10%產率)。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-2-(trifluoromethyl)-1,3-benzene Thiazole (4.52 g, 13.73 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.69 g , 16.48 mmol) were mixed together in water (2 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (2.91 g, 27.47 mmol, 1.15 mL) and [1,1'-bis() in water (2 mL) were added under argon. Diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (502.41 mg, 686.63 [mu]mol). The reaction mixture was stirred under argon at 100°C for 14h, then cooled and evaporated in vacuo, poured into water (120ml) and extracted with EtOAc (2x90ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 8g of crude product which was chromatographed on a silica gel column using a hexane/MTBE gradient (10 -100% MTBE) to give the product 3-methyl-6-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H- 3-butyl pyridine-1-carboxylate (4 g, 10.04 mmol, 73.10% yield).

1 H NMR(400MHz,CDCl3 )δ 1.02(s,9H),1.54(d,3H),2.01(m,2H),2.42(m,1H),3.02(m,1H),4.07(m,1H),5.42(m,1H),7.50(d,1H),7.86(d,1H),8.11(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.02(s, 9H), 1.54(d, 3H), 2.01(m, 2H), 2.42(m, 1H), 3.02(m, 1H), 4.07(m, 1H) ), 5.42(m, 1H), 7.50(d, 1H), 7.86(d, 1H), 8.11(s, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值342.2；實測值343.0；Rt=1.685min。LCMS (ESI): [M-tBu] + m/z: calculated 342.2; found 343.0; Rt=1.685 min.

步驟4：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2-(三氟甲基)-1,3-苯并噻唑之合成Step 4: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-2-(trifluoromethyl)-1,3-benzothiazole

將3-甲基-6-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，10.04mmol)於DCM(20mL)及三氟乙酸(22.89g，200.78mmol，15.47mL)中之溶液在0℃下攪拌8h，然後在真空中蒸發。將碎冰(50g)添加到殘餘物中且用10%碳酸氫鈉水溶液將pH調節至8。將所得混合物用乙酸乙酯(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到5-(3- 甲基-2,3,4,5-四氫吡啶-6-基)-2-(三氟甲基)-1,3-苯并噻唑(2.3g，7.71mmol，76.80%產率)。3-Methyl-6-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester ( A solution of 4 g, 10.04 mmol) in DCM (20 mL) and trifluoroacetic acid (22.89 g, 200.78 mmol, 15.47 mL) was stirred at 0 °C for 8 h, then evaporated in vacuo. Crushed ice (50 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(3- Methyl-2,3,4,5-tetrahydropyridin-6-yl)-2-(trifluoromethyl)-1,3-benzothiazole (2.3 g, 7.71 mmol, 76.80% yield).

1 H NMR(400MHz,CDCl3 )δ 1.02(d,3H),1.24(m,1H),1.48(m,1H),1.96(m,1H),2.90(m,2H),3.33(m,1H),4.04(m,1H),7.96(d,1H),8.19(d,1H),8.47(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.02(d,3H), 1.24(m,1H), 1.48(m,1H), 1.96(m,1H), 2.90(m,2H), 3.33(m,1H) ), 4.04(m, 1H), 7.96(d, 1H), 8.19(d, 1H), 8.47(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值298.2；實測值299.2；Rt=0.965min。LCMS (ESI): [M+H] + m/z: calculated 298.2; found 299.2; Rt=0.965 min.

步驟5：外消旋-5-(5-甲基-2-哌啶基)-2-(三氟甲基)-1,3-苯并噻唑之合成Step 5: Synthesis of racemic-5-(5-methyl-2-piperidinyl)-2-(trifluoromethyl)-1,3-benzothiazole

在0℃下，將硼氫化鈉(583.35mg，15.42mmol，545.19μL)一次性添加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2-(三氟甲基)-1,3-苯并噻唑(2.3g，7.71mmol)於MeOH(30mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌9h，然後在真空中蒸發。將殘餘物用水(40mL)稀釋且用二氯甲烷(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到外消旋-5-(5-甲基-2-哌啶基)-2-(三氟甲基)-1,3-苯并噻唑(1.8g，5.99mmol，77.74%產率)。Sodium borohydride (583.35 mg, 15.42 mmol, 545.19 μL) was added in one portion to 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-2- at 0 °C (Trifluoromethyl)-1,3-benzothiazole (2.3 g, 7.71 mmol) in a stirred solution of MeOH (30 mL). The resulting mixture was stirred at 0 °C for 9 h, then evaporated in vacuo. The residue was diluted with water (40 mL) and extracted with dichloromethane (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give rac-5-(5-methyl-2-piperidinyl)-2-(trifluoromethyl)-1,3 - benzothiazole (1.8 g, 5.99 mmol, 77.74% yield).

1 H NMR(400MHz,CDCl3 )δ 1.01(d,3H),1.14(m,2H),1.68(m,3H),2.45(m,1H),3.19(m,1H),3.73(m,1H),5.28(s,1H),7.62(d,1H),7.90(d,1H),8.16(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.01(d,3H), 1.14(m,2H), 1.68(m,3H), 2.45(m,1H), 3.19(m,1H), 3.73(m,1H) ), 5.28(s, 1H), 7.62(d, 1H), 7.90(d, 1H), 8.16(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值300.2；實測值301.2；Rt=0.977min。LCMS (ESI): [M+H] + m/z: calculated 300.2; found 301.2; Rt=0.977 min.

6LLL. 外消旋-6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-1,8-萘啶-2-酮之合成6LLL. Synthesis of racemic-6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-1,8-naphthyridin-2-one

Figure 110128222-A0202-12-0875-9
Figure 110128222-A0202-12-0875-9

步驟1：6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-1H-1,8-萘啶-2-Step 1: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-1H-1,8 -Naphthyridine-2- 酮之合成Synthesis of Ketones

將乙酸鉀(12.53g，127.72mmol，7.98mL)添加到6-溴-3,4-二氫-1H-1,8-萘啶-2-酮(14.5g，63.86mmol)於二噁烷(250mL)中之溶液中，隨後添加雙(頻哪醇)二硼(17.84g，70.25mmol)及Pd(dppf)Cl2‧DCM(2.61g，3.19mmol)。將所得溶液在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋，過濾且蒸發。使所得沉澱於MTBE中結晶，以獲得6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-1H-1,8-萘啶-2-酮(14.7g，53.63mmol，83.97%產率)。Potassium acetate (12.53 g, 127.72 mmol, 7.98 mL) was added to 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (14.5 g, 63.86 mmol) in dioxane ( 250 mL), followed by the addition of bis(pinacol)diboron (17.84 g, 70.25 mmol) and Pd(dppf)Cl2.DCM (2.61 g, 3.19 mmol). The resulting solution was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc, filtered and evaporated. The resulting precipitate was crystallized in MTBE to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-di Hydro-lH-l,8-naphthyridin-2-one (14.7 g, 53.63 mmol, 83.97% yield).

1 H NMR(600MHz,CDCl3 )δ 1.33(s,12H),2.67(t,2H),2.94(t2H),7.84(s,1H),8.56(s,1H),9.16(s,1H)。 1 H NMR (600 MHz, CDCl 3 ) δ 1.33(s,12H), 2.67(t,2H), 2.94(t2H), 7.84(s,1H), 8.56(s,1H), 9.16(s,1H).

步驟2：3-甲基-6-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: 3-Methyl-6-(7-oxy-6,8-dihydro-5H-1,8-naphthyridin-3-yl)-3,4-dihydro-2H-pyridine-1 -Synthesis of tert-butyl formate

向3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.70g，28.09mmol)於二噁烷(200mL)中之溶液中添加碳酸鈉(8.12g，76.61mmol，3.21mL)於水(50mL)中之溶液，隨後添加6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-1H-1,8-萘啶-2-酮(7g，25.54mmol)及Pd(dppf)Cl2* DCM(1.04g，1.28mmol)。將所得混合物在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋且用水(2x40mL)洗滌。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得3-甲基-6-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.5g，粗品)。To 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.70 g, 28.09 mmol) in dioxane ( 200 mL) was added a solution of sodium carbonate (8.12 g, 76.61 mmol, 3.21 mL) in water (50 mL) followed by 6-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborol-2-yl)-3,4-dihydro-1H-1,8-naphthyridin-2-one (7 g, 25.54 mmol) and Pd(dppf)Cl 2* DCM ( 1.04 g, 1.28 mmol). The resulting mixture was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc and washed with water (2x40 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to give 3-methyl-6-(7-oxy-6,8-dihydro-5H-1,8-naphthyridin-3-yl)-3 , 3-butyl 4-dihydro-2H-pyridine-1-carboxylate (9.5 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值343.2；實測值344.2；Rt=1.231min。LCMS (ESI): [M+H] + m/z: calculated 343.2; found 344.2; Rt=1.231 min.

步驟3：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-1H-1,8-萘啶-2-酮之合成Step 3: Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro-1H-1,8-naphthyridin-2-one

將3-甲基-6-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.5g，27.66mmol)於TFA(50mL)中之溶液在25℃下攪拌12h。將飽和碳酸鉀水溶液添加到該溶液(200ml)中，然後用DCM(2x300mL)萃取。將 有機相經硫酸鈉乾燥，過濾且蒸發，以獲得6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-1H-1,8-萘啶-2-酮(7.1.g，粗品)。3-Methyl-6-(7-oxy-6,8-dihydro-5H-1,8-naphthyridin-3-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid A solution of tert-butyl ester (9.5 g, 27.66 mmol) in TFA (50 mL) was stirred at 25 °C for 12 h. Saturated aqueous potassium carbonate solution was added to the solution (200 ml), then extracted with DCM (2 x 300 mL). Will The organic phase was dried over sodium sulfate, filtered and evaporated to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro-1H-1,8 -Naphthyridin-2-one (7.1.g, crude).

1 H NMR(400MHz,CDCl3 )δ 0.94(d,3H),1.01(m,2H),1.32(m,2H),2.02(m,2H),2.62(m,2H),2.94(m,2H),4.05(m,1H),8.01(s,1H),8.21(s,1H),9.12(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.94(d,3H), 1.01(m,2H), 1.32(m,2H), 2.02(m,2H), 2.62(m,2H), 2.94(m,2H) ), 4.05(m, 1H), 8.01(s, 1H), 8.21(s, 1H), 9.12(s, 1H).

步驟4：外消旋-6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-1,8-萘啶-2-酮之合成Step 4: Synthesis of racemic-6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-1,8-naphthyridin-2-one

將硼氫化鈉(2.21g，58.36mmol，2.06mL)分批添加到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-3,4-二氫-1H-1,8-萘啶-2-酮(7.1g，29.18mmol)於甲醇(100mL)中之溶液中。將混合物在室溫下攪拌12h。添加水(50mL)且將所得混合物用EtOAc(2x50mL)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發。藉由管柱層析純化所得粗產物，以獲得6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-1,8-萘啶-2-酮(1.2g，4.89mmol，16.76%產率)。Sodium borohydride (2.21 g, 58.36 mmol, 2.06 mL) was added portionwise to 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-3,4-dihydro- A solution of 1H-1,8-naphthyridin-2-one (7.1 g, 29.18 mmol) in methanol (100 mL). The mixture was stirred at room temperature for 12 h. Water (50 mL) was added and the resulting mixture was extracted with EtOAc (2 x 50 mL). The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting crude product was purified by column chromatography to obtain 6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-1,8-naphthyridine- 2-keto (1.2 g, 4.89 mmol, 16.76% yield).

LCMS(ESI)：[M+H]+ m/z：計算值245.2；實測值246.2；Rt=0.791min。LCMS (ESI): [M+H] + m/z: calculated 245.2; found 246.2; Rt=0.791 min.

6MMM.外消旋 -5-((2R,5S )-5-甲基哌啶-2-基)苯并[d ]噻唑-2-胺之合成6MMM. Synthesis of racemic -5-(( 2R,5S )-5-methylpiperidin-2-yl)benzo[ d ]thiazol-2-amine

Figure 110128222-A0202-12-0877-10
Figure 110128222-A0202-12-0877-10

步驟1：5-溴苯并[d]噻唑-2(3H)-酮之合成Step 1: Synthesis of 5-bromobenzo[d]thiazol-2(3H)-one

在氬氣下，將2-胺基-4-溴苯硫醇(30g，147.00mmol)溶解於無水THF(500mL)中。在氬氣下，向以上溶液中一次性添加二(咪唑-1-基)甲酮(26.5g，163.43mmol)且將反應混合物在氬氣、25℃下攪拌1h(觀察到輕微放熱反應)。然後將反應混合物在50℃下攪拌1h(在放熱反應過去之後)，然後冷卻且在真空中 濃縮。將殘餘物用水(300ml)稀釋，將沉澱過濾，用水(3*50ml)洗滌且在真空中乾燥，以得到呈白色固體之5-溴-3H -1,3-苯并噻唑-2-酮(33.5g，145.60mmol，99.05%產率)。2-Amino-4-bromobenzenethiol (30 g, 147.00 mmol) was dissolved in dry THF (500 mL) under argon. To the above solution was added bis(imidazol-1-yl)methanone (26.5 g, 163.43 mmol) in one portion under argon and the reaction mixture was stirred under argon at 25 °C for 1 h (a slight exothermic reaction was observed). The reaction mixture was then stirred at 50°C for 1 h (after the exothermic reaction had passed), then cooled and concentrated in vacuo. The residue was diluted with water (300ml), the precipitate was filtered, washed with water (3*50ml) and dried in vacuo to give 5-bromo- 3H -1,3-benzothiazol-2-one as a white solid ( 33.5 g, 145.60 mmol, 99.05% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)7.23(s,1H),7.31(d,1H),7.55(s,1H),12.05(bds,1H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 7.23 (s, 1H), 7.31 (d, 1H), 7.55 (s, 1H), 12.05 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值230.2；實測值231.2；Rt=1.083min。LCMS (ESI): [M] + m/z: calculated 230.2; found 231.2; Rt=1.083 min.

步驟2：5-溴-2-氯苯并[d]噻唑之合成Step 2: Synthesis of 5-bromo-2-chlorobenzo[d]thiazole

使用回流冷凝器將5-溴-3H -1,3-苯并噻唑-2-酮(33.5g，145.60mmol)於磷醯氯(431.84g，2.82mol，261.72mL)中之懸浮液在110℃下攪拌32h(在8h後形成澄清溶液)。將反應混合物冷卻且在真空中濃縮。將碎冰(300g)添加到殘餘物中，且過濾沉澱，用水(4*50ml)洗滌且風乾，以得到呈米色固體之5-溴-2-氯-1,3-苯并噻唑(34g，136.81mmol，93.96%產率)。A suspension of 5-bromo- 3H -1,3-benzothiazol-2-one (33.5 g, 145.60 mmol) in phosphine chloride (431.84 g, 2.82 mol, 261.72 mL) at 110 °C using a reflux condenser was stirred for 32 h (a clear solution formed after 8 h). The reaction mixture was cooled and concentrated in vacuo. Crushed ice (300 g) was added to the residue, and the precipitate was filtered, washed with water (4*50 ml) and air-dried to give 5-bromo-2-chloro-1,3-benzothiazole (34 g, 136.81 mmol, 93.96% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)7.68(d,1H),8.08(d,1H),8.20(s,1H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 7.68 (d, 1H), 8.08 (d, 1H), 8.20 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值248.2；實測值249.2；Rt=1.159min。LCMS (ESI): [M] + m/z: calculated 248.2; found 249.2; Rt=1.159 min.

步驟3：5-溴苯并[d]噻唑-2-胺之合成Step 3: Synthesis of 5-bromobenzo[d]thiazol-2-amine

在高壓釜中將5-溴-2-氯-1,3-苯并噻唑(30g，120.71mmol)及氫氧化銨(25% NH3 )(136.50g，150mL)於1.4-二噁烷(150mL)中之混合物在135℃(反應混合物之內部溫度)下攪拌40h。冷卻之後，打開高壓釜且在真空中將所得懸浮液濃縮至乾。將殘餘物用水(250ml)稀釋，將沉澱過濾，用水(3*50ml)、50%乙醇水溶液(20ml)及己烷(3*50ml)連續洗滌，然後在真空中乾燥，以得到呈淡黃色固體之5-溴-1,3-苯并噻唑-2-胺(25g，109.12mmol，90.40%產率)。5-Bromo-2-chloro-1,3-benzothiazole (30 g, 120.71 mmol) and ammonium hydroxide (25% NH3 ) (136.50 g, 150 mL) in 1.4-dioxane (150 mL) were combined in an autoclave ) was stirred at 135°C (internal temperature of the reaction mixture) for 40 h. After cooling, the autoclave was opened and the resulting suspension was concentrated to dryness in vacuo. The residue was diluted with water (250ml), the precipitate was filtered, washed successively with water (3*50ml), 50% aqueous ethanol (20ml) and hexanes (3*50ml), then dried in vacuo to give a pale yellow solid 5-Bromo-1,3-benzothiazol-2-amine (25 g, 109.12 mmol, 90.40% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)7.12(d,1H),7.48(s,1H),7.60(d,1H),7.69(s,2H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 7.12 (d, 1H), 7.48 (s, 1H), 7.60 (d, 1H), 7.69 (s, 2H).

LCMS(ESI)：[M]+ m/z：計算值229.2；實測值230.2；Rt=1.023min。LCMS (ESI): [M] + m/z: calculated 229.2; found 230.2; Rt=1.023 min.

步驟4：(5-溴苯并[d]噻唑-2-基)胺甲酸第三丁酯之合成Step 4: Synthesis of tert-butyl (5-bromobenzo[d]thiazol-2-yl)carbamate

在25℃下，將二碳酸二-第三丁酯(5.24g，24.01mmol，5.51mL)一次性添加到5-溴-1,3-苯并噻唑-2-胺(5g，21.82mmol)及N,N -二甲基吡啶-4-胺(266.63mg，2.18mmol)於THF(75mL)中之經攪拌之溶液中。將反應混合物在25℃下攪拌3h。將所得懸浮液在真空中濃縮至大約20mL，然後用己烷(50ml)稀釋。過濾沉澱，用己烷(2*20ml)洗滌且風乾，以得到呈白色固體之粗品N -(5-溴-1,3-苯并噻唑-2-基)胺甲酸第三丁 酯(6.2g，18.83mmol，86.29%產率)，其直接用於下一步驟中。At 25°C, di-tert-butyl dicarbonate (5.24 g, 24.01 mmol, 5.51 mL) was added in one portion to 5-bromo-1,3-benzothiazol-2-amine (5 g, 21.82 mmol) and In a stirred solution of N,N -lutidine-4-amine (266.63 mg, 2.18 mmol) in THF (75 mL). The reaction mixture was stirred at 25 °C for 3 h. The resulting suspension was concentrated in vacuo to approximately 20 mL, then diluted with hexanes (50 mL). The precipitate was filtered, washed with hexanes (2*20ml) and air-dried to give crude 3-butyl N- (5-bromo-1,3-benzothiazol-2-yl) carbamate (6.2g) as a white solid , 18.83 mmol, 86.29% yield), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.51(s,9H),7.42(d,1H),7.85(s,1H),7.91(d,1H),12.02(bds,1H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 1.51 (s, 9H), 7.42 (d, 1H), 7.85 (s, 1H), 7.91 (d, 1H), 12.02 (bds, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值229.2；實測值230.2；Rt=1.588min。LCMS (ESI): [M-Boc] + m/z: calculated 229.2; found 230.2; Rt=1.588 min.

步驟5：(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)胺甲酸第三丁酯之合成Step 5: (5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d]thiazol-2-yl)amine Synthesis of tert-butyl formate

將N -(5-溴-1,3-苯并噻唑-2-基)胺甲酸第三丁 酯(6.2g，18.83mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(5.26g，20.72mmol)及乙酸鉀(3.70g，37.67mmol，2.35mL)於1,4-二噁烷(120mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後添加Pd(dppf)Cl2 *DCM(1.54g，1.88mmol)且將反應混合物在氬氣、90℃下攪拌48h，然後冷卻，用MTBE(120ml)稀釋且透過短矽膠墊過濾。將濾餅用MTBE(2*50ml)洗滌且丟棄。在真空中濃縮濾液，以得到呈棕色膠狀物之粗品N -[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]胺甲酸第三丁 酯(12g，粗品)，其直接用於下一步驟中。3-butyl N- (5-bromo-1,3-benzothiazol-2-yl) carbamate (6.2 g, 18.83 mmol), 4,4,5,5-tetramethyl-2-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (5.26 g, 20.72 g mmol) and potassium acetate (3.70 g, 37.67 mmol, 2.35 mL) in 1,4-dioxane (120 mL) was evacuated and backfilled with argon. This operation was repeated twice, then Pd(dppf)Cl2*DCM (1.54 g , 1.88 mmol) was added and the reaction mixture was stirred under argon at 90 °C for 48 h, then cooled, diluted with MTBE (120 ml) and passed through for a short time Silicone pad filter. The filter cake was washed with MTBE (2*50ml) and discarded. The filtrate was concentrated in vacuo to give crude N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- as a brown gum yl)-1,3-benzothiazol-2-yl]carbamic acid tert-butyl ester (12 g, crude), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.12(s,12H),1.46(s,9H),7.48(d,1H),7.93(m,3H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 1.12 (s, 12H), 1.46 (s, 9H), 7.48 (d, 1H), 7.93 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值376.2；實測值377.2；Rt=1.601min。LCMS (ESI): [M] + m/z: calculated 376.2; found 377.2; Rt=1.601 min.

步驟6：6-(2-((第三丁氧基羰基)胺基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 6: 6-(2-((Third-butoxycarbonyl)amino)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)- Synthesis of tert-butyl formate

將N -[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]胺甲酸第三丁 酯(12g，19.13mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(6.5g，18.82mmol)及碳酸鈉(6.08g，57.40mmol，2.40mL)添加到1,4-二噁烷(100mL)及水(25mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(781.31mg，956.74μmol)。將反應混合物在氬氣、90℃下攪拌15h。將反應混合物冷卻且透過短矽膠墊過濾。將濾餅另外用1.4-二噁烷(2*25ml)洗滌且丟棄。在真空中濃縮濾液，且藉由矽膠管柱層析，使用己烷/MTBE梯度(0-100% MTBE)純化殘餘物(16g)，以得到呈淡黃色固體之6-[2-(第三丁氧基 羰基胺基)-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.8g，4.04mmol，21.11%產率)。 N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazol-2-yl ] tert- butyl carbamate (12 g, 19.13 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl The ester (6.5 g, 18.82 mmol) and sodium carbonate (6.08 g, 57.40 mmol, 2.40 mL) were added to a mixture of 1,4-dioxane (100 mL) and water (25 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM ( 781.31 mg, 956.74 μmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 15 h. The reaction mixture was cooled and filtered through a short pad of silica gel. The filter cake was additionally washed with 1.4-dioxane (2*25ml) and discarded. The filtrate was concentrated in vacuo, and the residue (16 g) was purified by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) to give 6-[2-( 3rd ) as a pale yellow solid Butoxycarbonylamino )-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.8 g, 4.04 mmol , 21.11% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.12(s,9H),1.51(s,9H),1.98(m,1H),2.04(m,1H),2.42(m,1H),3.05(m,1H),4.08(d,1H),5.37(m,1H),7.23(d,1H),7.68(d,1H),7.77(s,1H),10.25(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.12(s,9H), 1.51(s,9H), 1.98(m,1H), 2.04(m,1H), 2.42( m, 1H), 3.05(m, 1H), 4.08(d, 1H), 5.37(m, 1H), 7.23(d, 1H), 7.68(d, 1H), 7.77(s, 1H), 10.25(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值445.2；實測值446.2；Rt=1.714min。LCMS (ESI): [M] + m/z: calculated 445.2; found 446.2; Rt=1.714 min.

步驟7：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-胺之合成Step 7: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-amine

將6-[2-(第三丁氧基 羰基胺基)-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.8g，4.04mmol)於三氟乙酸(44.40g，389.41mmol，30mL)中之溶液在25℃下攪拌1h。1h之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用冰冷水(30mL)稀釋且用10% NaOH水溶液中和，直至pH=10。過濾沉澱，用水(2*10ml)洗滌且風乾，以得到呈淡黃色固體之5-(3-甲基-2,3,4,5-四 氫吡啶-6-基)-1,3-苯并噻唑-2-胺(0.8g，3.26mmol，80.72%產率)，其直接用於下一步驟中。6-[2-( Third- butoxycarbonylamino)-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid A solution of tributyl ester (1.8 g, 4.04 mmol) in trifluoroacetic acid (44.40 g, 389.41 mmol, 30 mL) was stirred at 25 °C for 1 h. After 1 h, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ice-cold water (30 mL) and neutralized with 10% aqueous NaOH until pH=10. The precipitate was filtered, washed with water (2*10ml) and air-dried to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzene as a pale yellow solid Thiazol-2-amine (0.8 g, 3.26 mmol, 80.72% yield), which was used directly in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.36(m,1H),1.65(m,1H),1.86(m,1H),2.78(m,3H),3.17(m,1H),3.87(m,1H),7.47(m,2H),7.61(d,1H),7.71(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.36(m,1H), 1.65(m,1H), 1.86(m,1H), 2.78(m,3H), 3.17(m, 1H), 3.87(m, 1H), 7.47(m, 2H), 7.61(d, 1H), 7.71(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值245.2；實測值246.2；Rt=0.734min。LCMS (ESI): [M] + m/z: calculated 245.2; found 246.2; Rt=0.734 min.

步驟8：外消旋-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-胺之合成Step 8: Synthesis of Racemic-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-amine

在0℃下，向5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑-2-胺(0.8g，3.26mmol)於MeOH(30mL)中之正攪拌懸浮液中分批添加硼氫化鈉(370.06mg，9.78mmol，345.85μL)。將所得反應混合物在0℃下攪拌1h，然後使其升溫至25℃且攪拌12h，且在減壓下濃縮。將殘餘物用水(20mL)稀釋且用二氯甲烷(80mL)萃取。將有機萃取物經硫酸鈉乾燥且在真空下濃縮，以獲得呈淡黃色固體之粗產物5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(700mg，2.83mmol，86.79%產率)，其直接用於下一步驟中。To 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazol-2-amine (0.8 g, 3.26 mmol) at 0 °C To a stirring suspension in MeOH (30 mL) was added sodium borohydride (370.06 mg, 9.78 mmol, 345.85 [mu]L) portionwise. The resulting reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to 25 °C and stirred for 12 h, and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with dichloromethane (80 mL). The organic extracts were dried over sodium sulfate and concentrated in vacuo to give the crude product 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzo as a pale yellow solid Thiazol-2-amine (700 mg, 2.83 mmol, 86.79% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.86(d,3H),1.22(m,2H),1.86(m,4H),2.44(m,1H),3.16(m,1H),3.62(m,1H),5.28(s,2H),7.18(d,1H),7.50(d,1H),7.53(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.86(d, 3H), 1.22(m, 2H), 1.86(m, 4H), 2.44(m, 1H), 3.16(m, 1H), 3.62( m, 1H), 5.28 (s, 2H), 7.18 (d, 1H), 7.50 (d, 1H), 7.53 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值247.2；實測值248.2；Rt=0.766min。LCMS (ESI): [M] + m/z: calculated 247.2; found 248.2; Rt=0.766 min.

6NNN. 6-(5-甲基-2-哌啶基)異喹啉-1-醇之合成6NNN. The synthesis of 6-(5-methyl-2-piperidinyl) isoquinolin-1-ol

Figure 110128222-A0202-12-0881-11
Figure 110128222-A0202-12-0881-11

步驟1：6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異喹啉-1-醇之合成Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)isoquinolin-1-ol

將乙酸鉀(8.76g，89.26mmol，5.58mL)添加到6-溴異喹啉-1-醇(10g，44.63mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(12.47g，49.10mmol)於二噁烷(150mL)中之溶液中。將反應燒瓶抽真空且用Ar再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2．DCM(1.82g，2.23mmol)。在90℃、惰性氣氛下將所得混合物攪拌14h。然後，將其冷卻，用EtOAc(400mL)稀釋且用水(2x200mL)洗滌。將有機層經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟層析，使用CHCl3 -MeCN體系溶析來純化殘餘物，以得到6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異喹啉-1-醇(9.3g，34.30mmol，76.86%產率)。Potassium acetate (8.76 g, 89.26 mmol, 5.58 mL) was added to 6-bromoisoquinolin-1-ol (10 g, 44.63 mmol) and 4,4,5,5-tetramethyl-2-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (12.47g, 49.10mmol) in dioxane (150 mL). The reaction flask was evacuated and refilled 3 times with Ar. Then, add Pd(dppf)Cl2 under argon flow. DCM (1.82 g, 2.23 mmol). The resulting mixture was stirred at 90 °C under an inert atmosphere for 14 h. It was then cooled, diluted with EtOAc (400 mL) and washed with water (2 x 200 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a CHCl3 -MeCN system to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)isoquinolin-1-ol (9.3 g, 34.30 mmol, 76.86% yield).

LCMS(ESI)：[M+H]+ m/z：計算值271.2；實測值272.2；Rt=1.133min。LCMS (ESI): [M+H] + m/z: calculated 271.2; found 272.2; Rt=1.133 min.

步驟2：6-(1-羥基-6-異喹啉基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(1-Hydroxy-6-isoquinolinyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.66g，4.79mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異喹啉-1-醇(1.3g，4.79mmol)及碳酸鈉(1.52g，14.38mmol，602.62μL)添加到水(5mL)及二噁烷(15mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2．DCM(195.79mg，239.75μmol)。將反應混合物在氬氣、70℃下攪拌14h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20mL)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之6-(1-羥基-6-異喹啉基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.5g，1.47mmol，30.63%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.66 g, 4.79 mmol), 6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)isoquinolin-1-ol (1.3g, 4.79mmol) and sodium carbonate (1.52g , 14.38 mmol, 602.62 μL) was added to a mixture of water (5 mL) and dioxane (15 mL). The resulting mixture was evacuated and backfilled with argon. This operation was repeated three times, and then Pd(dppf)Cl2 was added under argon. DCM (195.79 mg, 239.75 μmol). The reaction mixture was stirred under argon at 70 °C for 14 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20 mL) and discarded. The filtrate was evaporated in vacuo to give 6-(1-hydroxy-6-isoquinolinyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid third as a brown oil Butyl ester (0.5 g, 1.47 mmol, 30.63% yield) was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值340.2；實測值341.2；Rt=1.377min。LCMS (ESI): [M+H] + m/z: calculated 340.2; found 341.2; Rt=1.377 min.

步驟3：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異喹啉-1-醇之合成Step 3: Synthesis of 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)isoquinolin-1-ol

將6-(1-羥基-6-異喹啉基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯 (0.5g，1.47mmol)於TFA(2.51g，22.03mmol，1.70mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異喹啉-1-醇(0.35g，1.46mmol，99.16%產率)，其直接用於下一步驟中。6-(1-Hydroxy-6-isoquinolinyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.5 g, 1.47 mmol) in TFA (2.51 g, 22.03 mmol, 1.70 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)iso as a brown oil Quinolin-1-ol (0.35 g, 1.46 mmol, 99.16% yield), which was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值240.2；實測值241.2；Rt=0.684min。LCMS (ESI): [M+H] + m/z: calculated 240.2; found 241.2; Rt=0.684 min.

步驟4：6-(5-甲基-2-哌啶基)異喹啉-1-醇之合成Step 4: Synthesis of 6-(5-Methyl-2-piperidinyl)isoquinolin-1-ol

在0℃下，將硼氫化鈉(110.21mg，2.91mmol，103.00μL)一次性添加到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)異喹啉-1-醇(0.35g，1.46mmol)於MeOH(15mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌12h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以MeOH為溶析液混合物)，以得到6-(5-甲基-2-哌啶基)異喹啉-1-醇(0.1g，412.68μmol，28.33%產率)。Sodium borohydride (110.21 mg, 2.91 mmol, 103.00 μL) was added in one portion to 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)isoquinoline at 0 °C -1-ol (0.35 g, 1.46 mmol) in a stirred solution of MeOH (15 mL). The resulting mixture was stirred at 25 °C for 12 h, then evaporated in vacuo. The residue was diluted with water (20 ml) and extracted with dichloromethane (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The oil obtained was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with MeOH as eluent mixture) to give 6-(5-methyl-2-piperidinyl)isoquinoline-1 - Alcohol (0.1 g, 412.68 μmol, 28.33% yield).

LCMS(ESI)：[M+H]+ m/z：計算值242.2；實測值243.2；Rt=0.988min。LCMS (ESI): [M+H] + m/z: calculated 242.2; found 243.2; Rt=0.988 min.

6OOO. 6-(5-甲基-2-哌啶基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮之合成6OOO. Synthesis of 6-(5-methyl-2-piperidinyl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one

Figure 110128222-A0202-12-0883-12
Figure 110128222-A0202-12-0883-12

步驟1：3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合Step 1: The combination of 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 成to make

將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(10g，46.9mmol)於THF(200mL)中之混合物在真空下密封且除氣，且用氮氣吹掃三次，然後在-78℃下逐滴添加1M LiHMDS/THF(85mL，85mmol)，將混合物在-78℃下攪拌1.5小時，然後添加PhNTf2 (26g，72.8mmol)於THF(50mL)中之溶液。將溶液在25℃下攪拌12小時。藉由添加飽和NH4 Cl水溶液(100mL)淬滅所得混合物且用EtOAc(200mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；80g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~1%，流速=60mL/min，I2 )純化殘餘物，以得到呈黃色油狀物之3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(13g，80.3%產率)。1 H NMR(400MHz，氯仿-d )δ ppm 5.25(t,J =3.8Hz,1H),3.87(dd,J =12.7,3.2Hz,1H),3.00(dd,J =12.8,9.1Hz,1H),2.29-2.49(m,1H),1.77-2.00(m,2H),1.49(s,9H),0.99(d,J =6.6Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值346.1，實測值290.0(t-Bu裂解之質量)。A mixture of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (10 g, 46.9 mmol) in THF (200 mL) was sealed and degassed under vacuum and purged with nitrogen three times, Then 1M LiHMDS/THF (85 mL, 85 mmol) was added dropwise at -78 °C, the mixture was stirred at -78 °C for 1.5 h, then PhNTf2 (26 g, 72.8 mmol) in THF (50 mL) was added. The solution was stirred at 25°C for 12 hours. The resulting mixture was quenched by addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (200 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 80 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-1% EtOAc, flow = 60 mL/min, I2 ) to give a yellow oil 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (13 g, 80.3% yield) was obtained. 1 H NMR (400MHz, chloroform- d ) δ ppm 5.25 (t, J =3.8Hz, 1H), 3.87 (dd, J =12.7, 3.2Hz, 1H), 3.00 (dd, J =12.8, 9.1Hz, 1H) ), 2.29-2.49(m, 1H), 1.77-2.00(m, 2H), 1.49(s, 9H), 0.99(d, J =6.6Hz, 3H); LCMS(ESI)[M+H] + m /z: Calculated value of 346.1, found value of 290.0 (mass of t-Bu cracking).

步驟2：6-溴-2-碘吡啶-3-胺之合成Step 2: Synthesis of 6-bromo-2-iodopyridin-3-amine

向6-溴吡啶-3-胺(10g，57.8mmol)於EtOH(100mL)中之溶液中添加Ag2 SO4 (18g，57.7mmol)及I2 (16g，63.0mmol)。然後將混合物在25℃下攪拌3小時。將所得混合物在減壓下濃縮以移除EtOH，然後藉由添加水(100mL)淬滅粗品且用DCM(100mL * 3)萃取。將經合併之有機層用鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；40g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速=30mL/min，254nm)純化殘餘物，以得到呈紅色固體之6-溴-2-碘-吡啶-3-胺(9g，52.1%產率)。1 H NMR(400MHz，氯仿-d )δ ppm 7.18(d,J =8.3Hz,1H),6.82(d,J =8.3Hz,1H)；LCMS(ESI)[M+H]+ m/z：計算值298.9，實測值298.8。To a solution of 6-bromopyridin-3-amine (10 g, 57.8 mmol) in EtOH (100 mL) was added Ag2SO4 ( 18 g, 57.7 mmol) and I2 (16 g, 63.0 mmol). The mixture was then stirred at 25°C for 3 hours. The resulting mixture was concentrated under reduced pressure to remove EtOH, then the crude was quenched by adding water (100 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 40 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-20% EtOAc, flow rate = 30 mL/min, 254 nm) to give a red solid 6-Bromo-2-iodo-pyridin-3-amine (9 g, 52.1% yield). 1 H NMR (400 MHz, chloroform- d ) δ ppm 7.18 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1 H); LCMS (ESI) [M+H] + m/z: Calculated value 298.9, measured value 298.8.

步驟3：(E)-3-(3-胺基-6-溴-2-吡啶基)丙-2-烯酸乙酯之合成Step 3: Synthesis of (E)-3-(3-amino-6-bromo-2-pyridyl)prop-2-enoic acid ethyl ester

向6-溴-2-碘-吡啶-3-胺(9g，30.1mmol)於MeCN(100mL)中之溶液中添加Pd(OAc)2 (1.3g，5.79mmol)、TEA(16.5mL，0.118mol)、PPh3 (1.50g，5.72mmol)及丙-2-烯酸乙酯(3.2mL，29.5mmol)。將所得混合物在真空下密封且除氣，且用氮氣吹掃三次，然後在70℃、氮氣氣氛下攪拌12小時。將所得混合物在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；40g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速=30mL/min，254nm)進行純化，以得到呈淡黃色固體之(E)-3-(3-胺基-6-溴-2-吡啶基)丙-2-烯酸乙酯(4.4g，53.9%產率)。1 H NMR(400MHz，氯仿-d )δ ppm 7.67(d,J =15.1Hz,1H),7.21(d,J =8.3Hz,1H),6.86-7.03(m,2H),4.27(q,J =7.0Hz,2H),1.33(t,J =7.2Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值273.0，實測值273.0。To a solution of 6-bromo-2-iodo-pyridin-3-amine (9 g, 30.1 mmol) in MeCN (100 mL) was added Pd(OAc) 2 (1.3 g, 5.79 mmol), TEA (16.5 mL, 0.118 mol) ), PPh3 (1.50 g, 5.72 mmol) and ethyl prop-2-enoate (3.2 mL, 29.5 mmol). The resulting mixture was sealed and degassed under vacuum, and purged with nitrogen three times, then stirred at 70°C under a nitrogen atmosphere for 12 hours. The resulting mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® ; 40 g AgelaFlash® silica flash column, petroleum ether/EtOAc, where EtOAc was 0-20%, flow rate = 30 mL /min, 254 nm) to give (E)-ethyl 3-(3-amino-6-bromo-2-pyridyl)prop-2-enoate (4.4 g, 53.9%) as a pale yellow solid Yield). 1 H NMR (400 MHz, chloroform- d ) δ ppm 7.67(d, J =15.1 Hz, 1H), 7.21(d, J =8.3 Hz, 1H), 6.86-7.03(m, 2H), 4.27(q, J =7.0Hz,2H),1.33(t, J =7.2Hz,3H); LCMS(ESI)[M+H] + m/z: calculated 273.0, found 273.0.

步驟4：6-溴-1H-1,5-萘啶-2-酮之合成Step 4: Synthesis of 6-bromo-1H-1,5-naphthyridin-2-one

在20℃下，向(E)-3-(3-胺基-6-溴-2-吡啶基)丙-2-烯酸乙酯(2.2g，8.11mmol)於EtOH(20mL)中之溶液中添加DBU(6.1mL，40.9mmol)於EtOH(5mL)中之溶液。然後將混合物在100℃、氮氣下攪拌36小時。將所得混合物在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；40g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~100%，流速=50mL/min，254mm)進行純化，以得到呈棕色固體之6-溴-1H-1,5-萘啶-2-酮(2g，粗品)。LCMS(ESI)[M+H]+ m/z：計算值225.0，實測值225.0。To a solution of (E)-ethyl 3-(3-amino-6-bromo-2-pyridyl)prop-2-enoate (2.2 g, 8.11 mmol) in EtOH (20 mL) at 20 °C A solution of DBU (6.1 mL, 40.9 mmol) in EtOH (5 mL) was added. The mixture was then stirred at 100°C under nitrogen for 36 hours. The resulting mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® ; 40 g AgelaFlash® silica flash column, petroleum ether/EtOAc, where EtOAc was 0-100%, flow rate = 50 mL /min, 254 mm) was purified to give 6-bromo-lH-l,5-naphthyridin-2-one (2 g, crude) as a brown solid. LCMS (ESI) [M+H] + m/z: Calculated 225.0, found 225.0.

步驟6：3-甲基-6-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 6: 3-Methyl-6-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-yl]-3,4- Synthesis of tert-butyl dihydro-2H-pyridine-1-carboxylate

向6-溴-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(900mg，2.53mmol)及3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.3g，4.02mmol)於二噁烷(10mL)及H2 O(1mL)中之混合物 中添加Pd(OAc)2 (114mg，0.508mmol)、PPh3 (265mg，1.01mmol)及Cs2 CO3 (1.6g，4.91mmol)。將所得混合物在真空下密封且除氣，且用氮氣吹掃三次，然後在100℃、氮氣氣氛下攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；25g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之3-甲基-6-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(800mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值472.3，實測值472.2。To 6-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one (900 mg, 2.53 mmol) and 3-methyl-6-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.3g , 4.02 mmol) in dioxane (10 mL) and H 2 O (1 mL) was added Pd(OAc) 2 (114 mg, 0.508 mmol), PPh 3 (265 mg, 1.01 mmol) and Cs 2 CO 3 (1.6 g, 4.91 mmol). The resulting mixture was sealed and degassed under vacuum, and purged with nitrogen three times, then stirred at 100°C under nitrogen atmosphere for 12 hours. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL*2), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 25g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-20% EtOAc, flow = 30 mL/min, 254 nm) to give a yellow oil 3-methyl-6-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-yl]-3,4-di Hydro-2H-pyridine-1-carboxylic acid tert-butyl ester (800 mg, crude). LCMS (ESI) [M+H] + m/z: calcd 472.3, found 472.2.

步驟7：6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮之合成Step 7: 6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthalene Synthesis of pyridin-2-ones

向3-甲基-6-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(800mg，1.70mmol)於DCM(20mL)中之溶液中添加ZnBr2 (764mg，3.39mmol)。在20℃、氮氣下將混合物攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；25g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~50%，流速=30mL/min，245nm)純化殘餘物，以得到呈黃色固體之6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(600mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值372.3，實測值372.2。To 3-methyl-6-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-yl]-3,4-dihydro To a solution of -2H-pyridine-1-carboxylic acid tert-butyl ester (800 mg, 1.70 mmol) in DCM ( 20 mL) was added ZnBr2 (764 mg, 3.39 mmol). The mixture was stirred at 20°C under nitrogen for 12 hours. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL*2), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 25g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-50% EtOAc, flow rate = 30 mL/min, 245 nm) to give a yellow solid 6-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridine-2 - Ketone (600 mg, crude). LCMS (ESI) [M+H] + m/z: calcd 372.3, found 372.2.

步驟8：6-(5-甲基-2-哌啶基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮之合成Step 8: Synthesis of 6-(5-Methyl-2-piperidinyl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one

在0℃下，向6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(600mg，1.61mmol)於MeOH(10mL)中之溶液中添加NaBH4 (93.0mg，2.46mmol)。將混合物在20℃下攪拌30分鐘。所得混合物藉由添加水(10mL)來淬滅且用DCM(50mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色固體之6-(5-甲基-2-哌啶基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(800mg，粗品)，其不經進一步純化即用於下一步驟。At 0 °C, to 6-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1-(2-trimethylsilylethoxymethyl)-1, To a solution of 5-naphthyridin-2-one (600 mg, 1.61 mmol) in MeOH ( 10 mL) was added NaBH4 (93.0 mg, 2.46 mmol). The mixture was stirred at 20°C for 30 minutes. The resulting mixture was quenched by adding water (10 mL) and extracted with DCM (50 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 6-(5-methyl-2-piperidinyl)-1-(2-trimethyl) as a yellow solid silylethoxymethyl)-1,5-naphthyridin-2-one (800 mg, crude), which was used in the next step without further purification.

6PPP. 2-(4-氟苯基)-5-甲基哌啶-2-d之合成6PPP. Synthesis of 2-(4-fluorophenyl)-5-methylpiperidine-2-d

Figure 110128222-A0202-12-0887-13
Figure 110128222-A0202-12-0887-13

步驟1：5-甲基-2-側氧基哌啶-1-甲酸第三丁酯Step 1: tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate

將5-甲基哌啶-2-酮(1 )(3.0g，26.51mmol)溶解於THF(75mL)且在-78C下添加n-BuLi(17.7mL 1.5M於己烷中之溶液，26.51mmol)。攪拌30min之後，逐滴添加Boc2 O之THF(37.5mL)溶液(8.7g，9.14mmol)且將所得混合物在室溫下攪拌隔夜。將反應物用飽和NH4 Cl水溶液(30mL)及EtOAc(30mL)淬滅。分離各層，且用CH2 Cl2 (2*30mL)洗滌水層。將經合併之有機層乾燥(Na2 SO4 )，過濾，且在真空中濃縮。藉由矽膠管柱層析(10/0環己烷/乙酸乙酯至95/5)純化殘餘物，以得到呈無色油狀物之5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2 )(3.20mg，56%)5-Methylpiperidin-2-one ( 1 ) (3.0 g, 26.51 mmol) was dissolved in THF (75 mL) and n-BuLi (17.7 mL of a 1.5 M solution in hexanes, 26.51 mmol) was added at -78C ). After stirring for 30 min, a solution of Boc2O in THF (37.5 mL) (8.7 g, 9.14 mmol) was added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was washed with CH2Cl2 ( 2 *30 mL). The combined organic layers were dried ( Na2SO4 ) , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10/0 cyclohexane/ethyl acetate to 95/5) to give 5-methyl-2-oxypiperidine-1- as a colorless oil tert-butyl formate ( 2 ) (3.20mg, 56%)

1 H NMR(CDCl3 ,400MHz)δ 3.72(ddd,J =1.9,4.7,12.6Hz,1H),3.04(dd,J =10.4,12.6Hz,1H),2.54-2.35(m,2H),1.97-1.76(m,2H),1.46(s,9H),1.40-1.31(m,1H)0.97(d,J =6.6Hz,2.8H),0.83(d,J =6.6Hz,0.2H) 1 H NMR (CDCl 3 , 400MHz) δ 3.72 (ddd, J =1.9, 4.7, 12.6Hz, 1H), 3.04 (dd, J =10.4, 12.6Hz, 1H), 2.54-2.35 (m, 2H), 1.97 -1.76(m,2H),1.46(s,9H),1.40-1.31(m,1H)0.97(d, J =6.6Hz,2.8H),0.83(d, J =6.6Hz,0.2H)

步驟2：3-甲基-6-(((三氟甲基)磺醯基)氧基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 2: Synthesis of 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2 )(660mg，3.09mmol)於無水THF(23mL)中之溶液冷卻至-78℃。在5min內添加1M KHMDS溶液(4.64mL 1M於THF中之溶液，4.64mmol)，且將混合物攪拌70min。然後添加PhNTf2 之無水THF(6.8mL)溶液(1.1g，3.09mmol)且將混合物在-78℃下攪拌(2h)。添加飽和Na2 CO3 水溶液(30mL)及CH2 Cl2 (30mL)，且分離各層。將水層用CH2 Cl2 (2*30mL)洗滌。將經合併之有機層乾燥(Na2 SO4 )，過濾，且在真空中濃縮。藉由矽膠管柱層析(10/0環己烷/乙酸乙酯至85/15)純化殘餘物，以得到呈無色油狀物之3-甲基-6-(((三氟甲基)磺醯基)氧基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(3 )。A solution of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate ( 2 ) (660 mg, 3.09 mmol) in dry THF (23 mL) was cooled to -78 °C. 1 M KHMDS solution (4.64 mL of 1 M in THF, 4.64 mmol) was added over 5 min, and the mixture was stirred for 70 min. Then a solution of PhNTf2 in dry THF (6.8 mL) (1.1 g, 3.09 mmol) was added and the mixture was stirred at -78 °C (2 h). Saturated aqueous Na2CO3 (30 mL) and CH2Cl2 ( 30 mL) were added, and the layers were separated. The aqueous layer was washed with CH2Cl2 ( 2 *30 mL). The combined organic layers were dried ( Na2SO4 ) , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10/0 cyclohexane/ethyl acetate to 85/15) to give 3-methyl-6-(((trifluoromethyl) as a colorless oil Sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester ( 3 ).

1 H NMR(CDCl3 ,400MHz)δ 5.27(t,J =3.8Hz,1H),3.87(dd,J =3.3,12.7Hz,1H),3.00(dd,J =9.2,12.7Hz,1H),2.39(ddd,J =3.7,6.1,18.0Hz,1H),1.98-1.78(m,2H),1.49(s,9H),0.99(d,J =6.6Hz,3H)。 1 H NMR (CDCl 3 , 400MHz) δ 5.27 (t, J =3.8Hz, 1H), 3.87 (dd, J =3.3, 12.7Hz, 1H), 3.00 (dd, J =9.2, 12.7Hz, 1H), 2.39(ddd, J =3.7,6.1,18.0Hz,1H),1.98-1.78(m,2H),1.49(s,9H),0.99(d, J =6.6Hz,3H).

步驟3：6-(4-氟苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: Synthesis of 6-(4-fluorophenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

在氮氣氣氛下，向3-甲基-6-(((三氟甲基)磺醯基)氧基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(400mg，1.16mmol)於THF(11.6mL)中之溶液中添加(Ph3 P)2 PdCl2 (41mg，57.9μmol)、(4-氟苯基)硼酸(243mg，1.74mmol)及2M Na2 CO3 水溶液(9.3mL)。在40℃下，將混合物攪拌16h。然後添加水(10mL)且將混合物用乙醚萃取且乾燥(Na2 SO4 )。藉由矽膠管柱層析(10/0環己烷/乙酸乙酯至1/9)純化殘餘物，以得到呈無色油狀物之6-(4-氟苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(4 )(200mg，60%)。Under nitrogen atmosphere, 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (400 mg, To a solution of 1.16 mmol) in THF (11.6 mL) was added (Ph 3 P) 2 PdCl 2 (41 mg, 57.9 μmol), (4-fluorophenyl)boronic acid (243 mg, 1.74 mmol) and 2M aqueous Na 2 CO 3 (9.3 mL). The mixture was stirred for 16 h at 40 °C. Water (10 mL) was then added and the mixture was extracted with ether and dried ( Na2SO4 ) . The residue was purified by silica gel column chromatography (10/0 cyclohexane/ethyl acetate to 1/9) to give 6-(4-fluorophenyl)-3-methyl- 3,4-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester ( 4 ) (200 mg, 60%).

1 H NMR(CDCl3 ,400MHz)δ 7.28-7.23(m,2H),6.97(d,J =8.7Hz,2H),5.24(t,J =3.7Hz,1H),4.06(dd,J =3.4,12.7Hz,1H),3.00(dd,J =9.2,12.7Hz,1H),2.39(ddd,J =3.8,6.4,18.6Hz,1H),2.05-1.94(m,1H),1.84(ddd,J =3.7,8.6,18.6Hz,1H),1.10(s,9H),1.01(d,J =6.6Hz,3H)。 1 H NMR (CDCl 3 , 400MHz) δ 7.28-7.23 (m, 2H), 6.97 (d, J =8.7Hz, 2H), 5.24 (t, J =3.7Hz, 1H), 4.06 (dd, J =3.4 ,12.7Hz,1H),3.00(dd, J =9.2,12.7Hz,1H),2.39(ddd, J =3.8,6.4,18.6Hz,1H),2.05-1.94(m,1H),1.84(ddd, J =3.7, 8.6, 18.6Hz, 1H), 1.10 (s, 9H), 1.01 (d, J =6.6Hz, 3H).

步驟4：2-(4-氟苯基)-5-甲基哌啶-2-d之合成Step 4: Synthesis of 2-(4-Fluorophenyl)-5-methylpiperidine-2-d

將TFA(0.86mL)添加到6-(4-氟苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(50mg，0.17mmol)之CH2 Cl2 (0.86mL)溶液中。將溶液在室溫下攪拌1h且在真空下濃縮。添加飽和Na2 CO3 水溶液(3mL)及CH2 Cl2 (3mL)且分離各層。將水層用CH2 Cl2 (2x5mL)洗滌，將所有有機層合併，乾燥且在真空下濃縮。將甲醇-d 4 (1.7mL)添加到殘餘物中，隨後添加NaBD4 (11mg，0.26mmol)。將混合物在室溫下攪拌隔夜。蒸發揮發物且添加水。將水層用CH2 Cl2 (3x5mL)洗滌。將所有有機層合併，乾燥且在真空下濃縮，以獲得呈白色固體之2-(4-氟苯基)-5-甲基哌啶-2-d(23mg，69%)。TFA (0.86 mL) was added to 6-(4-fluorophenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (50 mg, 0.17 mmol) in CH 2 Cl 2 (0.86 mL) solution. The solution was stirred at room temperature for 1 h and concentrated in vacuo. Saturated aqueous Na2CO3 ( 3 mL) and CH2Cl2 ( 3 mL) were added and the layers were separated. The aqueous layer was washed with CH2Cl2 ( 2 x 5 mL), all organic layers were combined, dried and concentrated in vacuo. Methanol- d4 (1.7 mL) was added to the residue followed by NaBD4 ( 11 mg, 0.26 mmol). The mixture was stirred at room temperature overnight. The volatiles were evaporated and water was added. The aqueous layer was washed with CH2Cl2 ( 3x5 mL). All organic layers were combined, dried and concentrated in vacuo to give 2-(4-fluorophenyl)-5-methylpiperidine-2-d (23 mg, 69%) as a white solid.

1 H NMR(CDCl3 ,400MHz)δ 7.35-7.29(m,2H),6.98(d,J =8.8Hz,2H),3.15-3.08(m,1H),2.40(t,J =11.3Hz,1H),1.90-1.46(m,3H),1.14(d,J =7.1Hz,1H),0.89(d,J =6.6Hz,3H)。 1 H NMR (CDCl 3 , 400MHz) δ 7.35-7.29(m, 2H), 6.98(d, J =8.8Hz, 2H), 3.15-3.08(m, 1H), 2.40(t, J =11.3Hz, 1H ), 1.90-1.46(m, 3H), 1.14(d, J =7.1Hz, 1H), 0.89(d, J =6.6Hz, 3H).

6QQQ. 2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-2-d及2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-2-d之合成6QQQ. 2-(4-Fluorophenyl-2,3,5,6-d4)-5-methylpiperidine-2-d and 2-(4-fluorophenyl-2,3,5,6- Synthesis of d4)-5-methylpiperidine-2-d

Figure 110128222-A0202-12-0889-14
Figure 110128222-A0202-12-0889-14

步驟1：6-(4-氟苯基-2,3,5,6-d4)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(5)之合成Step 1: 6-(4-Fluorophenyl-2,3,5,6-d4)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5) synthesis

在氮氣氣氛下，向3-甲基-6-(((三氟甲基)磺醯基)氧基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(200mg，0.58mmol)於THF(3.9mL)中之溶液中添加(Ph3 P)2 PdCl2 (20mg，29.0μmol)、(4-氟苯基-2,3,5,6-d4)硼酸(243mg，0.58mmol)及2M Na2 CO3 水溶液(2.3mL)。在80℃下，將混合物攪拌16h。然後添加水(10mL) 且將混合物用乙醚萃取且乾燥(Na2 SO4 )。藉由矽膠管柱層析(10/0環己烷/乙酸乙酯至1/9)純化殘餘物，以得到呈黃色油狀物之6-(4-氟苯基-2,3,5,6-d4)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(5 )(80mg，47%)。Under nitrogen atmosphere, 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 0.58 mmol) in THF (3.9 mL) was added (Ph 3 P) 2 PdCl 2 (20 mg, 29.0 μmol), (4-fluorophenyl-2,3,5,6-d4)boronic acid (243 mg, 0.58 mmol) and 2M aqueous Na2CO3 ( 2.3 mL). The mixture was stirred at 80 °C for 16 h. Water (10 mL) was then added and the mixture was extracted with ether and dried ( Na2SO4 ) . The residue was purified by silica gel column chromatography (10/0 cyclohexane/ethyl acetate to 1/9) to give 6-(4-fluorophenyl-2,3,5,5,6-(4-fluorophenyl-2,3,5,5) as a yellow oil 6-d4)-3-Methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester ( 5 ) (80 mg, 47%).

1 H NMR(CDCl3 ,400MHz)5.24(t,J =3.8Hz,1H),4.06(dd,J =3.4,12.6Hz,1H),2.97(dd,J =9.4,12.2Hz,1H),2.39(ddd,J =3.9,6.4,18.6Hz,1H),2.06-1.95(m,1H),1.84(ddd,J =3.7,8.6,18.6Hz,1H),1.10(s,9H),1.01(d,J =6.7Hz,3H)。 1 H NMR (CDCl 3 , 400MHz) 5.24 (t, J =3.8Hz, 1H), 4.06 (dd, J =3.4, 12.6Hz, 1H), 2.97 (dd, J =9.4, 12.2Hz, 1H), 2.39 (ddd, J =3.9,6.4,18.6Hz,1H),2.06-1.95(m,1H),1.84(ddd, J =3.7,8.6,18.6Hz,1H),1.10(s,9H),1.01(d , J = 6.7Hz, 3H).

步驟2：2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-2-d之合成Step 2: Synthesis of 2-(4-Fluorophenyl-2,3,5,6-d4)-5-methylpiperidine-2-d

將TFA(0.4mL)添加到6-(4-氟苯基-2,3,5,6-d4)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(5 )(23mg，78μ mol)之CH2 Cl2 (0.4mL)溶液中。將溶液在室溫下攪拌1h且在真空下濃縮。添加飽和Na2 CO3 水溶液(2mL)及CH2 Cl2 (2mL)且分離各層。將水層用CH2 Cl2 (2x2mL)洗滌，將所有有機層合併，乾燥且在真空下濃縮。將甲醇(0.4mL)添加到殘餘物中，隨後添加NaBH4 (4mg，0.1mmol)。將混合物在室溫下攪拌隔夜。蒸發揮發物且添加水。將水層用CH2 Cl2 (3x5mL)洗滌。將所有有機層合併，乾燥且在真空下濃縮，以獲得呈白色固體之2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶(15mg，100%)。TFA (0.4 mL) was added to tert-butyl 6-(4-fluorophenyl-2,3,5,6-d4)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid Ester ( 5 ) (23 mg, 78 μmol ) in CH2Cl2 ( 0.4 mL). The solution was stirred at room temperature for 1 h and concentrated in vacuo. Saturated aqueous Na2CO3 ( 2 mL) and CH2Cl2 ( 2 mL) were added and the layers were separated. The aqueous layer was washed with CH2Cl2 ( 2 x 2 mL), all organic layers were combined, dried and concentrated in vacuo. Methanol (0.4 mL) was added to the residue followed by NaBH4 ( 4 mg, 0.1 mmol). The mixture was stirred at room temperature overnight. The volatiles were evaporated and water was added. The aqueous layer was washed with CH2Cl2 ( 3x5 mL). All organic layers were combined, dried and concentrated in vacuo to give 2-(4-fluorophenyl-2,3,5,6-d4)-5-methylpiperidine (15 mg, 100%) as a white solid ).

1 H NMR(CDCl3 ,400MHz)δ 3.53(dd,J =2.2,11.3Hz,1H),3.13(ddd,J =1.9,3.9,11.5Hz,1H),2.41(t,J =11.2Hz,1H),1.90-1.46(m,3H),1.16-1.12(m,1H),0.90(d,J =6.6Hz,3H)。 1 H NMR (CDCl 3 , 400MHz) δ 3.53 (dd, J =2.2, 11.3Hz, 1H), 3.13 (ddd, J =1.9, 3.9, 11.5Hz, 1H), 2.41 (t, J =11.2Hz, 1H) ), 1.90-1.46(m, 3H), 1.16-1.12(m, 1H), 0.90(d, J = 6.6Hz, 3H).

步驟3：2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-2-d之合成Step 3: Synthesis of 2-(4-Fluorophenyl-2,3,5,6-d4)-5-methylpiperidine-2-d

將TFA(2.0mL)添加到6-(4-氟苯基-2,3,5,6-d4)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(5 )(120mg，0.41mmol)之CH2 Cl2 (2.0mL)溶液中。將溶液在室溫下攪拌1h且在真空下濃縮。添加飽和Na2 CO3 水溶液(10mL)及CH2 Cl2 (10mL)且分離各層。將水層用CH2 Cl2 (2x10mL)洗滌，將所有有機層合併，乾燥且在真空下濃縮。將甲醇-d4 (2.0mL)添加到殘餘物中，隨後添加NaBD4 (22mg，0.53 mmol)。將混合物在室溫下攪拌隔夜。蒸發揮發物且添加水。將水層用CH2 Cl2 (3x5mL)洗滌。將所有有機層合併，乾燥且在真空下濃縮，以獲得呈白色固體之2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-2-d(81mg，100%)。TFA (2.0 mL) was added to tert-butyl 6-(4-fluorophenyl-2,3,5,6-d4)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid Ester ( 5 ) (120 mg, 0.41 mmol) in CH2Cl2 ( 2.0 mL). The solution was stirred at room temperature for 1 h and concentrated in vacuo. Saturated aqueous Na2CO3 (10 mL) and CH2Cl2 ( 10 mL) were added and the layers were separated. The aqueous layer was washed with CH2Cl2 ( 2 x 10 mL), all organic layers were combined, dried and concentrated in vacuo. Methanol- d4 (2.0 mL) was added to the residue followed by NaBD4 (22 mg, 0.53 mmol). The mixture was stirred at room temperature overnight. The volatiles were evaporated and water was added. The aqueous layer was washed with CH2Cl2 ( 3x5 mL). All organic layers were combined, dried and concentrated in vacuo to give 2-(4-fluorophenyl-2,3,5,6-d4)-5-methylpiperidine-2-d( as a white solid 81 mg, 100%).

1 H NMR(CDCl3 ,400MHz)δ 3.13(ddd,J =2.0,3.9,11.5Hz,1H),2.40(t,J =11.2Hz,1H),1.90-1.46(m,3H),1.19-1.12(m,1H),0.90(d,J =6.6Hz,3H)。 1 H NMR (CDCl 3 , 400MHz) δ 3.13 (ddd, J =2.0, 3.9, 11.5Hz, 1H), 2.40 (t, J =11.2Hz, 1H), 1.90-1.46 (m, 3H), 1.19-1.12 (m, 1H), 0.90 (d, J = 6.6Hz, 3H).

6RRR. 5-[(2S,5R)-5-甲基-2-哌啶基]噻唑之合成6RRR. Synthesis of 5-[(2S,5R)-5-methyl-2-piperidinyl]thiazole

Figure 110128222-A0202-12-0891-15
Figure 110128222-A0202-12-0891-15

步驟1：3-甲基-6-噻唑-5-基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-thiazol-5-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

在氬氣氣氛下，向3-甲基-6-噻唑-5-基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(14.61g，52.11mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)噻唑(10g，47.37mmol)、碳酸鈉(15.06g，142.12mmol，5.95mL)於二噁烷(150mL)及水(50mL)中之溶液中添加1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(1.55g，1.89mmol)。將所得混合物在90℃下攪拌48h，冷卻，過濾且蒸發。將殘餘物溶解於EtOAc中且經Na2 SO4 乾燥，在真空中蒸發且藉由梯度層析(己烷-MTBE)純化，以得到3-甲基-6-噻唑-5-基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.4g，1.43mmol，3.01%產率)。To 3-methyl-6-thiazol-5-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (14.61 g, 52.11 mmol), 5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)thiazole (10 g, 47.37 mmol), sodium carbonate (15.06 g, 142.12 mmol, 5.95 mL) To a solution in dioxane (150 mL) and water (50 mL) was added a complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1.55 g) , 1.89 mmol). The resulting mixture was stirred at 90 °C for 48 h, cooled, filtered and evaporated. The residue was dissolved in EtOAc and dried over Na 2 SO 4 , evaporated in vacuo and purified by gradient chromatography (hexane-MTBE) to give 3-methyl-6-thiazol-5-yl-3, 4-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.4 g, 1.43 mmol, 3.01% yield).

1 H NMR(CDCl3 ,400MHz)：δ 1.01(d,3H),1.19(s,9H),1.41(m,1H),1.86(m,1H),1.97(m,1H),2.37(d,1H),2.96(dd,1H),4.01(d,1H),5.47(t,1H),7.74(s,1H),8.63(s,1H)。 1 H NMR (CDCl 3 , 400MHz): δ 1.01 (d, 3H), 1.19 (s, 9H), 1.41 (m, 1H), 1.86 (m, 1H), 1.97 (m, 1H), 2.37 (d, 1H), 2.96 (dd, 1H), 4.01 (d, 1H), 5.47 (t, 1H), 7.74 (s, 1H), 8.63 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值280.15；實測值281.2；Rt=1.29min。LCMS (ESI): [M+H] + m/z: calculated 280.15; found 281.2; Rt=1.29 min.

步驟2：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)噻唑之合成Step 2: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)thiazole

將3-甲基-6-噻唑-5-基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.4g，1.43mmol)於三氟乙酸(8g，70.16mmol，5.41mL)中之溶液在25℃下攪拌2h且在真 空中蒸發。將殘餘物用NaHCO3 飽和溶液(50ml)稀釋，用DCM(3*30ml)萃取，用鹽水洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得5-(3-甲基-2,3,4,5-四氫吡啶-6-基)噻唑(0.25g，1.39mmol，97.21%產率)。3-Methyl-6-thiazol-5-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.4 g, 1.43 mmol) in trifluoroacetic acid (8 g, 70.16 mmol, 5.41 g) The solution in mL) was stirred at 25 °C for 2 h and evaporated in vacuo. The residue was diluted with saturated NaHCO3 solution (50ml), extracted with DCM (3*30ml), washed with brine, dried over Na2SO4 and evaporated in vacuo to give 5-(3-methyl-2, 3,4,5-Tetrahydropyridin-6-yl)thiazole (0.25 g, 1.39 mmol, 97.21% yield).

1 H NMR(CDCl3 ,500MHz)：δ 1.00(d,3H),1.41(m,1H),1.73(m,1H),1.93(m,1H),2.59(m,1H),2.80(dd,1H),3.23(m,1H),3.94(d,1H),8.03(s,1H),8.77(s,1H)。 1 H NMR (CDCl 3 , 500MHz): δ 1.00 (d, 3H), 1.41 (m, 1H), 1.73 (m, 1H), 1.93 (m, 1H), 2.59 (m, 1H), 2.80 (dd, 1H), 3.23 (m, 1H), 3.94 (d, 1H), 8.03 (s, 1H), 8.77 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值180.1；實測值181.2；Rt=0.466min。LCMS (ESI): [M+H] + m/z: calculated 180.1; found 181.2; Rt=0.466 min.

步驟3：5-[(2S,5R)-5-甲基-2-哌啶基]噻唑之合成Step 3: Synthesis of 5-[(2S,5R)-5-methyl-2-piperidinyl]thiazole

在0℃下，向5-(3-甲基-2,3,4,5-四氫吡啶-6-基)噻唑(0.25g，1.39mmol)於MeOH(30mL)中之溶液中添加硼氫化鈉(104.93mg，2.77mmol，98.07μL)。將所得混合物攪拌2h且真空蒸發。將殘餘物用水(20ml)稀釋且用DCM(3*20ml)萃取。將經合併之有機層用鹽水(20ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得5-[(2S,5R)-5-甲基-2-哌啶基]噻唑(0.25g，1.37mmol，98.89%產率)。To a solution of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)thiazole (0.25 g, 1.39 mmol) in MeOH (30 mL) at 0 °C was added hydroboration Sodium (104.93 mg, 2.77 mmol, 98.07 μL). The resulting mixture was stirred for 2 h and evaporated in vacuo. The residue was diluted with water (20ml) and extracted with DCM (3*20ml). The combined organic layers were washed with brine (20 ml), dried over Na 2 SO 4 and evaporated in vacuo to give 5-[(2S,5R)-5-methyl-2-piperidinyl]thiazole (0.25 g, 1.37 mmol, 98.89% yield).

1 H NMR(DMSO,400MHz)：δ 0.87(d,3H),1.13-1.20(m,2H),1.55-1.60(m,2H),1.60-1.84(m,2H),1.87(d,1H),1.97(d,1H),2.42(t,1H),3.11(d,1H),3.93(d,1H),7.72(s,1H),8.67(s,1H)。 1 H NMR (DMSO, 400MHz): δ 0.87(d,3H), 1.13-1.20(m,2H), 1.55-1.60(m,2H), 1.60-1.84(m,2H), 1.87(d,1H) , 1.97(d, 1H), 2.42(t, 1H), 3.11(d, 1H), 3.93(d, 1H), 7.72(s, 1H), 8.67(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值182.1；實測值183.0；Rt=0.684min。LCMS (ESI): [M+H] + m/z: calculated 182.1; found 183.0; Rt=0.684 min.

6SSS. 外消旋-4-((2R,5S )-5-甲基哌啶-2-基)吡啶之合成6SSS. Synthesis of racemic-4-(( 2R,5S )-5-methylpiperidin-2-yl)pyridine

Figure 110128222-A0202-12-0892-16
Figure 110128222-A0202-12-0892-16

步驟1：5-甲基-5,6-二氫-[2,4'-聯吡啶]-1(4H)-甲酸第三丁酯之合成Step 1: Synthesis of 5-methyl-5,6-dihydro-[2,4'-bipyridine]-1(4H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5.62g，16.27mmol)及4-吡啶基硼酸(2g，16.27mmol)溶解於二噁烷中且將反應混合物徹底除氣，隨後後續添加碳酸銫(26.51g，81.36mmol)、H2 O及 Pd(dppf)Cl2 *DCM(1.63mmol)。將所獲得之反應混合物在回流下攪拌隔夜；反應完成之後，在減壓下蒸發有機溶劑，且將粗混合物分配於EtOAc與H2 O之間。將水層另外用EtOAc萃取兩次；將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以得到3-甲基-6-(4-吡啶基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7g，粗品)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (5.62 g, 16.27 mmol) and 4-pyridyl Boronic acid (2 g, 16.27 mmol) was dissolved in dioxane and the reaction mixture was thoroughly degassed, followed by the subsequent addition of cesium carbonate (26.51 g , 81.36 mmol), H2O and Pd(dppf)Cl2*DCM (1.63 mmol) . The resulting reaction mixture was stirred at reflux overnight; after completion of the reaction, the organic solvent was evaporated under reduced pressure, and the crude mixture was partitioned between EtOAc and H2O . The aqueous layer was extracted two more times with EtOAc; the combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated to give 3-methyl-6-(4-pyridyl)-3,4-di Hydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7 g, crude) was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.08(s,9H),1.85(m,2H),2.32(m,1H),2.98(m,1H),3.83(d,1H),5.52(m,1H),7.18(d,2H),8.42(d,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.96(d,3H), 1.08(s,9H), 1.85(m,2H), 2.32(m,1H), 2.98(m,1H), 3.83(d,1H), 5.52(m,1H), 7.18(d,2H), 8.42(d,2H).

步驟2：5-甲基-3,4,5,6-四氫-2,4'-聯吡啶之合成Step 2: Synthesis of 5-methyl-3,4,5,6-tetrahydro-2,4'-bipyridine

將3-甲基-6-(4-吡啶基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(7g，25.51mmol)溶解於DCM(200mL)中，隨後添加TFA(2.91g，25.51mmol，1.97mL)且攪拌隔夜。反應完成之後，將混合物用10% NaOH水溶液洗滌，且將有機溶劑蒸發，以得到4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(3.5g，20.09mmol，78.73%產率)，其不經純化即用於下一步驟。3-Methyl-6-(4-pyridyl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (7 g, 25.51 mmol) was dissolved in DCM (200 mL) followed by the addition of TFA (2.91 g, 25.51 mmol, 1.97 mL) and stirred overnight. After the reaction was completed, the mixture was washed with 10% aqueous NaOH solution, and the organic solvent was evaporated to obtain 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine (3.5 g, 20.09 mmol, 78.73% yield), which was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.22(m,1H),1.73(m,1H),1.98(m,1H),2.45(m,1H),2.77(m,1H),3.27(m,1H),4.03(m,1H),7.62(d,2H),8.64(d,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.22(m,1H), 1.73(m,1H), 1.98(m,1H), 2.45(m,1H), 2.77( m, 1H), 3.27 (m, 1H), 4.03 (m, 1H), 7.62 (d, 2H), 8.64 (d, 2H).

步驟3：外消旋-4-((2R,5S)-5-甲基哌啶-2-基)吡啶之合成Step 3: Synthesis of racemic-4-((2R,5S)-5-methylpiperidin-2-yl)pyridine

將4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(3.5g，20.09mmol)溶解於MeOH(50mL)及H2 O(10mL)中且冷卻至0℃。將硼氫化鈉(759.89mg，20.09mmol，710.18μL)分批添加到所獲得之混合物中且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH=2，用MTBE洗滌(2*10mL)，用10% NaOH水溶液鹼化至pH=10且用DCM(50mL)萃取。蒸發溶劑，得到純的4-[(2S,5R )-5-甲基-2-哌啶基]吡啶(2.5g，14.18mmol，70.61%產率)。4-(3-Methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine (3.5 g, 20.09 mmol) was dissolved in MeOH (50 mL) and H2O (10 mL) and cooled to 0°C. Sodium borohydride (759.89 mg, 20.09 mmol, 710.18 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH=2 with 10% aqueous HCl, washed with MTBE (2*10 mL), basified with 10% aqueous NaOH to pH=10 and extracted with DCM (50 mL). The solvent was evaporated to give pure 4-[( 2S,5R )-5-methyl-2-piperidinyl]pyridine (2.5 g, 14.18 mmol, 70.61% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.86(d,3H),1.18(m,2H),1.75(m,4H),2.40(m, 1H),3.14(m,1H),3.56(m,1H),7.28(d,2H),8.53(d,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.86(d, 3H), 1.18(m, 2H), 1.75(m, 4H), 2.40(m, 1H), 3.14(m, 1H), 3.56( m, 1H), 7.28 (d, 2H), 8.53 (d, 2H).

LCMS(ESI)：[M]+ m/z：計算值176.2；實測值177.2；Rt=0.226min。LCMS (ESI): [M] + m/z: calculated 176.2; found 177.2; Rt=0.226 min.

方案A. 式1化合物之合成Scheme A. Synthesis of compounds of formula 1

式1、1a、1b、1c及1d化合物為式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所定義，且R1 或R2 中之至少一者為-NH2 ，R1a 為R1 或-NH-PG，R2a 為R2 或-NH-PG。PG為如本文所述之氮保護基(例如，-Boc)。Compounds of formula 1, 1a, 1b, 1c and 1d are compounds of formula (I), (Ia), (Ib), (Ic) and (Id), wherein R 1 , R 2 , R 3 , R 4 , R 6 , R7 and R8 are as defined herein, and at least one of R1 or R2 is -NH2 , R1a is R1 or -NH - PG, and R2a is R2 or -NH - PG. PG is a nitrogen protecting group as described herein (eg, -Boc).

一般程序1General Procedure 1

Figure 110128222-A0202-12-0894-17
注意，在某些情況下，起始哌啶已經呈順式或反式組態。在彼等情況下，掌性分離步驟僅得到四種所描繪鏡像異構物中之二者。
Figure 110128222-A0202-12-0894-17
 Note that in some cases the starting piperidine is already in the cis or trans configuration. In those cases, the chiral separation step yielded only two of the four depicted enantiomers.

如方案A中所示，式(Ia)、(Ib)、(Ic)及(Id)化合物可自式(I)化合物之混合物分離，其中R1 、R2 、R3 、R4 、R6 、R7 、R8 及n如本文所述。替代地，式(Ia)、(Ib)、(Ic)及(Id)化合物可由其經保護之前驅物製備。在一些實施例中，R1a 選自R1 及-NH-PG且R2a 選自R2 及-NH-PG，其中PG為如本文所定義之氮保護基(例如 ，-Boc)。在某些實施例中(例如， 當R1a 為NH-PG且R1 為-NH2 ，或R2a 為NH-PG且R2 為-NH2 時)，採用去保護步驟將R1a 轉化成R1 或將R2a 轉化成R2 。在一些實施例中，可在掌性分離之前或之後進行去保護。用於移除保護基-PG(例如， -Boc)之條件可採用例如酸性條件(例如， 水/二噁烷、於質子性溶劑(例如，甲醇 )中之鹽酸、於非質子性溶劑(例如， 二噁烷)中之鹽酸、於非質子性溶劑(例如，二氯甲烷 、氯仿等)中之TFA)。在一些實施例中，去保護步驟採用於二噁烷中之HCl(4.0M)。在一些實施例中，去保護步驟採用於DCM中之HCl(4.0M)。As shown in Scheme A, compounds of formula (Ia), (Ib), (Ic) and (Id) can be isolated from a mixture of compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and n are as described herein. Alternatively, compounds of formula (Ia), (Ib), (Ic) and (Id) can be prepared from their protected precursors. In some embodiments, R 1a is selected from R 1 and -NH-PG and R 2a is selected from R 2 and -NH-PG, wherein PG is a nitrogen protecting group as defined herein ( eg , -Boc). In certain embodiments ( eg, when R 1a is NH-PG and R 1 is -NH 2 , or R 2a is NH-PG and R 2 is -NH 2 ), a deprotection step is used to convert R 1a into R 1 or convert R 2a into R 2 . In some embodiments, deprotection can be performed before or after chiral separation. Conditions for removing the protecting group -PG ( e.g., -Boc) can employ, for example, acidic conditions ( e.g., water/dioxane, hydrochloric acid in a protic solvent ( e.g., methanol ), in an aprotic solvent ( e.g. , , hydrochloric acid in dioxane), TFA) in an aprotic solvent ( eg, dichloromethane , chloroform, etc.). In some embodiments, the deprotection step employs HCl (4.0 M) in dioxane. In some embodiments, the deprotection step employs HCl (4.0 M) in DCM.

掌性分離方法為熟習此項技術者已知的。例如，在一些實施例中，可透過使用掌性HPLC純化(管柱：AD-H III(250*20mm，5μm)完成掌性分離。示範性溶析液包括但不限於己烷、IPA、MeOH、MeCN及H2 O及其混合物。Methods of chiral separation are known to those skilled in the art. For example, in some embodiments, chiral separation can be accomplished by using chiral HPLC purification (column: AD-H III (250*20 mm, 5 μm). Exemplary eluents include, but are not limited to, hexane, IPA, MeOH , MeCN and H 2 O and mixtures thereof.

如方案A所示，本文所述之化合物之製備可包括醯胺鍵偶合步驟。在一些實施例中，醯胺鍵偶合包含使哌啶與2,2,2-三氟乙基酯在存在強鹼(例如，烷基鋰鹼)之情況下，在非質子性溶劑(例如，THF)中，在惰性氣氛下(例如，在氬氣下)偶合。在一些實施例中，反應在-100℃與-60℃之間的溫度下發生。在一些實施例中，反應在約-78℃之溫度下發生。在一些實施例中，醯胺鍵偶合包含在-78℃下使用於THF中之n -BuLi。As shown in Scheme A, the preparation of the compounds described herein can include an amide coupling step. In some embodiments, the amide linkage comprises coupling piperidine with 2,2,2-trifluoroethyl ester in the presence of a strong base (eg, an alkyl lithium base) in an aprotic solvent (eg, THF) under an inert atmosphere (eg, under argon). In some embodiments, the reaction occurs at a temperature between -100°C and -60°C. In some embodiments, the reaction occurs at a temperature of about -78°C. In some embodiments, the amide linkage coupling comprises n -BuLi used in THF at -78°C.

實例1. N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基-2-(2-苯基-3-氮雜雙環[3.2.1]辛-3-基)乙醯胺(化合物63、化合物62、化合物64、化合物65)之合成Example 1. N-(6-Amino-5-methylpyridin-3-yl)-2-oxy-2-(2-phenyl-3-azabicyclo[3.2.1]octane-3- Synthesis of acetamide (compound 63, compound 62, compound 64, compound 65)

Figure 110128222-A0202-12-0896-18
Figure 110128222-A0202-12-0896-18

步驟1：(3-甲基-5-(2-側氧基-2-(2-苯基-3-氮雜雙環[3.2.1]辛-3-基)乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-oxo-2-(2-phenyl-3-azabicyclo[3.2.1]oct-3-yl)acetamido)pyridine-2 -Synthesis of tertiary butyl carbamate

在-78℃、Ar氣氛下，向4-苯基-3-氮雜雙環[3.2.1 ]辛烷(0.5g，2.67mmol)及2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(1.01g，2.67mmol)於THF(50mL)中之溶液中添加正丁基鋰 (2.60g，9.34mmol，3.76mL，23%純度)。將所得混合物攪拌15min且升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(LC 11 60-60-70% 0-1-6min水-甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量464管柱：SunFire C18 100x19mm，5um)。純化後觀察到3種級分：第1級分(非鏡像異構物對)：181mg，第2級分(混合物)：127mg，第3級分(非鏡像異構物對)：65mg。任意分配組態。使級分1及3經歷掌性分離。D1： LCMS(ESI)：[M]+ m/z：計算值464.5；實測值465.2；Rt=4.122min。D2： LCMS(ESI)：[M]+ m/z：計算值464.5；實測值465.2；Rt=4.326min。To 4-phenyl-3-azabicyclo[ 3.2.1 ]octane (0.5 g, 2.67 mmol) and 2-[[6-( tert- butoxycarbonylamino) at -78°C under Ar atmosphere )-5-methyl-3-pyridyl]amino]-2-oxoacetate 2,2,2-trifluoroethyl ester (1.01 g, 2.67 mmol) in THF (50 mL) was added n- Butyllithium (2.60 g, 9.34 mmol, 3.76 mL, 23% pure). The resulting mixture was stirred for 15 min and warmed to room temperature, quenched with aq NH 4 Cl, extracted with EtOAc, dried over Na 2 SO 4 , evaporated and subjected to HPLC (LC 11 60-60-70% 0-1-6 min Water-methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 464 column: SunFire C18 100x19mm, 5um). 3 fractions were observed after purification: Fraction 1 (Astereoisomer pair): 181 mg, Fraction 2 (Mixture): 127 mg, Fraction 3 (Aspiperomer pair): 65 mg. Assign configuration arbitrarily. Fractions 1 and 3 were subjected to chiral separation. D1: LCMS (ESI): [M] + m/z: calculated 464.5; found 465.2; Rt=4.122 min. D2: LCMS (ESI): [M] + m/z: calculated 464.5; found 465.2; Rt=4.326 min.

步驟2：掌性分離(E1及E2)Step 2: Palmar Separation (E1 and E2)

在體系Hex-IPA-MeOH，80-10-10，12mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：700mkl。自181mg外消旋物獲得79mg及76mg 個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 80-10-10, 12 mL/min. Injection times: 1, injection volume: 700mkl. 79 mg and 76 mg were obtained from 181 mg of racemate individual mirror isomers.

E1： 保留時間：33.56min。LCMS(ESI)：[M]+ m/z：計算值364.5；實測值365.2；Rt=5.463min。 E1: retention time: 33.56min. LCMS (ESI): [M] + m/z: calculated 364.5; found 365.2; Rt=5.463 min.

E2： 保留時間：18.49min。LCMS(ESI)：[M]+ m/z：計算值364.5；實測值365.2；Rt=5.462min。 E2: Retention time: 18.49min. LCMS (ESI): [M] + m/z: calculated 364.5; found 365.2; Rt=5.462 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S,4R,5R)-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(化合物63 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-oxo-2-[(1S,4R,5R)-4-phenyl-3-azabicyclo[ 3.2.1] Synthesis of oct-3-yl]acetamide ( compound 63 )

將N -[3-甲基-5-[[2-側氧基-2-[(1S,4R,5R )-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(79mg，170.06μmol)溶解於於二噁烷中之4.0M氯化氫溶液(1.60g，43.88mmol，2mL)中，在25℃下攪拌12h，蒸發且乾燥，以獲得粗產物。藉由HPLC(LC 11 40-40-70% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量364管柱：YMC Actus Triart C18 100x20mm，5um)純化粗產物，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S,4R,5R )-4-苯基-3-氮雜雙環[3.2.1 ]辛-3-基]乙醯胺(23mg，63.11μmol，37.11%產率)。LCMS(ESI)：[M]+ m/z：計算值364.4；實測值365.2；Rt=2.661min。 N- [3-methyl-5-[[2-oxy-2-[( 1S,4R,5R )-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl ]Acetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (79 mg, 170.06 μmol) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (1.60 g, 43.88 mmol, 2 mL), in Stirred at 25°C for 12h, evaporated and dried to obtain crude product. By HPLC (LC 11 40-40-70% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 364 Column: YMC Actus Triart C18 100x20mm, 5um) to purify the crude product to obtain N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[( 1S,4R,5R )-4-phenyl-3 - Azabicyclo[ 3.2.1 ]oct-3-yl]acetamide (23 mg, 63.11 μmol, 37.11% yield). LCMS (ESI): [M] + m/z: calculated 364.4; found 365.2; Rt=2.661 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S,4S,5R)-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(化合物65 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-oxo-2-[(1S,4S,5R)-4-phenyl-3-azabicyclo[ 3.2.1] Synthesis of oct-3-yl]acetamide ( compound 65 )

將N -[3-甲基-5-[[2-側氧基-2-[(1S,4S,5R )-4-苯基-3-氮雜雙環[3.2.1 ]辛-3-基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(76mg，163.60μmol)溶解於於二噁烷中之4.0M氯化氫溶液(1.60g，43.88mmol，2mL)中，在25℃下攪拌12h，蒸發且乾燥，以獲得粗產物。藉由HPLC(LC 11 40-40-70% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量364管柱：YMC Actus Triart C18 100x20mm，5um)純化粗產物，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S,4S,5R )-4-苯基-3-氮雜雙環[3.2.1 ]辛-3-基]乙醯胺(21mg，57.62μmol， 35.22%產率)。1 H NMR(500MHz,CDCl3 )δ(ppm)1.36(m,1H),1.62(m,3H),1.76(m,2H),1.95(m,1H),2.15(m,3H),2.30(m,1H),2.78(m,1H),3.38(m,1H),4.47(m,1H),4.81(m,2H),5.88(m,1H),7.21(m,2H),7.35(m,2H),7.72(m,1H),8.06(m,1H),8.97(m,1H)。LCMS(ESI)：[M]+ m/z：計算值364.4；實測值365.2；Rt=2.640min。 N- [3-methyl-5-[[2-oxy-2-[( 1S,4S,5R )-4-phenyl-3-azabicyclo[ 3.2.1 ]oct-3-yl ]Acetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (76 mg, 163.60 μmol) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (1.60 g, 43.88 mmol, 2 mL), in Stirred at 25°C for 12h, evaporated and dried to obtain crude product. By HPLC (LC 11 40-40-70% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 364 Column: YMC Actus Triart C18 100x20mm, 5um) to purify the crude product to obtain N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[( 1S,4S,5R )-4-phenyl-3 - azabicyclo[ 3.2.1 ]oct-3-yl]acetamide (21 mg, 57.62 μmol, 35.22% yield). 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.36(m, 1H), 1.62(m, 3H), 1.76(m, 2H), 1.95(m, 1H), 2.15(m, 3H), 2.30( m, 1H), 2.78(m, 1H), 3.38(m, 1H), 4.47(m, 1H), 4.81(m, 2H), 5.88(m, 1H), 7.21(m, 2H), 7.35(m , 2H), 7.72 (m, 1H), 8.06 (m, 1H), 8.97 (m, 1H). LCMS (ESI): [M] + m/z: calculated 364.4; found 365.2; Rt=2.640 min.

步驟5：掌性分離(E3及E4)Step 5: Palmar Separation (E3 and E4)

在體系Hex-IPA-MeOH，60-20-20，12mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：40mkl。自65mg外消旋物獲得14mg及12mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 60-20-20, 12 mL/min. Injection times: 1, injection volume: 40mkl. 14 mg and 12 mg of individual enantiomers were obtained from 65 mg of racemate.

E3： 保留時間：27.78min。LCMS(ESI)：[M]+ m/z：計算值364.5；實測值365.2；Rt=5.640min。 E3: Retention time: 27.78min. LCMS (ESI): [M] + m/z: calculated 364.5; found 365.2; Rt=5.640 min.

E4： 保留時間：14.46min。LCMS(ESI)：[M]+ m/z：計算值364.5；實測值365.2；Rt=5.753min。 E4: Retention time: 14.46min. LCMS (ESI): [M] + m/z: calculated 364.5; found 365.2; Rt=5.753 min.

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1R,4S,5S)-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(化合物64 )之合成Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-oxo-2-[(1R,4S,5S)-4-phenyl-3-azabicyclo[ 3.2.1] Synthesis of oct-3-yl]acetamide ( compound 64 )

將N -[3-甲基-5-[[2-側氧基-2-[(1R,4S,5S )-4-苯基-3-氮雜雙環[3.2.1 ]辛-3-基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(14mg，30.14μmol)溶解於於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)中，在25℃下攪拌12h，蒸發且乾燥，以獲得粗產物。藉由HPLC(LC 11 40-40-70% 0-1-6min 0.1%3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量364管柱：YMC Actus Triart C18 100x20mm，5um)純化粗產物，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1R,4S,5S )-4-苯基-3-氮雜雙環[3.2.1 ]辛-3-基]乙醯胺(8mg，21.95μmol，72.84%產率)。LCMS(ESI)：[M]+ m/z：計算值364.4；實測值365.2；Rt=2.619min N- [3-methyl-5-[[2-oxy-2-[( 1R,4S,5S )-4-phenyl-3-azabicyclo[ 3.2.1 ]oct-3-yl ]Acetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (14 mg, 30.14 μmol) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL) in Stirred at 25°C for 12h, evaporated and dried to obtain crude product. By HPLC (LC 11 40-40-70% 0-1-6min 0.1% 3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 364 Column: YMC Actus Triart C18 100x20mm, 5um ) purification of the crude product to obtain N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[( 1R,4S,5S )-4-phenyl-3- Azabicyclo[ 3.2.1 ]oct-3-yl]acetamide (8 mg, 21.95 μmol, 72.84% yield). LCMS(ESI): [M] + m/z: Calculated 364.4; Measured 365.2; Rt=2.619min

步驟7：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1R,4R,5S)-4-苯基-3-氮雜雙環Step 7: N-(6-Amino-5-methyl-3-pyridyl)-2-oxo-2-[(1R,4R,5S)-4-phenyl-3-azabicyclo [3.2.1]辛-3-基]乙醯胺(化合物62 )之合成Synthesis of [3.2.1]oct-3-yl]acetamide ( compound 62 )

將N -[3-甲基-5-[[2-側氧基-2-[(1R,4R,5S )-4-苯基-3-氮雜雙環[3.2.1 ]辛-3-基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(12mg，25.83μmol)溶解於於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)中，在25℃下攪拌12h，蒸發且乾燥，以獲得粗產物。藉由HPLC(LC 11 40-40-70% 0-1-6min 0.1%3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量364管柱：YMC Actus Triart C18 100x20mm，5um)純化粗產物，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1R,4R,5S )-4-苯基-3-氮雜雙環[3.2.1 ]辛-3-基]乙醯胺(7mg，19.21μmol，74.36%產率)。1 H NMR(500MHz,CDCl3 )δ(ppm)1.36(m,1H),1.64(d,2H),1.75(d,3H),1.93(d,1H),2.16(m,3H),2.27(m,1H),2.78(m,1H),3.31(m,1H),4.54(m,1H),5.03(m,2H),5.87(m,1H),7.22(m,2H),7.36(m,2H),7.77(m,1H),8.08(m,1H),9.00(m,1H)。LCMS(ESI)：[M]+ m/z：計算值364.4；實測值365.2；Rt=2.608min。 N- [3-methyl-5-[[2-oxy-2-[( 1R,4R,5S )-4-phenyl-3-azabicyclo[ 3.2.1 ]oct-3-yl ]Acetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (12 mg, 25.83 μmol) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL), in Stirred at 25°C for 12h, evaporated and dried to obtain crude product. By HPLC (LC 11 40-40-70% 0-1-6min 0.1% 3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 364 Column: YMC Actus Triart C18 100x20mm, 5um ) purification of the crude product to obtain N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[( 1R,4R,5S )-4-phenyl-3- Azabicyclo[ 3.2.1 ]oct-3-yl]acetamide (7 mg, 19.21 μmol, 74.36% yield). 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.36(m,1H), 1.64(d,2H), 1.75(d,3H), 1.93(d,1H), 2.16(m,3H), 2.27( m, 1H), 2.78(m, 1H), 3.31(m, 1H), 4.54(m, 1H), 5.03(m, 2H), 5.87(m, 1H), 7.22(m, 2H), 7.36(m , 2H), 7.77 (m, 1H), 8.08 (m, 1H), 9.00 (m, 1H). LCMS (ESI): [M] + m/z: calculated 364.4; found 365.2; Rt=2.608 min.

實例2. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物233)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物242)之合成Example 2. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidine yl]-2-oxyacetamide (Compound 233) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4-fluoro Synthesis of Phenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 242)

Figure 110128222-A0202-12-0899-19
Figure 110128222-A0202-12-0899-19

步驟1. N-[5-[[2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基Step 1. N-[5-[[2-[2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3- methyl -2-吡啶基]胺甲酸第三丁酯之合成Synthesis of -2-pyridyl]carbamic acid tert-butyl ester

在-78℃、Ar氣氛下，向2-(4-氟苯基)-5-甲基哌啶(0.3g，1.55mmol)於THF(15mL)中之溶液中添加正丁基鋰(1.30g，4.66mmol，1.87mL，23%純度)。15min之後，一次性添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(585.71mg，1.55mmol)。將所得混合物升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(50-75% ACN，30ml/min，sunfire C18 19*100，5uM)。獲得呈淺黃色固體之N-[5-[[2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(181.7mg，386.16μmol，24.88%產率)。To a solution of 2-(4-fluorophenyl)-5-methylpiperidine (0.3 g, 1.55 mmol) in THF (15 mL) was added n-butyllithium (1.30 g) at -78°C under Ar atmosphere , 4.66 mmol, 1.87 mL, 23% purity). After 15 min, 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid 2,2,2-tris was added in one portion Fluoroethyl ester (585.71 mg, 1.55 mmol). The resulting mixture was warmed to room temperature, quenched with aqueous NH4Cl , extracted with EtOAc, dried over Na2SO4 , evaporated and subjected to HPLC (50-75% ACN, 30 ml/min, sunfire C18 19*100, 5uM). N-[5-[[2-[2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] was obtained as a pale yellow solid - 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (181.7 mg, 386.16 μmol, 24.88% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.07(d,3H),1.39(m,1H),1.48(s,9H),1.65-1.97(m,4H),2.17-2.31(m,4H),2.92-3.33(m,1H，兩種單獨旋轉異構體信號)，4.19-4.76(m,1H，兩種單獨旋轉異構體信號)，5.73-6.39(m,1H，兩種單獨旋轉異構體信號)，6.83(brs,1H),7.04(m,2H),8.05(s,1H),8.41(s,1H),8.40(m,1H),9.39(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.07(d,3H), 1.39(m,1H), 1.48(s,9H), 1.65-1.97(m,4H), 2.17-2.31(m,4H) ), 2.92-3.33 (m, 1H, two separate rotamer signals), 4.19-4.76 (m, 1H, two separate rotamer signals), 5.73-6.39 (m, 1H, two separate rotamers isomer signal), 6.83 (brs, 1H), 7.04 (m, 2H), 8.05 (s, 1H), 8.41 (s, 1H), 8.40 (m, 1H), 9.39 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值470.5；實測值471.2；Rt=1.495min。LCMS (ESI): [M+1] + m/z: calculated 470.5; found 471.2; Rt=1.495 min.

步驟2. N-[5-[[2-[(2S,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯、N-[5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯、N-[5-[[2-[(2R,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2. N-[5-[[2-[(2S,5S)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoethanoyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester, N-[5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl 3-butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester, N-[5-[[2-[( 2R,5R)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl] 3-butyl carbamate and N-[5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxygen Synthesis of Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

在以下條件下分離立體異構物之混合物：IC(250*30，5mkm)，己烷-IPA-MeOH，70-15-15，13ml/min。The mixture of stereoisomers was separated under the following conditions: IC (250*30, 5mkm), Hexane-IPA-MeOH, 70-15-15, 13ml/min.

N-[5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基 -2-吡啶基]胺甲酸第三丁酯峰1(P1)之RT=23.601minN-[5-[[2-[(2R,5S)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] -3-Methyl RT=23.601min of tert-butyl 2-pyridyl]carbamate peak 1 (P1)

N-[5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯峰2(P2)之RT=30.270minN-[5-[[2-[(2S,5R)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] -3-Methyl-2-pyridyl]carbamic acid tert-butyl ester peak 2 (P2) RT=30.270min

微量順式級分係在RT 20.5min及28.5min處。Micro cis fractions were run at RT 20.5 min and 28.5 min.

將N-[5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯峰1(P1)用於製備化合物242 。下文給出此級分之分析資料：N-[5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-methyl-2-pyridyl]carbamate tert-butyl ester Peak 1 (P1) was used to prepare compound 242 . The analytical data for this fraction are given below:

LCMS(ESI)：[M+1]+ m/z：計算值470.5；實測值472.0；Rt=5.536min。LCMS (ESI): [M+1] + m/z: calculated 470.5; found 472.0; Rt=5.536 min.

RT(IC，己烷-IPA-MeOH，70-15-15，0.6ml/min)=27.123minRT (IC, Hexane-IPA-MeOH, 70-15-15, 0.6ml/min)=27.123min

將N-[5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯峰2(P2)用於製備化合物233 N-[5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-Methyl-2-pyridyl]carbamic acid tert-butyl ester Peak 2 (P2) was used to prepare compound 233

LCMS(ESI)：[M+1]+ m/z：計算值470.5；實測值472.0；Rt=5.529min。LCMS (ESI): [M+1] + m/z: calculated 470.5; found 472.0; Rt=5.529 min.

RT(IC，己烷-IPA-MeOH，70-15-15，0.6ml/min)=36.392minRT (IC, Hexane-IPA-MeOH, 70-15-15, 0.6ml/min)=36.392min

步驟3. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物233 )之合成Step 3. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidine [Synthesis of]-2-oxyacetamide ( Compound 233 )

在21℃下，向N-[5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(32.43mg，68.92μmol)於二噁烷(1mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(12.56mg，344.61μmol，15.71μL)。將所得混合物攪拌2h。將所得混合物蒸發至乾且使其經歷HPLC(C18，H2 O-ACN，33-50% ACN，30ml/min)。獲得呈米色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(13.7mg，36.99μmol，53.66%產率)。At 21 °C, to N-[5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (32.43 mg, 68.92 μmol) in dioxane (1 mL) was added 4.0 M in dioxane Hydrogen chloride solution (12.56 mg, 344.61 μmol, 15.71 μL). The resulting mixture was stirred for 2 h. The resulting mixture was evaporated to dryness and subjected to HPLC (C18, H2O -ACN, 33-50% ACN, 30 ml/min). N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1- was obtained as a beige solid Piperidinyl]-2-oxoacetamide (13.7 mg, 36.99 μmol, 53.66% yield).

1 NMR(600MHz,DMSO-d 6 )δ 0.97-1.04(m,3H),1.24-1.37(m,1H),1.58-1.71(m,1H),1.82-1.91(m,1H),1.95-2.03(m,4H),2.12-2.26(m,1H),2.67-3.19(m,1H), 3.41-4.02(m,1H),5.10-5.56(m,1H),5.57-5.65(m,2H),7.17-7.22(m,2H),7.30-7.39(m,2H),7.43-7.51(m,1H),7.92-8.04(m,1H),10.43-10.53(m,1H)。 1 NMR (600MHz, DMSO- d 6 )δ 0.97-1.04(m,3H), 1.24-1.37(m,1H), 1.58-1.71(m,1H), 1.82-1.91(m,1H), 1.95-2.03 (m,4H), 2.12-2.26(m,1H), 2.67-3.19(m,1H), 3.41-4.02(m,1H), 5.10-5.56(m,1H), 5.57-5.65(m,2H) , 7.17-7.22(m, 2H), 7.30-7.39(m, 2H), 7.43-7.51(m, 1H), 7.92-8.04(m, 1H), 10.43-10.53(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值370.2；實測值371.2；Rt=2.774min。LCMS (ESI): [M+1] + m/z: calculated 370.2; found 371.2; Rt=2.774 min.

步驟3. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物242 )之合成Step 3. N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidine [Synthesis of]-2-oxoacetamide ( Compound 242 )

在21℃下，向N-[5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(34.38mg，73.07μmol)於二噁烷(1mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(13.32mg，365.33μmol，16.65μL)。將所得混合物攪拌2h。將所得混合物蒸發至乾且使其經歷HPLC(C18，H2 O-ACN，34-51% ACN，30ml/min)。獲得呈米色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(16.5mg，44.54μmol，60.96%產率)。At 21 °C, to N-[5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (34.38 mg, 73.07 μmol) in dioxane (1 mL) was added 4.0 M in dioxane Hydrogen chloride solution (13.32 mg, 365.33 μmol, 16.65 μL). The resulting mixture was stirred for 2 h. The resulting mixture was evaporated to dryness and subjected to HPLC (C18, H2O -ACN, 34-51% ACN, 30 ml/min). N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1- was obtained as a beige solid Piperidinyl]-2-oxoacetamide (16.5 mg, 44.54 μmol, 60.96% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.92-1.05(m,3H),1.26-1.38(m,1H),1.60-1.69(m,1H),1.80-1.90(m,1H),1.95-2.10(m,4H),2.12-2.25(m,1H),2.66-3.18(m,1H),3.41-4.03(m,1H),5.05-5.56(m,1H),5.57-6.08(m,2H),6.94-7.24(m,2H),7.28-7.40(m,2H),7.42-7.50(m,1H),7.62-8.08(m,1H),9.69-10.55(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.92-1.05(m,3H), 1.26-1.38(m,1H), 1.60-1.69(m,1H), 1.80-1.90(m,1H), 1.95- 2.10(m, 4H), 2.12-2.25(m, 1H), 2.66-3.18(m, 1H), 3.41-4.03(m, 1H), 5.05-5.56(m, 1H), 5.57-6.08(m, 2H ), 6.94-7.24(m, 2H), 7.28-7.40(m, 2H), 7.42-7.50(m, 1H), 7.62-8.08(m, 1H), 9.69-10.55(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值368.4；實測值369.2；Rt=2.787min。LCMS (ESI): [M+1] + m/z: calculated 368.4; found 369.2; Rt=2.787 min.

實例3. 2-(5,5-二甲基-2-苯基-1-哌啶基)-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物146)、N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物301)之合成及步驟5：N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物309)之合成Example 3. 2-(5,5-Dimethyl-2-phenyl-1-piperidinyl)-N-(5-methyl-3-pyridyl)-2 - oxoacetamide (compound 146), N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )-5-methyl-2-(3-pyridyl)-1-piperidine Synthesis of pyridyl]-2-oxoacetamide (compound 301) and step 5: N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxoacetamide (compound 309) synthesis

Figure 110128222-A0202-12-0903-20
Figure 110128222-A0202-12-0903-20

步驟1：N-[3-甲基-5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[5-methyl-2-(3-pyridinyl)-1-piperidinyl]-2-oxyacetyl]amino Synthesis of 3-butyl ]-2-pyridyl]carbamate

在-78℃、Ar氣氛下，向3-(5-甲基-2-哌啶基)吡啶(0.2g，1.13mmol)於THF(10mL)中之溶液中添加正丁基鋰(948.04mg，3.40mmol，1.37mL，23%純度)。15min之後，一次性添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(428.14mg，1.13mmol)。將所得混合物升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(2-7 30-55% ACN，30ML/MIN；SUNFIRE C18，100*19)。獲得呈灰白色固體之N-[3-甲基-5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.1277g，281.57μmol，24.81%產率)。To a solution of 3-(5-methyl-2-piperidinyl)pyridine (0.2 g, 1.13 mmol) in THF (10 mL) at -78°C under Ar atmosphere was added n-butyllithium (948.04 mg, 3.40 mmol, 1.37 mL, 23% purity). After 15 min, 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid 2,2,2-tris was added in one portion Fluoroethyl ester (428.14 mg, 1.13 mmol). The resulting mixture was warmed to room temperature, quenched with aqueous NH4Cl , extracted with EtOAc, dried over Na2SO4 , evaporated and subjected to HPLC (2-7 30-55% ACN, 30 ML/MIN; SUNFIRE C18, 100*19). N-[3-Methyl-5-[[2-[5-methyl-2-(3-pyridinyl)-1-piperidinyl]-2-oxyethanoyl] was obtained as an off-white solid Amino]-2-pyridyl]carbamic acid tert-butyl ester (0.1277 g, 281.57 μmol, 24.81% yield).

LCMS(ESI)：[M+H]+ m/z：計算值453.2；實測值454.2；Rt=1.063min。LCMS (ESI): [M+H] + m/z: calculated 453.2; found 454.2; Rt=1.063 min.

步驟2：N-[3-甲基-5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(化合物146 )之合成Step 2: N-[3-Methyl-5-[[2-[5-methyl-2-(3-pyridinyl)-1-piperidinyl]-2-oxyacetyl]amino Synthesis of 3-butyl]-2-pyridyl]carbamate ( Compound 146 )

在21℃下，向N-[3-甲基-5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(97.7mg，215.42μmol)於二噁烷(1mL) 中之溶液中添加於二噁烷中之4.0M氯化氫溶液(78.54mg，2.15mmol，98.18μL)。將所得混合物攪拌1h。藉由HNMR監測反應進展。過濾出沉澱，用MTBE洗滌且在高真空(0.3毫巴)下乾燥，以得到呈黃色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(8mg，22.64μmol，10.51%產率)。At 21 °C, to N-[3-methyl-5-[[2-[5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-side oxyethanoyl ]amino]-2-pyridyl]carbamic acid tert-butyl ester (97.7 mg, 215.42 μmol) in dioxane (1 mL) To this solution was added a 4.0 M solution of hydrogen chloride in dioxane (78.54 mg, 2.15 mmol, 98.18 [mu]L). The resulting mixture was stirred for 1 h. The progress of the reaction was monitored by HNMR. The precipitate was filtered off, washed with MTBE and dried under high vacuum (0.3 mbar) to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2S, 5R)-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyacetamide (8 mg, 22.64 μmol, 10.51% yield).

1 H NMR(氯仿-d,400MHz)：δ(ppm)0.84(m,1H),1.08(m,3H),1.42(m,1H),1.79(m,2H),2.00(m,1H),2.11(m,3H),2.19(m,1H),3.10(dd,1H),4.60(m,3H),6.15(m,1H),7.29(m,1H),7.60(dd,1H),7.71(s,1H),8.03(m,1H),8.51(m,1H),8.57(m,1H),9.18(m,1H) 1 H NMR (chloroform-d, 400MHz): δ (ppm) 0.84 (m, 1H), 1.08 (m, 3H), 1.42 (m, 1H), 1.79 (m, 2H), 2.00 (m, 1H), 2.11(m,3H),2.19(m,1H),3.10(dd,1H),4.60(m,3H),6.15(m,1H),7.29(m,1H),7.60(dd,1H),7.71 (s,1H),8.03(m,1H),8.51(m,1H),8.57(m,1H),9.18(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值353.4；實測值354.4；Rt=0.710min。LCMS (ESI): [M+H] + m/z: calculated 353.4; found 354.4; Rt=0.710 min.

步驟3：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之掌性純化Step 3: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-pendoxyl Acetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester and N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(3 Chiral purification of tert-butyl-pyridyl)-1-piperidinyl]-2-oxoacetyl]amino]-2-pyridyl]carbamate

使N -[3-甲基-5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(化合物146 ，75.8mg)經歷掌性掌性HPLC(管柱：AD，250 x 30mm，20um；溶析液：MeOH；流速：32mL/min)，以得到呈白色固體之N -[3-甲基-5-[[2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(17.25mg)及N -[3-甲基-5-[[2-[(2R ,5S )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(17.9mg)。Make N- [3-methyl-5-[[2-[5-methyl-2-(3-pyridinyl)-1-piperidinyl]-2-oxyacetyl]amino]- 3 -Butyl 2-pyridyl]carbamate ( compound 146 , 75.8 mg) was subjected to chiral chiral HPLC (column: AD, 250 x 30 mm, 20 um; eluent: MeOH; flow rate: 32 mL/min) to N- [3-methyl-5-[[2-[( 2S , 5R )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2 was obtained as a white solid -Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester ( 17.25mg ) and N- [3-methyl-5-[[2-[( 2R ,5S) -5-Methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (17.9 mg) .

N -[3-甲基-5-[[2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯 N -[3-Methyl-5-[[2-[(2 S ,5 R )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

LCMS(ESI)：[M+Boc]+ m/z：計算值453.2；實測值354.2；Rt=3.905min。LCMS (ESI): [M+Boc] + m/z: calculated 453.2; found 354.2; Rt=3.905 min.

掌性HPLC：Rt=10.33min(管柱：IC；溶析液：CO2 /MeOH，60/40；流速：2 mL/min)。Chiral HPLC: Rt=10.33 min (column: IC; eluent: CO2 /MeOH, 60/40; flow rate: 2 mL/min).

N -[3-甲基-5-[[2-[(2R ,5S )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯 N -[3-Methyl-5-[[2-[(2 R ,5 S )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

LCMS(ESI)：[M+Boc]+ m/z：計算值453.2；實測值354.2；Rt=3.908min。LCMS (ESI): [M+Boc] + m/z: calculated 453.2; found 354.2; Rt=3.908 min.

掌性HPLC：Rt=12.42min(管柱：IC；溶析液：CO2 /MeOH，60/40；流速：2mL/min)。Chiral HPLC: Rt=12.42 min (column: IC; eluent: CO2 /MeOH, 60/40; flow rate: 2 mL/min).

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物301 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(3-pyridyl)-1-piperidinyl Synthesis of ]-2-oxyacetamide ( Compound 301 )

在21℃下，向N -[3-甲基-5-[[2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(17.25mg，38.03μmol)於二噁烷(2mL)中之經攪拌之溶液中添加於二噁烷中之4M氯化氫(6.93mg，190.17μmol，8.67μL)。將所得反應混合物在同一溫度下攪拌2小時。完成之後，將反應混合物在減壓下濃縮且藉由HPLC(溶析液：30-80%，水-MeOH(NH3 )；流速：30mL/min；裝載泵：4mL/min，MeOH；管柱：X-Bridge 19*100mm，5um)純化粗產物，以得到呈米色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物301 ，6.9mg，19.52μmol，51.33%產率)。At 21 °C, to N- [3-methyl-5-[[2-[( 2S , 5R )-5-methyl-2-(3-pyridyl)-1-piperidinyl]- To a stirred solution of 2-pendoxetyl]amino]-2-pyridyl] carbamate (17.25 mg, 38.03 μmol) in dioxane (2 mL) was added to dioxane 4M hydrogen chloride (6.93 mg, 190.17 μmol, 8.67 μL). The resulting reaction mixture was stirred at the same temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure and analyzed by HPLC (eluent: 30-80%, water-MeOH( NH3 ); flow rate: 30 mL/min; loading pump: 4 mL/min, MeOH; column : X-Bridge 19*100mm, 5um) to purify the crude product to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )- as a beige solid 5-Methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyacetamide ( Compound 301 , 6.9 mg, 19.52 μmol, 51.33% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.98-1.10(m,3H),1.29-1.40(m,1H),1.62-1.72(m,1H),1.85-1.96(m,1H),1.98-2.05(m,3H),2.05-2.17(m,1H),2.17-2.32(m,1H),2.73-3.25(m,1H),3.48-4.08(m,1H),5.22-5.68(m,3H),7.38-7.52(m,2H),7.66-7.81(m,1H),7.95-8.09(m,1H),8.46-8.53(m,1H),8.53-8.61(m,1H),10.48-10.61(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.98-1.10 (m, 3H), 1.29-1.40 (m, 1H), 1.62-1.72 (m, 1H), 1.85-1.96 (m, 1H) ),1.98-2.05(m,3H),2.05-2.17(m,1H),2.17-2.32(m,1H),2.73-3.25(m,1H),3.48-4.08(m,1H),5.22-5.68 (m,3H),7.38-7.52(m,2H),7.66-7.81(m,1H),7.95-8.09(m,1H),8.46-8.53(m,1H),8.53-8.61(m,1H) , 10.48-10.61 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值353.2；實測值354.2；Rt=0.783min。LCMS (ESI): [M+H] + m/z: calculated 353.2; found 354.2; Rt=0.783 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-Step 5: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(3-pyridyl)-1-piperidinyl ]-2- 側氧基乙醯胺(化合物309 )之合成Synthesis of Pendant Oxyacetamide ( Compound 309 )

在21℃下，向N -[3-甲基-5-[[2-[(2R ,5S )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(17.9mg，39.47μmol)於二噁烷(2mL)中之經攪拌之溶液中添加於二噁烷中之4M氯化氫(7.20mg，197.34μmol，8.99μL)。將所得反應混合物在同一溫度下攪拌2小時。完成之後，將反應混合物在減壓下濃縮且藉由HPLC(溶析液：30-80%，水-MeOH(NH3 )；流速：30mL/min；裝載泵：4mL/min，MeOH；管柱：X-Bridge 19*100mm，5um)純化粗產物，以得到呈米色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物309 ，6.8mg，19.24μmol，48.75%產率)。At 21 ° C , to N- [3-methyl-5-[[2-[( 2R ,5S)-5-methyl-2-(3-pyridyl)-1-piperidinyl]- To a stirred solution of 2-pendoxetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (17.9 mg, 39.47 μmol) in dioxane (2 mL) was added in dioxane 4M hydrogen chloride (7.20 mg, 197.34 μmol, 8.99 μL). The resulting reaction mixture was stirred at the same temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure and analyzed by HPLC (eluent: 30-80%, water-MeOH( NH3 ); flow rate: 30 mL/min; loading pump: 4 mL/min, MeOH; column : X-Bridge 19*100mm, 5um) to purify the crude product to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )- as a beige solid 5-Methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyacetamide ( compound 309 , 6.8 mg, 19.24 μmol, 48.75% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)1.01-1.05(m,3H),1.31-1.40(m,1H),1.62-1.70(m,1H),1.84-1.91(m,1H),1.99-2.05(m,3H),2.13-2.32(m,2H),2.72-3.20(m,1H),3.38-4.10(m,1H),5.24-5.67(m,3H),7.38-7.44(m,1H),7.44-7.52(m,1H),7.69-7.78(m,1H),7.95-8.06(m,1H),8.46-8.53(m,1H),8.53-8.60(m,1H),10.40-10.60(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 1.01-1.05 (m, 3H), 1.31-1.40 (m, 1H), 1.62-1.70 (m, 1H), 1.84-1.91 (m, 1H) ),1.99-2.05(m,3H),2.13-2.32(m,2H),2.72-3.20(m,1H),3.38-4.10(m,1H),5.24-5.67(m,3H),7.38-7.44 (m,1H),7.44-7.52(m,1H),7.69-7.78(m,1H),7.95-8.06(m,1H),8.46-8.53(m,1H),8.53-8.60(m,1H) , 10.40-10.60 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值353.2；實測值354.2；Rt=0.783min。LCMS (ESI): [M+H] + m/z: calculated 353.2; found 354.2; Rt=0.783 min.

實例4. 5-[[2-[2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物26)之合成Example 4. 5-[[2-[2-(2-Methylpyrazol-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Synthesis of Amine (Compound 26)

Figure 110128222-A0202-12-0906-21
Figure 110128222-A0202-12-0906-21

步驟1：5-[[2-[2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯Step 1: 5-[[2-[2-(2-Methylpyrazol-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate 胺(化合物26 )之合成Synthesis of Amine ( Compound 26 )

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.2g，549.48μmol)、2-(2-甲基吡唑-3-基)哌啶(55.41mg，274.74μmol，HCl)及DIPEA(53.26mg，412.11μmol，71.78μL)一起混合於CH3 CN(2mL)中。將所得反應混合物在密封管中在100℃下加熱12小時。12小時之後，將反應混合物在減壓下濃縮且藉由反相HPLC(溶析液：CH3 CN 10-30%，0-5min，水-CH3 CN，流速：30mL/min，裝載泵：4mL/min CH3 CN；管柱：SunFire C18 100*19mm,5um)純化所獲得之粗產物且冷凍乾燥，以獲得呈淡黃色固體之純產物5-[[2-[2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(3.9mg，10.94μmol，3.98%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (0.2 g, 549.48 μmol), 2-(2- Methylpyrazol-3-yl)piperidine (55.41 mg, 274.74 μmol, HCl) and DIPEA (53.26 mg, 412.11 μmol, 71.78 μL) were mixed together in CH3CN (2 mL). The resulting reaction mixture was heated in a sealed tube at 100°C for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure and analyzed by reverse phase HPLC (eluent: CH3CN 10-30%, 0-5 min, water- CH3CN , flow rate: 30 mL/min, loading pump: 4mL/min CH3CN ; column: SunFire C18 100*19mm, 5um) The crude product obtained was purified and lyophilized to obtain the pure product 5-[[2-[2-(2-methyl as a pale yellow solid pyrazol-3-yl)-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (3.9 mg, 10.94 μmol, 3.98% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.82(m,3H),2.03(m,2H),2.20(m,1H),3.03(m,1H),3.85(m,3H),4.68(m,1H),5.94(m,2H),6.34(m,2H),7.43(m,1H),8.62(m,1H),8.81(m,1H),8.97(m,1H),9.69(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.82 (m, 3H), 2.03 (m, 2H), 2.20 (m, 1H), 3.03 (m, 1H), 3.85 (m, 3H), 4.68 (m,1H),5.94(m,2H),6.34(m,2H),7.43(m,1H),8.62(m,1H),8.81(m,1H),8.97(m,1H),9.69( m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值356.2；實測值357.2；Rt=0.858min。LCMS (ESI): [M+H] + m/z: calculated 356.2; found 357.2; Rt=0.858 min.

實例5. 5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(化合物29)之合成Example 5. Synthesis of 5-[[2-oxy-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (compound 29)

Figure 110128222-A0202-12-0907-22
Figure 110128222-A0202-12-0907-22

該化合物以與實例4類似之方式製備。This compound was prepared in an analogous manner to Example 4.

1 H NMR(600MHz,DMSO-d 6 )δ 1.44(m,2H),1.61(m,2H),1.86(m,1H),2.47(m,1H),2.89(m,1H),4.06(m,1H),5.48(m,1H),7.28(m,1H),7.34(m,2H),7.39(m,2H),7.59(m,1H),8.15(m,1H),8.49(m,1H),8.76(m,1H),8.87(m,1H),11.26(m, 1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.44(m, 2H), 1.61(m, 2H), 1.86(m, 1H), 2.47(m, 1H), 2.89(m, 1H), 4.06(m ,1H),5.48(m,1H),7.28(m,1H),7.34(m,2H),7.39(m,2H),7.59(m,1H),8.15(m,1H),8.49(m, 1H), 8.76 (m, 1H), 8.87 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值352.3；實測值353.2；Rt=1.147min。LCMS (ESI): [M+H] + m/z: calculated 352.3; found 353.2; Rt=1.147 min.

實例6.外消旋 -2-[(2R ,5S )-5-甲基-2-(間甲苯基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物8)之合成以及2-[(2S ,5R )-5-甲基-2-(間甲苯基 )-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物11)及2-[(2R ,5S )-5-甲基-2-(間甲苯基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物10)之分離Example 6. Racemic -2-[( 2R , 5S )-5-methyl-2-(m-tolyl)-1-piperidinyl]-N-(5-methyl - 3-pyridyl )-2-oxyacetamide (compound 8) and the synthesis of 2-[( 2S , 5R )-5-methyl-2-( m-tolyl )-1 - piperidinyl]-N- (5-Methyl-3-pyridyl)-2-oxoacetamide (Compound 11) and 2-[(2 R ,5 S )-5-methyl-2-(m-tolyl)-1 Isolation of -Piperidinyl]-N-(5-methyl - 3-pyridyl)-2-oxoacetamide (Compound 10)

Figure 110128222-A0202-12-0908-23
Figure 110128222-A0202-12-0908-23

步驟1. 外消旋-2-[(2R,5S)-5-甲基-2-(間甲苯基)-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物8 )之合成Step 1. Racemic-2-[(2R,5S)-5-methyl-2-(m-tolyl)-1-piperidinyl]-N-(5-methyl-3-pyridyl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 8 )

在-78℃、氬氣氣氛下，向5-甲基-2-(間甲苯基 )哌啶(0.2g，1.06mmol)於THF(20mL)中之經攪拌之溶液中逐滴添加正丁基鋰 (2.5M於己烷中，135.35mg，2.11mmol，0.84mL)。將所得溶液在同一溫度下攪拌5分鐘。5分鐘之後，將2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(277.01mg，1.06mmol)一次性添加到溶液中。使所得反應混合物升溫至室溫且在同一溫度下攪拌12小時。12小時之後，將反應混合物用飽和NH4 Cl水溶液淬滅。將所得混合物蒸發至乾。藉由HPLC純化所獲得之殘餘物(0.8g)，以獲得呈黃色固體之外消旋 - 2-[(2R ,5S)-5-甲基-2-(間甲苯基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物8 ，0.045g，128.04μmol，12.12%產率)。To a stirred solution of 5-methyl-2-( m-tolyl )piperidine (0.2 g, 1.06 mmol) in THF (20 mL) was added n-butyl dropwise at -78 °C under argon atmosphere Lithium (2.5M in hexanes, 135.35 mg, 2.11 mmol, 0.84 mL). The resulting solution was stirred at the same temperature for 5 minutes. After 5 minutes, 2-[(5-methyl-3-pyridinyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (277.01 mg, 1.06 mmol) was added in one portion to in solution. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was quenched with saturated aqueous NH4Cl . The resulting mixture was evaporated to dryness. The obtained residue (0.8 g) was purified by HPLC to obtain rac -2-[( 2R ,5S)-5-methyl-2-(m-tolyl)-1-piperidine as a yellow solid Peridyl]-N-(5-methyl - 3-pyridyl)-2-oxyacetamide ( compound 8 , 0.045 g, 128.04 μmol, 12.12% yield).

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.21(m,3H),1.46(m,1H),1.63(m,2H),1.87(m,1H),2.26(s,1H),2.31(s,2H),2.62(m,7.6H),2.98(t,0.4H),3.63(d,0.6H),4.30(d,0.4H),5.10(s,0.4H),5.64(s,0.6H),7.24(m,4H),7.89(s,0.4H),7.97(s,0.6H),8.15(s,0.4H),8.20(s,0.6H),8.55(s,0.4H),8.64(s,0.6H),11.06(s,0.4H),11.08(s,0.6H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 1.21 (m, 3H), 1.46 (m, 1H), 1.63 (m, 2H), 1.87 (m, 1H), 2.26 (s, 1H) ,2.31(s,2H),2.62(m,7.6H),2.98(t,0.4H),3.63(d,0.6H),4.30(d,0.4H),5.10(s,0.4H),5.64( s,0.6H),7.24(m,4H),7.89(s,0.4H),7.97(s,0.6H),8.15(s,0.4H),8.20(s,0.6H),8.55(s,0.4 H), 8.64(s, 0.6H), 11.06(s, 0.4H), 11.08(s, 0.6H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.4；Rt=3.361min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.4; Rt=3.361 min.

步驟2：2-[(2S,5R)-5-甲基-2-(間甲苯基)-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2R,5S)-5-甲基-2-(間甲苯基)-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物11 及化合物10 )之掌性分離Step 2: 2-[(2S,5R)-5-Methyl-2-(m-tolyl)-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen Ethylacetamide and 2-[(2R,5S)-5-methyl-2-(m-tolyl)-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2- Chiral separation of pendant oxyacetamides ( compounds 11 and 10 )

使外消旋 -2-[(2R ,5S)-5-甲基-2-(間甲苯基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物8 )經歷掌性層析(管柱：OJ-H 250*20mm，5um，溶析液：己烷-MeOH-IPA，70-15-15，流速：12mL/min)，以得到呈黃色固體之2-[(2S ,5R )-5-甲基-2-(間甲苯基 )-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物11 )及2-[(2R ,5S )-5-甲基-2-(間甲苯基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物10 )。Make rac -2-[( 2R ,5S)-5-methyl-2-(m-tolyl)-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2 - Pendant oxyacetamide ( compound 8 ) was subjected to chiral chromatography (column: OJ-H 250*20mm, 5um, eluent: hexane-MeOH-IPA, 70-15-15, flow rate: 12mL/ min) to give 2-[( 2S , 5R )-5-methyl-2-( m-tolyl )-1-piperidinyl]-N-(5 - methyl-3- Pyridyl)-2-oxyacetamide ( compound 11 ) and 2-[( 2R , 5S )-5-methyl-2-(m-tolyl)-1 - piperidinyl]-N- (5-Methyl-3-pyridyl)-2-oxoacetamide ( compound 10 ).

2-[(2S ,5R )-5-甲基-2-(間甲苯基 )-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物11)2-[(2 S ,5 R )-5-methyl-2-( m-tolyl )-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2-oxygen Acetamide (Compound 11)

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.10(m,3H),1.41(t,1H),1.77(m,1H),1.91(m,1H),2.13(m,1H),2.22(m,1H),2.35(m,6H),2.82(d,0.35H),3.29(d,0.65H),3.60(d,0.65H),4.09(d,0.35H),5.21(s,0.35H),5.65(s,0.65H),7.03(m,1H),7.10(m,2H),7.23(m,1H),7.94(s,0.35H),7.99(s,0.65H),8.05(s,0.35H),8.09(s,0.65H),8.52(s,0.35H),8.59(s,0.65H),10.86(s,0.35H),10.91(s,0.65H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 1.10 (m, 3H), 1.41 (t, 1H), 1.77 (m, 1H), 1.91 (m, 1H), 2.13 (m, 1H) ,2.22(m,1H),2.35(m,6H),2.82(d,0.35H),3.29(d,0.65H),3.60(d,0.65H),4.09(d,0.35H),5.21(s ,0.35H),5.65(s,0.65H),7.03(m,1H),7.10(m,2H),7.23(m,1H),7.94(s,0.35H),7.99(s,0.65H), 8.05(s, 0.35H), 8.09(s, 0.65H), 8.52(s, 0.35H), 8.59(s, 0.65H), 10.86(s, 0.35H), 10.91(s, 0.65H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.0；Rt=4.962min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.0; Rt=4.962 min.

掌性HPLC：Rt=23.37min(管柱：OJ-H；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=23.37 min (column: OJ-H; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

2-[(2R ,5S )-5-甲基-2-(間甲苯基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物10)2-[(2 R ,5 S )-5-methyl-2-(m-tolyl)-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2-oxygen Acetamide (Compound 10)

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.11(m,3H),1.44(m,1H),1.72(m,1H),1.91(m,1H),2.11(m,1H),2.22(m,1H),2.35(m,6H),2.83(d,0.35H),3.28(d,0.65H),3.60(d,0.65H),4.10(d,0.35H),5.21(s,0.35H),5.65(s,0.65H),7.03(m,1H),7.10(m,2H),7.23(m,1H),7.94(s,0.35H),7.99(s,0.65H),8.05(s,0.35H),8.09(s,0.65H),8.52(s,0.35H),8.59(s,0.65H),10.86(s,0.35H),10.91(s,0.65H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 1.11 (m, 3H), 1.44 (m, 1H), 1.72 (m, 1H), 1.91 (m, 1H), 2.11 (m, 1H) ,2.22(m,1H),2.35(m,6H),2.83(d,0.35H),3.28(d,0.65H),3.60(d,0.65H),4.10(d,0.35H),5.21(s ,0.35H),5.65(s,0.65H),7.03(m,1H),7.10(m,2H),7.23(m,1H),7.94(s,0.35H),7.99(s,0.65H), 8.05(s, 0.35H), 8.09(s, 0.65H), 8.52(s, 0.35H), 8.59(s, 0.65H), 10.86(s, 0.35H), 10.91(s, 0.65H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.0；Rt=4.966min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.0; Rt=4.966 min.

掌性HPLC：Rt=9.77min(管柱：OJ-H；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=9.77 min (column: OJ-H; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

實例7. 2-[(2S ,5R )-2-(3,4-二甲基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2R ,5S )-2-(3,4-二甲基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物21及化合物19)之合成Example 7. 2-[( 2S , 5R )-2-(3,4-dimethylphenyl)-5-methyl - 1-piperidinyl]-N-(5-methyl-3- Pyridyl)-2-oxyacetamide and 2-[( 2R , 5S )-2-(3,4-dimethylphenyl)-5-methyl-1-piperidinyl]- Synthesis of N- (5-methyl-3-pyridyl)-2-oxoacetamide (Compound 21 and Compound 19)

Figure 110128222-A0202-12-0910-24
Figure 110128222-A0202-12-0910-24

在-78℃、氬氣氣氛下，向2-(3,4-二甲基苯基)-5-甲基哌啶(0.7g，3.44mmol)於THF(10mL)中之經攪拌之溶液中添加正丁基鋰 (2.5M於己烷中，661.59mg，10.33mmol，4.13mL)。將所得混合物在同一溫度下攪拌5分鐘。5分鐘之後， 將於THF(10mL)中之2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(902.65mg，3.44mmol)添加到反應混合物中。使所得混合物升溫至室溫且在同一溫度下攪拌隔夜。完成之後，添加MeOH(5mL)且在真空中蒸發反應混合物。藉由反相HPLC(50%，水-乙腈，0.5-6.5min；流速：30mL/min；裝載泵：4mL/min乙腈；管柱：SunFire 100*19mm，5um)及掌性管柱層析(管柱：OJ-H 250*20mm，5um，溶析液：己烷-MeOH-IPA，70-15-15，流速：15mL/min)純化所獲得之粗殘餘物，以得到呈黃色固體之2-[(2S ,5R )-2-(3,4-二甲基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物21 ，48mg，131.34μmol，3.81%產率)及2-[(2R ,5S )-2-(3,4-二甲基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物19 ，55mg，150.49μmol，4.37%產率)。To a stirred solution of 2-(3,4-dimethylphenyl)-5-methylpiperidine (0.7 g, 3.44 mmol) in THF (10 mL) at -78 °C under argon atmosphere Add n-butyllithium (2.5M in hexanes, 661.59 mg, 10.33 mmol, 4.13 mL). The resulting mixture was stirred at the same temperature for 5 minutes. After 5 minutes, 2-[(5-methyl-3-pyridinyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (902.65 mg, 3.44 mmol) was added to the reaction mixture. The resulting mixture was warmed to room temperature and stirred at the same temperature overnight. After completion, MeOH (5 mL) was added and the reaction mixture was evaporated in vacuo. by reverse phase HPLC (50%, water-acetonitrile, 0.5-6.5min; flow rate: 30mL/min; loading pump: 4mL/min acetonitrile; column: SunFire 100*19mm, 5um) and chiral column chromatography ( Column: OJ-H 250*20mm, 5um, eluent: hexane-MeOH-IPA, 70-15-15, flow rate: 15mL/min) purify the obtained crude residue to obtain 2 as a yellow solid -[( 2S , 5R )-2-(3,4-dimethylphenyl)-5-methyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl)- 2-Pendant oxyacetamide ( compound 21 , 48 mg, 131.34 μmol, 3.81% yield) and 2-[( 2R ,5S)-2-(3,4-dimethylphenyl)-5- Methyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2-oxyacetamide ( Compound 19 , 55 mg, 150.49 μmol, 4.37% yield).

[(2S ,5R )-2-(3,4-二甲基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物21)：[(2 S ,5 R )-2-(3,4-dimethylphenyl)-5-methyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2 - Pendant oxyacetamide (compound 21):

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.07(m,3H),1.34(m,1H),1.89(m,2H),2.15(m,2H),2.22(m,6H),2.29(m,3H),3.20(m,1H),4.62(m,1H),5.95(m,1H),7.00(m,2H),7.09(m,1H),7.99(s,1H),8.19(m,1H),8.49(m,1H),9.65(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.07 (m, 3H), 1.34 (m, 1H), 1.89 (m, 2H), 2.15 (m, 2H), 2.22 (m, 6H), 2.29 (m,3H),3.20(m,1H),4.62(m,1H),5.95(m,1H),7.00(m,2H),7.09(m,1H),7.99(s,1H),8.19( m, 1H), 8.49 (m, 1H), 9.65 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值365.2；實測值366.2；Rt=1.397min。LCMS (ESI): [M+H] + m/z: calculated 365.2; found 366.2; Rt=1.397 min.

掌性HPLC：Rt=6.57min(管柱：OJ-3；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.155mL/min)。Chiral HPLC: Rt=6.57 min (column: OJ-3; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.155 mL/min).

2-[(2R ,5S )-2-(3,4-二甲基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物19)：2-[(2 R ,5 S )-2-(3,4-dimethylphenyl)-5-methyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl) -2-Pendant oxyacetamide (compound 19):

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.07(m,3H),1.34(m,1H),1.88(m,2H),2.15(m,2H),2.22(m,6H),2.30(m,3H),3.24(m,1H),4.40(m,1H),5.95(m,1H),7.00(m,2H),7.09(m,1H),7.99(s,1H),8.19(m,1H),8.50(m,1H),9.65(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.07 (m, 3H), 1.34 (m, 1H), 1.88 (m, 2H), 2.15 (m, 2H), 2.22 (m, 6H), 2.30 (m,3H),3.24(m,1H),4.40(m,1H),5.95(m,1H),7.00(m,2H),7.09(m,1H),7.99(s,1H),8.19( m, 1H), 8.50 (m, 1H), 9.65 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值365.2；實測值366.2；Rt=1.397min。LCMS (ESI): [M+H] + m/z: calculated 365.2; found 366.2; Rt=1.397 min.

掌性HPLC：Rt=33.27min(管柱：OJ-3；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.155mL/minChiral HPLC: Rt=33.27min (column: OJ-3; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.155mL/min

實例8. 2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物13)、2-((2R,5S)-2-(3-氯苯基)-5-甲基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物90)及2-((2S,5R)-2-(3-氯苯基)-5-甲基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物87)之合成Example 8. 2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2- Pendant oxyacetamide (compound 13), 2-((2R,5S)-2-(3-chlorophenyl)-5-methylpiperidin-1-yl)-N-(5-methylpyridine -3-yl)-2-oxyacetamide (compound 90) and 2-((2S,5R)-2-(3-chlorophenyl)-5-methylpiperidin-1-yl)- Synthesis of N-(5-methylpyridin-3-yl)-2-oxoacetamide (Compound 87)

Figure 110128222-A0202-12-0912-25
Figure 110128222-A0202-12-0912-25

在-78℃、Ar氣氛下，向[(5-甲基吡啶-3-基)胺基](側氧基)乙酸2,2,2-三氟乙酯(625.10mg，2.38mmol)於THF(10mL)中之溶液中添加正丁基鋰(1.33g，4.77mmol，1.92mL，23%純度)。15min分鐘之後，一次性添加2-(3-氯苯基)-5-甲基哌啶(0.5g，2.38mmol)。將所得混合物升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(2-7min 50-100% MeOH(0.1%氫氧化銨)，30mL/min；管柱：YMC-ACTUS TRIAT C18 100* 20 5微米)。獲得呈淡黃色膠狀物之2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(6.7mg，18.02μmol，7.56e-1%產率)，其緩慢結晶。To [(5-methylpyridin-3-yl)amino](pendant oxy)acetic acid 2,2,2-trifluoroethyl ester (625.10 mg, 2.38 mmol) in THF at -78°C under Ar atmosphere To a solution in (10 mL) was added n-butyllithium (1.33 g, 4.77 mmol, 1.92 mL, 23% purity). After 15 min, 2-(3-chlorophenyl)-5-methylpiperidine (0.5 g, 2.38 mmol) was added in one portion. The resulting mixture was warmed to room temperature, quenched with aq . NH4Cl , extracted with EtOAc, dried over Na2SO4 , evaporated and subjected to HPLC (2-7 min 50-100% MeOH (0.1% ammonium hydroxide), 30 mL/min; column: YMC-ACTUS TRIAT C18 100 * 20 5 microns). 2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridine was obtained as a pale yellow gum (6.7 mg, 18.02 μmol, 7.56e-1% yield), which crystallized slowly.

1 H NMR(400MHz,CDCl3 )δ 0.81(m,1H),1.09(m,3H),1.37(m,1H),1.84(m,1H), 1.97(m,1H),2.20(m,2H),2.33(m,3H),3.15(m,1H),4.53(m,1H),6.09(m,1H),7.16(m,1H),7.22(m,1H),7.29(m,2H),8.00(s,1H),8.22(m,1H),8.48(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.81(m,1H), 1.09(m,3H), 1.37(m,1H), 1.84(m,1H), 1.97(m,1H), 2.20(m,2H) ), 2.33(m, 3H), 3.15(m, 1H), 4.53(m, 1H), 6.09(m, 1H), 7.16(m, 1H), 7.22(m, 1H), 7.29(m, 2H) , 8.00(s, 1H), 8.22(m, 1H), 8.48(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值371.2；實測值372.2；Rt=1.236min。LCMS (ESI): [M+H] + m/z: calculated 371.2; found 372.2; Rt=1.236 min.

使用IC chiralpak(250* 20，5mkm)管柱，以Hex-IPA-MeOH為流動相，70-15-15，0.6mL/min；注入體積5mkL)進行掌性分離，得到2-((2R,5S)-2-(3-氯苯基)-5-甲基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物90 )(56.84mg，152.85μmol，32.80%產率)及2-((2S,5R)-2-(3-氯苯基)-5-甲基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物87 )(40.55mg，109.05μmol，23.40%產率)。Using an IC chiralpak (250 * 20, 5mkm) column with Hex-IPA-MeOH as mobile phase, 70-15-15, 0.6mL/min; injection volume 5mkL) for chiral separation, 2-((2R, 5S)-2-(3-Chlorophenyl)-5-methylpiperidin-1-yl)-N-(5-methylpyridin-3-yl)-2-oxoacetamide ( Compound 90 ) (56.84 mg, 152.85 μmol, 32.80% yield) and 2-((2S,5R)-2-(3-chlorophenyl)-5-methylpiperidin-1-yl)-N-(5- Methylpyridin-3-yl)-2-oxyacetamide ( Compound 87 ) (40.55 mg, 109.05 μmol, 23.40% yield).

2-((2S,5R)-2-(3-氯苯基)-5-甲基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物87)：2-((2S,5R)-2-(3-Chlorophenyl)-5-methylpiperidin-1-yl)-N-(5-methylpyridin-3-yl)-2-oxygen Acetamide (compound 87):

1 H NMR(600MHz,DMSO-d6 )δ 1.02(m,3H),1.33(m,1H),1.64(m,1H),1.89(m,1H),2.04(m,1H),2.19(m,1H),2.27(m,3H),3.02(m,1H),3.74(m,1H),5.35(m,1H),7.33(m,3H),7.43(m,1H),7.90(m,1H),8.16(m,1H),8.57(m,1H),11.06(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.02(m, 3H), 1.33(m, 1H), 1.64(m, 1H), 1.89(m, 1H), 2.04(m, 1H), 2.19(m ,1H),2.27(m,3H),3.02(m,1H),3.74(m,1H),5.35(m,1H),7.33(m,3H),7.43(m,1H),7.90(m, 1H), 8.16 (m, 1H), 8.57 (m, 1H), 11.06 (m, 1H).

LCMS(ESI)：[M+4H]+ m/z：計算值371.2；實測值375.3；Rt=5.04min。LCMS (ESI): [M+4H] + m/z: calculated 371.2; found 375.3; Rt=5.04 min.

RT(IC，Hex-IPA-MeOH，70-15-15，0.6mL/min)=30.688min。RT (IC, Hex-IPA-MeOH, 70-15-15, 0.6 mL/min) = 30.688 min.

2-((2R,5S)-2-(3-氯苯基)-5-甲基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物90)：2-((2R,5S)-2-(3-Chlorophenyl)-5-methylpiperidin-1-yl)-N-(5-methylpyridin-3-yl)-2-side oxy Acetamide (compound 90):

1 H NMR(600MHz,DMSO-d6 )δ 1.02(m,3H),1.32(m,1H),1.64(m,1H),1.89(m,1H),2.08(m,1H),2.19(m,1H),2.27(m,3H),2.94(m,1H),3.84(m,1H),5.35(m,1H),7.33(m,3H),7.43(m,1H),7.90(m,1H),8.16(m,1H),8.57(m,1H),11.06(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.02(m, 3H), 1.32(m, 1H), 1.64(m, 1H), 1.89(m, 1H), 2.08(m, 1H), 2.19(m ,1H),2.27(m,3H),2.94(m,1H),3.84(m,1H),5.35(m,1H),7.33(m,3H),7.43(m,1H),7.90(m, 1H), 8.16 (m, 1H), 8.57 (m, 1H), 11.06 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值371.2：實測值372.3；Rt=5.03min。LCMS (ESI): [M+H] + m/z: calculated 371.2: found 372.3; Rt=5.03 min.

RT(IC，Hex-IPA-MeOH，70-15-15，0.6mL/min)=20.398min。RT (IC, Hex-IPA-MeOH, 70-15-15, 0.6 mL/min) = 20.398 min.

實例9. 2-[(2S ,5R )-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物14)之合成Example 9. 2-[( 2S , 5R )-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]-N-(5 - methyl-3- Synthesis of Pyridyl)-2-Pendant Oxyacetamide (Compound 14)

Figure 110128222-A0202-12-0914-26
Figure 110128222-A0202-12-0914-26

在-78℃、氬氣氣氛下，向2-甲基-4-(5-甲基-2-哌啶基)吡啶(0.187g，982.74μmol)於THF(20mL)中之經攪拌之溶液中添加正丁基鋰 (2.5M於己烷中，125.90mg，1.97mmol，0.78mL)。將所得混合物在同一溫度下攪拌5分鐘。5分鐘之後，一次性添加2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(257.66mg，982.74μmol)。使所得混合物升溫至室溫且在同一溫度下攪拌12小時。12小時之後，將反應混合物用飽和NH4 Cl水溶液淬滅且在真空中蒸發。藉由反相HPLC純化粗產物(1g)，以獲得呈白色固體之產物2-[(2S ,5R )-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.058g，164.57μmol，16.75%產率)。To a stirred solution of 2-methyl-4-(5-methyl-2-piperidinyl)pyridine (0.187 g, 982.74 μmol) in THF (20 mL) at -78 °C under argon atmosphere Add n-butyllithium (2.5M in hexanes, 125.90 mg, 1.97 mmol, 0.78 mL). The resulting mixture was stirred at the same temperature for 5 minutes. After 5 minutes, 2-[(5-methyl-3-pyridinyl)amino]-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (257.66 mg, 982.74 μmol) was added in one portion. The resulting mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was quenched with saturated aqueous NH4Cl and evaporated in vacuo. The crude product (1 g) was purified by reverse phase HPLC to obtain the product 2-[( 2S , 5R )-5-methyl-2-(2-methyl-4-pyridinyl)-1 as a white solid -Piperidinyl]-N-(5-methyl - 3-pyridyl)-2-oxyacetamide (0.058 g, 164.57 μmol, 16.75% yield).

1 H NMR(DMSO-d 6 +CCl4 ,400MHz)：δ(ppm)1.11(d,3H),1.41(m,1H),1.69(m,1H),1.92(m,1H),2.19(m,2H),2.34(m,3H),2.53(m,3H),2.79(m,0.4H),3.25(m,0.6H),3.89(m,1H),5.42(m,1H),7.07(m,1H),7.13(m,1H),7.94(m,1H),8.08(m,1H),8.38(m,1H),8.57(m,1H),10.93(m,1H)。 1 H NMR (DMSO- d 6 +CCl 4 , 400MHz): δ (ppm) 1.11 (d, 3H), 1.41 (m, 1H), 1.69 (m, 1H), 1.92 (m, 1H), 2.19 (m ,2H),2.34(m,3H),2.53(m,3H),2.79(m,0.4H),3.25(m,0.6H),3.89(m,1H),5.42(m,1H),7.07( m, 1H), 7.13 (m, 1H), 7.94 (m, 1H), 8.08 (m, 1H), 8.38 (m, 1H), 8.57 (m, 1H), 10.93 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.2；Rt=1.923min。LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.2; Rt=1.923 min.

實例10. 2-[(2S ,5R )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物16)及2-[(2R ,5S )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物12)之合成Example 10. 2-[( 2S , 5R )-5-methyl-2-( p-tolyl )-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2- Pendant oxyacetamide (compound 16) and 2-[( 2R , 5S )-5-methyl-2-( p-tolyl )-1-piperidinyl]-N-(5-methyl- Synthesis of 3-pyridyl)-2-oxoacetamide (Compound 12)

Figure 110128222-A0202-12-0915-27
Figure 110128222-A0202-12-0915-27

步驟1：外消旋-2-[(2S,5R)-5-甲基-2-(對甲苯基)-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺之合成Step 1: Racemic-2-[(2S,5R)-5-methyl-2-(p-tolyl)-1-piperidinyl]-N-(5-methyl-3-pyridinyl)- Synthesis of 2-Pendant Oxyacetamide

在-78℃、氬氣氣氛下，向[(5-甲基吡啶-3-基)胺基](側氧基)乙酸2,2,2-三氟乙酯(1.39g，5.28mmol)於THF(25mL)中之經攪拌之溶液中逐滴添加正丁基鋰 (2.5M於己烷中，2.94g，10.57mmol，4.25mL)。將所得溶液在同一溫度下攪拌15分鐘。15分鐘之後，將5-甲基-2-(對甲苯基 )哌啶(1g，5.28mmol)一次性添加到溶液中。使所得反應混合物升溫至室溫且在同一溫度下攪拌1小時。1小時之後，將反應混合物用飽和NH4 Cl水溶液淬滅且用EtOAc萃取。將有機層經Na2 SO4 乾燥，過濾且在減壓下蒸發。藉由反相HPLC(溶析液：CH3 CN,50-55%，2-7min，流速：30mL/min；管柱：SunFire C18 100*19mm，5uM)純化粗產物，以獲得呈淡黃色膠狀物之外消旋 -2-[(2S ,5R )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.0731g，208.00μmol，3.94%產率)。To [(5-methylpyridin-3-yl)amino](pendant oxy)acetic acid 2,2,2-trifluoroethyl ester (1.39 g, 5.28 mmol) at -78°C under argon atmosphere To the stirred solution in THF (25 mL) was added n-butyllithium (2.5M in hexanes, 2.94 g, 10.57 mmol, 4.25 mL) dropwise. The resulting solution was stirred at the same temperature for 15 minutes. After 15 minutes, 5-methyl-2-( p-tolyl )piperidine (1 g, 5.28 mmol) was added to the solution in one portion. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 1 hour. After 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by reverse phase HPLC (eluent: CH3CN , 50-55%, 2-7 min, flow rate: 30 mL/min; column: SunFire C18 100*19 mm, 5 uM) to obtain a pale yellow gum Compound rac -2-[( 2S , 5R )-5-methyl-2-( p-tolyl )-1-piperidinyl]-N-(5-methyl - 3-pyridyl )-2-oxoacetamide (0.0731 g, 208.00 μmol, 3.94% yield).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=3.269min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.2; Rt=3.269 min.

步驟2：2-[(2S,5R)-5-甲基-2-(對甲苯基)-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2R,5S)-5-甲基-2-(對甲苯基)-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物16 及化合物12 )之掌性分離Step 2: 2-[(2S,5R)-5-methyl-2-(p-tolyl)-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen Ethylacetamide and 2-[(2R,5S)-5-methyl-2-(p-tolyl)-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2- Chiral separation of pendant oxyacetamides ( compounds 16 and 12 )

使外消旋 -2-[(2S ,5R )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.0621g，176.70μmol)經歷掌性層析(管柱：Chiralcel OJ-H 250*20mm，5um，溶析液：己烷-MeOH-IPA，70-15-15，流速：15mL/min)，以得到呈灰白色固體之2-[(2S ,5R )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物16 ，30.5mg)及2-[(2R ,5S )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物12 ，23.4mg)。Make rac -2-[( 2S , 5R )-5-methyl-2-( p-tolyl )-1-piperidinyl]-N-(5-methyl - 3-pyridinyl)- 2-Pendoxacetamide (0.0621 g, 176.70 μmol) was subjected to chiral chromatography (column: Chiralcel OJ-H 250*20 mm, 5 um, eluent: Hexane-MeOH-IPA, 70-15-15 , flow rate: 15 mL/min) to obtain 2-[( 2S , 5R )-5-methyl-2-( p-tolyl )-1-piperidinyl]-N-(5- Methyl-3-pyridyl)-2-oxyacetamide ( compound 16 , 30.5 mg) and 2-[( 2R , 5S )-5-methyl-2-( p-tolyl )-1 -Piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxoacetamide ( Compound 12 , 23.4 mg).

2-[(2S ,5R )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物16)：2-[(2 S ,5 R )-5-methyl-2-( p-tolyl )-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen Acetamide (compound 16):

1 H NMR(CD3 OD,400MHz)：δ(ppm)1.12(m,6H),1.40(m,1H),1.87(m,2H),2.28(m,3H),2.37(m,3H),3.52(m,1H),3.96(m,1H),5.47(m,1H),7.20(m,4H),7.90(m,1H),8.17(m,1H),8.57(m,1H)。 1 H NMR (CD 3 OD, 400MHz): δ (ppm) 1.12 (m, 6H), 1.40 (m, 1H), 1.87 (m, 2H), 2.28 (m, 3H), 2.37 (m, 3H), 3.52 (m, 1H), 3.96 (m, 1H), 5.47 (m, 1H), 7.20 (m, 4H), 7.90 (m, 1H), 8.17 (m, 1H), 8.57 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=1.218min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.2; Rt=1.218 min.

掌性HPLC：Rt=13.72min(管柱：OJ-3；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.15mL/min)。Chiral HPLC: Rt=13.72 min (column: OJ-3; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.15 mL/min).

2-[(2R ,5S )-5-甲基-2-(對甲苯基 )-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物12)：2-[(2 R ,5 S )-5-methyl-2-( p-tolyl )-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen Acetamide (compound 12):

1 H NMR(CD3 OD,400MHz)：δ(ppm)1.12(m,6H),1.41(m,1H),1.87(m,2H),2.25(m,3H),2.37(m,3H),3.51(m,1H),3.95(m,1H),5.47(m,1H),7.21(m,4H),7.90(m,1H),8.18(m,1H),8.57(m,1H)。 1 H NMR (CD 3 OD, 400MHz): δ (ppm) 1.12 (m, 6H), 1.41 (m, 1H), 1.87 (m, 2H), 2.25 (m, 3H), 2.37 (m, 3H), 3.51(m,1H), 3.95(m,1H), 5.47(m,1H), 7.21(m,4H), 7.90(m,1H), 8.18(m,1H), 8.57(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.0；Rt=1.218min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.0; Rt=1.218 min.

掌性HPLC：Rt=40.48min(管柱：OJ-3；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.15mL/min)。Chiral HPLC: Rt=40.48 min (column: OJ-3; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.15 mL/min).

實例11. 外消旋-2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物70)、2-[(2S,5S)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-Example 11. Racemic-2-[(2S,5R)-2-(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl )-2-oxyacetamide (compound 70), 2-[(2S,5S)-2-(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5 - 甲基-3-吡啶基)-2-側氧基乙醯胺(化合物1080)、2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基[-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物77)、2-[(2R,5S)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物84)及2-[(2R,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物93)之合成Methyl-3-pyridyl)-2-oxyacetamide (compound 1080), 2-[(2S,5R)-2-(3-fluorophenyl)-5-methyl-1-piperidine [-N-(5-methyl-3-pyridyl)-2-oxyacetamide (Compound 77), 2-[(2R,5S)-2-(3-fluorophenyl)-5 -Methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (Compound 84) and 2-[(2R,5R)-2-( Synthesis of 3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (compound 93)

Figure 110128222-A0202-12-0917-28
Figure 110128222-A0202-12-0917-28

步驟1：外消旋-2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物70 )之合成Step 1: Racemic-2-[(2S,5R)-2-(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridinyl )-2-side oxyacetamide ( compound 70 ) synthesis

在-78℃、Ar氣氛下，向[(5-甲基吡啶-3-基)胺基](側氧基)乙酸2,2,2-三氟乙酯(406.99mg，1.55mmol)於THF(50mL)中之溶液中添加正丁基鋰(864.64mg，3.10mmol，1.25mL，23%純度)。15min分鐘之後，一次性添加2-(3-氟苯基)-5-甲基哌啶(0.3g，1.55mmol)。將所得混合物升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(SunFira C18 19* 100mm 5mkm管柱；2-7min 40-65% MeCN，流速30ml/min)。HPLC之後，獲得兩種級分：呈非鏡像異構物之混合物之2-[2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(81.6mg，229.60μmol，14.79%產率)以及2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(9.9mg，27.86μmol，1.79%產率)。To [(5-methylpyridin-3-yl)amino](pendant oxy)acetic acid 2,2,2-trifluoroethyl ester (406.99 mg, 1.55 mmol) in THF at -78°C under Ar atmosphere To a solution in (50 mL) was added n-butyllithium (864.64 mg, 3.10 mmol, 1.25 mL, 23% purity). After 15 min, 2-(3-fluorophenyl)-5-methylpiperidine (0.3 g, 1.55 mmol) was added in one portion. The resulting mixture was warmed to room temperature, quenched with aq NH4Cl , extracted with EtOAc, dried over Na2SO4 , evaporated and subjected to HPLC (SunFira C18 19 * 100mm 5mkm column; 2-7 min 40-65% MeCN, flow rate 30ml/min). After HPLC, two fractions were obtained: 2-[2-(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl as a mixture of diastereoisomers -3-Pyridinyl)-2-oxyacetamide (81.6 mg, 229.60 μmol, 14.79% yield) and 2-[(2S,5R)-2-(3-fluorophenyl)-5-methyl yl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (9.9 mg, 27.86 μmol, 1.79% yield).

1 H NMR(500MHz,DMSO-d 6 )δ 1.02(m,3H),1.31(m,1H),1.63(m,1H),1.88(m, 1H),2.06(m,1H),2.20(m,1H),2.27(m,3H),3.24(m,1H),3.84(m,1H),5.36(m,1H),7.15(m,3H),7.44(m,1H),7.90(m,1H),8.16(m,1H),8.62(m,1H),11.04(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 1.02(m, 3H), 1.31(m, 1H), 1.63(m, 1H), 1.88(m, 1H), 2.06(m, 1H), 2.20(m ,1H),2.27(m,3H),3.24(m,1H),3.84(m,1H),5.36(m,1H),7.15(m,3H),7.44(m,1H),7.90(m, 1H), 8.16 (m, 1H), 8.62 (m, 1H), 11.04 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值355.1；實測值356.4；Rt=3.052min。LCMS (ESI): [M+H] + m/z: calculated 355.1; found 356.4; Rt=3.052 min.

步驟2：2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺之掌性分離Step 2: 2-[(2S,5R)-2-(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2- Chiral separation of pendant oxyacetamides

使用AD-H-III(250* 20，5mkm)Chiralpak管柱(以己烷-IPA-MeOH，60-20-20為流動相；流速12ml/min)進行2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺之掌性分離，得到化合物1080 2-[(2S,5S)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(4.77mg，5.85%；RT=21.76min)、化合物77 2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(27.41mg，33.62%；RT=33.70min)、化合物84 2-[(2R,5S)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(3.18mg，3.90%；RT=39.42min)及化合物93 2-[(2R,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(32.62mg，39.98%；RT=27.90min)。2-[(2S,5R)-2 was carried out using AD-H-III (250 * 20, 5mkm) Chiralpak column (hexane-IPA-MeOH, 60-20-20 as mobile phase; flow rate 12ml/min) Chiral separation of -(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridinyl)-2-oxoacetamide to give compound 1080 2-[(2S,5S)-2-(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen Ethylacetamide (4.77 mg, 5.85%; RT=21.76 min), Compound 77 2-[(2S,5R)-2-(3-fluorophenyl)-5-methyl-1-piperidinyl]- N-(5-methyl-3-pyridyl)-2-oxyacetamide (27.41 mg, 33.62%; RT=33.70 min), compound 84 2-[(2R,5S)-2-(3 -Fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (3.18 mg, 3.90%; RT=39.42 min) and compound 93 2-[(2R,5R)-2-(3-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)- 2-Pendant oxyacetamide (32.62 mg, 39.98%; RT=27.90 min).

2-[(2S,5S)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物1080)：2-[(2S,5S)-2-(3-Fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-side oxy Acetamide (compound 1080):

RT(OJ-H，己烷-IPA-MeOH，90-5-5，0.6ml/min)=21.760min。RT (OJ-H, Hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 21.760 min.

1 H NMR(500MHz,CDCl3 )δ 0.88(m,3H),1.27(m,1H),1.75(m,2H),1.88(m,1H),2.06(m,1H),2.43(m,3H),2.61(m,1H),4.67(m,1H),6.17(m,1H),6.99(m,2H),7.09(m,1H),7.37(m,1H),8.21(m,1H),8.28(m,1H),8.73(m,1H),9.63(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.88(m,3H), 1.27(m,1H), 1.75(m,2H), 1.88(m,1H), 2.06(m,1H), 2.43(m,3H) ), 2.61(m, 1H), 4.67(m, 1H), 6.17(m, 1H), 6.99(m, 2H), 7.09(m, 1H), 7.37(m, 1H), 8.21(m, 1H) , 8.28 (m, 1H), 8.73 (m, 1H), 9.63 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值355.2；實測值356.2；Rt=4.859min。LCMS (ESI): [M+H] + m/z: calculated 355.2; found 356.2; Rt=4.859 min.

2-[(2S,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺2-[(2S,5R)-2-(3-Fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-pendoxyl Acetamide (化合物77)：(Compound 77):

RT(OJ-H，己烷-IPA-MeOH，90-5-5，0.6ml/min)=33.704min。RT (OJ-H, Hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 33.704 min.

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.11(m,3H),1.40(m,1H),1.76(m,1H),1.92(m,1H),2.18(m,2H),2.33(m,3H),3.27(m,1H),3.87(m,1H),5.45(m,1H),6.99(m,1H),7.12(m,2H),7.38(m,1H),7.97(m,1H),8.08(m,1H),8.56(m,1H),10.91(m,1H)。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.11 (m, 3H), 1.40 (m, 1H), 1.76 (m, 1H), 1.92 (m, 1H), 2.18 (m, 2H) ,2.33(m,3H),3.27(m,1H),3.87(m,1H),5.45(m,1H),6.99(m,1H),7.12(m,2H),7.38(m,1H), 7.97 (m, 1H), 8.08 (m, 1H), 8.56 (m, 1H), 10.91 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值355.2；實測值356.2；Rt=4.808min。LCMS (ESI): [M+H] + m/z: calculated 355.2; found 356.2; Rt=4.808 min.

2-[(2R,5S)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物84)2-[(2R,5S)-2-(3-Fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-side oxy Acetamide (Compound 84)

RT(OJ-H，己烷-IPA-MeOH，90-5-5，0.6ml/min)=39.426min。RT (OJ-H, Hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 39.426 min.

1 H NMR(氯仿-d,500MHz)：δ(ppm)0.88(m,3H),1.27(m,1H),1.75(m,2H),2.06(m,1H),2.34(m,1H),2.43(m,3H),2.60(m,1H),4.60(m,1H),6.17(m,1H),6.99(m,2H),7.08(m,1H),7.37(m,1H),8.22(m,1H),8.29(m,1H),8.75(m,1H),9.66(m,1H)。 1 H NMR (chloroform-d, 500MHz): δ (ppm) 0.88 (m, 3H), 1.27 (m, 1H), 1.75 (m, 2H), 2.06 (m, 1H), 2.34 (m, 1H), 2.43(m, 3H), 2.60(m, 1H), 4.60(m, 1H), 6.17(m, 1H), 6.99(m, 2H), 7.08(m, 1H), 7.37(m, 1H), 8.22 (m, 1H), 8.29 (m, 1H), 8.75 (m, 1H), 9.66 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值355.2；實測值356.0；Rt=4.705min。LCMS (ESI): [M+H] + m/z: calculated 355.2; found 356.0; Rt=4.705 min.

2-[(2R,5R)-2-(3-氟苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物93)：2-[(2R,5R)-2-(3-Fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-side oxy Acetamide (compound 93):

RT(OJ-H，己烷-IPA-MeOH，90-5-5，0.6ml/min)=27.991min。RT (OJ-H, Hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 27.991 min.

1 H NMR(500MHz,DMSO-d6 )δ 1.10(m,3H),1.41(m,1H),1.78(m,1H),1.92(m,1H),2.22(m,2H),2.33(m,3H),2.80(m,0H),3.28(m,1H),3.87(m,1H),5.46(m,1H),6.99(m,1H),7.12(m,2H),7.38(m,1H),7.97(m,1H),8.08(m,1H),8.56(m,1H),10.91(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.10(m, 3H), 1.41(m, 1H), 1.78(m, 1H), 1.92(m, 1H), 2.22(m, 2H), 2.33(m ,3H),2.80(m,0H),3.28(m,1H),3.87(m,1H),5.46(m,1H),6.99(m,1H),7.12(m,2H),7.38(m, 1H), 7.97 (m, 1H), 8.08 (m, 1H), 8.56 (m, 1H), 10.91 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值355.2；實測值356.2；Rt=4.821min。LCMS (ESI): [M+H] + m/z: calculated 355.2; found 356.2; Rt=4.821 min.

實例12. 2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-N -(5-甲基吡啶-3-基)-2-側氧基乙Example 12. 2-(5-Methyl-2-(thiophen-2-yl)piperidin-1 - yl)-N-(5-methylpyridin-3-yl)-2-side oxyethyl 醯胺(化合物60、化合物68、化合物76)之合成Synthesis of amides (compound 60, compound 68, compound 76)

Figure 110128222-A0202-12-0920-29
Figure 110128222-A0202-12-0920-29

步驟1：外消旋-2-((2R,5S)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物60 )之合成Step 1: Racemic-2-((2R,5S)-5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-N-(5-methylpyridin-3-yl )-2-side oxyacetamide ( compound 60 ) synthesis

在-78℃、Ar氣氛下，向[(5-甲基吡啶-3-基)胺基](側氧基)乙酸2,2,2-三氟乙酯(433.85mg，1.65mmol)於THF(15mL)中之溶液中添加正丁基鋰 (921.70mg，3.31mmol，1.33mL，23%純度)。15min分鐘之後，一次性添加5-甲基-2-(2-噻吩基)哌啶(0.3g，1.65mmol)。將所得混合物升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(2-7 35-60% acn，30ml/min；sunfire C18 100*19，5uM)。HPLC之後，獲得N -(5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(2-噻吩基)-1-哌啶基]-2-側氧基乙醯胺(84.5mg，246.04μmol，14.87%產率)之2種級分：49.8mg(98.98%純度)及34.7mg(96.38%純度)。To [(5-methylpyridin-3-yl)amino](pendant oxy)acetic acid 2,2,2-trifluoroethyl ester (433.85 mg, 1.65 mmol) in THF at -78 °C under Ar atmosphere To a solution in (15 mL) was added n-butyllithium (921.70 mg, 3.31 mmol, 1.33 mL, 23% purity). After 15 min, 5-methyl-2-(2-thienyl)piperidine (0.3 g, 1.65 mmol) was added in one portion. The resulting mixture was warmed to room temperature, quenched with aq NH4Cl , extracted with EtOAc, dried over Na2SO4 , evaporated and subjected to HPLC (2-7 35-60% acn, 30 ml/min; sunfire C18 100 *19, 5uM). After HPLC, N- (5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-(2-thienyl)-1-piperidinyl]-2- Two fractions of pendant oxyacetamide (84.5 mg, 246.04 μmol, 14.87% yield): 49.8 mg (98.98% pure) and 34.7 mg (96.38% pure).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.02(t,3H),1.45(m,1H),1.89(m,2H),2.06(m,2H),2.29(m,3H),2.78(m,1H),3.65(m,1H),5.64(m,1H),7.05(m,2H),7.50(m,1H),7.94(m,1H),8.18(m,1H),8.62(s,1H),11.05(s,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.02(t, 3H), 1.45(m, 1H), 1.89(m, 2H), 2.06(m, 2H), 2.29(m, 3H), 2.78(m, 1H), 3.65(m, 1H), 5.64(m, 1H), 7.05(m, 2H), 7.50(m, 1H), 7.94(m, 1H), 8.18(m, 1H), 8.62 (s, 1H), 11.05 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值343.4；實測值344.2；Rt=3.273min。LCMS (ESI): [M] + m/z: calculated 343.4; found 344.2; Rt=3.273 min.

步驟2：掌性分離(化合物68 及化合物76 )Step 2: Chiral separation ( compound 68 and compound 76 )

在體系Hex-IPA-MeOH，70-15-15，0.6mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：5mkl。自39mg外消旋物獲得17.01mg及17.38mg個別 鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 70-15-15, 0.6 mL/min. Injection times: 1, injection volume: 5mkl. 17.01 mg and 17.38 mg individually from 39 mg racemate mirror image isomers.

2-((2R,5S)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物68)：2-((2R,5S)-5-Methyl-2-(thiophen-2-yl)piperidin-1-yl)-N-(5-methylpyridin-3-yl)-2-oxygen Acetamide (compound 68):

保留時間：17.81minRetention time: 17.81min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.43(m,1H),1.89(m,2H),2.05(m,2H),2.29(m,3H),3.28(m,1H),3.46(m,1H),5.84(m,1H),7.04(m,2H),7.50(m,1H),7.94(m,1H),8.18(m,1H),8.61(m,1H),11.03(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.02(m, 3H), 1.43(m, 1H), 1.89(m, 2H), 2.05(m, 2H), 2.29(m, 3H), 3.28(m, 1H), 3.46(m, 1H), 5.84(m, 1H), 7.04(m, 2H), 7.50(m, 1H), 7.94(m, 1H), 8.18(m, 1H), 8.61 (m, 1H), 11.03 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值343.4；實測值344.2；Rt=4.460min。LCMS (ESI): [M] + m/z: calculated 343.4; found 344.2; Rt=4.460 min.

2-((2S,5R)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物76)：2-((2S,5R)-5-Methyl-2-(thiophen-2-yl)piperidin-1-yl)-N-(5-methylpyridin-3-yl)-2-oxygen Acetamide (compound 76):

保留時間：22.70minRetention time: 22.70min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.43(m,1H),1.88(m,2H),2.05(m,2H),2.29(m,3H),3.36(m,1H),3.44(m,1H),5.83(m,1H),7.04(m,2H),7.49(m,1H),7.94(m,1H),8.18(m,1H),8.61(m,1H),11.03(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.02(m,3H), 1.43(m,1H), 1.88(m,2H), 2.05(m,2H), 2.29(m,3H), 3.36(m, 1H), 3.44(m, 1H), 5.83(m, 1H), 7.04(m, 2H), 7.49(m, 1H), 7.94(m, 1H), 8.18(m, 1H), 8.61 (m, 1H), 11.03 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值343.4；實測值344.2；Rt=4.475min。LCMS (ESI): [M] + m/z: calculated 343.4; found 344.2; Rt=4.475 min.

實例13.外消旋 -2-((2R,5S )-2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-N -(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物44)之合成Example 13. Racemic -2-(( 2R,5S )-2-(3-(1-acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)- Synthesis of N- (5-methylpyridin-3-yl)-2-oxoacetamide (Compound 44)

Figure 110128222-A0202-12-0921-30
Figure 110128222-A0202-12-0921-30

在-78℃、Ar氣氛下，向1-[4-[3-[(2S,5R )-5-甲基-2-哌啶基]苯基]-1-哌啶基]乙酮(500.00mg，1.66mmol)及2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(479.97mg，1.83mmol)於THF(50mL)中之溶液中添加正丁基鋰 (1.16g，4.16mmol，1.67mL，23%純度)。將所得混合物攪拌15min且將其升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(19_R1+FA 1-6min 55-55%水-MeOH+FA，流速30ml/min(裝載泵4ml/min MeOH+FA))，以獲得2-[(2S,5R )-2-[3-(1-乙醯基-4-哌啶基)苯基]-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(7mg，15.13μmol，9.09e-1%產率)。Add 1-[4-[3-[( 2S,5R )-5-methyl-2-piperidinyl]phenyl]-1-piperidinyl]ethanone (500.00 mg, 1.66 mmol) and 2-[(5-methyl-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (479.97 mg, 1.83 mmol) in THF ( 50 mL) was added n-butyllithium (1.16 g, 4.16 mmol, 1.67 mL, 23% purity). The resulting mixture was stirred for 15 min and allowed to warm to room temperature, quenched with aq NH 4 Cl, extracted with EtOAc, dried over Na 2 SO 4 , evaporated and subjected to HPLC (19_R1 + FA 1-6 min 55-55% water -MeOH+FA, flow rate 30ml/min (load pump 4ml/min MeOH+FA)) to obtain 2-[( 2S,5R )-2-[3-(1-acetyl-4-piperidinyl) Phenyl]-5-methyl - 1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (7 mg, 15.13 μmol, 9.09e-1% yield Rate).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.12(d,3H),1.41(m,1H),1.54(m,2H),1.82(m,4H),2.04(s,3H),2.26(m,2H),2.36(m,3H),2.78(m,2H),3.15(m,2H),3.61(m,1H),3.93(m,1H),4.61(d,1H),5.55(m,1H),7.27(m,4H),8.06(m,1H),8.11(m,1H),8.61(m,1H),10.91(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.12(d,3H), 1.41(m,1H), 1.54(m,2H), 1.82(m,4H), 2.04(s,3H), 2.26(m, 2H), 2.36(m, 3H), 2.78(m, 2H), 3.15(m, 2H), 3.61(m, 1H), 3.93(m, 1H), 4.61(d, 1H), 5.55 (m, 1H), 7.27 (m, 4H), 8.06 (m, 1H), 8.11 (m, 1H), 8.61 (m, 1H), 10.91 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值462.6；實測值463.2；Rt=1.206min。LCMS (ESI): [M] + m/z: calculated 462.6; found 463.2; Rt=1.206 min.

實例14. rel-(R)-5-(2-(2-(1-甲基-1H-吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物59)及rel-(S)-5-(2-(2-(1-甲基-1H-吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物46)之合成Example 14. rel-(R)-5-(2-(2-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-oxyacetamido) Nicotinamide (Compound 59) and rel-(S)-5-(2-(2-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-oxygen Synthesis of acetylacetamido)nicotinamide (compound 46)

Figure 110128222-A0202-12-0922-31
Figure 110128222-A0202-12-0922-31

步驟1：5-[[2-[2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(2-Methylpyrazol-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Synthesis of Amines

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.5 g，1.72mmol)、2-(2-甲基吡唑-3-基)哌啶(283.73mg，1.41mmol，HCl)及dipea(443.85mg，3.43mmol，598.19μL)混合於乙腈(5mL)中且在劇烈攪拌之情況下在密封管中在100℃下加熱。16h之後，過濾混合物，蒸發溶劑且使粗產物經歷HPLC(H2 O/MeOH+NH3 為溶劑混合物；YMC-ACTUS TRIART C18,100* 20mm，5um管柱)，以得到5-[[2-[2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(24mg，67.34μmol，3.92%產率)。1 H NMR(400MHz,CD3 OD)δ 1.82(m,3H),2.12(m,3H),2.65(m,1H),3.19(m,1H),3.80(s,3H),3.85(m,1H),5.91(m,1H),6.52(d,1H),7.40(d,1H),8.55(s,1H),8.77(s,1H),8.89(s,1H)，未觀察到NH2 。LCMS(ESI)：[M+H]+ m/z：計算值356.2；實測值357.2；Rt=2.056min。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (0.5 g, 1.72 mmol), 2-(2- Methylpyrazol-3-yl)piperidine (283.73 mg, 1.41 mmol, HCl) and dipea (443.85 mg, 3.43 mmol, 598.19 μL) were mixed in acetonitrile (5 mL) and in a sealed tube with vigorous stirring Heated at 100°C. After 16h, the mixture was filtered, the solvent was evaporated and the crude product was subjected to HPLC ( H2O /MeOH+ NH3 was the solvent mixture; YMC-ACTUS TRIART C18, 100 * 20mm, 5um column) to give 5-[[2- [2-(2-Methylpyrazol-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (24 mg, 67.34 μmol, 3.92% Yield). 1 H NMR (400MHz, CD 3 OD) δ 1.82(m, 3H), 2.12(m, 3H), 2.65(m, 1H), 3.19(m, 1H), 3.80(s, 3H), 3.85(m, 1H), 5.91(m, 1H), 6.52(d, 1H), 7.40(d, 1H), 8.55(s, 1H), 8.77(s, 1H), 8.89(s, 1H), NH 2 not observed . LCMS (ESI): [M+H] + m/z: calculated 356.2; found 357.2; Rt=2.056 min.

步驟2：rel-(R)-5-(2-(2-(1-甲基-1H-吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物59 )及rel-(S)-5-(2-(2-(1-甲基-1H-吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物46 )之合成Step 2: rel-(R)-5-(2-(2-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-oxyacetamido) Nicotinamide ( Compound 59 ) and rel-(S)-5-(2-(2-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-oxygen Synthesis of acetylacetamido)nicotinamide ( compound 46 )

使用AD-HII Chiralpak管柱及作為流動相之50-25-25己烷-IPA-MeOH(流速12mL/min)掌性分離5-[[2-[2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(24.0mg，67.34μmol)，得到化合物59 rel-(R)-5-(2-(2-(1-甲基-1H-吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(8.04mg，22.56μmol；33.5%產率；RT(AD-HII，己烷-IPA-MeOH，50-25-25，流速12mL/min)=32.552min)及化合物46 rel-(S)-5-(2-(2-(1-甲基-1H-吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(8.8mg，24.69μmol；36.67%產率；RT(AD-HII，己烷-IPA-MeOH，50-25-25，12mL/min)=18.482min)。Chiral separation of 5-[[2-[2-(2-methylpyrazole-3 using AD-HII Chiralpak column and 50-25-25 hexane-IPA-MeOH (flow rate 12 mL/min) as mobile phase -yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (24.0 mg, 67.34 μmol) to give compound 59 rel-(R)-5-( 2-(2-(1-Methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (8.04 mg, 22.56 μmol; 33.5 % yield; RT (AD-HII, hexane-IPA-MeOH, 50-25-25, flow rate 12 mL/min) = 32.552 min) and compound 46 rel-(S)-5-(2-(2-( 1-Methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (8.8 mg, 24.69 μmol; 36.67% yield; RT ( AD-HII, Hexane-IPA-MeOH, 50-25-25, 12 mL/min) = 18.482 min).

化合物46： RT(AD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=22.757min。 Compound 46: RT (AD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 22.757 min.

1 H NMR(500MHz,CDCl3 )δ 1.86(m,3H),2.12(m,3H),3.10(m,1H),3.86(m,3H),4.61(m,1H),6.11(m,2H),6.40(m,2H),7.44(m,1H),8.68(m,1H),8.92(m,1H),9.01(m,1H),9.83(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值356.2；實測值356.9； Rt=3.484min。 1 H NMR (500MHz, CDCl 3 )δ 1.86(m,3H), 2.12(m,3H), 3.10(m,1H), 3.86(m,3H), 4.61(m,1H), 6.11(m,2H) ), 6.40(m, 2H), 7.44(m, 1H), 8.68(m, 1H), 8.92(m, 1H), 9.01(m, 1H), 9.83(m, 1H). LCMS (ESI): [M+H] + m/z: calculated 356.2; found 356.9; Rt=3.484 min.

化合物59： RT(AD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=38.353min。 Compound 59: RT (AD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 38.353 min.

1 H NMR(500MHz,CDCl3 )δ 1.83(m,3H),2.12(m,3H),3.01(m,1H),3.86(m,3H),4.62(m,1H),6.12(m,2H),6.40(m,2H),7.45(m,1H),8.67(m,1H),8.91(m,1H),9.02(m,1H),9.75(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值356.2；實測值356.9；Rt=3.480min。 1 H NMR (500MHz, CDCl 3 )δ 1.83(m,3H), 2.12(m,3H), 3.01(m,1H), 3.86(m,3H), 4.62(m,1H), 6.12(m,2H) ), 6.40(m, 2H), 7.45(m, 1H), 8.67(m, 1H), 8.91(m, 1H), 9.02(m, 1H), 9.75(m, 1H). LCMS (ESI): [M+H] + m/z: calculated 356.2; found 356.9; Rt=3.480 min.

實例15. 5-(2-(5,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物45)之合成Example 15. Synthesis of 5-(2-(5,5-Dimethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 45)

Figure 110128222-A0202-12-0924-32
Figure 110128222-A0202-12-0924-32

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(150mg，515.14μmol)、5,5-二甲基-2-苯基哌啶(97.51mg，515.14μmol)及DIPEA(66.58mg，515.14μmol，89.73μL)混合於乙腈(1mL)中且在劇烈攪拌之情況下在100℃下加熱16h。冷卻至室溫之後，過濾混合物，在真空中蒸發且使其經歷HPLC(管柱：YMC Actus Triart C18 100x20mm，5um且MeOH+NH3 為流動相)，獲得5-[[2-(5,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(3.9mg，10.25μmol，1.99%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxyacetate 2,2,2-trifluoroethyl ester (150 mg, 515.14 μmol), 5,5-dimethylacetate Alkyl-2-phenylpiperidine (97.51 mg, 515.14 μmol) and DIPEA (66.58 mg, 515.14 μmol, 89.73 μL) were mixed in acetonitrile (1 mL) and heated at 100 °C for 16 h with vigorous stirring. After cooling to room temperature, the mixture was filtered, evaporated in vacuo and subjected to HPLC (column: YMC Actus Triart C18 100x20mm, 5um and MeOH+ NH3 as mobile phase) to give 5-[[2-(5,5 -Dimethyl-2-phenyl-1-piperidinyl)-2-oxoacetoxy]amino]pyridine-3-carboxamide (3.9 mg, 10.25 μmol, 1.99% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.86(m,3H),1.03(m,3H),1.37(m,1H),1.50(m,1H),2.16(m,1H),2.31(m,1H),2.87(m,1H),4.34(m,1H),6.11(m,3H),7.26(m,4H),7.35(m,2H),8.62(m,1H),8.79(m,1H),8.95(m,1H)。LCMS(ESI)：[M]+ m/z：計算值380.4；實測值381.2；Rt=1.192min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.86(m, 3H), 1.03(m, 3H), 1.37(m, 1H), 1.50(m, 1H), 2.16(m, 1H), 2.31( m, 1H), 2.87(m, 1H), 4.34(m, 1H), 6.11(m, 3H), 7.26(m, 4H), 7.35(m, 2H), 8.62(m, 1H), 8.79(m , 1H), 8.95 (m, 1H). LCMS (ESI): [M] + m/z: calculated 380.4; found 381.2; Rt=1.192 min.

實例16.外消旋 -2-((2R,5S )-2-(4-氟苯基)-5-甲基哌啶-1-基)-N -(5-甲基吡啶-3-Example 16. Racemic -2-(( 2R,5S )-2-(4-fluorophenyl)-5-methylpiperidin - 1-yl)-N-(5-methylpyridine-3- 基)-2-側氧基乙醯胺(化合物89)之合成Synthesis of yl)-2-oxoacetamide (Compound 89)

Figure 110128222-A0202-12-0925-33
Figure 110128222-A0202-12-0925-33

在-78℃、Ar氣氛下，向[(5-甲基吡啶-3-基)胺基](側氧基)乙酸2,2,2-三氟乙酯(406.99mg，1.55mmol)於THF(15mL)中之溶液中添加正丁基鋰(864.64mg，3.10mmol，1.25mL，23%純度)。15min分鐘之後，一次性添加2-(4-氟苯基)-5-甲基哌啶(0.3g，1.55mmol)。將所得混合物升溫至室溫，用NH4 Cl水溶液淬滅，用EtOAc萃取，經Na2 SO4 乾燥，蒸發且使其經歷HPLC(管柱SunFire 100*19mm 5um，ACN+FA(0.01%)作為溶析液混合物)。獲得2-[(2S,5R )-2-(4-氟苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(13.1mg，36.86μmol，2.37%產率)之兩種級分：7.4mg(藉由LCMS測得98.21%，單非鏡像異構物)及5.7mg(藉由LCMS測得100%，非鏡像異構物之混合物)。淺黃色膠狀物，其緩慢結晶。To [(5-methylpyridin-3-yl)amino](pendant oxy)acetic acid 2,2,2-trifluoroethyl ester (406.99 mg, 1.55 mmol) in THF at -78°C under Ar atmosphere To a solution in (15 mL) was added n-butyllithium (864.64 mg, 3.10 mmol, 1.25 mL, 23% purity). After 15 min, 2-(4-fluorophenyl)-5-methylpiperidine (0.3 g, 1.55 mmol) was added in one portion. The resulting mixture was warmed to room temperature, quenched with aqueous NH4Cl , extracted with EtOAc, dried over Na2SO4 , evaporated and subjected to HPLC (column SunFire 100*19mm 5um, ACN+FA (0.01%) as solution mixture). 2-[( 2S,5R )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2-oxygen Two fractions of acetylacetamide (13.1 mg, 36.86 μmol, 2.37% yield): 7.4 mg (98.21% by LCMS, single diastereomer) and 5.7 mg (100 by LCMS) %, mixture of diastereoisomers). Pale yellow gum which crystallizes slowly.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(d,3H),1.33(m,1H),1.66(m,1H),1.87(m,1H),2.11(m,2H),2.27(m,3H),2.99(m,1H),3.82(m,1H),5.34(m,1H),7.21(m,2H),7.38(m,2H),7.90(m,1H),8.16(m,1H),8.58(m,1H),11.02(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(d,3H), 1.33(m,1H), 1.66(m,1H), 1.87(m,1H), 2.11(m,2H), 2.27(m,3H),2.99(m,1H),3.82(m,1H),5.34(m,1H),7.21(m,2H),7.38(m,2H),7.90(m,1H),8.16 (m, 1H), 8.58 (m, 1H), 11.02 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值355.4；實測值356.2；Rt=3.033min。LCMS (ESI): [M] + m/z: calculated 355.4; found 356.2; Rt=3.033 min.

實例17.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-環己基哌啶-1-基)-2-側氧基乙醯胺(化合物30、化合物42、化合物34)之合成Example 17. N- (6-amino-5-methylpyridin-3-yl)-2-(2-cyclohexylpiperidin-1-yl)-2-oxyacetamide (compound 30, compound 42. Synthesis of compound 34)

Figure 110128222-A0202-12-0926-34
Figure 110128222-A0202-12-0926-34

步驟1：(5-(2-(2-環己基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-Cyclohexylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester synthesis

在-70℃、Ar下，向2-環己基哌啶(306.90mg，1.19mmol)於THF(15mL)中之溶液中逐滴添加於己烷中之2.5M正丁基鋰 溶液(458.37mg，7.16mmol，3mL)。將反應混合物在-70℃下攪拌20min，然後分批添加2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.45g，1.19mmol)。將所得溶液在-70℃下攪拌30min且在室溫下攪拌1h。將所得溶液冷卻至-50℃且用飽和NH4 Cl(水溶液)(50ml)淬滅。分離有機層且將水層用EtOAc(20mL×2)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且濃縮至乾燥，以得到N -[5-[[2-(2-環己基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.5g，粗品)。To a solution of 2-cyclohexylpiperidine (306.90 mg, 1.19 mmol) in THF (15 mL) was added dropwise a 2.5 M solution of n-butyllithium in hexanes (458.37 mg, 15 mL) at -70 °C under Ar 7.16 mmol, 3 mL). The reaction mixture was stirred at -70°C for 20 min, then 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen was added in portions 2,2,2-trifluoroethyl acetate (0.45 g, 1.19 mmol). The resulting solution was stirred at -70 °C for 30 min and at room temperature for 1 h. The resulting solution was cooled to -50°C and quenched with saturated NH4Cl (aq) (50ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to give N- [5-[[2-(2-cyclohexyl-1-piperidinyl)-2- pendantoxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.5 g, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.85(m,6H),1.26(m,6H),1.45(s,9H),1.69(m,6H),2.14(s,3H),2.22(m,1H),2.98(d,1H),8.02(m,1H),8.49(m,1H),9.06(m,1H),9.65(m,1H)。LCMS(ESI)：[M+1]+ m/z：計算值444.5；實測值445.2；Rt=1.572min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.85(m,6H), 1.26(m,6H), 1.45(s,9H), 1.69(m,6H), 2.14(s,3H), 2.22(m,1H), 2.98(d,1H), 8.02(m,1H), 8.49(m,1H), 9.06(m,1H), 9.65(m,1H). LCMS (ESI): [M+1] + m/z: calculated 444.5; found 445.2; Rt=1.572 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-環己基哌啶-1-基)-2-側氧基乙醯胺(化合物30 、化合物42 、化合物34 )之合成Step 2: N-(6-amino-5-methylpyridin-3-yl)-2-(2-cyclohexylpiperidin-1-yl)-2-oxyacetamide ( compound 30 , compound 42 , the synthesis of compound 34 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(732.27mg，2.81mmol， 697.40μL，14%純度)小心添加到N -[5-[[2-(2-環己基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.5g，281.17μmol)於DCM(20mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑，以得到0.5g粗材料。使其經歷RP-HPLC(管柱：YMC Actus Triart C18 100x20mm，5um；55%；0-5min以0.1% NH3 -甲醇為流動相)，以得到化合物30 N -(6-胺基-5-甲基-3-吡啶基)-2-[2-環己基-1-哌啶基]-2-側氧基乙醯胺(33mg)。藉由掌性HPLC(管柱：OJ-H(250*20，5mkm)，以己烷-IPA-MeOH 90-5-5%為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物34 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S )-2-環己基-1-哌啶基]-2-側氧基乙醯胺(12mg，34.84μmol，24.78%產率)及化合物42 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R )-2-環己基-1-哌啶基]-2-側氧基乙醯胺(12.1mg，35.13μmol，24.99%產率)。A 4.0 M solution of hydrogen chloride in dioxane (732.27 mg, 2.81 mmol, 697.40 μL, 14% purity) was added carefully to N- [5-[[2-(2-cyclohexyl-1-piperidine at room temperature A solution of tert-butyl pyridinyl)-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate (0.5 g, 281.17 [mu]mol) in DCM (20 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo to give 0.5 g of crude material. It was subjected to RP-HPLC (column: YMC Actus Triart C18 100x20mm, 5um; 55%; 0-5 min with 0.1% NH3 -methanol as mobile phase) to give compound 30 N- (6-amino-5- Methyl-3-pyridyl)-2-[2-cyclohexyl-1-piperidinyl]-2-oxyacetamide (33 mg). Separation of the enantiomers by chiral HPLC (column: OJ-H (250*20, 5mkm) with hexane-IPA-MeOH 90-5-5% as mobile phase) to give two separate mirror images Isomer compound 34 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S )-2-cyclohexyl-1-piperidinyl]-2-pendant oxyacetyl Amine (12 mg, 34.84 μmol, 24.78% yield) and compound 42 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R )-2-cyclohexyl-1-piperidine yl]-2-oxoacetamide (12.1 mg, 35.13 μmol, 24.99% yield).

化合物30： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.94(m,3H),1.20(m,4H),1.52(m,2H),1.64(m,5H),1.80(m,4H),2.08(s,3H),3.68(dd,1H),4.23(dd,1H),5.20(s,2H),7.53(s,1H),8.01(s,1H),10.13(s,1H)。LCMS(ESI)：[M+1]+ m/z：計算值344.2；實測值345.2；Rt=2.912min。 Compound 30: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.94 (m, 3H), 1.20 (m, 4H), 1.52 (m, 2H), 1.64 (m, 5H), 1.80 (m, 4H), 2.08(s, 3H), 3.68(dd, 1H), 4.23(dd, 1H), 5.20(s, 2H), 7.53(s, 1H), 8.01(s, 1H), 10.13(s, 1H) ). LCMS (ESI): [M+1] + m/z: calculated 344.2; found 345.2; Rt=2.912 min.

化合物42：保留時間：32.70min 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.94(m,3H),1.19(m,3H),1.48(m,2H),1.65(m,5H),1.78(m,4H),2.08(m,3H),3.05(m,1H),3.68(m,1H),4.22(m,1H),5.20(s,2H),7.53(m,1H),8.01(m,1H),10.13(s,1H)。LCMS(ESI)：[M+1]+ m/z：計算值344.2；實測值345.2；Rt=1.103min。 Compound 42: Retention time: 32.70 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.94 (m, 3H), 1.19 (m, 3H), 1.48 (m, 2H), 1.65 (m, 5H) ,1.78(m,4H),2.08(m,3H),3.05(m,1H),3.68(m,1H),4.22(m,1H),5.20(s,2H),7.53(m,1H), 8.01 (m, 1H), 10.13 (s, 1H). LCMS (ESI): [M+1] + m/z: calculated 344.2; found 345.2; Rt=1.103 min.

化合物34：保留時間：24.50min 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.92(m,3H),1.20(m,3H),1.48(m,2H),1.63(m,5H),1.78(m,4H),2.08(m,3H),3.05(m,1H),3.68(m,1H),4.23(m,1H),5.20(s,2H),7.52(m,1H),8.01(m,1H),10.13(s,1H)。LCMS(ESI)：[M+1]+ m/z：計算值344.2；實測值345.2；Rt=4.052min。 Compound 34: Retention time: 24.50 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.92 (m, 3H), 1.20 (m, 3H), 1.48 (m, 2H), 1.63 (m, 5H) ,1.78(m,4H),2.08(m,3H),3.05(m,1H),3.68(m,1H),4.23(m,1H),5.20(s,2H),7.52(m,1H), 8.01 (m, 1H), 10.13 (s, 1H). LCMS (ESI): [M+1] + m/z: calculated 344.2; found 345.2; Rt=4.052 min.

實例18. N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(3-吡啶基)-1-哌啶Example 18. N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-(3-pyridyl)-1-piperidine 基]乙醯胺(化合物74)及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(3-吡啶基)-1-哌啶基]乙醯胺(化合物69)之合成yl]acetamide (compound 74) and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2S)-2-(3-pyridyl) Synthesis of -1-Piperidinyl]acetamide (Compound 69)

Figure 110128222-A0202-12-0928-35
Figure 110128222-A0202-12-0928-35

步驟1：N-[3-甲基-5-[[2-側氧基-2-[2-(3-吡啶基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-oxy-2-[2-(3-pyridyl)-1-piperidinyl]acetyl]amino]-2-pyridine Synthesis of tert-butyl]carbamate

在-78℃、Ar下，向3-(2-哌啶基)吡啶(300.97mg，1.86mmol)於THF(29mL)中之溶液中逐滴添加丁基鋰(392.19mg，6.12mmol，2.45mL)。將反應混合物在-78℃下攪拌20min，然後分批添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.7g，1.86mmol)。將所得溶液在-78℃下攪拌30min且在室溫下攪拌1h。將所得溶液冷卻至-50℃且用飽和NH4 Cl(水溶液)(30ml)淬滅。分離有機層且將水層用EtOAc(20mL×2)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且濃縮至乾燥，以得到N-[3-甲基-5-[[2-側氧基-2-[2-(3-吡啶基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.51g，1.16mmol，62.55%產率)。To a solution of 3-(2-piperidinyl)pyridine (300.97 mg, 1.86 mmol) in THF (29 mL) at -78°C under Ar was added butyllithium (392.19 mg, 6.12 mmol, 2.45 mL) dropwise ). The reaction mixture was stirred at -78 °C for 20 min, then 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen was added portionwise 2,2,2-trifluoroethyl acetate (0.7 g, 1.86 mmol). The resulting solution was stirred at -78 °C for 30 min and at room temperature for 1 h. The resulting solution was cooled to -50°C and quenched with saturated NH4Cl (aq) (30ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to give N-[3-methyl-5-[[2-oxy-2-[2-(3-pyridine (0.51 g, 1.16 mmol, 62.55% yield).

LCMS(ESI)：[M+H]+ m/z：計算值439.2；實測值440.2；Rt=1.058min。LCMS (ESI): [M+H] + m/z: calculated 439.2; found 440.2; Rt=1.058 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(3-吡啶基)-1-哌啶基]乙醯胺(化合物38 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-oxo-2-[2-(3-pyridyl)-1-piperidinyl]acetamide ( Synthesis of compound 38 )

將於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)添加到N-[3-甲基-5-[[2-側氧基-2-[2-(3-吡啶基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.51g，1.16mmol)於DCM(5mL)中之溶液中。將反應混合物在25 ℃下攪拌1h，然後在真空中蒸發且藉由製備型HPLC(100%甲醇-水，流速30ml/min)純化0.3g所獲得之粗產物，以得到產物N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(3-吡啶基)-1-哌啶基]乙醯胺(0.0381g，101.37μmol，8.74%產率，HCl)。A 4.0M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL) was added to N-[3-methyl-5-[[2-oxy-2-[2-(3-pyridyl )-1-piperidinyl]acetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.51 g, 1.16 mmol) in DCM (5 mL). Put the reaction mixture at 25 It was stirred at °C for 1 h, then evaporated in vacuo and 0.3 g of the obtained crude product was purified by preparative HPLC (100% methanol-water, flow rate 30 ml/min) to give the product N-(6-amino-5- Methyl-3-pyridyl)-2-oxy-2-[2-(3-pyridyl)-1-piperidinyl]acetamide (0.0381 g, 101.37 μmol, 8.74% yield, HCl) .

1 H NMR(500MHz,DMSO-d6 )δ 1.53(m,2H),1.66(m,2H),1.74(m,1H),1.96(m,1H),2.08(m,3H),2.40(m,1H),4.10(m,1H),5.28(m,2H),5.57(m,1H),7.35(m,1H),7.55(m,1H),7.70(m,1H),8.03(m,1H),8.45(m,1H),8.54(m,1H),10.43(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.53(m, 2H), 1.66(m, 2H), 1.74(m, 1H), 1.96(m, 1H), 2.08(m, 3H), 2.40(m ,1H),4.10(m,1H),5.28(m,2H),5.57(m,1H),7.35(m,1H),7.55(m,1H),7.70(m,1H),8.03(m, 1H), 8.45 (m, 1H), 8.54 (m, 1H), 10.43 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值339.2；實測值340.2；Rt=0.622min。LCMS (ESI): [M+H] + m/z: calculated 339.2; found 340.2; Rt=0.622 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(3-吡啶基)-1-哌啶基]乙醯胺(化合物74 )及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(3-吡啶基)-1-哌啶基]乙醯胺(化合物69 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-(3-pyridyl)-1-piperidinyl] Acetamide ( compound 74 ) and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2S)-2-(3-pyridyl)-1 Synthesis of -Piperidinyl]acetamide ( Compound 69 )

藉由掌性HPLC(管柱：AD-H(250* 20，5mkm)Chiralpak管柱，以IPA-MeOH-DEA，50-50-0.2，0.5ml/min為流動相)，以得到兩種單獨的鏡像異構物化合物74 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(3-吡啶基)-1-哌啶基]乙醯胺(0.01467g，39.03μmol，36.67%產率，HCl；RT=80.477min)及化合物69 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(3-吡啶基)-1-哌啶基]乙醯胺(8.15mg，21.68μmol，20.37%產率，HCl；RT=51.702min)。By chiral HPLC (column: AD-H (250 * 20, 5mkm) Chiralpak column, with IPA-MeOH-DEA, 50-50-0.2, 0.5ml/min as mobile phase) to obtain two separate The enantiomer of compound 74 N-(6-amino-5-methyl-3-pyridyl)-2-oxo-2-[(2R)-2-(3-pyridyl)-1- Piperidinyl]acetamide (0.01467 g, 39.03 μmol, 36.67% yield, HCl; RT=80.477 min) and compound 69 N-(6-amino-5-methyl-3-pyridyl)-2- Pendant oxy-2-[(2S)-2-(3-pyridinyl)-1-piperidinyl]acetamide (8.15 mg, 21.68 μmol, 20.37% yield, HCl; RT=51.702 min).

化合物74 RT(AD-H，IPA-MeOH-DEA，50-50-0.2，0.5ml/min)=80.789min。 Compound 74 RT (AD-H, IPA-MeOH-DEA, 50-50-0.2, 0.5 ml/min) = 80.789 min.

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.41(m,1H),1.62(m,2H),1.88(m,1H),2.03(m,3H),2.41(m,2H),2.97(m,1H),4.00(m,1H),5.66(m,3H),7.43(m,1H),7.50(m,1H),7.75(m,1H),8.02(m,1H),8.51(m,1H),8.57(m,1H),10.59(s,1H)LCMS(ESI)：[M+H]+ m/z：計算值339.2；實測值340.2；Rt=2.562min。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.41 (m, 1H), 1.62 (m, 2H), 1.88 (m, 1H), 2.03 (m, 3H), 2.41 (m, 2H) ,2.97(m,1H),4.00(m,1H),5.66(m,3H),7.43(m,1H),7.50(m,1H),7.75(m,1H),8.02(m,1H), 8.51(m, 1H), 8.57(m, 1H), 10.59(s, 1H) LCMS(ESI): [M+H] + m/z: calculated 339.2; found 340.2; Rt=2.562min.

化合物74 RT(AD-H，IPA-MeOH-DEA，50-50-0.2，0.5ml/min)=51.702min。 Compound 74 RT (AD-H, IPA-MeOH-DEA, 50-50-0.2, 0.5 ml/min) = 51.702 min.

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.41(m,1H),1.60(m,3H),1.89(m,1H), 2.03(m,3H),2.94(m,1H),4.00(m,1H),5.49(m,3H),7.44(m,1H),7.51(m,1H),7.75(m,1H),8.02(m,1H),8.51(m,1H),8.57(m,1H),10.59(s,1H) 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.41 (m, 1H), 1.60 (m, 3H), 1.89 (m, 1H), 2.03 (m, 3H), 2.94 (m, 1H) ,4.00(m,1H),5.49(m,3H),7.44(m,1H),7.51(m,1H),7.75(m,1H),8.02(m,1H),8.51(m,1H), 8.57(m,1H),10.59(s,1H)

LCMS(ESI)：[M+H]+ m/z：計算值339.2；實測值340.2；Rt=2.570min。LCMS (ESI): [M+H] + m/z: calculated 339.2; found 340.2; Rt=2.570 min.

實例19. 2-(2-(3-(二甲胺基)苯基)哌啶-1-基)-N -(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物15)之合成Example 19. 2-(2-(3-(Dimethylamino)phenyl)piperidin-1-yl)-N-(5-methylpyridin - 3-yl)-2-oxyacetamide Synthesis of (Compound 15)

Figure 110128222-A0202-12-0930-36
Figure 110128222-A0202-12-0930-36

步驟1：2-(2-(3-(二甲胺基)苯基)哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物15 )之合成Step 1: 2-(2-(3-(Dimethylamino)phenyl)piperidin-1-yl)-N-(5-methylpyridin-3-yl)-2-oxoacetamide Synthesis of ( Compound 15 )

在-78℃下，將正丁基鋰 (250.82mg，3.92mmol)(2.5M於己烷中)逐滴添加到N,N -二甲基-3-(2-哌啶基)苯胺(0.4g，1.96mmol)於THF(20mL)中之溶液中。將所得混合物攪拌5min，隨後添加2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(513.31mg，1.96mmol)。將所得混合物升溫至室溫且在該溫度下攪拌12h.向其中添加NH4 Cl(0.6g)水溶液。將所得混合物蒸發至乾。使殘餘物(1g)經歷HPLC(流動相，管柱)：16_ACN 36% 0.5-6.5min；水-乙腈；流速30ml/min；(裝載泵4ml/min乙腈)；目標質量366；管柱SunFire 100*19mm 5um)，以獲得2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.054g，147.36μmol，7.53%產率)。At -78°C, n-butyllithium (250.82 mg, 3.92 mmol) (2.5 M in hexanes) was added dropwise to N,N -dimethyl-3-(2-piperidinyl)aniline (0.4 g, 1.96 mmol) in THF (20 mL). The resulting mixture was stirred for 5 min, followed by the addition of 2-[(5-methyl-3-pyridyl)amino]-2-oxoacetate 2,2,2-trifluoroethyl ester (513.31 mg, 1.96 mmol). The resulting mixture was warmed to room temperature and stirred at this temperature for 12 h. To it was added aqueous NH4Cl (0.6 g). The resulting mixture was evaporated to dryness. The residue (1 g) was subjected to HPLC (mobile phase, column): 16_ACN 36% 0.5-6.5 min; water-acetonitrile; flow rate 30 ml/min; (loading pump 4 ml/min acetonitrile); target mass 366; column SunFire 100 *19mm 5um) to obtain 2-[2-[3-(dimethylamino)phenyl]-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen Ethylacetamide (0.054 g, 147.36 μmol, 7.53% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.50(m,2H),1.60(m,2H),1.80(m,1H),2.29(m,3H),2.89(m,6H),3.08(m,1H),3.42(m,1H),3.97(m,1H),5.35(m,1H),6.62(m,3H),7.21(m,1H),7.94(m,1H),8.18(m,1H),8.59(m,1H),11.09(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.50(m, 2H), 1.60(m, 2H), 1.80(m, 1H), 2.29(m, 3H), 2.89(m, 6H), 3.08(m, 1H), 3.42(m, 1H), 3.97(m, 1H), 5.35(m, 1H), 6.62(m, 3H), 7.21(m, 1H), 7.94(m, 1H), 8.18 (m, 1H), 8.59 (m, 1H), 11.09 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.5；實測值367.2；Rt=2.518min。LCMS (ESI): [M] + m/z: calculated 366.5; found 367.2; Rt=2.518 min.

實例20.外消旋 -2-((2R,5S )-2-(3-甲氧基苯基)-5-甲基哌啶-1-基)-N -(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物28)之合成Example 20. Racemic -2-(( 2R,5S )-2-(3-methoxyphenyl)-5-methylpiperidin - 1-yl)-N-(5-methylpyridine-3 Synthesis of -yl)-2-oxoacetamide (Compound 28)

Figure 110128222-A0202-12-0931-37
Figure 110128222-A0202-12-0931-37

在-78℃下，將丁基鋰(187.21mg，2.92mmol)(2.5M於己烷中)逐滴添加到2-(3-甲氧基苯基)-5-甲基哌啶(0.3g，1.46mmol)於THF(20mL)中之溶液中。將所得混合物攪拌5min，隨後添加2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(383.13mg，1.46mmol)。將所得混合物升溫至室溫且在該溫度下攪拌12h。向其中添加NH4 Cl(0.6g)水溶液。將所得混合物蒸發至乾。藉由HPLC(管柱SunFire 100*19mm 5um，以水-MeCN為溶析液混合物)純化殘餘物(4g)，以獲得2-[(2S,5R )-2-(3-甲氧基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(130.90mg，356.25μmol，24.38%產率)。At -78°C, butyllithium (187.21 mg, 2.92 mmol) (2.5 M in hexanes) was added dropwise to 2-(3-methoxyphenyl)-5-methylpiperidine (0.3 g , 1.46 mmol) in THF (20 mL). The resulting mixture was stirred for 5 min, followed by the addition of 2-[(5-methyl-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (383.13 mg, 1.46 mmol). The resulting mixture was warmed to room temperature and stirred at this temperature for 12 h. To this was added aqueous NH4Cl (0.6 g). The resulting mixture was evaporated to dryness. The residue (4g) was purified by HPLC (column SunFire 100*19mm 5um with water-MeCN as eluent mixture) to obtain 2-[( 2S,5R )-2-(3-methoxyphenyl )-5-methyl - 1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (130.90 mg, 356.25 μmol, 24.38% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.34(m,1H),1.67(m,1H),1.91(m,1H),2.15(m,3H),2.29(m,3H),3.45(m,1H),3.75(m,3H),5.35(m,1H),6.88(m,3H),7.33(m,1H),7.92(m,1H),8.17(m,1H),8.59(m,1H),11.06(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.34(m, 1H), 1.67(m, 1H), 1.91(m, 1H), 2.15(m, 3H), 2.29(m,3H),3.45(m,1H),3.75(m,3H),5.35(m,1H),6.88(m,3H),7.33(m,1H),7.92(m,1H),8.17 (m, 1H), 8.59 (m, 1H), 11.06 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值367.4；實測值368.2；Rt=1.193min。LCMS (ESI): [M] + m/z: calculated 367.4; found 368.2; Rt=1.193 min.

方案B. 式2化合物之合成Scheme B. Synthesis of compounds of formula 2

式2、2a、2b、2c及2d化合物為式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 2, 2a, 2b, 2c and 2d are compounds of formula (I), (Ia), (Ib), (Ic) and (Id), wherein R 1 , R 2 , R 3 , R 4 , R 6 , R7 and R8 are as described herein.

一般程序2General Procedure 2

Figure 110128222-A0202-12-0932-38
Figure 110128222-A0202-12-0932-38

注意，分離步驟為視情況任選的，且在某些情況下用於分離順式/反式非鏡像異構物，且在某些情況下分離不同的鏡像異構物，如詳細程序中所述。在某些情況下，起始哌啶呈限定順式或反式組態，在彼等情況下，掌性分離步驟僅得到所描繪之四種鏡像異構物中之兩者。Note that the separation step is optional and in some cases is used to separate cis/trans non-spiroisomers, and in some cases different enantiomers, as described in the detailed procedure described. In some cases, the starting piperidine is in a defined cis or trans configuration, in which case the chiral separation step yields only two of the four enantiomers depicted.

掌性分離方法為熟習此項技術者已知的。例如，在一些實施例中，可透過使用掌性HPLC純化(管柱：AD-H III(250*20mm，5μm)完成掌性分離。示範性溶析液包括但不限於己烷、IPA、MeOH、MeCN及H2 O及其混合物。Methods of chiral separation are known to those skilled in the art. For example, in some embodiments, chiral separation can be accomplished by using chiral HPLC purification (column: AD-H III (250*20 mm, 5 μm). Exemplary eluents include, but are not limited to, hexane, IPA, MeOH , MeCN and H 2 O and mixtures thereof.

在一些實施例中，本揭露之化合物可透過包含醯胺鍵偶合之方法來製備。在一些實施例中，醯胺鍵偶合採用哌啶及羧酸。已知促進醯胺鍵偶合之條件之實例包括但不限於：添加偶合劑(諸如CDI、HATU、HOBT、HBTU或PyBOP)、鹼(諸如氫化物鹼(例如 NaH或KH)、胺鹼(諸如DBU、NEt3 及NEt( i Pr)2 )或碳酸鹽鹼(例如， Na2 CO3 、K2 CO3 或Cs2 CO3 ))；以及在一個實施例中在0℃至室溫下或在另一個實施例中在70℃或更高溫度下(例如在70℃至110℃範圍內或在70℃至80℃範圍內的溫度下、或在80℃下)攪拌反應物。可在諸如但不限於DMF及MTBE之溶劑中進行反應。在一些實施例中，反應包含HATU、Et3 N及DMF。在一些實施例中，反應包含採用HATU、Et3 N及MeCN。在一些實施例中，反應包含TATU、Et3 N及DMF。在一些實施例中，反應包含HATU、DIPEA及DMSO。在一些實施例中，反應包含HATU、DIPEA及DMF。在一些實施例中，反應包含HATU、TEA及DMSO。In some embodiments, the compounds of the present disclosure can be prepared by methods involving coupling of amide linkages. In some embodiments, the amide linkage coupling employs a piperidine and a carboxylic acid. Examples of conditions known to promote the coupling of amide linkages include, but are not limited to, the addition of a coupling agent (such as CDI, HATU, HOBT, HBTU, or PyBOP), a base (such as a hydride base ( such as NaH or KH), an amine base (such as DBU) , NEt 3 and NEt( iPr ) 2 ) or a carbonate base ( eg, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 )); and in one embodiment at 0°C to room temperature or at In another embodiment the reactants are stirred at a temperature of 70°C or higher (eg, at a temperature in the range of 70°C to 110°C or at a temperature in the range of 70°C to 80°C, or at 80°C). The reaction can be carried out in solvents such as, but not limited to, DMF and MTBE. In some embodiments, the reaction comprises HATU, Et3N , and DMF. In some embodiments, the reaction comprises employing HATU, Et3N , and MeCN. In some embodiments, the reaction comprises TATU, Et3N , and DMF. In some embodiments, the reaction comprises HATU, DIPEA, and DMSO. In some embodiments, the reaction comprises HATU, DIPEA, and DMF. In some embodiments, the reaction comprises HATU, TEA and DMSO.

實例21. 5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物300)之合成Example 21. 5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Synthesis of pyridine-3-carboxamide (compound 300)

Figure 110128222-A0202-12-0933-39
Figure 110128222-A0202-12-0933-39

在0℃下，向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(鹽酸鹽，5.34g，21.73mmol)及(2R ,5S )-2-(4-氟苯基)-5-甲基哌啶(4.2g，21.73mmol)(中間物4A)於DMF(70mL)中之經攪拌之溶液中分別添加HATU(8.26g，21.73mmol)及Et3 N(8.80g，86.93mmol，12.12mL)。將所得反應混合物在周圍溫度下攪拌9小時。9小時之後，將反應混合物在減壓下濃縮且倒入到水(300mL)中。將水層用EtOAc(2 x 150mL)萃取。將經合併之有機相用水(2 x 40mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得粗產物(8g)。藉由管柱層析(SiO2 ，溶析液：10-100%於MTBE中之CH3 OH)純化粗產物，以獲得(5.2g，13.53mmol，62.25%產率)產物。使產物經歷掌性HPLC純化(管柱：AD-H III(250*20mm,5um)，溶析液：己烷-IPA-MeOH，70-15-15，流速：12mL/min)。將2種不同的級分混合，用MeOH稀釋，在旋轉蒸發儀中在30℃下蒸發然後在油泵(0.5mm Hg)下在35℃下乾燥8小時，以獲得呈白色固體之純產物5-[[2-[(2R ,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物300 _3，3.6g，9.37mmol，52.94%產率)。1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.65(m,1H),1.88(m,1H),2.02(m,1H),2.19(m,1H),2.99(m,1H),3.73(m,1H),5.35(m,1H),7.22(m,2H),7.36(m,2H),7.59(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.86(m,1H),11.22(m,1H)。To 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (hydrochloride, 5.34 g, 21.73 mmol) and ( 2R ,5S) at 0 ° C )-2-(4-fluorophenyl)-5-methylpiperidine (4.2 g, 21.73 mmol) (Intermediate 4A) to a stirred solution of DMF (70 mL) was added HATU (8.26 g, 21.73 mmol) separately mmol) and Et3N (8.80 g, 86.93 mmol, 12.12 mL). The resulting reaction mixture was stirred at ambient temperature for 9 hours. After 9 hours, the reaction mixture was concentrated under reduced pressure and poured into water (300 mL). The aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with water (2 x 40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain crude product (8 g). The crude product was purified by column chromatography ( SiO2 , eluent: 10-100% CH3OH in MTBE ) to obtain (5.2 g, 13.53 mmol, 62.25% yield) product. The product was subjected to chiral HPLC purification (column: AD-H III (250*20mm, 5um), eluent: hexane-IPA-MeOH, 70-15-15, flow rate: 12 mL/min). The 2 different fractions were combined, diluted with MeOH, evaporated in a rotary evaporator at 30°C and then dried under oil pump (0.5 mm Hg) at 35°C for 8 hours to obtain pure product 5- as a white solid [[2-[( 2R , 5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -formamide ( compound 300_3, 3.6 g, 9.37 mmol, 52.94% yield). 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.65 (m, 1H), 1.88 (m, 1H), 2.02 (m, 1H) ,2.19(m,1H),2.99(m,1H),3.73(m,1H),5.35(m,1H),7.22(m,2H),7.36(m,2H),7.59(m,1H), 8.14 (m, 1H), 8.46 (m, 1H), 8.75 (m, 1H), 8.86 (m, 1H), 11.22 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值384.2；實測值385.0；Rt=3.021min。LCMS (ESI): [M+H] + m/z: calculated 384.2; found 385.0; Rt=3.021 min.

掌性HPLC：Rt=35.17min(管柱：AD-H；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=35.17 min (column: AD-H; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

α21 D=+98.75(EtOH,0.25M)α 21 D=+98.75(EtOH, 0.25M)

mp=100-122℃mp=100-122℃

實例22. 5-(2-(5-甲基-2-(1-甲基-1H -吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物72、化合物81)之合成Example 22. 5-(2-(5-Methyl-2-(1-methyl- 1H -pyrazol-5-yl)piperidin-1-yl)-2-oxoacetamido) nicotine Synthesis of Alkaline Amide (Compound 72, Compound 81)

Figure 110128222-A0202-12-0934-40
Figure 110128222-A0202-12-0934-40

在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸酯；三乙基銨(0.25g，805.55μmol)、HATU(336.92mg，886.10μmol)及三乙胺(244.54mg，2.42mmol，336.83μL)混合於無水ACN(20mL)且將所得混合物攪拌6h。向其中添加5-甲基-2-(1-甲基-1H -吡唑-5-基)哌啶(203.15mg，805.55μmol，2HCl)且將所得混合物在21℃下攪拌隔夜。將所得混合物蒸發至乾且使其經歷HPLC(2-7min 15-30% acn，30ml/min；管柱：SunFire C18 100*19 5微米)。獲得3種級分：7.5mg(藉由LCMS測得95.65%)5-[[2-[(2R,5S )-5-甲基-2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(7.5mg，20.25μmol，2.51%產率)及23mg(藉由LCMS測得100%)+99mg(藉由LCMS測得95.17%)5-[[2-[(2S,5S )-5-甲基-2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(122.9mg，331.80μmol，41.19%產率)。At 21 °C, 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-side oxyacetate; triethylammonium (0.25 g, 805.55 μmol), HATU (336.92 mg, 886.10 μmol) and triethylamine (244.54 mg, 2.42 mmol, 336.83 μL) were mixed in dry ACN (20 mL) and the resulting mixture was stirred for 6 h. To this was added 5-methyl-2-(1-methyl- 1H -pyrazol-5-yl)piperidine (203.15 mg, 805.55 μmol, 2HCl) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was evaporated to dryness and subjected to HPLC (2-7 min 15-30% acn, 30 ml/min; column: SunFire C18 100*19 5 microns). 3 fractions were obtained: 7.5 mg (95.65% by LCMS) 5-[[2-[( 2R,5S )-5-methyl-2-(2-methylpyrazol-3-yl)- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (7.5 mg, 20.25 μmol, 2.51% yield) and 23 mg (100% by LCMS)+ 99 mg (95.17% by LCMS) 5-[[2-[( 2S,5S )-5-methyl-2-(2-methylpyrazol-3-yl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (122.9 mg, 331.80 μmol, 41.19% yield).

化合物72： 1 H NMR(500MHz,CDCl3 )δ(ppm)0.98(m,3H),1.83(m,5H),2.08(m,1H),2.23(m,1H),2.66(m,1H),3.86(m,3H),4.57(m,1H),6.11(m,1H),6.37(m,1H),7.46(m,1H),8.66(m,1H),8.93(m,2H),9.68(m,1H)。 Compound 72: 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 0.98 (m, 3H), 1.83 (m, 5H), 2.08 (m, 1H), 2.23 (m, 1H), 2.66 (m, 1H) ,3.86(m,3H),4.57(m,1H),6.11(m,1H),6.37(m,1H),7.46(m,1H),8.66(m,1H),8.93(m,2H), 9.68 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值370.4；實測值371.2；Rt=2.432min。LCMS (ESI): [M+1] m/z: calculated 370.4; found 371.2; Rt=2.432 min.

化合物81： 1 H NMR(500MHz,CDCl3 )δ(ppm)1.08(m,3H),1.52(m,2H),2.15(m,5H),3.40(m,1H),3.86(m,3H),4.60(m,1H),6.07(m,1H),6.39(m,1H),7.43(m,1H),8.67(m,1H),8.89(m,2H),9.60(m,1H)。 Compound 81: 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 1.08 (m, 3H), 1.52 (m, 2H), 2.15 (m, 5H), 3.40 (m, 1H), 3.86 (m, 3H) , 4.60(m, 1H), 6.07(m, 1H), 6.39(m, 1H), 7.43(m, 1H), 8.67(m, 1H), 8.89(m, 2H), 9.60(m, 1H).

LCMS(ESI)：[M+1]m/z：計算值370.4；實測值371.2；Rt=2.432min。LCMS (ESI): [M+1] m/z: calculated 370.4; found 371.2; Rt=2.432 min.

實例23. 5-[[2-側氧基-2-[2-(2-噻吩基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物120)之合成Example 23. Of 5-[[2-oxy-2-[2-(2-thienyl)-1-piperidinyl]acetoxy]amino]pyridine-3-carbamide (compound 120) synthesis

Figure 110128222-A0202-12-0935-41
Figure 110128222-A0202-12-0935-41

在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(991.96mg，4.74mmol，Et3 N)、TATU(1.68g，5.22mmol)及三乙胺(959.81mg，9.49mmol，1.32mL)混合於無水DMF(50mL)中且將所得混合物攪拌16h。向其中添加2-(2-噻吩基)哌啶(1.06g，5.22mmol，HCl)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取三次，將經合併之有機物用水、鹽水洗滌，乾燥且蒸發。藉由CC(SiO2 ，以Hex-EtOAc為流動相)純化殘餘物，以得到5-[[2-側氧基-2-[2-(2-噻吩基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(0.26g，725.42μmol，15.30%產率)之兩種級分：0.26g(藉由LCMS測得96.9%)及0.6g(藉由LCMS測得84.77%)。At 21 °C, 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (991.96 mg, 4.74 mmol, Et3N ), TATU (1.68 g, 5.22 mmol) and triethylamine (959.81 mg, 9.49 mmol, 1.32 mL) were mixed in dry DMF (50 mL) and the resulting mixture was stirred for 16 h. To this was added 2-(2-thienyl)piperidine (1.06 g, 5.22 mmol, HCl) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted three times with EtOAc, the combined organics were washed with water, brine, dried and evaporated. The residue was purified by CC ( SiO2 with Hex-EtOAc as mobile phase) to give 5-[[2-oxy-2-[2-(2-thienyl)-1-piperidinyl]ethyl Two fractions of acyl]amino]pyridine-3-carboxamide (0.26 g, 725.42 μmol, 15.30% yield): 0.26 g (96.9% by LCMS) and 0.6 g (by LCMS) 84.77%).

1 H NMR(500MHz,DMSO-d6 +CCl4 )δ 1.51(m,1H),1.67(m,3H),1.95(m,1H),2.26(m,1H),2.94(m,1H),4.01(m,1H),5.66(m,1H),7.05(m,2H),7.51(m,1H),7.61(m,1H),8.17(m,1H),8.52(m,1H),8.79(m,1H),8.90(m,1H),11.26(m,1H)。 1 H NMR (500MHz, DMSO-d 6 +CCl 4 )δ 1.51(m, 1H), 1.67(m, 3H), 1.95(m, 1H), 2.26(m, 1H), 2.94(m, 1H), 4.01(m, 1H), 5.66(m, 1H), 7.05(m, 2H), 7.51(m, 1H), 7.61(m, 1H), 8.17(m, 1H), 8.52(m, 1H), 8.79 (m, 1H), 8.90 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.1；實測值359.2；Rt=1.029min。LCMS (ESI): [M+H] + m/z: calculated 358.1; found 359.2; Rt=1.029 min.

實例24. 5-(2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺Example 24. 5-(2-(5-Methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (化合物99、化合物198、化合物201)之合成(Compound 99, Compound 198, Compound 201) Synthesis

Figure 110128222-A0202-12-0936-42
Figure 110128222-A0202-12-0936-42

步驟1：5-(2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: Synthesis of 5-(2-(5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide

在21℃下，將5-甲基-2-(2-噻吩基)哌啶(0.3g，1.65mmol)、2-(7-氮雜苯并三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸鹽(532.94mg，1.65mmol)及三乙胺(334.89mg，3.31mmol，461.28μL)混合於無水MeCN(25mL)中且將所得混合物攪拌6h。向其中添加[(5-胺甲醯基吡啶-3-基)胺基](側氧基)乙酸鋰(355.92mg，1.65mmol)且將所得混合物在21℃下攪拌隔夜。將反應混合物蒸發且使其經歷HPLC(20-45% MeCN，30ml/min；SUNFIRE C18，100*19,5μM)。獲得呈淺黃色固體之5-[[2-[(2R,5S )-5-甲基-2-(2-噻吩基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(10.5mg，28.19μmol，1.70%產率)。At 21°C, 5-methyl-2-(2-thienyl)piperidine (0.3 g, 1.65 mmol), 2-(7-azabenzotriazol-1-yl)-1,1, 3,3-Tetramethylurea tetrafluoroborate (532.94 mg, 1.65 mmol) and triethylamine (334.89 mg, 3.31 mmol, 461.28 μL) were mixed in dry MeCN (25 mL) and the resulting mixture was stirred for 6 h. To this was added lithium [(5-aminocarboxypyridin-3-yl)amino](pentoxy)acetate (355.92 mg, 1.65 mmol) and the resulting mixture was stirred at 21 °C overnight. The reaction mixture was evaporated and subjected to HPLC (20-45% MeCN, 30 ml/min; SUNFIRE C18, 100*19, 5 μM). 5-[[2-[( 2R,5S )-5-methyl-2-(2-thienyl)-1-piperidinyl]-2-oxyethanoyl]amine was obtained as a pale yellow solid yl]pyridine-3-carboxamide (10.5 mg, 28.19 μmol, 1.70% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.09(m,3H),1.46(m,1H),2.06(m,4H),2.27(m,1H),3.35(m,1H),4.41(m,1H),6.24(m,3H),6.96(m,2H),8.62(s,1H),8.79(s,1H),8.98(m,1H),9.90(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.09(m, 3H), 1.46(m, 1H), 2.06(m, 4H), 2.27(m, 1H), 3.35(m, 1H), 4.41( m, 1H), 6.24 (m, 3H), 6.96 (m, 2H), 8.62 (s, 1H), 8.79 (s, 1H), 8.98 (m, 1H), 9.90 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值372.4；實測值373.2；Rt=1.213min。LCMS (ESI): [M] + m/z: calculated 372.4; found 373.2; Rt=1.213 min.

步驟2：掌性分離(化合物198 及化合物201 )Step 2: Chiral separation ( compound 198 and compound 201 )

在體系Hex-IPA-MeOH，60-20-20，0.6mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：2mkl。自46mg外消旋物獲得23mg及23mg個 別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 60-20-20, 0.6 mL/min. Injection times: 1, injection volume: 2mkl. 23 mg and 23 mg were obtained from 46 mg of racemate Do not mirror isomers.

rel-5-(2-((2R,5S)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物198)：rel-5-(2-((2R,5S)-5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 198):

保留時間：31.34minRetention time: 31.34min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00(m,3H),1.41(m,1H),1.89(m,2H),2.03(m,1H),2.13(m,1H),3.34(m,1H),3.75(m,1H),5.63(m,1H),7.02(m,2H),7.47(m,1H),7.59(m,1H),8.14(m,1H),8.49(m,1H),8.76(m,1H),8.88(s,1H),11.21(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00(m, 3H), 1.41(m, 1H), 1.89(m, 2H), 2.03(m, 1H), 2.13(m, 1H), 3.34(m, 1H), 3.75(m, 1H), 5.63(m, 1H), 7.02(m, 2H), 7.47(m, 1H), 7.59(m, 1H), 8.14(m, 1H), 8.49 (m, 1H), 8.76 (m, 1H), 8.88 (s, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值372.4；實測值373.2；Rt=4.479min。LCMS (ESI): [M] + m/z: calculated 372.4; found 373.2; Rt=4.479 min.

rel-5-(2-((2S,5R)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物201)：rel-5-(2-((2S,5R)-5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 201):

保留時間：21.28minRetention time: 21.28min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00(m,3H),1.41(m,1H),1.88(m,2H),2.03(m,1H),2.14(m,1H),3.34(m,1H),3.74(m,1H),5.63(m,1H),7.02(m,2H),7.47(m,1H),7.59(m,1H),8.14(m,1H),8.49(m,1H),8.76(m,1H),8.88(s,1H),11.21(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00(m, 3H), 1.41(m, 1H), 1.88(m, 2H), 2.03(m, 1H), 2.14(m, 1H), 3.34(m, 1H), 3.74(m, 1H), 5.63(m, 1H), 7.02(m, 2H), 7.47(m, 1H), 7.59(m, 1H), 8.14(m, 1H), 8.49 (m, 1H), 8.76 (m, 1H), 8.88 (s, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值372.4；實測值373.2；Rt=4.478min。LCMS (ESI): [M] + m/z: calculated 372.4; found 373.2; Rt=4.478 min.

實例25. 2-甲氧基-5-(2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物310、化合物303)之合成Example 25. 2-Methoxy-5-(2-(5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of Amines (Compound 310, Compound 303)

Figure 110128222-A0202-12-0937-43
Figure 110128222-A0202-12-0937-43

步驟1：2-甲氧基-5-(2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 2-Methoxy-5-(2-(5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of Amines

在21℃下，將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸 (0.5g，1.47mmol，Et3 N)、TATU(567.73mg，1.76mmol)及三乙胺(148.64mg，1.47mmol，204.74μL)混合於無水DMF(25mL)中且將所得混合物攪拌1h。向其中添加5-甲基-2-(2-噻吩基)哌啶(266.32mg，1.47mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(40-40-80% 0-1-6min 0.1%NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)；管柱：XBridge C18 100x20mm，5um)。獲得呈白色固體之2-甲氧基-5-[[2-[5-甲基-2-(2-噻吩基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(258.7mg，642.79μmol，43.76%產率)。At 21 °C, 2-[(5-aminocarbamoyl-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (0.5 g, 1.47 mmol, Et 3 N), TATU (567.73 mg, 1.76 mmol) and triethylamine (148.64 mg, 1.47 mmol, 204.74 μL) were mixed in dry DMF (25 mL) and the resulting mixture was stirred for 1 h. To this was added 5-methyl-2-(2-thienyl)piperidine (266.32 mg, 1.47 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (40-40-80% 0-1-6min 0.1% NH3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol); column: XBridge C18 100x20mm, 5um). 2-Methoxy-5-[[2-[5-methyl-2-(2-thienyl)-1-piperidinyl]-2-oxyethanoyl]amino was obtained as a white solid ]pyridine-3-carboxamide (258.7 mg, 642.79 μmol, 43.76% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.07(m,1H),1.28(d,3H),1.64(m,1H),2.19(m,2H),2.49(m,1H),3.64(m,1H),4.28(s,3H),4.43(m,1H),6.40(m,1H),7.15(m,2H),7.42(m,2H),7.93(m,1H),8.94(m,1H),9.09(m,1H),10.07(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.07(m,1H), 1.28(d,3H), 1.64(m,1H), 2.19(m,2H), 2.49(m,1H), 3.64( m, 1H), 4.28(s, 3H), 4.43(m, 1H), 6.40(m, 1H), 7.15(m, 2H), 7.42(m, 2H), 7.93(m, 1H), 8.94(m , 1H), 9.09 (m, 1H), 10.07 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值402.4；實測值403.2；Rt=3.394min。LCMS (ESI): [M] + m/z: calculated 402.4; found 403.2; Rt=3.394 min.

步驟2：掌性分離(化合物310 及化合物303 )Step 2: Chiral separation ( compound 310 and compound 303 )

在體系Hex-IPA-MeOH，80-10-10，25mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：5mkl。自250mg外消旋物獲得107.68mg及111.65mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 80-10-10, 25 mL/min. Injection times: 1, injection volume: 5mkl. 107.68 mg and 111.65 mg of individual enantiomers were obtained from 250 mg of racemate.

rel-2-甲氧基-5-(2-((2R,5S)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物310)：rel-2-methoxy-5-(2-((2R,5S)-5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamide base) nicotinamide (compound 310):

保留時間：23.85minRetention time: 23.85min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.99-1.08(m,3H),1.29-1.48(m,1H),1.82-2.00(m,2H),2.01-2.22(m,2H),2.87-3.27(m,1H),3.50-4.07(m,4H),5.42-5.89(m,1H),6.99-7.08(m,2H),7.43-7.54(m,1H),7.70-7.79(m,2H),8.44-8.52(m,1H),8.53-8.61(m,1H),11.00-11.07(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.99-1.08(m,3H), 1.29-1.48(m,1H), 1.82-2.00(m,2H), 2.01-2.22(m,2H) ,2.87-3.27(m,1H),3.50-4.07(m,4H),5.42-5.89(m,1H),6.99-7.08(m,2H),7.43-7.54(m,1H),7.70-7.79( m, 2H), 8.44-8.52 (m, 1H), 8.53-8.61 (m, 1H), 11.00-11.07 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值402.4；實測值403.2；Rt=3.297min。LCMS (ESI): [M] + m/z: calculated 402.4; found 403.2; Rt=3.297 min.

rel-2-甲氧基-5-(2-((2S,5R)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物303)：rel-2-methoxy-5-(2-((2S,5R)-5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamide base) nicotinamide (compound 303):

保留時間：29.57minRetention time: 29.57min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96-1.11(m,3H),1.26-1.46(m,1H),1.66-2.00(m,2H),2.00-2.34(m,2H),2.87-3.28(m,1H),3.48-4.06(m,4H),5.44-5.89(m,1H),6.95-7.11(m,2H),7.42-7.55(m,1H),7.70-7.81(m,2H),8.44-8.51(m,1H),8.53-8.64(m,1H),11.03(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96-1.11(m,3H), 1.26-1.46(m,1H), 1.66-2.00(m,2H), 2.00-2.34(m,2H) ,2.87-3.28(m,1H),3.48-4.06(m,4H),5.44-5.89(m,1H),6.95-7.11(m,2H),7.42-7.55(m,1H),7.70-7.81( m, 2H), 8.44-8.51 (m, 1H), 8.53-8.64 (m, 1H), 11.03 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值402.4；實測值403.2；Rt=3.295min。LCMS (ESI): [M] + m/z: calculated 402.4; found 403.2; Rt=3.295 min.

實例26. 2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N -(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物7、化合物78、化合物73)之合成Example 26. 2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1 - yl)-N-(5-methylpyridin-3-yl)-2 - Synthesis of Pendant Oxyacetamide (Compound 7, Compound 78, Compound 73)

Figure 110128222-A0202-12-0939-44
Figure 110128222-A0202-12-0939-44

步驟1 2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物7 )之合成Step 1 2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1-yl)-N-(5-methylpyridin-3-yl)-2- Synthesis of Pendant Oxyacetamide ( Compound 7 )

向1-[4-[3-(2-哌啶基)苯基]-1-哌啶基]乙酮(0.4g，1.40mmol)、2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(392.93mg，1.40mmol，Et3 N)及HATU(584.13 mg，1.54mmol)於DMF(3mL)中之懸浮液中添加三乙胺(423.96mg，4.19mmol，583.97μL)。將所得混合物在25℃下攪拌3h。藉由HPLC(LC 09 40-40-75% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量448，管柱：YMC Triart C18 100x20mm，5um)純化所得混合物，以獲得2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.395g，880.60μmol，63.05%產率)。To 1-[4-[3-(2-piperidinyl)phenyl]-1-piperidinyl]ethanone (0.4 g, 1.40 mmol), 2-[(5-methyl-3-pyridyl) Amino]-2-oxoacetic acid (392.93 mg, 1.40 mmol, Et3N ) and HATU (584.13 mg, 1.54 mmol) in DMF (3 mL) was added triethylamine (423.96 mg, 4.19 mmol) , 583.97 μL). The resulting mixture was stirred at 25 °C for 3 h. By HPLC (LC 09 40-40-75% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 448, column: YMC Triart C18 100x20mm, 5um) to purify the resulting mixture to obtain 2-[2-[3-(1-acetyl-4-piperidinyl)phenyl]-1 - piperidinyl]-N-(5-methyl-3- Pyridinyl)-2-oxoacetamide (0.395 g, 880.60 μmol, 63.05% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.63(m,4H),1.71(m,2H),1.91(m,4H),2.13(m,3H),2.34(m,3H),2.49(m,1H),2.61(m,1H),2.98(m,3H),4.29(m,1H),4.84(m,1H),6.14(m,1H),7.11(m,3H),7.32(m,1H),8.03(m,1H),8.23(m,1H),8.53(m,1H),9.46(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.63(m, 4H), 1.71(m, 2H), 1.91(m, 4H), 2.13(m, 3H), 2.34(m, 3H), 2.49( m, 1H), 2.61(m, 1H), 2.98(m, 3H), 4.29(m, 1H), 4.84(m, 1H), 6.14(m, 1H), 7.11(m, 3H), 7.32(m , 1H), 8.03 (m, 1H), 8.23 (m, 1H), 8.53 (m, 1H), 9.46 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值448.6；實測值449.2；Rt=3.090min。LCMS (ESI): [M] + m/z: calculated 448.6; found 449.2; Rt=3.090 min.

步驟2：掌性分離(化合物78 及化合物73 )Step 2: Chiral separation ( compound 78 and compound 73 )

在體系Hex-IPA-MeOH，60-20-20，0.6mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：40mkl。自38.82mg外消旋物獲得15.34mg及14.79mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 60-20-20, 0.6 mL/min. Injection times: 1, injection volume: 40mkl. 15.34 mg and 14.79 mg of the individual enantiomers were obtained from 38.82 mg of the racemate.

rel-(R)-2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺峰2(化合物78)：rel-(R)-2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1-yl)-N-(5-methylpyridin-3-yl )-2-oxyacetamide peak 2 (compound 78):

保留時間：38.02minRetention time: 38.02min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.41(m,2H),1.55(m,2H),1.62(m,2H),1.80(m,3H),2.01(m,3H),2.27(m,3H),2.66(m,3H),3.05(m,2H),3.78(m,2H),4.51(m,1H),5.47(m,1H),7.15(m,3H),7.33(m,1H),7.92(m,1H),8.16(m,1H),8.57(m,1H),11.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.41(m, 2H), 1.55(m, 2H), 1.62(m, 2H), 1.80(m, 3H), 2.01(m, 3H), 2.27(m, 3H), 2.66(m, 3H), 3.05(m, 2H), 3.78(m, 2H), 4.51(m, 1H), 5.47(m, 1H), 7.15(m, 3H), 7.33 (m, 1H), 7.92 (m, 1H), 8.16 (m, 1H), 8.57 (m, 1H), 11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值448.6；實測值449.2；Rt=3.909min。LCMS (ESI): [M] + m/z: calculated 448.6; found 449.2; Rt=3.909 min.

rel-(S)-2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧rel-(S)-2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1-yl)-N-(5-methylpyridin-3-yl )-2-side oxygen 基乙醯胺峰1(化合物73)：Acetamide Peak 1 (Compound 73):

保留時間：27.22minRetention time: 27.22min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.41(m,2H),1.57(m,2H),1.62(m,2H),1.75(m,3H),2.01(m,3H),2.27(m,3H),2.69(m,3H),3.05(m,2H),3.78(m,2H),4.51(m,1H),5.65(m,1H),7.15(m,3H),7.33(m,1H),7.95(m,1H),8.18(m,1H),8.62(m,1H),11.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.41(m, 2H), 1.57(m, 2H), 1.62(m, 2H), 1.75(m, 3H), 2.01(m, 3H), 2.27(m, 3H), 2.69(m, 3H), 3.05(m, 2H), 3.78(m, 2H), 4.51(m, 1H), 5.65(m, 1H), 7.15(m, 3H), 7.33 (m, 1H), 7.95 (m, 1H), 8.18 (m, 1H), 8.62 (m, 1H), 11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值448.6；實測值449.2；Rt=3.910min。LCMS (ESI): [M] + m/z: calculated 448.6; found 449.2; Rt=3.910 min.

實例27. 5-(2-(2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物346、化合物332)之合成Example 27. 5-(2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetyl Synthesis of Amino) Nicotinamide (Compound 346, Compound 332)

Figure 110128222-A0202-12-0941-45
Figure 110128222-A0202-12-0941-45

步驟1：2-(2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺之合成Step 1: 2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(5-methylpyridine-3 -Base)-2-Side Oxyacetamide Synthesis

向1-[4-[3-(5-甲基-2-哌啶基)苯基]-1-哌啶基]乙酮(0.3g，998.54μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(245.26mg，998.54μmol，HCl)及三乙胺(101.04mg，998.54μmol，139.18μL)於DMF(5mL)中之懸浮液中 添加HATU(379.68mg，998.54μmol)。將反應混合物在40℃下攪拌24h且使其經歷HPLC：20-20-65% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量491，管柱：XBridge C18 100x20mm，5um)，以獲得5-[[2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.150g，305.14μmol，30.56%產率)。To 1-[4-[3-(5-methyl-2-piperidinyl)phenyl]-1-piperidinyl]ethanone (0.3 g, 998.54 μmol), 2-[(5-aminocarbamide yl-3-pyridinyl)amino]-2-oxoacetic acid (245.26 mg, 998.54 μmol, HCl) and triethylamine (101.04 mg, 998.54 μmol, 139.18 μL) in suspension in DMF (5 mL) HATU (379.68 mg, 998.54 μmol) was added. The reaction mixture was stirred at 40 °C for 24 h and subjected to HPLC: 20-20-65% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 491 , column: XBridge C18 100x20mm, 5um) to obtain 5-[[2-[2-[3-(1-acetyl-4-piperidinyl)phenyl]-5-methyl-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.150 g, 305.14 μmol, 30.56% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.34(m,2H),1.75(m,6H),2.02(s,3H),2.24(m,1H),2.58(m,1H),2.77(m,1H),3.12(m,1H),3.27(m,1H),3.47(m,1H),3.90(m,1H),4.01(m,1H),4.52(m,1H),5.52(m,1H),7.21(m,2H),7.34(m,1H),7.61(m,1H),8.18(m,1H),8.49(m,1H),8.79(m,1H),8.92(m,1H),11.31(m,1H)。 1 H NMR (500MHz, DMSO- d 6 ) δ(ppm) 1.03(m, 3H), 1.34(m, 2H), 1.75(m, 6H), 2.02(s, 3H), 2.24(m, 1H), 2.58(m, 1H), 2.77(m, 1H), 3.12(m, 1H), 3.27(m, 1H), 3.47(m, 1H), 3.90(m, 1H), 4.01(m, 1H), 4.52 (m,1H),5.52(m,1H),7.21(m,2H),7.34(m,1H),7.61(m,1H),8.18(m,1H),8.49(m,1H),8.79( m, 1H), 8.92 (m, 1H), 11.31 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值491.6；實測值492.2；Rt=3.016min。LCMS (ESI): [M] + m/z: calculated 491.6; found 492.2; Rt=3.016 min.

步驟2：掌性分離(化合物332 及化合物346 )Step 2: Chiral separation ( compound 332 and compound 346 )

在體系Hex-IPA-MeOH，70-5-15，12mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：900mkl。自150mg外消旋物獲得57mg及69mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 70-5-15, 12 mL/min. Injection times: 1, injection volume: 900mkl. 57 mg and 69 mg of individual enantiomers were obtained from 150 mg of racemate.

rel-5-(2-((2R,5S)-2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺峰1rel-5-(2-((2R,5S)-2-(3-(1-acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-2- pendant oxyacetamido) nicotinamide peak 1

保留時間：18.32minRetention time: 18.32min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.32(m,1H),1.42(m,1H),1.67(m,4H),1.87(m,1H),1.99(m,3H),2.08(m,1H),2.22(m,1H),2.54(m,1H),2.82(m,2H),3.15(m,1H),3.78(m,2H),4.50(m,1H),5.35(m,1H),7.15(m,3H),7.31(m,1H),7.60(m,1H),8.15(m,1H),8.47(m,1H),8.75(m,1H),8.85(m,1H),11.23(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(m, 3H), 1.32(m, 1H), 1.42(m, 1H), 1.67(m, 4H), 1.87(m, 1H), 1.99(m, 3H), 2.08(m, 1H), 2.22(m, 1H), 2.54(m, 1H), 2.82(m, 2H), 3.15(m, 1H), 3.78(m, 2H), 4.50 (m,1H),5.35(m,1H),7.15(m,3H),7.31(m,1H),7.60(m,1H),8.15(m,1H),8.47(m,1H),8.75( m, 1H), 8.85 (m, 1H), 11.23 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值491.6；實測值492.2；Rt=2.867min。LCMS (ESI): [M] + m/z: calculated 491.6; found 492.2; Rt=2.867 min.

rel-5-(2-((2R,5S)-2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺峰2(化合物346)：rel-5-(2-((2R,5S)-2-(3-(1-acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-2- Pendant oxyacetamido)nicotinamide peak 2 (compound 346):

保留時間：31.56minRetention time: 31.56min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.32(m,1H),1.42(m,1H),1.66(m,4H),1.87(m,1H),1.99(m,3H),2.04(m,1H),2.22(m,1H),2.54(m,1H),2.77(m,2H),3.17(m,1H),3.78(m,2H),4.50(m,1H),5.35(m,1H),7.14(m,3H),7.31(m,1H),7.60(m,1H),8.15(m,1H),8.47(m,1H),8.75(m,1H),8.85(m,1H),11.23(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(m, 3H), 1.32(m, 1H), 1.42(m, 1H), 1.66(m, 4H), 1.87(m, 1H), 1.99(m, 3H), 2.04(m, 1H), 2.22(m, 1H), 2.54(m, 1H), 2.77(m, 2H), 3.17(m, 1H), 3.78(m, 2H), 4.50 (m,1H),5.35(m,1H),7.14(m,3H),7.31(m,1H),7.60(m,1H),8.15(m,1H),8.47(m,1H),8.75( m, 1H), 8.85 (m, 1H), 11.23 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值491.6；實測值492.2；Rt=2.865min。LCMS (ESI): [M] + m/z: calculated 491.6; found 492.2; Rt=2.865 min.

實例28. 外消旋-5-[[2-側氧基-2-[(1R,4R,5S)-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(化合物86)、5-[[2-側氧基-2-[(1R ,4R ,5S )-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-側氧基-2-[(1S ,4S ,5R )-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(化合物205及化合物194)之合成Example 28. Racemic-5-[[2-Pendox-2-[(1R,4R,5S)-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl]ethane Acyl]amino]pyridine-3-carboxamide (compound 86), 5-[[2-oxy-2-[(1 R ,4 R ,5 S )-4-phenyl-3-nitrogen Heterobicyclo[3.2.1]oct-3-yl]acetyl]amino]pyridine-3-carboxamide and 5-[[2-oxy-2-[(1 S ,4 S ,5 R )-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl]acetyl]amino]pyridine-3-carbamide (compound 205 and compound 194) synthesis

Figure 110128222-A0202-12-0943-46
Figure 110128222-A0202-12-0943-46

步驟1：外消旋-5-[[2-側氧基-2-[(1R,4R,5S)-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(化合物86)之合成Step 1: Racemic-5-[[2-Pendox-2-[(1R,4R,5S)-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl]ethane Synthesis of Acyl]amino]pyridine-3-carbamoylamine (Compound 86)

向外消旋 -(1R ,4R ,5S )-4-苯基-3-氮雜雙環[3.2.1]辛烷(200.00mg，1.07mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(Et3 N鹽，331.43mg，1.07mmol)及HATU(446.66mg，1.17mmol)於DMF(3mL)中之經攪拌懸浮液中添加三乙胺(540.31mg，5.34mmol，744.23μL)。將所得反應混合物在40℃下攪拌5 小時。5小時之後，藉由反相HPLC(流動相：水-MeOH+0.1% NH3 ,0-5min，15-65%，流速：30mL/min；裝載泵：4mL/min，MeOH+0.1% NH3 ；管柱：YMC-Actus Triart C18 100*20mm，5um)純化粗反應混合物，以得到呈白色固體之產物外消旋 -5-[[2-側氧基-2-[(1R ,4R ,5S )-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(150mg，396.38μmol，37.12%產率)。 Racemic- (1 R ,4 R ,5 S )-4-phenyl-3-azabicyclo[3.2.1]octane (200.00 mg, 1.07 mmol), 2-[(5-aminocarboxylate In a stirred suspension of HATU (446.66 mg, 1.17 mmol) in DMF ( 3 mL) Triethylamine (540.31 mg, 5.34 mmol, 744.23 μL) was added. The resulting reaction mixture was stirred at 40°C for 5 hours. After 5 hours, by reverse phase HPLC (mobile phase: water-MeOH+0.1% NH3 , 0-5 min, 15-65%, flow rate: 30 mL/min; loading pump: 4 mL/min, MeOH+0.1% NH3 ; Column: YMC-Actus Triart C18 100*20mm, 5um) The crude reaction mixture was purified to give the product racemic -5-[[2-oxy-2-[( 1R , 4R as a white solid ,5 S )-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl]acetoxy]amino]pyridine-3-carboxamide (150 mg, 396.38 μmol, 37.12% yield ).

LCMS(ESI)：[M+H]+ m/z：計算值378.2；實測值379.2；Rt=2.755min。LCMS (ESI): [M+H] + m/z: calculated 378.2; found 379.2; Rt=2.755 min.

步驟2：5-[[2-側氧基-2-[(1R,4R,5S)-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-側氧基-2-[(1S,4S,5R)-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(化合物205 及化合物194 )之掌性分離Step 2: 5-[[2-Pendox-2-[(1R,4R,5S)-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl]acetoxy]amine yl]pyridine-3-carboxamide and 5-[[2-oxy-2-[(1S,4S,5R)-4-phenyl-3-azabicyclo[3.2.1]octane-3- Chiral Separation of [Acetyl] Acetyl] Amino] Pyridin-3-Carboxyamide ( Compound 205 and Compound 194 )

使外消旋 -5-[[2-側氧基-2-[(1R ,4R ,5S )-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(100mg，264.25μmol)經歷掌性層析(管柱：YMC 250*20mm，5um，溶析液：己烷-IPA-MeOH，40-30-30；流速：12mL/min)，以獲得5-[[2-側氧基-2-[(1R ,4R ,5S )-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(46mg，化合物205 )及5-[[2-側氧基-2-[(1S ,4S ,5R )-4-苯基-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(48mg，化合物194 )。make rac -5-[[2-oxo-2-[(1 R ,4 R ,5 S )-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl] Acetyl]amino]pyridine-3-carboxamide (100 mg, 264.25 μmol) was subjected to chiral chromatography (column: YMC 250*20 mm, 5 um, eluent: hexane-IPA-MeOH, 40-30 -30; flow rate: 12 mL/min) to obtain 5-[[2-oxy-2-[(1 R ,4 R ,5 S )-4-phenyl-3-azabicyclo[3.2.1 ]oct-3-yl]acetyl]amino]pyridine-3-carboxamide (46mg, compound 205 ) and 5-[[2-oxy-2-[( 1S , 4S , 5R )-4-phenyl-3-azabicyclo[3.2.1]oct-3-yl]acetyl]amino]pyridine-3-carboxamide (48 mg, compound 194 ).

化合物205 ：1 H NMR(DMSO,600MHz)：δ(ppm)1.24(m,2H),1.53(m,3H),1.78(m,1H),2.40(m,1H),2.61(m,1H),3.49(m,1H),3.85(m,1H),5.27(m,1H),7.12(m,4H),7.31(t,1H),7.55(m,1H),7.99(m,1H),8.23(m,1H),8.53(m,1H),8.82(m,1H),10.73(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值378.2；實測值379.0；Rt=4.240min。掌性HPLC：Rt=16.26min(管柱：IC；流動相：己烷-MeOH-IPA，40-30-30；流速：0.6mL/min)。 Compound 205 : 1 H NMR (DMSO, 600 MHz): δ (ppm) 1.24 (m, 2H), 1.53 (m, 3H), 1.78 (m, 1H), 2.40 (m, 1H), 2.61 (m, 1H) ,3.49(m,1H),3.85(m,1H),5.27(m,1H),7.12(m,4H),7.31(t,1H),7.55(m,1H),7.99(m,1H), 8.23 (m, 1H), 8.53 (m, 1H), 8.82 (m, 1H), 10.73 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 378.2; found 379.0; Rt=4.240 min. Chiral HPLC: Rt=16.26 min (column: IC; mobile phase: Hexane-MeOH-IPA, 40-30-30; flow rate: 0.6 mL/min).

化合物194： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.24(m,2H),1.53(m,3H),1.76(m,1H),2.36(m,1H),2.62(m,1H),3.49(m,1H),3.85(m,1H),5.27(m,1H),7.00(m,3H),7.28(m,2H),7.55(m,1H),7.99(m,1H),8.23(m,1H),8.53(m,1H),8.82 (m,1H),10.74(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值378.2；實測值379.0；Rt=4.237min。掌性HPLC：Rt=38.56min(管柱：IC；流動相：己烷-MeOH-IPA，40-30-30；流速：0.6mL/min)。 Compound 194: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 1.24 (m, 2H), 1.53 (m, 3H), 1.76 (m, 1H), 2.36 (m, 1H), 2.62 (m ,1H),3.49(m,1H),3.85(m,1H),5.27(m,1H),7.00(m,3H),7.28(m,2H),7.55(m,1H),7.99(m, 1H), 8.23 (m, 1H), 8.53 (m, 1H), 8.82 (m, 1H), 10.74 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 378.2; found 379.0; Rt=4.237 min. Chiral HPLC: Rt=38.56 min (column: IC; mobile phase: Hexane-MeOH-IPA, 40-30-30; flow rate: 0.6 mL/min).

實例29. 5-(2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物289、化合物294)之合成Example 29. Of 5-(2-(2-cyclopentylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 289, compound 294) synthesis

Figure 110128222-A0202-12-0945-47
Figure 110128222-A0202-12-0945-47

步驟1：5-(2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺之合成Step 1: Synthesis of 5-(2-(2-cyclopentylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide

在21℃下，將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.5g，1.47mmol，Et3 N)、TATU(567.73mg，1.76mmol)及TEA(148.65mg，1.47mmol，204.75μL)混合於無水DMF(15mL)中且將所得混合物攪拌1h。向其中添加2-環戊基哌啶(225.14mg，1.47mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(40-90% 0.5-5min；水-MeOH(+NH3 )；30ml/min；裝載泵4ml/min；管柱xbridge 20*100mm)。獲得呈黃色膠狀物之5-[[2-(2-環戊基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(251.3mg，671.15μmol，45.69%產率)。At 21 °C, 2-[(5-aminocarbamoyl-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (0.5 g, 1.47 mmol, Et 3 N), TATU (567.73 mg, 1.76 mmol) and TEA (148.65 mg, 1.47 mmol, 204.75 μL) were mixed in dry DMF (15 mL) and the resulting mixture was stirred for 1 h. To this was added 2-cyclopentylpiperidine (225.14 mg, 1.47 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (40-90% 0.5-5 min; water-MeOH (+ NH3 ); 30 ml/min; loading pump 4 ml/min; column xbridge 20*100 mm). 5-[[2-(2-cyclopentyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-methoxypyridine-3-methyl was obtained as a yellow gum Amide (251.3 mg, 671.15 μmol, 45.69% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.61(m,15H),3.21(t,1H),3.56(t,1H),3.96(s,3H),4.22(d,1H),7.75(m,2H),8.46(m,1H),8.56(m,1H),10.89(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.61(m, 15H), 3.21(t, 1H), 3.56(t, 1H), 3.96(s, 3H), 4.22(d, 1H), 7.75 (m, 2H), 8.46 (m, 1H), 8.56 (m, 1H), 10.89 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值374.4；實測值375.2；Rt=1.257min。LCMS (ESI): [M+1] m/z: calculated 374.4; found 375.2; Rt=1.257 min.

步驟2：掌性分離(化合物289 、化合物294 )Step 2: Chiral separation ( Compound 289 , Compound 294 )

在體系己烷-IPA-MeOH，60-20-20，0.6mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：1mkl。自251.3mg外消旋物獲得112.88mg及109.48mg個別鏡像異構物。Purification was performed on a chiral column in the system hexane-IPA-MeOH, 60-20-20, 0.6 mL/min. Injection times: 1, injection volume: 1mkl. 112.88 mg and 109.48 mg of individual enantiomers were obtained from 251.3 mg of racemate.

化合物289：保留時間：22.02min 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03-1.26(m,2H),1.37-1.80(m,13H),2.78-3.19(m,1H),3.57(t,1H),3.95(s,3H),4.19-4.27(m,1H),7.74(s,2H),8.42-8.49(m,1H),8.50-8.58(m,1H),10.81-10.93(m,1H)。LCMS(ESI)：[M+1]m/z：計算值374.2；實測值375.2；Rt=3.305min。 Compound 289: Retention time: 22.02 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.03-1.26 (m, 2H), 1.37-1.80 (m, 13H), 2.78-3.19 (m, 1H), 3.57(t,1H),3.95(s,3H),4.19-4.27(m,1H),7.74(s,2H),8.42-8.49(m,1H),8.50-8.58(m,1H),10.81- 10.93 (m, 1H). LCMS (ESI): [M+1]m/z: calculated 374.2; found 375.2; Rt=3.305 min.

化合物294：保留時間：30.45min 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.99-1.23(m,2H),1.31-1.80(m,13H),2.77-3.17(m,1H),3.56(t,1H),3.95(s,3H),4.16-4.27(m,1H),7.70-7.85(m,2H),8.43-8.48(m,1H),8.50-8.58(m,1H),10.80-10.93(m,1H)。LCMS(ESI)：[M+1]m/z：計算值374.2；實測值375.2；Rt=3.313min。 Compound 294: Retention time: 30.45 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.99-1.23 (m, 2H), 1.31-1.80 (m, 13H), 2.77-3.17 (m, 1H), 3.56(t,1H),3.95(s,3H),4.16-4.27(m,1H),7.70-7.85(m,2H),8.43-8.48(m,1H),8.50-8.58(m,1H), 10.80-10.93 (m, 1H). LCMS (ESI): [M+1]m/z: calculated 374.2; found 375.2; Rt=3.313 min.

實例30. 5-(2-(3,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物183、化合物275、化合物311、化合物267、化合物286)之合成Example 30. 5-(2-(3,5-Dimethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 183, Compound 275, Synthesis of compound 311, compound 267, compound 286)

Figure 110128222-A0202-12-0946-48
Figure 110128222-A0202-12-0946-48

步驟1：5-(2-(3,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物183 )之合成Step 1: Synthesis of 5-(2-(3,5-Dimethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide ( Compound 183 )

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.4g，1.29mmol，Et3 N)、3,5-二甲基-2-苯基哌啶(268.38mg，1.42mmol)及HATU(539.08mg，1.42mmol)於DMF(4mL)中之懸浮液中添加TEA(652.11mg，6.44mmol，898.22μL)。將所得混合物在40℃下攪拌3h且使其經歷HPLC；20-45% 0-5min水-0.1% FA-ACN流速30ml/min(裝載泵4ml/min 0.1% FA-ACN)；目標質量380.45管柱： SunFire C18 100x18mm 5um)，以得到5-[[2-(3,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(120mg，315.42μmol，24.47%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.4 g, 1.29 mmol, Et3N ), 3,5-dimethyl-2-benzene To a suspension of ylpiperidine (268.38 mg, 1.42 mmol) and HATU (539.08 mg, 1.42 mmol) in DMF (4 mL) was added TEA (652.11 mg, 6.44 mmol, 898.22 μL). The resulting mixture was stirred at 40°C for 3h and subjected to HPLC; 20-45% 0-5min water-0.1% FA-ACN flow rate 30ml/min (loading pump 4ml/min 0.1%FA-ACN); target mass 380.45 tubes Column: SunFire C18 100x18mm 5um) to give 5-[[2-(3,5-dimethyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine -3-Carboxamide (120 mg, 315.42 μmol, 24.47% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),0.96(d,3H),1.07(m,1H),1.91(m,1H),2.06(m,1H),2.16(m,1H),3.84(m,2H),4.52(m,1H),7.42(m,4H),7.62(m,1H),8.17(m,1H),8.42(m,1H),8.82(m,1H)。LCMS(ESI)：[M]+ m/z：計算值380.4；實測值381.2；Rt=4.616min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.86(d,3H), 0.96(d,3H), 1.07(m,1H), 1.91(m,1H), 2.06(m,1H), 2.16(m,1H),3.84(m,2H),4.52(m,1H),7.42(m,4H),7.62(m,1H),8.17(m,1H),8.42(m,1H),8.82 (m, 1H). LCMS (ESI): [M] + m/z: calculated 380.4; found 381.2; Rt=4.616 min.

步驟2：掌性分離(化合物275 、化合物311 、化合物267 及化合物286 )Step 2: Chiral separation ( Compound 275 , Compound 311 , Compound 267 and Compound 286 )

在體系Hex-IPA-MeOH，70-15-15，0.6mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：2mkl。由120mg外消旋物獲得8.5mg，14mg，37mg及40mg單獨的鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 70-15-15, 0.6 mL/min. Injection times: 1, injection volume: 2mkl. From 120 mg of the racemate, 8.5 mg, 14 mg, 37 mg and 40 mg of the individual enantiomers were obtained.

化合物275：保留時間：26.07min LCMS(ESI)：[M]+ m/z：計算值380.4；實測值381.2；Rt=4.834min。 Compound 275: Retention time: 26.07 min LCMS (ESI): [M] + m/z: calcd 380.4; found 381.2; Rt=4.834 min.

化合物311：保留時間：38.08min1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.83-0.87(m,3H),0.94-0.99(m,3H),1.85-1.95(m,1H),1.99-2.10(m,1H),2.09-2.25(m,1H),3.45-3.61(m,1H),3.79-3.92(m,1H),4.46-4.66(m,1H),7.11-7.43(m,6H),7.59(s,1H),8.12-8.29(m,1H),8.38-8.62(m,1H),8.67-8.88(m,2H),10.61-11.17(m,1H)。LCMS(ESI)：[M]+ m/z：計算值380.4；實測值381.2；Rt=4.838min。Compound 311: Retention time: 38.08 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.83-0.87 (m, 3H), 0.94-0.99 (m, 3H), 1.85-1.95 (m, 1H), 1.99-2.10(m, 1H), 2.09-2.25(m, 1H), 3.45-3.61(m, 1H), 3.79-3.92(m, 1H), 4.46-4.66(m, 1H), 7.11-7.43(m , 6H), 7.59(s, 1H), 8.12-8.29(m, 1H), 8.38-8.62(m, 1H), 8.67-8.88(m, 2H), 10.61-11.17(m, 1H). LCMS (ESI): [M] + m/z: calculated 380.4; found 381.2; Rt=4.838 min.

化合物267：保留時間：32.12min 1 H NMR(500MHz,DMSO-d 6 )δ (ppm)0.64-0.76(m,3H),1.00-1.10(m,3H),1.35-1.43(m,1H),1.87-2.00(m,1H),2.11-2.24(m,1H),2.25-2.36(m,1H),3.37-3.96(m,2H),4.97-5.43(m,1H),7.25-7.29(m,1H),7.29-7.36(m,2H),7.36-7.48(m,2H),7.55-7.64(m,1H),8.10-8.20(m,1H),8.41-8.51(m,1H),8.71-8.77(m,1H),8.79-8.86(m,1H),10.89-11.23(m,1H)。LCMS(ESI)：[M]+ m/z：計算值380.4；實測值381.2；Rt=4.841min。 Compound 267: Retention time: 32.12 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.64-0.76 (m, 3H), 1.00-1.10 (m, 3H), 1.35-1.43 (m, 1H), 1.87-2.00(m, 1H), 2.11-2.24(m, 1H), 2.25-2.36(m, 1H), 3.37-3.96(m, 2H), 4.97-5.43(m, 1H), 7.25-7.29(m ,1H),7.29-7.36(m,2H),7.36-7.48(m,2H),7.55-7.64(m,1H),8.10-8.20(m,1H),8.41-8.51(m,1H),8.71 -8.77(m, 1H), 8.79-8.86(m, 1H), 10.89-11.23(m, 1H). LCMS (ESI): [M] + m/z: calculated 380.4; found 381.2; Rt=4.841 min.

化合物286：保留時間：23.06min LCMS(ESI)：[M]+ m/z：計算值380.4；實測 值381.2；Rt=4.840min。 Compound 286: Retention time: 23.06 min LCMS (ESI): [M] + m/z: calcd 380.4; found 381.2; Rt=4.840 min.

實例31. 5-(2-(2-環己基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物101、化合物113、化合物108)之合成Example 31. Synthesis of 5-(2-(2-cyclohexylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 101, Compound 113, Compound 108)

Figure 110128222-A0202-12-0948-49
Figure 110128222-A0202-12-0948-49

步驟1：5-(2-(2-環己基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物101 )之合成Step 1: Synthesis of 5-(2-(2-cyclohexylpiperidin-1-yl)-2-oxyacetamido)nicotinamide ( compound 101 )

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(507.49mg，1.39mmol)及2-環己基哌啶(246.67mg，958.59μmol)混合於DMF(10mL)中。將反應懸浮液冷卻至0℃且添加HATU(728.97mg，1.92mmol)，隨後添加TEA(582.00mg，5.75mmol，801.65μL)。將澄清溶液在周圍溫度下攪拌36h，然後在減壓下蒸發揮發物，且使殘餘物(1.5g)經歷RP-HPLC(管柱：YMC Actus Triart C18 100x20mm，5um；40-70%，0-5min，以0.1% NH3 -甲醇為流動相)，以得到化合物101 5-[[2-(2-環己基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(68.5mg，191.11μmol，19.94%產率)。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (507.49 mg, 1.39 mmol) and 2-cyclohexylpiperidine (246.67 mg, 958.59 μmol) were mixed in in DMF (10 mL). The reaction suspension was cooled to 0°C and HATU (728.97 mg, 1.92 mmol) was added followed by TEA (582.00 mg, 5.75 mmol, 801.65 μL). The clear solution was stirred at ambient temperature for 36h, then the volatiles were evaporated under reduced pressure and the residue (1.5g) was subjected to RP-HPLC (column: YMC Actus Triart C18 100x20mm, 5um; 40-70%, 0- 5min, with 0.1% NH3 -methanol as mobile phase), to obtain compound 101 5-[[2-(2-cyclohexyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine -3-Carboxamide (68.5 mg, 191.11 μmol, 19.94% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.93(m,2H),1.17(m,3H),1.59(m,8H),1.77(m,4H),1.93(m,1H),2.89(m,1H),4.49(m,2H),6.13(m,1H),8.60(m,1H),8.79(s,1H),8.93(m,1H),9.68(m,1H)。LCMS(ESI)：[M+1]+ m/z：計算值358.4；實測值359.2；Rt=3.222min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.93(m, 2H), 1.17(m, 3H), 1.59(m, 8H), 1.77(m, 4H), 1.93(m, 1H), 2.89( m, 1H), 4.49 (m, 2H), 6.13 (m, 1H), 8.60 (m, 1H), 8.79 (s, 1H), 8.93 (m, 1H), 9.68 (m, 1H). LCMS (ESI): [M+1] + m/z: calculated 358.4; found 359.2; Rt=3.222 min.

步驟2：掌性分離(化合物113 、化合物108 )Step 2: Chiral separation ( Compound 113 , Compound 108 )

在體系Hex-IPA-MeOH，60-20-20，0.6mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：1mkl。自30mg外消旋物獲得14.2mg及14.5mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 60-20-20, 0.6 mL/min. Injection times: 1, injection volume: 1mkl. 14.2 mg and 14.5 mg of individual enantiomers were obtained from 30 mg of racemate.

化合物113：保留時間：15.27min 1 H NMR(500MHz,DMSO-d 6 )δ (ppm)0.85(m,2H),1.20(m,4H),1.43(m,2H),1.64(m,7H),1.86(m,2H),3.00(m,1H),3.49(m,1H),4.18(m,1H),7.61(m,1H),8.17(m,1H),8.49(s,1H),8.77(s,1H),8.88(m,1H),11.06(m,1H)。LCMS(ESI)：[M+1]+ m/z：計算值358.2；實測值359.2；Rt=4.677min。Compound 113: Retention time: 15.27 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.85 (m, 2H), 1.20 (m, 4H), 1.43 (m, 2H), 1.64 (m, 7H) ,1.86(m,2H),3.00(m,1H),3.49(m,1H),4.18(m,1H),7.61(m,1H),8.17(m,1H),8.49(s,1H), 8.77(s, 1H), 8.88(m, 1H), 11.06(m, 1H). LCMS (ESI): [M+1] + m/z: calculated 358.2; found 359.2; Rt=4.677 min.

化合物108：保留時間：11.84min 1 H NMR(500MHz,DMSO-d 6 )δ (ppm)0.84(m,2H),1.24(m,4H),1.68(m,11H),2.86(m,1H),3.51(m,1H),4.18(m,1H),7.61(m,1H),8.17(m,1H),8.49(s,1H),8.77(s,1H),8.88(m,1H),11.06(s,1H)。LCMS(ESI)：[M+1]+ m/z：計算值358.2；實測值359.2；Rt=4.676min。Compound 108: Retention time: 11.84 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.84 (m, 2H), 1.24 (m, 4H), 1.68 (m, 11H), 2.86 (m, 1H) ,3.51(m,1H),4.18(m,1H),7.61(m,1H),8.17(m,1H),8.49(s,1H),8.77(s,1H),8.88(m,1H), 11.06(s, 1H). LCMS (ESI): [M+1] + m/z: calculated 358.2; found 359.2; Rt=4.676 min.

實例32. 5-(2-(2-環己基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物347、化合物317)之合成Example 32. Synthesis of 5-(2-(2-cyclohexylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 347, compound 317)

Figure 110128222-A0202-12-0949-50
Figure 110128222-A0202-12-0949-50

步驟1：5-(2-(2-環己基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺之合成Step 1: Synthesis of 5-(2-(2-cyclohexylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide

將2-環己基哌啶(0.25g，1.49mmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(508.66mg，1.49mmol，Et3 N)及TEA(1.51g，14.94mmol，2.08mL)一起混合於DMF(5mL)中且向其中添加HATU(852.33mg，2.24mmol)。攪拌所得混合物18h。將反應混合物倒入水(20ml)中且將所得混合物用EtOAc(2*40ml)萃取。將經合併之有機層用水(3*20ml)、鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由HPLC(2-10min 60-85% MeOH/H2 O，30ml/min(裝載泵4ml MeOH)，管柱：SunFire 100*19mm，5微米)純化殘餘物，以獲得5-[[2-(2-環己基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(76.90mg，197.96μmol，13.25%產率)。2-Cyclohexylpiperidine (0.25 g, 1.49 mmol), 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (508.66 mg) , 1.49 mmol, Et3N ) and TEA (1.51 g, 14.94 mmol, 2.08 mL) were mixed together in DMF (5 mL) and HATU (852.33 mg, 2.24 mmol) was added to it. The resulting mixture was stirred for 18 h. The reaction mixture was poured into water (20ml) and the resulting mixture was extracted with EtOAc (2*40ml). The combined organic layers were washed with water (3*20ml), brine, dried over Na2SO4 , filtered and evaporated. The residue was purified by HPLC (2-10 min 60-85% MeOH/ H2O , 30 ml/min (loading pump 4 ml MeOH), column: SunFire 100*19 mm, 5 microns) to obtain 5-[[2- (2-Cyclohexyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (76.90 mg, 197.96 μmol, 13.25% yield) .

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.86(m,2H),1.08(m,3H),1.23(m,2H),1.58(m,8H),1.86(m,2H),2.66(m,1H),3.57(m,1H),3.98(s,3H),4.22(m,1H), 7.75(m,2H),8.53(m,2H),10.86(m,1H)。LCMS(ESI)：[M+1]+ m/z：計算值388.4；實測值389.2；Rt=1.436min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.86(m, 2H), 1.08(m, 3H), 1.23(m, 2H), 1.58(m, 8H), 1.86(m, 2H), 2.66(m, 1H), 3.57(m, 1H), 3.98(s, 3H), 4.22(m, 1H), 7.75(m, 2H), 8.53(m, 2H), 10.86(m, 1H). LCMS (ESI): [M+1] + m/z: calculated 388.4; found 389.2; Rt=1.436 min.

步驟2：掌性分離(化合物347 、化合物317 )Step 2: Chiral separation ( Compound 347 , Compound 317 )

在體系CO2 -MeOH，50-50，2mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：1mkl。自76.9mg外消旋物獲得28.47mg及27.6mg個別鏡像異構物。Purification was performed on a chiral column in system CO2-MeOH, 50-50, 2 mL/min. Injection times: 1, injection volume: 1mkl. 28.47 mg and 27.6 mg of individual enantiomers were obtained from 76.9 mg of racemate.

化合物347：保留時間：6.93min 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.83(m,2H),1.17(m,3H),1.41(m,1H),1.62(m,9H),1.84(m,2H),3.07(m,1H),3.56(m,1H),3.95(s,3H),4.19(m,1H),7.74(m,2H),8.46(s,1H),8.54(m,1H),10.85(s,1H)。LCMS(ESI)：[M+1]+ m/z：計算值388.2；實測值389.2；Rt=5.449min。 Compound 347: Retention time: 6.93 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.83 (m, 2H), 1.17 (m, 3H), 1.41 (m, 1H), 1.62 (m, 9H) ,1.84(m,2H),3.07(m,1H),3.56(m,1H),3.95(s,3H),4.19(m,1H),7.74(m,2H),8.46(s,1H), 8.54 (m, 1H), 10.85 (s, 1H). LCMS (ESI): [M+1] + m/z: calculated 388.2; found 389.2; Rt=5.449 min.

化合物317：保留時間：5.78min 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.83(m,2H),1.14(m,3H),1.39(m,1H),1.65(m,9H),1.83(m,2H),2.85(m,1H),3.48(m,1H),3.93(s,3H),4.13(m,1H),7.73(m,2H),8.44(m,1H),8.51(m,1H),10.84(m,1H)。LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=5.454min。 Compound 317: Retention time: 5.78 min 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.83 (m, 2H), 1.14 (m, 3H), 1.39 (m, 1H), 1.65 (m, 9H) ,1.83(m,2H),2.85(m,1H),3.48(m,1H),3.93(s,3H),4.13(m,1H),7.73(m,2H),8.44(m,1H), 8.51 (m, 1H), 10.84 (m, 1H). LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=5.454 min.

實例33. 2-[(2R,5S)-2-(3-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物91)及2-[(2S,5R)-2-(3-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物110)之合成Example 33. 2-[(2R,5S)-2-(3-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2 -Pendant oxyacetamide (compound 91) and 2-[(2S,5R)-2-(3-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(5 Synthesis of -methyl-3-pyridyl)-2-oxoacetamide (Compound 110)

Figure 110128222-A0202-12-0950-51
Figure 110128222-A0202-12-0950-51

步驟1：2-[(2R,5S)-2-(3-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物91 )之合成Step 1: 2-[(2R,5S)-2-(3-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridinyl)-2 - Synthesis of Pendant Oxyacetamide ( Compound 91 )

將2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(297.00mg，1.37mmol，HCl)溶解於DMF(5mL)中，隨後添加DIPEA(1.07g，8.24mmol，1.44mL)及HATU (626.82mg，1.65mmol)。將所得混合物攪拌10min(觀察到顏色變化)且一次性添加3-(5-甲基-2-哌啶基)苯胺(0.5g，1.65mmol，TFA)。將反應混合物攪拌隔夜。蒸發溶劑藉由HPLC(27% 0.5-6.5min；水-乙腈；流速30mL/min；(裝載泵4mL/min乙腈)；目標質量352；管柱SunFire 100* 19mm 5um)純化，得到2-[(2R,5S)-2-(3-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.035g，99.31μmol，6.02%產率)。藉由2D NMR確認反式組態。2-[(5-Methyl-3-pyridinyl)amino]-2-oxoacetic acid (297.00 mg, 1.37 mmol, HCl) was dissolved in DMF (5 mL) followed by the addition of DIPEA (1.07 g, 8.24 g mmol, 1.44 mL) and HATU (626.82 mg, 1.65 mmol). The resulting mixture was stirred for 10 min (color change observed) and 3-(5-methyl-2-piperidinyl)aniline (0.5 g, 1.65 mmol, TFA) was added in one portion. The reaction mixture was stirred overnight. The evaporated solvent was purified by HPLC (27% 0.5-6.5 min; water-acetonitrile; flow rate 30 mL/min; (loading pump 4 mL/min acetonitrile); target mass 352; column SunFire 100 * 19mm 5um) to give 2-[( 2R,5S)-2-(3-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (0.035 g, 99.31 μmol, 6.02% yield). The trans configuration was confirmed by 2D NMR.

1 H NMR(400MHz,DMSO-d6 )δ 0.99(m,3H),1.30(m,1H),1.69(m,1H),1.81(m,1H),1.95(m,1H),2.08(m,1H),2.25(m,3H),3.22(m,1H),3.42(m,1H),5.17(m,3H),6.44(m,3H),6.98(m,1H),7.89(m,1H),8.14(m,1H),8.60(m,1H),10.99(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.99(m, 3H), 1.30(m, 1H), 1.69(m, 1H), 1.81(m, 1H), 1.95(m, 1H), 2.08(m ,1H),2.25(m,3H),3.22(m,1H),3.42(m,1H),5.17(m,3H),6.44(m,3H),6.98(m,1H),7.89(m, 1H), 8.14 (m, 1H), 8.60 (m, 1H), 10.99 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.2；Rt=2.214min。LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.2; Rt=2.214 min.

步驟2：2-[(2S,5R)-2-(3-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物110 )之合成Step 2: 2-[(2S,5R)-2-(3-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl) Synthesis of -2-oxoacetamide ( Compound 110 )

將2-[(2S,5R)-2-(3-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(15.00mg，42.56μmol)溶解於DCM中且添加TEA(4.31mg，42.56μmol，5.93μL)。將所得混合物冷卻至0℃且逐滴添加乙醯氯(3.34mg，42.56μmol，2.59μL)。將反應混合物攪拌2h。然後，在減壓下移除溶劑。使用HPLC(40-90% 0.5-6.5min；水-MeOH；流速30mL/min；(裝載泵4mL/min MeOH)；目標質量394；管柱SunFire 100* 19mm 5um)純化所獲得之殘餘物，以得到2-[(2S,5R)-2-(3-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(13mg，32.96μmol，77.43%產率)。2-[(2S,5R)-2-(3-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-side Oxyacetamide (15.00 mg, 42.56 μmol) was dissolved in DCM and TEA (4.31 mg, 42.56 μmol, 5.93 μL) was added. The resulting mixture was cooled to 0 °C and acetyl chloride (3.34 mg, 42.56 μmol, 2.59 μL) was added dropwise. The reaction mixture was stirred for 2 h. Then, the solvent was removed under reduced pressure. The residue obtained was purified using HPLC (40-90% 0.5-6.5 min; water-MeOH; flow rate 30 mL/min; (loading pump 4 mL/min MeOH); target mass 394; column SunFire 100 * 19mm 5um) to give yields 2-[(2S,5R)-2-(3-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridinyl)-2 - Pendant oxyacetamide (13 mg, 32.96 μmol, 77.43% yield).

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.03(dd,3H),1.34(m,1H),1.71(m,1H),1.91(m,1H),2.03(m,3H),2.12(m,2H),2.28(d,3H),3.05(m,1H),3.77(m,1H),5.36(m,1H),7.00(dd,1H),7.31(m,1H),7.49(m,1H),7.57(d,1H),7.92(m,1H), 8.17(m,1H),8.60(m,1H),9.95(m,1H),10.98(m,1H)。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.03 (dd, 3H), 1.34 (m, 1H), 1.71 (m, 1H), 1.91 (m, 1H), 2.03 (m, 3H) ,2.12(m,2H),2.28(d,3H),3.05(m,1H),3.77(m,1H),5.36(m,1H),7.00(dd,1H),7.31(m,1H), 7.49(m,1H), 7.57(d,1H), 7.92(m,1H), 8.17(m,1H), 8.60(m,1H), 9.95(m,1H), 10.98(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.2；Rt=2.671min。LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.2; Rt=2.671 min.

實例34. 5-[[2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物316)及5-[[2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物334)之合成Example 34. 5-[[2-[(2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 -Carboxamide (compound 316) and 5-[[2-[(2S)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl] Synthesis of amino]pyridine-3-carboxamide (compound 334)

Figure 110128222-A0202-12-0952-52
Figure 110128222-A0202-12-0952-52

將N-甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺(1.2g，6.37mmol)及N-甲基-3-(2,3,4,5-四氫吡啶-6-基)苯胺(1.2g，6.37mmol)溶解於MeOH(20mL)及H2 O(20mL)中。將所得混合物冷卻至25℃且一次性添加硼氫化鈉(482.28mg，12.75mmol，450.73μL)。然後，將反應混合物再攪拌隔夜。反應完成之後，將混合物用10% HCl水溶液酸化至pH 2。將所獲得之混合物用MTBE(2* 10mL)洗滌，用10% NaOH水溶液鹼化至pH 10且用DCM(50mL)萃取。蒸發溶劑，得到純的N-甲基-3-(2-哌啶基)苯胺(0.9g，4.73mmol，74.21%產率)。N-methyl-3-(2,3,4,5-tetrahydropyridin-6-yl)aniline (1.2 g, 6.37 mmol) and N-methyl-3-(2,3,4,5- Tetrahydropyridin-6-yl)aniline (1.2 g, 6.37 mmol) was dissolved in MeOH (20 mL) and H2O (20 mL). The resulting mixture was cooled to 25°C and sodium borohydride (482.28 mg, 12.75 mmol, 450.73 μL) was added in one portion. Then, the reaction mixture was stirred for an additional overnight. After the reaction was completed, the mixture was acidified to pH 2 with 10% aqueous HCl. The obtained mixture was washed with MTBE (2 * 10 mL), basified to pH 10 with 10% aq. NaOH and extracted with DCM (50 mL). The solvent was evaporated to give pure N-methyl-3-(2-piperidinyl)aniline (0.9 g, 4.73 mmol, 74.21% yield).

1 H NMR(400MHz,CDCl3 )δ 1.74(m,8H),2.82(m,4H),3.12(m,1H),3.51(m,1H),6.47(d,1H),6.65(s,1H),6.68(d,1H),7.11(dd,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.74(m, 8H), 2.82(m, 4H), 3.12(m, 1H), 3.51(m, 1H), 6.47(d, 1H), 6.65(s, 1H) ), 6.68(d, 1H), 7.11(dd, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值190.1；實測值191.2；Rt=0.539min。LCMS (ESI): [M+H] + m/z: calculated 190.1; found 191.2; Rt=0.539 min.

步驟1：5-[[2-[2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-[3-(Methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide synthesis

將DIPEA(368.33mg，2.85mmol，496.41μL)添加到相應2-[(5-胺甲 醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.2g，814.27μmol，HCl)及N-甲基-3-(2-哌啶基)苯胺(154.94mg，814.27μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(340.57mg，895.69μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。將所獲得之固體經歷HPLC(2-10min 0-85% MeOH-H2 O；流速30mL/min；裝載泵4mL MeOH；SunFire 100* 19mm,5mkm管柱)，以得到純的5-[[2-[2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.15g，393.26μmol，48.30%產率)。DIPEA (368.33 mg, 2.85 mmol, 496.41 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.2 g, 814.27 μmol, HCl) and N-methyl-3-(2-piperidinyl)aniline (154.94 mg, 814.27 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (340.57 mg, 895.69 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 0-85% MeOH-H 2 O; flow rate 30 mL/min; loading pump 4 mL MeOH; SunFire 100 * 19 mm, 5 mkm column) to obtain pure 5-[[2 -[2-[3-(Methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.15 g, 393.26 μmol, 48.30 %Yield).

1 H NMR(400MHz,CDCl3 )δ 1.55(m,4H),1.87(m,1H),2.47(m,1H),2.81(m,3H),3.12(m,1H),3.52(s,3H),4.52(m,1H),6.15(m,2H),6.62(m,2H),7.20(m,1H),8.52(m,1H),8.78(s,1H),9.02(m,1H),10.05(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.55(m, 4H), 1.87(m, 1H), 2.47(m, 1H), 2.81(m, 3H), 3.12(m, 1H), 3.52(s, 3H) ),4.52(m,1H),6.15(m,2H),6.62(m,2H),7.20(m,1H),8.52(m,1H),8.78(s,1H),9.02(m,1H) , 10.05 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=2.061min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=2.061 min.

步驟2：5-[[2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物316 )及5-[[2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物334 )之合成Step 2: 5-[[2-[(2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 -Carboxamide ( compound 316 ) and 5-[[2-[(2S)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl] Synthesis of amino]pyridine-3-carboxamide ( compound 334 )

使用IB(250* 20，5mkm)(Chiralpak管柱；以己烷-MeOH-IPA，60-20-20為流動相；流速12mL/min)進行5-[[2-[2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性分離，得到化合物316 5-[[2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(61.9mg，41.27%產率；RT=11.456min)及化合物334 5-[[2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(58.4mg，38.93%產率；RT=15.476min)。5-[[2-[2-[ 3- ( 5-[[2-[2-[3-( Chiral isolation of methylamino)phenyl]-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide to give compound 316 5-[[2-[( 2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (61.9 mg, 41.27% yield rate; RT=11.456 min) and compound 334 5-[[2-[(2S)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (58.4 mg, 38.93% yield; RT=15.476 min).

化合物316：Compound 316:

RT(IB，己烷-IPA-MeOH，50-25-25，0.6mL/min)=16.409min。RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 16.409 min.

1 H NMR(400MHz,CDCl3 )δ 1.60(m,1H),1.90(m,2H),2.42(m,1H),2.63(m,1H), 2.80(m,3H),3.03(m,2H),4.48(m,1H),5.98(m,2H),6.42(m,1H),6.55(m,2H),6.63(m,1H),7.18(t,1H),8.57(m,1H),8.78(m,1H),8.96(m,1H),9.88(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.60 (m, 1H), 1.90 (m, 2H), 2.42 (m, 1H), 2.63 (m, 1H), 2.80 (m, 3H), 3.03 (m, 2H) ), 4.48(m, 1H), 5.98(m, 2H), 6.42(m, 1H), 6.55(m, 2H), 6.63(m, 1H), 7.18(t, 1H), 8.57(m, 1H) , 8.78 (m, 1H), 8.96 (m, 1H), 9.88 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=3.376min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=3.376 min.

化合物334：Compound 334:

RT(IB，己烷-IPA-MeOH，50-25-25，0.6mL/min)=11.846min。RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 11.846 min.

1 H NMR(400MHz,cdcl3)δ 1.55(m,1H),1.96(m,2H),2.43(m,1H),2.61(m,1H),2.80(s,3H),2.95(m,2H),4.49(m,1H),5.97(m,2H),6.42(m,1H),6.55(m,2H),6.63(m,1H),7.18(t,1H),8.57(m,1H),8.78(m,1H),8.97(m,1H),9.91(m,1H)。 1 H NMR(400MHz,cdcl3)δ 1.55(m,1H),1.96(m,2H),2.43(m,1H),2.61(m,1H),2.80(s,3H),2.95(m,2H) ,4.49(m,1H),5.97(m,2H),6.42(m,1H),6.55(m,2H),6.63(m,1H),7.18(t,1H),8.57(m,1H), 8.78 (m, 1H), 8.97 (m, 1H), 9.91 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=3.375min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=3.375 min.

實例35. 5-[[2-[(2R)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物366)及5-[[2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物365)之合成Example 35. 5-[[2-[(2R)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- 3-Carboxamide (Compound 366) and 5-[[2-[(2S)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxoacetamide Synthesis of yl]amino]pyridine-3-carboxamide (compound 365)

Figure 110128222-A0202-12-0954-53
Figure 110128222-A0202-12-0954-53

步驟1：5-[[2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-[3-(Dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Synthesis of Amines

將DIPEA(336.76mg，2.61mmol，453.86μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.16g，651.41μmol，HCl)及N,N-二甲基-3-(2-哌啶基)苯胺(133.09mg，651.41μmol)於DMF(5mL)中之溶液中。將所得混合物 攪拌5min，隨後添加HATU(272.46mg，716.56μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min，35-60% H2 O-MeCN；裝載泵4mL MeCN；Triart C18 100* 20 5mkm管柱)，以得到純的5-[[2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.12g，303.45μmol，46.58%產率)。DIPEA (336.76 mg, 2.61 mmol, 453.86 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.16 g, 651.41 μmol, HCl) and N,N-dimethyl-3-(2-piperidinyl)aniline (133.09 mg, 651.41 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (272.46 mg, 716.56 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min, 35-60% H2O -MeCN; loading pump 4 mL MeCN; Triart C18 100 * 20 5mkm column) to give pure 5-[[2-[2- [3-(Dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.12 g, 303.45 μmol, 46.58% yield ).

1 H NMR(400MHz,CDCl3 )δ 1.42(m,3H),1.96(m,2H),2.40(m,1H),2.92(s,6H),3.18(m,1H),3.47(s,2H),4.49(m,1H),6.08(m,2H),6.72(m,3H),8.54(d,1H),8.81(s,1H),9.01(m,1H),9.87(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.42(m,3H), 1.96(m,2H), 2.40(m,1H), 2.92(s,6H), 3.18(m,1H), 3.47(s,2H) ), 4.49(m, 1H), 6.08(m, 2H), 6.72(m, 3H), 8.54(d, 1H), 8.81(s, 1H), 9.01(m, 1H), 9.87(m, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=0.993min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=0.993 min.

步驟2：5-[[2-[(2R)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物366 )及5-[[2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物365 )之合成Step 2: 5-[[2-[(2R)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxyacetoxy]amino]pyridine- 3-Carboxamide ( Compound 366 ) and 5-[[2-[(2S)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-pendant oxyacetamide Synthesis of yl]amino]pyridine-3-carboxamide ( compound 365 )

使用OJ-H(250* 30，20mkm)(Chiralpak管柱；以CO2 -MeOH，60-40為流動相；流速80mL/min)進行5-[[2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性分離，得到化合物366 5-[[2-[(2R)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(40.3mg，33.58%產率；RT=10.140min)及化合物365 5-[[2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(41.1mg，34.25%產率；RT=4.335min)。5-[[2-[ 2- [3-( Dimethy Chiral separation of amino)phenyl]-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide to give compound 366 5-[[2-[(2R )-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (40.3 mg, 33.58% yield rate; RT=10.140 min) and compound 365 5-[[2-[(2S)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-side oxyacetyl yl]amino]pyridine-3-carboxamide (41.1 mg, 34.25% yield; RT=4.335 min).

化合物366： RT(OJ-H，CO2 -MeOH，60-40，2.0mL/min)=7.26min。 Compound 366: RT (OJ-H, CO2 -MeOH, 60-40, 2.0 mL/min) = 7.26 min.

1 H NMR(600MHz,DMSO-d6 )δ 1.40-1.56(m,2H),1.57-1.68(m,2H),1.76-1.94(m,1H),2.41-2.44(m,1H),2.61-2.67(m,0H),2.84-2.88(m,6H),3.03-3.10(m,1H),3.63-4.29(m,1H),5.08-5.63(m,1H),6.59-6.64(m,3H),7.15-7.21(m,1H),7.53-7.65(m,1H),8.09-8.20(m,1H),8.44-8.54(m,1H),8.72-8.79(m,1H),8.80 -8.90(m,1H),11.23-11.39(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.40-1.56(m,2H), 1.57-1.68(m,2H), 1.76-1.94(m,1H), 2.41-2.44(m,1H), 2.61- 2.67(m,0H),2.84-2.88(m,6H),3.03-3.10(m,1H),3.63-4.29(m,1H),5.08-5.63(m,1H),6.59-6.64(m,3H ),7.15-7.21(m,1H),7.53-7.65(m,1H),8.09-8.20(m,1H),8.44-8.54(m,1H),8.72-8.79(m,1H),8.80-8.90 (m, 1H), 11.23-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=0.932min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=0.932 min.

化合物365： RT(OJ-H，CO2 -MeOH，60-40，2.0mL/min)=4.07min。 Compound 365: RT (OJ-H, CO2 -MeOH, 60-40, 2.0 mL/min) = 4.07 min.

1 H NMR(600MHz,DMSO-d6 )δ 1.37-1.54(m,2H),1.56-1.68(m,2H),1.77-1.94(m,1H),2.41-2.44(m,1H),2.59-2.67(m,0.3H),2.84-2.89(m,6H),3.02-3.12(m,0.7H),3.64-4.33(m,1H),5.07-5.64(m,1H),6.58-6.67(m,3H),7.15-7.22(m,1H),7.53-7.66(m,1H),8.11-8.23(m,1H),8.43-8.54(m,1H),8.70-8.79(m,1H),8.80-8.91(m,1H),11.22-11.35(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.37-1.54(m, 2H), 1.56-1.68(m, 2H), 1.77-1.94(m, 1H), 2.41-2.44(m, 1H), 2.59- 2.67(m, 0.3H), 2.84-2.89(m, 6H), 3.02-3.12(m, 0.7H), 3.64-4.33(m, 1H), 5.07-5.64(m, 1H), 6.58-6.67(m ,3H),7.15-7.22(m,1H),7.53-7.66(m,1H),8.11-8.23(m,1H),8.43-8.54(m,1H),8.70-8.79(m,1H),8.80 -8.91(m, 1H), 11.22-11.35(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=0.931min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=0.931 min.

實例36. 5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物321)及5-[[2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物348)之合成Example 36. 5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (Compound 321) and 5-[[2-[(2S,5R)-5-methyl-2-[3-(methylamino)phenyl]-1- Synthesis of piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 348)

Figure 110128222-A0202-12-0956-54
Figure 110128222-A0202-12-0956-54

步驟1：5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-pendoxoethanoyl Synthesis of ]amino]pyridine-3-carboxamide

將DIPEA(331.50mg，2.56mmol，446.77μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.18g，732.84μmol，HCl)及N-甲基-3-[(2S,5R)-5-甲基-2-哌啶基]苯胺(149.73mg，732.84μmol)於DMF(10mL)中之 溶液中。將所得混合物攪拌5min，隨後添加HATU(306.51mg，806.12μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min，以0-85% MeCN-H2 O為流動相，流速30mL/min；裝載泵4mL MeCN；SunFire C18 19* 100mm 5mkm管柱)，以得到純的5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.17g，429.89μmol，58.66%產率)。DIPEA (331.50 mg, 2.56 mmol, 446.77 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.18 g, 732.84 μmol, HCl) and N-methyl-3-[(2S,5R)-5-methyl-2-piperidinyl]aniline (149.73 mg, 732.84 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (306.51 mg, 806.12 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 0-85% MeCN- H2O as mobile phase, flow rate 30 mL/min; loading pump 4 mL MeCN; SunFire C18 19 * 100 mm 5mkm column) to obtain pure 5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (0.17 g, 429.89 μmol, 58.66% yield).

1 H NMR(400MHz,CDCl3 )δ 1.08(m,3H),1.37(m,1H),1.94(m,3H),2.21(m,2H),2.77(s,3H),3.41(m,1H),3.49(m,1H),4.34(m,1H),6.28(m,3H),7.22(m,1H),8.58(m,1H),8.72(s,1H),8.99(m,1H),9.89(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.08(m,3H), 1.37(m,1H), 1.94(m,3H), 2.21(m,2H), 2.77(s,3H), 3.41(m,1H) ),3.49(m,1H),4.34(m,1H),6.28(m,3H),7.22(m,1H),8.58(m,1H),8.72(s,1H),8.99(m,1H) ,9.89(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=2.354min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=2.354 min.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物321 )及5-[[2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物348 )之合成Step 2: 5-[[2-[(2R,5S)-5-Methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-pendoxoethanoyl ]amino]pyridine-3-carboxamide ( compound 321 ) and 5-[[2-[(2S,5R)-5-methyl-2-[3-(methylamino)phenyl]-1- Synthesis of piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 348 )

使用IC(250* 20，5mkm)管柱(以CO2 -MeOH，55-45為流動相；流速40mL/min)進行5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性分離，得到化合物321 5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(65.2mg，38.35%產率；RT=16.522min)及化合物348 5-[[2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(59.8mg，35.18%產率；RT=10.591min)。5-[[2-[(2R,5S)-5-methyl-2 was carried out using an IC (250 * 20, 5mkm) column (with CO2 -MeOH, 55-45 as mobile phase; flow rate 40mL/min) Chiral separation of -[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide to give compound 321 5-[ [2-[(2R,5S)-5-Methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (65.2 mg, 38.35% yield; RT=16.522 min) and compound 348 5-[[2-[(2S,5R)-5-methyl-2-[3-(methylamino) Phenyl]-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (59.8 mg, 35.18% yield; RT=10.591 min).

化合物321 ：RT(IC，CO2 -MeOH，50-50，2.0mL/min)=7.03min。 Compound 321 : RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 7.03 min.

1 H NMR(600MHz,DMSO-d6 )δ 1.01(m,3H),1.32(m,1H),1.70(m,1H),1.87(m,1H),2.06(m,2H),2.63(m,3H),2.83(m,1H),3.73(m,1H),5.28(m,1H),5.59(m, 1H),6.40(m,1H),6.48(m,2H),7.07(m,1H),7.59(m,1H),8.15(m,1H),8.47(m,1H),8.75(m,1H),8.87(m,1H),11.19(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.01 (m, 3H), 1.32 (m, 1H), 1.70 (m, 1H), 1.87 (m, 1H), 2.06 (m, 2H), 2.63 (m ,3H),2.83(m,1H),3.73(m,1H),5.28(m,1H),5.59(m,1H),6.40(m,1H),6.48(m,2H),7.07(m, 1H), 7.59 (m, 1H), 8.15 (m, 1H), 8.47 (m, 1H), 8.75 (m, 1H), 8.87 (m, 1H), 11.19 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=3.582min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=3.582 min.

化合物348 RT(IC，CO2 -MeOH，50-50，2.0mL/min)=5.40min。 Compound 348 RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 5.40 min.

1 H NMR(600MHz,DMSO-d6 )δ 1.01(m,3H),1.32(m,1H),1.70(m,1H),1.87(m,1H),2.06(m,2H),2.63(m,3H),2.83(m,1H),3.73(m,1H),5.29(m,1H),5.62(m,1H),6.40(m,1H),6.49(m,2H),7.07(m,1H),7.59(m,1H),8.15(m,1H),8.48(m,1H),8.75(m,1H),8.88(m,1H),11.19(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.01 (m, 3H), 1.32 (m, 1H), 1.70 (m, 1H), 1.87 (m, 1H), 2.06 (m, 2H), 2.63 (m ,3H),2.83(m,1H),3.73(m,1H),5.29(m,1H),5.62(m,1H),6.40(m,1H),6.49(m,2H),7.07(m, 1H), 7.59 (m, 1H), 8.15 (m, 1H), 8.48 (m, 1H), 8.75 (m, 1H), 8.88 (m, 1H), 11.19 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=3.575min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=3.575 min.

實例37. 5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物374)及5-[[2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物375)之合成Example 37. 5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide (Compound 374) and 5-[[2-[(2S,5R)-2-[3-(dimethylamino)phenyl]-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carboxamide (Compound 375)

Figure 110128222-A0202-12-0958-55
Figure 110128222-A0202-12-0958-55

步驟1：5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-pendoxetylacetone Synthesis of amino]pyridine-3-carboxamide

將DIPEA(315.72mg，2.44mmol，425.49μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.15g，610.70μmol，HCl)及N,N-二甲基-3-[(2S,5R)-5-甲基-2-哌啶基]苯胺(133.34mg，610.70μmol)於DMF(5mL)中之溶 液中。將所得混合物攪拌5min，隨後添加HATU(255.43mg，671.77μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min 85-100% H2 O-MeOH-NH3 為流動相；裝載泵4mL MeOH；Triart C18 100* 20mm 5mkm管柱)，以得到純的5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1g，244.21μmol，39.99%產率)。DIPEA (315.72 mg, 2.44 mmol, 425.49 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.15 g, 610.70 μmol, HCl) and N,N-dimethyl-3-[(2S,5R)-5-methyl-2-piperidinyl]aniline (133.34 mg, 610.70 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (255.43 mg, 671.77 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 85-100% H2O -MeOH- NH3 as mobile phase; loading pump 4mL MeOH; Triart C18 100 * 20mm 5mkm column) to obtain pure 5-[[ 2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (0.1 g, 244.21 μmol, 39.99% yield).

1 H NMR(400MHz,CDCl3 )δ 1.04(m,2H),1.41(m,1H),1.82(m,2H),2.21(m,2H),2.84(m,6H),3.14(m,1H),3.71(m,2H),4.32(m,1H),5.87(m,1H),6.37(m,1H),6.68(m,3H),7.21(m,1H),8.03(m,1H),8.82(m,2H),10.12(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.04 (m, 2H), 1.41 (m, 1H), 1.82 (m, 2H), 2.21 (m, 2H), 2.84 (m, 6H), 3.14 (m, 1H) ), 3.71(m, 2H), 4.32(m, 1H), 5.87(m, 1H), 6.37(m, 1H), 6.68(m, 3H), 7.21(m, 1H), 8.03(m, 1H) , 8.82 (m, 2H), 10.12 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.2；Rt=2.354min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.2; Rt=2.354 min.

步驟2：5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物374 )及5-[[2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物375 )之合成Step 2: 5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-pendoxetylacetone ( Compound 374 ) and 5-[[2-[(2S,5R)-2-[3-(dimethylamino)phenyl]-5-methyl- Synthesis of 1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide ( compound 375 )

使用AD-H-II(250* 20，5mkm)管柱(以己烷(0.001% EDA)-IPA-MeOH，60-20-20為流動相；流速12mL/min)進行5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性分離，得到化合物374 5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(42.8mg，42.8%產率；RT=14.388min)及化合物375 5-[[2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(47.2mg，47.20%產率；RT=19.902min)。5-[[ 2- [(2R,5S)-2-[3-(Dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Chiral separation of carboxamide to give compound 374 5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (42.8 mg, 42.8% yield; RT=14.388 min) and compound 375 5-[[2-[(2S,5R)- 2-[3-(Dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (47.2 mg, 47.20% yield; RT=19.902 min).

化合物374： RT(AD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=14.74min。 Compound 374: RT (AD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 14.74 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.96-1.06(m,3H),1.26-1.40(m,1H),1.66-1.80(m,1H),1.83-1.95(m,1H),1.98-2.13(m,1H),2.15-2.25(m,1H),2.78-3.06(m,7H),3.41-4.05(m,1H),5.06-5.57(m,1H),6.52-6.66(m,3H),7.12-7.22(m,1H), 7.52-7.67(m,1H),8.09-8.22(m,1H),8.44-8.54(m,1H),8.70-8.80(m,1H),8.81-8.92(m,1H),11.06-11.35(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.96-1.06(m,3H), 1.26-1.40(m,1H), 1.66-1.80(m,1H), 1.83-1.95(m,1H), 1.98- 2.13(m, 1H), 2.15-2.25(m, 1H), 2.78-3.06(m, 7H), 3.41-4.05(m, 1H), 5.06-5.57(m, 1H), 6.52-6.66(m, 3H ), 7.12-7.22(m, 1H), 7.52-7.67(m, 1H), 8.09-8.22(m, 1H), 8.44-8.54(m, 1H), 8.70-8.80(m, 1H), 8.81-8.92 (m, 1H), 11.06-11.35 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.2；Rt=3.721min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.2; Rt=3.721 min.

化合物375： RT(AD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=21.07min。 Compound 375: RT (AD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 21.07 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.99-1.05(m,3H),1.20-1.39(m,2H),1.65-1.78(m,1H),1.81-1.95(m,1H),1.98-2.14(m,1H),2.15-2.26(m,1H),2.83-2.88(m,6H),3.43-4.04(m,1H),5.04-5.60(m,1H),6.58-6.66(m,3H),7.09-7.21(m,1H),7.51-7.69(m,1H),8.10-8.21(m,1H),8.42-8.53(m,1H),8.69-8.80(m,1H),8.80-8.92(m,1H),10.92-11.59(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.99-1.05(m,3H), 1.20-1.39(m,2H), 1.65-1.78(m,1H), 1.81-1.95(m,1H), 1.98- 2.14(m, 1H), 2.15-2.26(m, 1H), 2.83-2.88(m, 6H), 3.43-4.04(m, 1H), 5.04-5.60(m, 1H), 6.58-6.66(m, 3H ),7.09-7.21(m,1H),7.51-7.69(m,1H),8.10-8.21(m,1H),8.42-8.53(m,1H),8.69-8.80(m,1H),8.80-8.92 (m, 1H), 10.92-11.59 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.2；Rt=3.718min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.2; Rt=3.718 min.

實例38. 5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物300)及5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物302)之合成Example 38. 5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (compound 300) and 5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side Synthesis of oxyacetyl]amino]pyridine-3-carboxamide (compound 302)

Figure 110128222-A0202-12-0960-56
Figure 110128222-A0202-12-0960-56

步驟1. 5-[[2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1. 5-[[2-[2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Synthesis of Amines

在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.5g，2.04mmol，HCl)、HATU(837.98mg，2.44mmol)及三乙胺(617.97mg，6.11mmol，851.20μL)混合於無水DMF(25mL)中且將所得混合物攪拌12h。向其中添加2-(4-氟苯基)-5-甲基哌啶(393.41mg，2.04mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(0-5min 20-70%水-甲醇(NH3 0.1%)，流速30 ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)。獲得呈灰白色固體之5-[[2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(151.4mg，393.86μmol，19.35%產率)。At 21°C, 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.5 g, 2.04 mmol, HCl), HATU (837.98 mg, 2.44 mmol) were combined and triethylamine (617.97 mg, 6.11 mmol, 851.20 μL) were mixed in dry DMF (25 mL) and the resulting mixture was stirred for 12 h. To this was added 2-(4-fluorophenyl)-5-methylpiperidine (393.41 mg, 2.04 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (0-5 min 20-70% water-methanol ( NH3 0.1%), flow rate 30 ml/min (load pump 4 ml/min methanol ( NH3 0.1%)), column: YMC-Actus Triart C18 100*20mml.DS-5um). 5-[[2-[2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- was obtained as an off-white solid Formamide (151.4 mg, 393.86 μmol, 19.35% yield).

LCMS(ESI)：[M+1]+ m/z：計算值384.4；實測值385.2；Rt=3.156min。LCMS (ESI): [M+1] + m/z: calculated 384.4; found 385.2; Rt=3.156 min.

步驟2. 5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物300 )及5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物302 )之合成Step 2. 5-[[2-[(2R,5S)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide ( compound 300 ) and 5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side Synthesis of oxyacetyl]amino]pyridine-3-carboxamide ( compound 302 )

在以下條件下將外消旋物分離成鏡像異構物：AD-H I(250*20，5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min，以得到5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50.04mg，130.18μmol，33.05%產率)化合物300 (其中RT=31.416min)及5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(53.89mg，140.19μmol，35.59%產率)化合物302 (其中RT=23.788min)。將樣品於水-乙腈溶液中冷凍乾燥，以得到白色粉末。The racemate was separated into the enantiomers under the following conditions: AD-HI (250*20, 5mkm), Hexane-IPA-MeOH, 70-15-15, 12ml/min to give 5-[ [2-[(2R,5S)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (50.04 mg, 130.18 μmol, 33.05% yield) compound 300 (where RT=31.416 min) and 5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (53.89 mg, 140.19 μmol, 35.59% yield) compound 302 (wherein RT=23.788 min). The sample was lyophilized in water-acetonitrile solution to give a white powder.

化合物300Compound 300

1 H NMR(500MHz,DMSO-d 6 )δ 1.00-1.07(m,3H),1.29-1.42(m,1H),1.62-1.74(m,1H),1.84-1.98(m,1H),2.03-2.15(m,1H),2.17-2.29(m,1H),2.76-3.25(m,1H),3.45-4.09(m,1H),5.12-5.62(m,1H),7.16-7.30(m,2H),7.34-7.49(m,2H),7.57-7.66(m,1H),8.10-8.24(m,1H),8.42-8.57(m,1H),8.74-8.84(m,1H),8.84-8.99(m,1H),11.17-11.34(m,1H)。 1 H NMR (500MHz, DMSO- d 6 ) δ 1.00-1.07(m,3H), 1.29-1.42(m,1H), 1.62-1.74(m,1H), 1.84-1.98(m,1H), 2.03- 2.15(m, 1H), 2.17-2.29(m, 1H), 2.76-3.25(m, 1H), 3.45-4.09(m, 1H), 5.12-5.62(m, 1H), 7.16-7.30(m, 2H ),7.34-7.49(m,2H),7.57-7.66(m,1H),8.10-8.24(m,1H),8.42-8.57(m,1H),8.74-8.84(m,1H),8.84-8.99 (m, 1H), 11.17-11.34 (m, 1H).

5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50.04mg，130.18μmol，33.05%產率)之RT=34.379min(AD-H，己烷-IPA-MeOH，70-15-15，0.6ml/min)5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -formamide (50.04 mg, 130.18 μmol, 33.05% yield) RT=34.379 min (AD-H, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min)

LCMS(ESI)：[M+1]+ m/z：計算值384.2；實測值385.4；Rt=3.034min。LCMS (ESI): [M+1] + m/z: calculated 384.2; found 385.4; Rt=3.034 min.

化合物302Compound 302

1 H NMR(500MHz,DMSO-d 6 )δ 1.01-1.06(m,3H),1.29-1.44(m,1H),1.61-1.76(m,1H),1.81-1.97(m,1H),2.05-2.28(m,2H),2.77-3.25(m,1H),3.47-4.06(m,1H),5.08-5.66(m,1H),7.15-7.30(m,2H),7.32-7.47(m,2H),7.56-7.69(m,1H),8.11-8.22(m,1H),8.44-8.55(m,1H),8.72-8.82(m,1H),8.84-9.01(m,1H),11.10-11.38(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 1.01-1.06(m,3H), 1.29-1.44(m,1H), 1.61-1.76(m,1H), 1.81-1.97(m,1H), 2.05- 2.28(m, 2H), 2.77-3.25(m, 1H), 3.47-4.06(m, 1H), 5.08-5.66(m, 1H), 7.15-7.30(m, 2H), 7.32-7.47(m, 2H) ),7.56-7.69(m,1H),8.11-8.22(m,1H),8.44-8.55(m,1H),8.72-8.82(m,1H),8.84-9.01(m,1H),11.10-11.38 (m, 1H).

5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(53.89mg，140.19μmol，35.59%產率)之RT=26.492min(AD-H，己烷-IPA-MeOH，70-15-15，0.6ml/min)5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -formamide (53.89 mg, 140.19 μmol, 35.59% yield) RT=26.492 min (AD-H, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min)

LCMS(ESI)：[M+1]+ m/z：計算值384.2；實測值385.4；Rt=3.04min。LCMS (ESI): [M+1] + m/z: calculated 384.2; found 385.4; Rt=3.04 min.

實例39. 5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物446)及5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物445)之合成Example 39. 5-[[2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] -2-Methoxypyridine-3-carboxamide (Compound 446) and 5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidine [Synthesis of]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (compound 445)

Figure 110128222-A0202-12-0962-57
Figure 110128222-A0202-12-0962-57

步驟1. 5-[[2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1. 5-[[2-[2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxy Synthesis of pyridine-3-carboxamide

在21℃下，將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.3，881.38μmol，Et3N)、HATU(335.13mg，881.38μmol)及三乙胺(89.19mg，881.38μmol，122.85μL)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加2-(4-氟苯基)-5-甲基哌啶(170.34mg，881.38μmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(2-7min；水-r1(+NH3 )；30 ml/min；裝載泵4ml/min R1+NH3 ；管柱YMC-ACTUS TRIAT 20*100mm)。獲得呈白色固體之5-[[2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(129.1mg，311.51μmol，35.34%產率)。At 21 °C, 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (0.3, 881.38 μmol, Et3N), HATU (335.13 mg, 881.38 μmol) and triethylamine (89.19 mg, 881.38 μmol, 122.85 μL) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added 2-(4-fluorophenyl)-5-methylpiperidine (170.34 mg, 881.38 μmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (2-7 min; water-r1 (+ NH3 ); 30 ml/min; loading pump 4 ml/min R1+ NH3 ; column YMC-ACTUS TRIAT 20*100 mm). 5-[[2-[2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methyl was obtained as a white solid Oxypyridine-3-carboxamide (129.1 mg, 311.51 μmol, 35.34% yield).

LCMS(ESI)：[M+1]+ m/z：計算值414.2；實測值415.2；Rt=1.195min。LCMS (ESI): [M+1] + m/z: calculated 414.2; found 415.2; Rt=1.195 min.

步驟2. 5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物446 )及5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物445 )之分離Step 2. 5-[[2-[(2S,5R)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] -2-Methoxypyridine-3-carboxamide ( Compound 446 ) and 5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidine Isolation of [methyl]-2-pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide ( compound 445 )

在以下條件下進行掌性分離：IA(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，13ml/min，RT化合物445=34.429min，RT化合物446=26.540min。 Chiral separation was performed under the following conditions: IA (250*20mm, 5mkm), Hexane-IPA-MeOH, 50-25-25, 13ml/min, RT compound 445=34.429min, RT compound 446=26.540min.

5-[[2-[(2S,5R)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(48.42mg，116.84μmol，40.35%產率)之RT=14.6942min(IA，己烷-IPA-MeOH，50-25-25，0.15ml/min)5-[[2-[(2S,5R)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2- Methoxypyridine-3-carboxamide (48.42 mg, 116.84 μmol, 40.35% yield) RT = 14.6942 min (IA, Hexane-IPA-MeOH, 50-25-25, 0.15 ml/min)

5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(43.64mg，105.30μmol，36.37%產率)之RT=18.7292min(IA，己烷-IPA-MeOH，50-25-25，0.15ml/min)5-[[2-[(2R,5S)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2- Methoxypyridine-3-carboxamide (43.64 mg, 105.30 μmol, 36.37% yield) RT = 18.7292 min (IA, Hexane-IPA-MeOH, 50-25-25, 0.15 ml/min)

化合物445： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.64(t,1H),1.88(m,1H),2.13(m,2H),2.97(m,1H),3.93(m,4H),5.34(m,1H),7.20(m,2H),7.34(m,2H),7.72(dd,2H),8.43(m,1H),8.52(m,1H),11.01(m,1H)。 Compound 445: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.64 (t, 1H), 1.88 (m, 1H), 2.13 (m, 2H), 2.97(m, 1H), 3.93(m, 4H), 5.34(m, 1H), 7.20(m, 2H), 7.34(m, 2H), 7.72(dd, 2H), 8.43(m, 1H) ), 8.52 (m, 1H), 11.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.2；Rt=3.291min。LCMS (ESI): [M+H] + m/z: calculated 414.2; found 415.2; Rt=3.291 min.

化合物446： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.64(t,1H),1.88(m,1H),2.13(m,2H),2.97(m,1H),3.93(m,4H),5.34(m,1H),7.20(m,2H),7.34(m,2H),7.72(dd,2H),8.43(m,1H),8.52(m,1H),11.01(m,1H)。 Compound 446: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.64 (t, 1H), 1.88 (m, 1H), 2.13 (m, 2H), 2.97(m, 1H), 3.93(m, 4H), 5.34(m, 1H), 7.20(m, 2H), 7.34(m, 2H), 7.72(dd, 2H), 8.43(m, 1H) ), 8.52 (m, 1H), 11.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.2；Rt=3.291min。LCMS (ESI): [M+H] + m/z: calculated 414.2; found 415.2; Rt=3.291 min.

實例40.N -(6-胺基-5-乙基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側Example 40. N- (6-amino-5-ethylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-side 氧基乙醯胺(化合物710)之合成Synthesis of Oxyacetamide (Compound 710)

Figure 110128222-A0202-12-0964-58
Figure 110128222-A0202-12-0964-58

在21℃下，將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(234.90mg，1.12mmol)及TEA(340.86mg，3.37mmol，469.50μL)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加HATU(426.94mg，1.12mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-90% 0.5-6.5min；水-MeOH+NH3 ；流速30ml/min(裝載泵4ml/min MeOH-NH3 )；管柱：YMS-actus triat100x19mm 5um(R))。獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(185.6mg，482.77μmol，43.00%產率)之兩種級分：第1級分-24.7mg(藉由LCMS測得96.16%，無順式雜質)；第2級分-160.9mg(92.1%反式；7.9%順式雜質)；ee-94-95%。At 21 °C, 2-[(6-amino-5-ethyl-3-pyridinyl)amino]-2-oxoacetic acid (234.90 mg, 1.12 mmol) and TEA (340.86 mg, 3.37 mmol) were combined , 469.50 μL) in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added HATU (426.94 mg, 1.12 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-90% 0.5-6.5 min; water-MeOH+ NH3 ; flow rate 30ml/min (loading pump 4ml/min MeOH- NH3 ); column: YMS-actus triat 100x19mm 5um(R)) . Obtained N- (6-amino-5-ethyl-3-pyridinyl)-2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl] - Two fractions of 2-oxoacetamide (185.6 mg, 482.77 μmol, 43.00% yield): Fraction 1 - 24.7 mg (96.16% by LCMS, no cis impurity); Fraction 2 - 160.9 mg (92.1% trans; 7.9% cis impurity); ee-94-95%.

化合物710： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.07(m,3H),1.28(m,1H),1.65(m,1H),1.88(m,1H),2.01(m,1H),2.14(m,1H),2.39(m,2H),3.02(m,1H),3.98(m,1H),5.12(m,1H),5.63(m,2H),7.20(m,2H),7.32(m,2H),7.48(m,1H),8.04(m,1H),10.50(m,1H)。 Compound 710: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98 (d, 3H), 1.07 (m, 3H), 1.28 (m, 1H), 1.65 (m, 1H), 1.88 (m, 1H), 2.01(m, 1H), 2.14(m, 1H), 2.39(m, 2H), 3.02(m, 1H), 3.98(m, 1H), 5.12(m, 1H), 5.63(m, 2H) ), 7.20(m, 2H), 7.32(m, 2H), 7.48(m, 1H), 8.04(m, 1H), 10.50(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值384.2；實測值385.2；Rt=1.724min。LCMS (ESI): [M] + m/z: calculated 384.2; found 385.2; Rt=1.724 min.

實例41. 5-(2-((2S,5R)-2-(4-胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物398)及5-(2-((2R,5S)-2-(4-胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物381)之合成Example 41. 5-(2-((2S,5R)-2-(4-aminophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotine Amide (compound 398) and 5-(2-((2R,5S)-2-(4-aminophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamide Synthesis of base) nicotinamide (compound 381)

Figure 110128222-A0202-12-0965-59
Figure 110128222-A0202-12-0965-59

步驟1：5-[[2-[2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(4-Aminophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Synthesis of Amide

將DIPEA(644.58mg，4.99mmol，868.71μL)添加到2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.35g，1.42mmol，HCl)及4-(5-甲基-2-哌啶基)苯胺(271.15mg，1.42mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(596.00mg，1.57mmol)於DMF(5mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(SnFire C18 100* 18mm，5mkm管柱；2-10min 30-55% MeCN-H2 O為流動相；流速30mL/min(裝載泵4mL，MeCN))，以得到純的5-[[2-[2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.13g，340.83μmol，23.92%產率)。DIPEA (644.58 mg, 4.99 mmol, 868.71 μL) was added to 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.35 g, 1.42 mmol, HCl) and A solution of 4-(5-methyl-2-piperidinyl)aniline (271.15 mg, 1.42 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (596.00 mg, 1.57 mmol) in DMF (5 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (SnFire C18 100 * 18mm, 5mkm column; 2-10min 30-55% MeCN- H2O as mobile phase; flow rate 30mL/min (loading pump 4mL, MeCN)) to obtain pure 5-[[2-[2-(4-Aminophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (0.13 g, 340.83 μmol, 23.92% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.05(m,2H),1.31(m,1H),1.85(m,2H),3.09(d,3H),3.23(m,1H),3.34(m,1H),4.05(m,2H),5.21(m,2H),6.61(m,2H),7.82(m,2H),7.71(m,1H),8.36(m,1H),8.49(m,1H),8.77(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.05(m, 2H), 1.31(m, 1H), 1.85(m, 2H), 3.09(d, 3H), 3.23(m, 1H), 3.34(m ,1H),4.05(m,2H),5.21(m,2H),6.61(m,2H),7.82(m,2H),7.71(m,1H),8.36(m,1H),8.49(m, 1H), 8.77 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值381.1；實測值382.2；Rt=2.033min。LCMS (ESI): [M+H] + m/z: calculated 381.1; found 382.2; Rt=2.033 min.

步驟2：5-[[2-[2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性拆分Step 2: 5-[[2-[2-(4-Aminophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl chiral resolution of amide

使用OJ-H(250* 20，5mkm)(Chiralpak管柱；以己烷-MeOH-IPA，50-25-25為流動相；流速15mL/min；注入體積900mkL)進行掌性分離，以得到呈黃色油狀物之化合物398 5-(2-((2S,5R)-2-(4-胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(8.9mg，6.85%產率)及呈黃色油狀物之化合物381 5-(2-((2R,5S)-2-(4-胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(60.1mg，46.23%產率)。Chiral separation was performed using OJ-H (250 * 20, 5mkm) (Chiralpak column; hexane-MeOH-IPA, 50-25-25 as mobile phase; flow rate 15mL/min; injection volume 900mkL) to obtain Compound 398 as a yellow oil 5-(2-((2S,5R)-2-(4-aminophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamide yl)nicotinamide (8.9 mg, 6.85% yield) and compound 381 as a yellow oil 5-(2-((2R,5S)-2-(4-aminophenyl)-5-methyl) (60.1 mg, 46.23% yield).

化合物398： RT(IB(250* 20,5mkm)管柱；己烷-MeOH-IPA，50-25-25，15mL/min)=26.42min。 Compound 398: RT (IB (250 * 20,5mkm) column; Hexane-MeOH-IPA, 50-25-25, 15mL/min)=26.42min.

1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.04(m,3H),1.25-1.36(m,1H),1.66-1.78(m,1H),1.79-1.90(m,1H),1.91-2.07(m,1H),2.08-2.17(m,1H),2.74-3.16(m,1H),3.38-3.99(m,1H),4.93-5.58(m,3H),6.51-6.60(m,2H),6.92-7.03(m,2H),7.54-7.64(m,1H),8.09-8.22(m,1H),8.41-8.50(m,1H),8.71-8.79(m,1H),8.80-8.90(m,1H),11.05-11.38(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.97-1.04(m,3H), 1.25-1.36(m,1H), 1.66-1.78(m,1H), 1.79-1.90(m,1H), 1.91- 2.07(m, 1H), 2.08-2.17(m, 1H), 2.74-3.16(m, 1H), 3.38-3.99(m, 1H), 4.93-5.58(m, 3H), 6.51-6.60(m, 2H ),6.92-7.03(m,2H),7.54-7.64(m,1H),8.09-8.22(m,1H),8.41-8.50(m,1H),8.71-8.79(m,1H),8.80-8.90 (m, 1H), 11.05-11.38 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.1；實測值382.0；Rt=3.265min。LCMS (ESI): [M+H] + m/z: calculated 381.1; found 382.0; Rt=3.265 min.

化合物381： RT(IB(250* 20,5mkm)管柱；己烷-MeOH-IPA，50-25-25，15mL/min)=14.61min。 Compound 381: RT (IB (250 * 20,5mkm) column; Hexane-MeOH-IPA, 50-25-25, 15 mL/min) = 14.61 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.02(m,3H),1.25-1.35(m,1H),1.66-1.78(m,1H),1.79-1.90(m,1H),1.92-2.05(m,1H),2.09-2.17(m,1H),2.73-3.19(m,1H),3.36-3.97(m,1H),4.87-5.55(m,3H),6.48-6.62(m,2H),6.90-7.04(m,2H),7.51-7.68(m,1H),8.07-8.22(m,1H),8.42-8.52(m,1H),8.70-8.80(m,1H),8.82-8.94(m,1H),11.05-11.34(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.97-1.02(m,3H), 1.25-1.35(m,1H), 1.66-1.78(m,1H), 1.79-1.90(m,1H), 1.92- 2.05(m, 1H), 2.09-2.17(m, 1H), 2.73-3.19(m, 1H), 3.36-3.97(m, 1H), 4.87-5.55(m, 3H), 6.48-6.62(m, 2H ),6.90-7.04(m,2H),7.51-7.68(m,1H),8.07-8.22(m,1H),8.42-8.52(m,1H),8.70-8.80(m,1H),8.82-8.94 (m, 1H), 11.05-11.34 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.1；實測值382.0；Rt=3.265min。LCMS (ESI): [M+H] + m/z: calculated 381.1; found 382.0; Rt=3.265 min.

實例42. 5-(2-((2R,5S)-2-(4-乙醯胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物451)及5-(2-((2S,5R)-2-(4-乙醯胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物452)之合成Example 42. 5-(2-((2R,5S)-2-(4-acetamidophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido) Nicotinamide (Compound 451) and 5-(2-((2S,5R)-2-(4-acetamidophenyl)-5-methylpiperidin-1-yl)-2-oxygen Synthesis of acetylacetamido)nicotinamide (compound 452)

Figure 110128222-A0202-12-0967-60
Figure 110128222-A0202-12-0967-60

步驟1與以上相同Step 1 is the same as above

步驟2：5-(2-(2-(4-乙醯胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 2: Synthesis of 5-(2-(2-(4-acetamidophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide

向5-(2-(2-(4-胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(0.15g，393.26μmol)於THF(10mL)中之經預冷卻之溶液中添加吡啶(77.77mg，983.15μmol，79.52μL)。將所得混合物攪拌5min，隨後在0℃下逐滴添加乙醯氯(33.96mg，432.59μmol，26.32μL)。然後，將反應混合物在室溫下攪拌10h。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min，以40-60%水/MeCN+NH3 為流動相；裝載泵4mL MeCN+NH3 ；TRIART 100* 20 5微米管柱；注入體積：1500.0mL)，以得到純的5-[[2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(76.3mg，180.18μmol，45.82%產率)。To 5-(2-(2-(4-aminophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (0.15 g, 393.26 μmol ) to a precooled solution in THF (10 mL) was added pyridine (77.77 mg, 983.15 μmol, 79.52 μL). The resulting mixture was stirred for 5 min, then acetyl chloride (33.96 mg, 432.59 μmol, 26.32 μL) was added dropwise at 0 °C. Then, the reaction mixture was stirred at room temperature for 10 h. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeCN+ NH3 as mobile phase; loading pump 4 mL MeCN+ NH3 ; TRIART 100 * 20 5 micron column; injection volume: 1500.0 mL) , to obtain pure 5-[[2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide yl]amino]pyridine-3-carboxamide (76.3 mg, 180.18 μmol, 45.82% yield).

LCMS(ESI)：[M+H]+ m/z：計算值423.2；實測值424.2；Rt=0.939min。LCMS (ESI): [M+H] + m/z: calculated 423.2; found 424.2; Rt=0.939 min.

步驟3：5-(2-(2-(4-乙醯胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之掌性分離Step 3: Palm of 5-(2-(2-(4-Acetamidophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide Sexual separation

使用IB(250* 20，5mkm)Chiralpak管柱；以己烷-MoOH-IPA,50-25-25為流動相；流速12mL/min來進行掌性分離，以得到化合物451 5-(2-((2R,5S)-2-(4- 乙醯胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(25.37mg；33.25%產率)及化合物452 5-(2-((2S,5R)-2-(4-乙醯胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(25.56mg；33.50%產率)。Chiralpak column using IB (250 * 20, 5mkm); hexane-MoOH-IPA, 50-25-25 as mobile phase; flow rate 12mL/min for chiral separation to give compound 451 5-(2-( (2R,5S)-2-(4-Acetamidophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (25.37 mg; 33.25 % yield) and compound 452 5-(2-((2S,5R)-2-(4-acetamidophenyl)-5-methylpiperidin-1-yl)-2-side oxyethyl amide) nicotinamide (25.56 mg; 33.50% yield).

化合物451： RT(IB管柱，己烷-IPA-MeOH，50-25-25，0.6mL/min)=10.74min Compound 451: RT (IB column, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 10.74 min

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.04(m,3H),1.35(m,1H),1.74(m,1H),2.03(m,3H),2.22(m,1H),2.64(s,2H),3.08(m,1H),3.74(m,1H),5.40(m,1H),7.27(m,2H),7.60(m,3H),8.17(m,1H),8.50(m,1H),8.78(m,1H),8.89(m,1H),9.95(m,1H),11.21(m,1H)。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.04 (m, 3H), 1.35 (m, 1H), 1.74 (m, 1H), 2.03 (m, 3H), 2.22 (m, 1H) ,2.64(s,2H),3.08(m,1H),3.74(m,1H),5.40(m,1H),7.27(m,2H),7.60(m,3H),8.17(m,1H), 8.50 (m, 1H), 8.78 (m, 1H), 8.89 (m, 1H), 9.95 (m, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值423.2；實測值424.0；Rt=2.447min。LCMS (ESI): [M+H] + m/z: calculated 423.2; found 424.0; Rt=2.447 min.

化合物452： RT(IB管柱，己烷-IPA-MeOH，50-25-25，0.6mL/min)=24.15min Compound 452: RT (IB column, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 24.15 min

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.04(m,3H),1.36(m,1H),1.69(m,1H),1.89(m,1H),2.03(m,4H),2.19(m,1H),2.93(m,1H),3.66(m,1H),5.35(m,1H),7.27(dd,2H),7.58(m,3H),8.17(m,1H),8.49(m,1H),8.78(m,1H),8.90(m,1H),9.95(m,1H),11.21(m,1H)。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.04 (m, 3H), 1.36 (m, 1H), 1.69 (m, 1H), 1.89 (m, 1H), 2.03 (m, 4H) ,2.19(m,1H),2.93(m,1H),3.66(m,1H),5.35(m,1H),7.27(dd,2H),7.58(m,3H),8.17(m,1H), 8.49 (m, 1H), 8.78 (m, 1H), 8.90 (m, 1H), 9.95 (m, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值423.2；實測值424.0；Rt=2.446min。LCMS (ESI): [M+H] + m/z: calculated 423.2; found 424.0; Rt=2.446 min.

實例43. 5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物469)及5-[[2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物462)之合成Example 43. 5-[[2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carbamoylamine (Compound 469) and 5-[[2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 462)

Figure 110128222-A0202-12-0969-61
Figure 110128222-A0202-12-0969-61

步驟1與以上相同Step 1 is the same as above

步驟2：5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 2: 5-[[2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-pendoxoethyl Synthesis of Acyl]amino]pyridine-3-carbamoylamine

向5-[[2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.26g，681.65μmol)於THF(5mL)中之經預冷卻之溶液中添加吡啶(134.80mg，1.70mmol，137.83μL)。此後，在0℃下逐滴添加甲磺醯氯(85.89mg，749.82μmol，58.04μL)。然後，將反應混合物在室溫下攪拌12h。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min，以40-60%水/MeOH+NH3 為流動相；裝載泵4ml MeOH+NH3 ；TRIART 100* 20 5微米管柱)，以得到純的5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.19g，413.48μmol，60.66%產率)。To 5-[[2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine To a pre-cooled solution of -3-carboxamide (0.26 g, 681.65 μmol) in THF (5 mL) was added pyridine (134.80 mg, 1.70 mmol, 137.83 μL). After this time, mesylate chloride (85.89 mg, 749.82 μmol, 58.04 μL) was added dropwise at 0°C. Then, the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeOH+ NH3 as mobile phase; loading pump 4 ml MeOH+ NH3 ; TRIART 100 * 20 5 micron column) to give pure 5 -[[2-[(2R,5S)-2-[4-(Methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (0.19 g, 413.48 μmol, 60.66% yield).

LCMS(ESI)：[M+H]+ m/z：計算值459.2；實測值460.2；Rt=2.760min。LCMS (ESI): [M+H] + m/z: calculated 459.2; found 460.2; Rt=2.760 min.

步驟3：5-[(2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物469 )及5-[[2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物462 )之合成Step 3: 5-[(2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-pendoxoethyl Acyl]amino]pyridine-3-carbamoylamine ( Compound 469 ) and 5-[[2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 462 )

使用AS-H(250* 20，10mkm)管柱；以CO2 -MeOH，60-40為流動相； 流速40mL/min進行5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性分離，得到呈淡黃色油狀物之化合物469 5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(73.14mg，38.49%產率；RT(AS-H，CO2 -MeOH，15mL/min)=8.44min)及呈淡黃色油狀物之化合物462 5-[[2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(76.84min；40.44%產率；RT(AS-H,CO2 -MeOH，15mL/min)=6.62min)。Using AS-H (250 * 20, 10mkm) column; with CO 2 -MeOH, 60-40 as mobile phase; flow rate 40mL/min for 5-[[2-[(2R,5S)-2-[4- Chiral separation of (methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide to give a pale Compound 469 as yellow oil 5-[[2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (73.14 mg, 38.49% yield; RT (AS-H, CO 2 -MeOH, 15 mL/min) = 8.44 min) as a pale yellow oil Compound 462 5-[[2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (76.84 min; 40.44% yield; RT (AS-H, CO2 -MeOH, 15 mL/min) = 6.62 min).

化合物469： RT(AS-H，CO2 -MeOH，60-40，2.0mL/min)=5.22min Compound 469: RT (AS-H, CO2 -MeOH, 60-40, 2.0 mL/min) = 5.22 min

1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.05(m,3H),1.28-1.39(m,1H),1.63-1.74(m,1H),1.80-1.94(m,1H),2.00-2.13(m,1H),2.13-2.23(m,1H),2.72-3.28(m,4H),3.41-4.04(m,1H),5.05-5.68(m,1H),7.14-7.24(m,2H),7.24-7.32(m,2H),7.52-7.65(m,1H),8.10-8.21(m,1H),8.41-8.53(m,1H),8.72-8.80(m,1H),8.82-8.93(m,1H),9.71(s,1H),11.11-11.37(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.97-1.05(m,3H), 1.28-1.39(m,1H), 1.63-1.74(m,1H), 1.80-1.94(m,1H), 2.00- 2.13(m, 1H), 2.13-2.23(m, 1H), 2.72-3.28(m, 4H), 3.41-4.04(m, 1H), 5.05-5.68(m, 1H), 7.14-7.24(m, 2H ),7.24-7.32(m,2H),7.52-7.65(m,1H),8.10-8.21(m,1H),8.41-8.53(m,1H),8.72-8.80(m,1H),8.82-8.93 (m, 1H), 9.71 (s, 1H), 11.11-11.37 (m, 1H).

LCMS(ESI)：[M+3H]+ m/z：計算值459.2；實測值462.2；Rt=4.067min。LCMS (ESI): [M+3H] + m/z: calculated 459.2; found 462.2; Rt=4.067 min.

化合物462： RT(AS-H，CO2 -MeOH，60-40，2.0mL/min)=3.77min Compound 462: RT (AS-H, CO2 -MeOH, 60-40, 2.0 mL/min) = 3.77 min

1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.05(m,3H),1.27-1.39(m,1H),1.62-1.72(m,1H),1.81-1.94(m,1H),2.01-2.13(m,1H),2.14-2.23(m,1H),2.76-3.21(m,4H),3.43-4.03(m,1H),5.07-5.57(m,1H),7.17-7.24(m,2H),7.24-7.32(m,2H),7.54-7.63(m,1H),8.11-8.19(m,1H),8.41-8.51(m,1H),8.71-8.79(m,1H),8.83-8.92(m,1H),9.71(s,1H),11.09-11.28(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.97-1.05(m,3H), 1.27-1.39(m,1H), 1.62-1.72(m,1H), 1.81-1.94(m,1H), 2.01- 2.13(m,1H), 2.14-2.23(m,1H), 2.76-3.21(m,4H), 3.43-4.03(m,1H), 5.07-5.57(m,1H), 7.17-7.24(m,2H) ),7.24-7.32(m,2H),7.54-7.63(m,1H),8.11-8.19(m,1H),8.41-8.51(m,1H),8.71-8.79(m,1H),8.83-8.92 (m, 1H), 9.71 (s, 1H), 11.09-11.28 (m, 1H).

LCMS(ESI)：[M+3H]+ m/z：計算值459.2；實測值462.2；Rt=4.067min。LCMS (ESI): [M+3H] + m/z: calculated 459.2; found 462.2; Rt=4.067 min.

實例44. 2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物67)及2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物111)之合成Example 44. 2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2 -Pendant oxyacetamide (compound 67) and 2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(5 Synthesis of -methyl-3-pyridyl)-2-oxoacetamide (Compound 111)

Figure 110128222-A0202-12-0971-62
Figure 110128222-A0202-12-0971-62

步驟1：2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物67 )之合成Step 1: 2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2 -Synthesis of Pendant Oxyacetamide ( Compound 67 )

將2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(446.39mg，1.65mmol，HCl)溶解於DMF(5mL)中。將所得混合物攪拌5min，隨後添加DIPEA(1.07g，8.24mmol，1.44mL)及HATU(626.82mg，1.65mmol)。攪拌10min(觀察到顏色變化)之後，一次性添加4-(5-甲基-2-哌啶基)苯胺(0.5g，1.65mmol，TFA)且將反應混合物攪拌隔夜。蒸發溶劑且藉由HPLC(27% 0.5-6.5min；水-乙腈；流速30mL/min；(裝載泵4mL/min乙腈)；管柱SunFire 100* 19mm 5um)純化，得到2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.017g，48.24μmol，2.93%產率)。2-[(5-Methyl-3-pyridyl)amino]-2-oxoacetic acid (446.39 mg, 1.65 mmol, HCl) was dissolved in DMF (5 mL). The resulting mixture was stirred for 5 min, then DIPEA (1.07 g, 8.24 mmol, 1.44 mL) and HATU (626.82 mg, 1.65 mmol) were added. After stirring for 10 min (color change observed), 4-(5-methyl-2-piperidinyl)aniline (0.5 g, 1.65 mmol, TFA) was added in one portion and the reaction mixture was stirred overnight. The solvent was evaporated and purified by HPLC (27% 0.5-6.5 min; water-acetonitrile; flow rate 30 mL/min; (loading pump 4 mL/min acetonitrile); column SunFire 100 * 19mm 5um) to give 2-[(2R,5S )-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxoacetamide (0.017g , 48.24 μmol, 2.93% yield).

1 H NMR(400MHz,DMSO-d6 )δ 0.98(m,3H),1.26(m,1H),1.70(m,1H),1.81(m,1H),1.92(m,1H),2.09(m,1H),2.25(m,3H),3.02(m,1H),3.35(m,1H),5.23(m,3H),6.53(m,2H),6.94(m,2H),7.88(m,1H),8.14(m,1H),8.59(m,1H),10.95(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.98(m, 3H), 1.26(m, 1H), 1.70(m, 1H), 1.81(m, 1H), 1.92(m, 1H), 2.09(m ,1H),2.25(m,3H),3.02(m,1H),3.35(m,1H),5.23(m,3H),6.53(m,2H),6.94(m,2H),7.88(m, 1H), 8.14 (m, 1H), 8.59 (m, 1H), 10.95 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.2；Rt=2.420min。LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.2; Rt=2.420 min.

步驟2：2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物111 )之合成Step 2: 2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl) -Synthesis of 2-oxoacetamide ( Compound 111 )

將2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(10.00mg，25.54μmol)溶解於DCM(1mL)中。將所得混合物攪拌5min，隨後添加TEA(2.58mg，25.54μmol，3.56μL)及乙醯氯(2.00mg，25.54μmol，1.55μL)。蒸發溶劑且使用HPLC(50% 0.5-6.5min；水-MeOH；流速30 mL/min；裝載泵4mL/min MeOH；管柱SunFire 100* 19mm 5um)純化，以得到2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.005g，12.68μmol，49.64%產率)。2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-side Oxyacetamide (10.00 mg, 25.54 μmol) was dissolved in DCM (1 mL). The resulting mixture was stirred for 5 min before TEA (2.58 mg, 25.54 μmol, 3.56 μL) and acetyl chloride (2.00 mg, 25.54 μmol, 1.55 μL) were added. The solvent was evaporated and purified using HPLC (50% 0.5-6.5 min; water-MeOH; flow rate 30 mL/min; loading pump 4 mL/min MeOH; column SunFire 100 * 19mm 5um) to give 2-[(2R,5S) -2-(4-Acetylaminophenyl)-5-methyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (0.005 g, 12.68 μmol, 49.64% yield).

1 H NMR(氯仿-d,600MHz)：δ(ppm)0.92(m,3H),1.17(m,1H),1.68(m,4H),1.83(m,5H),1.97(m,3H),2.67(m,1H),3.75(m,1H),5.06(m,1H),6.04(m,2H),6.26(m,2H),6.72(m,1H),6.87(m,1H),7.11(m,1H),7.83(m,1H)。 1 H NMR (chloroform-d, 600MHz): δ (ppm) 0.92 (m, 3H), 1.17 (m, 1H), 1.68 (m, 4H), 1.83 (m, 5H), 1.97 (m, 3H), 2.67(m, 1H), 3.75(m, 1H), 5.06(m, 1H), 6.04(m, 2H), 6.26(m, 2H), 6.72(m, 1H), 6.87(m, 1H), 7.11 (m, 1H), 7.83 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.4；Rt=2.464min。LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.4; Rt=2.464 min.

實例45. 5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物424)及5-[[2-[(2R,5S)5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物438)之合成Example 45. 5-[[2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (Compound 424) and 5-[[2-[(2R,5S)5-methyl-2-[4-(methylamino)phenyl]-1-piperidine Synthesis of pyridyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 438)

Figure 110128222-A0202-12-0972-63
Figure 110128222-A0202-12-0972-63

步驟1：5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]-1-piperidinyl]-2-pendoxetylacetyl Synthesis of ]amino]pyridine-3-carboxamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(223.89mg，721.42μmol，N(C2H5)3)、N-甲基-4-[(2S,5R)-5-甲基-2-哌啶基]苯胺(0.2g，721.42μmol，2HCl)、HATU(301.73mg，793.56μmol)及DIPEA(279.71mg，2.16mmol，376.96μL)一起混合於DMSO(4mL)中。將所得混合物在室溫下攪拌16h。然後，使所獲得之於DMSO中之溶液經歷HPLC(2-10min 35-100% MeOH/H2 O為流動相；30mL/min；裝載泵4mL MeOH；SunFire 100* 19mm，5微米管柱)，以得到 5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.086g，217.47μmol，30.15%產率)。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (223.89 mg, 721.42 μmol, N(C2H5)3), N-methyl-4-[( 2S,5R)-5-methyl-2-piperidinyl]aniline (0.2 g, 721.42 μmol, 2HCl), HATU (301.73 mg, 793.56 μmol) and DIPEA (279.71 mg, 2.16 mmol, 376.96 μL) were mixed together in in DMSO (4 mL). The resulting mixture was stirred at room temperature for 16 h. Then, the obtained solution in DMSO was subjected to HPLC (2-10 min 35-100% MeOH/H 2 O as mobile phase; 30 mL/min; loading pump 4 mL MeOH; SunFire 100 * 19 mm, 5 micron column), to give 5-[[2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]-1-piperidinyl]-2-side oxyacetyl] Amino]pyridine-3-carboxamide (0.086 g, 217.47 μmol, 30.15% yield).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=2.233min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=2.233 min.

步驟2：5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物424 )及5-[[2-[(2R,5S)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物438 )之合成Step 2: 5-[[2-[(2S,5R)-5-Methyl-2-[4-(methylamino)phenyl]-1-piperidinyl]-2-pendoxoethanoyl ]amino]pyridine-3-carboxamide ( compound 424 ) and 5-[[2-[(2R,5S)-5-methyl-2-[4-(methylamino)phenyl]-1- Synthesis of piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 438 )

使用Chiralpak AD-HIII(250* 20mm，5mkm)管柱；以己烷-IPA-MeOH，50-25-25為流動相；流速：12mL/min；(m=0.085g，3次注入，Vph=3L，4.5h)進行5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性分離，得到呈淡黃色固體之化合物424 5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(17.7mg，20.58%產率；RT=22.230min)及呈淡黃色固體之化合物438 5-[[2-[(2R,5S)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(22.1mg，25.70%產率，RT=54.618min)。Using Chiralpak AD-HIII (250 * 20mm, 5mkm) column; with hexane-IPA-MeOH, 50-25-25 as mobile phase; flow rate: 12mL/min; (m=0.085g, 3 injections, Vph= 3L, 4.5h) 5-[[2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]-1-piperidinyl]-2-side oxy Chiral isolation of acetyl]amino]pyridine-3-carboxamide to give compound 424 as a pale yellow solid 5-[[2-[(2S,5R)-5-methyl-2-[4- (Methylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (17.7 mg, 20.58% yield; RT=22.230 min) and Compound 438 as pale yellow solid 5-[[2-[(2R,5S)-5-methyl-2-[4-(methylamino)phenyl]-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (22.1 mg, 25.70% yield, RT=54.618 min).

化合物438： RT(AD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min=59.935min Compound 438: RT (AD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min=59.935 min

1 H NMR(500MHz,DMSO-d6 )δ 0.90-1.16(m,3H),1.28-1.38(m,1H),1.68-1.93(m,2H),1.93-2.11(m,1H),2.12-2.22(m,1H),2.63-2.75(m,3H),2.77-3.25(m,1H),3.36-4.02(m,1H),5.00-5.59(m,1H),5.59-5.65(m,1H),6.46-6.66(m,2H),6.97-7.13(m,2H),7.51-7.73(m,1H),8.11-8.27(m,1H),8.41-8.58(m,1H),8.69-8.85(m,1H),8.85-8.97(m,1H),11.10-11.30(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.90-1.16(m,3H), 1.28-1.38(m,1H), 1.68-1.93(m,2H), 1.93-2.11(m,1H), 2.12- 2.22(m, 1H), 2.63-2.75(m, 3H), 2.77-3.25(m, 1H), 3.36-4.02(m, 1H), 5.00-5.59(m, 1H), 5.59-5.65(m, 1H) ),6.46-6.66(m,2H),6.97-7.13(m,2H),7.51-7.73(m,1H),8.11-8.27(m,1H),8.41-8.58(m,1H),8.69-8.85 (m, 1H), 8.85-8.97 (m, 1H), 11.10-11.30 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=1.975min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=1.975 min.

化合物424： RT(AD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min=20.107min Compound 424: RT (AD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min=20.107 min

1 H NMR(500MHz,DMSO-d6 )δ 0.95-1.14(m,3H),1.26-1.40(m,1H),1.65-1.94(m,2H),1.94-2.11(m,1H),2.13-2.24(m,1H),2.64-2.69(m,3H),2.74-3.27(m, 1H),3.36-4.01(m,1H),4.98-5.58(m,1H),5.58-5.67(m,1H),6.44-6.67(m,2H),6.99-7.14(m,2H),7.52-7.70(m,1H),8.08-8.27(m,1H),8.40-8.56(m,1H),8.69-8.84(m,1H),8.84-8.98(m,1H),11.12-11.31(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.95-1.14(m,3H), 1.26-1.40(m,1H), 1.65-1.94(m,2H), 1.94-2.11(m,1H), 2.13- 2.24(m, 1H), 2.64-2.69(m, 3H), 2.74-3.27(m, 1H), 3.36-4.01(m, 1H), 4.98-5.58(m, 1H), 5.58-5.67(m, 1H) ),6.44-6.67(m,2H),6.99-7.14(m,2H),7.52-7.70(m,1H),8.08-8.27(m,1H),8.40-8.56(m,1H),8.69-8.84 (m, 1H), 8.84-8.98 (m, 1H), 11.12-11.31 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=1.976min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=1.976 min.

實例46. N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物630)及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物621)之合成Example 46. N-(5,6-Dimethyl-3-pyridyl)-2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide (Compound 630) and N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-2-[4 Synthesis of -(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 621)

Figure 110128222-A0202-12-0974-64
Figure 110128222-A0202-12-0974-64

步驟1：N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(5,6-Dimethyl-3-pyridyl)-2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl- Synthesis of 1-Piperidinyl]-2-Pendant Oxyacetamide

在25℃下，在0.5h內，向4-[(2S,5R)-5-甲基-2-哌啶基]苯胺(250mg，1.31mmol)、2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(388.07mg，1.31mmol，N(C2 H5 )3 )及三乙胺(1.33g，13.14mmol，1.83mL)於DMF(5mL)中之經攪拌之溶液中小批量添加HATU(549.51mg，1.45mmol)。將所得反應混合物在25℃下攪拌18h。將反應混合物樣品提交用於LCMS分析。LCMS指示在RT=0.862min處26.88%之所要產物質量曲線下面積。然後，逐滴添加甲磺醯氯(180.60mg，1.58mmol，122.03μL)，且將反應混合物在25℃下再攪拌3h。藉由反相HPLC(管柱：YMC Triart C18 100* 20mm，5um，流動相：40-90% 1-6min水-甲醇(NH3 0.1%)，流速：30mL/min，裝載泵4mL/min甲醇(NH3 0.1%))純化粗反應混合物，以得到呈黃色膠狀物之N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(65mg，146.22μmol，11.13%產率)，其直 接用於下一步驟(掌性分離)。To 4-[(2S,5R)-5-methyl-2-piperidinyl]aniline (250 mg, 1.31 mmol), 2-[(5,6-dimethyl -3-Pyridinyl)amino]-2-side oxyacetic acid (388.07 mg, 1.31 mmol, N(C 2 H 5 ) 3 ) and triethylamine (1.33 g, 13.14 mmol, 1.83 mL) in DMF (5 mL) ) was added HATU (549.51 mg, 1.45 mmol) in small portions to the stirred solution. The resulting reaction mixture was stirred at 25 °C for 18 h. A sample of the reaction mixture was submitted for LCMS analysis. LCMS indicated 26.88% area under the curve for the mass of the desired product at RT=0.862 min. Then, mesylate chloride (180.60 mg, 1.58 mmol, 122.03 μL) was added dropwise, and the reaction mixture was stirred at 25 °C for an additional 3 h. by reverse phase HPLC (column: YMC Triart C18 100 * 20mm, 5um, mobile phase: 40-90% 1-6 min water-methanol ( NH3 0.1%), flow rate: 30 mL/min, loading pump 4 mL/min methanol ( NH3 0.1%)) The crude reaction mixture was purified to give N-(5,6-dimethyl-3-pyridinyl)-2-[(2S,5R)-2-[4 as a yellow gum -(Methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (65 mg, 146.22 μmol, 11.13% yield), which was used directly in the next step (chiral separation).

LCMS(ESI)：[M+H]+ m/z：計算值444.2；實測值445.2；Rt=2.092min。LCMS (ESI): [M+H] + m/z: calculated 444.2; found 445.2; Rt=2.092 min.

步驟2：N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物630 )及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物621 )之合成Step 2: N-(5,6-Dimethyl-3-pyridyl)-2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide ( Compound 630 ) and N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-2-[4 Synthesis of -(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 621 )

將外消旋N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(65mg，146.22μmol)提交至製備型掌性HPLC(管柱：Chiralpak IA-II(250* 20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：12mL/min)，以得到呈白色固體之化合物630 N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(21.2mg，47.69μmol，32.62%產率)(RT=31.713min)及化合物621 N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(21.7mg，48.81μmol，33.38%產率)(RT=46.866min)。Racemic N-(5,6-dimethyl-3-pyridinyl)-2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl -1-Piperidinyl]-2-oxyacetamide (65 mg, 146.22 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IA-II (250 * 20 mm, 5 mkm); mobile phase: hexane -IPA-MeOH 50-25-25; flow rate: 12 mL/min) to give compound 630 as a white solid N-(5,6-dimethyl-3-pyridyl)-2-[(2S,5R) -2-[4-(Methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (21.2 mg, 47.69 μmol, 32.62% yield) ( RT=31.713 min) and compound 621 N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]- 5-Methyl-1-piperidinyl]-2-oxoacetamide (21.7 mg, 48.81 μmol, 33.38% yield) (RT=46.866 min).

化合物630： RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=33.389min。 Compound 630: RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 33.389 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.98(m,3H),1.23(m,1H),1.54(m,1H),1.69(m,1H),2.12(s,3H),2.24(s,3H),2.87(m,6H),3.21(dd,1H),3.41(dd,1H),4.01(m,2H),7.19(m,4H),7.79(d,1H),8.42(d,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.98(m, 3H), 1.23(m, 1H), 1.54(m, 1H), 1.69(m, 1H), 2.12(s, 3H), 2.24(s ,3H),2.87(m,6H),3.21(dd,1H),3.41(dd,1H),4.01(m,2H),7.19(m,4H),7.79(d,1H),8.42(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值444.2；實測值445.2；Rt=1.963min。LCMS (ESI): [M+H] + m/z: calculated 444.2; found 445.2; Rt=1.963 min.

化合物621： RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=50.039min。 Compound 621: RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 50.039 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.98(m,3H),1.23(m,1H),1.54(m,1H),1.69(m,1H),2.14(s,3H),2.20(s,3H),2.87(m,6H),3.17(m,1H),3.40(m,1H),4.01(m,2H),7.21(m,4H),7.80(d,1H),8.42(d,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.98(m, 3H), 1.23(m, 1H), 1.54(m, 1H), 1.69(m, 1H), 2.14(s, 3H), 2.20(s ,3H),2.87(m,6H),3.17(m,1H),3.40(m,1H),4.01(m,2H),7.21(m,4H),7.80(d,1H),8.42(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值444.2；實測值445.2；Rt=1.969min。LCMS (ESI): [M+H] + m/z: calculated 444.2; found 445.2; Rt=1.969 min.

實例47.外消旋 -2-((2R,5S )-2-(4-羥基苯基)-5-甲基哌啶-1-基)-N -(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物557)之合成Example 47. Racemic -2-(( 2R,5S )-2-(4-hydroxyphenyl)-5-methylpiperidin - 1-yl)-N-(5-methylpyridin-3-yl )-2-oxyacetamide (Compound 557) Synthesis

Figure 110128222-A0202-12-0976-65
Figure 110128222-A0202-12-0976-65

在室溫下將HATU(283.88mg，746.59μmol)分批添到2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(210.05mg，746.59μmol),4-(5-甲基-2-哌啶基)苯酚(0.21g，746.59μmol)及TEA(453.29mg，4.48mmol，624.36μL)於DMF(10mL)中之懸浮液中。將澄清溶液在25℃下攪拌32h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：SunFireC18 100x19mm 5um；38-60% 0-5min水-MeOH 30ml/min為流動相)，以得到化合物557 2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(42mg，118.84μmol，15.92%產率)。HATU (283.88 mg, 746.59 μmol) was added portionwise at room temperature to 2-[(5-methyl-3-pyridyl)amino]-2-oxoacetic acid (210.05 mg, 746.59 μmol), 4 -(5-Methyl-2-piperidinyl)phenol (0.21 g, 746.59 μmol) and TEA (453.29 mg, 4.48 mmol, 624.36 μL) in suspension in DMF (10 mL). The clear solution was stirred at 25 °C for 32 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: SunFire C18 100x19mm 5um; 38-60% 0-5min water-MeOH 30ml/min as mobile phase) to give compound 557 2-[( 2S,5R )-2-(4- Hydroxyphenyl)-5-methyl - 1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (42 mg, 118.84 μmol, 15.92% yield) .

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.05(m,3H),1.25-1.37(m,1H),1.63-1.77(m,1H),1.78-1.93(m,1H),1.93-2.10(m,1H),2.10-2.20(m,1H),2.22-2.32(m,3H),2.71-3.21(m,1H),3.39-4.03(m,1H),4.98-5.63(m,1H),6.71-6.78(m,2H),7.05-7.17(m,2H),7.86-7.97(m,1H),8.09-8.22(m,1H),8.51-8.63(m,1H),9.35(s,1H),10.79-11.13(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.05(m,3H), 1.25-1.37(m,1H), 1.63-1.77(m,1H), 1.78-1.93(m,1H) ,1.93-2.10(m,1H),2.10-2.20(m,1H),2.22-2.32(m,3H),2.71-3.21(m,1H),3.39-4.03(m,1H),4.98-5.63( m,1H),6.71-6.78(m,2H),7.05-7.17(m,2H),7.86-7.97(m,1H),8.09-8.22(m,1H),8.51-8.63(m,1H), 9.35(s, 1H), 10.79-11.13(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值353.4；實測值354.2；Rt=1.781min。LCMS (ESI): [M] + m/z: calculated 353.4; found 354.2; Rt=1.781 min.

實例48. 5-(2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物288、化合物292)之合成Example 48. 5-(2-(2-(4-Hydroxyphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide Synthesis of Amines (Compound 288, Compound 292)

Figure 110128222-A0202-12-0976-66
Figure 110128222-A0202-12-0976-66

步驟1：5-(2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼Step 1: 5-(2-(2-(4-Hydroxyphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotine 醯胺之合成Synthesis of Amide

將4-[(2R,5S )-5-甲基-2-哌啶基]苯酚(200mg，597.20μmol，HCl)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(203.27mg，597.20μmol，Et3 N)及TEA(151.08mg，1.49mmol，208.09μL)溶解於DMF(3mL)中。在5min期間分批添加HATU(249.78mg，656.92μmol)。將所得溶液在25℃下攪拌12h。然後使其經歷HPLC(管柱：SunFireC18 100*19mm，5um；0-5min 20-45%水-MeCN，流速30ml/min)，得到5-[[2-[(2R,5S )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(40mg，96.98μmol，16.24%產率)。4-[( 2R,5S )-5-methyl-2-piperidinyl]phenol (200 mg, 597.20 μmol, HCl), 2-[(5-aminocarbamoyl-6-methoxy-3- Pyridyl)amino]-2-oxoacetic acid (203.27 mg, 597.20 μmol, Et3N ) and TEA (151.08 mg, 1.49 mmol, 208.09 μL) were dissolved in DMF (3 mL). HATU (249.78 mg, 656.92 μmol) was added in portions during 5 min. The resulting solution was stirred at 25 °C for 12 h. It was then subjected to HPLC (column: SunFire C18 100*19mm, 5um; 0-5min 20-45% water-MeCN, flow rate 30ml/min) to give 5-[[2-[( 2R,5S )-2-( 4-Hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (40 mg, 96.98 μmol, 16.24% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值412.4；實測值413.2；Rt=2.814min。LCMS (ESI): [M] + m/z: calculated 412.4; found 413.2; Rt=2.814 min.

步驟2：掌性分離(化合物288 及化合物292 )Step 2: Chiral separation ( compound 288 and compound 292 )

使外消旋物經歷掌性HPLC(管柱：Chiralpak IA II(250 * 20mm，5um)；流動相：己烷-IPA-MeOH，60-20-20；流速：12mL/min；m=0.04g，3次注入，12mg/注入V=2,2L.時間=3,5h.)，得到5-[[2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(13mg，31.52μmol，63.41%產率)(保留時間=33.85min)及5-[[2-[(2R,5S )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(12mg，29.10μmol，58.54%產率)(保留時間=47.087min)。化合物288 於分析條件下(管柱：IA，己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為44.81min且化合物292 之保留時間為32.41min。The racemate was subjected to chiral HPLC (column: Chiralpak IA II (250*20mm, 5um); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12 mL/min; m=0.04 g , 3 injections, 12mg/injection V=2, 2L. Time=3, 5h.) to obtain 5-[[2-[( 2S,5R )-2-(4-hydroxyphenyl)-5-methyl -1-Piperidinyl]-2-Oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (13 mg, 31.52 μmol, 63.41% yield) (retention time = 33.85 min ) and 5-[[2-[( 2R,5S )-2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]- 2-Methoxypyridine-3-carboxamide (12 mg, 29.10 μmol, 58.54% yield) (retention time = 47.087 min). The retention time of compound 288 under analytical conditions (column: IA, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 44.81 min and the retention time of compound 292 was 32.41 min.

化合物288：保留時間：44.81minCompound 288: retention time: 44.81min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.98-1.06(m,3H),1.27-1.40(m,1H),1.63-1.77(m,1H),1.80-1.93(m,1H),1.96-2.12(m,1H),2.12-2.25(m,1H),2.72-3.20(m,1H),3.39-3.47(m,1H),3.93-4.01(m,3H),4.95-5.66(m,1H),6.68-6.81(m, 2H),7.06-7.21(m,2H),7.68-7.82(m,2H),8.41-8.49(m,1H),8.50-8.60(m,1H),9.37(s,1H),10.86-11.11(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.98-1.06(m,3H), 1.27-1.40(m,1H), 1.63-1.77(m,1H), 1.80-1.93(m,1H) ,1.96-2.12(m,1H),2.12-2.25(m,1H),2.72-3.20(m,1H),3.39-3.47(m,1H),3.93-4.01(m,3H),4.95-5.66( m,1H),6.68-6.81(m,2H),7.06-7.21(m,2H),7.68-7.82(m,2H),8.41-8.49(m,1H),8.50-8.60(m,1H), 9.37(s, 1H), 10.86-11.11(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.4；實測值413.2；Rt=2.861min。LCMS (ESI): [M] + m/z: calculated 412.4; found 413.2; Rt=2.861 min.

化合物292：保留時間：32.41minCompound 292: retention time: 32.41min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.99-1.06(m,3H),1.28-1.42(m,1H),1.66-1.81(m,1H),1.82-1.94(m,1H),1.97-2.11(m,1H),2.12-2.22(m,1H),2.75-3.20(m,1H),3.39-3.48(m,1H),3.94-4.04(m,3H),5.01-5.61(m,1H),6.69-6.87(m,2H),7.07-7.18(m,2H),7.67-7.79(m,2H),8.42-8.51(m,1H),8.50-8.60(m,1H),9.37(s,1H),10.91-11.13(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.99-1.06(m,3H), 1.28-1.42(m,1H), 1.66-1.81(m,1H), 1.82-1.94(m,1H) ,1.97-2.11(m,1H),2.12-2.22(m,1H),2.75-3.20(m,1H),3.39-3.48(m,1H),3.94-4.04(m,3H),5.01-5.61( m,1H),6.69-6.87(m,2H),7.07-7.18(m,2H),7.67-7.79(m,2H),8.42-8.51(m,1H),8.50-8.60(m,1H), 9.37(s, 1H), 10.91-11.13(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.4；實測值413.2；Rt=2.859min。LCMS (ESI): [M] + m/z: calculated 412.4; found 413.2; Rt=2.859 min.

實例49. 5-(2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物287、化合物297)之合成Example 49. 5-(2-(2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 287, compound 297) synthesis

Figure 110128222-A0202-12-0978-67
Figure 110128222-A0202-12-0978-67

將TEA(1.76g，17.41mmol，2.43mL)添加到4-(5-甲基-2-哌啶基)苯酚(0.65g，1.74mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(540.35mg，1.74mmol)及HATU(662.02mg，1.74mmol)於DMF(10mL)中之經攪拌之混合物中。將反應混合物在25℃下攪拌2h，然後提交至反相HPLC(管柱：XBridge C18 100x19mm，5um，流動相：10-10-40% 0-2-6min 0.1%NH3 -MeOH)，以得到95mg呈淡黃色固體之外消旋醯胺。然後將其提交至掌性HPLC(管柱：Chiralpak AD-H I，(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 70-15-15；流速：12mL/min)，以得到化合物287 5-[[2-[(2R,5S )-2-(4-羥基苯基)-5-甲基-1-哌 啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(28mg，73.22μmol，4.21%產率)(RT=29.61)及化合物297 5-[[2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(24mg，62.76μmol，3.60%產率)(RT=20.32)。化合物287 於分析條件下(管柱：AD-H，己烷-IPA-MeOH 70-15-15，0.6ml/min為流動相)之保留時間為31.37min且化合物297 之保留時間為22.48min。TEA (1.76 g, 17.41 mmol, 2.43 mL) was added to 4-(5-methyl-2-piperidinyl)phenol (0.65 g, 1.74 mmol, HCl), 2-[(5-aminocarbamoyl- In a stirred mixture of 3-pyridyl)amino]-2-pendoxoacetic acid (540.35 mg, 1.74 mmol) and HATU (662.02 mg, 1.74 mmol) in DMF (10 mL). The reaction mixture was stirred at 25°C for 2h, then submitted to reverse phase HPLC (column: XBridge C18 100x19mm, 5um, mobile phase: 10-10-40% 0-2-6min 0.1% NH3 -MeOH) to give 95 mg of racemic amide as a pale yellow solid. It was then submitted to chiral HPLC (column: Chiralpak AD-HI, (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH 70-15-15; flow rate: 12mL/min) to give Compound 287 5-[[2-[( 2R,5S )-2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide (28 mg, 73.22 μmol, 4.21% yield) (RT=29.61) and compound 297 5-[[2-[( 2S,5R )-2-(4-hydroxyphenyl)-5- Methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (24 mg, 62.76 μmol, 3.60% yield) (RT=20.32). The retention time of compound 287 under analytical conditions (column: AD-H, hexane-IPA-MeOH 70-15-15, 0.6 ml/min as mobile phase) was 31.37 min and that of compound 297 was 22.48 min.

化合物287：保留時間：31.37minCompound 287: retention time: 31.37min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.27-1.38(m,1H),1.65-1.77(m,1H),1.80-1.91(m,1H),1.96-2.11(m,1H),2.12-2.20(m,1H),2.74-3.21(m,1H),3.37-4.02(m,1H),5.01-5.56(m,1H),6.70-6.78(m,2H),7.04-7.15(m,2H),7.53-7.68(m,1H),8.10-8.22(m,1H),8.41-8.51(m,1H),8.69-8.81(m,1H),8.82-8.93(m,1H),9.36(s,1H),11.11-11.28(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.04(m,3H), 1.27-1.38(m,1H), 1.65-1.77(m,1H), 1.80-1.91(m,1H) ,1.96-2.11(m,1H),2.12-2.20(m,1H),2.74-3.21(m,1H),3.37-4.02(m,1H),5.01-5.56(m,1H),6.70-6.78( m,2H),7.04-7.15(m,2H),7.53-7.68(m,1H),8.10-8.22(m,1H),8.41-8.51(m,1H),8.69-8.81(m,1H), 8.82-8.93 (m, 1H), 9.36 (s, 1H), 11.11-11.28 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值382.5；實測值383.2；Rt=2.558min。LCMS (ESI): [M] + m/z: calculated 382.5; found 383.2; Rt=2.558 min.

化合物297：保留時間：22.48minCompound 297: retention time: 22.48min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.24-1.37(m,1H),1.61-1.76(m,1H),1.79-1.92(m,1H),1.94-2.10(m,1H),2.12-2.19(m,1H),2.73-3.21(m,1H),3.38-4.01(m,1H),5.01-5.59(m,1H),6.71-6.81(m,2H),7.05-7.20(m,2H),7.52-7.69(m,1H),8.07-8.21(m,1H),8.42-8.59(m,1H),8.70-8.80(m,1H),8.82-8.95(m,1H),9.35(s,1H),11.11-11.27(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.05(m,3H), 1.24-1.37(m,1H), 1.61-1.76(m,1H), 1.79-1.92(m,1H) ,1.94-2.10(m,1H),2.12-2.19(m,1H),2.73-3.21(m,1H),3.38-4.01(m,1H),5.01-5.59(m,1H),6.71-6.81( m,2H),7.05-7.20(m,2H),7.52-7.69(m,1H),8.07-8.21(m,1H),8.42-8.59(m,1H),8.70-8.80(m,1H), 8.82-8.95(m,1H), 9.35(s,1H), 11.11-11.27(m,1H).

LCMS(ESI)：[M]+ m/z：計算值382.5；實測值383.2；Rt=2.560min。LCMS (ESI): [M] + m/z: calculated 382.5; found 383.2; Rt=2.560 min.

實例50. 5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物473)、5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物457)之合成Example 50. 5-[[2-[(2R,5R)-4,4-difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (Compound 473), 5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-phenyl-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide (compound 457)

Figure 110128222-A0202-12-0979-68
Figure 110128222-A0202-12-0979-68

將(2S,5S)-4,4-二氟-5-甲基-2-苯基哌啶(200.00mg，946.75μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(293.82mg，946.75μmol，Et3N)、TEA(958.01mg，9.47mmol，1.32mL)及HATU(539.97mg，1.42mmol)溶解於DMF(7mL)中且在20℃下攪拌3h。將反應混合物用水稀釋且用EA萃取三次，然後將EA用鹽水萃取三次。將有機相經Na2 SO4 乾燥，過濾且在40℃下蒸發，以得到粗產物，其藉由HPLC(40-60%水/MeCN+NH3 ，2-10min，流速30ml/min(裝載泵4ml/min MeCN+NH3 )管柱：TRIART 100*20 5mM)進行純化，以得到2種鏡像異構物之純混合物。(2S,5S)-4,4-difluoro-5-methyl-2-phenylpiperidine (200.00 mg, 946.75 μmol), 2-[(5-aminocarbamoyl-3-pyridyl)amine [methyl]-2-oxoacetic acid (293.82 mg, 946.75 μmol, Et3N), TEA (958.01 mg, 9.47 mmol, 1.32 mL) and HATU (539.97 mg, 1.42 mmol) were dissolved in DMF (7 mL) and at 20°C under stirring for 3h. The reaction mixture was diluted with water and extracted three times with EA, then EA three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and evaporated at 40° C. to give the crude product, which was obtained by HPLC (40-60% water/MeCN+NH 3 , 2-10 min, flow rate 30 ml/min (loading pump) 4ml/min MeCN+ NH3 ) column: TRIART 100*20 5mM) was purified to give a pure mixture of the 2 enantiomers.

使用管柱：Chiralpak IB(250 * 20mm，5mkm)；注入體積900mkl；流動相：己烷-IPA-MeOH 60-20-20；流速：15mL/min進行掌性分離，以得到呈單一鏡像異構物之5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.034g，84.49μmol，8.92%產率)及呈單一鏡像異構物之5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.035g，86.98μmol，9.19%產率)。Using column: Chiralpak IB (250*20mm, 5mkm); Injection volume 900mkl; Mobile phase: Hexane-IPA-MeOH 60-20-20; Flow rate: 15mL/min for chiral separation to obtain a single mirror image 5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (0.034 g, 84.49 μmol, 8.92% yield) and 5-[[2-[(2R,5R)-4,4-difluoro-5- as a single enantiomer Methyl-2-phenyl-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (0.035 g, 86.98 μmol, 9.19% yield).

化合物473： RT(IB，Hex-IPA-MeOH，50-25-25，0.6ml/min)=14.870min Compound 473: RT (IB, Hex-IPA-MeOH, 50-25-25, 0.6 ml/min) = 14.870 min

1 H NMR(600MHz,DMSO-d 6 )δ 1.09(d,3H),2.09-2.28(m,1H),2.42-2.46(m,1H),2.80-2.91(m,1H),3.02-3.09(m,0.4H),3.44-3.52(m,0.6H),3.78-4.35(m,1H),5.53-5.96(m,1H),7.21-7.30(m,1H),7.30-7.37(m,3H),7.37-7.41(m,1H),7.55-7.67(m,1H),8.09-8.21(m,1H),8.41-8.56(m,1H),8.69-8.81(m,1H),8.81-8.96(m,1H),11.13-11.49(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.09(d,3H), 2.09-2.28(m,1H), 2.42-2.46(m,1H), 2.80-2.91(m,1H), 3.02-3.09( m,0.4H),3.44-3.52(m,0.6H),3.78-4.35(m,1H),5.53-5.96(m,1H),7.21-7.30(m,1H),7.30-7.37(m,3H) ),7.37-7.41(m,1H),7.55-7.67(m,1H),8.09-8.21(m,1H),8.41-8.56(m,1H),8.69-8.81(m,1H),8.81-8.96 (m, 1H), 11.13-11.49 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值402.2；實測值403.2；Rt=2.994minLCMS(ESI): [M+1] + m/z: Calculated 402.2; Measured 403.2; Rt=2.994min

化合物457： RT(IB，Hex-IPA-MeOH，50-25-25，0.6ml/min)=10.108min Compound 457: RT (IB, Hex-IPA-MeOH, 50-25-25, 0.6 ml/min) = 10.108 min

1 H NMR(600MHz,DMSO-d 6 )δ 1.09(d,3H),2.09-2.28(m,1H),2.42-2.46(m,1H),2.80-2.91(m,1H),3.02-3.09(m,0.4H),3.44-3.52(m,0.6H),3.78-4.35(m, 1H),5.53-5.96(m,1H),7.21-7.30(m,1H),7.30-7.37(m,3H),7.37-7.41(m,1H),7.55-7.67(m,1H),8.09-8.21(m,1H),8.41-8.56(m,1H),8.69-8.81(m,1H),8.81-8.96(m,1H),11.13-11.49(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.09(d,3H), 2.09-2.28(m,1H), 2.42-2.46(m,1H), 2.80-2.91(m,1H), 3.02-3.09( m, 0.4H), 3.44-3.52(m, 0.6H), 3.78-4.35(m, 1H), 5.53-5.96(m, 1H), 7.21-7.30(m, 1H), 7.30-7.37(m, 3H) ),7.37-7.41(m,1H),7.55-7.67(m,1H),8.09-8.21(m,1H),8.41-8.56(m,1H),8.69-8.81(m,1H),8.81-8.96 (m, 1H), 11.13-11.49 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值402.2；實測值403.2；Rt=2.996minLCMS(ESI): [M+1] + m/z: Calculated 402.2; Measured 403.2; Rt=2.996min

5-(2-(5-氟-5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物795、化合物798)之合成Synthesis of 5-(2-(5-fluoro-5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 795, Compound 798)

Figure 110128222-A0202-12-0981-69
Figure 110128222-A0202-12-0981-69

步驟1：5-(2-(5-氟-5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: Synthesis of 5-(2-(5-fluoro-5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(17.79mg，72.44μmol，HCl)及TEA(73.30mg，724.41μmol，100.97μL)溶解於DMF(2mL)中且冷卻至0℃，添加HATU(41.32mg，108.66μmol)且將混合物在0℃下攪拌15min。添加(2R,5R )-5-氟-5-甲基-2-苯基哌啶(0.014g，72.44μmol)且將混合物升溫至室溫且攪拌3h。添加10ml乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(5-95% MeCN 6min.Poroshell 120 EC-C18 4,6*100mm)進行純化，以得到5-[[2-[(2R,5R )-5-氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.013g，33.82μmol，46.68%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (17.79 mg, 72.44 μmol, HCl) and TEA (73.30 mg, 724.41 μmol, 100.97 μL) were dissolved in In DMF (2 mL) and cooled to 0 °C, HATU (41.32 mg, 108.66 μmol) was added and the mixture was stirred at 0 °C for 15 min. ( 2R,5R )-5-fluoro-5-methyl-2-phenylpiperidine (0.014 g, 72.44 μmol) was added and the mixture was warmed to room temperature and stirred for 3 h. 10 ml of ethyl acetate were added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45°C to give the crude product, which was carried out by HPLC (5-95% MeCN 6 min. Poroshell 120 EC-C18 4, 6*100mm) Purification to give 5-[[2-[( 2R,5R )-5-fluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (0.013 g, 33.82 μmol, 46.68% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm) 1 H NMR (400MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值384.2；實測值385.2；Rt=3.852min。LCMS (ESI): [M] + m/z: calculated 384.2; found 385.2; Rt=3.852 min.

步驟2：掌性分離(化合物795 及化合物798 )Step 2: Chiral separation ( compound 795 and compound 798 )

藉由掌性層析(IA-II(250*20,5mkm)，IPA-MeOH，50-50，12ml/min)分離非鏡像異構物之混合物，以獲得N -[5-[[2-[(2S,5R )-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(21.02mg，43.56μmol，34.12%產率)(RT=19.23)。The mixture of diastereomers was separated by chiral chromatography (IA-II (250*20, 5mkm), IPA-MeOH, 50-50, 12ml/min) to obtain N- [5-[[2- [( 2S,5R )-2-(6-amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-ethyl - 3 -Butyl 2-pyridyl]carbamate (21.02 mg, 43.56 μmol, 34.12% yield) (RT=19.23).

使用管柱：Chiralpak AD-H-III(250*20，5mkm)，己烷-MeOH-IPA，60-20-20，12ml/min進行掌性分離，以得到5-[[2-[(2R,5R )-5-氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0044g，11.45μmol，33.85%產率)(RT=42.39)。Chiralpak separation was performed using column: Chiralpak AD-H-III (250*20, 5mkm), Hexane-MeOH-IPA, 60-20-20, 12ml/min to give 5-[[2-[( 2R ,5R )-5-fluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.0044g, 11.45μmol , 33.85% yield) (RT=42.39).

化合物795 於分析條件下(管柱：IA，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為17.48min且化合物798 之保留時間為11.91min。The retention time of compound 795 under analytical conditions (column: IA, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 17.48 min and the retention time of compound 798 was 11.91 min.

化合物795：保留時間：17.48minCompound 795: retention time: 17.48min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm) 1 H NMR (600MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值384.2；實測值385.2；Rt=3.859min。LCMS (ESI): [M] + m/z: calculated 384.2; found 385.2; Rt=3.859 min.

化合物798：保留時間：11.91minCompound 798: retention time: 11.91min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm) 1 H NMR (600MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值384.2；實測值385.2；Rt=3.858min。LCMS (ESI): [M] + m/z: calculated 384.2; found 385.2; Rt=3.858 min.

實例51.外消旋 -2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺及外消旋 -2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物25及化合物23)之合成；2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺、2-[(2R ,3S ,6R )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物39及化合物32)、2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2S ,3S ,6R )-2,3-二甲基-6-苯基-1-哌啶Example 51. Racemic -2-[( 2R , 3R , 6S )-2,3-dimethyl-6-phenyl-1-piperidinyl] -N- (5-methyl-3 -Pyridyl )-2-oxyacetamide and racemic -2-[( 2S , 3R ,6S)-2,3-dimethyl-6-phenyl-1-piperidinyl ]-N-(5-methyl - 3-pyridyl)-2-oxyacetamide (compound 25 and compound 23) synthesis; 2-[( 2S , 3R , 6S )-2, 3-Dimethyl-6-phenyl - 1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide, 2-[(2 R ,3 S ,6 R )-2,3- dimethyl -6-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxoacetamide (compound 39 and compound 32), 2-[(2 R ,3 R ,6 S )-2,3-dimethyl-6-phenyl-1-piperidinyl] -N- (5-methyl-3-pyridine yl)-2-oxyacetamide and 2-[(2 S ,3 S ,6 R )-2,3-dimethyl-6-phenyl-1-piperidine 基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物41及化合物35)之掌性分離Chiral Isolation of Radix]-N-(5-methyl - 3-pyridyl)-2-oxoacetamide (Compound 41 and Compound 35)

Figure 110128222-A0202-12-0983-70
Figure 110128222-A0202-12-0983-70

步驟1-外消旋-2-[(2R,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺及外消旋-2-[(2S,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺之合成Step 1 - Racemic-2-[(2R,3R,6S)-2,3-dimethyl-6-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridinyl )-2-oxyacetamide and racemic-2-[(2S,3R,6S)-2,3-dimethyl-6-phenyl-1-piperidinyl]-N-(5 Synthesis of -methyl-3-pyridyl)-2-oxoacetamide

在-78℃、氬氣氣氛下，向2,3-二甲基-6-苯基哌啶(1.7g，8.98mmol)於THF(20mL)中之經攪拌之溶液中逐滴添加正丁基鋰 (2.5M於己烷中，1.15g，17.96mmol，7.18mL)。將所得混合物在同一溫度下攪拌5分鐘。5分鐘之後，添加2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(2.35g，8.98mmol)。使所得混合物升溫至室溫且在同一溫度下攪拌12小時。完成之後，將反應混合物用飽和NH4 Cl水溶液淬滅。將所得混合物蒸發至乾。藉由反相HPLC(溶析液：0.5-6.5min；水-乙腈；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFire 100*19mm，5um)純化所獲得之殘餘物(1g)，以獲得呈黃色固體之外消旋 -2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物25 ，41.30mg)及外消旋 -2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物23 ，35.9mg)。To a stirred solution of 2,3-dimethyl-6-phenylpiperidine (1.7 g, 8.98 mmol) in THF (20 mL) was added n-butyl dropwise at -78°C under argon atmosphere Lithium (2.5M in hexanes, 1.15 g, 17.96 mmol, 7.18 mL). The resulting mixture was stirred at the same temperature for 5 minutes. After 5 minutes, 2-[(5-methyl-3-pyridinyl)amino]-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (2.35 g, 8.98 mmol) was added. The resulting mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl . The resulting mixture was evaporated to dryness. The obtained residue was purified by reverse phase HPLC (eluent: 0.5-6.5 min; water-acetonitrile; flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile; column: SunFire 100*19 mm, 5 um) (1 g) to obtain rac -2-[( 2R , 3R , 6S )-2,3- dimethyl -6-phenyl-1-piperidinyl]-N- as a yellow solid (5-Methyl-3-pyridyl)-2-oxyacetamide ( compound 25 , 41.30 mg) and rac -2-[( 2S , 3R , 6S )-2,3- Dimethyl-6-phenyl - 1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide ( compound 23 , 35.9 mg).

化合物25： 1 H NMR(DMSO-d 6 +CCl4 ,400MHz)：δ(ppm)0.66(m,3H),0.98(m,3H),1.65(m,2H),1.99(m,2H),2.34(m,3H),2.61(m,1H),4.30(m,1H),5.49(m,1H),7.21(m,1H),7.31(m,2H),7.43(m,2H),7.99(m,1H),8.08(m,1H),8.55(m,1H),10.90(m,1H)。 Compound 25: 1 H NMR (DMSO- d 6 +CCl 4 , 400 MHz): δ (ppm) 0.66 (m, 3H), 0.98 (m, 3H), 1.65 (m, 2H), 1.99 (m, 2H), 2.34(m, 3H), 2.61(m, 1H), 4.30(m, 1H), 5.49(m, 1H), 7.21(m, 1H), 7.31(m, 2H), 7.43(m, 2H), 7.99 (m, 1H), 8.08 (m, 1H), 8.55 (m, 1H), 10.90 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=3.380min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.2; Rt=3.380 min.

化合物23： 1 H NMR(DMSO-d 6 +CCl4 ,400MHz)：δ(ppm)0.76(m,3H),1.11(m,3H),1.51(m,1H),1.71(m,1H),1.98(m,1H),2.12(m,1H),2.34(m,3H),2.61(m,1H),3.84(m,1H),5.57(m,1H),7.21(m,1H),7.31(m,2H),7.43(m,2H),7.97(m,1H),8.10(m,1H),8.57(m,1H),10.89(m,1H)。 Compound 23: 1 H NMR (DMSO- d 6 +CCl 4 , 400 MHz): δ (ppm) 0.76 (m, 3H), 1.11 (m, 3H), 1.51 (m, 1H), 1.71 (m, 1H), 1.98(m, 1H), 2.12(m, 1H), 2.34(m, 3H), 2.61(m, 1H), 3.84(m, 1H), 5.57(m, 1H), 7.21(m, 1H), 7.31 (m, 2H), 7.43 (m, 2H), 7.97 (m, 1H), 8.10 (m, 1H), 8.57 (m, 1H), 10.89 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=3.365min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.2; Rt=3.365 min.

步驟2.2-[(2R,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2S,3S,6R)-2,3-二甲基-6-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺之掌性分離Step 2. 2-[(2R,3R,6S)-2,3-Dimethyl-6-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen Ethylacetamide and 2-[(2S,3S,6R)-2,3-dimethyl-6-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)- Chiral separation of 2-oxyacetamide

使外消旋 -2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物25， 41mg)經歷掌性分離(Chiralcel OJ-H(250 * 20mm，5um；流動相：己烷-IPA-MeOH 90-5-5；流速：12mL/min)，以獲得呈黃色固體之(化合物35 ，10mg)及(化合物41 ，10mg)。Make rac -2-[( 2R , 3R , 6S )-2,3-dimethyl-6-phenyl-1-piperidinyl] -N- (5-methyl-3-pyridine yl)-2-oxoacetamide ( compound 25, 41 mg) was subjected to chiral separation (Chiralcel OJ-H (250*20mm, 5um; mobile phase: hexane-IPA-MeOH 90-5-5; flow rate: 12 mL/min) to obtain ( Compound 35 , 10 mg) and ( Compound 41 , 10 mg) as yellow solids.

化合物41： LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=1.270min。 Compound 41: LCMS (ESI): [M+H] + m/z: calcd 351.2; found 352.2; Rt=1.270 min.

掌性HPLC：Rt=28.22min(管柱：Chiralcel OJ-H；流動相：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=28.22 min (column: Chiralcel OJ-H; mobile phase: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

化合物35： LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=1.270min。 Compound 35: LCMS (ESI): [M+H] + m/z: calcd 351.2; found 352.2; Rt=1.270 min.

掌性HPLC：Rt=8.69min(管柱：Chiralcel OJ-H；流動相：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=8.69 min (column: Chiralcel OJ-H; mobile phase: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

步驟3.2-[(2S,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基Step 3. 2-[(2S,3R,6S)-2,3-Dimethyl-6-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxygen base 乙醯胺及2-[(2R,3S,6R)-2,3-二甲基-6-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺之掌性分離Acetamide and 2-[(2R,3S,6R)-2,3-dimethyl-6-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2 - Chiral separation of pendant oxyacetamides

使外消旋 -2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物23 ，35.9mg)經歷掌性分離(Chiralcel OJ-H(250 * 20mm，5um；流動相：己烷-IPA-MeOH 90-5-5；流速：12mL/min)，以獲得呈黃色固體之(化合物39 ，12mg)及(化合物32 ，10mg)。Make rac -2-[( 2S , 3R , 6S )-2,3-dimethyl-6-phenyl-1-piperidinyl] -N- (5-methyl-3-pyridine yl)-2-oxoacetamide ( compound 23 , 35.9 mg) was subjected to chiral separation (Chiralcel OJ-H (250*20mm, 5um; mobile phase: hexane-IPA-MeOH 90-5-5; flow rate) : 12 mL/min) to obtain ( Compound 39 , 12 mg) and ( Compound 32 , 10 mg) as yellow solids.

化合物39： LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=1.202min。 Compound 39: LCMS (ESI): [M+H] + m/z: calcd 351.2; found 352.2; Rt=1.202 min.

掌性HPLC：Rt=14.78min(管柱：Chiralcel OJ-H；流動相：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=14.78 min (column: Chiralcel OJ-H; mobile phase: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

化合物32： LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=1.266min。 Compound 32: LCMS (ESI): [M+H] + m/z: calcd 351.2; found 352.2; Rt=1.266 min.

掌性HPLC：Rt=23.10min(管柱：Chiralcel OJ-H；流動相：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=23.10 min (column: Chiralcel OJ-H; mobile phase: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

實例52. 5-[[2-[5-甲基-2-(3-吡哌基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物102)、5-[[2-[(2S ,5S )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、5-[[2-[(2R ,5S )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、5-[[2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(+-*化合物104、化合物105、化合物106及化合物98)之合成Example 52. 5-[[2-[5-Methyl-2-(3-piperidyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (Compound 102), 5-[[2-[(2 S ,5 S )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carbamide, 5-[[2-[( 2R , 5S )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carbamide, 5-[[2-[( 2S , 5R )-5-methyl-2-(3-pyridyl)-1-piperidine Peridyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide and 5-[[2-[( 2R , 5R )-5-methyl-2-(3-pyridine (+-*Compound 104, Compound 105, Compound 106 and Compound 98) Synthesis

Figure 110128222-A0202-12-0986-71
Figure 110128222-A0202-12-0986-71

步驟1：5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物102 )之合成Step 1: 5-[[2-[5-Methyl-2-(3-pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carbamide Synthesis of ( Compound 102 )

在21℃下，向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.4，1.29mmol，Et3 N鹽)、TATU(622.66mg，1.93mmol)及三乙胺(130.42mg，1.29mmol，179.64μL)於無水CH3 CN(25mL)中之經攪拌之溶液中添加3-(5-甲基-2-哌啶基)吡啶(272.61mg，1.55mmol)。將所得反應混合物在21℃下攪拌隔夜。將所得反應混合物蒸發至乾且使其經歷HPLC(溶析液：20-70%，0-11.5min，水-甲醇；流速：30mL/min；裝載泵4mL/min，甲醇；管柱：SunFireC18 100*19mm，5um)，以得到5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物102 ，37.2mg，101.25μmol，7.86%產率)。To 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.4, 1.29 mmol, Et 3 N salt), TATU (622.66 mg, 1.93 mmol) at 21 °C mmol) and triethylamine (130.42 mg, 1.29 mmol, 179.64 μL) in anhydrous CH3CN (25 mL) was added 3-(5-methyl-2-piperidinyl)pyridine (272.61 mg) , 1.55 mmol). The resulting reaction mixture was stirred at 21 °C overnight. The resulting reaction mixture was evaporated to dryness and subjected to HPLC (eluent: 20-70%, 0-11.5 min, water-methanol; flow rate: 30 mL/min; loading pump 4 mL/min, methanol; column: SunFire C18 100 *19mm, 5um) to give 5-[[2-[5-methyl-2-(3-pyridinyl)-1-piperidinyl]-2-pendoxetyl]amino]pyridine- 3-Carboxamide ( Compound 102 , 37.2 mg, 101.25 μmol, 7.86% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.10(m,3H),1.42(m,1H),1.86(m,2H),2.01(m,1H),2.24(m,1H),3.14(m,1H),4.50(m,1H),6.35(m,1H),7.32(m,1H),7.63(m,1H),8.52(m,1H),8.60(m,3H),8.80(m,1H),8.95(m,1H),9.84(s,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.10 (m, 3H), 1.42 (m, 1H), 1.86 (m, 2H), 2.01 (m, 1H), 2.24 (m, 1H), 3.14 (m,1H),4.50(m,1H),6.35(m,1H),7.32(m,1H),7.63(m,1H),8.52(m,1H),8.60(m,3H),8.80( m, 1H), 8.95 (m, 1H), 9.84 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=1.699min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=1.699 min.

步驟2：5-[[2-[(2S,5S)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、5-[[2-[(2R,5S)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、5-[[2-[(2S,5R)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]Step 2: 5-[[2-[(2S,5S)-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide, 5-[[2-[(2R,5S)-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-side oxyacetyl] Amino]pyridine-3-carbamide, 5-[[2-[(2S,5R)-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-side oxy Acetyl] 胺基]吡啶-3-甲醯胺及5-[[2-[(2R,5R)-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物104 、化合物105 、化合物106 及化合物98 )之掌性分離Amino]pyridine-3-carboxamide and 5-[[2-[(2R,5R)-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-side oxy Chiral Separation of Acetyl]amino]pyridine-3-carboxamide ( Compound 104 , Compound 105 , Compound 106 and Compound 98 )

使5-[[2-[5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物102 ，37.2mg，101.25μmol)經歷掌性HPLC純化，以得到呈白色固體之5-[[2-[(2S ,5S )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物104 ，3.72mg)、5-[[2-[(2R ,5S )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物105 ，9.15mg)、5-[[2-[(2S ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物106 ，8.49mg)及5-[[2-[(2R ,5R )-5-甲基-2-(3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物98 ，3.72mg)。Make 5-[[2-[5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 102 , 37.2 mg, 101.25 μmol) was purified by chiral HPLC to give 5-[[2-[( 2S ,5S)-5-methyl-2-(3-pyridinyl)-1- as a white solid Piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 104 , 3.72mg ), 5-[[2-[( 2R ,5S)-5-methyl base-2-(3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 105 , 9.15mg), 5-[[2 -[(2 S ,5 R )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 106 , 8.49 mg) and 5-[[2-[(2 R ,5 R )-5-methyl-2-(3-pyridyl)-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carboxamide ( compound 98 , 3.72 mg).

化合物104 ： Compound 104 :

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.90(m,3H),1.29(m,2H),1.83(m,2H),2.10(m,1H),2.52(m,2H),4.63(m,1H),6.26(m,1H),7.37(m,1H),7.66(m,1H),8.61(m,3H),8.84(m,1H),8.94(m,1H),9.63(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.90 (m, 3H), 1.29 (m, 2H), 1.83 (m, 2H), 2.10 (m, 1H), 2.52 (m, 2H), 4.63 (m,1H),6.26(m,1H),7.37(m,1H),7.66(m,1H),8.61(m,3H),8.84(m,1H),8.94(m,1H),9.63( m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=2.889min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=2.889 min.

掌性HPLC：Rt=21.83min(管柱：AD-H；溶析液：己烷-MeOH-IPA，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=21.83 min (column: AD-H; eluent: hexane-MeOH-IPA, 50-25-25; flow rate: 0.6 mL/min).

化合物105 ： Compound 105 :

1 H NMR(CDCl3 ,500MHz)：δ(ppm)1.14(m,3H),1.46(m,1H),1.90(d,1H),2.05(m,1H),2.27(m,2H),3.25(m,1H),4.54(m,1H),6.16(m,2H),7.35(m,1H),7.66(m,1H),8.59(m,3H),8.84(m,1H),8.92(m,1H),9.67(s,1H)。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 1.14 (m, 3H), 1.46 (m, 1H), 1.90 (d, 1H), 2.05 (m, 1H), 2.27 (m, 2H), 3.25 (m,1H),4.54(m,1H),6.16(m,2H),7.35(m,1H),7.66(m,1H),8.59(m,3H),8.84(m,1H),8.92( m, 1H), 9.67 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=2.844min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=2.844 min.

掌性HPLC：Rt=47.00min(管柱：AD-H；溶析液：己烷-MeOH-IPA，50-25-25； 流速：0.6mL/min)。Chiral HPLC: Rt=47.00min (column: AD-H; eluent: hexane-MeOH-IPA, 50-25-25; Flow rate: 0.6 mL/min).

化合物106 ： Compound 106 :

1 H NMR(CDCl3 ,600MHz)：δ(ppm)0.95(m,3H),1.22(m,1H),1.58(m,1H),1.70(m,1H),1.91(m,2H),2.65(m,1H),3.77(m,1H),5.16(m,2H),6.13(m,1H),6.38(m,1H),7.15(m,3H),7.36(s,1H),7.44(m,1H),8.09(s,1H)。 1 H NMR (CDCl 3 , 600MHz): δ (ppm) 0.95 (m, 3H), 1.22 (m, 1H), 1.58 (m, 1H), 1.70 (m, 1H), 1.91 (m, 2H), 2.65 (m,1H),3.77(m,1H),5.16(m,2H),6.13(m,1H),6.38(m,1H),7.15(m,3H),7.36(s,1H),7.44( m, 1H), 8.09 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=2.843min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=2.843 min.

掌性HPLC：Rt=36.06min(管柱：AD-H；溶析液：己烷-MeOH-IPA，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=36.06 min (column: AD-H; eluent: hexane-MeOH-IPA, 50-25-25; flow rate: 0.6 mL/min).

化合物98 ： Compound 98 :

1 H NMR(CDCl3 ,500MHz)：δ(ppm)0.90(m,3H),1.27(m,1H),1.81(m,2H),1.91(m,1H),2.10(m,1H),2.52(m,2H),4.63(m,1H),6.27(m,1H),7.38(m,1H),7.67(m,1H),8.62(m,3H),8.85(m,1H),8.97(m,1H),9.62(m,1H)。 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 0.90 (m, 3H), 1.27 (m, 1H), 1.81 (m, 2H), 1.91 (m, 1H), 2.10 (m, 1H), 2.52 (m,2H),4.63(m,1H),6.27(m,1H),7.38(m,1H),7.67(m,1H),8.62(m,3H),8.85(m,1H),8.97( m, 1H), 9.62 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=2.890min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=2.890 min.

掌性HPLC：Rt=24.08min(管柱：AD-H；溶析液：己烷-MeOH-IPA，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=24.08 min (column: AD-H; eluent: hexane-MeOH-IPA, 50-25-25; flow rate: 0.6 mL/min).

實例53. 化合物369、化合物370、化合物371及化合物389之合成Example 53. Synthesis of Compound 369, Compound 370, Compound 371 and Compound 389

Figure 110128222-A0202-12-0988-72
Figure 110128222-A0202-12-0988-72

步驟1：5-[[2-(2-環己基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-甲氧基吡啶Step 1: 5-[[2-(2-Cyclohexyl-5-methyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-methoxypyridine -3-甲醯胺之合成-Synthesis of 3-formamide

將2-環己基-5-甲基哌啶(0.219g，1.01mmol，HCl)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(342.28mg，1.01mmol)及三乙胺(1.02g，10.06mmol，1.40mL)一起混合於DMF(5mL)中且向其中添加HATU(573.55mg，1.51mmol)。將反應混合物攪拌18h。然後，將反應混合物倒入到水(20mL)中且將所得混合物用EtOAc(2* 30mL)萃取。將經合併之有機層用水(3* 25mL)、鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由HPLC(2-10min 60-85% MeOH/H2 O+甲酸，30mL/min(裝載泵4mL+甲酸)，管柱：SunFire 100* 19mm，5微米)純化殘餘物，以獲得5-[[2-(2-環己基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.0428g，106.34μmol，10.57%產率)。2-Cyclohexyl-5-methylpiperidine (0.219 g, 1.01 mmol, HCl), 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2- Pendant oxyacetic acid (342.28 mg, 1.01 mmol) and triethylamine (1.02 g, 10.06 mmol, 1.40 mL) were mixed together in DMF (5 mL) and HATU (573.55 mg, 1.51 mmol) was added to it. The reaction mixture was stirred for 18 h. Then, the reaction mixture was poured into water (20 mL) and the resulting mixture was extracted with EtOAc (2 * 30 mL). The combined organic layers were washed with water (3 * 25 mL), brine, dried over Na2SO4 , filtered and evaporated. The residue was purified by HPLC (2-10 min 60-85% MeOH/ H2O + formic acid, 30 mL/min (load pump 4 mL + formic acid), column: SunFire 100 * 19 mm, 5 microns) to obtain 5-[[2 -(2-Cyclohexyl-5-methyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (0.0428 g, 106.34 μmol , 10.57% yield).

1 H NMR(400MHz,DMSO-d6 )δ 0.82(m,2H),0.94(m,3H),1.19(m,4H),1.64(m,10H),2.85(m,1H),3.47(m,1H),3.96(s,3H),4.13(m,1H),7.75(s,1H),8.53(m,1H),8.55(s,1H),10.87(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.82(m, 2H), 0.94(m, 3H), 1.19(m, 4H), 1.64(m, 10H), 2.85(m, 1H), 3.47(m , 1H), 3.96(s, 3H), 4.13(m, 1H), 7.75(s, 1H), 8.53(m, 1H), 8.55(s, 1H), 10.87(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值403.2；Rt=1.475min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 403.2; Rt=1.475 min.

步驟2：5-[[2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物369 )、5-[[2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物370 )、5-[[2-[(2S,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物371 )及5-[[2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物389 )之合成Step 2: 5-[[2-[(2R,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxy pyridine-3-carboxamide ( compound 369 ), 5-[[2-[(2S,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-side oxyacetamide yl]amino]-2-methoxypyridine-3-carboxamide ( Compound 370 ), 5-[[2-[(2S,5S)-2-cyclohexyl-5-methyl-1-piperidine yl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 371 ) and 5-[[2-[(2R,5R)-2-cyclohexyl Synthesis of -5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 389 )

對5-[[2-(2-環己基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.0428g，106.34μmol)進行掌性分離(IC管柱(250* 20，5mkm)，CO2 -MeOH，50-50，2.0mL/min及AS-H，CO2 -MeOH，80-20，3.0mL/min)，以獲得化合物369 5-[[2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺 基]-2-甲氧基吡啶-3-甲醯胺(0.01316g，32.70μmol，30.75%產率)、化合物370 5-[[2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.00924g，22.96μmol，21.59%產率)、化合物371 5-[[2-[(2S,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.00277g，6.88μmol，6.47%產率)及化合物389 5-[[2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.009g，22.36μmol，21.03%產率)。p-5-[[2-(2-Cyclohexyl-5-methyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (0.0428 g, 106.34 μmol) for chiral separation (IC column (250 * 20, 5 mkm), CO2 -MeOH, 50-50, 2.0 mL/min and AS-H, CO2 -MeOH, 80-20, 3.0 mL/min) to obtain compound 369 5-[[2-[(2R,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]-2-methoxypyridine-3-carboxamide (0.01316 g, 32.70 μmol, 30.75% yield), compound 370 5-[[2-[(2S,5R)-2-cyclohexyl-5- Methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (0.00924g, 22.96μmol, 21.59% yield), compound 371 5-[[2-[(2S,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine- 3-Carboxamide (0.00277 g, 6.88 μmol, 6.47% yield) and compound 389 5-[[2-[(2R,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (0.009 g, 22.36 μmol, 21.03% yield).

化合物369：Compound 369:

1 H NMR(600MHz,DMSO-d6 )δ 0.67-0.87(m,2H),0.91-0.96(m,3H),1.04-1.28(m,4H),1.52-1.63(m,4H),1.65-1.71(m,2H),1.74-1.79(m,1H),1.80-1.98(m,3H),2.82-3.25(m,1H),3.32-3.48(m,1H),3.93-3.95(m,3H),3.98-4.13(m,1H),7.68-7.76(m,2H),8.40-8.48(m,1H),8.50-8.56(m,1H),10.78-10.88(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.67-0.87(m, 2H), 0.91-0.96(m, 3H), 1.04-1.28(m, 4H), 1.52-1.63(m, 4H), 1.65- 1.71(m, 2H), 1.74-1.79(m, 1H), 1.80-1.98(m, 3H), 2.82-3.25(m, 1H), 3.32-3.48(m, 1H), 3.93-3.95(m, 3H) ), 3.98-4.13(m, 1H), 7.68-7.76(m, 2H), 8.40-8.48(m, 1H), 8.50-8.56(m, 1H), 10.78-10.88(m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值402.2；實測值404.2；Rt=5.763min。LCMS (ESI): [M+2H] + m/z: calculated 402.2; found 404.2; Rt=5.763 min.

RT(IC,CO2 -MeOH,50-50,2.0mL/min)=6.246min。RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 6.246 min.

化合物370：Compound 370:

1 H NMR(600MHz,DMSO-d6 )δ 0.68-0.90(m,2H),0.91-0.98(m,3H),1.04-1.28(m,4H),1.53-1.65(m,4H),1.65-1.72(m,2H),1.73-1.78(m,1H),1.80-1.99(m,3H),2.51-2.88(m,1H),3.32-3.48(m,1H),3.92-3.96(m,3H),3.97-4.15(m,1H),7.67-7.78(m,2H),8.39-8.47(m,1H),8.50-8.56(m,1H),10.76-10.89(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.68-0.90(m, 2H), 0.91-0.98(m, 3H), 1.04-1.28(m, 4H), 1.53-1.65(m, 4H), 1.65- 1.72(m, 2H), 1.73-1.78(m, 1H), 1.80-1.99(m, 3H), 2.51-2.88(m, 1H), 3.32-3.48(m, 1H), 3.92-3.96(m, 3H) ), 3.97-4.15(m, 1H), 7.67-7.78(m, 2H), 8.39-8.47(m, 1H), 8.50-8.56(m, 1H), 10.76-10.89(m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值402.2；實測值404.2；Rt=5.759min。LCMS (ESI): [M+2H] + m/z: calculated 402.2; found 404.2; Rt=5.759 min.

RT(IC,CO2 -MeOH,50-50,2.0mL/min)=5.387min。RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 5.387 min.

化合物371：Compound 371:

LCMS(ESI)：[M+2H]+ m/z：計算值402.2；實測值404.2；Rt=5.811min。LCMS (ESI): [M+2H] + m/z: calculated 402.2; found 404.2; Rt=5.811 min.

RT(AS-H,CO2 -MeOH,80-20,3.0mL/min)=3.657及5.686min。RT (AS-H, CO2 -MeOH, 80-20, 3.0 mL/min) = 3.657 and 5.686 min.

化合物389：Compound 389:

1 H NMR(600MHz,DMSO-d6 )δ 0.66-1.03(m,6H),1.05-1.22(m,3H),1.26-1.45(m,1H),1.52-1.60(m,3H),1.61-1.72(m,3H),1.73-1.90(m,3H),2.25-2.31(m,0.4H),2.63-2.88(m,0.6H),3.33-3.52(m,1H),3.91-3.95(m,3H),3.98-4.17(m,1H),7.66-7.78(m,2H),8.39-8.46(m,1H),8.48-8.55(m,1H),10.77-10.87(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.66-1.03(m,6H), 1.05-1.22(m,3H), 1.26-1.45(m,1H), 1.52-1.60(m,3H), 1.61- 1.72(m, 3H), 1.73-1.90(m, 3H), 2.25-2.31(m, 0.4H), 2.63-2.88(m, 0.6H), 3.33-3.52(m, 1H), 3.91-3.95(m , 3H), 3.98-4.17(m, 1H), 7.66-7.78(m, 2H), 8.39-8.46(m, 1H), 8.48-8.55(m, 1H), 10.77-10.87(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值404.2；Rt=5.802min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 404.2; Rt=5.802 min.

RT(AS-H,CO2 -MeOH,80-20,3.0mL/min)=3.295及3.932min。RT (AS-H, CO2 -MeOH, 80-20, 3.0 mL/min) = 3.295 and 3.932 min.

實例54. 化合物130、化合物127、化合物121及化合物117之合成Example 54. Synthesis of Compound 130, Compound 127, Compound 121 and Compound 117

Figure 110128222-A0202-12-0991-73
Figure 110128222-A0202-12-0991-73

步驟1：5-[[2-(2-環己基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Synthesis of 5-[[2-(2-Cyclohexyl-5-methyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(402.37mg，1.10mmol，C6H15N)及2-環己基-5-甲基哌啶(300mg，1.10mmol，HCl)混合於DMF(10mL)中。將反應懸浮液冷卻至0℃且添加HATU(419.03mg，1.10mmol)，隨後添加TEA(557.58mg，5.51mmol，768.01μL)。將澄清溶液在周圍溫度下攪拌12h。然後在減壓下蒸發揮發物，且使殘餘物(1g)經歷RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；50-50-85% 0-1-5min 0.1%NH3 -甲醇為流動相)，以得到呈非 鏡像異構物混合物之三種級分20、141及41mg之5-[[2-(2-環己基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(202mg，542.34μmol，49.21%產率)。2-[(5-Aminocarboxy-3-pyridinyl)amino]-2-oxoacetic acid (402.37mg, 1.10mmol, C6H15N) and 2-cyclohexyl-5-methylpiperidine (300mg , 1.10 mmol, HCl) in DMF (10 mL). The reaction suspension was cooled to 0°C and HATU (419.03 mg, 1.10 mmol) was added followed by TEA (557.58 mg, 5.51 mmol, 768.01 μL). The clear solution was stirred at ambient temperature for 12 h. The volatiles were then evaporated under reduced pressure and the residue (1 g) was subjected to RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; 50-50-85% 0-1-5 min 0.1% NH3 -methanol as mobile phase) to give three fractions 20, 141 and 41 mg of 5-[[2-(2-cyclohexyl-5-methyl-1-piperidinyl)-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (202 mg, 542.34 μmol, 49.21% yield).

1 H NMR(500MHz,DMSO-d6 +CCl4 )δ 0.83(m,2H),0,98(m,3H),1.24(m,4H),1.67(m,6H),1.88(m,4H),2.81(m,1H),3.49(m,1H),4.08(m,1H),7.62(m,1H),8.17(m,1H),8.48(m,1H),8.78(m,1H),8.90(m,1H),11.05(m,1H)。 1 H NMR (500MHz, DMSO-d 6 +CCl 4 )δ 0.83(m, 2H), 0,98(m, 3H), 1.24(m, 4H), 1.67(m, 6H), 1.88(m, 4H) ), 2.81(m, 1H), 3.49(m, 1H), 4.08(m, 1H), 7.62(m, 1H), 8.17(m, 1H), 8.48(m, 1H), 8.78(m, 1H) , 8.90 (m, 1H), 11.05 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值372.4；實測值373.2；Rt=3.461min。LCMS (ESI): [M+H] + m/z: calculated 372.4; found 373.2; Rt=3.461 min.

步驟2：5-[[2-[(2S,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物121 )、5-[[2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物127 )、5-[[2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物117 )及5-[[2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物130 )之合成Step 2: 5-[[2-[(2S,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide ( Compound 121 ), 5-[[2-[(2R,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide ( Compound 127 ), 5-[[2-[(2R,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide ( compound 117 ) and 5-[[2-[(2S,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxygen Synthesis of Acetyl] Amino] Pyridine-3-Carboxamide ( Compound 130 )

藉由掌性HPLC(管柱：IA(250* 20，5mkm)，以己烷-IPA-MeOH，80-10-10，14mL/min為流動相，然後對前二者藉由另一管柱：IC(250* 20，5mkm)，己烷-IPA-MeOH，60-20-20，12mL/min為流動相)分離鏡像異構物，以得到兩種單獨的順式鏡像異構物化合物121 5-[[2-[(2S,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(15mg，40.27μmol，42.55%產率)及化合物127 5-[[2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(15mg，40.27μmol，42.55%產率)以及兩種單獨的反式鏡像異構物化合物117 5-[[2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(30mg，80.55μmol，85.11%產率)及化合物130 5-[[2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(28mg，75.18μmol，79.43%產率)。By chiral HPLC (column: IA (250 * 20, 5mkm), with hexane-IPA-MeOH, 80-10-10, 14mL/min as mobile phase, and then the former two by another column : IC (250 * 20, 5mkm), hexane-IPA-MeOH, 60-20-20, 12mL/min as mobile phase) to separate the enantiomers to give two separate cis-enantiomers compound 121 5-[[2-[(2S,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( 15 mg, 40.27 μmol, 42.55% yield) and compound 127 5-[[2-[(2R,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-side oxyacetyl yl]amino]pyridine-3-carboxamide (15 mg, 40.27 μmol, 42.55% yield) and two individual trans-enantiomers Compound 117 5-[[2-[(2R,5S)-2 -Cyclohexyl-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (30 mg, 80.55 μmol, 85.11% yield) and compound 130 5 -[[2-[(2S,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (28mg , 75.18 μmol, 79.43% yield).

化合物121：Compound 121:

1 H NMR(500MHz,DMSO-d6 +CCl4 )δ 0.83(m,2H),0.98(m,3H),1.24(m,4H),1.67 (m,6H),1.88(m,4H),2.81(m,1H),3.49(m,1H),4.08(m,1H),7.62(m,1H),8.17(m,1H),8.48(m,1H),8.78(m,1H),8.90(m,1H),11.05(m,1H)。 1 H NMR (500MHz, DMSO-d 6 +CCl 4 )δ 0.83 (m, 2H), 0.98 (m, 3H), 1.24 (m, 4H), 1.67 (m, 6H), 1.88 (m, 4H), 2.81(m,1H),3.49(m,1H),4.08(m,1H),7.62(m,1H),8.17(m,1H),8.48(m,1H),8.78(m,1H),8.90 (m, 1H), 11.05 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值372.2；實測值374.2；Rt=5.022min。LCMS (ESI): [M+2H] + m/z: calculated 372.2; found 374.2; Rt=5.022 min.

RT(IC，Hex-IPA-MeOH，60-20-20，0.6mL/min)=15.851min。RT (IC, Hex-IPA-MeOH, 60-20-20, 0.6 mL/min) = 15.851 min.

化合物127：Compound 127:

1 H NMR(500MHz,DMSO-d6 +CCl4 )δ 0.83(m,2H),0.98(m,3H),1.19(m,4H),1.67(m,6H),1.83(m,4H),2.58(m,1H),3.40(m,1H),4.08(m,1H),7.62(m,1H),8.17(m,1H),8.49(m,1H),8.78(m,1H),8.90(m,1H),11.05(m,1H)。 1 H NMR (500MHz, DMSO-d 6 +CCl 4 )δ 0.83(m, 2H), 0.98(m, 3H), 1.19(m, 4H), 1.67(m, 6H), 1.83(m, 4H), 2.58(m, 1H), 3.40(m, 1H), 4.08(m, 1H), 7.62(m, 1H), 8.17(m, 1H), 8.49(m, 1H), 8.78(m, 1H), 8.90 (m, 1H), 11.05 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值372.2；實測值374.2；Rt=5.019min。LCMS (ESI): [M+2H] + m/z: calculated 372.2; found 374.2; Rt=5.019 min.

RT(IC，Hex-IPA-MeOH，60-20-20，0.6mL/min)=28.529min。RT (IC, Hex-IPA-MeOH, 60-20-20, 0.6 mL/min) = 28.529 min.

化合物117：Compound 117:

1 H NMR(400MHz,CDCl3 )δ 0.93(m,5H),1.18(m,8H),1.57(m,4H),1.94(m,1H),2.66(m,1H),3.65(m,1H),4.32(m,1H),4.58(m,1H),6.24(m,2H),8.62(s,1H),8.81(s,1H),8.96(s,1H),9.70(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.93 (m, 5H), 1.18 (m, 8H), 1.57 (m, 4H), 1.94 (m, 1H), 2.66 (m, 1H), 3.65 (m, 1H) ), 4.32(m, 1H), 4.58(m, 1H), 6.24(m, 2H), 8.62(s, 1H), 8.81(s, 1H), 8.96(s, 1H), 9.70(m, 1H) .

LCMS(ESI)：[M+2H]+ m/z：計算值372.2；實測值374.2；Rt=4.930min。LCMS (ESI): [M+2H] + m/z: calculated 372.2; found 374.2; Rt=4.930 min.

RT(IC，Hex-IPA-MeOH，60-20-20，0.6mL/min)=19.507min。RT (IC, Hex-IPA-MeOH, 60-20-20, 0.6 mL/min) = 19.507 min.

化合物130：Compound 130:

1 H NMR(400MHz,CDCl3 )δ 0.93(m,5H),1.21(m,8H),1.64(m,4H),1.94(m,1H),2.55(m,1H),4.00(m,1H),4.33(m,1H),4.57(m,1H),6.44(m,2H),8.61(s,1H),8.81(s,1H),8.96(s,1H),9.76(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.93 (m, 5H), 1.21 (m, 8H), 1.64 (m, 4H), 1.94 (m, 1H), 2.55 (m, 1H), 4.00 (m, 1H) ),4.33(m,1H),4.57(m,1H),6.44(m,2H),8.61(s,1H),8.81(s,1H),8.96(s,1H),9.76(m,1H) .

LCMS(ESI)：[M+2H]+ m/z：計算值372.2；實測值374.2；Rt=4.929min。LCMS (ESI): [M+2H] + m/z: calculated 372.2; found 374.2; Rt=4.929 min.

RT(IC，Hex-IPA-MeOH，60-20-20，0.6mL/min)=24.368min。RT (IC, Hex-IPA-MeOH, 60-20-20, 0.6 mL/min) = 24.368 min.

實例55. 5-(2-(2-(1H -吲哚-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物372、化合物481)之合成Example 55. 5-(2-(2-( 1H -indol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 372, the synthesis of compound 481)

Figure 110128222-A0202-12-0994-74
Figure 110128222-A0202-12-0994-74

步驟1：5-(2-(2-(1H-吲哚-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成 在室溫下，將HATU(603.24mg，1.59mmol)分批添加到2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(389.68mg，1.59mmol，HCl)、5-(5-甲基-2-哌啶基)-1H -吲哚(400mg，1.59mmol)及TEA(963.24mg，9.52mmol，1.33mL)於DMF(5mL)中之懸浮液中。將澄清溶液在30℃下攪拌32h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：SunFireC18 100x19mm 5um；20-20-45% 0-1-6min 0.2% FA-MeCN為流動相)，以得到5-[[2-[2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(84mg，207.18μmol，13.06%產率)。 Step 1: Synthesis of 5-(2-(2-(1H-indol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide HATU (603.24 mg, 1.59 mmol) was added portionwise to 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-pendoxoacetic acid (389.68 mg, 1.59 mmol) at room temperature , HCl), a suspension of 5-(5-methyl-2-piperidinyl)-1H-indole (400 mg, 1.59 mmol) and TEA ( 963.24 mg, 9.52 mmol, 1.33 mL) in DMF (5 mL) middle. The clear solution was stirred at 30 °C for 32 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: SunFireC18 100x19mm 5um; 20-20-45% 0-1-6 min 0.2% FA-MeCN as mobile phase) to give 5-[[2-[2-( 1H -indium Indol-5-yl)-5-methyl-1-piperidinyl]-2-oxoethanoyl]amino]pyridine-3-carboxamide (84 mg, 207.18 μmol, 13.06% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值405.2；實測值406.2；Rt=1.141min。LCMS (ESI): [M] + m/z: calculated 405.2; found 406.2; Rt=1.141 min.

步驟2：掌性分離(化合物372 及化合物481 )Step 2: Chiral separation ( compound 372 and compound 481 )

藉由掌性HPLC(管柱：IA-I(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物372 5-[[2-[(2S,5R )-2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(21mg，51.79μmol，50.00%產率)(保留時間=23.35min)及化合物481 (35mg)(保留時間=45.08min)，其另外在以下條件下純化-管柱：Chiralpak IB(250*20mm，5m)；流動相：己烷-IPA-MeOH，50-25-25；流速：10mL/min；管柱溫度：24℃；波長：205nm、225nm、260nm)，保留時間(異構物A)=10.33min)，以得到(18mg，44.40μmol，42.86%產率)化合物481 5-[[2-[(2R,5S )-2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3- 甲醯胺(18mg，44.40μmol，42.86%產率)。化合物372 於分析條件下(管柱：IA，己烷-IPA-MeOH,50-25-25,0.6ml/min為流動相)之保留時間為17.31min且化合物481 之保留時間為38.68min。The enantiomers were separated by chiral HPLC (column: IA-I (250*20, 5mkm), hexane-IPA-MeOH, 50-25-25, 12ml/min as mobile phase) to give two Separate enantiomer compound 372 5-[[2-[( 2S,5R )-2-( 1H -indol-5-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (21 mg, 51.79 μmol, 50.00% yield) (retention time = 23.35 min) and compound 481 (35 mg) (retention time = 45.08 min), which were additionally in Purification under the following conditions - Column: Chiralpak IB (250*20mm, 5m); Mobile Phase: Hexane-IPA-MeOH, 50-25-25; Flow Rate: 10mL/min; Column Temperature: 24°C; Wavelength: 205nm , 225 nm, 260 nm), retention time (isomer A)=10.33 min) to obtain (18 mg, 44.40 μmol, 42.86% yield) compound 481 5-[[2-[( 2R,5S )-2-( 1H -Indol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (18 mg, 44.40 μmol, 42.86% yield Rate). The retention time of compound 372 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 17.31 min and the retention time of compound 481 was 38.68 min.

化合物372：保留時間：17.31minCompound 372: retention time: 17.31min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.08(m,3H),1.29-1.42(m,1H),1.74-1.93(m,2H),2.04-2.21(m,1H),2.25-2.34(m,1H),2.78-3.25(m,1H),3.42-4.07(m,1H),5.20-5.73(m,1H),6.36-6.43(m,1H),7.00-7.13(m,1H),7.28-7.34(m,1H),7.34-7.42(m,1H),7.45-7.54(m,1H),7.54-7.66(m,1H),8.04-8.22(m,1H),8.41-8.54(m,1H),8.70-8.80(m,1H),8.80-8.94(m,1H),10.97-11.15(m,1H),11.15-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.08(m,3H), 1.29-1.42(m,1H), 1.74-1.93(m,2H), 2.04-2.21(m,1H) ,2.25-2.34(m,1H),2.78-3.25(m,1H),3.42-4.07(m,1H),5.20-5.73(m,1H),6.36-6.43(m,1H),7.00-7.13( m,1H),7.28-7.34(m,1H),7.34-7.42(m,1H),7.45-7.54(m,1H),7.54-7.66(m,1H),8.04-8.22(m,1H), 8.41-8.54(m,1H), 8.70-8.80(m,1H), 8.80-8.94(m,1H), 10.97-11.15(m,1H), 11.15-11.39(m,1H).

LCMS(ESI)：[M]+ m/z：計算值405.2；實測值406.2；Rt=2.865min。LCMS (ESI): [M] + m/z: calculated 405.2; found 406.2; Rt=2.865 min.

化合物481：保留時間：38.68minCompound 481: retention time: 38.68min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.00-1.14(m,3H),1.32-1.47(m,1H),1.69-2.07(m,2H),2.07-2.30(m,1H),2.30-2.38(m,1H),2.82-3.25(m,1H),3.43-4.07(m,1H),5.21-5.80(m,1H),6.36-6.47(m,1H),7.01-7.16(m,1H),7.26-7.46(m,2H),7.47-7.68(m,2H),8.08-8.27(m,1H),8.43-8.60(m,1H),8.70-8.84(m,1H),8.84-9.02(m,1H),10.99-11.16(m,1H),11.16-11.34(m,1H)。 1 H NMR (500MHz, DMSO- d 6 ) δ (ppm) 1.00-1.14 (m, 3H), 1.32-1.47 (m, 1H), 1.69-2.07 (m, 2H), 2.07-2.30 (m, 1H) ,2.30-2.38(m,1H),2.82-3.25(m,1H),3.43-4.07(m,1H),5.21-5.80(m,1H),6.36-6.47(m,1H),7.01-7.16( m,1H),7.26-7.46(m,2H),7.47-7.68(m,2H),8.08-8.27(m,1H),8.43-8.60(m,1H),8.70-8.84(m,1H), 8.84-9.02 (m, 1H), 10.99-11.16 (m, 1H), 11.16-11.34 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值405.2；實測值406.2；Rt=2.811min。LCMS (ESI): [M] + m/z: calculated 405.2; found 406.2; Rt=2.811 min.

實例56. 5-(2-(2-(1H -苯并[d ]咪唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物344、化合物362)之合成Example 56. 5-(2-(2-( 1H -benzo[ d ]imidazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotine Synthesis of amide (compound 344, compound 362)

Figure 110128222-A0202-12-0995-75
Figure 110128222-A0202-12-0995-75

步驟1：5-(2-(2-(1H-苯并[d]咪唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼Step 1: 5-(2-(2-(1H-benzo[d]imidazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotine 醯胺之合成Synthesis of Amide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(342.26mg，1.39 mmol，HCl)及5-(5-甲基-2-哌啶基)-1H -苯并咪唑(400.00mg，1.39mmol)混合於DME(5mL)中。將反應懸浮液冷卻至0℃且添加HATU(529.83mg，1.39mmol)，隨後添加TEA(846.02mg，8.36mmol，1.17mL)。將澄清溶液在30℃下攪拌72h，然後在減壓下蒸發揮發物，且使殘餘物(1g)經歷RP-HPLC(管柱：XBridge C18 100x19mm，5um；20-20-70% 0-1-6min以0.1% NH3 -MeOH為流動相)，以得到5-[[2-[2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(55mg，135.32μmol，9.71%產率)及250mg反應物雜質5-(5-甲基-2-哌啶基)-1H -苯并咪唑。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (342.26 mg, 1.39 mmol, HCl) and 5-(5-methyl-2-piperidinyl ) -1H -benzimidazole (400.00 mg, 1.39 mmol) was mixed in DME (5 mL). The reaction suspension was cooled to 0°C and HATU (529.83 mg, 1.39 mmol) was added followed by TEA (846.02 mg, 8.36 mmol, 1.17 mL). The clear solution was stirred at 30°C for 72h, then the volatiles were evaporated under reduced pressure and the residue (1 g) was subjected to RP-HPLC (column: XBridge C18 100x19mm, 5um; 20-20-70% 0-1- 6min with 0.1% NH3 -MeOH as mobile phase) to obtain 5-[[2-[2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (55 mg, 135.32 μmol, 9.71% yield) and 250 mg reactant impurity 5-(5-methyl-2-piperidinyl) -1H- Benzimidazole.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=1.877min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=1.877 min.

步驟2：掌性分離(化合物344 及化合物362 )Step 2: Chiral separation ( compound 344 and compound 362 )

藉由掌性HPLC(管柱：Chiralcel OJ-H(250*20，5mkm)，以己烷-IPA-MeOH，70-15-15，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物344 5-[[2-[(2S,5R )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(22mg，54.13μmol，80.00%產率)(保留時間=16.21min)及化合物362 5-[[2-[(2R,5S )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(18.5mg，45.52μmol，67.27%產率)(保留時間=43.90min)。藉由HPLC(管柱：C18，以H2 O-ACN，15-40% ACN，30ml/min為流動相)再純化後一種。The enantiomers were separated by chiral HPLC (column: Chiralcel OJ-H (250*20, 5mkm) with hexane-IPA-MeOH, 70-15-15, 12ml/min as mobile phase) to give Two separate enantiomers Compound 344 5-[[2-[( 2S,5R )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carboxamide (22 mg, 54.13 μmol, 80.00% yield) (retention time=16.21 min) and compound 362 5-[[2-[( 2R,5S )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (18.5mg , 45.52 μmol, 67.27% yield) (retention time=43.90 min). The latter was repurified by HPLC (column: C18 with H2O -ACN, 15-40% ACN, 30 ml/min as mobile phase).

化合物344：保留時間：16.21minCompound 344: retention time: 16.21min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.04(m,3H),1.36(m,1H),1.74(m,1H),1.87(m,1H),2.13(m,1H),2.29(m,1H),2.94(m,1H),3.75(m,1H),5.49(m,1H), 7.17(m,1H),7.49(m,1H),7.63(m,2H),8.19(m,2H),8.47(m,1H),8.75(m,1H),8.87(m,1H),11.26(m,1H),12.38(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.04(m, 3H), 1.36(m, 1H), 1.74(m, 1H), 1.87(m, 1H), 2.13(m, 1H), 2.29(m, 1H), 2.94(m, 1H), 3.75(m, 1H), 5.49(m, 1H), 7.17(m, 1H), 7.49(m, 1H), 7.63(m, 2H), 8.19 (m, 2H), 8.47 (m, 1H), 8.75 (m, 1H), 8.87 (m, 1H), 11.26 (m, 1H), 12.38 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=1.688min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=1.688 min.

化合物362：保留時間：43.90minCompound 362: retention time: 43.90min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.08(m,3H),1.30-1.42(m,1H),1.71-1.81(m,1H),1.83-1.94(m,1H),2.03-2.22(m,1H),2.25-2.35(m,1H),2.79-3.24(m,1H),3.43-4.07(m,1H),5.23-5.78(m,1H),7.11-7.26(m,1H),7.41-7.54(m,1H),7.54-7.69(m,2H),8.07-8.22(m,2H),8.40-8.53(m,1H),8.68-8.79(m,1H),8.81-8.95(m,1H),11.11-11.39(m,1H),12.26-12.49(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.08(m,3H), 1.30-1.42(m,1H), 1.71-1.81(m,1H), 1.83-1.94(m,1H) ,2.03-2.22(m,1H),2.25-2.35(m,1H),2.79-3.24(m,1H),3.43-4.07(m,1H),5.23-5.78(m,1H),7.11-7.26( m,1H),7.41-7.54(m,1H),7.54-7.69(m,2H),8.07-8.22(m,2H),8.40-8.53(m,1H),8.68-8.79(m,1H), 8.81-8.95 (m, 1H), 11.11-11.39 (m, 1H), 12.26-12.49 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=1.947min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=1.947 min.

實例57. 2-(2-(1H -苯并[d ]咪唑-5-基)-5-甲基哌啶-1-基)-N -(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺(化合物771、化合物748)之合成Example 57. 2-(2-( 1H -benzo[ d ]imidazol-5-yl)-5-methylpiperidin - 1-yl)-N-(6-amino-5-ethylpyridine-3 Synthesis of -yl)-2-oxoacetamide (Compound 771, Compound 748)

Figure 110128222-A0202-12-0997-76
Figure 110128222-A0202-12-0997-76

步驟1：2-(2-(1H-苯并[d]咪唑-5-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺之合成Step 1: 2-(2-(1H-Benzo[d]imidazol-5-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5-ethylpyridine-3 -Base)-2-Side Oxyacetamide Synthesis

在室溫下，將HATU(353.22mg，928.96μmol)分批添加到2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(194.34mg，928.96μmol)、5-(5-甲基-2-哌啶基)-1H -苯并咪唑(200.00mg，928.96μmol)及TEA(564.01mg，5.57mmol，776.88μL)於DMF(13mL)中之懸浮液中。將澄清溶液在周圍溫度下攪拌32h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100x20mm，5um；15-70% 0-5min，以水-MeOH(0.1% NH3 )為流動相)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基 乙醯胺(69mg，169.75μmol，18.27%產率)。HATU (353.22 mg, 928.96 μmol) was added portionwise to 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid (194.34 mg) at room temperature , 928.96 μmol), 5-(5-methyl-2-piperidinyl)-1H-benzimidazole (200.00 mg, 928.96 μmol) and TEA (564.01 mg, 5.57 mmol, 776.88 μL) in DMF (13 mL) in the suspension. The clear solution was stirred at ambient temperature for 32 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100x20mm, 5um; 15-70% 0-5 min with water-MeOH (0.1% NH3 ) as mobile phase) to give N- (6-amine yl-5-ethyl-3-pyridyl)-2-[2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (69 mg, 169.75 μmol, 18.27% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=0.952min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=0.952 min.

步驟2：掌性分離(化合物771 及化合物748 )Step 2: Chiral separation ( compound 771 and compound 748 )

藉由掌性HPLC(管柱：IA-II(250*20，5mkm)，以己烷-IPA-MeOH,60-20-20,12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物771 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(23.8mg，58.55μmol，68.99%產率)(保留時間=27.2min)及化合物748 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(26.2mg，64.46μmol，75.94%產率)(保留時間=38.7min)。The enantiomers were separated by chiral HPLC (column: IA-II (250*20, 5mkm) with hexane-IPA-MeOH, 60-20-20, 12ml/min as mobile phase) to give two An individual enantiomer compound 771 N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5R )-2-( 1H -benzimidazol-5-yl) -5-Methyl-1-piperidinyl]-2-oxyacetamide (23.8 mg, 58.55 μmol, 68.99% yield) (retention time = 27.2 min) and compound 748 N- (6-amino) -5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetamide (26.2 mg, 64.46 μmol, 75.94% yield) (retention time = 38.7 min).

化合物771：保留時間：27.20minCompound 771: retention time: 27.20min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.04(m,3H),1.05-1.16(m,3H),1.28-1.41(m,1H),1.68-1.80(m,1H),1.81-1.92(m,1H),2.01-2.18(m,1H),2.21-2.30(m,1H),2.36-2.43(m,2H),2.74-3.27(m,1H),3.44-4.05(m,1H),5.22-5.60(m,1H),5.61-5.74(m,2H),7.10-7.26(m,1H),7.35-7.54(m,2H),7.54-7.68(m,1H),7.96-8.09(m,1H),8.18(s,1H),10.44-10.60(m,1H),12.27-12.49(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.04(m,3H), 1.05-1.16(m,3H), 1.28-1.41(m,1H), 1.68-1.80(m,1H) ,1.81-1.92(m,1H),2.01-2.18(m,1H),2.21-2.30(m,1H),2.36-2.43(m,2H),2.74-3.27(m,1H),3.44-4.05( m,1H),5.22-5.60(m,1H),5.61-5.74(m,2H),7.10-7.26(m,1H),7.35-7.54(m,2H),7.54-7.68(m,1H), 7.96-8.09(m,1H), 8.18(s,1H), 10.44-10.60(m,1H), 12.27-12.49(m,1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=1.400min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=1.400 min.

化合物748：保留時間：38.70minCompound 748: retention time: 38.70min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.04(m,3H),1.05-1.15(m,3H),1.29-1.41(m,1H),1.70-1.80(m,1H),1.81-1.92(m,1H),2.01-2.19(m,1H),2.19-2.31(m,1H),2.36-2.43(m,2H),2.75-3.26(m,1H),3.41-4.05(m,1H),5.24-5.60(m,1H),5.60-5.74(m,2H),7.07-7.26(m,1H),7.37-7.55(m,2H),7.55-7.67(m,1H),7.96-8.23(m,2H),10.43-10.60(m,1H),12.30-12.47(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.04(m,3H), 1.05-1.15(m,3H), 1.29-1.41(m,1H), 1.70-1.80(m,1H) ,1.81-1.92(m,1H),2.01-2.19(m,1H),2.19-2.31(m,1H),2.36-2.43(m,2H),2.75-3.26(m,1H),3.41-4.05( m,1H),5.24-5.60(m,1H),5.60-5.74(m,2H),7.07-7.26(m,1H),7.37-7.55(m,2H),7.55-7.67(m,1H), 7.96-8.23 (m, 2H), 10.43-10.60 (m, 1H), 12.30-12.47 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=1.385min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=1.385 min.

實例58. 5-(2-(2-(1H -苯并[d]咪唑-5-基]-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物805、化合物794)之合成Example 58. 5-(2-(2-( 1H -benzo[d]imidazol-5-yl]-5-methylpiperidin-1-yl)-2-oxyacetamido)-2 - Synthesis of Methoxynicotinamide (Compound 805, Compound 794)

Figure 110128222-A0202-12-0999-77
Figure 110128222-A0202-12-0999-77

步驟1：5-(2-(2-(1H-苯并[d]咪唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺之合成Step 1: 5-(2-(2-(1H-benzo[d]imidazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-2 -Synthesis of Methoxynicotinamide

在室溫下，將HATU(392.76mg，1.03mmol)分批添加到2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(351.59mg，1.03mmol)、5-(5-甲基-2-哌啶基)-1H -苯并咪唑(222.39mg，1.03mmol)及TEA(627.15mg，6.20mmol，863.84μL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌48h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；0-5min，以5-30%水-MeCN-NH4 OH，流速：30ml/min為流動相)，以得到5-[[2-[2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(130mg，297.85μmol，28.83%產率)。HATU (392.76 mg, 1.03 mmol) was added portionwise to 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid at room temperature (351.59 mg, 1.03 mmol), 5-(5-methyl-2-piperidinyl)-1H-benzimidazole ( 222.39 mg, 1.03 mmol) and TEA (627.15 mg, 6.20 mmol, 863.84 μL) in DMF ( 10mL) in the suspension. The clear solution was stirred at 20 °C for 48 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 0-5min, with 5-30% water-MeCN- NH4OH , flow rate: 30ml/min as mobile phase), to give 5-[[2-[2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2- Methoxypyridine-3-carboxamide (130 mg, 297.85 μmol, 28.83% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值436.2；實測值437.2；Rt=1.267min。LCMS (ESI): [M] + m/z: calculated 436.2; found 437.2; Rt=1.267 min.

步驟2：掌性分離(化合物805 及化合物794 )Step 2: Chiral separation ( compound 805 and compound 794 )

藉由掌性HPLC(管柱：IC-II(250*20,5mkm)，己烷-IPA-MeOH,70-15-15,12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物794 5-[[2-[(2S,5R )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(56mg，128.30μmol，86.15%產率)(保留時間=85.1min)及化合物805 5-[[2-[(2R,5S )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧 基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(57mg，130.60μmol，87.69%產率)(保留時間=115.5min)。化合物805 於分析條件下(管柱：IC，己烷-IPA-MeOH,60-20-20,0.6ml/min為流動相)之保留時間為45.22min且化合物794 之保留時間為58.76min。The enantiomers were separated by chiral HPLC (column: IC-II (250*20, 5mkm), hexane-IPA-MeOH, 70-15-15, 12ml/min as mobile phase) to give two Separate enantiomer compound 794 5-[[2-[( 2S,5R )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (56 mg, 128.30 μmol, 86.15% yield) (retention time=85.1 min) and compound 805 5-[[2-[ ( 2R,5S )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxy Pyridine-3-carboxamide (57 mg, 130.60 μmol, 87.69% yield) (retention time = 115.5 min). The retention time of compound 805 under analytical conditions (column: IC, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 45.22 min and the retention time of compound 794 was 58.76 min.

化合物805：保留時間：45.22minCompound 805: retention time: 45.22min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.05(d,3H),1.38(m,1H),1.96(m,2H),2.25(m,2H),3.48(m,1H),3.56(m,1H),3.96(s,3H),5.52(m,1H),7.56(m,5H),8.46(m,3H),11.05(m,1H),12.41(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.05(d,3H), 1.38(m,1H), 1.96(m,2H), 2.25(m,2H), 3.48(m,1H), 3.56(m, 1H), 3.96(s, 3H), 5.52(m, 1H), 7.56(m, 5H), 8.46(m, 3H), 11.05(m, 1H), 12.41(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值436.2；實測值437.2；Rt=0.942min。LCMS (ESI): [M] + m/z: calculated 436.2; found 437.2; Rt=0.942 min.

化合物794：保留時間：58.76minCompound 794: retention time: 58.76min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.05(d,3H),1.38(m,1H),1.94(m,2H),2.18(m,2H),3.48(m,1H),3.56(m,1H),3.96(s,3H),5.52(m,1H),7.56(m,5H),8.09(m,1H),8.26(m,2H),11.05(m,1H),12.41(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.05(d,3H), 1.38(m,1H), 1.94(m,2H), 2.18(m,2H), 3.48(m,1H), 3.56(m, 1H), 3.96(s, 3H), 5.52(m, 1H), 7.56(m, 5H), 8.09(m, 1H), 8.26(m, 2H), 11.05(m, 1H), 12.41 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值436.2；實測值437.2；Rt=0.942min。LCMS (ESI): [M] + m/z: calculated 436.2; found 437.2; Rt=0.942 min.

實例59. 5-[[2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物360)及5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物361)之合成Example 59. 5-[[2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (Compound 360) and 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidine [Synthesis of]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 361)

Figure 110128222-A0202-12-1000-78
Figure 110128222-A0202-12-1000-78

步驟1：5-[[2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -Synthesis of formamide

向5-(5-甲基-2-哌啶基)-1H-吲唑(0.23g，1.07mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(262.40mg，1.07mmol，HCl)及三乙胺(540.51mg， 5.34mmol，744.51μL)於DMF(5mL)中之懸浮液中添加HATU(446.82mg，1.18mmol)。將反應混合物在30℃下攪拌12h且使其經歷HPLC(10-10-30% 0-1-6min 0.2% TFA-乙腈，流速：30ml/min(裝載泵4ml/min乙腈)，目標質量406，管柱：SunFireC18 100* 19mm 5um)，以獲得5-[[2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(110mg，270.64μmol，25.33%產率)。To 5-(5-methyl-2-piperidinyl)-1H-indazole (0.23 g, 1.07 mmol), 2-[(5-aminocarboxy-3-pyridinyl)amino]-2- To a suspension of oxoacetic acid (262.40 mg, 1.07 mmol, HCl) and triethylamine (540.51 mg, 5.34 mmol, 744.51 μL) in DMF (5 mL) was added HATU (446.82 mg, 1.18 mmol). The reaction mixture was stirred at 30 °C for 12 h and subjected to HPLC (10-10-30% 0-1-6 min 0.2% TFA-acetonitrile, flow rate: 30 ml/min (loading pump 4 ml/min acetonitrile), target mass 406, Column: SunFire C18 100 * 19mm 5um) to obtain 5-[[2-[2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-pendoxoethyl Acyl]amino]pyridine-3-carboxamide (110 mg, 270.64 μmol, 25.33% yield).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=2.559min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=2.559 min.

步驟2：5-[[2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物360 )及5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物361 )之合成Step 2: 5-[[2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoethanoyl] Amino]pyridine-3-carboxamide ( compound 360 ) and 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidine Synthesis of [methyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 361 )

使5-[[2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(110mg，270.64μmol)經歷HPLC(OJ-H(250* 20，5mkm)管柱；己烷-IPA-MeOH，60-20-20為流動相；流速15ml/min)，以得到化合物360 5-[[2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(39.0mg，70.91%產率；RT=31.364min)及化合物361 5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(38.0mg，69.09%產率；RT=12.133min)。make 5-[[2-[2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (110 mg, 270.64 μmol) was subjected to HPLC (OJ-H (250 * 20, 5 mkm) column; hexane-IPA-MeOH, 60-20-20 as mobile phase; flow rate 15 ml/min) to give compound 360 5-[[2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (39.0 mg, 70.91% yield; RT=31.364 min) and compound 361 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)- 5-Methyl-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (38.0 mg, 69.09% yield; RT=12.133 min).

化合物360： RT(OJ-3，己烷-IPA-MeOH，50-25-25，0.15ml/min)=16.677min。 Compound 360: RT (OJ-3, Hexane-IPA-MeOH, 50-25-25, 0.15 ml/min) = 16.677 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.06(m,3H),1.32-1.40(m,1H),1.75-1.83(m,1H),1.83-1.94(m,1H),2.09-2.23(m,1H),2.26-2.34(m,1H),2.78-3.26(m,1H),3.40-4.05(m,1H),5.20-5.71(m,1H),7.26-7.39(m,1H),7.47-7.64(m,2H),7.67-7.76(m,1H),8.01-8.08(m,1H),8.10-8.21(m,1H),8.40-8.53(m,1H),8.70-8.80(m,1H),8.82-8.95(m,1H),11.18-11.33(m,1H),12.98-13.07(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.01-1.06(m,3H), 1.32-1.40(m,1H), 1.75-1.83(m,1H), 1.83-1.94(m,1H), 2.09- 2.23(m,1H), 2.26-2.34(m,1H), 2.78-3.26(m,1H), 3.40-4.05(m,1H), 5.20-5.71(m,1H), 7.26-7.39(m,1H) ),7.47-7.64(m,2H),7.67-7.76(m,1H),8.01-8.08(m,1H),8.10-8.21(m,1H),8.40-8.53(m,1H),8.70-8.80 (m, 1H), 8.82-8.95 (m, 1H), 11.18-11.33 (m, 1H), 12.98-13.07 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=3.992min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=3.992 min.

化合物361： RT(OJ-3，己烷-IPA-MeOH，50-25-25，0.15ml/min)= Compound 361: RT (OJ-3, Hexane-IPA-MeOH, 50-25-25, 0.15ml/min)=

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.06(m,3H),1.30-1.43(m,1H),1.73-1.83(m,1H),1.83-1.93(m,1H),2.07-2.23(m,1H),2.25-2.35(m,1H),2.78-3.26(m,1H),3.44-4.06(m,1H),5.20-5.74(m,1H),7.27-7.39(m,1H),7.49-7.64(m,2H),7.69-7.75(m,1H),8.00-8.07(m,1H),8.08-8.21(m,1H),8.42-8.55(m,1H),8.71-8.80(m,1H),8.80-8.96(m,1H),11.16-11.33(m,1H),12.96-13.07(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.00-1.06(m,3H), 1.30-1.43(m,1H), 1.73-1.83(m,1H), 1.83-1.93(m,1H), 2.07- 2.23(m,1H), 2.25-2.35(m,1H), 2.78-3.26(m,1H), 3.44-4.06(m,1H), 5.20-5.74(m,1H), 7.27-7.39(m,1H) ),7.49-7.64(m,2H),7.69-7.75(m,1H),8.00-8.07(m,1H),8.08-8.21(m,1H),8.42-8.55(m,1H),8.71-8.80 (m, 1H), 8.80-8.96 (m, 1H), 11.16-11.33 (m, 1H), 12.96-13.07 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=4.010min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=4.010 min.

實例60. 5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物465)及5-[[2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物464)之合成Example 60. 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-2-methoxypyridine-3-carboxamide (Compound 465) and 5-[[2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (compound 464)

Figure 110128222-A0202-12-1002-79
Figure 110128222-A0202-12-1002-79

步驟1：5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Synthesis of Amino]-2-methoxypyridine-3-carboxamide

向5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(0.3g，975.41μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(332.00mg，975.41μmol，Et3 N)及三乙胺(493.51mg，4.88mmol，679.77μL)之溶液中分批添加HATU(407.97mg，1.07mrmol)。將所得混合物在25℃下攪拌3h且使其經歷HPLC(0-5min 20-70%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，管柱：YMC-Actus Triart C18 100* 20mml.D.S-5um)，以得到5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(150mg，343.67μmol，35.23%產率)。LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=2.886min。To 5-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (0.3 g, 975.41 μmol), 2-[(5-aminocarbamoyl-6-methoxy To a solution of -3-pyridyl)amino]-2-oxoacetic acid (332.00 mg, 975.41 μmol, Et 3 N) and triethylamine (493.51 mg, 4.88 mmol, 679.77 μL) was added HATU (407.97 μL) in portions mg, 1.07 mmol). The resulting mixture was stirred at 25°C for 3 h and subjected to HPLC (0-5 min 20-70% water-methanol ( NH3 0.1%), flow rate 30 ml/min (loading pump 4 ml/min methanol ( NH3 0.1%)) , column: YMC-Actus Triart C18 100 * 20mml.DS-5um) to give 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl -1-Piperidinyl]-2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (150 mg, 343.67 μmol, 35.23% yield). LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=2.886 min.

步驟2：5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物465 )及5-[[2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物464 )之合成Step 2: 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoethanoyl] Amino]-2-methoxypyridine-3-carboxamide ( Compound 465 ) and 5-[[2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 464 )

對5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(150mg，343.67μmol)進行掌性分離(IC_I(250* 20，5mkm)，己烷-IPA-MeOH，40-30-30，10ml/min)，以獲得化合物465 5-[[2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(45mg，103.10μmol，60.00%產率；RT=30.290min)及化合物464 5-[[2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(44mg，100.81μmol，58.67%產率；RT=23.440min)。p-5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-2-Methoxypyridine-3-carboxamide (150 mg, 343.67 μmol) for chiral separation (IC_I (250 * 20, 5mkm), Hexane-IPA-MeOH, 40-30-30, 10ml/min ) to obtain compound 465 5-[[2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-methoxypyridine-3-carboxamide (45 mg, 103.10 μmol, 60.00% yield; RT=30.290 min) and compound 464 5-[[2-[(2R,5S) -2-(1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxylate Amine (44 mg, 100.81 μmol, 58.67% yield; RT=23.440 min).

化合物465： RT(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)=49.555min。 Compound 465: RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 49.555 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.06(m,3H),1.30-1.42(m,1H),1.66-1.81(m,1H),1.81-1.96(m,1H),2.02-2.23(m,1H),2.24-2.35(m,1H),2.74-3.28(m,1H),3.48-4.04(m,4H),5.24-5.73(m,1H),7.26-7.39(m,1H),7.49-7.55(m,1H),7.67-7.75(m,3H),8.01-8.06(m,1H),8.42-8.61(m,2H),10.98-11.11(m,1H),13.00-13.04(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.01-1.06(m,3H), 1.30-1.42(m,1H), 1.66-1.81(m,1H), 1.81-1.96(m,1H), 2.02- 2.23(m,1H), 2.24-2.35(m,1H), 2.74-3.28(m,1H), 3.48-4.04(m,4H), 5.24-5.73(m,1H), 7.26-7.39(m,1H) ),7.49-7.55(m,1H),7.67-7.75(m,3H),8.01-8.06(m,1H),8.42-8.61(m,2H),10.98-11.11(m,1H),13.00-13.04 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=2.909min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=2.909 min.

化合物464： RT(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)=45.171min。 Compound 464: RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 45.171 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.05(m,3H),1.28-1.42(m,1H),1.71-1.82(m,1H),1.83-1.94(m,1H),2.02-2.23(m,1H),2.24-2.34(m,1H),2.76-3.26(m,1H),3.48-4.03(m,4H),5.18-5.76(m,1H),7.25-7.38(m,1H),7.49-7.57(m,1H),7.67-7.76(m,3H),8.01-8.08(m,1H),8.42-8.47(m,1H),8.47-8.60(m,1H),10.91-11.17(m,1H),12.95-13.12(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.00-1.05(m,3H), 1.28-1.42(m,1H), 1.71-1.82(m,1H), 1.83-1.94(m,1H), 2.02- 2.23(m, 1H), 2.24-2.34(m, 1H), 2.76-3.26(m, 1H), 3.48-4.03(m, 4H), 5.18-5.76(m, 1H), 7.25-7.38(m, 1H ),7.49-7.57(m,1H),7.67-7.76(m,3H),8.01-8.08(m,1H),8.42-8.47(m,1H),8.47-8.60(m,1H),10.91-11.17 (m, 1H), 12.95-13.12 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=2.907min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=2.907 min.

實例61. N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物631)及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Example 61. N-(5,6-Dimethyl-3-pyridinyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperin Imidyl]-2-oxoacetamide (Compound 631) and N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazole Synthesis of -5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide

Figure 110128222-A0202-12-1004-81
Figure 110128222-A0202-12-1004-81

步驟1：N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(5,6-Dimethyl-3-pyridinyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperin Synthesis of Peridyl]-2-Pendant Oxyacetamide

在25℃下，在0.5h內，向5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(250mg，1.16mmol)、2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(342.99mg，1.16mmol，N(C2 H5 )3 )及三乙胺(1.18g，11.61mmol，1.62mL)於DMF(8mL)中之經攪拌之溶液中小批量添加HATU(485.68mg，1.28mmol)。將所得反應混合物在25℃下攪拌12h。藉由反相HPLC(管柱：YMC Triart C18 100* 20mm，5um，流動相：50-50-80% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min，裝載泵4ml/min甲醇)純化粗反應混合物，以得到呈淡黃色固體之N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(240mg，613.08μmol，52.80%產率)。To 5-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (250 mg, 1.16 mmol), 2-[(5,6 -Dimethyl-3-pyridyl)amino]-2-side oxyacetic acid (342.99 mg, 1.16 mmol, N(C 2 H 5 ) 3 ) and triethylamine (1.18 g, 11.61 mmol, 1.62 mL) To a stirred solution in DMF (8 mL) was added HATU (485.68 mg, 1.28 mmol) in small portions. The resulting reaction mixture was stirred at 25 °C for 12 h. by reverse phase HPLC (column: YMC Triart C18 100 * 20mm, 5um, mobile phase: 50-50-80% 0-1-5min 0.1% NH3 -methanol, flow rate: 30ml/min, loading pump 4ml/min methanol) to purify the crude reaction mixture to give N-(5,6-dimethyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazole-5- as a pale yellow solid (240 mg, 613.08 μmol, 52.80% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.03(d,3H),1.32(m,1H),1.49(s,3H),1.78(m,2H),2.26(s,5H),3.28(s,3H),7.28(d,1H),7.52(d,1H),7.69(s,1H),7.83(s,1H),8.05(s,1H),8.52(s,1H),10.90(m,1H),13.03(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.03(d, 3H), 1.32(m, 1H), 1.49(s, 3H), 1.78(m, 2H), 2.26(s, 5H), 3.28(s ,3H),7.28(d,1H),7.52(d,1H),7.69(s,1H),7.83(s,1H),8.05(s,1H),8.52(s,1H),10.90(m, 1H), 13.03 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值391.2；實測值392.2；Rt=1.468min。LCMS (ESI): [M+H] + m/z: calculated 391.2; found 392.2; Rt=1.468 min.

步驟2：N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物631 )及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(5,6-Dimethyl-3-pyridinyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidine Imidyl]-2-oxyacetamide ( Compound 631 ) and N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazole Synthesis of -5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide

將外消旋N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(240mg，613.08μmol)提交至製備型掌性HPLC(管柱：Chiralpak IB-I(250* 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：10mL/min；管柱溫度：23℃；波長：205nm.)，以得到呈白色固體之化合物631 N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(111mg，283.55μmol，46.25%產率)(保留時間=12.32min)；及化合物620 N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(112mg，286.10μmol，46.67%產率)(保留時間=20.73min)。The racemic N-(5,6-dimethyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1- Piperidinyl]-2-oxyacetamide (240 mg, 613.08 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IB-I (250 * 20 mm, 5 mkm); mobile phase: hexane-IPA- MeOH, 50-25-25; flow rate: 10 mL/min; column temperature: 23°C; wavelength: 205 nm.) to give compound 631 N-(5,6-dimethyl-3-pyridyl as a white solid) )-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (111 mg, 283.55 μmol, 46.25% yield) (retention time = 12.32 min); and compound 620 N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazole- 5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (112 mg, 286.10 μmol, 46.67% yield) (retention time = 20.73 min).

化合物631： RT(IB，己烷-IPA-MeOH，50-25-25，0.6ml/min)=7.939min。 Compound 631: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 7.939 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.06(m,3H),1.30-1.40(m,1H),1.70-1.80(m,1H),1.82-1.93(m,1H),2.04-2.14(m,1H),2.15-2.25(m,3H),2.25-2.31(m,1H),2.31-2.38(m,3H),2.77-3.25(m,1H),3.37-4.05(m,1H),5.14-5.76(m,1H),7.25-7.39(m,1H),7.45-7.56(m,1H),7.66-7.72(m,1H),7.72-7.85(m,1H),7.98-8.08(m,1H),8.38-8.55(m,1H),10.73-11.11(m,1H),12.95-13.14(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.06(m,3H), 1.30-1.40(m,1H), 1.70-1.80(m,1H), 1.82-1.93(m,1H), 2.04- 2.14(m,1H),2.15-2.25(m,3H),2.25-2.31(m,1H),2.31-2.38(m,3H),2.77-3.25(m,1H),3.37-4.05(m,1H ), 5.14-5.76(m, 1H), 7.25-7.39(m, 1H), 7.45-7.56(m, 1H), 7.66-7.72(m, 1H), 7.72-7.85(m, 1H), 7.98-8.08 (m, 1H), 8.38-8.55 (m, 1H), 10.73-11.11 (m, 1H), 12.95-13.14 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值391.2；實測值392.2；Rt=1.918min。LCMS (ESI): [M+H] + m/z: calculated 391.2; found 392.2; Rt=1.918 min.

化合物620： RT(IB，己烷-IPA-MeOH，50-25-25，0.6ml/min)=12.720min。 Compound 620: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 12.720 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.05(m,3H),1.29-1.41(m,1H),1.71-1.80(m,1H),1.81-1.92(m,1H),2.04-2.14(m,1H),2.16-2.24(m,3H),2.24-2.30(m,1H),2.31-2.37(m,3H),2.77-3.26(m,1H),3.42-4.06(m,1H),5.16-5.73(m,1H),7.24-7.40(m,1H),7.47-7.57(m,1H),7.66-7.72(m,1H),7.72-7.85(m,1H),8.00-8.06(m,1H),8.38-8.53(m,1H),10.79-11.01(m,1H),12.93-13.12(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.99-1.05(m,3H), 1.29-1.41(m,1H), 1.71-1.80(m,1H), 1.81-1.92(m,1H), 2.04- 2.14(m,1H), 2.16-2.24(m,3H), 2.24-2.30(m,1H), 2.31-2.37(m,3H), 2.77-3.26(m,1H), 3.42-4.06(m,1H) ), 5.16-5.73(m, 1H), 7.24-7.40(m, 1H), 7.47-7.57(m, 1H), 7.66-7.72(m, 1H), 7.72-7.85(m, 1H), 8.00-8.06 (m, 1H), 8.38-8.53 (m, 1H), 10.79-11.01 (m, 1H), 12.93-13.12 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值391.2；實測值392.2；Rt=1.946min。LCMS (ESI): [M+H] + m/z: calculated 391.2; found 392.2; Rt=1.946 min.

實例62. 5-[[2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物440)及5-[[2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側Example 62. 5-[[2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (Compound 440) and 5-[[2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-side 氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物441)之合成Synthesis of oxyacetyl]amino]pyridine-3-carboxamide (compound 441)

Figure 110128222-A0202-12-1006-82
Figure 110128222-A0202-12-1006-82

以與以上所述之化合物類似之方式製備Rel 5-[[2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺。Rel 5-[[2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-side was prepared in a similar manner to the compound described above Oxyacetyl]amino]pyridine-3-carboxamide.

使用Chiralpak IA-II(250 * 20mm,5mkm)管柱(以己烷-IPA-MeOH為流動相，70-15-15流速：12mL/min)進行掌性分離，得到呈白色固體之化合物440 5-[[2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(46.05mg，114.88μmol，35.78%產率)及呈白色固體之化合物441 5-[[2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(48.11mg，120.02μmol，37.38%產率)。Chiralpak IA-II (250*20mm, 5mkm) column (with hexane-IPA-MeOH as mobile phase, 70-15-15 flow rate: 12mL/min) was used for chiral separation to give compound 440 5 as a white solid -[[2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Formamide (46.05 mg, 114.88 μmol, 35.78% yield) and compound 441 as a white solid 5-[[2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (48.11 mg, 120.02 μmol, 37.38% yield).

化合物440： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.64(m,1H),1.89(m,1H),2.14(m,2H),3.01(m,1H),3.76(m,1H),5.36(m,1H),7.32(m,3H),7.42(m,1H),7.59(m,1H),8.14(m,1H),8.47(m,1H),8.76(m,1H),8.86(m,1H),11.26(m,1H) Compound 440: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.64 (m, 1H), 1.89 (m, 1H), 2.14 (m, 2H), 3.01(m, 1H), 3.76(m, 1H), 5.36(m, 1H), 7.32(m, 3H), 7.42(m, 1H), 7.59(m, 1H), 8.14(m, 1H) ),8.47(m,1H),8.76(m,1H),8.86(m,1H),11.26(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值400.1；實測值401.1；Rt=3.179min。LCMS (ESI): [M+H] + m/z: calculated 400.1; found 401.1; Rt=3.179 min.

化合物441： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.34(m,1H),1.63(m,1H),1.89(m,1H),2.14(m,2H),2.96(m,1H),3.66(m,1H),5.37(d,1H),7.32(m,3H),7.43(m,1H),7.59(m,1H),8.14(m,1H),8.47(m,1H),8.76(m,1H),8.86(m,1H),11.26(m,1H) Compound 441: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.01 (m, 3H), 1.34 (m, 1H), 1.63 (m, 1H), 1.89 (m, 1H), 2.14 (m, 2H), 2.96(m, 1H), 3.66(m, 1H), 5.37(d, 1H), 7.32(m, 3H), 7.43(m, 1H), 7.59(m, 1H), 8.14(m, 1H) ),8.47(m,1H),8.76(m,1H),8.86(m,1H),11.26(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值400.1；實測值401.1；Rt=3.179min。LCMS (ESI): [M+H] + m/z: calculated 400.1; found 401.1; Rt=3.179 min.

實例63. 5-[[2-[(2R ,5S )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙Example 63. 5-[[2-[( 2R , 5S )-2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxygen Second 醯基]胺基]吡啶-3-甲醯胺及 5-[[2-[(2S ,5R )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物330及化合物323)之合成Acrylo]amino]pyridine-3-carboxamide and 5-[[2-[( 2S , 5R )-2-(4-hydroxy-3-methylphenyl)-5-methyl-1 Synthesis of -piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (compound 330 and compound 323)

Figure 110128222-A0202-12-1007-83
Figure 110128222-A0202-12-1007-83

步驟1：5-[[2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(4-Hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -Synthesis of 3-formamide

向2-甲基-4-(5-甲基-2-哌啶基)苯酚(0.21g，1.02mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(317.46mg，1.02mmol，Et3 N鹽)及HATU(427.84mg，1.13mmol)於DMSO(4mL)中之經攪拌之溶液中添加DIPEA(264.40mg，2.05mmol，356.34μL)。將反應混合物在25℃下攪拌16小時。16小時之後，藉由反相HPLC(溶析液：2-10min，35-100%，CH3 CN+甲酸/H2 O；流速：30mL/min；裝載泵：4mL，CH3 CN+甲酸；管柱：SunFireC18 100 x 19mm，5um)純化反應混合物，以獲得呈白色固體之5-[[2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(100mg，252.25μmol，24.66%產率)。To 2-methyl-4-(5-methyl-2-piperidinyl)phenol (0.21 g, 1.02 mmol), 2-[(5-aminocarboxy-3-pyridinyl)amino]-2 - To a stirred solution of oxyacetic acid (317.46 mg, 1.02 mmol, Et3N salt) and HATU (427.84 mg, 1.13 mmol) in DMSO (4 mL) was added DIPEA (264.40 mg, 2.05 mmol, 356.34 μL) . The reaction mixture was stirred at 25°C for 16 hours. After 16 hours, by reverse phase HPLC (eluent: 2-10 min, 35-100%, CH3CN +formic acid/ H2O ; flow rate: 30 mL/min; loading pump: 4 mL, CH3CN +formic acid; column : SunFire C18 100 x 19mm, 5um) The reaction mixture was purified to obtain 5-[[2-[2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl as a white solid ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (100 mg, 252.25 μmol, 24.66% yield).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.0；Rt=1.165min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.0; Rt=1.165 min.

步驟2：5-[[2-[(2R,5S)-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S,5R)-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物330 及化合物323 )之掌性分離Step 2: 5-[[2-[(2R,5S)-2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide and 5-[[2-[(2S,5R)-2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidine Chiral Separation of Radix]-2-Pendant Oxyacetyl]amino]pyridine-3-carboxamide ( Compound 330 and Compound 323 )

使5-[[2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基] 胺基]吡啶-3-甲醯胺(100mg，252.25μmol)經歷掌性HPLC純化(管柱：Chiralpak IC-I(250 x 20mm，5um)；流動相：己烷-IPA-MeOH，60-20-20；流速：12mL/min)，以得到呈淡黃色固體之5-[[2-[(2R ,5S )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物330 ，28.37mg)及5-[[2-[(2S ,5R )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物323 ，28.46mg)。make 5-[[2-[2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 - Formamide (100 mg, 252.25 μmol) was purified by chiral HPLC (column: Chiralpak IC-I (250 x 20 mm, 5 um); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12 mL /min) to obtain 5-[[2-[( 2R , 5S )-2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidine as a pale yellow solid yl]-2- oxyethanoyl ]amino]pyridine-3-carboxamide ( compound 330 , 28.37mg ) and 5-[[2-[(2S,5R)-2-(4- Hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 323 , 28.46 mg).

化合物330： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.95-1.10(m,3H),1.27-1.38(m,1H),1.66-1.79(m,1H),1.81-1.94(m,1H),1.95-2.21(m,5H),2.77-3.21(m,1H),3.45-4.01(m,1H),4.99-5.57(m,1H),6.69-6.83(m,1H),6.90-6.99(m,1H),6.99-7.08(m,1H),7.54-7.67(m,1H),8.10-8.24(m,1H),8.41-8.55(m,1H),8.71-8.82(m,1H),8.82-8.94(m,1H),9.20-9.29(s,1H),11.12-11.29(m,1H)。 Compound 330: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.95-1.10 (m, 3H), 1.27-1.38 (m, 1H), 1.66-1.79 (m, 1H), 1.81-1.94 ( m,1H),1.95-2.21(m,5H),2.77-3.21(m,1H),3.45-4.01(m,1H),4.99-5.57(m,1H),6.69-6.83(m,1H), 6.90-6.99(m,1H),6.99-7.08(m,1H),7.54-7.67(m,1H),8.10-8.24(m,1H),8.41-8.55(m,1H),8.71-8.82(m , 1H), 8.82-8.94 (m, 1H), 9.20-9.29 (s, 1H), 11.12-11.29 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=2.862min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=2.862 min.

掌性HPLC：Rt=30.96min(管柱：IC；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=30.96 min (column: IC; mobile phase: Hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

化合物323： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.94-1.10(m,3H),1.26-1.40(m,1H),1.66-1.79(m,1H),1.80-1.94(m,1H),1.93-2.23(m,5H),2.78-3.22(m,1H),3.44-4.01(m,1H),4.98-5.57(m,1H),6.68-6.82(m,1H),6.86-6.98(m,1H),6.98-7.07(m,1H),7.51-7.72(m,1H),8.06-8.28(m,1H),8.37-8.61(m,1H),8.69-8.82(m,1H),8.82-8.97(m,1H),9.16-9.32(s,1H),11.09-11.32(m,1H)。 Compound 323: 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.94-1.10 (m, 3H), 1.26-1.40 (m, 1H), 1.66-1.79 (m, 1H), 1.80-1.94 ( m,1H),1.93-2.23(m,5H),2.78-3.22(m,1H),3.44-4.01(m,1H),4.98-5.57(m,1H),6.68-6.82(m,1H), 6.86-6.98(m,1H),6.98-7.07(m,1H),7.51-7.72(m,1H),8.06-8.28(m,1H),8.37-8.61(m,1H),8.69-8.82(m , 1H), 8.82-8.97 (m, 1H), 9.16-9.32 (s, 1H), 11.09-11.32 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=2.863min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=2.863 min.

掌性HPLC：Rt=19.20min(管柱：IC；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=19.20 min (column: IC; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

實例64. 5-[[2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-Example 64. 5-[[2-[( 2S , 5R )-5-methyl-2-(2-side oxyindolin-5-yl)-1-piperidinyl]-2-side Oxyacetyl ]amino]pyridine-3-carboxamide and 5-[[2-[( 2R ,5S)-5-methyl-2-(2-side oxyindoline-5 -base)-1- 哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物325及化合物319)之合成Synthesis of piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 325 and compound 319)

Figure 110128222-A0202-12-1009-84
Figure 110128222-A0202-12-1009-84

步驟1：5-[[2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[5-Methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide

在室溫下，向5-(5-甲基-2-哌啶基)吲哚啉-2-酮(0.4g，1.74mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(426.60mg，1.74mmol，鹽酸鹽)及三乙胺(1.76g，17.37mmol，2.42mL)於DMF(5mL)中之經攪拌之溶液中添加HATU(990.59mg，2.61mmol)。將所得反應混合物在同一溫度下攪拌18小時。18小時之後，在減壓下濃縮反應混合物。藉由HPLC(溶析液：2-10min，60-85%，MeOH/H2 O；流速：30mL/min；裝載泵：4mL，MeOH；管柱：SunFire 100 x19mm，5μM)純化所獲得之殘餘物，以得到呈紅色固體之5-[[2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.09g，213.55μmol，12.30%產率)。To 5-(5-methyl-2-piperidinyl)indolin-2-one (0.4 g, 1.74 mmol), 2-[(5-aminocarbamoyl-3-pyridyl at room temperature )amino]-2-oxoacetic acid (426.60 mg, 1.74 mmol, hydrochloride) and triethylamine (1.76 g, 17.37 mmol, 2.42 mL) in DMF (5 mL) was added HATU to a stirred solution (990.59 mg, 2.61 mmol). The resulting reaction mixture was stirred at the same temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by HPLC (eluent: 2-10 min, 60-85%, MeOH/ H2O ; flow rate: 30 mL/min; loading pump: 4 mL, MeOH; column: SunFire 100 x 19 mm, 5 μM) to give 5-[[2-[5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyethyl as a red solid Acyl]amino]pyridine-3-carboxamide (0.09 g, 213.55 μmol, 12.30% yield).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=1.067min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=1.067 min.

步驟2：5-[[2-[(2S,5R)-5-甲基-2-[2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶Step 2: 5-[[2-[(2S,5R)-5-methyl-2-[2-oxyindolin-5-yl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide and 5-[[2-[(2R,5S)-5-methyl-2-(2-oxyindolin-5-yl)- 1-piperidine 基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物325 及化合物319 )之掌性分離Chiral Separation of Radix]-2-Pendant Oxyacetyl]amino]pyridine-3-carboxamide ( Compound 325 and Compound 319 )

使5-[[2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.09g，213.55μmol)經歷掌性HPLC(管柱：IC(250 x 20mm，5um)，溶析液：CO2 -MeOH，50-50；流速：40mL/min)，以得到呈淡紅色固體之5-[[2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物325 ，26.54mg，62.97μmol，29.49%產率)及5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物319 ，0.0312g，74.03μmol，34.67%產率)。make 5-[[2-[5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine -3-Carboxamide (0.09 g, 213.55 μmol) was subjected to chiral HPLC (column: IC (250 x 20 mm, 5 um), eluent: CO2 -MeOH, 50-50; flow rate: 40 mL/min), to give 5-[[2-[( 2S , 5R )-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl] as a pale red solid -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 325 , 26.54 mg, 62.97 μmol, 29.49% yield) and 5-[[2-[(2 R ,5 S ) -5-Methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 319 , 0.0312 g, 74.03 μmol, 34.67% yield).

化合物319：Compound 319:

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)1.03(m,3H),1.33(m,1H),1.72(m,1H),1.89(m,1H),2.02(m,1H),2.18(m,1H),2.83(m,1H),3.64(m,3H),5.33(m,1H),6.81(m,1H),7.16(m,2H),7.60(m,1H),8.15(m,1H),8.47(m,1H),8.75(m,1H),8.90(m,1H),10.35(m,1H),11.26(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 1.03 (m, 3H), 1.33 (m, 1H), 1.72 (m, 1H), 1.89 (m, 1H), 2.02 (m, 1H) ,2.18(m,1H),2.83(m,1H),3.64(m,3H),5.33(m,1H),6.81(m,1H),7.16(m,2H),7.60(m,1H), 8.15(m, 1H), 8.47(m, 1H), 8.75(m, 1H), 8.90(m, 1H), 10.35(m, 1H), 11.26(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=2.467min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=2.467 min.

掌性HPLC：Rt=17.33min(管柱：IC；溶析液：CO2 -MeOH，60-40；流速：3.0mL/min)。Chiral HPLC: Rt=17.33 min (column: IC; eluent: CO2 -MeOH, 60-40; flow rate: 3.0 mL/min).

化合物325：Compound 325:

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)1.03(m,3H),1.33(m,1H),1.72(m,1H),1.88(m,1H),2.04(m,1H),2.19(m,1H),3.09(m,1H),3.64(m,3H),5.33(m,1H),6.81(m,1H),7.16(m,2H),7.61(m,1H),8.16(m,1H),8.48(m,1H),8.76(m,1H),8.86(m,1H),10.36(m,1H),11.26(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 1.03 (m, 3H), 1.33 (m, 1H), 1.72 (m, 1H), 1.88 (m, 1H), 2.04 (m, 1H) ,2.19(m,1H),3.09(m,1H),3.64(m,3H),5.33(m,1H),6.81(m,1H),7.16(m,2H),7.61(m,1H), 8.16(m, 1H), 8.48(m, 1H), 8.76(m, 1H), 8.86(m, 1H), 10.36(m, 1H), 11.26(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=2.486min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=2.486 min.

掌性HPLC：Rt=12.75min(管柱：IC；溶析液：CO2 -MeOH，60-40；流速：3.0mL/min)。Chiral HPLC: Rt=12.75 min (column: IC; eluent: CO2 -MeOH, 60-40; flow rate: 3.0 mL/min).

實例65. 2-甲氧基-5-[[2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及2-甲氧基-5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物453及化合物454)之合成Example 65. 2-Methoxy-5-[[2-[( 2S , 5R )-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidine base]-2-oxyethanoyl]amino]pyridine-3-carboxamide and 2-methoxy-5-[[2-[(2 R ,5 S )-5-methyl-2 Of -(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 453 and compound 454) synthesis

Figure 110128222-A0202-12-1011-85
Figure 110128222-A0202-12-1011-85

步驟1：2-甲氧基-5-(5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-(5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl] Synthesis of Amino]Pyridine-3-Carboxyamide

在室溫下，向5-(5-甲基-2-哌啶基)吲哚啉-2-酮(200mg，868.41μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(295.58mg，868.41μmol，Et3 N鹽)及三乙胺(439.37mg，4.34mmol，605.19μL)於DMF(4mL)中之經攪拌之溶液中添加HATU(495.30mg，1.30mmol)。將所得反應混合物在同一溫度下攪拌12小時。12小時之後，在減壓下濃縮反應混合物。藉由HPLC純化所獲得之殘餘物，以得到呈淡黃色固體之2-甲氧基-5-(5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(67.3mg，149.07μmol，17.17%產率)。To 5-(5-methyl-2-piperidinyl)indolin-2-one (200 mg, 868.41 μmol), 2-[(5-aminocarbamoyl-6-methoxyl) at room temperature -3-Pyridinyl)amino]-2-oxoacetic acid (295.58 mg, 868.41 μmol, Et 3 N salt) and triethylamine (439.37 mg, 4.34 mmol, 605.19 μL) in DMF (4 mL) To the stirred solution was added HATU (495.30 mg, 1.30 mmol). The resulting reaction mixture was stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by HPLC to give 2-methoxy-5-(5-methyl-2-(2-oxyindolin-5-yl)-1- as a pale yellow solid Piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (67.3 mg, 149.07 μmol, 17.17% yield).

LCMS(ESI)：[M+H]+ m/z：計算值451.2；實測值452.2；Rt=1.158min。LCMS (ESI): [M+H] + m/z: calculated 451.2; found 452.2; Rt=1.158 min.

步驟2：2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物453 及化合物454 )之掌性分離Step 2: 2-Methoxy-5-[[2-[(2S,5R)-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide and 2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(2- Chiral isolation of pendant oxyindolin-5-yl)-1-piperidinyl]-2- pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 453 and compound 454 )

使2-甲氧基-5-(5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(67.3mg，149.07μmol)經歷掌性HPLC(管柱：Chiralpak IB(250 x 30mm，5um)；流動相：CO2 -MeOH，70-30；流速：80mL/min)，以得到呈白色固體之2-甲氧基-5-[[2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物453 ，17.04mg，37.74μmol，25.32%產率)及2-甲氧基-5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物454 ，18.37mg，40.69μmol，27.30%產率)。make 2-methoxy-5-(5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyacetyl]amino ] Pyridine-3-carboxamide (67.3 mg, 149.07 μmol) was subjected to chiral HPLC (column: Chiralpak IB (250 x 30 mm, 5 um); mobile phase: CO2 -MeOH, 70-30; flow rate: 80 mL/min ) to give 2-methoxy-5-[[2-[( 2S , 5R )-5-methyl-2-(2-oxyindolin-5-yl) as a white solid -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( Compound 453 , 17.04 mg, 37.74 μmol, 25.32% yield) and 2-methoxy-5 -[[2-[(2 R ,5 S )-5-methyl-2-(2-oxoindolin-5-yl)-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide ( Compound 454 , 18.37 mg, 40.69 μmol, 27.30% yield).

化合物453：Compound 453:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.31(m,1H),1.83(m,3H),2.14(m,1H),3.01(m,1H),3.45(m,3H),3.93(m,3H),5.30(m,1H),6.78(d,1H),7.14(m,2H),7.71(m,2H),8.48(m,2H),10.33(m,1H),10.98(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.31 (m, 1H), 1.83 (m, 3H), 2.14 (m, 1H), 3.01 (m, 1H) ,3.45(m,3H),3.93(m,3H),5.30(m,1H),6.78(d,1H),7.14(m,2H),7.71(m,2H),8.48(m,2H), 10.33 (m, 1H), 10.98 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值451.2；實測值452.2；Rt=2.688min。LCMS (ESI): [M+H] + m/z: calculated 451.2; found 452.2; Rt=2.688 min.

掌性HPLC：Rt=13.46min(管柱：IB；溶析液：CO2 -MeOH，75-25；流速：2.0mL/min)。Chiral HPLC: Rt=13.46 min (column: IB; eluent: CO2 -MeOH, 75-25; flow rate: 2.0 mL/min).

化合物454：Compound 454:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.71(m,1H),1.87(m,1H),2.07(m,2H),3.01(m,1H),3.45(m,2H),3.93(m,3H),5.30(m,1H),6.79(dd,1H),7.13(m,2H),7.72(m,2H),8.48(m,2H),10.33(m,1H),10.98(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.32 (m, 1H), 1.71 (m, 1H), 1.87 (m, 1H), 2.07 (m, 2H) ,3.01(m,1H),3.45(m,2H),3.93(m,3H),5.30(m,1H),6.79(dd,1H),7.13(m,2H),7.72(m,2H), 8.48 (m, 2H), 10.33 (m, 1H), 10.98 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值451.2；實測值452.2；Rt=2.687min。LCMS (ESI): [M+H] + m/z: calculated 451.2; found 452.2; Rt=2.687 min.

掌性HPLC：Rt=16.19min(管柱：IB；溶析液：CO2 -MeOH，75-25；流速：2.0mL/min)。Chiral HPLC: Rt=16.19 min (column: IB; eluent: CO2 -MeOH, 75-25; flow rate: 2.0 mL/min).

實例66. 5-[[2-[(2R,4R,5S]-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物231)及5-[[2-[(2S,4S,5S]-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物229)之合成Example 66. 5-[[2-[(2R,4R,5S]-4,5-Dimethyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (Compound 231) and 5-[[2-[(2S,4S,5S]-4,5-dimethyl-2-phenyl-1-piperidinyl]-2-side Synthesis of oxyacetyl]amino]pyridine-3-carboxamide (compound 229)

Figure 110128222-A0202-12-1013-86
Figure 110128222-A0202-12-1013-86

將4,5-二甲基-2-苯基哌啶(0.076g，401.49μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(83.97mg，401.49μmol)、TEA(406.27mg，4.01mmol，559.59μL)及HATU(228.99mg，602.23μmol)溶解於DMF(2mL)中。將反應混合物在20℃下攪拌3h。將所得混合物用水稀釋且用EtOAc萃取三次。然後，將EtOAc用鹽水萃取三次。將有機相經Na2 SO4 乾燥，過濾出且在40℃下蒸發，以得到粗產物。藉由HPLC(0-50%甲醇，2-10min，流速30ml/min(裝載泵4ml/min甲醇)管柱：SunFire C18 100x20mm)純化所獲得之殘餘物，以得到化合物229 5-[[2-[(2S,4S,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.017g，44.69μmol，11.13%產率)及化合物231 5-[[2-[(2R,4R,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.035g，92.00μmol，22.91%產率)。4,5-Dimethyl-2-phenylpiperidine (0.076 g, 401.49 μmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid ( 83.97 mg, 401.49 μmol), TEA (406.27 mg, 4.01 mmol, 559.59 μL) and HATU (228.99 mg, 602.23 μmol) were dissolved in DMF (2 mL). The reaction mixture was stirred at 20 °C for 3 h. The resulting mixture was diluted with water and extracted three times with EtOAc. Then, EtOAc was extracted three times with brine. The organic phase was dried over Na2SO4 , filtered off and evaporated at 40°C to give crude product. The obtained residue was purified by HPLC (0-50% methanol, 2-10 min, flow rate 30 ml/min (loading pump 4 ml/min methanol) column: SunFire C18 100x20 mm) to give compound 229 5-[[2- [(2S,4S,5S)-4,5-Dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (0.017 g, 44.69 μmol, 11.13% yield) and compound 231 5-[[2-[(2R,4R,5S)-4,5-dimethyl-2-phenyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.035 g, 92.00 μmol, 22.91% yield).

化合物231： 1 H NMR(甲醇-d 4 ,400MHz)：δ(ppm)1.05(dd,6H),1.64(m,3H),2.07(m,1H),3.80(m,2H),5.19(m,1H),7.26(m,5H),8.70(m,3H)。 Compound 231: 1 H NMR (methanol- d 4 , 400 MHz): δ (ppm) 1.05 (dd, 6H), 1.64 (m, 3H), 2.07 (m, 1H), 3.80 (m, 2H), 5.19 (m , 1H), 7.26 (m, 5H), 8.70 (m, 3H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=1.167min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=1.167 min.

化合物229： 1 H NMR(氯仿-d,400MHz)：δ(ppm)0.77(m,6H),2.04(m,6H),2.88(m,1H),4.52(m,1H),6.24(m,2H),7.27(m,4H),8.52(m,1H),8.84(m,2H),9.90(m,1H)。 Compound 229: 1 H NMR (chloroform-d, 400 MHz): δ (ppm) 0.77 (m, 6H), 2.04 (m, 6H), 2.88 (m, 1H), 4.52 (m, 1H), 6.24 (m, 2H), 7.27 (m, 4H), 8.52 (m, 1H), 8.84 (m, 2H), 9.90 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=1.180min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=1.180 min.

實例67. 5-[[2-[(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物455)及5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物456)之合成Example 67. 5-[[2-[(2S,5R)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 455) and 5-[[2-[(2R,5S)-5-methyl-2-[4-(2, Synthesis of 2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-oxoethanoyl]amino]pyridine-3-carbamide (compound 456)

Figure 110128222-A0202-12-1014-87
Figure 110128222-A0202-12-1014-87

步驟1：4-[(2S,5R)-5-甲基-2-哌啶基]-N-(2,2,2-三氟乙基)苯胺之合成Step 1: Synthesis of 4-[(2S,5R)-5-methyl-2-piperidinyl]-N-(2,2,2-trifluoroethyl)aniline

將(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]哌啶-1-甲酸第三丁酯(1.85g，4.97mmol)溶解於二氯甲烷(20mL)中且添加於二噁烷中之4.0M氯化氫溶液(18.11g，49.67mmol，17.93mL，10%純度)。將所得混合物在25℃下攪拌15h，且在減壓下濃縮。將殘餘物用乙酸乙酯(25ml)研磨。將所獲得之灰色沉澱過濾且乾燥，得到4-[(2S,5R)-5-甲基-2-哌啶基]-N-(2,2,2-三氟乙基)苯胺(1.2g，3.48mmol，69.97%產率，2HCl)。(2S,5R)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.85 g, 4.97 mmol) Dissolve in dichloromethane (20 mL) and add a 4.0 M solution of hydrogen chloride in dioxane (18.11 g, 49.67 mmol, 17.93 mL, 10% purity). The resulting mixture was stirred at 25 °C for 15 h and concentrated under reduced pressure. The residue was triturated with ethyl acetate (25 ml). The obtained grey precipitate was filtered and dried to give 4-[(2S,5R)-5-methyl-2-piperidinyl]-N-(2,2,2-trifluoroethyl)aniline (1.2 g , 3.48 mmol, 69.97% yield, 2HCl).

1 H NMR(400MHz,DMSO-d6 )δ 0.87(m,1H),1.05(d,3H),1.49(m,1H),1.75(m,2H),1.97(m,2H),2.83(m,1H),3.09(m,1H),3.88(m,2H),4.04(m,1H),5.74(s,1H),6.71(d,2H),7.26(d,2H),8.53(m,1H),9.43(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.87(m, 1H), 1.05(d, 3H), 1.49(m, 1H), 1.75(m, 2H), 1.97(m, 2H), 2.83(m ,1H),3.09(m,1H),3.88(m,2H),4.04(m,1H),5.74(s,1H),6.71(d,2H),7.26(d,2H),8.53(m, 1H), 9.43 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值272.2；實測值273.2；Rt=0.967min。LCMS (ESI): [M+H] + m/z: calculated 272.2; found 273.2; Rt=0.967 min.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 2: 5-[[2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetyl] Amino] Pyridine-3-Carboxyamide

將4-[(2R,5S)-5-甲基-2-哌啶基]-N-(2,2,2-三氟乙基)苯胺(300mg，1.10mmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(270.60mg，1.10mmol，HCl)及三乙胺(557.40mg，5.51mmol，767.77μL)一起混合於二甲基甲醯胺(3mL)中。將所獲得之混合物簡單加熱至60-70℃，直到形成澄清溶液。冷卻至5-10℃之後，在5min期間分批添加HATU(460.78mg，1.21mmol)。將所得溶液在25℃下攪拌15h。然後使其經歷HPLC(管柱：YMC-Triart C18 100* 20mm，5um；30-85% 0-5min 0.1% NH3 -甲醇，流速30ml/min)，得到5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(274mg，591.22μmol，53.66%產率)。4-[(2R,5S)-5-methyl-2-piperidinyl]-N-(2,2,2-trifluoroethyl)aniline (300 mg, 1.10 mmol, 2HCl), 2-[( 5-Aminocarboxy-3-pyridinyl)amino]-2-oxoacetic acid (270.60 mg, 1.10 mmol, HCl) and triethylamine (557.40 mg, 5.51 mmol, 767.77 μL) were mixed together in dimethyl formamide (3 mL). The obtained mixture was heated briefly to 60-70°C until a clear solution formed. After cooling to 5-10 °C, HATU (460.78 mg, 1.21 mmol) was added portionwise over 5 min. The resulting solution was stirred at 25 °C for 15 h. It was then subjected to HPLC (column: YMC-Triart C18 100 * 20mm, 5um; 30-85% 0-5min 0.1% NH3 -methanol, flow rate 30ml/min) to give 5-[[2-[(2R, 5S)-5-Methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine -3-Carboxamide (274 mg, 591.22 μmol, 53.66% yield).

LCMS(ESI)：[M+H]+ m/z：計算值463.2；實測值464.2；Rt=3.207min。LCMS (ESI): [M+H] + m/z: calculated 463.2; found 464.2; Rt=3.207 min.

步驟3：5-[[2-[(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物455 )及5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物456 )之合成Step 3: 5-[[2-[(2S,5R)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 455 ) and 5-[[2-[(2R,5S)-5-methyl-2-[4-(2, Synthesis of 2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 456 )

藉由掌性HPLC(管柱：Chiralpak OJ(250* 30mm，20mkm)；流動相：CO2 -MeOH，60-40%；流速：90mL/min；40℃；波長：215nm.)將5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(226mg，487.64μmol)分離成鏡像異構物，得到：化合物455 5-[[2-[(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(61mg，131.62μmol，53.98%產率)(保留時間=2.92min)及化合物456 5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(61mg，131.62μmol，53.98%產率)(保留時間=8,11min) 5- [ [2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carboxamide (226 mg, 487.64 μmol) was isolated as the enantiomer to give: compound 455 5-[[2-[(2S,5R)-5-methyl-2- [4-(2,2,2-Trifluoroethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (61 mg, 131.62 μmol, 53.98% yield) (retention time=2.92 min) and compound 456 5-[[2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethyl Amino)phenyl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (61 mg, 131.62 μmol, 53.98% yield) (retention time = 8, 11min)

化合物455： RT(OJ-H，CO2-MeOH，50-50，2.0mL/min)=2.786min。 Compound 455: RT (OJ-H, CO2-MeOH, 50-50, 2.0 mL/min) = 2.786 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)0.74(m,3H),1.13(m,1H),1.63(m,2H), 1.83(m,1H),2.37(m,2H),3.76(m,3H),5.27(d,1H),6.20(t,1H),6.72(m,2H),7.03(d,1H),7.07(d,1H),7.58(m,1H),8.14(m,1H),8.47(m,1H),8.75(m,1H),8.86(m,1H),11.22(m,1H) 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 0.74 (m, 3H), 1.13 (m, 1H), 1.63 (m, 2H), 1.83 (m, 1H), 2.37 (m, 2H) ,3.76(m,3H),5.27(d,1H),6.20(t,1H),6.72(m,2H),7.03(d,1H),7.07(d,1H),7.58(m,1H), 8.14(m, 1H), 8.47(m, 1H), 8.75(m, 1H), 8.86(m, 1H), 11.22(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值463.2；實測值464.2；Rt=3.067min。LCMS (ESI): [M+H] + m/z: calculated 463.2; found 464.2; Rt=3.067 min.

化合物456： RT(OJ-H，CO2-MeOH，50-50，2.0mL/min)=8.110min。 Compound 456: RT (OJ-H, CO2-MeOH, 50-50, 2.0 mL/min) = 8.110 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)0.74(m,3H),1.12(m,1H),1.64(m,2H),1.81(m,1H),2.37(m,2H),3.76(m,3H),5.27(m,1H),6.20(t,1H),6.72(m,2H),7.03(d,1H),7.07(d,1H),7.58(m,1H),8.14(m,1H),8.47(m,1H),8.75(m,1H),8.86(m,1H),11.23(m,1H) 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 0.74 (m, 3H), 1.12 (m, 1H), 1.64 (m, 2H), 1.81 (m, 1H), 2.37 (m, 2H) ,3.76(m,3H),5.27(m,1H),6.20(t,1H),6.72(m,2H),7.03(d,1H),7.07(d,1H),7.58(m,1H), 8.14(m, 1H), 8.47(m, 1H), 8.75(m, 1H), 8.86(m, 1H), 11.23(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值463.2；實測值464.2；Rt=3.064min。LCMS (ESI): [M+H] + m/z: calculated 463.2; found 464.2; Rt=3.064 min.

實例68. 5-[[2-[(2R,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物422)、5-[[2-[(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物437)及5-[[2-[(2R,5S)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1082)之合成Example 68. 5-[[2-[(2R,5R)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl yl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 422), 5-[[2-[(2S,5R)-2-[4 -[[2-(Dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino ]pyridine-3-carboxamide (compound 437) and 5-[[2-[(2R,5S)-2-[4-[[2-(dimethylamino)-2-pendant oxyethyl] Synthesis of Amino]phenyl]-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 1082)

Figure 110128222-A0202-12-1016-88
Figure 110128222-A0202-12-1016-88

步驟1：5-[[2-[(2R,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物422 )之合成Step 1: 5-[[2-[(2R,5R)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 422 )

將N,N-二甲基-2-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]乙醯胺(400mg，1.45mmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(321.09mg，1.31mmol，HCl)及三乙胺(734.89mg，7.26mmol，1.01mL)一起混合於二甲基甲醯胺(4mL)中。將所獲得之混合物簡單加熱至60-70℃，直到形成澄清溶液。冷卻至5-10℃之後，在5min期間分批添加HATU(552.28mg，1.45mmol)。將所得溶液在25℃下攪拌15h。然後，使其經歷HPLC(管柱：YMC-Triart C18 100* 20mm，5um；30-30-60% 0-1-6min 0.1% NH3 -甲醇，流速30ml/min.)，得到5-[[2-[(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(227mg，486.57μmol，33.50%產率)及5-[[2-[(2R,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(19mg，40.73μmol，2.80%產率)。N,N-Dimethyl-2-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]acetamide (400 mg, 1.45 mmol, 2HCl), 2-[ (5-Aminocarbamoyl-3-pyridyl)amino]-2-pendoxoacetic acid (321.09 mg, 1.31 mmol, HCl) and triethylamine (734.89 mg, 7.26 mmol, 1.01 mL) were mixed together in two in methylformamide (4 mL). The obtained mixture was heated briefly to 60-70°C until a clear solution formed. After cooling to 5-10°C, HATU (552.28 mg, 1.45 mmol) was added portionwise over 5 min. The resulting solution was stirred at 25 °C for 15 h. Then, it was subjected to HPLC (column: YMC-Triart C18 100 * 20mm, 5um; 30-30-60% 0-1-6min 0.1% NH3 -methanol, flow rate 30ml/min.) to give 5-[[ 2-[(2S,5R)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (227 mg, 486.57 μmol, 33.50% yield) and 5-[[2-[(2R,5R)-2-[4 -[[2-(Dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino ]pyridine-3-carboxamide (19 mg, 40.73 μmol, 2.80% yield).

1 H NMR(500MHz,DMSO-d6 )δ 0.71-0.91(m,3H),1.10-1.23(m,1H),1.57-1.74(m,2H),1.77-1.95(m,1H),2.40-2.44(m,1H),2.57-2.60(m,1H),2.79-2.94(m,3H),2.93-3.09(m,3H),3.53-4.23(m,3H),5.00-5.61(m,2H),6.60-6.78(m,2H),6.99-7.14(m,2H),7.57-7.68(m,1H),8.12-8.23(m,1H),8.44-8.57(m,1H),8.73-8.84(m,1H),8.84-8.96(m,1H),11.23-11.30(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.71-0.91(m,3H), 1.10-1.23(m,1H), 1.57-1.74(m,2H), 1.77-1.95(m,1H), 2.40- 2.44(m, 1H), 2.57-2.60(m, 1H), 2.79-2.94(m, 3H), 2.93-3.09(m, 3H), 3.53-4.23(m, 3H), 5.00-5.61(m, 2H ),6.60-6.78(m,2H),6.99-7.14(m,2H),7.57-7.68(m,1H),8.12-8.23(m,1H),8.44-8.57(m,1H),8.73-8.84 (m, 1H), 8.84-8.96 (m, 1H), 11.23-11.30 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值467.2；Rt=2.659min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 467.2; Rt=2.659 min.

步驟2：5-[[2-[(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物437 )及5-[[2-[(2R,5S)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1082 )之合成Step 2: 5-[[2-[(2S,5R)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl yl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 437 ) and 5-[[2-[(2R,5S)-2-[4 -[[2-(Dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino ] Synthesis of pyridine-3-carboxamide ( Compound 1082 )

藉由掌性HPLC(管柱：Chiralpak IB(250* 20mm，5mkm)；流動相： 己烷-IPA-MeOH，50-25-25；流速：12mL/min；m 200mg，2次注入，100mg/注入，V=2l，時間2,5h.))將5-[[2-[(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(200mg，428.70μmol)分離成鏡像異構物，得到：化合物437 5-[[2-[(2S,5R)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(78mg，167.19μmol，78.00%產率)(其中保留時間26.49min)及化合物1082 5-[[2-[(2R,5S)-2-[4-[[2-(二甲胺基)-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(78mg，167.19μmol，78.00%產率)(其中保留時間42.74min)。By chiral HPLC (column: Chiralpak IB (250 * 20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12mL/min; m 200mg, 2 injections, 100mg/ Inject, V=2l, time 2,5h.)) will 5-[[2-[(2S,5R)-2-[4-[[2-(dimethylamino)-2-side oxyethyl ]amino]phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (200 mg, 428.70 μmol) was isolated as a mirror isomer to obtain: compound 437 5-[[2-[(2S,5R)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]- and Compound 1082 5-[[2-[(2R,5S)-2-[4-[[2-(dimethylamino)-2-oxyethyl]amino]phenyl]-5-methyl -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (78 mg, 167.19 μmol, 78.00% yield) (wherein retention time 42.74 min).

化合物437： RT(IB，己烷-IPA-MeOH，50-25-25，0.6mL/min)=25.532min。 Compound 437: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 25.532 min.

1 H NMR(500MHz,DMSO-d6 )δ 1.01-1.06(m,3H),1.28-1.42(m,1H),1.67-1.94(m,2H),1.94-2.12(m,1H),2.12-2.22(m,1H),2.76-2.82(m,0.3H),2.82-2.93(m,3H),2.96-3.07(m,3H),3.21-3.26(m,0.7H),3.41-3.97(m,3H),4.98-5.58(m,2H),6.57-6.77(m,2H),6.97-7.13(m,2H),7.46-7.73(m,1H),8.11-8.26(m,1H),8.41-8.57(m,1H),8.70-8.85(m,1H),8.85-8.98(m,1H),11.08-11.33(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.01-1.06(m,3H), 1.28-1.42(m,1H), 1.67-1.94(m,2H), 1.94-2.12(m,1H), 2.12- 2.22(m, 1H), 2.76-2.82(m, 0.3H), 2.82-2.93(m, 3H), 2.96-3.07(m, 3H), 3.21-3.26(m, 0.7H), 3.41-3.97(m ,3H),4.98-5.58(m,2H),6.57-6.77(m,2H),6.97-7.13(m,2H),7.46-7.73(m,1H),8.11-8.26(m,1H),8.41 -8.57(m, 1H), 8.70-8.85(m, 1H), 8.85-8.98(m, 1H), 11.08-11.33(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值467.2；Rt=2.595min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 467.2; Rt=2.595 min.

化合物1082： RT(IB，己烷-IPA-MeOH，50-25-25，0.6mL/min)=50.919min。 Compound 1082: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 50.919 min.

1 H NMR(500MHz,DMSO-d6 )δ 1.01-1.05(m,3H),1.28-1.41(m,1H),1.66-1.94(m,2H),1.94-2.11(m,1H),2.11-2.21(m,1H),2.76-2.82(m,0.4H),2.85-2.89(m,3H),2.98-3.03(m,3H),3.17-3.23(m,0.6H),3.43-3.98(m,3H),4.95-5.60(m,2H),6.54-6.75(m,2H),6.98-7.14(m,2H),7.52-7.74(m,1H),8.09-8.27(m,1H),8.39-8.57(m,1H),8.70-8.82(m,1H),8.82-8.97(m,1H),11.15-11.29(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.01-1.05(m,3H), 1.28-1.41(m,1H), 1.66-1.94(m,2H), 1.94-2.11(m,1H), 2.11- 2.21(m, 1H), 2.76-2.82(m, 0.4H), 2.85-2.89(m, 3H), 2.98-3.03(m, 3H), 3.17-3.23(m, 0.6H), 3.43-3.98(m ,3H),4.95-5.60(m,2H),6.54-6.75(m,2H),6.98-7.14(m,2H),7.52-7.74(m,1H),8.09-8.27(m,1H),8.39 -8.57(m, 1H), 8.70-8.82(m, 1H), 8.82-8.97(m, 1H), 11.15-11.29(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值467.2；Rt=2.593min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 467.2; Rt=2.593 min.

實例69. 5-[[2-[(2S,5R)-5-甲基-2-[4-[[(3R)-1-甲基-2-側氧基-吡咯啶-3-基]胺Example 69. 5-[[2-[(2S,5R)-5-methyl-2-[4-[[(3R)-1-methyl-2-oxy-pyrrolidin-3-yl] amine 基]苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物430)及5-[[2-[(2R,5R)-5-甲基-2-[4-[[(3R)-1-甲基-2-側氧基-吡咯啶-3-基]胺基]苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物427)之合成yl]phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 430) and 5-[[2-[(2R,5R)- 5-Methyl-2-[4-[[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]amino]phenyl]-1-piperidinyl]-2- Synthesis of pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 427)

Figure 110128222-A0202-12-1019-89
Figure 110128222-A0202-12-1019-89

將(3R)-1-甲基-3-[4-[(2S,5R)-5-甲基-2-哌啶基]苯胺基]吡咯啶-2-酮(500.00mg，1.74mmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(427.31mg，1.74mmol，HCl)及三乙胺(880.22mg，8.70mmol，1.21mL)一起混合於二甲基甲醯胺(5mL)中。將所獲得之混合物簡單加熱至60-70℃，直到形成澄清溶液。冷卻至5-10℃之後，在5min期間分批添加HATU(727.65mg，1.91mmol)。將所得溶液在25℃下攪拌15h。然後使其經歷HPLC(管柱：YMC Triart C18 100* 20mm，5um；30-30-65% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min)，得到5-[[2-[(2S,5R)-5-甲基-2-[4-[[(3R)-1-甲基-2-側氧基-吡咯啶-3-基]胺基]苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(180mg，376.14μmol，21.62%產率)及5-[[2-[(2R,5R)-5-甲基-2-[4-[[(3R)-1-甲基-2-側氧基-吡咯啶-3-基]胺基]苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(28mg，58.51μmol，3.36%產率)。(3R)-1-methyl-3-[4-[(2S,5R)-5-methyl-2-piperidinyl]anilino]pyrrolidin-2-one (500.00 mg, 1.74 mmol, 2HCl ), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (427.31 mg, 1.74 mmol, HCl) and triethylamine (880.22 mg, 8.70 mmol, 1.21 mL) ) were mixed together in dimethylformamide (5 mL). The obtained mixture was heated briefly to 60-70°C until a clear solution formed. After cooling to 5-10 °C, HATU (727.65 mg, 1.91 mmol) was added portionwise over 5 min. The resulting solution was stirred at 25 °C for 15 h. It was then subjected to HPLC (column: YMC Triart C18 100 * 20mm, 5um; 30-30-65% 0-1-5min 0.1% NH3 -methanol, flow rate: 30ml/min) to give 5-[[2- [(2S,5R)-5-methyl-2-[4-[[(3R)-1-methyl-2-oxy-pyrrolidin-3-yl]amino]phenyl]-1- Piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (180 mg, 376.14 μmol, 21.62% yield) and 5-[[2-[(2R,5R)-5 -Methyl-2-[4-[[(3R)-1-methyl-2-side oxy-pyrrolidin-3-yl]amino]phenyl]-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (28 mg, 58.51 μmol, 3.36% yield).

化合物430：Compound 430:

1 H NMR(500MHz,DMSO-d6 )δ 0.96-1.07(m,3H),1.27-1.41(m,1H),1.65-1.79(m,2H),1.79-2.02(m,2H),2.07-2.24(m,2H),2.56-2.61(m,1H),2.75-3.27(m,4H),3.34-3.99(m,2H),4.00-4.07(m,1H),5.00-5.55(m,1H),5.63-5.78(m,1H),6.60-6.78(m,2H),6.96-7.13(m,2H),7.53-7.68(m,1H),8.10-8.25(m,1H),8.38 -8.57(m,1H),8.68-8.84(m,1H),8.84-8.97(m,1H),11.06-11.32(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.96-1.07(m,3H), 1.27-1.41(m,1H), 1.65-1.79(m,2H), 1.79-2.02(m,2H), 2.07- 2.24(m, 2H), 2.56-2.61(m, 1H), 2.75-3.27(m, 4H), 3.34-3.99(m, 2H), 4.00-4.07(m, 1H), 5.00-5.55(m, 1H) ),5.63-5.78(m,1H),6.60-6.78(m,2H),6.96-7.13(m,2H),7.53-7.68(m,1H),8.10-8.25(m,1H),8.38-8.57 (m, 1H), 8.68-8.84 (m, 1H), 8.84-8.97 (m, 1H), 11.06-11.32 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值478.2；foun 479.2；Rt=2.707min。LCMS (ESI): [M+H] + m/z: calcd. 478.2; foun 479.2; Rt=2.707 min.

化合物427：Compound 427:

1 H NMR(500MHz,DMSO-d6 )δ 0.72-0.82(m,3H),1.09-1.25(m,1H),1.56-1.70(m,2H),1.70-1.84(m,2H),1.84-2.23(m,1H),2.39-2.44(m,1H),2.58-2.61(m,1H),2.77-2.79(m,3H),3.30-3.31(m,1H),3.35-3.37(m,1H),3.53-4.21(m,2H),4.98-5.61(m,1H),5.70-5.84(m,1H),6.67-6.72(m,2H),7.01-7.10(m,2H),7.57-7.66(m,1H),8.14-8.21(m,1H),8.47-8.55(m,1H),8.76-8.81(m,1H),8.86-8.94(m,1H),11.24-11.28(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.72-0.82(m,3H), 1.09-1.25(m,1H), 1.56-1.70(m,2H), 1.70-1.84(m,2H), 1.84- 2.23(m,1H), 2.39-2.44(m,1H), 2.58-2.61(m,1H), 2.77-2.79(m,3H), 3.30-3.31(m,1H), 3.35-3.37(m,1H) ),3.53-4.21(m,2H),4.98-5.61(m,1H),5.70-5.84(m,1H),6.67-6.72(m,2H),7.01-7.10(m,2H),7.57-7.66 (m,1H),8.14-8.21(m,1H),8.47-8.55(m,1H),8.76-8.81(m,1H),8.86-8.94(m,1H),11.24-11.28(m,1H) .

LCMS(ESI)：[M+H]+ m/z：計算值478.2；foun 479.2；Rt=2.636min。LCMS (ESI): [M+H] + m/z: calcd. 478.2; foun 479.2; Rt=2.636 min.

實例70. 5-[[2-[(2R,5S)-2-[4-[[(1R)-2-(二甲胺基)-1-甲基-2-側氧基乙基]胺基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物414)之合成Example 70. 5-[[2-[(2R,5S)-2-[4-[[(1R)-2-(dimethylamino)-1-methyl-2-oxyethyl]amine Synthesis of [methyl]phenyl]-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 414)

Figure 110128222-A0202-12-1020-90
Figure 110128222-A0202-12-1020-90

將(2R)-N,N-二甲基-2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯胺基]丙醯胺(0.69g，2.38mmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(585.59mg，2.38mmol，HCl)及三乙胺(1.21g，11.92mmol，1.66mL)一起混合於二甲基甲醯胺(8mL)中。將所獲得之混合物簡單加熱至60-70℃，直到形成澄清溶液。冷卻至5-10℃之後，在5min期間分批添加HATU(997.17mg，2.62mmol)。將所得溶液在25℃下攪拌15h。然後使其經歷HPLC(管柱：YMC-Triart C18 100* 20mm，5um；10-10-50% 0-1-6min 0.1% NH3 -甲醇，流速30ml/min.)，得到5-[[2-[(2R,5S)-2-[4-[[(1R)-2-(二甲胺基)-1-甲基-2-側氧基乙基]胺基]苯基]-5-甲基 -1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(467mg，971.79μmol，40.76%產率)。(2R)-N,N-dimethyl-2-[4-[(2R,5S)-5-methyl-2-piperidinyl]anilino]propionamide (0.69 g, 2.38 mmol, 2HCl ), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (585.59 mg, 2.38 mmol, HCl) and triethylamine (1.21 g, 11.92 mmol, 1.66 mL) ) were mixed together in dimethylformamide (8 mL). The obtained mixture was heated briefly to 60-70°C until a clear solution formed. After cooling to 5-10 °C, HATU (997.17 mg, 2.62 mmol) was added portionwise over 5 min. The resulting solution was stirred at 25 °C for 15 h. It was then subjected to HPLC (column: YMC-Triart C18 100 * 20mm, 5um; 10-10-50% 0-1-6min 0.1% NH3 -methanol, flow rate 30ml/min.) to give 5-[[2 -[(2R,5S)-2-[4-[[(1R)-2-(dimethylamino)-1-methyl-2-oxyethyl]amino]phenyl]-5- Methyl-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (467 mg, 971.79 μmol, 40.76% yield).

1 H NMR(500MHz,DMSO-d6 )δ 1.00-1.19(m,3H),1.20-1.31(m,3H),1.34-1.45(m,1H),1.78-1.98(m,2H),2.00-2.22(m,2H),2.86-2.92(m,3H),3.10-3.15(m,3H),3.19-3.32(m,1H),3.55-4.10(m,1H),4.32-4.47(m,1H),5.08-5.65(m,2H),6.48-6.65(m,2H),6.94-7.10(m,2H),7.25-7.43(m,1H),7.95-8.12(m,1H),8.46-8.56(m,1H),8.63-8.77(m,1H),8.81-9.04(m,1H),10.99-11.17(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.00-1.19(m,3H), 1.20-1.31(m,3H), 1.34-1.45(m,1H), 1.78-1.98(m,2H), 2.00- 2.22(m, 2H), 2.86-2.92(m, 3H), 3.10-3.15(m, 3H), 3.19-3.32(m, 1H), 3.55-4.10(m, 1H), 4.32-4.47(m, 1H ),5.08-5.65(m,2H),6.48-6.65(m,2H),6.94-7.10(m,2H),7.25-7.43(m,1H),7.95-8.12(m,1H),8.46-8.56 (m, 1H), 8.63-8.77 (m, 1H), 8.81-9.04 (m, 1H), 10.99-11.17 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值480.2；實測值481.2；Rt=2.687min。LCMS (ESI): [M+H] + m/z: calculated 480.2; found 481.2; Rt=2.687 min.

實例71. 5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物426)及5-[[2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物432)之合成Example 71. 5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 426) and 5-[[2-[(2S,5R)-5-methyl-2-(1,2,3, Synthesis of 4-tetrahydroquinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 432)

Figure 110128222-A0202-12-1021-91
Figure 110128222-A0202-12-1021-91

步驟1：5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1-piperidinyl]-2 -Synthesis of pendant oxyacetyl]amino]pyridine-3-carboxamide

將6-[(2R,5S)-5-甲基-2-哌啶基]-1,2,3,4-四氫喹啉(0.1g，377.69μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.148g，707.60μmol，TEA)、HATU(0.217g，570.71μmol)、DIPEA(0.086g，665.41μmol，115.90μL)置於8mL小瓶中且在25℃下於DMSO(1mL)中攪拌12h。反應混合物之LCMS光譜顯示38%所要產物。將反應混合物提交至HPLC，以得到5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.048g，113.88μmol，30.15%產率)。6-[(2R,5S)-5-methyl-2-piperidinyl]-1,2,3,4-tetrahydroquinoline (0.1 g, 377.69 μmol), 2-[(5-aminomethane Acyl-3-pyridyl)amino]-2-oxoacetic acid (0.148g, 707.60μmol, TEA), HATU (0.217g, 570.71μmol), DIPEA (0.086g, 665.41μmol, 115.90μL) were placed in in an 8 mL vial and stirred in DMSO (1 mL) at 25 °C for 12 h. The LCMS spectrum of the reaction mixture showed 38% of the desired product. The reaction mixture was submitted to HPLC to give 5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1- Piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.048 g, 113.88 μmol, 30.15% yield).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=0.959min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=0.959 min.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物426 )及5-[[2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物432 )之合成Step 2: 5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 426 ) and 5-[[2-[(2S,5R)-5-methyl-2-(1,2,3, Synthesis of 4-tetrahydroquinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 432 )

將初始外消旋物提交至掌性分離，以得到5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.04g，94.90μmol，42.11%產率，化合物426 )及5-[[2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.03g，71.18μmol，31.58%產率，化合物432 )。The initial racemate was submitted to chiral separation to give 5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinoline-6- (0.04 g, 94.90 μmol, 42.11% yield, compound 426 ) and 5-[[2 -[(2S,5R)-5-Methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1-piperidinyl]-2-oxoacetyl] Amino]pyridine-3-carboxamide (0.03 g, 71.18 μmol, 31.58% yield, compound 432 ).

製備性樣品資訊：IA(250* 30,5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min，及HPLC樣品資訊：注入體積900.000μl，C18，H2 O-MeCN，15-45% MeCN，30ml/minPreparative sample information: IA (250 * 30,5mkm), Hexane-IPA-MeOH, 50-25-25, 12ml/min, and HPLC sample information: Injection volume 900.000μl, C18, H2O -MeCN, 15 -45% MeCN, 30ml/min

化合物426：Compound 426:

RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=21.419min。RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 21.419 min.

1 H NMR(500MHz,DMSO-d6 )δ 1.00-1.05(m,3H),1.27-1.38(m,1H),1.72-1.85(m,4H),1.93-2.06(m,1H),2.10-2.18(m,1H),2.64-2.70(m,2H),2.86-3.23(m,3H),3.37-4.00(m,1H),4.92-5.51(m,1H),5.58-5.63(m,1H),6.39-6.46(m,1H),6.78-6.86(m,2H),7.58-7.66(m,1H),8.13-8.20(m,1H),8.45-8.53(m,1H),8.75-8.81(m,1H),8.83-8.93(m,1H),11.12-11.30(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.00-1.05(m,3H), 1.27-1.38(m,1H), 1.72-1.85(m,4H), 1.93-2.06(m,1H), 2.10- 2.18(m, 1H), 2.64-2.70(m, 2H), 2.86-3.23(m, 3H), 3.37-4.00(m, 1H), 4.92-5.51(m, 1H), 5.58-5.63(m, 1H) ),6.39-6.46(m,1H),6.78-6.86(m,2H),7.58-7.66(m,1H),8.13-8.20(m,1H),8.45-8.53(m,1H),8.75-8.81 (m, 1H), 8.83-8.93 (m, 1H), 11.12-11.30 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=3.526min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=3.526 min.

化合物432：Compound 432:

RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=47.532min。RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 47.532 min.

1 H NMR(500MHz,DMSO-d6 )δ 1.00-1.06(m,3H),1.25-1.37(m,1H),1.69-1.90(m,4H),1.92-2.06(m,1H),2.08-2.18(m,1H),2.63-2.72(m,2H),2.84-3.25(m,3H),3.36-3.97(m,1H),4.91-5.56(m,1H),5.57-5.67(m,1H),6.35-6.49(m,1H), 6.72-6.90(m,2H),7.50-7.73(m,1H),8.07-8.24(m,1H),8.41-8.60(m,1H),8.70-8.83(m,1H),8.83-8.97(m,1H),11.08-11.29(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.00-1.06(m,3H), 1.25-1.37(m,1H), 1.69-1.90(m,4H), 1.92-2.06(m,1H), 2.08- 2.18(m,1H), 2.63-2.72(m,2H), 2.84-3.25(m,3H), 3.36-3.97(m,1H), 4.91-5.56(m,1H), 5.57-5.67(m,1H) ), 6.35-6.49(m, 1H), 6.72-6.90(m, 2H), 7.50-7.73(m, 1H), 8.07-8.24(m, 1H), 8.41-8.60(m, 1H), 8.70-8.83 (m, 1H), 8.83-8.97 (m, 1H), 11.08-11.29 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=3.582min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=3.582 min.

實例72. 5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物479)及5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物480)之合成Example 72. 5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidine Iridinyl]-2-side oxyethanoyl]amino]pyridine-3-carboxamide (Compound 479) and 5-[[2-[(2S,5R)-5-methyl-2-(2 - Side oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 480) synthesis

Figure 110128222-A0202-12-1023-92
Figure 110128222-A0202-12-1023-92

步驟1：5-(2-[(2R,5S)-5-甲基-2-(2-側氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-[(2R,5S)-5-methyl-2-(2-oxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1 Synthesis of -yl)-2-side oxyacetamido)nicotinamide

將6-(5-甲基-2-哌啶基)-3,4-二氫-1H-喹啉-2-酮(0.4g，1.24mmol，HCl)、C8 H7 N3 O4 (311.06mg，1.49mmol，TEA)、HATU(612.61mg，1.61mmol)及DIPEA(742.00mg，5.74mmol，1mL)之混合物在DMSO(5mL)中攪拌隔夜。反應混合物之LCMS分析顯示24%所要產物。此後，將反應混合物提交至HPLC(2-10min 40-60%水/MeCN+NH3 (裝載泵4ml MeCN+NH3 ))管柱：TRIART 100* 20mm 5微米)，以得到5-(2-((2R,5S)-5-甲基-2-(2-側氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(0.084g，192.89μmol，15.56%產率)。6-(5-Methyl-2-piperidinyl)-3,4-dihydro-1H-quinolin-2-one (0.4 g, 1.24 mmol, HCl), C 8 H 7 N 3 O 4 ( A mixture of 311.06 mg, 1.49 mmol, TEA), HATU (612.61 mg, 1.61 mmol) and DIPEA (742.00 mg, 5.74 mmol, 1 mL) was stirred in DMSO (5 mL) overnight. LCMS analysis of the reaction mixture showed 24% of the desired product. After this time, the reaction mixture was submitted to HPLC (2-10 min 40-60% water/MeCN+ NH3 (loading pump 4 ml MeCN+ NH3 )) column: TRIART 100 * 20mm 5 microns) to give 5-(2- ((2R,5S)-5-methyl-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1-yl)-2-oxo (0.084 g, 192.89 μmol, 15.56% yield).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=2.416min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=2.416 min.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物479 )及5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物480 )之合成Step 2: 5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidine Imidyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 479 ) and 5-[[2-[(2S,5R)-5-methyl-2-(2 - Side oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 480 ) synthesis

將5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.084g，192.89μmol)提交至掌性分離(注入體積：100mkl；樣品資訊：IC-I(250* 20，5mic)，IPA-MeOH，50-50，10ml/min)，以得到純的化合物479 5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.038g，87.26μmol，45.24%產率)及化合物480 5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.035g，80.37μmol，41.67%產率)。5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.084g, 192.89μmol) was submitted to chiral separation (injection volume: 100mkl; sample information: IC-I (250 * 20, 5mic), IPA-MeOH, 50-50, 10 ml/min) to give pure compound 479 5-[[2-[(2R,5S)-5-methyl-2-(2-oxygen-3 ,4-Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.038g, 87.26μmol, 45.24 % yield) and compound 480 5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl) -1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carboxamide (0.035 g, 80.37 μmol, 41.67% yield).

化合物479： RT(IC，MeOH-IPA，50-50，0.6mL/min)=26.004min。 Compound 479: RT (IC, MeOH-IPA, 50-50, 0.6 mL/min) = 26.004 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.98-1.04(m,3H),1.27-1.37(m,1H),1.59-1.77(m,1H),1.80-1.94(m,1H),1.95-2.11(m,1H),2.12-2.23(m,1H),2.37-2.44(m,2H),2.83-3.25(m,3H),3.43-4.00(m,1H),5.01-5.57(m,1H),6.78-6.94(m,1H),7.04-7.17(m,2H),7.53-7.63(m,1H),8.06-8.20(m,1H),8.41-8.53(m,1H),8.69-8.79(m,1H),8.79-8.93(m,1H),10.00-10.06(m,1H),11.09-11.40(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.98-1.04(m,3H), 1.27-1.37(m,1H), 1.59-1.77(m,1H), 1.80-1.94(m,1H), 1.95- 2.11(m,1H), 2.12-2.23(m,1H), 2.37-2.44(m,2H), 2.83-3.25(m,3H), 3.43-4.00(m,1H), 5.01-5.57(m,1H) ),6.78-6.94(m,1H),7.04-7.17(m,2H),7.53-7.63(m,1H),8.06-8.20(m,1H),8.41-8.53(m,1H),8.69-8.79 (m, 1H), 8.79-8.93 (m, 1H), 10.00-10.06 (m, 1H), 11.09-11.40 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=2.215min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=2.215 min.

化合物480： RT(IC，MeOH-IPA，50-50，0.6mL/min)=17.820min。 Compound 480: RT (IC, MeOH-IPA, 50-50, 0.6 mL/min) = 17.820 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.06(m,3H),1.27-1.39(m,1H),1.65-1.76(m,1H),1.81-1.94(m,1H),1.94-2.12(m,1H),2.13-2.21(m,1H),2.38-2.44(m,2H),2.81-3.26(m,3H),3.42-4.00(m,1H),5.02-5.60(m,1H),6.79-6.89(m,1H),7.05-7.19(m,2H),7.54-7.67(m,1H),8.08-8.20(m,1H),8.41-8.53(m,1H),8.68-8.79(m,1H),8.79-8.93(m,1H),10.00-10.11(m,1H),11.12-11.30(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.97-1.06(m,3H), 1.27-1.39(m,1H), 1.65-1.76(m,1H), 1.81-1.94(m,1H), 1.94- 2.12(m, 1H), 2.13-2.21(m, 1H), 2.38-2.44(m, 2H), 2.81-3.26(m, 3H), 3.42-4.00(m, 1H), 5.02-5.60(m, 1H ),6.79-6.89(m,1H),7.05-7.19(m,2H),7.54-7.67(m,1H),8.08-8.20(m,1H),8.41-8.53(m,1H),8.68-8.79 (m, 1H), 8.79-8.93 (m, 1H), 10.00-10.11 (m, 1H), 11.12-11.30 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=2.213min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=2.213 min.

實例73. 2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物673)及2-甲氧基Example 73. 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6- yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 673) and 2-methoxy -5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物674)之合成-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 674) Synthesis

Figure 110128222-A0202-12-1025-93
Figure 110128222-A0202-12-1025-93

步驟1：2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6- Synthesis of )-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide

向6-[(2R,5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-喹啉-2-酮(0.4g，1.64mmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(469.89mg，1.96mmol，TEA)及DIPEA(1.06g，8.19mmol，1.43mL)於DMSO(5mL)中之經攪拌之溶液中添加HATU(746.98mg，1.96mmol)。將所得反應混合物在25℃下攪拌16h。完成之後，將反應混合物提交至反相HPLC(2-10min 50-60%水/MeOH(裝載泵4mL MeOH)管柱：TRIART 100* 20 5微米)，以得到呈淡黃色固體之2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.228g，489.79μmol，29.92%產率)。To 6-[(2R,5S)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-quinolin-2-one (0.4 g, 1.64 mmol), 2-[(5 -Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (469.89 mg, 1.96 mmol, TEA) and DIPEA (1.06 g, 8.19 mmol, 1.43 mL) in DMSO To the stirred solution in (5 mL) was added HATU (746.98 mg, 1.96 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was submitted to reverse phase HPLC (2-10 min 50-60% water/MeOH (load pump 4 mL MeOH) column: TRIART 100 * 20 5 microns) to give 2-methoxy as a pale yellow solid Base-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidine yl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.228 g, 489.79 μmol, 29.92% yield).

LCMS(ESI)：[M+H]+ m/z：計算值465.2；實測值466.4；Rt=0.934min。LCMS (ESI): [M+H] + m/z: calculated 465.2; found 466.4; Rt=0.934 min.

步驟2：2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物673 )及2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物674 )之合成Step 2: 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6- ( Compound 673 ) and 2-methoxy-5-[[2-[(2S, 5R)-5-methyl-2-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetyl] Synthesis of amino]pyridine-3-carboxamide ( compound 674 )

將2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.228g，489.80μmol)提交至掌性分離(IA-II(250* 20，5mkm)，MeOH，100，16mL/min)，以得到化合物673 2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.063g，135.34μmol，27.63%產率)及化合物674 2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.066g，141.78μmol，28.95%產率)。2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl) -1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carboxamide (0.228g, 489.80μmol) was submitted to chiral separation (IA-II (250 * 20, 5mkm) , MeOH, 100, 16 mL/min) to give compound 673 2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(2-side oxy-3,4 -Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.063 g, 135.34 μmol, 27.63% yield rate) and compound 674 2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline- 6-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.066 g, 141.78 μmol, 28.95% yield).

化合物673： RT(IC,CO2 -MeOH,50-50,2.0mL/min)=22.191min。 Compound 673: RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 22.191 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.92(m,5H),2.95(m,4H),3.93(m,4H),5.27(m,1H),6.86(m,1H),7.09(m,2H),7.72(m,2H),8.47(m,2H),10.03(m,1H),10.98(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.32(m, 1H), 1.92(m, 5H), 2.95(m, 4H), 3.93(m, 4H), 5.27 (m, 1H), 6.86 (m, 1H), 7.09 (m, 2H), 7.72 (m, 2H), 8.47 (m, 2H), 10.03 (m, 1H), 10.98 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值465.2；實測值466.0；Rt=2.279min。LCMS (ESI): [M+H] + m/z: calculated 465.2; found 466.0; Rt=2.279 min.

化合物674： RT(IC，CO2 -MeOH，50-50，2.0mL/min)=28.266min。 Compound 674: RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 28.266 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.68(m,1H),1.86(m,1H),2.09(m,2H),2.43(m,2H),2.86(m,3H),3.93(m,4H),5.28(m,1H),6.84(m,1H),7.09(m,2H),7.72(m,2H),8.47(m,2H),10.03(m,1H),10.99(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.32(m, 1H), 1.68(m, 1H), 1.86(m, 1H), 2.09(m, 2H), 2.43(m, 2H), 2.86(m, 3H), 3.93(m, 4H), 5.28(m, 1H), 6.84(m, 1H), 7.09(m, 2H), 7.72(m, 2H), 8.47 (m, 2H), 10.03 (m, 1H), 10.99 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值465.2；實測值466.0；Rt=2.279min。LCMS (ESI): [M+H] + m/z: calculated 465.2; found 466.0; Rt=2.279 min.

實例74. N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物632)及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物619)之合成Example 74. N-(5,6-Dimethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-oxy-3,4,4a,8a -Tetrahydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (compound 632) and N-(5,6-dimethyl-3-pyridyl) -2-[(2R,5S)-5-methyl-2-(2-oxy-3,4,4a,8a-tetrahydro-1H-quinolin-6-yl)-1-piperidinyl Synthesis of ]-2-oxoacetamide (Compound 619)

Figure 110128222-A0202-12-1026-94
Figure 110128222-A0202-12-1026-94

步驟1：N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(5,6-Dimethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4,4a,8a -Synthesis of -tetrahydro-1H-quinolin-6-yl)-1-piperidinyl]-2-side oxyacetamide

向6-[(2R,5S)-5-甲基-2-哌啶基]-3,4,4a,8a-四氫-1H-喹啉-2-酮(300mg，1.22mmol)、2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(359.71mg，1.22mmol，Et3 N)及三乙胺(123.23mg，1.22mmol，169.74μL)於DMF(3mL)中之溶液中分批添加HATU(463.04mg，1.22mmol)。將混合物在25℃下攪拌3h。然後藉由反相HPLC(40-40-65% 0-1-5min 0.2% TFA-甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量420，管柱：YMC Triart C18 100* 20mm,5um)純化反應混合物，以得到呈2種級分之N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(320mg，757.36μmol，62.19%產率)：To 6-[(2R,5S)-5-methyl-2-piperidinyl]-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (300 mg, 1.22 mmol), 2- [(5,6-Dimethyl-3-pyridyl)amino]-2-oxoacetic acid (359.71 mg, 1.22 mmol, Et 3 N) and triethylamine (123.23 mg, 1.22 mmol, 169.74 μL) To a solution in DMF (3 mL) was added HATU (463.04 mg, 1.22 mmol) portionwise. The mixture was stirred at 25 °C for 3 h. Then by reverse phase HPLC (40-40-65% 0-1-5min 0.2% TFA-methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 420, column: YMC Triart C18 100 * 20mm, 5um) to purify the reaction mixture to give N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-( in 2 fractions 2-oxy-3,4,4a,8a-tetrahydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (320 mg, 757.36 μmol, 62.19% Yield):

第1級分：120mg(96% LCMS；含有4%順式異構物)。(將第1級分提交用於掌性分離)Fraction 1: 120 mg (96% LCMS; contains 4% cis isomer). (Submit fraction 1 for chiral separation)

第2級分：200mg(91% LCMS；含有9%順式異構物)。Fraction 2: 200 mg (91% LCMS; contains 9% cis isomer).

LCMS(ESI)：[M+H]+ m/z：計算值422.2；實測值421.2；Rt=1.894min。LCMS (ESI): [M+H] + m/z: calculated 422.2; found 421.2; Rt=1.894 min.

步驟2：N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物632 )及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物619 )之合成Step 2: N-(5,6-Dimethyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(2-oxy-3,4,4a,8a -Tetrahydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide ( Compound 632 ) and N-(5,6-dimethyl-3-pyridyl) -2-[(2R,5S)-5-methyl-2-(2-oxy-3,4,4a,8a-tetrahydro-1H-quinolin-6-yl)-1-piperidinyl Synthesis of ]-2-oxyacetamide ( Compound 619 )

使外消旋N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(120mg，284.01μmol)經歷掌性HPLC(Chiralpak IA 250* 20mm，5mkm；己烷-IPA-MeOH，50-25-25，15ml/min)，以得到呈白色固體之化合物632 N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(34mg，80.47μmol，56.67%產率)(保留時間：23.778min)及化合物619 N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4,4a,8a-四氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(36mg，85.20μmol，60.00%產率)(保留時間：35.085min)。Make racemic N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4,4a, 8a-Tetrahydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (120 mg, 284.01 μmol) was subjected to chiral HPLC (Chiralpak IA 250 * 20 mm, 5 mkm; alkane-IPA-MeOH, 50-25-25, 15 ml/min) to give compound 632 as a white solid N-(5,6-dimethyl-3-pyridinyl)-2-[(2S,5R) -5-Methyl-2-(2-oxy-3,4,4a,8a-tetrahydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetyl Amine (34 mg, 80.47 μmol, 56.67% yield) (retention time: 23.778 min) and compound 619 N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-5- Methyl-2-(2-oxo-3,4,4a,8a-tetrahydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (36mg , 85.20 μmol, 60.00% yield) (retention time: 35.085 min).

化合物632： RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=23.778min。 Compound 632: RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 23.778 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.95-1.04(m,3H),1.27-1.37(m,1H),1.62-1.74(m,1H),1.81-1.92(m,1H),1.95-2.12(m,1H),2.12-2.17(m,1H),2.17-2.24(m,3H),2.32-2.36(m,3H),2.39-2.45(m,2H),2.78-3.22(m,3H),3.38-3.98(m,1H),4.98-5.54(m,1H),6.78-6.88(m,1H),7.03-7.16(m,2H),7.70-7.85(m,1H),8.38-8.53(m,1H),10.00-10.07(m,1H),10.80-10.95(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.95-1.04(m,3H), 1.27-1.37(m,1H), 1.62-1.74(m,1H), 1.81-1.92(m,1H), 1.95- 2.12(m,1H), 2.12-2.17(m,1H), 2.17-2.24(m,3H), 2.32-2.36(m,3H), 2.39-2.45(m,2H), 2.78-3.22(m,3H) ),3.38-3.98(m,1H),4.98-5.54(m,1H),6.78-6.88(m,1H),7.03-7.16(m,2H),7.70-7.85(m,1H),8.38-8.53 (m, 1H), 10.00-10.07 (m, 1H), 10.80-10.95 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=1.959min。LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=1.959 min.

化合物619： RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=35.085min。 Compound 619: RT (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 35.085 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.96-1.04(m,3H),1.26-1.36(m,1H),1.63-1.74(m,1H),1.79-1.92(m,1H),1.95-2.10(m,1H),2.10-2.17(m,1H),2.17-2.23(m,3H),2.32-2.36(m,3H),2.41-2.46(m,2H),2.81-3.23(m,3H),3.36-3.99(m,1H),4.98-5.56(m,1H),6.79-6.88(m,1H),7.04-7.14(m,2H),7.71-7.83(m,1H),8.39-8.51(m,1H),9.94-10.14(m,1H),10.73-11.07(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.96-1.04(m,3H), 1.26-1.36(m,1H), 1.63-1.74(m,1H), 1.79-1.92(m,1H), 1.95- 2.10(m,1H), 2.10-2.17(m,1H), 2.17-2.23(m,3H), 2.32-2.36(m,3H), 2.41-2.46(m,2H), 2.81-3.23(m,3H) ),3.36-3.99(m,1H),4.98-5.56(m,1H),6.79-6.88(m,1H),7.04-7.14(m,2H),7.71-7.83(m,1H),8.39-8.51 (m, 1H), 9.94-10.14 (m, 1H), 10.73-11.07 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=1.960min。LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=1.960 min.

實例75. N-(5-氯-6-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物639)、N-(5-氯-6-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物727)及N-(5-氯-6-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物726)之合成Example 75. N-(5-Chloro-6-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro -1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (compound 639), N-(5-chloro-6-methyl-3-pyridyl)-2 -[(2R,5S)-5-methyl-2-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxo Ethylacetamide (Compound 727) and N-(5-Chloro-6-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-pendoxyloxy- Synthesis of 3,4-Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 726)

Figure 110128222-A0202-12-1029-95
Figure 110128222-A0202-12-1029-95

步驟1：N-(5-氯-6-甲基3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物639 )Step 1: N-(5-Chloro-6-methyl 3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro- 1H-Quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide ( Compound 639 )

在輕微加熱下，將2-[(5-氯-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸(250mg，1.13mmol，Li+)、6-[(2R,5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-喹啉-2-酮(275.71mg，1.13mmol)及DIPEA(175.01mg，1.35mmol，235.86μL)溶解於DMSO(3mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(643.60mg，1.69mmol)。反應混合物之LCMS顯示形成產物；使粗反應混合物經歷HPLC(28% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量440；管柱SunFireC18 100x19mm 5um(R))及再純化(61% 0.5-6.5min水-MeOH；流速：30ml/min；(裝載泵4ml/min MeOH)；目標質量440；管柱SunFire 100x19mm 5um(L))，以得到N-(5-氯-6-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(50mg，113.40μmol，10.05%產率)及2%雜質N-(5-氯-6-甲基-3-吡啶基)-N',N'-二甲基草醯胺。2-[(5-Chloro-6-methyl-3-pyridinyl)amino]-2-pendoxoacetic acid (250 mg, 1.13 mmol, Li+), 6-[(2R,5S )-5-methyl-2-piperidinyl]-3,4-dihydro-1H-quinolin-2-one (275.71 mg, 1.13 mmol) and DIPEA (175.01 mg, 1.35 mmol, 235.86 μL) were dissolved in in DMSO (3 mL). With vigorous stirring and occasional heating, HATU (643.60 mg, 1.69 mmol) was added in small batches. LCMS of the reaction mixture showed product formation; crude reaction mixture was subjected to HPLC (28% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (load pump 4 ml/min acetonitrile); target mass 440; column SunFire C18 100x19mm 5um (R) ) and repurification (61% 0.5-6.5min water-MeOH; flow rate: 30ml/min; (load pump 4ml/min MeOH); target mass 440; column SunFire 100x19mm 5um (L)) to give N-(5 -Chloro-6-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6 -yl)-1-piperidinyl]-2-oxyacetamide (50 mg, 113.40 μmol, 10.05% yield) and 2% impurity N-(5-chloro-6-methyl-3-pyridyl) )-N',N'-dimethyloxamide.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.70(m,1H),1.86(m,1H),2.01(m,1H),2.15(m,1H),2.39(m,4H),2.60(m,1H),3.03(m,3H),3.61(m,1H),5.28(m,1H),6.83(m,1H),7.08(m,2H),8.15(m,1H),8.58(m,1H),10.02(m,1H),11.15(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.32 (m, 1H), 1.70 (m, 1H), 1.86 (m, 1H), 2.01 (m, 1H) ,2.15(m,1H),2.39(m,4H),2.60(m,1H),3.03(m,3H),3.61(m,1H),5.28(m,1H),6.83(m,1H), 7.08 (m, 2H), 8.15 (m, 1H), 8.58 (m, 1H), 10.02 (m, 1H), 11.15 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值440.2；實測值441.4；Rt=2.971min。LCMS (ESI): [M+H] + m/z: calculated 440.2; found 441.4; Rt=2.971 min.

步驟2：N-(5-氯-6-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物727 )及N-(5-氯-6-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物726 )之合成Step 2: N-(5-Chloro-6-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-oxo-3,4-dihydro -1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide ( compound 727 ) and N-(5-chloro-6-methyl-3-pyridyl)-2 -[(2S,5R)-5-methyl-2-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxo Synthesis of Ethylacetamide ( Compound 726 )

使用Chiralpak AD-H-III(250* 20mm,5mkm)管柱(以己烷-IPA-MeOH，50-25-25為流動相，速率：12mL/min；管柱溫度：24℃；波長：210nm、254nm)進行N-(5-氯-6-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(29.8mg，67.59μmol)之掌性分離，得到呈黃色固體之化合物727 N-(5-氯-6-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(18.63mg，42.25μmol，62.52%產率)(RT=55.148min)及呈黃色固體之化合物726 N-(5-氯-6-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(19.71mg，44.70μmol，66.14%產率)(RT=39.309min)。Using Chiralpak AD-H-III (250 * 20mm, 5mkm) column (with hexane-IPA-MeOH, 50-25-25 as mobile phase, rate: 12mL/min; column temperature: 24°C; wavelength: 210nm , 254 nm) for N-(5-chloro-6-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxygen-3,4-di Chiral isolation of hydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (29.8 mg, 67.59 μmol) afforded compound 727 N-(5 as a yellow solid -Chloro-6-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6 -yl)-1-piperidinyl]-2-oxyacetamide (18.63 mg, 42.25 μmol, 62.52% yield) (RT=55.148 min) and compound 726 N-(5-chloro) as a yellow solid -6-Methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl )-1-piperidinyl]-2-oxoacetamide (19.71 mg, 44.70 μmol, 66.14% yield) (RT=39.309 min).

化合物727： RT(AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=66.902min Compound 727: RT (AD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 66.902 min

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.01(m,3H),1.30(m,1H),1.68(m,1H),1.86(m,1H),1.98(s,1H),2.07(m,1H),2.15(m,1H),2.40(m,3H),2.94(m,3H),3.42(m,2H),4.18(m,1H),5.27(m,1H),6.82(m,1H),7.08(m,2H),8.15(m,1H),8.57(m,1H),10.02(m,1H),11.16(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ(ppm) 1.01(m, 3H), 1.30(m, 1H), 1.68(m, 1H), 1.86(m, 1H), 1.98(s, 1H) ,2.07(m,1H),2.15(m,1H),2.40(m,3H),2.94(m,3H),3.42(m,2H),4.18(m,1H),5.27(m,1H), 6.82 (m, 1H), 7.08 (m, 2H), 8.15 (m, 1H), 8.57 (m, 1H), 10.02 (m, 1H), 11.16 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值440.1；實測值441.2；Rt=1.129min。LCMS (ESI): [M+H] + m/z: calculated 440.1; found 441.2; Rt=1.129 min.

化合物726： RT(AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=47.393min Compound 726: RT (AD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 47.393 min

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.03(m,3H),1.31(m,1H),1.69(m,1H),1.86(m,1H),2.03(m,1H),2.15(m,1H),2.41(m,3H),2.86(m,3H),3.43(m,2H),4.18(m,1H),5.28(m,1H),6.82(m,1H),7.08(m,2H),8.15(m,1H),8.58(m,1H), 10.02(m,1H),11.15(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.03 (m, 3H), 1.31 (m, 1H), 1.69 (m, 1H), 1.86 (m, 1H), 2.03 (m, 1H) ,2.15(m,1H),2.41(m,3H),2.86(m,3H),3.43(m,2H),4.18(m,1H),5.28(m,1H),6.82(m,1H), 7.08(m, 2H), 8.15(m, 1H), 8.58(m, 1H), 10.02(m, 1H), 11.15(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值440.1；實測值441.2；Rt=1.129min。LCMS (ESI): [M+H] + m/z: calculated 440.1; found 441.2; Rt=1.129 min.

實例76. 2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(化合物697)及2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(化合物698)之合成Example 76. 2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]- N-[6-Methyl-5-(trifluoromethyl)-3-pyridinyl]-2-oxyacetamide (Compound 697) and 2-[(2R,5S)-5-methyl- 2-(2-Oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-N-[6-methyl-5-(trifluoromethyl)- Synthesis of 3-pyridyl]-2-oxoacetamide (Compound 698)

Figure 110128222-A0202-12-1031-96
Figure 110128222-A0202-12-1031-96

步驟1：2-[5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺之合成 將DIPEA(203.12mg，1.57mmol，273.74μL)添加到相應2-[[6-甲基-5-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸(0.13g，523.86μmol)及6-[(2R,5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-喹啉-2-酮(127.99mg，523.86μmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(219.11mg，576.24μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20* 100 5mkm管柱且以H2 O-MeCN為溶析液混合物)，以得到2-[5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(0.11g，231.84μmol， 44.26%產率)。 Step 1: 2-[5-Methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-N-[6-methyl Synthesis of yl-5-(trifluoromethyl)-3-pyridyl]-2- oxoacetamide DIPEA (203.12 mg, 1.57 mmol, 273.74 μL) was added to the corresponding 2-[[6-methyl -5-(Trifluoromethyl)-3-pyridyl]amino]-2-oxoacetic acid (0.13 g, 523.86 μmol) and 6-[(2R,5S)-5-methyl-2-piperidine A solution of pyridinyl]-3,4-dihydro-1H-quinolin-2-one (127.99 mg, 523.86 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (219.11 mg, 576.24 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20 * 100 5mkm column with H2O -MeCN as eluent mixture) to give 2-[5-methyl-2-(2-pendoxo- 3,4-Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-N-[6-methyl-5-(trifluoromethyl)-3-pyridyl]-2-side Oxyacetamide (0.11 g, 231.84 μmol, 44.26% yield).

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.2；Rt=3.264min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.2; Rt=3.264 min.

步驟2：2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(化合物697 )及2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(化合物698 )之合成Step 2: 2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]- N-[6-Methyl-5-(trifluoromethyl)-3-pyridinyl]-2-oxyacetamide ( Compound 697 ) and 2-[(2R,5S)-5-methyl- 2-(2-Oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-N-[6-methyl-5-(trifluoromethyl)- Synthesis of 3-pyridyl]-2-oxoacetamide ( Compound 698 )

使用OJ-H-I(250*20，5mkm)管柱(以己烷-IPA-MeOH 60-20-20為流動相，流速13mL/min)掌性分離2-[5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(110mg)，得到化合物697 2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(32.87mg，29.88%產率；RT=9.077min)及化合物698 2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[6-甲基-5-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(42.43mg，38.57%產率；RT=16.671min)。Using OJ-HI (250*20, 5mkm) column (with hexane-IPA-MeOH 60-20-20 as mobile phase, flow rate 13mL/min) chiral separation of 2-[5-methyl-2-(2 -Pendant oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-N-[6-methyl-5-(trifluoromethyl)-3-pyridyl ]-2-oxoacetamide (110 mg) to give compound 697 2-[(2S,5R)-5-methyl-2-(2-oxo-3,4-dihydro-1H-quinoline Lin-6-yl)-1-piperidinyl]-N-[6-methyl-5-(trifluoromethyl)-3-pyridyl]-2-oxyacetamide (32.87 mg, 29.88 g % yield; RT=9.077 min) and compound 698 2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl )-1-piperidinyl]-N-[6-methyl-5-(trifluoromethyl)-3-pyridyl]-2-oxyacetamide (42.43 mg, 38.57% yield; RT =16.671min).

化合物697： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6mL/min)=15.362min。 Compound 697: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 15.362 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)0.99(m,3H),1.30(m,1H),1.70(m,1H),1.87(m,1H),2.02(m,1H),2.16(m,1H),2.43(m,2H),2.56(m,3H),2.86(m,3H),3.78(m,1H),5.29(m,1H),6.83(m,1H),7.08(t,2H),8.39(m,1H),8.87(m,1H),10.02(m,1H),11.29(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 0.99 (m, 3H), 1.30 (m, 1H), 1.70 (m, 1H), 1.87 (m, 1H), 2.02 (m, 1H) ,2.16(m,1H),2.43(m,2H),2.56(m,3H),2.86(m,3H),3.78(m,1H),5.29(m,1H),6.83(m,1H), 7.08 (t, 2H), 8.39 (m, 1H), 8.87 (m, 1H), 10.02 (m, 1H), 11.29 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.4；Rt=1.311min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.4; Rt=1.311 min.

化合物698： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6mL/min)=51.594min。 Compound 698: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 51.594 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.69(m,1H),1.88(m,1H),2.04(m,1H),2.16(m,1H),2.37(m,1H),2.43(m,2H),2.56(m,3H),2.99(m,2H),3.79(m,1H),5.30(m,1H),6.83(m,1H),7.08(m,2H),8.39(m,1H), 8.88(m,1H),10.02(m,1H),11.28(m,1H) 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.32 (m, 1H), 1.69 (m, 1H), 1.88 (m, 1H), 2.04 (m, 1H) ,2.16(m,1H),2.37(m,1H),2.43(m,2H),2.56(m,3H),2.99(m,2H),3.79(m,1H),5.30(m,1H), 6.83(m, 1H), 7.08(m, 2H), 8.39(m, 1H), 8.88(m, 1H), 10.02(m, 1H), 11.28(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.2；Rt=1.311min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.2; Rt=1.311 min.

實例77. 2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[5-甲基-6-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(化合物650)之合成Example 77. 2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]- Synthesis of N-[5-methyl-6-(trifluoromethyl)-3-pyridyl]-2-oxyacetamide (Compound 650)

Figure 110128222-A0202-12-1033-97
Figure 110128222-A0202-12-1033-97

在輕微加熱下，將2-[[5-甲基-6-(三氟甲基)-3-吡啶基]胺基]-2-側氧基乙酸(0.25g，980.01μmol，Li+)、6-[(2R,5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-喹啉-2-酮(239.45mg，980.01μmol)及DIPEA(151.99mg，1.18mmol，204.84μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(558.94mg，1.47mmol)。反應混合物之LCMS顯示形成產物；使粗反應混合物經歷HPLC(37% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量474；管柱SunFireC18 100x19mm 5um(R))及再純化(62% 0.5-5min水-MeOH；流速：30ml/min；(裝載泵4ml/min MeOH)；目標質量474；管柱SunFire 100x19mm 5um(L))，以得到2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-N-[5-甲基-6-(三氟甲基)-3-吡啶基]-2-側氧基乙醯胺(18mg，37.94μmol，3.87%產率)及2%雜質N',N'-二甲基-N-[5-甲基-6-(三氟甲基)-3-吡啶基]草醯胺。2-[[5-Methyl-6-(trifluoromethyl)-3-pyridinyl]amino]-2-oxoacetic acid (0.25 g, 980.01 μmol, Li+), 6 -[(2R,5S)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-quinolin-2-one (239.45 mg, 980.01 μmol) and DIPEA (151.99 mg, 1.18 mmol) , 204.84 μL) was dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (558.94 mg, 1.47 mmol) was added in small batches. LCMS of the reaction mixture showed product formation; crude reaction mixture was subjected to HPLC (37% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (load pump 4 ml/min acetonitrile); target mass 474; column SunFire C18 100x19 mm 5um (R) ) and repurification (62% 0.5-5min water-MeOH; flow rate: 30ml/min; (load pump 4ml/min MeOH); target mass 474; column SunFire 100x19mm 5um (L)) to give 2-[(2R ,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-N-[5-methyl- 6-(Trifluoromethyl)-3-pyridyl]-2-oxoacetamide (18 mg, 37.94 μmol, 3.87% yield) and 2% impurity N',N'-dimethyl-N- [5-Methyl-6-(trifluoromethyl)-3-pyridyl]oxamide.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.00(dd,3H),1.31(m,1H),1.71(m,1H),1.88(m,1H),2.02(m,1H),2.16(m,1H),2.37(m,3H),2.44(m,3H),2.85(m,2H),3.68(m,1H),5.26(m,1H),6.83(m,1H),7.09(m,2H),8.16(m,1H),8.70(m,1H),10.03(m,1H),11.37(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.00 (dd, 3H), 1.31 (m, 1H), 1.71 (m, 1H), 1.88 (m, 1H), 2.02 (m, 1H) ,2.16(m,1H),2.37(m,3H),2.44(m,3H),2.85(m,2H),3.68(m,1H),5.26(m,1H),6.83(m,1H), 7.09 (m, 2H), 8.16 (m, 1H), 8.70 (m, 1H), 10.03 (m, 1H), 11.37 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.0；Rt=3.166min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.0; Rt=3.166 min.

實例78. 外消旋-N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物803)、及N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物874)、及N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物903)之合成Example 78. Racemic-N-[5-(difluoromethyl)-6-methyl-3-pyridyl]-2-[(2S,5R)-5-methyl-2-(2-side Oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (compound 803), and N-[5-(difluoromethyl) base)-6-methyl-3-pyridyl]-2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6 -yl)-1-piperidinyl]-2-oxoacetamide (compound 874), and N-[5-(difluoromethyl)-6-methyl-3-pyridyl]-2- [(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxy Synthesis of Acetamide (Compound 903)

Figure 110128222-A0202-12-1034-98
Figure 110128222-A0202-12-1034-98

步驟1：N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物803 )之合成Step 1: N-[5-(Difluoromethyl)-6-methyl-3-pyridinyl]-2-[(2S,5R)-5-methyl-2-(2-sideoxy-3 Synthesis of ,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-side oxyacetamide ( compound 803 )

將6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-喹啉-2-酮(309.14mg，1.27mmol)及TEA(1.28g，12.65mmol，1.76mL)溶解於DMF(10mL)且冷卻至0℃，添加HATU(721.62mg，1.90mmol)且將混合物在0℃下攪拌15min。添加2-[[5-(二氟甲基)-6-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.27mmol，Li)且將混合物升溫至室溫且攪拌3h。添加10ml乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(2-10min 20-30% MeCN/H2 O 30ml/min(裝載泵4ml MeCN)；管柱：SunFire C18,5 micro)進行純化，以得到N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基 乙醯胺(0.053g，116.10μmol，9.18%產率)。6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-quinolin-2-one (309.14 mg, 1.27 mmol) and TEA (1.28 g, 12.65 mmol, 1.76 mL) was dissolved in DMF (10 mL) and cooled to 0 °C, HATU (721.62 mg, 1.90 mmol) was added and the mixture was stirred at 0 °C for 15 min. 2-[[5-(Difluoromethyl)-6-methyl-3-pyridinyl]amino]-2-oxoacetic acid (0.3 g, 1.27 mmol, Li) was added and the mixture was warmed to room temperature And stirred for 3h. 10 ml of ethyl acetate were added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product, which was obtained by HPLC (2-10 min 20-30% MeCN/H 2 O 30 ml/min (load pump 4 ml) MeCN); column: SunFire C18, 5 micro) was purified to give N-[5-(difluoromethyl)-6-methyl-3-pyridinyl]-2-[(2S,5R)-5 -Methyl-2-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (0.053g, 116.10 μmol, 9.18% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.99(d,3H),1.29(m,1H),1.89(m,4H),2.16(m,2H),2.43(s,3H),2.84(m,3H),3.96(m,1H),5.06(m,1H),5.25(d,1H),6.85(m,1H),7.09(m,2H),8.27(s,1H),8.78(s,1H),10.04(m,1H),11.22(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.99(d,3H), 1.29(m,1H), 1.89(m,4H), 2.16(m,2H), 2.43(s,3H), 2.84(m ,3H),3.96(m,1H),5.06(m,1H),5.25(d,1H),6.85(m,1H),7.09(m,2H),8.27(s,1H),8.78(s, 1H), 10.04 (m, 1H), 11.22 (m, 1H).

步驟2：N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物874 )及N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物903 )之合成Step 2: N-[5-(Difluoromethyl)-6-methyl-3-pyridinyl]-2-[(2S,5R)-5-methyl-2-(2-pendoxyloxy-3 ,4-Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide ( compound 874 ) and N-[5-(difluoromethyl)-6- Methyl-3-pyridyl]-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1 Synthesis of -Piperidinyl]-2-oxyacetamide ( Compound 903 )

使用管柱：Chiralcel OJ-H 250*20(5-I己烷-IPA-MeOH，50-25-25，12ml/min，RT=12.43min，0.36l/注入，16mg/注入，每兩次運行為0.6小時)進行掌性分離，以得到化合物874 N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.02g，43.81μmol，37.74%產率)及化合物903 N-[5-(二氟甲基)-6-甲基-3-吡啶基]-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.017g，37.24μmol，32.08%產率)。Use column: Chiralcel OJ-H 250*20 (5-I hexane-IPA-MeOH, 50-25-25, 12ml/min, RT=12.43min, 0.36l/injection, 16mg/injection, every two runs 0.6 h) for chiral separation to give compound 874 N-[5-(difluoromethyl)-6-methyl-3-pyridinyl]-2-[(2S,5R)-5-methyl- 2-(2-Oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (0.02 g, 43.81 μmol, 37.74% yield) and compound 903 N-[5-(difluoromethyl)-6-methyl-3-pyridyl]-2-[(2R,5S)-5-methyl-2-(2-oxygen (0.017 g, 37.24 μmol, 32.08% yield).

化合物874： RT(Chiracel OJ-3，己烷-IPA-MeOH，50-25-25，0.15mL/min)=6.864min。 Compound 874: RT (Chiracel OJ-3, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 6.864 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.99(d,3H),1.29(m,1H),2.06(m,4H),2.16(m,3H),2.58(s,3H),2.83(m,3H),3.96(m,1H),5.30(m,1H),6.84(m,1H),7.08(m,2H),8.25(s,1H),8.74(s,1H),10.04(m,1H),11.22(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.99(d,3H), 1.29(m,1H), 2.06(m,4H), 2.16(m,3H), 2.58(s,3H), 2.83(m ,3H),3.96(m,1H),5.30(m,1H),6.84(m,1H),7.08(m,2H),8.25(s,1H),8.74(s,1H),10.04(m, 1H), 11.22 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值456.2；實測值457.2；Rt=2.794min。LCMS (ESI): [M+H] + m/z: calculated 456.2; found 457.2; Rt=2.794 min.

化合物903： RT(Chiracel OJ-3，己烷-IPA-MeOH，50-25-25，0.15mL/min)=12.683min。 Compound 903: RT (Chiracel OJ-3, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 12.683 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.99(m,3H),1.27(m,1H),2.08(m,4H),2.23(m, 3H),2.88(s,3H),2.61(m,3H),3.98(m,1H),5.32(m,1H),7.10(m,1H),7.63(m,2H),8.26(s,1H),8.76(s,1H),10.03(m,1H),11.25(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.99(m, 3H), 1.27(m, 1H), 2.08(m, 4H), 2.23(m, 3H), 2.88(s, 3H), 2.61(m ,3H),3.98(m,1H),5.32(m,1H),7.10(m,1H),7.63(m,2H),8.26(s,1H),8.76(s,1H),10.03(m, 1H), 11.25 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值456.2；實測值457.2；Rt=2.794min。LCMS (ESI): [M+H] + m/z: calculated 456.2; found 457.2; Rt=2.794 min.

實例79. N-[6-(二氟甲基)-5-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物641)之合成Example 79. N-[6-(Difluoromethyl)-5-methyl-3-pyridinyl]-2-[(2S,5R)-5-methyl-2-(2-sideoxy-3 Synthesis of ,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 641)

Figure 110128222-A0202-12-1036-99
Figure 110128222-A0202-12-1036-99

在輕微加熱下，將2-[[6-(二氟甲基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.25g，1.05mmol，Li+)、6-[(2R,5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-喹啉-2-酮(257.62mg，1.05mmol)及DIPEA(163.52mg，1.27mmol，220.38μL)溶解於DMSO(3mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(601.35mg，1.58mmol)。反應混合物之LCMS顯示形成產物；使反應混合物經歷HPLC(28% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量440；管柱SunFireC18 100x19mm 5um(R))及再純化(56% 0.5-6.5min水-MeOH；流速：30ml/min；(裝載泵4ml/min MeOH)；目標質量456；管柱SunFire 100x19mm 5um(L))，以得到N-[6-(二氟甲基)-5-甲基-3-吡啶基]-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(18mg，39.43μmol，3.74%產率)及3%雜質N-[6-(二氟甲基)-5-甲基-3-吡啶基]-N',N'-二甲基草醯胺。2-[[6-(Difluoromethyl)-5-methyl-3-pyridinyl]amino]-2-oxoacetic acid (0.25 g, 1.05 mmol, Li+), 6 -[(2R,5S)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-quinolin-2-one (257.62 mg, 1.05 mmol) and DIPEA (163.52 mg, 1.27 mmol) , 220.38 μL) was dissolved in DMSO (3 mL). With vigorous stirring and occasional heating, HATU (601.35 mg, 1.58 mmol) was added in small batches. LCMS of the reaction mixture showed product formation; the reaction mixture was subjected to HPLC (28% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 440; column SunFire C18 100x19 mm 5um(R)) and repurified (56% 0.5-6.5min water-MeOH; flow rate: 30ml/min; (load pump 4ml/min MeOH); target mass 456; column SunFire 100x19mm 5um (L)) to give N-[6- (Difluoromethyl)-5-methyl-3-pyridyl]-2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H- Quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (18 mg, 39.43 μmol, 3.74% yield) and 3% impurity N-[6-(difluoromethyl)- 5-Methyl-3-pyridyl]-N',N'-dimethyloxamide.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.69(m,1H),1.88(m,1H),2.03(m,1H),2.16(m,1H),2.36(m,3H),2.42(m,2H),2.87(m,2H),3.23(m,1H),3.68(m,1H),5.27(m,1H),6.83(m,1H),7.03(m,3H),8.04(m,1H), 8.65(m,1H),10.03(m,1H),11.23(m,1H) 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.32 (m, 1H), 1.69 (m, 1H), 1.88 (m, 1H), 2.03 (m, 1H) ,2.16(m,1H),2.36(m,3H),2.42(m,2H),2.87(m,2H),3.23(m,1H),3.68(m,1H),5.27(m,1H), 6.83(m, 1H), 7.03(m, 3H), 8.04(m, 1H), 8.65(m, 1H), 10.03(m, 1H), 11.23(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值456.2；實測值457.4；Rt=2.799min。LCMS (ESI): [M+H] + m/z: calculated 456.2; found 457.4; Rt=2.799 min.

實例80. 2-甲氧基-5-(2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物308、化合物291、化合物333、化合物322)及外消旋 -2-羥基-5-(2-((2R,5S )-5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物494)之合成Example 80. 2-methoxy-5-(2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 308, Compound 291, compound 333, compound 322) and racemic -2-hydroxy-5-(2-(( 2R,5S )-5-methyl-2-phenylpiperidin-1-yl)-2-side Synthesis of oxyacetamido)nicotinamide (compound 494)

Figure 110128222-A0202-12-1037-100
Figure 110128222-A0202-12-1037-100

步驟1：2-甲氧基-5-(2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: Synthesis of 2-methoxy-5-(2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide

在21℃下，將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.5g，1.47mmol，Et3 N)、TATU(567.73mg，1.76mmol)、5-甲基-2-苯基哌啶(257.47mg，1.47mmol)及三乙胺(148.64mg，1.47mmol，204.74μL)混合於無水DMF(25mL)中且將所得混合物攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(0-5min 30-80%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)。獲得呈白色固體之2-甲氧基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.211g，532.24μmol，36.23%產率)。At 21 °C, 2-[(5-aminocarbamoyl-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (0.5 g, 1.47 mmol, Et 3 N), TATU (567.73 mg, 1.76 mmol), 5-methyl-2-phenylpiperidine (257.47 mg, 1.47 mmol) and triethylamine (148.64 mg, 1.47 mmol, 204.74 μL) were mixed in dry DMF (25 mL) and The resulting mixture was stirred overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (0-5 min 30-80% water-methanol ( NH3 0.1%), flow rate 30 ml/min (load pump 4 ml/min methanol ( NH3 0.1%)), column: YMC-Actus Triart C18 100*20mml.DS-5um). 2-Methoxy-5-[[2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3 was obtained as a white solid - Formamide (0.211 g, 532.24 μmol, 36.23% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.86(d,3H),1.11(m,1H),1.40(m,2H),1.96(m,2H),2.24(m,2H),3.72(m,1H),4.12(s,3H),5.83(m,1H),6.03(m,1H),7.40(m,4H),7.76(m,1H),8.80(m,2H),9.62(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.86(d,3H), 1.11(m,1H), 1.40(m,2H), 1.96(m,2H), 2.24(m,2H), 3.72( m, 1H), 4.12(s, 3H), 5.83(m, 1H), 6.03(m, 1H), 7.40(m, 4H), 7.76(m, 1H), 8.80(m, 2H), 9.62(m , 1H).

LCMS(ESI)：[M+1]m/z：計算值396.4；實測值397.2；Rt=3.545min。LCMS (ESI): [M+1]m/z: calculated 396.4; found 397.2; Rt=3.545 min.

步驟3：掌性分離(化合物308、化合物291、化合物333 及化合物322 )Step 3: Chiral separation ( Compound 308, Compound 291, Compound 333 and Compound 322 )

使用Chiralpak OJ-H 250*20(5mkm管柱；以CO2 -MeOH，60-40為流動相；流速2mL/min)分離2-甲氧基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(211mg，532.24μmol)，得到呈白色固體之化合物308 2-甲氧基-5-[[2-[(2R,5R )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(15.38mg，38.80μmol，7.29%產率)(RT=15.74min)、呈白色固體之化合物291 2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(63.97mg，161.36μmol，30.32%產率)(RT=19.53min)、呈白色固體之化合物333 2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(70.77mg，178.51μmol，33.54%產率)(RT=22.71min)及呈白色固體之化合物322 2-甲氧基-5-[[2-[(2S,5S )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(10.02mg，25.28μmol，4.75%產率)(RT=20.29min)。Separation of 2 -methoxy-5-[[[2-(5-methyl- 2-Phenyl-1-piperidinyl)-2-oxyacetyl]amino]pyridine-3-carboxamide (211 mg, 532.24 μmol) to give compound 308 as a white solid 2-methoxy -5-[[2-[( 2R,5R )-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (15.38 mg, 38.80 μmol, 7.29% yield) (RT=15.74 min), compound 291 as a white solid 2-methoxy-5-[[2-[( 2R,5S )-5-methyl-2 -Phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (63.97 mg, 161.36 μmol, 30.32% yield) (RT=19.53 min), as Compound 333 as a white solid 2-methoxy-5-[[2-[( 2S,5R )-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (70.77 mg, 178.51 μmol, 33.54% yield) (RT=22.71 min) and compound 322 as a white solid 2-methoxy-5-[[2-[( 2S ,5S )-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (10.02 mg, 25.28 μmol, 4.75% yield rate) (RT=20.29min).

化合物308： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.70-0.84(m,3H),1.02-1.09(m,2H),1.56-1.82(m,2H),1.82-2.02(m,1H),2.59-2.66(m,1H),3.59-4.35(m,4H),5.17-5.72(m,1H),7.28-7.39(m,3H),7.39-7.46(m,2H),7.70-7.85(m,2H),8.41-8.52(m,1H),8.52-8.63(m,1H),11.03-11.17(m,1H)。 Compound 308: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.70-0.84 (m, 3H), 1.02-1.09 (m, 2H), 1.56-1.82 (m, 2H), 1.82-2.02 (m) ,1H),2.59-2.66(m,1H),3.59-4.35(m,4H),5.17-5.72(m,1H),7.28-7.39(m,3H),7.39-7.46(m,2H),7.70 -7.85(m, 2H), 8.41-8.52(m, 1H), 8.52-8.63(m, 1H), 11.03-11.17(m, 1H).

LCMS(ESI)：[M+1]m/z：計算值396.4；實測值397.2；Rt=5.305min。LCMS (ESI): [M+1] m/z: calculated 396.4; found 397.2; Rt=5.305 min.

化合物291： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.01-1.07(m,3H),1.30-1.40(m,1H),1.62-1.75(m,1H),1.83-1.99(m,1H),2.04-2.19(m,1H),2.20-2.31(m,1H),2.76-3.24(m,1H),3.48-4.07(m,4H),5.15-5.67(m,1H),7.25-7.33(m,2H), 7.34-7.45(m,3H),7.67-7.81(m,2H),8.42-8.50(m,1H),8.50-8.61(m,1H),10.98-11.13(m,1H)。 Compound 291: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.01-1.07 (m, 3H), 1.30-1.40 (m, 1H), 1.62-1.75 (m, 1H), 1.83-1.99 (m ,1H),2.04-2.19(m,1H),2.20-2.31(m,1H),2.76-3.24(m,1H),3.48-4.07(m,4H),5.15-5.67(m,1H),7.25 -7.33(m, 2H), 7.34-7.45(m, 3H), 7.67-7.81(m, 2H), 8.42-8.50(m, 1H), 8.50-8.61(m, 1H), 10.98-11.13(m, 1H).

LCMS(ESI)：[M+1]m/z：計算值396.4；實測值397.2；Rt=3.338min。LCMS (ESI): [M+1] m/z: calculated 396.4; found 397.2; Rt=3.338 min.

化合物333： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.04(m,3H),1.35(m,1H),1.67(m,1H),1.89(m,1H),2.06(m,1H),2.23(m,1H),3.47(m,1H),3.96(m,3H),4.22(m,1H),5.40(m,1H),7.32(m,2H),7.40(m,3H),7.75(m,2H),8.47(m,1H),8.55(m,1H),11.04(m,1H)。 Compound 333: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.04 (m, 3H), 1.35 (m, 1H), 1.67 (m, 1H), 1.89 (m, 1H), 2.06 (m, 1H), 2.23(m, 1H), 3.47(m, 1H), 3.96(m, 3H), 4.22(m, 1H), 5.40(m, 1H), 7.32(m, 2H), 7.40(m, 3H ), 7.75(m, 2H), 8.47(m, 1H), 8.55(m, 1H), 11.04(m, 1H).

LCMS(ESI)：[M+1]m/z：計算值396.4；實測值397.2；Rt=3.361min。LCMS (ESI): [M+1] m/z: calculated 396.4; found 397.2; Rt=3.361 min.

化合物322： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.77(m,3H),1.06(m,2H),1.66(m,2H),1.99(m,1H),3.57(m,1H),3.96(m,3H),4.28(m,1H),5.55(m,1H),7.31(m,2H),7.37(m,1H),7.41(m,2H),7.75(m,2H),8.52(m,2H),11.09(m,1H)。 Compound 322: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.77 (m, 3H), 1.06 (m, 2H), 1.66 (m, 2H), 1.99 (m, 1H), 3.57 (m, 1H), 3.96(m, 3H), 4.28(m, 1H), 5.55(m, 1H), 7.31(m, 2H), 7.37(m, 1H), 7.41(m, 2H), 7.75(m, 2H) ), 8.52 (m, 2H), 11.09 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值396.4；實測值397.2；Rt=3.405min。LCMS (ESI): [M+1]m/z: calculated 396.4; found 397.2; Rt=3.405 min.

步驟4：外消旋-2-羥基-5-(2-((2R,5S)-5-甲基-2-苯基-哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物494 )之合成Step 4: Racemic-2-hydroxy-5-(2-((2R,5S)-5-methyl-2-phenyl-piperidin-1-yl)-2-oxoacetamido ) Synthesis of Nicotinamide ( Compound 494 )

向2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(350mg，882.86μmol)於MeCN(15mL)中之經攪拌之溶液中添加碘化鈉(423.47mg，2.83mmol，115.39μL)，隨後添加對甲苯磺酸 單水合物(503.81mg，2.65mmol，406.29μL)。將所得混合物在80℃下攪拌2h。蒸發乙腈。藉由反相HPLC(15-70% 0-1-6min 0.1%NH3 -甲醇30ml/min(裝載泵4ml/min 0.1% NH3 -甲醇)；管柱：YMC-Triart C18 100x20mm 5um)純化殘餘物，以得到2-羥基-5-[[2-[(2R,5S )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(53mg，138.59μmol，15.70%產率)。to 2-methoxy-5-[[2-[( 2R,5S )-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine - To a stirred solution of 3-carboxamide (350 mg, 882.86 μmol) in MeCN (15 mL) was added sodium iodide (423.47 mg, 2.83 mmol, 115.39 μL) followed by p -toluenesulfonic acid monohydrate (503.81 mg, 2.65 mmol, 406.29 μL). The resulting mixture was stirred at 80 °C for 2 h. Acetonitrile was evaporated. The residue was purified by reverse phase HPLC (15-70% 0-1-6min 0.1% NH3 -methanol 30ml/min (loading pump 4ml/min 0.1% NH3 -methanol); column: YMC-Triart C18 100x20mm 5um) to give 2-hydroxy-5-[[2-[( 2R,5S )-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (53 mg, 138.59 μmol, 15.70% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.90-1.11(m,3H),1.26-1.43(m,1H),1.60-1.75(m,1H),1.78-1.95(m,1H),1.95-2.19(m,1H),2.19-2.37(m,1H),2.70-3.26 (m,1H),3.47-4.11(m,1H),5,07-5.72(m,1H),7.25-7.46(m,5H),7.59-7.77(m,1H),8.03-8.26(m,1H),8.40-8.60(m,1H),9.01-9.21(m,1H),10.78-10.94(m,1H),12.28-12.57(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.90-1.11(m,3H), 1.26-1.43(m,1H), 1.60-1.75(m,1H), 1.78-1.95(m,1H) ,1.95-2.19(m,1H),2.19-2.37(m,1H),2.70-3.26(m,1H),3.47-4.11(m,1H),5,07-5.72(m,1H),7.25- 7.46(m, 5H), 7.59-7.77(m, 1H), 8.03-8.26(m, 1H), 8.40-8.60(m, 1H), 9.01-9.21(m, 1H), 10.78-10.94(m, 1H) ), 12.28-12.57 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值382.4；實測值383.2；Rt=2.950min。LCMS (ESI): [M+1] m/z: calculated 382.4; found 383.2; Rt=2.950 min.

實例81.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(化合物736及化合物709)之合成Example 81. N- (6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxoacetamide Synthesis of (Compound 736 and Compound 709)

Figure 110128222-A0202-12-1040-101
Figure 110128222-A0202-12-1040-101

在輕微加熱下，將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(0.5g，2.39mmol)、(2R,5S )-5-甲基-2-苯基哌啶(418.90mg，2.39mmol)及DIPEA(926.67mg，7.17mmol，1.25mL)溶解於DMF(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(1.09g，2.87mmol)。反應完成之後，藉由HPLC(35% 0.5-6.5min水-MeCN；流速30ml/min；(裝載泵4ml/min MeCN)；目標質量366；管柱SunFireC18 100x19mm 5um(L))純化混合物且再純化(58% 0.5-6.5min水-MeOH+NH3 ；流速30ml/min；(裝載泵4ml/min MeOH)；目標質量366；管柱SunFireC18 100x19mm 5um(L))，以得到外消旋產物，使其經歷掌性HPLC(OJ-H-I(250*20，0,5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.02g，54.58μmol，2.28%產率)(10%雜質順式異構哌啶)及N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.022g，60.03μmol，2.51%產率)。2-[(6-Amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid (0.5 g, 2.39 mmol), ( 2R,5S )-5 under gentle heating - Methyl-2-phenylpiperidine (418.90 mg, 2.39 mmol) and DIPEA (926.67 mg, 7.17 mmol, 1.25 mL) were dissolved in DMF (6 mL). With vigorous stirring and occasional heating, HATU (1.09 g, 2.87 mmol) was added in small batches. After the reaction was complete, the mixture was purified by HPLC (35% 0.5-6.5 min water-MeCN; flow rate 30 ml/min; (loading pump 4 ml/min MeCN); target mass 366; column SunFire C18 100x19mm 5um (L)) and repurified (58% 0.5-6.5min water-MeOH+ NH3 ; flow rate 30ml/min; (loading pump 4ml/min MeOH); target mass 366; column SunFireC18 100x19mm 5um (L)) to obtain racemic product so that It was subjected to chiral HPLC (OJ-HI (250*20, 0,5mkm), Hexane-IPA-MeOH, 60-20-20, 12ml/min) to give N- (6-amino-5-ethyl) yl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (0.02 g, 54.58 μmol, 2.28 g % yield) (10% impurity cis-piperidine) and N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2 -Phenyl-1-piperidinyl]-2-oxoacetamide (0.022 g, 60.03 μmol, 2.51% yield).

化合物736 於分析條件下(管柱：OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為11.91min且化合物709 之保留時間為24.37min。The retention time of compound 736 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 11.91 min and the retention time of compound 709 was 24.37 min .

化合物736：保留時間：11.91minCompound 736: retention time: 11.91min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(d,3H),1.08(m,3H),1.31(m,1H),1.63(m,1H),1.83(m,1H),2.01(m,1H),2.22(m,1H),2.39(m,2H),3.19(m,1H),4.00(m,1H),5.15(m,1H),5.58(m,2H),7.28(m,2H),7.38(m,3H),7.49(m,1H),8.05(m,1H),10.48(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99(d,3H), 1.08(m,3H), 1.31(m,1H), 1.63(m,1H), 1.83(m,1H), 2.01(m, 1H), 2.22(m, 1H), 2.39(m, 2H), 3.19(m, 1H), 4.00(m, 1H), 5.15(m, 1H), 5.58(m, 2H), 7.28 (m, 2H), 7.38 (m, 3H), 7.49 (m, 1H), 8.05 (m, 1H), 10.48 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=1.645min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=1.645 min.

化合物709：保留時間：24.37minCompound 709: retention time: 24.37min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(d,3H),1.06(m,3H),1.31(m,1H),1.65(m,1H),1.83(m,1H),2.01(m,1H),2.20(m,1H),2.39(m,2H),3.19(m,1H),4.00(m,1H),5.15(m,1H),5.58(m,2H),7.28(m,2H),7.38(m,3H),7.49(m,1H),8.05(m,1H),10.48(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99(d,3H), 1.06(m,3H), 1.31(m,1H), 1.65(m,1H), 1.83(m,1H), 2.01(m, 1H), 2.20(m, 1H), 2.39(m, 2H), 3.19(m, 1H), 4.00(m, 1H), 5.15(m, 1H), 5.58(m, 2H), 7.28 (m, 2H), 7.38 (m, 3H), 7.49 (m, 1H), 8.05 (m, 1H), 10.48 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=1.638min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=1.638 min.

實例82. rel-5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物493)及rel-5-[[2-[(2S,SR)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物492)之合成Example 82. rel-5-[[2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carbamoylamine (Compound 493) and rel-5-[[2-[(2S,SR)-2-(6-amino-3-pyridyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 492)

Figure 110128222-A0202-12-1041-102
Figure 110128222-A0202-12-1041-102

步驟1：5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide

將5-(5-甲基-2-哌啶基)吡啶-2-胺(0.3g，1.57mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(385.24mg，1.57mmol，HCl)及三乙胺(1.59g，15.68mmol，2.19mL)一起混合於DMF(6mL)中且添加HATU(894.56mg，2.35mmol)。將反應混合物攪拌20h。將反應混合物在真空中濃縮且藉由HPLC(2-10min 35-100% MeCN/H2 O 30mL/min(裝載泵4mL MeCN管柱：SunFire 100* 19mm，5微米)純化殘餘物，以獲得5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2533g，662.37μmol，42.23%產率)。5-(5-Methyl-2-piperidinyl)pyridin-2-amine (0.3 g, 1.57 mmol), 2-[(5-aminocarboxy-3-pyridinyl)amino]-2- Pendant oxyacetic acid (385.24 mg, 1.57 mmol, HCl) and triethylamine (1.59 g, 15.68 mmol, 2.19 mL) were mixed together in DMF (6 mL) and HATU (894.56 mg, 2.35 mmol) was added. The reaction mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 35-100% MeCN/ H2O 30 mL/min (loading pump 4 mL MeCN column: SunFire 100 * 19 mm, 5 microns) to obtain 5 -[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (0.2533 g, 662.37 μmol, 42.23% yield).

LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.2；Rt=0.778min。LCMS (ESI): [M+H] + m/z: calculated 382.2; found 383.2; Rt=0.778 min.

步驟2：rel-5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物493 )及rel-5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物492 )之合成Step 2: rel-5-[[2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide ( compound 493 ) and rel-5-[[2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 492 )

對5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2533g，662.37μmol)進行掌性分離(管柱：Chiralpak IC(250* 20mm，5mkm)；流動相：己烷-IPA-MeOH-DEA，40-30-30-0.1；流速：12mL/min；管柱溫度：40℃；波長：205nm；保留時間(異構物A)=36.22min且保留時間(異構物B)=53.07min)，以獲得化合物493 5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(27.46mg，71.81μmol，10.84%產率；Rt=53.07)及化合物492 5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.02459g，64.30μmol，9.71%產率；Rt=36.22)。p-5-[[2-[2-(6-Amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Formamide (0.2533 g, 662.37 μmol) for chiral separation (column: Chiralpak IC (250 * 20 mm, 5 mkm); mobile phase: hexane-IPA-MeOH-DEA, 40-30-30-0.1; flow rate: 12 mL/min; column temperature: 40°C; wavelength: 205 nm; retention time (isomer A) = 36.22 min and retention time (isomer B) = 53.07 min) to obtain compound 493 5-[[2- [(2R,5S)-2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (27.46 mg, 71.81 μmol, 10.84% yield; Rt=53.07) and compound 492 5-[[2-[(2S,5R)-2-(6-amino-3-pyridyl)-5- Methyl-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (0.02459 g, 64.30 μmol, 9.71% yield; Rt=36.22).

化合物493： RT(IC，己烷-IPA-MeOH，40-30-30，0.6mL/min)=55.490min。 Compound 493: RT (IC, Hexane-IPA-MeOH, 40-30-30, 0.6 mL/min) = 55.490 min.

1 H NMR(600MHz,DMSO-d6)δ 0.96-1.05(m,3H),1.27-1.39(m,1H),1.65-1.78(m,1H),1.82-1.92(m,1H),1.94-2.05(m,1H),2.06-2.16(m,1H),2.75-3.25(m,1H),3.38-3.99(m,1H),4.96-5.54(m,1H),5.86(s,2H),6.38-6.51(m,1H),7.24- 7.38(m,1H),7.55-7.66(m,1H),7.85(s,1H),8.05-8.22(m,1H),8.43-8.53(m,1H),8.70-8.81(m,1H),8.82-8.91(m,1H),11.05-11.33(m,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.96-1.05(m,3H), 1.27-1.39(m,1H), 1.65-1.78(m,1H), 1.82-1.92(m,1H), 1.94-2.05 (m,1H),2.06-2.16(m,1H),2.75-3.25(m,1H),3.38-3.99(m,1H),4.96-5.54(m,1H),5.86(s,2H),6.38 -6.51(m,1H),7.24- 7.38(m,1H),7.55-7.66(m,1H),7.85(s,1H),8.05-8.22(m,1H),8.43-8.53(m,1H) , 8.70-8.81 (m, 1H), 8.82-8.91 (m, 1H), 11.05-11.33 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.2；Rt=2.940min。LCMS (ESI): [M+H] + m/z: calculated 382.2; found 383.2; Rt=2.940 min.

化合物492： RT(IC，己烷-IPA-MeOH，40-30-30，0.6mL/min)=33.637min。 Compound 492: RT (IC, Hexane-IPA-MeOH, 40-30-30, 0.6 mL/min) = 33.637 min.

1 H NMR(600MHz,DMSO-d6)δ 0.97-1.04(m,3H),1.28-1.39(m,1H),1.66-1.77(m,1H),1.78-1.92(m,1H),1.93-2.05(m,1H),2.05-2.15(m,1H),2.73-3.23(m,1H),3.38-3.98(m,1H),4.95-5.50(m,1H),5.87(s,2H),6.39-6.49(m,1H),7.21-7.38(m,1H),7.56-7.63(m,1H),7.85(s,1H),8.11-8.21(m,1H),8.41-8.50(m,1H),8.73-8.80(m,1H),8.83-8.91(m,1H),11.15-11.37(m,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.97-1.04(m,3H), 1.28-1.39(m,1H), 1.66-1.77(m,1H), 1.78-1.92(m,1H), 1.93-2.05 (m,1H),2.05-2.15(m,1H),2.73-3.23(m,1H),3.38-3.98(m,1H),4.95-5.50(m,1H),5.87(s,2H),6.39 -6.49(m,1H),7.21-7.38(m,1H),7.56-7.63(m,1H),7.85(s,1H),8.11-8.21(m,1H),8.41-8.50(m,1H) , 8.73-8.80 (m, 1H), 8.83-8.91 (m, 1H), 11.15-11.37 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.0；Rt=2.948min。LCMS (ESI): [M+H] + m/z: calculated 382.2; found 383.0; Rt=2.948 min.

實例83. rel-5-[[2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1003)及rel-5-[[2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基1-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物985)之合成Example 83. rel-5-[[2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carbamide (compound 1003) and rel-5-[[2-[(2R,5S)-2-[6-(methanesulfonamido) Synthesis of -3-pyridyl]-5-methyl-1-piperidinyl 1-2-pendoxetyl]amino]pyridine-3-carboxamide (compound 985)

Figure 110128222-A0202-12-1043-103
Figure 110128222-A0202-12-1043-103

步驟1：5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide

在室溫下將HATU(496.98mg，1.31mmol)分批添加到2-[(5-胺甲醯基 -3-吡啶基)胺基]-2-側氧基乙酸(369.19mg，1.50mmol，HCl)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[(5-aminocarbamoyl at room temperature -3-Pyridinyl)amino]-2-oxoacetic acid (369.19 mg, 1.50 mmol, HCl), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) ) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) in a suspension of DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 5-[[2-[2-(6-amino-3-pyridinyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.2；Rt=0.723min。LCMS (ESI): [M+H] + m/z: calculated 382.2; found 383.2; Rt=0.723 min.

步驟2：5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 2: 5-[[2-[2-[6-(Methylsulfonamido)-3-pyridinyl]-5-methyl-1-piperidinyl]-2-oxoethanoyl] Synthesis of Amino]Pyridine-3-Carboxyamide

在室溫下，將甲磺醯氯(165.07mg，1.44mmol，111.53μL)逐滴添加到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(982.28mg，1.31mmol)、TEA(795.35mg，7.86mmol，1.10mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：Chromatorex 18 SMB100-5T 100* 19mm 5um；0-20% 0-5min H2 O/MeCN/0.1% TFA，流速：30mL/min為流動相)純化殘餘物，以得到5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(103mg，223.67μmol，17.07%產率)。Methanesulfonyl chloride (165.07 mg, 1.44 mmol, 111.53 μL) was added dropwise to 5-[[2-[2-(6-amino-3-pyridyl)-5-methyl- 1-Piperidinyl]-2-oxyacetoxy]amino]pyridine-3-carboxamide (982.28 mg, 1.31 mmol), TEA (795.35 mg, 7.86 mmol, 1.10 mL) in DMF (10 mL) in suspension. The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: Chromatorex 18 SMB100-5T 100 * 19mm 5um; 0-20% 0-5 min H2O /MeCN/0.1% TFA, flow rate: 30 mL/min as mobile phase) to give to give 5-[[2-[2-[6-(methylsulfonamido)-3-pyridinyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (103 mg, 223.67 μmol, 17.07% yield).

LCMS(ESI)：[M+H]+ m/z：計算值460.0；實測值461.0；Rt=1.568min。LCMS (ESI): [M+H] + m/z: calculated 460.0; found 461.0; Rt=1.568 min.

步驟3：rel-5-[[2-[(2S,5R)-2-[6-(甲磺基胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1003 )及rel-5-[[2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物985 )之合成Step 3: rel-5-[[2-[(2S,5R)-2-[6-(methylsulfoamino)-3-pyridyl]-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carbamide ( compound 1003 ) and rel-5-[[2-[(2R,5S)-2-[6-(methanesulfonamido) Synthesis of -3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 985 )

藉由掌性HPLC(管柱：AS(250* 20，5mkm)，CO2 -MeOH，65-35，50mL/min補充流速-15mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物1003 rel-5-[[2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌 啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(30.2mg，65.58μmol，54.91%產率)(保留時間=6.20min)及化合物985 rel-5-[[2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(25.4mg，55.16μmol，46.18%產率)(保留時間=9.28min)。Separation of the enantiomers by chiral HPLC (column: AS (250 * 20, 5mkm), CO2 -MeOH, 65-35, 50mL/min supplemental flow - 15mL/min as mobile phase) to give two Separate enantiomer compound 1003 rel-5-[[2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidine Iridinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (30.2 mg, 65.58 μmol, 54.91% yield) (retention time=6.20 min) and compound 985 rel-5-[ [2-[(2R,5S)-2-[6-(Methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (25.4 mg, 55.16 μmol, 46.18% yield) (retention time = 9.28 min).

化合物1003： RT(AS-H(250* 4.6，5mkm，CO2 -MeOH，65-35，3.0mL/min)=3.413min。 Compound 1003: RT (AS-H(250 * 4.6, 5mkm, CO2 -MeOH, 65-35, 3.0mL/min)=3.413min.

LCMS(ESI)：[M+H]+ m/z：計算值460.0；實測值461.0；Rt=0.772min。LCMS (ESI): [M+H] + m/z: calculated 460.0; found 461.0; Rt=0.772 min.

化合物985： RT(AS-H(250* 4.6，5mkm，CO2 -MeOH，65-35，3.0mL/min)=4.856min。 Compound 985: RT (AS-H(250 * 4.6, 5mkm, CO2 -MeOH, 65-35, 3.0mL/min)=4.856min.

LCMS(ESI)：[M+H]+ m/z：計算值460.0；實測值461.0；Rt=0.772min。LCMS (ESI): [M+H] + m/z: calculated 460.0; found 461.0; Rt=0.772 min.

實例84. rel-5-[[2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物934)及rel-5-[[2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物905)之合成Example 84. rel-5-[[2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carbamoylamine (Compound 934) and rel-5-[[2-[(2R,5S)-2-(6-acetamido-3-pyridyl) Synthesis of -5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 905)

Figure 110128222-A0202-12-1045-104
Figure 110128222-A0202-12-1045-104

步驟1：5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide

在室溫下將HATU(496.98mg，1.31mmol)分批添加到2-[(5-胺甲醯基 -3-吡啶基)胺基]-2-側氧基乙酸(353.14mg，1.44mmol，HCl)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DME(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[(5-aminocarbamoyl at room temperature -3-Pyridinyl)amino]-2-oxoacetic acid (353.14 mg, 1.44 mmol, HCl), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) ) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) in a suspension of DME (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 5-[[2-[2-(6-amino-3-pyridinyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.2；Rt=0.706min。LCMS (ESI): [M+H] + m/z: calculated 382.2; found 383.2; Rt=0.706 min.

步驟2：5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 2: 5-[[2-[2-(6-Acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amino] Synthesis of pyridine-3-carboxamide

在室溫下，將乙醯氯(113.11mg，1.44mmol，87.69μL)逐滴添加到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(705.58mg，1.31mmol)、TEA(795.35mg，7.86mmol，1.10mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：YMC Triart C18 100* 20mml.D.S-5um；0-1-6min 15-15-50%水-甲醇-NH4 OH 0.1%，流速30mL/min為流動相)純化殘餘物，以得到5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(113mg，266.23μmol，20.32%產率)。Acetyl chloride (113.11 mg, 1.44 mmol, 87.69 μL) was added dropwise to 5-[[2-[2-(6-amino-3-pyridyl)-5-methyl-1 at room temperature -Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (705.58 mg, 1.31 mmol), TEA (795.35 mg, 7.86 mmol, 1.10 mL) in DMF (10 mL) in the suspension. The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. Purified by RP-HPLC (column: YMC Triart C18 100 * 20mml.DS-5um; 0-1-6min 15-15-50% water-methanol- NH4OH 0.1%, flow rate 30mL/min as mobile phase) residue to give 5-[[2-[2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amine yl]pyridine-3-carboxamide (113 mg, 266.23 μmol, 20.32% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值424.2；實測值426.2；Rt=1.735min。LCMS (ESI): [M+2H] + m/z: calculated 424.2; found 426.2; Rt=1.735 min.

步驟3：rel-5-[[2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物934 )及rel-5-[[2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物905 )之合成Step 3: rel-5-[[2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carbamoylamine ( Compound 934 ) and rel-5-[[2-[(2R,5S)-2-(6-acetamido-3-pyridyl) Synthesis of -5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide ( compound 905 )

藉由掌性HPLC(管柱：Chiralpak IA(250* 20，5mkm)，己烷-IPA-MeOH，50-25-25,12mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物934 rel-5-[[2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(41.8mg，98.48μmol，73.98%產率)(保 留時間=150.7min)及化合物905 rel-5-[[2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(35mg，82.46μmol，61.95%產率)(保留時間=256.3min)。The enantiomers were separated by chiral HPLC (column: Chiralpak IA (250 * 20, 5mkm), hexane-IPA-MeOH, 50-25-25, 12 mL/min as mobile phase) to give two separate The enantiomer of compound 934 rel-5-[[2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (41.8 mg, 98.48 μmol, 73.98% yield) (retention time=150.7 min) and compound 905 rel-5-[[2-[ (2R,5S)-2-(6-Acetylamino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3- Formamide (35 mg, 82.46 μmol, 61.95% yield) (retention time = 256.3 min).

化合物934： RT(IA(250* 4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.155mL/min)=63.750min。 Compound 934: RT (IA(250 * 4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.155mL/min)=63.750min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.32(m,1H),1.68(m,1H),1.89(m,1H),2.06(m,4H),2.20(m,1H),3.01(m,1H),3.73(dd,1H),5.37(m,1H),7.59(m,1H),7.71(m,1H),8.10(m,2H),8.24(m,1H),8.46(m,1H),8.75(m,1H),8.86(m,1H),10.49(s,1H),11.22(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.32(m, 1H), 1.68(m, 1H), 1.89(m, 1H), 2.06(m, 4H), 2.20(m,1H),3.01(m,1H),3.73(dd,1H),5.37(m,1H),7.59(m,1H),7.71(m,1H),8.10(m,2H),8.24 (m,1H),8.46(m,1H),8.75(m,1H),8.86(m,1H),10.49(s,1H),11.22(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=0.784min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=0.784 min.

化合物905： RT(IA(250* 4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.155mL/min)=98.302min。 Compound 905: RT (IA(250 * 4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.155mL/min)=98.302min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.69(m,1H),1.88(m,1H),2.06(m,4H),2.18(m,1H),3.02(m,1H),3.82(m,1H),5.37(m,1H),7.59(m,1H),7.71(m,1H),8.15(m,3H),8.46(d,1H),8.75(m,1H),8.86(m,1H),10.49(s,1H),11.22(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.33(m, 1H), 1.69(m, 1H), 1.88(m, 1H), 2.06(m, 4H), 2.18(m, 1H), 3.02(m, 1H), 3.82(m, 1H), 5.37(m, 1H), 7.59(m, 1H), 7.71(m, 1H), 8.15(m, 3H), 8.46 (d, 1H), 8.75 (m, 1H), 8.86 (m, 1H), 10.49 (s, 1H), 11.22 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.0；Rt=0.784min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.0; Rt=0.784 min.

實例85. rel-5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物471)及rel-5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物460)之合成Example 85. rel-5-[[2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]-2-methoxypyridine-3-carboxamide (Compound 471) and rel-5-[[2-[(2R,5S)-2-(6-amino-3-pyridine Synthesis of )-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (Compound 460)

Figure 110128222-A0202-12-1048-105
Figure 110128222-A0202-12-1048-105

步驟1：5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,5R)-2-(6-amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxoethanoyl Synthesis of ]amino]-2-methoxypyridine-3-carboxamide

將5-[(2R,5S)-5-甲基-2-哌啶基]吡啶-2-胺(168.58mg，881.38μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(300mg，881.38μmol，Et3 N)、三乙胺(445.94mg，4.41mmol，614.24μL)混合於DMF(5mL)中，然後添加HATU(502.69mg，1.32mmol)。將所得混合物在25℃下攪拌12h。將混合物在減壓下蒸發，且使用HPLC(2-10min 35-100% MeCN/H2 O 30mL/min)純化，以獲得5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(61.6mg，149.35μmol，16.95%產率)。5-[(2R,5S)-5-methyl-2-piperidinyl]pyridin-2-amine (168.58 mg, 881.38 μmol), 2-[(5-aminocarboxy-6-methoxy -3-Pyridinyl)amino]-2-side oxyacetic acid (300 mg, 881.38 μmol, Et3N ), triethylamine (445.94 mg, 4.41 mmol, 614.24 μL) were mixed in DMF (5 mL), then added HATU (502.69 mg, 1.32 mmol). The resulting mixture was stirred at 25 °C for 12 h. The mixture was evaporated under reduced pressure and purified using HPLC (2-10 min 35-100% MeCN/H 2 O 30 mL/min) to obtain 5-[[2-[(2S,5R)-2-(6- Amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (61.6 mg, 149.35 μmol, 16.95% yield).

LCMS(ESI)：[M+H]+ m/z：計算值412.2；實測值413.2；Rt=0.869min。LCMS (ESI): [M+H] + m/z: calculated 412.2; found 413.2; Rt=0.869 min.

步驟2：rel-5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物471 )及rel-5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物460 )之合成Step 2: rel-5-[[2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-methoxypyridine-3-carbamide ( Compound 471 ) and rel-5-[[2-[(2R,5S)-2-(6-amino-3-pyridine Synthesis of )-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 460 )

藉由掌性層析(管柱：Chiralcel OD-H(250* 30mm，5m)；流動相：己烷-IPA-MeOH，70-15-15；流速：25mL/min；管柱溫度：24℃；波長：205nm、245nm、300nm；保留時間(異構物A)=20.78min；保留時間(異構物B)=29.49 min)分離非鏡像異構物之混合物，以獲得化合物471 rel-5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(10.95mg，26.55μmol，17.78%產率)(RT=20.78)及化合物460 rel-5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(10.13mg，24.56μmol，16.44%產率)(RT=29.49)。By chiral chromatography (column: Chiralcel OD-H (250 * 30mm, 5m); mobile phase: hexane-IPA-MeOH, 70-15-15; flow rate: 25mL/min; column temperature: 24°C ; wavelength: 205 nm, 245 nm, 300 nm; retention time (isomer A) = 20.78 min; retention time (isomer B) = 29.49 min) to separate the mixture of diastereomers to obtain compound 471 rel-5- [[2-[(2S,5R)-2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]- 2-Methoxypyridine-3-carboxamide (10.95 mg, 26.55 μmol, 17.78% yield) (RT=20.78) and compound 460 rel-5-[[2-[(2R,5S)-2-( 6-Amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (10.13 mg, 24.56 μmol, 16.44% yield) (RT=29.49).

化合物460： RT(OD-3，己烷-IPA-MeOH，70-15-15，0.6mL/min)=12.283min。 Compound 460: RT (OD-3, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 12.283 min.

1 H NMR(600MHz,DMSO-d6)δ 0.96-1.04(m,3H),1.26-1.38(m,1H),1.64-1.74(m,1H),1.74-1.90(m,1H),1.90-2.05(m,1H),2.05-2.16(m,1H),2.70-3.26(m,1H),3.39-3.98(m,4H),4.95-5.50(m,1H),5.86(s,2H),6.39-6.47(m,1H),7.24-7.37(m,1H),7.69-7.76(m,2H),7.84(s,1H),8.40-8.47(m,1H),8.50-8.58(m,1H),10.87-11.11(m,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.96-1.04(m,3H), 1.26-1.38(m,1H), 1.64-1.74(m,1H), 1.74-1.90(m,1H), 1.90-2.05 (m,1H),2.05-2.16(m,1H),2.70-3.26(m,1H),3.39-3.98(m,4H),4.95-5.50(m,1H),5.86(s,2H),6.39 -6.47(m,1H),7.24-7.37(m,1H),7.69-7.76(m,2H),7.84(s,1H),8.40-8.47(m,1H),8.50-8.58(m,1H) , 10.87-11.11 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值412.2；實測值413.2；Rt=3.290min。LCMS (ESI): [M+H] + m/z: calculated 412.2; found 413.2; Rt=3.290 min.

化合物471： RT(OD-3，己烷-IPA-MeOH，70-15-15，0.6mL/min)=8.759min。 Compound 471: RT (OD-3, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 8.759 min.

1 H NMR(600MHz,DMSO-d6)δ 0.96-1.03(m,3H),1.23-1.37(m,1H),1.66-1.76(m,1H),1.78-2.06(m,2H),2.06-2.15(m,1H),2.74-3.21(m,1H),3.36-3.91(m,1H),3.92-3.97(m,3H),4.93-5.49(m,1H),5.86(s,2H),6.41-6.48(m,1H),7.25-7.37(m,1H),7.68-7.78(m,2H),7.84(s,1H),8.40-8.47(m,1H),8.49-8.58(m,1H),10.94-11.03(m,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.96-1.03(m,3H), 1.23-1.37(m,1H), 1.66-1.76(m,1H), 1.78-2.06(m,2H), 2.06-2.15 (m,1H),2.74-3.21(m,1H),3.36-3.91(m,1H),3.92-3.97(m,3H),4.93-5.49(m,1H),5.86(s,2H),6.41 -6.48(m,1H),7.25-7.37(m,1H),7.68-7.78(m,2H),7.84(s,1H),8.40-8.47(m,1H),8.49-8.58(m,1H) , 10.94-11.03 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值412.2；實測值413.2；Rt=3.288min。LCMS (ESI): [M+H] + m/z: calculated 412.2; found 413.2; Rt=3.288 min.

實例86. rel-5-[[2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物986)及rel-5-[[2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物999)之合成Example 86. rel-5-[[2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (compound 986) and rel-5-[[2-[(2R,5S)-2-[6-( Methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carbamide Synthesis of (Compound 999)

Figure 110128222-A0202-12-1050-106
Figure 110128222-A0202-12-1050-106

步驟1：5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2 -Synthesis of -methoxypyridine-3-carboxamide

在室溫下將HATU(496.98mg，1.31mmol)分批添加到2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(359.52mg，1.50mmol)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid ( 359.52 mg, 1.50 mmol), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) in DMF (10 mL) in the suspension. The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 5-[[2-[2-(6-amino-3-pyridinyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值412.2；實測值413.2；Rt=0.819min。LCMS (ESI): [M+H] + m/z: calculated 412.2; found 413.2; Rt=0.819 min.

步驟2：5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 2: 5-[[2-[2-[6-(Methylsulfonamido)-3-pyridinyl]-5-methyl-1-piperidinyl]-2-oxoethanoyl] Synthesis of Amino]-2-methoxypyridine-3-carboxamide

在室溫下將甲磺醯氯(165.07mg，1.44mmol，111.53μL)逐滴添加到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(1.10g，1.31mmol)、TEA(795.35mg，7.86mmol，1.10mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：Chromatorex 18 SMB100-5T 100* 19mm 5um；0-40% 0-5min H2 O/MeCN/0.1% TFA，流速：30mL/min為流動相)純化殘餘物，以得到 5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(158mg，322.10μmol，24.59%產率)。Methanesulfonyl chloride (165.07 mg, 1.44 mmol, 111.53 μL) was added dropwise to 5-[[2-[2-(6-amino-3-pyridinyl)-5-methyl-1 at room temperature -Piperidinyl]-2-oxoacetyl]amino]-2-methoxypyridine-3-carboxamide (1.10 g, 1.31 mmol), TEA (795.35 mg, 7.86 mmol, 1.10 mL) Suspension in DMF (10 mL). The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: Chromatorex 18 SMB100-5T 100 * 19mm 5um; 0-40% 0-5 min H2O /MeCN/0.1% TFA, flow rate: 30 mL/min as mobile phase) to give to give 5-[[2-[2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxoacetamido]amino ]-2-Methoxypyridine-3-carboxamide (158 mg, 322.10 μmol, 24.59% yield).

LCMS(ESI)：[M+H]+ m/z：計算值490.2；實測值491.2；Rt=1.857min。LCMS (ESI): [M+H] + m/z: calculated 490.2; found 491.2; Rt=1.857 min.

步驟3：rel-5-[[2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物986 )及rel-5-[[2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物999 )之合成Step 3: rel-5-[[2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide ( compound 986 ) and rel-5-[[2-[(2R,5S)-2-[6-( Methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carbamide Synthesis of ( Compound 999 )

藉由掌性HPLC(管柱：AS(250* 20，5mkm)，CO2 -MeOH，60-40，50mL/min補充流速-15mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物986 rel-5-[[2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(29.4mg，59.93μmol，37.22%產率)(保留時間=6.52min)及化合物999 rel-5-[[2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(30.7mg，62.59μmol，38.86%產率)(保留時間=8.26min)。Separation of the enantiomers by chiral HPLC (column: AS (250 * 20, 5mkm), CO2 -MeOH, 60-40, 50mL/min supplemental flow - 15mL/min as mobile phase) to give two Separate enantiomer compound 986 rel-5-[[2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidine Peridyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (29.4 mg, 59.93 μmol, 37.22% yield) (retention time=6.52 min) and compounds 999 rel-5-[[2-[(2R,5S)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (30.7 mg, 62.59 μmol, 38.86% yield) (retention time = 8.26 min).

化合物986： RT(AS(250* 20，5mkm)，CO2 -MeOH，60-40，2.0mL/min)=4.972min。 Compound 986: RT (AS (250 * 20, 5mkm), CO2 -MeOH, 60-40, 2.0mL/min)=4.972min.

LCMS(ESI)：[M+H]+ m/z：計算值490.2；實測值491.2；Rt=0.827min。LCMS (ESI): [M+H] + m/z: calculated 490.2; found 491.2; Rt=0.827 min.

化合物999： RT(AS(250* 20，5mkm)，CO2 -MeOH，60-40，2.0mL/min)=6.367min。 Compound 999: RT (AS (250 * 20, 5mkm), CO2 -MeOH, 60-40, 2.0mL/min)=6.367min.

LCMS(ESI)：[M+H]+ m/z：計算值490.2；實測值491.2；Rt=0.828min。LCMS (ESI): [M+H] + m/z: calculated 490.2; found 491.2; Rt=0.828 min.

實例87. rel-5-[[2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物930)及rel-5-[[2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物910)之合成Example 87. rel-5-[[2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-2-methoxypyridine-3-carboxamido (Compound 930) and rel-5-[[2-[(2R,5S)-2-(6-acetamido) Synthesis of -3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (compound 910)

Figure 110128222-A0202-12-1052-107
Figure 110128222-A0202-12-1052-107

步驟1：5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2 -Synthesis of -methoxypyridine-3-carboxamide

在室溫下將HATU(496.98mg，1.31mmol)分批添加到2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(359.52mg，1.50mmol)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid ( 359.52 mg, 1.50 mmol), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) in DMF (10 mL) in the suspension. The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 5-[[2-[2-(6-amino-3-pyridinyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值412.2；實測值413.2；Rt=0.788min。LCMS (ESI): [M+H] + m/z: calculated 412.2; found 413.2; Rt=0.788 min.

步驟2：5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 2: 5-[[2-[2-(6-Acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amino] Synthesis of -2-methoxypyridine-3-carboxamide

在室溫下將乙醯氯(113.11mg，1.44mmol，87.69μL)逐滴添加到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(1.17g，1.31mmol)、TEA(795.35mg，7.86mmol，1.10mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：Chromatorex 18 SMB100-5T 100* 19mm 5um；5-22% 0-5min H2 O/MeCN/0.1% TFA，流速：30mL/min為流動相)純化殘餘物，以得到5-[[2-[2-(6- 乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(77mg，169.43μmol，12.93%產率)。Acetyl chloride (113.11 mg, 1.44 mmol, 87.69 μL) was added dropwise to 5-[[2-[2-(6-amino-3-pyridyl)-5-methyl-1- Piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (1.17g, 1.31mmol), TEA (795.35mg, 7.86mmol, 1.10mL) in suspension in DMF (10 mL). The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: Chromatorex 18 SMB100-5T 100 * 19mm 5um; 5-22% 0-5 min H2O /MeCN/0.1% TFA, flow rate: 30 mL/min as mobile phase) to give to give 5-[[2-[2-(6-acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amino]-2 -Methoxypyridine-3-carboxamide (77 mg, 169.43 μmol, 12.93% yield).

LCMS(ESI)：[M+H]+ m/z：計算值454.2；實測值455.4；Rt=2.009min。LCMS (ESI): [M+H] + m/z: calculated 454.2; found 455.4; Rt=2.009 min.

步驟3：rel-5-[[2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物930 )及rel-5-[[2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物910 )之合成Step 3: rel-5-[[2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-2-methoxypyridine-3-carboxamido ( Compound 930 ) and rel-5-[[2-[(2R,5S)-2-(6-acetamido) Synthesis of -3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 910 )

藉由掌性HPLC(管柱：AS(250* 20，10mkm)，CO2 -MeOH，65-35，50mL/min補充流速-20mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物930 rel-5-[[2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(19mg，41.81μmol，49.35%產率)(保留時間=7.33min)及化合物910 rel-5-[[2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(16mg，35.21μmol，41.56%產率)(保留時間=9.85min)。Separation of the mirror isomers by chiral HPLC (column: AS (250 * 20, 10mkm), CO2 -MeOH, 65-35, 50mL/min supplemental flow - 20mL/min as mobile phase) to give two Separate enantiomer compound 930 rel-5-[[2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl] -2-Oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (19 mg, 41.81 μmol, 49.35% yield) (retention time=7.33 min) and compound 910 rel-5 -[[2-[(2R,5S)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amine yl]-2-methoxypyridine-3-carboxamide (16 mg, 35.21 μmol, 41.56% yield) (retention time = 9.85 min).

化合物930： RT(IC(250* 4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=25.671min。 Compound 930: RT (IC(250 * 4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=25.671min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.34(m,1H),1.68(m,1H),1.89(m,1H),2.06(m,4H),2.18(m,1H),3.09(m,1H),3.93(m,4H),5.36(m,1H),7.72(m,3H),8.05(m,1H),8.23(m,1H),8.47(m,2H),10.48(s,1H),11.01(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.68(m, 1H), 1.89(m, 1H), 2.06(m, 4H), 2.18(m, 1H), 3.09(m, 1H), 3.93(m, 4H), 5.36(m, 1H), 7.72(m, 3H), 8.05(m, 1H), 8.23(m, 1H), 8.47 (m, 2H), 10.48 (s, 1H), 11.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值454.2；實測值455.2；Rt=1.032min。LCMS (ESI): [M+H] + m/z: calculated 454.2; found 455.2; Rt=1.032 min.

化合物910： RT(IC(250* 4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=18.813min。 Compound 910: RT (IC(250 * 4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=18.813min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.35(m,1H),1.68(m,1H),1.89(m,1H),2.06(m,4H),2.18(m,1H),3.09(m,1H),3.77(m,4H),5.36(m,1H), 7.71(m,3H),8.04(m,1H),8.23(m,1H),8.47(m,2H),10.48(s,1H),11.01(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.35(m, 1H), 1.68(m, 1H), 1.89(m, 1H), 2.06(m, 4H), 2.18(m, 1H), 3.09(m, 1H), 3.77(m, 4H), 5.36(m, 1H), 7.71(m, 3H), 8.04(m, 1H), 8.23(m, 1H), 8.47 (m, 2H), 10.48 (s, 1H), 11.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值454.2；實測值455.2；Rt=1.030min。LCMS (ESI): [M+H] + m/z: calculated 454.2; found 455.2; Rt=1.030 min.

實例88. rel-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物444)及rel-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物443)之合成Example 88. rel-5-[[2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carbamide (compound 444) and rel-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino )-3-pyridyl]-1-piperidinyl]-2-oxoacetoxyl]amino]pyridine-3-carboxamide (compound 443) synthesis

Figure 110128222-A0202-12-1054-108
Figure 110128222-A0202-12-1054-108

步驟1：5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[5-Methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide

將N-甲基-5-(5-甲基-2-哌啶基)吡啶-2-胺(0.3g，1.46mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(358.92mg，1.46mmol，HCl)及三乙胺(1.48g，14.61mmol，2.04mL)一起混合於DMF(6mL)中且添加HATU(833.44mg，2.19mmol)。攪拌所得混合物20h。將反應混合物在真空中濃縮且藉由HPLC(2-10min 40-60%水/MeCN+NH3 (裝載泵4mL MeCN+NH3 ))管柱：TRIART 100* 20mm 5微米)純化殘餘物，以獲得5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2864g，722.43μmol，49.44%產率)。N-methyl-5-(5-methyl-2-piperidinyl)pyridin-2-amine (0.3 g, 1.46 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amine [methyl]-2-oxoacetic acid (358.92 mg, 1.46 mmol, HCl) and triethylamine (1.48 g, 14.61 mmol, 2.04 mL) were mixed together in DMF (6 mL) and HATU (833.44 mg, 2.19 mmol) was added . The resulting mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 40-60% water/MeCN+ NH3 (loading pump 4 mL MeCN+ NH3 )) column: TRIART 100 * 20 mm 5 microns) to give 5-[[2-[5-Methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine -3-Carboxamide (0.2864 g, 722.43 μmol, 49.44% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.03(d,3H),1.34(m,1H),1.86(m,2H),2.74(d, 3H),3.17(s,3H),3.25(m,1H),4.08(m,2H),5.50(m,1H),6.45(m,1H),7.31(d,1H),7.64(d,1H),8.19(s,1H),8.51(s,1H),8.80(s,1H),8.91(s,1H),11.21(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.03(d, 3H), 1.34(m, 1H), 1.86(m, 2H), 2.74(d, 3H), 3.17(s, 3H), 3.25(m ,1H),4.08(m,2H),5.50(m,1H),6.45(m,1H),7.31(d,1H),7.64(d,1H),8.19(s,1H),8.51(s, 1H), 8.80(s, 1H), 8.91(s, 1H), 11.21(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=0.737min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=0.737 min.

步驟2：rel-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物444 )及rel-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物443 )之合成Step 2: rel-5-[[2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carbamide ( compound 444 ) and rel-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino )-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 443 ) synthesis

對5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2863g，722.17μmol)進行掌性分離(注入體積：1mkL；樣品資訊：IC，己烷-IPA-MeOH，50-25-25，0.15mL/min)，以獲得化合物444 5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(120.44mg，303.80μmol，42.07%產率)及化合物443 5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.11031g，278.25μmol，38.53%產率)。p-5-[[2-[5-Methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine -3-Carboxamide (0.2863 g, 722.17 μmol) for chiral separation (injection volume: 1 mkL; sample information: IC, hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) to obtain the compound 444 5-[[2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyacetate (120.44 mg, 303.80 μmol, 42.07% yield) and compound 443 5-[[2-[(2S,5R)-5-methyl-2-[6- (Methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.11031 g, 278.25 μmol, 38.53% yield) .

化合物444： RT(IC，己烷-IPA-MeOH，50-25-25，0.15mL/min)=44.121min。 Compound 444: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 44.121 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.00(m,4H),1.32(m,1H),1.73(m,1H),1.94(m,1H),2.12(m,1H),2.72(m,3H),3.00(m,1H),3.75(m,1H),5.24(m,1H),6.44(m,2H),7.32(m,1H),7.59(m,1H),7.93(s,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.86(m,1H),11.17(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.00 (m, 4H), 1.32 (m, 1H), 1.73 (m, 1H), 1.94 (m, 1H), 2.12 (m, 1H) ,2.72(m,3H),3.00(m,1H),3.75(m,1H),5.24(m,1H),6.44(m,2H),7.32(m,1H),7.59(m,1H), 7.93(s, 1H), 8.14(m, 1H), 8.46(m, 1H), 8.75(m, 1H), 8.86(m, 1H), 11.17(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=1.638min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=1.638 min.

化合物443： RT(IC，己烷-IPA-MeOH，50-25-25，0.15mL/min)=32.216min。 Compound 443: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 32.216 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.00(m,4H),1.32(m,1H),1.75(m,2H),1.95(m,1H),2.72(m,3H),3.08(m,1H),4.04(m,1H),5.24(m,1H),6.43(m,2H),7.33(m,1H),7.59(m,1H),7.93(s,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H), 8.86(m,1H),11.17(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ(ppm) 1.00(m, 4H), 1.32(m, 1H), 1.75(m, 2H), 1.95(m, 1H), 2.72(m, 3H) ,3.08(m,1H),4.04(m,1H),5.24(m,1H),6.43(m,2H),7.33(m,1H),7.59(m,1H),7.93(s,1H), 8.14 (m, 1H), 8.46 (m, 1H), 8.75 (m, 1H), 8.86 (m, 1H), 11.17 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=1.633min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=1.633 min.

實例89. rel-2-甲氧基-5-[[2-[(2R,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物467)、rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物447)、rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物448)及rel-2-甲氧基-5-[[2-[(2S,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物468)之合成Example 89. rel-2-methoxy-5-[[2-[(2R,5R)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidine yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 467), rel-2-methoxy-5-[[2-[(2R,5S)-5- Methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 447) , rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 448) and rel-2-methoxy-5-[[2-[(2S,5S)-5-methyl - Synthesis of 2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 468)

Figure 110128222-A0202-12-1056-109
Figure 110128222-A0202-12-1056-109

步驟1：2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl] Synthesis of -2-Oxyacetyl]amino]pyridine-3-carboxamide

將N-甲基-5-[(2R,5S)-5-甲基-2-哌啶基]吡啶-2-胺(180.95mg，881.38μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(300mg，881.38μmol，Et3 N)、三乙胺(445.94mg，4.41mmol，614.24μL)混合於DMF(5mL)中然後添加HATU(502.69mg，1.32mmol)。將所得混合物在25℃下攪拌12h。將混合物在減壓下蒸發，且使用HPLC(2-10min 40-60%水/MeCN+NH3 )純化，以獲得2-甲氧基-5-[[2-[(2S,SR)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙 醯基]胺基]吡啶-3-甲醯胺(86.2mg，202.13μmol，22.93%產率)。N-methyl-5-[(2R,5S)-5-methyl-2-piperidinyl]pyridin-2-amine (180.95 mg, 881.38 μmol), 2-[(5-aminocarbamoyl- 6-Methoxy-3-pyridyl)amino]-2-oxoacetic acid (300 mg, 881.38 μmol, Et3N ), triethylamine (445.94 mg, 4.41 mmol, 614.24 μL) were mixed in DMF (5 mL) ) and then HATU (502.69 mg, 1.32 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The mixture was evaporated under reduced pressure and purified using HPLC (2-10 min 40-60% water/MeCN+ NH3 ) to obtain 2-methoxy-5-[[2-[(2S,SR)-5 -Methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (86.2mg , 202.13 μmol, 22.93% yield).

1 H NMR(400MHz,DMSO-d6)δ 1.02(d,3H),1.03(m,1H),1.95(m,4H),2.75(d,3H),3.17(m,1H),3.24(m,1H),3.34(m,2H),3.97(s,3H),5.27(m,1H),6.45(m,2H),7.80(s,1H),7.82(s,1H),8.52(m,1H),11.05(m,1H)。 1 H NMR (400MHz, DMSO-d6)δ 1.02(d,3H), 1.03(m,1H), 1.95(m,4H), 2.75(d,3H), 3.17(m,1H), 3.24(m, 1H), 3.34(m, 2H), 3.97(s, 3H), 5.27(m, 1H), 6.45(m, 2H), 7.80(s, 1H), 7.82(s, 1H), 8.52(m, 1H) ), 11.05 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值426.2；實測值427.2；Rt=0.824min。LCMS (ESI): [M+H] + m/z: calculated 426.2; found 427.2; Rt=0.824 min.

步驟2：rel-2-甲氧基-5-[[2-[(2R,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物467 )、rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物447 )、rel-2-甲氧基-5-[[2-[(2.S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物448 )及rel-2-甲氧基-5-[[2-[(2S,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物468 )之合成Step 2: rel-2-methoxy-5-[[2-[(2R,5R)-5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidine yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 467 ), rel-2-methoxy-5-[[2-[(2R,5S)-5- Methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 447 ) , rel-2-methoxy-5-[[2-[(2.S,5R)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidine yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 448 ) and rel-2-methoxy-5-[[2-[(2S,5S)-5- Methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 468 ) synthesis

藉由掌性層析(管柱：Chiralpak IC(250，20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min；管柱溫度：24℃；波長：205nm、252nm、306nm；保留時間(異構物A)=23.52min；保留時間(異構物B)=29.28min；保留時間(異構物C)=36.86min；保留時間(異構物D)=51.27min)分離非鏡像異構物之混合物，以獲得化合物467 2-甲氧基-5-[[2-[(2R,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(8.01mg，18.78μmol；RT=29.28)、化合物447 2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(23.01mg，53.95μmol，26.69%產率；RT=51.27)、化合物448 2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(24.25mg，56.86μmol，28.13%產率：RT=36.86)、化合物468 2-甲氧基-5-[[2-[(2S,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺 (6.87mg，16.11μmol，7.97%產率；RT=23.53)。By chiral chromatography (column: Chiralpak IC (250, 20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12mL/min; column temperature: 24°C; wavelength : 205nm, 252nm, 306nm; retention time (isomer A)=23.52min; retention time (isomer B)=29.28min; retention time (isomer C)=36.86min; retention time (isomer D) )=51.27 min) to separate the mixture of diastereoisomers to obtain compound 467 2-methoxy-5-[[2-[(2R,5R)-5-methyl-2-[6-(methylamine) (8.01 mg, 18.78 μmol; RT=29.28), compound 447 2 -Methoxy-5-[[2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (23.01 mg, 53.95 μmol, 26.69% yield; RT=51.27), compound 448 2-methoxy-5-[[2-[(2S ,5R)-5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (24.25 mg, 56.86 μmol, 28.13% yield: RT=36.86), compound 468 2-methoxy-5-[[2-[(2S,5S)-5-methyl-2-[6- (Methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (6.87 mg, 16.11 μmol, 7.97% yield; RT=23.53).

化合物467：Compound 467:

RT(IC-3，己烷-IPA-MeOH，40-30-30，0.15mL/min)=15.419min。RT (IC-3, Hexane-IPA-MeOH, 40-30-30, 0.15 mL/min) = 15.419 min.

1 H NMR(DMSO-d6,600MHz)δ 0.92-1.06(m,3H),1.26-1.38(m,1H),1.65-1.77(m,1H),1.79-2.06(m,2H),2.06-2.17(m,1H),2.70-2.75(m,3H),3.15-3.42(m,1H),3.91-3.95(m,3H),4.95-5.51(m,1H),6.37-6.46(m,2H),7.23-7.40(m,1H),7.65-7.77(m,2H),7.93(s,1H),8.38-8.47(m,1H),8.47-8.57(m,1H),10.89-11.03(m,1H)。 1 H NMR(DMSO-d6,600MHz)δ 0.92-1.06(m,3H),1.26-1.38(m,1H),1.65-1.77(m,1H),1.79-2.06(m,2H),2.06-2.17 (m,1H),2.70-2.75(m,3H),3.15-3.42(m,1H),3.91-3.95(m,3H),4.95-5.51(m,1H),6.37-6.46(m,2H) ,7.23-7.40(m,1H),7.65-7.77(m,2H),7.93(s,1H),8.38-8.47(m,1H),8.47-8.57(m,1H),10.89-11.03(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值426.2；實測值427.2；Rt=3.452min。LCMS (ESI): [M+H] + m/z: calculated 426.2; found 427.2; Rt=3.452 min.

化合物447： RT(IC-3，己烷-IPA-MeOH，40-30-30，0.15mL/min)=26.173min。 Compound 447: RT (IC-3, Hexane-IPA-MeOH, 40-30-30, 0.15 mL/min) = 26.173 min.

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.36(m,1H),1.75(m,1H),2.00(m,3H),2.75(m,3H),3.24(m,1H),3.41(m,1H),3.96(m,3H),5.25(m,1H),6.46(m,2H),7.34(m,1H),7.75(m,2H),7.95(s,1H),8.46(m,1H),8.54(m,1H),10.98(m,1H)。 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.03(m, 3H), 1.36(m, 1H), 1.75(m, 1H), 2.00(m, 3H), 2.75(m, 3H), 3.24(m, 1H), 3.41(m, 1H), 3.96(m, 3H), 5.25(m, 1H), 6.46(m, 2H), 7.34(m, 1H), 7.75(m, 2H), 7.95 (s, 1H), 8.46 (m, 1H), 8.54 (m, 1H), 10.98 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值426.2；實測值427.2；Rt=3.339min。LCMS (ESI): [M+H] + m/z: calculated 426.2; found 427.2; Rt=3.339 min.

化合物448： RT(IC-3，己烷-IPA-MeOH，40-30-30，0.15mL/min)=18.859min。 Compound 448: RT (IC-3, Hexane-IPA-MeOH, 40-30-30, 0.15 mL/min) = 18.859 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.31(m,1H),1.71(m,1H),1.87(m,1H),1.95(m,1H),2.10(m,1H),2.72(m,3H),3.20(m,1H),3.93(m,4H),5.23(m,1H),6.43(m,2H),7.31(m,1H),7.72(m,2H),7.93(s,1H),8.43(m,1H),8.52(m,1H),10.96(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.31(m, 1H), 1.71(m, 1H), 1.87(m, 1H), 1.95(m, 1H), 2.10(m, 1H), 2.72(m, 3H), 3.20(m, 1H), 3.93(m, 4H), 5.23(m, 1H), 6.43(m, 2H), 7.31(m, 1H), 7.72 (m, 2H), 7.93 (s, 1H), 8.43 (m, 1H), 8.52 (m, 1H), 10.96 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值426.2；實測值427.2；Rt=3.342min。LCMS (ESI): [M+H] + m/z: calculated 426.2; found 427.2; Rt=3.342 min.

化合物468： RT(IC-3，己烷-IPA-MeOH，40-30-30，0.15mL/min)=12.322min。 Compound 468: RT (IC-3, Hexane-IPA-MeOH, 40-30-30, 0.15 mL/min) = 12.322 min.

1 H NMR(DMSO-d6,600MHz)δ 0.92-1.06(m,3H),1.26-1.38(m,1H),1.65-1.77(m,1H),1.79-2.06(m,2H),2.06-2.17(m,1H),2.70-2.75(m,3H),3.15-3.42(m, 1H),3.91-3.95(m,3H),4.95-5.51(m,1H),6.37-6.46(m,2H),7.23-7.40(m,1H),7.65-7.77(m,2H),7.93(s,1H),8.38-8.47(m,1H),8.47-8.57(m,1H),10.89-11.03(m,1H)。 1 H NMR(DMSO-d6,600MHz)δ 0.92-1.06(m,3H),1.26-1.38(m,1H),1.65-1.77(m,1H),1.79-2.06(m,2H),2.06-2.17 (m,1H),2.70-2.75(m,3H),3.15-3.42(m,1H),3.91-3.95(m,3H),4.95-5.51(m,1H),6.37-6.46(m,2H) ,7.23-7.40(m,1H),7.65-7.77(m,2H),7.93(s,1H),8.38-8.47(m,1H),8.47-8.57(m,1H),10.89-11.03(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值426.2；實測值427.2；Rt=3.428min。LCMS (ESI): [M+H] + m/z: calculated 426.2; found 427.2; Rt=3.428 min.

實例90. 外消旋-5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物409)、5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物586)及5-[[2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物585)之合成Example 90. Racemic-5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide (compound 409), 5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1- Piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 586) and 5-[[2-[(2R,5S)-2-(benzothiophene-5 Synthesis of -yl)-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 585)

Figure 110128222-A0202-12-1059-110
Figure 110128222-A0202-12-1059-110

步驟1：外消旋-5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物409 )之合成Step 1: Racemic-5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-pendoxoethyl Synthesis of Acyl]amino]pyridine-3-carbamoylamine ( Compound 409 )

向(2S,SR)-2-(苯并噻吩-5-基)-5-甲基哌啶(0.3g，1.30mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(318.50mg，1.30mmol，HCl)及三乙胺(656.07mg，6.48mmol，903.67μL)之溶液中添加HATU(542.35mg，1.43mmol)。將所得混合物在25℃下攪拌3h且使其經歷HPLC：50-50-90% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量414，管柱：YMC Triart C18 100x20mm，5um)，以得到5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2- 側氧基乙醯基]胺基]吡啶-3-甲醯胺(278mg，657.99μmol，50.74%產率)。To (2S,SR)-2-(benzothiophen-5-yl)-5-methylpiperidine (0.3 g, 1.30 mmol), 2-[(5-aminocarboxy-3-pyridinyl)amine To a solution of oxo]-2-oxoacetic acid (318.50 mg, 1.30 mmol, HCl) and triethylamine (656.07 mg, 6.48 mmol, 903.67 μL) was added HATU (542.35 mg, 1.43 mmol). The resulting mixture was stirred at 25°C for 3 h and subjected to HPLC: 50-50-90% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 414 , column: YMC Triart C18 100x20mm, 5um) to give 5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (278 mg, 657.99 μmol, 50.74% yield).

1 H NMR(500MHz,DMSO)δ 1.03-1.07(m,3H),1.32-1.49(m,1H),1.72-1.84(m,1H),1.86-1.99(m,1H),2.09-2.27(m,1H),2.29-2.36(m,1H),2.83-3.27(m,1H),3.54-4.11(m,1H),5.26-5.81(m,1H),7.32-7.43(m,1H),7.43-7.51(m,1H),7.56-7.68(m,1H),7.73-7.84(m,1H),7.84-7.93(m,1H),7.95-8.08(m,1H),8.09-8.25(m,1H),8.44-8.58(m,1H),8.71-8.83(m,1H),8.83-8.98(m,1H),11.18-11.43(m,1H)。 1 H NMR (500MHz, DMSO)δ 1.03-1.07(m,3H), 1.32-1.49(m,1H), 1.72-1.84(m,1H), 1.86-1.99(m,1H), 2.09-2.27(m ,1H),2.29-2.36(m,1H),2.83-3.27(m,1H),3.54-4.11(m,1H),5.26-5.81(m,1H),7.32-7.43(m,1H),7.43 -7.51(m,1H),7.56-7.68(m,1H),7.73-7.84(m,1H),7.84-7.93(m,1H),7.95-8.08(m,1H),8.09-8.25(m, 1H), 8.44-8.58 (m, 1H), 8.71-8.83 (m, 1H), 8.83-8.98 (m, 1H), 11.18-11.43 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值422.2；實測值423.0；Rt=3.485min。LCMS (ESI): [M+1] + m/z: calculated 422.2; found 423.0; Rt=3.485 min.

步驟2：5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物586 )及5-[[2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物585 )之合成Step 2: 5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide ( Compound 586 ) and 5-[[2-[(2R,5S)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide ( compound 585 )

使用Chiralpak IA 250*20，5mkm管柱(以己烷-IPA-MeOH，50-25-25為流動相；流速25mL/min；注入體積：900mkl；3pins；56mg/1pin)分離5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(169.5mg，401.18μmol)；得到呈黃色固體之化合物586 5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(59.73mg，141.37μmol，35.24%產率)(RT(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=10.599min)及呈米色固體之化合物585 5-[[2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(60.8mg，143.91μmol，35.87%產率)(RT(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=14.975min)。5-[[2 -[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (169.5 mg, 401.18 μmol); gave compound 586 as a yellow solid 5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidine yl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (59.73 mg, 141.37 μmol, 35.24% yield) (RT(IA-3, hexane-IPA-MeOH, 50- 25-25, 0.155ml/min)=10.599min) and compound 585 as a beige solid 5-[[2-[(2R,5S)-2-(benzothiophen-5-yl)-5-methyl- 1-Piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (60.8 mg, 143.91 μmol, 35.87% yield) (RT(IA-3, hexane-IPA- MeOH, 50-25-25, 0.155ml/min)=14.975min).

化合物586： 1 H NMR(500MHz,DMSO)δ 1.03-1.07(m,3H),1.32-1.49(m,1H),1.72-1.84(m,1H),1.86-1.99(m,1H),2.09-2.27(m,1H),2.29-2.36(m,1H),2.83-3.27(m,1H),3.54-4.11(m,1H),5.26-5.81(m,1H),7.32-7.43(m,1H),7.43-7.51 (m,1H),7.56-7.68(m,1H),7.73-7.84(m,1H),7.84-7.93(m,1H),7.95-8.08(m,1H),8.09-8.25(m,1H),8.44-8.58(m,1H),8.71-8.83(m,1H),8.83-8.98(m,1H),11.18-11.43(m,1H)。 Compound 586: 1 H NMR (500 MHz, DMSO) δ 1.03-1.07 (m, 3H), 1.32-1.49 (m, 1H), 1.72-1.84 (m, 1H), 1.86-1.99 (m, 1H), 2.09- 2.27(m,1H), 2.29-2.36(m,1H), 2.83-3.27(m,1H), 3.54-4.11(m,1H), 5.26-5.81(m,1H), 7.32-7.43(m,1H) ),7.43-7.51(m,1H),7.56-7.68(m,1H),7.73-7.84(m,1H),7.84-7.93(m,1H),7.95-8.08(m,1H),8.09-8.25 (m, 1H), 8.44-8.58 (m, 1H), 8.71-8.83 (m, 1H), 8.83-8.98 (m, 1H), 11.18-11.43 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值422.2；實測值423.0；Rt=2.884min。LCMS (ESI): [M+1] + m/z: calculated 422.2; found 423.0; Rt=2.884 min.

RT(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=10.599minRT(IA-3, Hexane-IPA-MeOH, 50-25-25, 0.155ml/min)=10.599min

化合物585： 1 H NMR(500MHz,DMSO)δ 1.03-1.07(m,3H),1.32-1.49(m,1H),1.72-1.84(m,1H),1.86-1.99(m,1H),2.09-2.27(m,1H),2.29-2.36(m,1H),2.83-3.27(m,1H),3.54-4.11(m,1H),5.26-5.81(m,1H),7.32-7.43(m,1H),7.43-7.51(m,1H),7.56-7.68(m,1H),7.73-7.84(m,1H),7.84-7.93(m,1H),7.95-8.08(m,1H),8.09-8.25(m,1H),8.44-8.58(m,1H),8.71-8.83(m,1H),8.83-8.98(m,1H),11.18-11.43(m,1H)。 Compound 585: 1 H NMR (500 MHz, DMSO) δ 1.03-1.07 (m, 3H), 1.32-1.49 (m, 1H), 1.72-1.84 (m, 1H), 1.86-1.99 (m, 1H), 2.09- 2.27(m,1H), 2.29-2.36(m,1H), 2.83-3.27(m,1H), 3.54-4.11(m,1H), 5.26-5.81(m,1H), 7.32-7.43(m,1H) ),7.43-7.51(m,1H),7.56-7.68(m,1H),7.73-7.84(m,1H),7.84-7.93(m,1H),7.95-8.08(m,1H),8.09-8.25 (m, 1H), 8.44-8.58 (m, 1H), 8.71-8.83 (m, 1H), 8.83-8.98 (m, 1H), 11.18-11.43 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值422.2；實測值423.0；Rt=2.884min。LCMS (ESI): [M+1] + m/z: calculated 422.2; found 423.0; Rt=2.884 min.

RT(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=14.975minRT(IA-3, Hexane-IPA-MeOH, 50-25-25, 0.155ml/min)=14.975min

實例91. 5-[[2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物618)及5-[[2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物633)之合成Example 91. 5-[[2-[(2R,5S)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]-2-methoxypyridine-3-carboxamide (Compound 618) and 5-[[2-[(2R,5S)-2-(benzothiophen-5-yl)-5-methyl- Synthesis of 1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 633)

Figure 110128222-A0202-12-1061-111
Figure 110128222-A0202-12-1061-111

步驟1：5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of yl]-2-methoxypyridine-3-carboxamide

向(2S,5R)-2-(苯并噻吩-5-基)-5-甲基哌啶(0.3g，1.30mmol)、2-[(5- 胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(441.36mg，1.30mmol，Et3N)及三乙胺(656.07mg，6.48mmol，903.67μL)中之溶液中分批添加HATU(542.35mg，1.43mmol)。將所得混合物在25℃下攪拌3h且藉由HPLC(50-100% 1-6min水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，目標質量453，管柱：SunFireC18 100*19mm 5um)純化，以獲得5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(190mg，419.87μmol，32.38%產率)。To (2S,5R)-2-(benzothiophen-5-yl)-5-methylpiperidine (0.3 g, 1.30 mmol), 2-[(5-aminocarboxy-6-methoxy- HATU (542.35 mg, 542.35 mg, 903.67 μL) was added portionwise to a solution of 3-pyridyl)amino]-2-oxoacetic acid (441.36 mg, 1.30 mmol, Et3N) and triethylamine (656.07 mg, 6.48 mmol, 903.67 μL). 1.43 mmol). The resulting mixture was stirred at 25°C for 3 h and analyzed by HPLC (50-100% 1-6 min water-methanol ( NH3 0.1%), flow rate 30 ml/min (loading pump 4 ml/min methanol ( NH3 0.1%)), Target mass 453, column: SunFireC18 100*19mm 5um) purification to obtain 5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (190 mg, 419.87 μmol, 32.38% yield).

LCMS(ESI)：[M+1]+ m/z：計算值452.2；實測值453.2；Rt=1.381min。LCMS (ESI): [M+1] + m/z: calculated 452.2; found 453.2; Rt=1.381 min.

步驟2：5-[[2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物618 )及5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物633 )之合成Step 2: 5-[[2-[(2R,5S)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]-2-methoxypyridine-3-carboxamide ( Compound 618 ) and 5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl- Synthesis of 1-Piperidinyl]-2-Pendant Oxyacetyl]Amino]-2-Methoxypyridine-3-Carboxamide ( Compound 633 )

對5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(190mg，419.87μmol)進行掌性分離(注入體積：900mkl；樣品資訊：IC_II，己烷-IPA-MeOH，50-25-25，12ml/min)，以獲得5-[[2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(57mg，125.96μmol，60.00%產率)及5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(44mg，97.23μmol，46.32%產率)。p-5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] -2-Methoxypyridine-3-carboxamide (190 mg, 419.87 μmol) for chiral separation (injection volume: 900 mkl; sample information: IC_II, Hexane-IPA-MeOH, 50-25-25, 12 ml/min ) to obtain 5-[[2-[(2R,5S)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-2-methoxypyridine-3-carboxamide (57 mg, 125.96 μmol, 60.00% yield) and 5-[[2-[(2S,5R)-2-(benzothiophene-5- (44 mg, 97.23 μmol, 46.32% yield) ).

化合物618： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.08(m,3H),1.30-1.42(m,1H),1.67-1.80(m,1H),1.81-1.95(m,1H),2.05-2.21(m,1H),2.22-2.33(m,1H),2.77-3.25(m,1H),3.47-4.07(m,4H),5.16-5.88(m,1H),7.27-7.38(m,1H),7.41-7.47(m,1H),7.66-7.73(m,1H),7.73-7.78(m,2H),7.81-7.88(m,1H),7.96-8.03(m,1H),8.39-8.60(m,2H),10.91-11.23(m,1H)。 Compound 618: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.08 (m, 3H), 1.30-1.42 (m, 1H), 1.67-1.80 (m, 1H), 1.81-1.95 (m, 1H) ,2.05-2.21(m,1H),2.22-2.33(m,1H),2.77-3.25(m,1H),3.47-4.07(m,4H),5.16-5.88(m,1H),7.27-7.38( m,1H),7.41-7.47(m,1H),7.66-7.73(m,1H),7.73-7.78(m,2H),7.81-7.88(m,1H),7.96-8.03(m,1H), 8.39-8.60 (m, 2H), 10.91-11.23 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值452.2；實測值453.0；Rt=3.159min。LCMS (ESI): [M+1] + m/z: calculated 452.2; found 453.0; Rt=3.159 min.

RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=30.076minRT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6ml/min)=30.076min

化合物633： 1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.13(m,3H),1.29-1.43(m,1H),1.71-1.80(m,1H),1.82-1.95(m,1H),2.05-2.23(m,1H),2.26-2.36(m,1H),2.78-3.27(m,1H),3.49-4.09(m,4H),5.23-5.81(m,1H),7.28-7.38(m,1H),7.41-7.47(m,1H),7.66-.7.73(m,1H),7.73-7.78(m,2H),7.80-7.88(m,1H),7.96-8.04(m,1H),8.40-8.60(m,2H),10.98-11.13(m,1H)。 Compound 633: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.13 (m, 3H), 1.29-1.43 (m, 1H), 1.71-1.80 (m, 1H), 1.82-1.95 (m, 1H) ,2.05-2.23(m,1H),2.26-2.36(m,1H),2.78-3.27(m,1H),3.49-4.09(m,4H),5.23-5.81(m,1H),7.28-7.38( m,1H),7.41-7.47(m,1H),7.66-.7.73(m,1H),7.73-7.78(m,2H),7.80-7.88(m,1H),7.96-8.04(m,1H) , 8.40-8.60 (m, 2H), 10.98-11.13 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值452.2；實測值453.2；Rt=3.159min，其中順式雜質少於5%LCMS(ESI): [M+1] + m/z: calculated value 452.2; found value 453.2; Rt=3.159min, in which cis impurity is less than 5%

RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=25.019min，其中順式雜質少於5%RT(IC, Hexane-IPA-MeOH, 50-25-25, 0.6ml/min)=25.019min, with less than 5% cis impurities

實例92. 5-(2-(5-甲基-2-(2-甲基苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物702及化合物693)之合成Example 92. 5-(2-(5-Methyl-2-(2-methylbenzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido) Synthesis of Nicotinamide (Compound 702 and Compound 693)

Figure 110128222-A0202-12-1063-112
Figure 110128222-A0202-12-1063-112

步驟1：5-(2-(5-甲基-2-(2-甲基苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido) Synthesis of Nicotinamide

在室溫下，將HATU(463.00mg，1.22mmol)分批添加到2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(299.09mg，1.22mmol，HCl)、2-甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(300mg，1.22mmol)及TEA(739.30mg，7.31mmol，1.02mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；1-6min 45-60%水-MeOH(NH3 0.1%)，流速：30ml/min為流動相)，以得到5-[[2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧 基乙醯基]胺基]吡啶-3-甲醯胺(249mg，569.12μmol，46.74%產率)。HATU (463.00 mg, 1.22 mmol) was added portionwise to 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-pendoxoacetic acid (299.09 mg, 1.22 mmol) at room temperature , HCl), 2-methyl-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (300 mg, 1.22 mmol) and TEA (739.30 mg, 7.31 mmol, 1.02 mL) in suspension in DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 1-6min 45-60% water-MeOH ( NH3 0.1%), flow rate: 30ml/min as mobile phase), to give 5-[[2-[5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (249 mg, 569.12 μmol, 46.74% yield).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=2.680min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=2.680 min.

步驟2：掌性分離(化合物702 及化合物693 )Step 2: Chiral separation ( compound 702 and compound 693 )

藉由掌性HPLC(管柱：OJ(250*30，20mkm)，CO2 -MeOH，70-30，80ml/min補充流速-30ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物693 5-[[2-[(2S,5R )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(74mg，169.14μmol，76.68%產率)(保留時間=6.46min)及化合物702 5-[[2-[(2R,5S )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(72.3mg，165.25μmol，74.92%產率)(保留時間=9.11min)。The mirror isomers were separated by chiral HPLC (column: OJ (250*30, 20mkm), CO2 -MeOH, 70-30, 80ml/min supplemental flow - 30ml/min as mobile phase) to give two Separate enantiomer compound 693 5-[[2-[( 2S,5R )-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidine Peridyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (74 mg, 169.14 μmol, 76.68% yield) (retention time=6.46 min) and compound 702 5-[[2- [( 2R,5S )-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (72.3 mg, 165.25 μmol, 74.92% yield) (retention time = 9.11 min).

化合物693 於分析條件下(管柱：OJ-H，CO2 -MeOH，70-30，3ml/min為流動相)之保留時間為3.18min且化合物702 之保留時間為5.82min。The retention time of compound 693 under analytical conditions (column: OJ-H, CO 2 -MeOH, 70-30, 3 ml/min as mobile phase) was 3.18 min and the retention time of compound 702 was 5.82 min.

化合物693：保留時間：3.18minCompound 693: retention time: 3.18min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.37(m,1H),1.71(m,1H),1.89(m,1H),2.19(m,2H),2.77(m,3H),3.04(m,1H),3.76(m,1H),5.49(m,1H),7.37(m,1H),7.59(m,1H),7.86(m,1H),8.01(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.87(m,1H),11.26(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.37(m, 1H), 1.71(m, 1H), 1.89(m, 1H), 2.19(m, 2H), 2.77(m, 3H), 3.04(m, 1H), 3.76(m, 1H), 5.49(m, 1H), 7.37(m, 1H), 7.59(m, 1H), 7.86(m, 1H), 8.01 (m, 1H), 8.14 (m, 1H), 8.46 (m, 1H), 8.75 (m, 1H), 8.87 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=1.143min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=1.143 min.

化合物702：保留時間：5.82minCompound 702: retention time: 5.82min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.37(m,1H),1.71(m,1H),1.88(m,1H),2.13(m,1H),2.29(m,1H),2.77(m,3H),2.85(m,1H),3.67(m,1H),5.49(m,1H),7.37(m,1H),7.58(m,1H),7.86(m,1H),8.02(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.87(m,1H),11.26(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.37(m, 1H), 1.71(m, 1H), 1.88(m, 1H), 2.13(m, 1H), 2.29(m, 1H), 2.77(m, 3H), 2.85(m, 1H), 3.67(m, 1H), 5.49(m, 1H), 7.37(m, 1H), 7.58(m, 1H), 7.86 (m, 1H), 8.02 (m, 1H), 8.14 (m, 1H), 8.46 (m, 1H), 8.75 (m, 1H), 8.87 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=1.143min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=1.143 min.

實例93. 2-甲氧基-5-(2-(5-甲基-2-(2-甲基苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物797及化合物808)之合成Example 93. 2-Methoxy-5-(2-(5-methyl-2-(2-methylbenzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxygen Synthesis of acetylacetamido)nicotinamide (compound 797 and compound 808)

Figure 110128222-A0202-12-1065-113
Figure 110128222-A0202-12-1065-113

步驟1：2-甲氧基-5-(2-(5-甲基-2-(2-甲基苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 2-Methoxy-5-(2-(5-methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxygen Synthesis of acetylacetamido)nicotinamide

在室溫下，將HATU(390.98mg，1.03mmol)分批添加到2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(350mg，1.03mmol)、2-甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(253.34mg，1.03mmol)及TEA(624.31mg，6.17mmol，859.93μL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；1-6min 60-70%水-MeOH(NH3 0.1%)，流速：30ml/min為流動相)，以得到2-甲氧基-5-[[2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(260mg，556.10μmol，54.08%產率)。HATU (390.98 mg, 1.03 mmol) was added portionwise to 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid at room temperature (350 mg, 1.03 mmol), 2-methyl-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (253.34 mg, 1.03 mmol) and TEA (624.31 mg, 6.17 mmol, 859.93 μL) in DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 1-6min 60-70% water-MeOH ( NH3 0.1%), flow rate: 30ml/min as mobile phase), to give 2-methoxy-5-[[2-[5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (260 mg, 556.10 μmol, 54.08% yield).

LCMS(ESI)：[M]+ m/z：計算值467.2；實測值468.2；Rt=3.043min。LCMS (ESI): [M] + m/z: calculated 467.2; found 468.2; Rt=3.043 min.

步驟2：掌性分離(化合物808 及化合物797 )Step 2: Chiral separation ( compound 808 and compound 797 )

藉由掌性HPLC(管柱：IA-I，己烷-IPA-MeOH，40-30-30，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物808 2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(45.7mg，97.75μmol，91.40%產率)(保留時間=52.2min)及化合物797 2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(48.1mg，102.88μmol，96.20%產率)(保 留時間=96.7min)。The enantiomers were separated by chiral HPLC (column: IA-I, hexane-IPA-MeOH, 40-30-30, 12 ml/min as mobile phase) to give two separate enantiomer compounds 808 2-Methoxy-5-[[2-[( 2S,5R )-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidine yl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (45.7 mg, 97.75 μmol, 91.40% yield) (retention time=52.2 min) and compound 797 2-methoxy- 5-[[2-[( 2R,5S )-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (48.1 mg, 102.88 μmol, 96.20% yield) (retention time = 96.7 min).

化合物808 於分析條件下(管柱：IA，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為39.25min且化合物797 之保留時間為51.68min。The retention time of compound 808 under analytical conditions (column: IA, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 39.25 min and the retention time of compound 797 was 51.68 min.

化合物808：保留時間：39.25minCompound 808: retention time: 39.25min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.06(m,3H),1.30-1.40(m,1H),1.64-1.76(m,1H),1.81-1.94(m,1H),2.07-2.21(m,1H),2.25-2.34(m,1H),2.73-2.80(m,3H),2.80-3.27(m,1H),3.37-3.54(m,0.6H),3.86-3.98(m,3H),3.99-4.06(m,0.4H),5.26-5.75(m,1H),7.31-7.42(m,1H),7.63-7.78(m,2H),7.80-7.88(m,1H),7.97-8.10(m,1H),8.37-8.60(m,2H),10.93-11.23(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.06(m,3H), 1.30-1.40(m,1H), 1.64-1.76(m,1H), 1.81-1.94(m,1H) ,2.07-2.21(m,1H),2.25-2.34(m,1H),2.73-2.80(m,3H),2.80-3.27(m,1H),3.37-3.54(m,0.6H),3.86-3.98 (m,3H),3.99-4.06(m,0.4H),5.26-5.75(m,1H),7.31-7.42(m,1H),7.63-7.78(m,2H),7.80-7.88(m,1H) ), 7.97-8.10(m, 1H), 8.37-8.60(m, 2H), 10.93-11.23(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值467.2；實測值468.2；Rt=3.030min。LCMS (ESI): [M] + m/z: calculated 467.2; found 468.2; Rt=3.030 min.

化合物797：保留時間：51.68minCompound 797: retention time: 51.68min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.06(m,3H),1.29-1.41(m,1H),1.60-1.78(m,1H),1.79-1.93(m,1H),2.05-2.21(m,1H),2.25-2.34(m,1H),2.73-2.79(m,3H),2.79-3.27(m,1H),3.42-3.52(m,0.6H),3.85-3.98(m,3H),3.99-4.07(m,0.4H),5.22-5.77(m,1H),7.30-7.44(m,1H),7.65-7.78(m,2H),7.81-7.89(m,1H),7.96-8.11(m,1H),8.37-8.61(m,2H),10.98-11.18(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.06(m,3H), 1.29-1.41(m,1H), 1.60-1.78(m,1H), 1.79-1.93(m,1H) ,2.05-2.21(m,1H),2.25-2.34(m,1H),2.73-2.79(m,3H),2.79-3.27(m,1H),3.42-3.52(m,0.6H),3.85-3.98 (m,3H),3.99-4.07(m,0.4H),5.22-5.77(m,1H),7.30-7.44(m,1H),7.65-7.78(m,2H),7.81-7.89(m,1H) ), 7.96-8.11(m, 1H), 8.37-8.61(m, 2H), 10.98-11.18(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值467.2；實測值468.2；Rt=3.032min。LCMS (ESI): [M] + m/z: calculated 467.2; found 468.2; Rt=3.032 min.

實例94.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(2-甲基苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物801及化合物800)之合成Example 94. N- (6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2-methylbenzo[ d ]thiazol-5-yl)piperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 801 and Compound 800)

Figure 110128222-A0202-12-1066-114
Figure 110128222-A0202-12-1066-114

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(2-甲基苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidine Synthesis of -1-yl)-2-oxyacetamide

在室溫下將HATU(363.51mg，956.01μmol)分批添加到2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(200mg，956.02μmol)、2-甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(235.53mg，956.01μmol)及TEA(580.43mg，5.74mmol，799.50μL)於DME(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；1-6min 60-70%水-MeOH(NH3 0.1%)，流速：30ml/min為流動相)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(249mg，569.07μmol，59.53%產率)。HATU (363.51 mg, 956.01 μmol) was added portionwise at room temperature to 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid (200 mg, 956.02 μmol), 2-methyl-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (235.53 mg, 956.01 μmol) and TEA (580.43 mg, 5.74 mmol, 799.50 μL) in suspension in DME (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 1-6min 60-70% water-MeOH ( NH3 0.1%), flow rate: 30ml/min as mobile phase), to give N- (6-amino-5-ethyl-3-pyridyl)-2-[5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)- 1-Piperidinyl]-2-oxoacetamide (249 mg, 569.07 μmol, 59.53% yield).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=2.393min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=2.393 min.

步驟2：掌性分離(化合物800 及化合物808 )Step 2: Chiral separation ( compound 800 and compound 808 )

藉由掌性HPLC(管柱：IC，己烷-IPA-MeOH，50-25-25，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物801 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(75mg，171.41μmol，62.50%產率)(保留時間=29.5min)及化合物800 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(99mg，226.26μmol，82.50%產率)(保留時間=49.4min)。The enantiomers were separated by chiral HPLC (column: IC, hexane-IPA-MeOH, 50-25-25, 12 ml/min as mobile phase) to give two separate enantiomers Compound 801N -(6-Amino-5-ethyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-(2-methyl-1,3-benzothiazole-5- yl)-1-piperidinyl]-2-oxyacetamide (75 mg, 171.41 μmol, 62.50% yield) (retention time=29.5 min) and compound 800 N- (6-amino-5-ethyl) yl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]- 2-Pendant oxyacetamide (99 mg, 226.26 μmol, 82.50% yield) (retention time = 49.4 min).

化合物800 於分析條件下(管柱：IC，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為47.90min且化合物801 之保留時間為29.65min。The retention time of compound 800 under analytical conditions (column: IC, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 47.90 min and that of compound 801 was 29.65 min.

化合物800：保留時間：47.90minCompound 800: retention time: 47.90min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.04-1.15(m,3H),1.30-1.41(m,1H),1.65-1.73(m,1H),1.80-1.91(m,1H),2.02-2.21(m,1H),2.25-2.33(m,1H),2.35-2.41(m,2H),2.75-2.78(m,3H),2.80-3.27(m,1H),3.41-4.09(m,1H),5.24-5.59(m,1H),5.60-5.72(m,2H),7.30-7.41(m,1H),7.42-7.55(m,1H), 7.79-7.88(m,1H),7.97-8.07(m,2H),10.48-10.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.04(m,3H), 1.04-1.15(m,3H), 1.30-1.41(m,1H), 1.65-1.73(m,1H) ,1.80-1.91(m,1H),2.02-2.21(m,1H),2.25-2.33(m,1H),2.35-2.41(m,2H),2.75-2.78(m,3H),2.80-3.27( m,1H),3.41-4.09(m,1H),5.24-5.59(m,1H),5.60-5.72(m,2H),7.30-7.41(m,1H),7.42-7.55(m,1H), 7.79-7.88 (m, 1H), 7.97-8.07 (m, 2H), 10.48-10.63 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=2.313min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=2.313 min.

化合物801：保留時間：29.65minCompound 801: retention time: 29.65min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.04(m,3H),1.04-1.15(m,3H),1.30-1.42(m,1H),1.63-1.75(m,1H),1.81-1.93(m,1H),2.01-2.21(m,1H),2.24-2.32(m,1H),2.36-2.43(m,2H),2.77(s,3H),2.79-3.26(m,1H),3.42-4.08(m,1H),5.23-5.60(m,1H),5.60-5.75(m,2H),7.30-7.41(m,1H),7.41-7.59(m,1H),7.79-7.89(m,1H),7.95-8.09(m,2H),10.44-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.04(m,3H), 1.04-1.15(m,3H), 1.30-1.42(m,1H), 1.63-1.75(m,1H) ,1.81-1.93(m,1H),2.01-2.21(m,1H),2.24-2.32(m,1H),2.36-2.43(m,2H),2.77(s,3H),2.79-3.26(m, 1H), 3.42-4.08(m, 1H), 5.23-5.60(m, 1H), 5.60-5.75(m, 2H), 7.30-7.41(m, 1H), 7.41-7.59(m, 1H), 7.79- 7.89 (m, 1H), 7.95-8.09 (m, 2H), 10.44-10.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=2.313min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=2.313 min.

實例95. 5-(2-(2-(3,4-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物475、化合物474)之合成Example 95. 5-(2-(2-(3,4-Difluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 475, the synthesis of compound 474)

Figure 110128222-A0202-12-1068-115
Figure 110128222-A0202-12-1068-115

步驟1：5-(2-(2-(3,4-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: Synthesis of 5-(2-(2-(3,4-difluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide

將DIPEA(385.43mg，2.98mmol，519.45μL)添加到相應2-(3,4-二氟苯基)-5-甲基哌啶(0.18g，852.07μmol)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(178.22mg，725.59μmol，HCl)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(356.38mg，937.28μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(管柱：Triart 100*20，5mkl；以MeOH+NH3 為溶析液混合物)，以得到純的5-[[2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.19g，472.17μmol，55.41%產率)。DIPEA (385.43 mg, 2.98 mmol, 519.45 μL) was added to the corresponding 2-(3,4-difluorophenyl)-5-methylpiperidine (0.18 g, 852.07 μmol) and 2-[(5-aminomethane Acyl-3-pyridyl)amino]-2-pendoxoacetic acid (178.22 mg, 725.59 μmol, HCl) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (356.38 mg, 937.28 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (column: Triart 100*20, 5mkl; with MeOH+ NH3 as eluent mixture) to give pure 5-[[2-[( 2R,5S )-2-( 3,4-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.19 g, 472.17 μmol, 55.41% Yield).

1 H NMR(400MHz,CDCl3 )δ(ppm) 1 H NMR (400MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值402.2；實測值403.2；Rt=3.380min。LCMS (ESI): [M] + m/z: calculated 402.2; found 403.2; Rt=3.380 min.

步驟2：掌性分離(化合物475 及化合物474 )Step 2: Chiral separation ( compound 475 and compound 474 )

使用Chiralpak IC-II 250*20，5mkm管柱(以己烷-IPA-MeOH，50-25-25為流動相；流速12mL/min；注入體積：900mkl)分離5-[[2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(108mg，268.39μmol)，得到呈黃色固體之化合物475 5-[[2-[(2.S,5R )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(56.59mg，140.63μmol，52.40%產率)(RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=24.70min)及呈黃色固體之化合物474 5-[[2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50.99mg，126.72μmol，47.21%產率)(RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=15.21min)。Separation of 5-[[2-[ ( ,5S )-2-(3,4-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (108mg , 268.39 μmol) to give compound 475 as a yellow solid 5-[[2-[( 2.S,5R )-2-(3,4-difluorophenyl)-5-methyl-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (56.59 mg, 140.63 μmol, 52.40% yield) (RT(IC, hexane-IPA-MeOH, 50-25-25 , 0.6ml/min)=24.70min) and compound 474 as a yellow solid 5-[[2-[( 2R,5S )-2-(3,4-difluorophenyl)-5-methyl-1- Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (50.99 mg, 126.72 μmol, 47.21% yield) (RT(IC, hexane-IPA-MeOH, 50- 25-25, 0.6ml/min)=15.21min).

化合物475：保留時間：24.70minCompound 475: retention time: 24.70min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.26-1.37(m,1H),1.58-1.71(m,1H),1.82-1.97(m,1H),2.00-2.13(m,1H),2.14-2.25(m,1H),2.74-3.24(m,1H),3.42-4.02(m,1H),5.11-5.58(m,1H),7.11-7.22(m,1H),7.32-7.50(m,2H),7.55-7.64(m,1H),8.08-8.21(m,1H),8.42-8.52(m,1H),8.71-8.80(m,1H),8.81-8.92(m,1H),11.15-11.40(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,3H), 1.26-1.37(m,1H), 1.58-1.71(m,1H), 1.82-1.97(m,1H) ,2.00-2.13(m,1H),2.14-2.25(m,1H),2.74-3.24(m,1H),3.42-4.02(m,1H),5.11-5.58(m,1H),7.11-7.22( m,1H),7.32-7.50(m,2H),7.55-7.64(m,1H),8.08-8.21(m,1H),8.42-8.52(m,1H),8.71-8.80(m,1H), 8.81-8.92 (m, 1H), 11.15-11.40 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值402.2；實測值403.2；Rt=1.225min。LCMS (ESI): [M] + m/z: calculated 402.2; found 403.2; Rt=1.225 min.

化合物474：保留時間：15.21minCompound 474: retention time: 15.21min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.08(m,3H),1.21-1.43(m,1H),1.59-1.74(m,1H),1.83-1.98(m,1H),1.99-2.16(m,1H),2.17-2.30(m,1H),2.74-3.31(m,1H),3.43-4.11(m,1H),5.12-5.63(m,1H),7.14-7.27(m,1H),7.33-7.53(m,2H),7.58-7.69(m,1H),8.12-8.24(m,1H),8.44-8.56(m,1H),8.73-8.85(m,1H), 8.85-8.98(m,1H),11.18-11.36(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.08(m,3H), 1.21-1.43(m,1H), 1.59-1.74(m,1H), 1.83-1.98(m,1H) ,1.99-2.16(m,1H),2.17-2.30(m,1H),2.74-3.31(m,1H),3.43-4.11(m,1H),5.12-5.63(m,1H),7.14-7.27( m,1H),7.33-7.53(m,2H),7.58-7.69(m,1H),8.12-8.24(m,1H),8.44-8.56(m,1H),8.73-8.85(m,1H), 8.85-8.98 (m, 1H), 11.18-11.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值402.2；實測值403.2；Rt=1.226min。LCMS (ESI): [M] + m/z: calculated 402.2; found 403.2; Rt=1.226 min.

實例96. 5-(2-(5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物476、化合物477)之合成Example 96. 5-(2-(5-Methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of (Compound 476, Compound 477)

Figure 110128222-A0202-12-1070-116
Figure 110128222-A0202-12-1070-116

步驟1：5-(2-(5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide synthesis

將DIPEA(394.65mg，3.05mmol，531.87μL)添加到相應5-甲基-2-(3,4,5-三氟苯基)哌啶(0.2g，872.44μmol)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(182.48mg，742.94μmol，HCl)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(364.90mg，959.69μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到純的5-[[2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(209mg，497.16μmol，56.99%產率)。DIPEA (394.65 mg, 3.05 mmol, 531.87 μL) was added to the corresponding 5-methyl-2-(3,4,5-trifluorophenyl)piperidine (0.2 g, 872.44 μmol) and 2-[(5- A solution of aminocarbamoyl-3-pyridyl)amino]-2-pendoxoacetic acid (182.48 mg, 742.94 μmol, HCl) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (364.90 mg, 959.69 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure 5-[[2-[( 2R,5S )-5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (209 mg, 497.16 μmol, 56.99% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm) 1 H NMR (400MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值420.2；實測值421.2；Rt=3.479min。LCMS (ESI): [M] + m/z: calculated 420.2; found 421.2; Rt=3.479 min.

步驟2：掌性分離(化合物476 及化合物477 )Step 2: Chiral separation ( compound 476 and compound 477 )

使用Chiralpak IC-II 250*20，5mkm管柱(己烷-IPA-MeOH，70-15-15為流動相；流速14mL/min；注入體積：900mkl)分離5-[[2-[(2R,5S )-5-甲基-2-(3,4,5- 三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(209mg，497.16μmol)，得到呈黃色固體之化合物476 5-[[2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(104.08mg，247.58μmol，49.80%產率)(RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=143.22min)及呈黃色固體之化合物477 5-[[2-[(2S,5R )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(104.85mg，249.41μmol，50.17%產率)(RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=19.38min)。5-[[2-[( 2R, 5-[[2-[( 2R, 5-[[2-[( 2R, 5S )-5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( 209 mg, 497.16 μmol) to give compound 476 as a yellow solid 5-[[2-[( 2R,5S )-5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidine [methyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (104.08 mg, 247.58 μmol, 49.80% yield) (RT(IC, hexane-IPA-MeOH, 50-25- 25, 0.6ml/min)=143.22min) and compound 477 as a yellow solid 5-[[2-[( 2S,5R )-5-methyl-2-(3,4,5-trifluorophenyl) -1-Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (104.85 mg, 249.41 μmol, 50.17% yield) (RT(IC, Hexane-IPA-MeOH) , 50-25-25, 0.6ml/min)=19.38min).

化合物476：保留時間：13.22minCompound 476: retention time: 13.22min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.01(m,3H),1.24-1.38(m,1H),1.58-1.68(m,1H),1.82-1.94(m,1H),1.98-2.12(m,1H),2.13-2.24(m,1H),2.76-3.28(m,1H),3.45-4.05(m,1H),5.10-5.53(m,1H),7.22-7.31(m,2H),7.55-7.63(m,1H),8.11-8.22(m,1H),8.42-8.52(m,1H),8.73-8.81(m,1H),8.81-8.93(m,1H),11.20-11.32(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.01(m,3H), 1.24-1.38(m,1H), 1.58-1.68(m,1H), 1.82-1.94(m,1H) ,1.98-2.12(m,1H),2.13-2.24(m,1H),2.76-3.28(m,1H),3.45-4.05(m,1H),5.10-5.53(m,1H),7.22-7.31( m,2H),7.55-7.63(m,1H),8.11-8.22(m,1H),8.42-8.52(m,1H),8.73-8.81(m,1H),8.81-8.93(m,1H), 11.20-11.32 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值420.2；實測值421.2；Rt=3.351min。LCMS (ESI): [M] + m/z: calculated 420.2; found 421.2; Rt=3.351 min.

化合物477：保留時間：19.38minCompound 477: retention time: 19.38min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.01(m,3H),1.24-1.38(m,1H),1.57-1.69(m,1H),1.79-1.94(m,1H),1.94-2.11(m,1H),2.11-2.23(m,1H),2.77-3.28(m,1H),3.44-4.04(m,1H),5.11-5.53(m,1H),7.20-7.33(m,2H),7.54-7.65(m,1H),8.10-8.21(m,1H),8.42-8.51(m,1H),8.72-8.81(m,1H),8.81-8.92(m,1H),11.11-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.01(m,3H), 1.24-1.38(m,1H), 1.57-1.69(m,1H), 1.79-1.94(m,1H) ,1.94-2.11(m,1H),2.11-2.23(m,1H),2.77-3.28(m,1H),3.44-4.04(m,1H),5.11-5.53(m,1H),7.20-7.33( m,2H),7.54-7.65(m,1H),8.10-8.21(m,1H),8.42-8.51(m,1H),8.72-8.81(m,1H),8.81-8.92(m,1H), 11.11-11.39 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值420.2；實測值421.2；Rt=3.348min。LCMS (ESI): [M] + m/z: calculated 420.2; found 421.2; Rt=3.348 min.

實例97. 2-甲氧基-5-(2-(5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物739、化合物742)之合成Example 97. 2-Methoxy-5-(2-(5-methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl)-2-oxyacetamide Synthesis of base) nicotinamide (compound 739, compound 742)

Figure 110128222-A0202-12-1072-117
Figure 110128222-A0202-12-1072-117

步驟1：2-甲氧基-5-(2-(5-甲基-2-(3,4，5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 2-Methoxy-5-(2-(5-methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl)-2-oxyacetamide Base) Synthesis of Nicotinamide

將DIPEA(398.69mg，3.08mmol，537.32μL)添加到相應5-甲基-2-(3,4,5-三氟苯基)哌啶(202.05mg，760.44μmol，HCl)及2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.3g，881.38μmol，Et3 N)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(368.64mg，969.52μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH+NH3 為溶析液混合物)，以得到2-甲氧基-5-[[2-[5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(166mg，368.55μmol，41.82%產率)。DIPEA (398.69 mg, 3.08 mmol, 537.32 μL) was added to the corresponding 5-methyl-2-(3,4,5-trifluorophenyl)piperidine (202.05 mg, 760.44 μmol, HCl) and 2-[( 5-Aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid (0.3 g, 881.38 μmol, Et3N ) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (368.64 mg, 969.52 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH+ NH3 as eluent mixture) to give 2-methoxy-5-[[2-[5 -Methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (166 mg, 368.55 μmol , 41.82% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.02(d,3H),1.24(m,1H),1.58(m,1H),1.98(m,1H),2.24(m,2H),3.36(m,1H),3.96(s,3H),4.02(m,1H),5.48(m,1H),7.28(m,2H),7.86(m,2H),8.52(m,1H),8.62(m,1H),11.12(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.02(d,3H), 1.24(m,1H), 1.58(m,1H), 1.98(m,1H), 2.24(m,2H), 3.36(m,1H),3.96(s,3H),4.02(m,1H),5.48(m,1H),7.28(m,2H),7.86(m,2H),8.52(m,1H),8.62 (m, 1H), 11.12 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值450.2；實測值451.2；Rt=3.229min。LCMS (ESI): [M] + m/z: calculated 450.2; found 451.2; Rt=3.229 min.

步驟2：掌性分離(化合物739 及化合物742 )Step 2: Chiral separation ( compound 739 and compound 742 )

使用Chiralpak IA 250*20,5mkm管柱(己烷-IPA-MeOH，60-20-20為流動相；流速12mL/min；注入體積：900mkl)分離2-甲氧基-5-[[2-[5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(100mg，222.02μmol)，得到呈黃色固體之化合物739 2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(49.57mg，110.06μmol，49.57%產率) (RT(IC，CO2 -MeOH，60-40，2ml/min)=6.03min)及呈黃色固體之化合物742 -甲氧基-5-[[2-[(2S,5R )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(45.74mg，101.55μmol，45.74%產率)(RT(IC，CO2 -MeOH，60-40,2ml/min)=8.50min)。Separation of 2-methoxy-5-[[2- [5-Methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (100 mg, 222.02 μmol) to give compound 739 as a yellow solid 2-methoxy-5-[[2-[( 2R,5S )-5-methyl-2-(3,4,5-trifluorophenyl)- 1-Piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (49.57 mg, 110.06 μmol, 49.57% yield) (RT(IC, CO 2 -MeOH, 60- 40, 2ml/min)=6.03min) and compound 742 -methoxy-5-[[2-[( 2S,5R )-5-methyl-2-(3,4,5-tris) as a yellow solid Fluorophenyl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (45.74 mg, 101.55 μmol, 45.74% yield) (RT (IC, CO 2 ) -MeOH, 60-40, 2ml/min)=8.50min).

化合物739：保留時間：6.03minCompound 739: retention time: 6.03min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.27(m,1H),1.63(m,1H),1.87(m,1H),2.01(m,1H),2.16(m,1H),3.01(m,1H),3.78(m,4H),5.30(m,1H),7.25(m,2H),7.72(m,2H),8.48(m,2H),11.04(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99(m, 3H), 1.27(m, 1H), 1.63(m, 1H), 1.87(m, 1H), 2.01(m, 1H), 2.16(m, 1H), 3.01(m, 1H), 3.78(m, 4H), 5.30(m, 1H), 7.25(m, 2H), 7.72(m, 2H), 8.48(m, 2H), 11.04 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值450.2；實測值451.2；Rt=1.158min。LCMS (ESI): [M] + m/z: calculated 450.2; found 451.2; Rt=1.158 min.

化合物742：保留時間：8.50minCompound 742: retention time: 8.50min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.28(m,1H),1.62(m,1H),1.87(m,1H),2.02(m,1H),2.18(m,1H),2.92(m,1H),3.93(m,4H),5.30(m,1H),7.26(m,2H),7.72(m,2H),8.48(m,2H),11.04(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99(m, 3H), 1.28(m, 1H), 1.62(m, 1H), 1.87(m, 1H), 2.02(m, 1H), 2.18(m, 1H), 2.92(m, 1H), 3.93(m, 4H), 5.30(m, 1H), 7.26(m, 2H), 7.72(m, 2H), 8.48(m, 2H), 11.04 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值450.2；實測值451.2；Rt=1.159min。LCMS (ESI): [M] + m/z: calculated 450.2; found 451.2; Rt=1.159 min.

實例98. 5-(2-(2-(4-羥基環己基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物393、化合物382及化合物394、化合物395)之合成Example 98. 5-(2-(2-(4-hydroxycyclohexyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 393, compound 382 and the synthesis of compound 394 and compound 395)

Figure 110128222-A0202-12-1073-118
Figure 110128222-A0202-12-1073-118

步驟1：5-(2-(2-(4-羥基環己基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之Step 1: 5-(2-(2-(4-hydroxycyclohexyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide 合成synthesis

在25℃下，將4-(5-甲基-2-哌啶基)環己醇(0.4g，2.03mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(566.22mg，1.82mmol)及TEA(2.05g，20.27mmol，2.83mL)於DMF(20mL)中之混合物攪拌0.25h，然後在0.5h內小批量添加HATU(693.72mg，1.82mmol)。將反應混合物在25℃下攪拌2h，然後在真空中濃縮至5ml且提交至反相HPLC(管柱：SunFireC18 100x19mm 5um，流動相：20-65% 0-5min水-MeOH+FA，流速：30ml/min)，這得到呈淡黃色膠狀物之5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(148mg，380.99μmol，18.79%產率)及5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(212mg，545.75μmol，26.92%產率)。4-(5-Methyl-2-piperidinyl)cyclohexanol (0.4 g, 2.03 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino] at 25°C - A mixture of 2-oxoacetic acid (566.22 mg, 1.82 mmol) and TEA (2.05 g, 20.27 mmol, 2.83 mL) in DMF (20 mL) was stirred for 0.25 h, then HATU (693.72 mg) was added in small portions over 0.5 h , 1.82 mmol). The reaction mixture was stirred at 25°C for 2h, then concentrated in vacuo to 5ml and submitted to reverse phase HPLC (column: SunFire C18 100x19mm 5um, mobile phase: 20-65% 0-5min water-MeOH+FA, flow rate: 30ml /min), which gave 5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2- as a pale yellow gum Pendant oxyacetyl]amino]pyridine-3-carboxamide (148 mg, 380.99 μmol, 18.79% yield) and 5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl) )-5-methyl-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (212 mg, 545.75 μmol, 26.92% yield).

D1： 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.28(m,8H),1.62(m,4H),1.84(m,4H),3.71(m,1H),4.23(m,2H),7.57(s,1H),8.10(m,1H),8.47(m,1H),8.73(s,1H),8.87(m,1H),11.06(m,1H)。 D1: 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 0.96 (d, 3H), 1.28 (m, 8H), 1.62 (m, 4H), 1.84 (m, 4H), 3.71 (m, 1H) ), 4.23(m, 2H), 7.57(s, 1H), 8.10(m, 1H), 8.47(m, 1H), 8.73(s, 1H), 8.87(m, 1H), 11.06(m, 1H) .

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.388min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.388 min.

D2： 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.28(m,8H),1.62(m,4H),1.84(m,4H),3.71(m,1H),4.23(m,2H),7.57(s,1H),8.10(m,1H),8.47(m,1H),8.73(s,1H),8.87(m,1H),11.06(m,1H)。 D2: 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 0.96 (d, 3H), 1.28 (m, 8H), 1.62 (m, 4H), 1.84 (m, 4H), 3.71 (m, 1H) ), 4.23(m, 2H), 7.57(s, 1H), 8.10(m, 1H), 8.47(m, 1H), 8.73(s, 1H), 8.87(m, 1H), 11.06(m, 1H) .

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.595min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.595min.

步驟2：掌性分離(化合物393、化合物382 及化合物394、化合物395 )Step 2: chiral separation ( compound 393, compound 382 and compound 394, compound 395 )

將外消旋5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(212.00mg，545.75μmol)提交至製備型掌性HPLC(管柱：Chiralcel IA(250*20，5mkm)，流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min.24℃，波長：205nm、225nm)，以得到化合物382 5-[[2-[(2S,5R )-2-(4- 羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(63.1mg，162.44μmol，29.76%產率)(保留時間=13.45min)及化合物393 5-[[2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(63.3mg，162.95μmol，29.86%產率)(保留時間=31.52min)。The racemic 5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino group ]pyridine-3-carboxamide (212.00 mg, 545.75 μmol) was submitted to preparative chiral HPLC (column: Chiralcel IA (250*20, 5 mkm), mobile phase: hexane-IPA-MeOH, 60-20- 20; flow rate: 12ml/min. 24°C, wavelength: 205nm, 225nm) to obtain compound 382 5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl- 1-Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (63.1 mg, 162.44 μmol, 29.76% yield) (retention time=13.45 min) and compound 393 5- [[2-[( 2R,5S )-2-(4-Hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-methyl Amide (63.3 mg, 162.95 μmol, 29.86% yield) (retention time = 31.52 min).

將外消旋5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(148mg，380.99μmol)提交至製備型掌性HPLC(管柱：Chiralpak IB(250*20,5mkm)；流動相：己烷-IPA-MeOH，80-10-10；流速：15ml/min)，以得到化合物395 5-[[2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(47.9mg，123.31μmol，32.36%產率)(保留時間=17.290min)及化合物394 5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(43.6mg，112.24μmol，29.46%產率)(保留時間=24.069min)。The racemic 5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino group ] pyridine-3-carboxamide (148 mg, 380.99 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IB (250*20,5 mkm); mobile phase: Hexane-IPA-MeOH, 80-10-10 ; flow rate: 15ml/min) to obtain compound 395 5-[[2-[( 2R,5S )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (47.9 mg, 123.31 μmol, 32.36% yield) (retention time=17.290 min) and compound 394 5-[[2-[( 2S,5R ) -2-(4-Hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (43.6 mg, 112.24 μmol, 29.46 % yield) (retention time = 24.069 min).

化合物393 ：保留時間：31.52min Compound 393 : retention time: 31.52min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.92-1.02(m,3H),1.09-1.21(m,1H),1.21-1.32(m,3H),1.33-1.45(m,3H),1.45-1.57(m,1H),1.58-1.67(m,3H),1.81-2.00(m,3H),2.84-3.25(m,1H),3.33-3.57(m,1H),3.69-3.80(m,1H),3.95-4.37(m,2H),7.59(s,1H),8.15(s,1H),8.42-8.53(m,1H),8.71-8.80(m,1H),8.84-8.92(m,1H),10.98-11.16(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.92-1.02(m,3H), 1.09-1.21(m,1H), 1.21-1.32(m,3H), 1.33-1.45(m,3H) ,1.45-1.57(m,1H),1.58-1.67(m,3H),1.81-2.00(m,3H),2.84-3.25(m,1H),3.33-3.57(m,1H),3.69-3.80( m,1H),3.95-4.37(m,2H),7.59(s,1H),8.15(s,1H),8.42-8.53(m,1H),8.71-8.80(m,1H),8.84-8.92( m, 1H), 10.98-11.16 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.415min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.415 min.

化合物382 ：保留時間：13.45min Compound 382 : retention time: 13.45min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.89-1.04(m,3H),1.07-1.29(m,3H),1.29-1.45(m,4H),1.45-1.57(m,1H),1.57-1.66(m,3H),1.80-1.99(m,3H),2.84-3.22(m,1H),3.34-3.58(m,1H),3.67-3.81(m,1H),3.98-4.33(m,2H),7.59(s,1H),8.15(s,1H),8.43-8.51(m,1H),8.65-8.80(m,1H),8.84-8.93(m,1H),10.95-11.13 (m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.89-1.04(m,3H), 1.07-1.29(m,3H), 1.29-1.45(m,4H), 1.45-1.57(m,1H) ,1.57-1.66(m,3H),1.80-1.99(m,3H),2.84-3.22(m,1H),3.34-3.58(m,1H),3.67-3.81(m,1H),3.98-4.33( m, 2H), 7.59(s, 1H), 8.15(s, 1H), 8.43-8.51(m, 1H), 8.65-8.80(m, 1H), 8.84-8.93(m, 1H), 10.95-11.13 ( m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.417min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.417 min.

化合物394 ：保留時間：24.07min Compound 394 : retention time: 24.07min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.77-0.87(m,1H),0.89-1.02(m,5H),1.07-1.16(m,2H),1.21-1.30(m,1H),1.50-1.68(m,3H),1.72-2.00(m,6H),2.86-3.19(m,1H),3.35-3.78(m,1H),3.95-4.11(m,1H),4.31-4.50(m,1H),7.59(s,1H),8.09-8.23(m,1H),8.37-8.52(m,1H),8.70-8.79(m,1H),8.82-8.92(m,1H),10.94-11.13(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.77-0.87(m,1H),0.89-1.02(m,5H),1.07-1.16(m,2H),1.21-1.30(m,1H) ,1.50-1.68(m,3H),1.72-2.00(m,6H),2.86-3.19(m,1H),3.35-3.78(m,1H),3.95-4.11(m,1H),4.31-4.50( m,1H),7.59(s,1H),8.09-8.23(m,1H),8.37-8.52(m,1H),8.70-8.79(m,1H),8.82-8.92(m,1H),10.94- 11.13 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.225min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.225 min.

化合物395 ：保留時間：17.29min Compound 395 : retention time: 17.29min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.71-0.91(m,2H),0.91-1.01(m,4H),1.04-1.18(m,2H),1.22-1.34(m,1H),1.50-1.68(m,3H),1.72-1.98(m,6H),2.85-3.24(m,1H),3.40-3.76(m,1H),3.96-4.11(m,1H),4.31-4.51(m,1H),7.59(s,1H),8.07-8.22(m,1H),8.42-8.50(m,1H),8.72-8.79(m,1H),8.81-8.95(m,1H),10.97-11.09(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.71-0.91(m, 2H), 0.91-1.01(m, 4H), 1.04-1.18(m, 2H), 1.22-1.34(m, 1H) ,1.50-1.68(m,3H),1.72-1.98(m,6H),2.85-3.24(m,1H),3.40-3.76(m,1H),3.96-4.11(m,1H),4.31-4.51( m,1H),7.59(s,1H),8.07-8.22(m,1H),8.42-8.50(m,1H),8.72-8.79(m,1H),8.81-8.95(m,1H),10.97- 11.09 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.222min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.222 min.

實例99. 5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物550及5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物574)之合成Example 99. 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 550 and 5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[ Synthesis of 3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 574)

Figure 110128222-A0202-12-1077-119
Figure 110128222-A0202-12-1077-119

步驟1：5-[[2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[5-Methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-pendoxoethyl Synthesis of Acyl]amino]pyridine-3-carbamoylamine

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(340.69mg，1.39mmol，HCl)(190.00mg，1.01mmol)及5-(5-甲基-2-哌啶基)-1H-吡唑并[3,4-b]吡啶(0.3g，1.39mmol)混合於DMF(10mL)中。將反應懸浮液冷卻至20℃且添加HATU(527.41mg，1.39mmol)，隨後添加TEA(421.08mg，4.16mmol，579.99μL)，且在周圍溫度下攪拌14h。在真空中蒸發反應混合物且藉由製備型20-70% 0-9.5min水-甲醇(NH3 0.1%)(流速30ml/min)純化所獲得之粗產物0.41g，以得到產物5-[[2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.045g，110.45μmol，7.96%產率)。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (340.69 mg, 1.39 mmol, HCl) (190.00 mg, 1.01 mmol) and 5-(5-methyl) yl-2-piperidinyl)-1H-pyrazolo[3,4-b]pyridine (0.3 g, 1.39 mmol) was mixed in DMF (10 mL). The reaction suspension was cooled to 20°C and HATU (527.41 mg, 1.39 mmol) was added followed by TEA (421.08 mg, 4.16 mmol, 579.99 μL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and the obtained crude product 0.41 g was purified by preparative 20-70% 0-9.5 min water-methanol ( NH3 0.1%) (flow rate 30 ml/min) to give the product 5-[[ 2-[5-Methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine -3-Carboxamide (0.045 g, 110.45 μmol, 7.96% yield).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.2；Rt=1.945min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.2; Rt=1.945 min.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物550 )及5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物574 )之合成Step 2: 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( Compound 550 ) and 5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazolo Synthesis of [3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 574 )

藉由掌性HPLC(管柱：OJ-H(250*20,5mkm))，以己烷-IPA-MeOH，60-20-20，14ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物574 5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(11.97mg，29.38μmol，26.60%產率)及化合物550 5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.01063g，26.09μmol，23.62%產率)。The enantiomers were separated by chiral HPLC (column: OJ-H (250*20, 5mkm) with hexane-IPA-MeOH, 60-20-20, 14ml/min as mobile phase) to give Two separate enantiomers Compound 574 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (11.97 mg, 29.38 μmol, 26.60% yield) and compound 550 5-[[2-[(2S ,5R)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (0.01063 g, 26.09 μmol, 23.62% yield).

化合物550： 1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.06(m,3H),1.32-1.43(m,1H),1.73-1.81(m,1H),1.86-1.93(m,1H),2.08-2.23(m,1H),2.26-2.33(m,1H),2.84-3.05(m,1H),3.47-4.02(m,1H),5.33-5.75(m,1H),7.51-7.65(m,1H),8.09-8.22(m,3H),8.40-8.56(m,2H),8.69-8.79(m,1H),8.79-8.95(m,1H),11.11-11.46(m,1H),13.56-13.81(m,1H)。 Compound 550: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.06 (m, 3H), 1.32-1.43 (m, 1H), 1.73-1.81 (m, 1H), 1.86-1.93 (m, 1H) ,2.08-2.23(m,1H),2.26-2.33(m,1H),2.84-3.05(m,1H),3.47-4.02(m,1H),5.33-5.75(m,1H),7.51-7.65( m,1H),8.09-8.22(m,3H),8.40-8.56(m,2H),8.69-8.79(m,1H),8.79-8.95(m,1H),11.11-11.46(m,1H), 13.56-13.81 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值407.4；實測值408.2；Rt=3.677min。LCMS (ESI): [M+H] + m/z: calculated 407.4; found 408.2; Rt=3.677 min.

RT(己烷-IPA-MeOH，60-20-20，14ml/min)=16.901min。RT (Hexane-IPA-MeOH, 60-20-20, 14 ml/min) = 16.901 min.

化合物574： 1 H NMR(600MHz,DMSO-d 6 )δ 1.02-1.07(m,3H),1.30-1.44(m,1H),1.71-1.84(m,1H),1.84-1.96(m,1H),2.06-2.28(m,1H),2.28-2.36(m,1H),2.80-3.22(m,1H),3.49-4.07(m,1H),5.27-5.73(m,1H),7.50-7.65(m,1H),8.06-8.21(m,3H),8.41-8.57(m,2H),8.70-8.79(m,1H),8.79-8.96(m,1H),11.07-11.56(m,1H),13.42-13.84(m,1H)。 Compound 574: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.02-1.07 (m, 3H), 1.30-1.44 (m, 1H), 1.71-1.84 (m, 1H), 1.84-1.96 (m, 1H) ,2.06-2.28(m,1H),2.28-2.36(m,1H),2.80-3.22(m,1H),3.49-4.07(m,1H),5.27-5.73(m,1H),7.50-7.65( m,1H),8.06-8.21(m,3H),8.41-8.57(m,2H),8.70-8.79(m,1H),8.79-8.96(m,1H),11.07-11.56(m,1H), 13.42-13.84 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值407.4；實測值408.2；Rt=3.676min。LCMS (ESI): [M+H] + m/z: calculated 407.4; found 408.2; Rt=3.676 min.

RT(己烷-IPA-MeOH，60-20-20，14ml/min)=22.91min。RT (Hexane-IPA-MeOH, 60-20-20, 14 ml/min) = 22.91 min.

實例100. 2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物537)及2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(IH-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物546)之合成Example 100. 2-Methoxy-5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1 -Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (Compound 537) and 2-methoxy-5-[[2-[(2R,5S)-5 -Methyl-2-(IH-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Synthesis of amide (compound 546)

Figure 110128222-A0202-12-1079-120
Figure 110128222-A0202-12-1079-120

步驟1：2-甲氧基-5-[[2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetyl] Amino] Pyridine-3-Carboxyamide

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(472.13mg，1.39mmol，C6H15N)及5-(5-甲基-2-哌啶基)-1H-吡唑并[3,4-b]吡啶(0.3g，1.39mmol)混合於DMF中。將反應懸浮液冷卻至0℃且添加HATU(527.41mg，1.39mmol)，隨後添加TEA(421.08mg，4.16mmol，579.99μL)，且在周圍溫度下攪拌12h。在真空中蒸發反應混合物且藉由製備型HPLC(C18管柱，30-80% 0-9.5min水-甲醇(NH3 0.1%)，流速30ml/min)純化所獲得之粗產物0.4g，以得到產物2-甲氧基-5-[[2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.11g，251.46μmol，18.13%產率)。2-[(5-Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (472.13 mg, 1.39 mmol, C6H15N) and 5-(5-methyl) -2-Piperidinyl)-1H-pyrazolo[3,4-b]pyridine (0.3 g, 1.39 mmol) was mixed in DMF. The reaction suspension was cooled to 0°C and HATU (527.41 mg, 1.39 mmol) was added followed by TEA (421.08 mg, 4.16 mmol, 579.99 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and the obtained crude product 0.4 g was purified by preparative HPLC (C18 column, 30-80% 0-9.5 min water-methanol ( NH3 0.1%), flow rate 30 ml/min), with The product 2-methoxy-5-[[2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2 was obtained -Pendant oxyacetoxy]amino]pyridine-3-carboxamide (0.11 g, 251.46 μmol, 18.13% yield).

LCMS(ESI)：[M+H]+ m/z：計算值437.2；實測值438.2；Rt=1.037min。LCMS (ESI): [M+H] + m/z: calculated 437.2; found 438.2; Rt=1.037 min.

步驟2：2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物537 )及2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物546 )之合成Step 2: 2-Methoxy-5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1 -Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( Compound 537 ) and 2-methoxy-5-[[2-[(2R,5S)-5 -Methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Synthesis of amide ( compound 546 )

藉由HPLC(30-80% 0-9.5min水-甲醇(NH3 0.1%)，流速30mL/min；(裝 載泵4mL/min甲醇(NH3 0.1%))；目標質量438；管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物537 rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.03614g，82.61μmol，32.85%產率)及化合物546 rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.04262g，97.43μmol，38.75%產率)。By HPLC (30-80% 0-9.5 min water-methanol ( NH3 0.1%), flow rate 30 mL/min; (loading pump 4 mL/min methanol ( NH3 0.1%)); target mass 438; column: YMC -Actus Triart C18 100*20mml.DS-5um) as mobile phase) to separate enantiomers to obtain two separate enantiomers compound 537 rel-2-methoxy-5-[[2-[( 2S,5R)-5-Methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (0.03614g, 82.61μmol, 32.85% yield) and compound 546 rel-2-methoxy-5-[[2-[(2R,5S)-5-methyl-2 -(1H-Pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.04262 g , 97.43 μmol, 38.75% yield).

化合物537： 1 H NMR(600MHz,DMSO-d 6 )δ 0.97-1.09(m,3H),1.28-1.43(m,1H),1.69-1.81(m,1H),1.84-1.96(m,1H),2.05-2.23(m,1H),2.23-2.35(m,1H),2.64-3.27(m,1H),3.45-4.04(m,4H),5.27-5.77(m,1H),7.63-7.82(m,2H),8.06-8.22(m,2H),8.39-8.59(m,3H),10.99-11.11(m,1H),13.57-13.67(m,1H)。 Compound 537: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.97-1.09 (m, 3H), 1.28-1.43 (m, 1H), 1.69-1.81 (m, 1H), 1.84-1.96 (m, 1H) ,2.05-2.23(m,1H),2.23-2.35(m,1H),2.64-3.27(m,1H),3.45-4.04(m,4H),5.27-5.77(m,1H),7.63-7.82( m, 2H), 8.06-8.22 (m, 2H), 8.39-8.59 (m, 3H), 10.99-11.11 (m, 1H), 13.57-13.67 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值437.5；實測值438.0；Rt=4.053min。LCMS (ESI): [M+H] + m/z: calculated 437.5; found 438.0; Rt=4.053 min.

RT(IB，CO2-MeOH，70-30，2.0mL/min)=8.8722min。RT (IB, CO2-MeOH, 70-30, 2.0 mL/min) = 8.8722 min.

化合物546： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.07(m,3H),1.28-1.43(m,1H),1.71-1.81(m,1H),1.84-1.95(m,1H),2.07-2.23(m,1H),2.24-2.34(m,1H),2.63-3.26(m,1H),3.47-4.04(m,4H),5.25-5.80(m,1H),7.62-7.81(m,2H),8.03-8.26(m,2H),8.37-8.62(m,3H),10.97-11.12(m,1H),13.57-13.68(m,1H)。 Compound 546: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.07 (m, 3H), 1.28-1.43 (m, 1H), 1.71-1.81 (m, 1H), 1.84-1.95 (m, 1H) ,2.07-2.23(m,1H),2.24-2.34(m,1H),2.63-3.26(m,1H),3.47-4.04(m,4H),5.25-5.80(m,1H),7.62-7.81( m, 2H), 8.03-8.26 (m, 2H), 8.37-8.62 (m, 3H), 10.97-11.12 (m, 1H), 13.57-13.68 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值437.5；實測值438.0；Rt=4.051min。LCMS (ESI): [M+H] + m/z: calculated 437.5; found 438.0; Rt=4.051 min.

RT(IB，CO2-MeOH，70-30，2.0mL/min)=12.1912min。RT (IB, CO2-MeOH, 70-30, 2.0 mL/min) = 12.1912 min.

實例101. 5-[[2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物513)及5-[[2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物512)之合成Example 101. 5-[[2-[(2S,5R)-2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (Compound 513) and 5-[[2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methyl-1- Synthesis of piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 512)

Figure 110128222-A0202-12-1081-121
Figure 110128222-A0202-12-1081-121

步驟1：5-[[2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide

在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(545.17mg，1.76mmol，Et3N)、HATU(667.93mg，1.76mmol)及三乙胺(177.76mg，1.76mmol，244.84μL)混合於無水DMF(5mL)中且將所得混合物攪拌1h。向其中添加2-(3-氯-4-氟苯基)-5-甲基哌啶(0.4g，1.76mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-80% 2-7min；水-r1+nh3；30ml/min；裝載泵4ml/min r1+nh3；管柱SunFire 19*100mm)。獲得兩種級分之5-[[2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(404.2mg，965.03μmol，54.94%產率)：第1級分-95.9mg(92.55%反式)及第2級分-308.3mg(88.21%反式)。At 21 °C, 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (545.17 mg, 1.76 mmol, Et3N), HATU (667.93 mg, 1.76 mmol) and triethylamine (177.76 mg, 1.76 mmol, 244.84 μL) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 1 h. To this was added 2-(3-chloro-4-fluorophenyl)-5-methylpiperidine (0.4 g, 1.76 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-80% 2-7min; water-r1+nh3; 30ml/min; loading pump 4ml/min r1+nh3; column SunFire 19*100mm). 5-[[2-[2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxetyl]amine was obtained in two fractions ] Pyridine-3-carboxamide (404.2 mg, 965.03 μmol, 54.94% yield): Fraction 1 - 95.9 mg (92.55% trans) and Fraction 2 - 308.3 mg (88.21% trans).

LCMS(ESI)：[M+H]+ m/z：計算值418.1；實測值419.2；Rt=3.248min。LCMS (ESI): [M+H] + m/z: calculated 418.1; found 419.2; Rt=3.248 min.

步驟2：5-[[2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物513 )及5-[[2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶Step 2: 5-[[2-[(2S,5R)-2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide ( compound 513 ) and 5-[[2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methyl-1- piperidine 基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物512 )之合成[Synthesis of]-2-oxyacetyl]amino]pyridine-3-carboxamide ( Compound 512 )

掌性分離：IA(100*20,5mkm)，己烷-IPA-MeOH，50-25-25，15ml/min，V(溶劑)=0.225L/注入；V注入=10mL/注入；時間為0.5小時/注入；Rt(化合物513 )=11.9min；Rt(化合物512 )=15.07min；Palm separation: IA (100*20,5mkm), hexane-IPA-MeOH, 50-25-25, 15ml/min, V(solvent)=0.225L/injection; Vinjection=10mL/injection; time 0.5 hours/injection; Rt ( Compound 513 )=11.9 min; Rt ( Compound 512 )=15.07 min;

5-[[2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(36.54mg，87.24μmol，38.10%產率)之RT=7.7912min(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)5-[[2-[(2S,5R)-2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] pyridine-3-carboxamide (36.54 mg, 87.24 μmol, 38.10% yield) RT=7.7912 min (IA-3, hexane-IPA-MeOH, 50-25-25, 0.155 ml/min)

5-[[2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(31.56mg，75.35μmol，32.91%產率)之RT=10.0042min(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)5-[[2-[(2R,5S)-2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] pyridine-3-carboxamide (31.56 mg, 75.35 μmol, 32.91% yield) RT=10.0042 min (IA-3, hexane-IPA-MeOH, 50-25-25, 0.155 ml/min)

化合物512： 1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.05(m,3H),1.25-1.41(m,1H),1.59-1.69(m,1H),1.81-1.95(m,1H),1.99-2.14(m,1H),2.14-2.28(m,1H),2.77-3.24(m,1H),3.46-4.06(m,1H),5.11-5.59(m,1H),7.29-7.38(m,1H),7.38-7.46(m,1H),7.46-7.53(m,1H),7.56-7.66(m,1H),8.08-8.23(m,1H),8.43-8.53(m,1H),8.71-8.81(m,1H),8.81-8.92(m,1H),11.09-11.39(m,1H)。 Compound 512: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.05 (m, 3H), 1.25-1.41 (m, 1H), 1.59-1.69 (m, 1H), 1.81-1.95 (m, 1H) ,1.99-2.14(m,1H),2.14-2.28(m,1H),2.77-3.24(m,1H),3.46-4.06(m,1H),5.11-5.59(m,1H),7.29-7.38( m,1H),7.38-7.46(m,1H),7.46-7.53(m,1H),7.56-7.66(m,1H),8.08-8.23(m,1H),8.43-8.53(m,1H), 8.71-8.81 (m, 1H), 8.81-8.92 (m, 1H), 11.09-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.1；實測值419.2；Rt=2.789min。LCMS (ESI): [M+H] + m/z: calculated 418.1; found 419.2; Rt=2.789 min.

RT(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=10.0042minRT(IA-3, Hexane-IPA-MeOH, 50-25-25, 0.155ml/min)=10.0042min

化合物513： 1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.05(m,3H),1.26-1.39(m,1H),1.61-1.71(m,1H),1.81-1.96(m,1H),2.00-2.14(m,1H),2.14-2.25(m,1H),2.77-3.23(m,1H),3.46-4.04(m,1H),5.08-5.58(m,1H),7.28-7.38(m,1H),7.38-7.46(m,1H),7.46-7.54(m,1H),7.55-7.64(m,1H),8.02-8.22(m,1H),8.37-8.54(m,1H),8.71-8.80(m,1H),8.81-8.95(m,1H),11.01-11.49(m,1H)。 Compound 513: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.05 (m, 3H), 1.26-1.39 (m, 1H), 1.61-1.71 (m, 1H), 1.81-1.96 (m, 1H) ,2.00-2.14(m,1H),2.14-2.25(m,1H),2.77-3.23(m,1H),3.46-4.04(m,1H),5.08-5.58(m,1H),7.28-7.38( m,1H),7.38-7.46(m,1H),7.46-7.54(m,1H),7.55-7.64(m,1H),8.02-8.22(m,1H),8.37-8.54(m,1H), 8.71-8.80 (m, 1H), 8.81-8.95 (m, 1H), 11.01-11.49 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.1；實測值419.2；Rt=2.787min。LCMS (ESI): [M+H] + m/z: calculated 418.1; found 419.2; Rt=2.787 min.

RT(IA-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=7.7912minRT(IA-3, Hexane-IPA-MeOH, 50-25-25, 0.155ml/min)=7.7912min

實例102. 5-[[2-[(2S,5R)-2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物488)及5-[[2-[(2R,5S)-2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物489)之合成Example 102. 5-[[2-[(2S,5R)-2-(3,4-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (Compound 488) and 5-[[2-[(2R,5S)-2-(3,4-dichlorophenyl)-5-methyl-1-piperidine Synthesis of [methyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 489)

Figure 110128222-A0202-12-1083-122
Figure 110128222-A0202-12-1083-122

步驟1：5-[[2-[2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(-[[2-[2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(3,4-Dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -Carboxyamide (-[[2-[2-(3,4-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide

將DIPEA(762.25mg，5.90mmol，1.03mL)添加到相應2-(3,4-二氯苯基)-5-甲基哌啶(0.36g，1.47mmol)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(308.39mg，1.26mmol，HCl)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(616.69mg，1.62mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min 40-60%水/乙腈+NH3 (裝載泵4ml)管柱：TRIART 100*20 5微米)，以得到純的5-[[2-[2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.43g，987.82μmol，67.00%產率)。DIPEA (762.25 mg, 5.90 mmol, 1.03 mL) was added to the corresponding 2-(3,4-dichlorophenyl)-5-methylpiperidine (0.36 g, 1.47 mmol) and 2-[(5-aminomethane) Acyl-3-pyridyl)amino]-2-pendoxoacetic acid (308.39 mg, 1.26 mmol, HCl) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (616.69 mg, 1.62 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 40-60% water/acetonitrile + NH3 (loading pump 4 ml) column: TRIART 100*20 5 microns) to give pure 5-[[2-[2- (3,4-Dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.43 g, 987.82 μmol, 67.00 %Yield).

1 H NMR(400MHz,DMSO)1.03(d,3H),1.23(m,1H),1.62(m,1H),2.10(m,3H),2.39(s,3H),4.10(m,1H),2.35(m,1H),7.38(s,1H),7.61(d,1H),8.10(d,1H),8.28(s,1H),8.52(s,1H),8.92(s,1H),11.30(s,1H)。 1 H NMR (400MHz, DMSO) 1.03(d,3H), 1.23(m,1H), 1.62(m,1H), 2.10(m,3H), 2.39(s,3H), 4.10(m,1H), 2.35(m, 1H), 7.38(s, 1H), 7.61(d, 1H), 8.10(d, 1H), 8.28(s, 1H), 8.52(s, 1H), 8.92(s, 1H), 11.30 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值434.1；實測值435.2；Rt=3.547min。LCMS (ESI): [M+H] + m/z: calculated 434.1; found 435.2; Rt=3.547 min.

步驟2：5-[[2-[(2S,5R)-2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物488 )及5-[[2-[(2R,5S)-2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物489 )之合成Step 2: 5-[[2-[(2S,5R)-2-(3,4-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide ( Compound 488 ) and 5-[[2-[(2R,5S)-2-(3,4-dichlorophenyl)-5-methyl-1-piperidine [Synthesis of]-2-oxoacetyl]amino]pyridine-3-carboxamide ( compound 489 )

對5-[[2-[2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.43g，987.82μmol)進行掌性分離，得到化合物489 rel-5-[[2-[(2R,5S)-2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(125.57mg，29.20%產率)及化合物488 rel-5-[[2-[(2S,5R)-2-(3,4-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(132.39mg，30.79%產率)。p-5-[[2-[2-(3,4-Dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Chiral separation of amide (0.43 g, 987.82 μmol) afforded compound 489 rel-5-[[2-[(2R,5S)-2-(3,4-dichlorophenyl)-5-methyl- 1-Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (125.57 mg, 29.20% yield) and compound 488 rel-5-[[2-[(2S, 5R)-2-(3,4-Dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (132.39mg , 30.79% yield).

掌性分離條件：Chiralpak IA(250* 30mm，5mkm)；己烷-IPA-MeOH，50-25-25。Chiral separation conditions: Chiralpak IA (250 * 30mm, 5mkm); Hexane-IPA-MeOH, 50-25-25.

流速：28mL/min；管柱溫度：21℃；波長：205nm。保留時間(異構物A)=12.85min；保留時間(異構物B)=13.87min；保留時間(異構物C)=16.97min；保留時間(異構物D)=24.58minFlow rate: 28 mL/min; column temperature: 21°C; wavelength: 205 nm. Retention time (Isomer A)=12.85min; Retention time (Isomer B)=13.87min; Retention time (Isomer C)=16.97min; Retention time (Isomer D)=24.58min

化合物488： 1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.04(m,3H),1.26-1.38(m,1H),1.59-1.68(m,1H),1.82-1.95(m,1H),1.99-2.12(m,1H),2.13-2.25(m,1H),2.75-3.27(m,1H),3.42-4.05(m,1H),5.12-5.56(m,1H),7.26-7.36(m,1H),7.51-7.56(m,1H),7.5-7.62(m,1H),7.62-7.68(m,1H),8.09-8.19(m,1H),8.42-8.52(m,1H),8.71-8.80(m,1H),8.81-8.91(m,1H),11.21-11.39(m,1H)。 Compound 488: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.04 (m, 3H), 1.26-1.38 (m, 1H), 1.59-1.68 (m, 1H), 1.82-1.95 (m, 1H) ,1.99-2.12(m,1H),2.13-2.25(m,1H),2.75-3.27(m,1H),3.42-4.05(m,1H),5.12-5.56(m,1H),7.26-7.36( m,1H),7.51-7.56(m,1H),7.5-7.62(m,1H),7.62-7.68(m,1H),8.09-8.19(m,1H),8.42-8.52(m,1H), 8.71-8.80 (m, 1H), 8.81-8.91 (m, 1H), 11.21-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值434.1；實測值435.0；Rt=1.324min。LCMS (ESI): [M+H] + m/z: calculated 434.1; found 435.0; Rt=1.324 min.

RT(己烷-IPA-MeOH，50-25-25，0.155ml/min)=14.85min。RT (Hexane-IPA-MeOH, 50-25-25, 0.155 ml/min) = 14.85 min.

化合物489： 1 H NMR(600MHz,DMSO-d 6 )δ 0.94-1.04(m,3H),1.24-1.40(m,1H),1.56-1.71(m,1H),1.83-1.96(m,1H),2.00-2.13(m,1H),2.14-2.25(m,1H),2.75-3.27(m,1H),3.45-4.08(m,1H),5.13-5.59(m,1H),7.27-7.36(m,1H),7.51-7.57(m,1H),7.57-7.62(m,1H),7.62-7.68(m,1H),8.09-8.19(m,1H),8.42-8.52(m,1H),8.70-8.80(m,1H),8.80-8.92(m,1H),11.13-11.37(m,1H)。 Compound 489: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.94-1.04 (m, 3H), 1.24-1.40 (m, 1H), 1.56-1.71 (m, 1H), 1.83-1.96 (m, 1H) ,2.00-2.13(m,1H),2.14-2.25(m,1H),2.75-3.27(m,1H),3.45-4.08(m,1H),5.13-5.59(m,1H),7.27-7.36( m,1H),7.51-7.57(m,1H),7.57-7.62(m,1H),7.62-7.68(m,1H),8.09-8.19(m,1H),8.42-8.52(m,1H), 8.70-8.80 (m, 1H), 8.80-8.92 (m, 1H), 11.13-11.37 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值434.1；實測值435.2；Rt=1.325min。LCMS (ESI): [M+1] + m/z: calculated 434.1; found 435.2; Rt=1.325 min.

RT(己烷-IPA-MeOH，50-25-25，0.155ml/min)=9.49min。RT (Hexane-IPA-MeOH, 50-25-25, 0.155 ml/min) = 9.49 min.

實例103. 5-[[2-[(2S,SR)-2-(3-氯-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物484)及5-[[2-[(2R,5S)-2-(3-氯-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物485)之合成Example 103. 5-[[2-[(2S,SR)-2-(3-Chloro-4-methylphenyl)-5-methyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide (Compound 484) and 5-[[2-[(2R,5S)-2-(3-chloro-4-methylphenyl)-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carboxamide (Compound 485)

Figure 110128222-A0202-12-1085-123
Figure 110128222-A0202-12-1085-123

步驟1：5-[[2-[2-(3-氯-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(3-Chloro-4-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -Synthesis of 3-formamide

將DIPEA(554.54mg，4.29mmol，747.36μL)添加到相應2-(3-氯-4-甲基苯基)-5-甲基哌啶(0.24g，1.07mmol)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(263.47mg，1.07mmol，HCl)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(448.65mg，1.18mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters SunFire C18 19*100mm 5mkm管柱，以己烷-MeOH 50-50為流動相，流速12mL/min)，以得到5-[[2-[2-(3-氯-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]哌啶-3-甲醯胺(0.349g，841.20μmol，78.42%產率)。DIPEA (554.54 mg, 4.29 mmol, 747.36 μL) was added to the corresponding 2-(3-chloro-4-methylphenyl)-5-methylpiperidine (0.24 g, 1.07 mmol) and 2-[(5- Aminocarboxy-3-pyridyl)amino]-2-pendoxoacetic acid (263.47 mg, 1.07 mmol, HCl) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (448.65 mg, 1.18 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters SunFire C18 19*100mm 5mkm column with hexane-MeOH 50-50 as mobile phase, flow rate 12mL/min) to give 5-[[2-[2-(3- Chloro-4-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]piperidine-3-carboxamide (0.349 g, 841.20 μmol, 78.42 %Yield).

LCMS(ESI)：[M+H]+ m/z：計算值414.1；實測值415.2；Rt=3.513min。LCMS (ESI): [M+H] + m/z: calculated 414.1; found 415.2; Rt=3.513 min.

步驟2：5-[[2-[(2S,5R)-2-(3-氯-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物484 )及5-[[2-[(2R,5S)-2-(3-氯-4-甲基苯基)-5-甲基-1-Step 2: 5-[[2-[(2S,5R)-2-(3-Chloro-4-methylphenyl)-5-methyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide ( compound 484 ) and 5-[[2-[(2R,5S)-2-(3-chloro-4-methylphenyl)-5-methyl- 1- 哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物485 )之合成Synthesis of piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 485 )

管柱：IA(100* 20mm，5mkm)Chiralpak管柱；反相及梯度：己烷-IPA-MeOH，50-25-25，15.0mL/minColumn: IA (100 * 20mm, 5mkm) Chiralpak column; reverse phase and gradient: Hexane-IPA-MeOH, 50-25-25, 15.0 mL/min

5-[[2-[(2R,5S)-2-(3-氯-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(64.53mg，18.49%產率)化合物485 於分析條件下之保留時間46.81min5-[[2-[(2R,5S)-2-(3-Chloro-4-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (64.53 mg, 18.49% yield) Retention time of compound 485 under analytical conditions 46.81 min

5-[[2-[(2S,5R)-2-(3-氯-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(62.68mg，17.96%產率)化合物484 於分析條件下之保留時間15.45min化合物485： RT(IA，己烷-IPa-MeOH，50-25-25，0.6mL/min)=46.840min。5-[[2-[(2S,5R)-2-(3-Chloro-4-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (62.68 mg, 17.96% yield) Compound 484 Retention time under analytical conditions 15.45 min Compound 485: RT(IA, Hexane-IPa-MeOH, 50-25-25, 0.6 mL/min)=46.840min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.04(m,3H),1.26-1.39(m,1H),1.60-1.69(m,1H),1.81-1.93(m,1H),1.97-2.13(m,1H),2.14-2.23(m,1H),2.25-2.32(m,3H),2.75-3.25(m,1H),3.43-4.05(m,1H),5.08-5.58(m,1H),7.16-7.24(m,1H),7.28-7.40(m,2H),7.54-7.66(m,1H),8.10-8.20(m,1H),8.42-8.52(m,1H),8.72-8.79(m,1H),8.80-8.93(m,1H),11.11-11.46(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.04(m,3H), 1.26-1.39(m,1H), 1.60-1.69(m,1H), 1.81-1.93(m,1H), 1.97- 2.13(m,1H), 2.14-2.23(m,1H), 2.25-2.32(m,3H), 2.75-3.25(m,1H), 3.43-4.05(m,1H), 5.08-5.58(m,1H) ),7.16-7.24(m,1H),7.28-7.40(m,2H),7.54-7.66(m,1H),8.10-8.20(m,1H),8.42-8.52(m,1H),8.72-8.79 (m, 1H), 8.80-8.93 (m, 1H), 11.11-11.46 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.2；Rt=1.324min。LCMS (ESI): [M+H] + m/z: calculated 414.2; found 415.2; Rt=1.324 min.

化合物484： RT(IA，己烷-IPa-MeOH，50-25-25，0.6mL/min)=15.499min。 Compound 484: RT (IA, Hexane-IPa-MeOH, 50-25-25, 0.6 mL/min) = 15.499 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.05(m,3H),1.24-1.36(m,1H),1.58-1.69(m,1H),1.80-1.94(m,1H),1.96-2.14(m,1H),2.14-2.22(m,1H),2.26-2.32(m,3H),2.74-3.25(m,1H),3.43-4.05(m,1H),5.10-5.58(m,1H),7.15-7.24(m,1H),7.28-7.40(m,2H),7.51-7.64(m,1H),8.08-8.21(m,1H),8.40-8.52(m,1H),8.69-8.80(m,1H),8.80-8.92(m,1H),11.05-11.44(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.05(m,3H), 1.24-1.36(m,1H), 1.58-1.69(m,1H), 1.80-1.94(m,1H), 1.96- 2.14(m,1H), 2.14-2.22(m,1H), 2.26-2.32(m,3H), 2.74-3.25(m,1H), 3.43-4.05(m,1H), 5.10-5.58(m,1H) ),7.15-7.24(m,1H),7.28-7.40(m,2H),7.51-7.64(m,1H),8.08-8.21(m,1H),8.40-8.52(m,1H),8.69-8.80 (m, 1H), 8.80-8.92 (m, 1H), 11.05-11.44 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.2；Rt=1.325min。LCMS (ESI): [M+H] + m/z: calculated 414.2; found 415.2; Rt=1.325 min.

實例104. 5-[[2-[(2R ,5S )-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基1-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S ,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶Example 104. 5-[[2-[( 2R , 5S )-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl 1-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide and 5-[[2-[( 2S ,5R)-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidine pyridine 基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物534及化合物519)之合成[Synthesis of]-2-oxyacetyl]amino]pyridine-3-carboxamide (Compound 534 and Compound 519)

Figure 110128222-A0202-12-1087-124
Figure 110128222-A0202-12-1087-124

在輕微加熱下，將2-甲基-4-(5-甲基-2-哌啶基)吡啶(0.3g，1.58mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(Et3 N鹽，362.73mg，1.73mmol)及DIPEA(611.28mg，4.73mmol，823.82μL)溶解於DMF(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(719.36mg，1.89mmol)。將反應混合物在50℃下攪拌3小時。完成之後，藉由反相HPLC(溶析液：水-乙腈，10% 0.5-6.5min；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱SunFire 19*100mm，5um)及掌性HPLC(管柱：Chiralpak AD-H(250 x 20mm x 5um)；流動相：己烷-IPA-MeOH，60-20-20；流速：12mL/min)純化反應混合物，以得到呈白色固體之5-[[2-[(2R ,5S )-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物534 ，80mg，209.74μmol，13.30%產率)及5-[[2-[(2S ,5R )-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物519 ，90mg，235.96μmol，14.97%產率)。2-Methyl-4-(5-methyl-2-piperidinyl)pyridine (0.3 g, 1.58 mmol), 2-[(5-aminocarbamoyl-3-pyridyl) Amino]-2-oxoacetic acid ( Et3N salt, 362.73 mg, 1.73 mmol) and DIPEA (611.28 mg, 4.73 mmol, 823.82 μL) were dissolved in DMF (6 mL). With vigorous stirring and occasional heating, HATU (719.36 mg, 1.89 mmol) was added in small batches. The reaction mixture was stirred at 50°C for 3 hours. After completion, by reverse phase HPLC (eluent: water-acetonitrile, 10% 0.5-6.5min; flow rate: 30mL/min; loading pump: 4mL/min, acetonitrile; column SunFire 19*100mm, 5um) and palm The reaction mixture was purified by HPLC (column: Chiralpak AD-H (250 x 20mm x 5um); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12 mL/min) to give as a white solid 5-[[2-[(2 R ,5 S )-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide ( compound 534 , 80 mg, 209.74 μmol, 13.30% yield) and 5-[[2-[(2S, 5R )-5-methyl-2-(2- Methyl-4-pyridyl)-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide ( compound 519 , 90 mg, 235.96 μmol, 14.97% yield).

化合物534： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.56(m,1H),2.06(m,3H),2.44(s,2H),2.77(m,0.4H),3.23(m,0.6H),3.51(m,0.6H),4.06(d,0.4H),5.17(s,0.4H),5.52(s,0.6H),7.14(m,2H),7.59(m,1H),8.14(m,1H),8.44(m,2H),8.82(m,2H),11.25(m,1H)。 Compound 534: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.56 (m, 1H), 2.06 (m, 3H), 2.44 (s ,2H),2.77(m,0.4H),3.23(m,0.6H),3.51(m,0.6H),4.06(d,0.4H),5.17(s,0.4H),5.52(s,0.6H) ), 7.14(m, 2H), 7.59(m, 1H), 8.14(m, 1H), 8.44(m, 2H), 8.82(m, 2H), 11.25(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=2.926min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=2.926 min.

掌性HPLC：Rt=33.14min(管柱：AD-H；溶析液：己烷-IPA-MeOH，60-20-20；流速：0.6mL/min)。Chiral HPLC: Rt=33.14 min (column: AD-H; eluent: hexane-IPA-MeOH, 60-20-20; flow rate: 0.6 mL/min).

化合物519： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.56(m,1H),2.06(m,3H),2.44(s,2H),2.77(m,0.4H),3.23(m,0.6H),3.51(m,0.6H),4.06(d,0.4H),5.17(s,0.4H),5.52(s,0.6H),7.14(m,2H),7.59(m,1H),8.14(m,1H),8.44(m,2H),8.82(m,2H),11.25(m,1H)。 Compound 519: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.56 (m, 1H), 2.06 (m, 3H), 2.44 (s ,2H),2.77(m,0.4H),3.23(m,0.6H),3.51(m,0.6H),4.06(d,0.4H),5.17(s,0.4H),5.52(s,0.6H) ), 7.14(m, 2H), 7.59(m, 1H), 8.14(m, 1H), 8.44(m, 2H), 8.82(m, 2H), 11.25(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=2.922min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=2.922 min.

掌性HPLC：Rt=19.89min(管柱：AD-H；溶析液：己烷-IPA-MeOH，60-20-20；流速：0.6mL/min)。Chiral HPLC: Rt=19.89 min (column: AD-H; eluent: hexane-IPA-MeOH, 60-20-20; flow rate: 0.6 mL/min).

實例105. 外消旋-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物524)、5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-3-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物626)及5-[[2-[(2R,5S)-5-甲基-2-[4-(1H-吡唑-3-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物627)之合成Example 105. Racemic-5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 524), 5-[[2-[(2S,5R)-5-methyl-2-[4-(1H -Pyrazol-3-yl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 626) and 5-[[2-[ (2R,5S)-5-Methyl-2-[4-(1H-pyrazol-3-yl)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine -Synthesis of 3-formamide (compound 627)

Figure 110128222-A0202-12-1088-125
Figure 110128222-A0202-12-1088-125

步驟1：外消旋-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物524 )之合成Step 1: Racemic-5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide (compound 524 )

向(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]哌啶(125mg，397.77μmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(97.70mg，397.77 μmol，HCl)及三乙胺(241.50mg，2.39mmol，332.65μL)之溶液中分批添加HATU(166.37mg，437.55μmol)。將所得混合物在25℃下攪拌3h且使其經歷HPLC：30-30-70% 0-1-6min水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)，以得到5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(92mg，212.73μmol，53.48%產率)。To (2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]piperidine (125 mg, 397.77 μmol, 2HCl), 2-[(5-aminocarboxylate HATU (166.37 mg) was added portion-wise to a solution of triethylamine (241.50 mg, 2.39 mmol, 332.65 μL) in a solution of yl-3-pyridyl)amino]-2-oxoacetic acid (97.70 mg, 397.77 μmol, HCl) and triethylamine (241.50 mg, 2.39 mmol, 332.65 μL). , 437.55 μmol). The resulting mixture was stirred at 25°C for 3 h and subjected to HPLC: 30-30-70% 0-1-6 min water-methanol (NH 3 0.1%), flow rate 30 ml/min (load pump 4 ml/min methanol (NH 3 ) 0.1%)) column: YMC-Actus Triart C18 100*20mml.DS-5um) to get 5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyridine) oxazol-5-yl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (92 mg, 212.73 μmol, 53.48% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.06(m,3H),1.29-1.43(m,1H),1.65-1.76(m,1H),1.79-1.97(m,1H),2.02-2.16(m,1H),2.16-2.30(m,1H),2.75-3.27(m,1H),3.47-4.07(m,1H),5.13-5.65(m,1H),6.66-6.73(m,1H),7.32-7.39(m,2H),7.39-7.98(m,5H),8.07-8.23(m,1H),8.44-8.53(m,1H),8.65-8.80(m,1H),8.82-8.96(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.00-1.06(m,3H), 1.29-1.43(m,1H), 1.65-1.76(m,1H), 1.79-1.97(m,1H), 2.02- 2.16(m, 1H), 2.16-2.30(m, 1H), 2.75-3.27(m, 1H), 3.47-4.07(m, 1H), 5.13-5.65(m, 1H), 6.66-6.73(m, 1H ),7.32-7.39(m,2H),7.39-7.98(m,5H),8.07-8.23(m,1H),8.44-8.53(m,1H),8.65-8.80(m,1H),8.82-8.96 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值432.2；實測值433.2；Rt=2.020min。LCMS (ESI): [M+H] + m/z: calculated 432.2; found 433.2; Rt=2.020 min.

步驟2：5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-3-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物626 )及5-[[2-[(2R,5S)-5-甲基-2-[4-(1H-吡唑-3-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物627 )之合成Step 2: 5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-3-yl)phenyl]-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (compound 626 ) and 5-[[2-[(2R,5S)-5-methyl-2-[4-(1H-pyrazole- Synthesis of 3-yl)phenyl]-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide ( compound 627 )

5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-3-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(82.7mg，191.23μmol)(化合物524 )之掌性分離使用Chiralpak IC(250* 20mm，5mkm)管柱(191.23μmol)，以己烷-IPA-MeOH，50-25-25為流動相；流速：12mL/min；管柱溫度：21℃；波長：205nm進行，得到化合物626 rel-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-3-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(19.1mg，44.16μmol，23.10%產率)(保留時間=138.94min)及化合物627 rel-5-[[2-[(2R,5S)-5-甲基-2-[4-(1H-吡唑-3-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(22.03mg，50.94μmol，26.64%產率)(保留時間(異構物B)=158.77min)。5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-3-yl)phenyl]-1-piperidinyl]-2-side oxyethyl Chiral separation of acyl]amino]pyridine-3-carboxamide (82.7 mg, 191.23 μmol) (compound 524 ) using a Chiralpak IC (250 * 20 mm, 5 mkm) column (191.23 μmol) in hexane-IPA -MeOH, 50-25-25 is the mobile phase; flow rate: 12 mL/min; column temperature: 21 °C; wavelength: 205 nm to obtain compound 626 rel-5-[[2-[(2S,5R)-5- Methyl-2-[4-(1H-pyrazol-3-yl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (19.1 mg, 44.16 μmol, 23.10% yield) (retention time=138.94 min) and compound 627 rel-5-[[2-[(2R,5S)-5-methyl-2-[4-(1H-pyrazole -3-yl)phenyl]-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (22.03 mg, 50.94 μmol, 26.64% yield) (retention time) (Isomer B) = 158.77 min).

化合物626： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.06(m,3H),1.29-1.43(m,1H),1.64-1.76(m,1H),1.83-1.96(m,1H),2.00-2.19(m,1H),2.20-2.31(m,1H),2.77-3.28(m,1H),3.45-4.08(m,1H),5.15-5.67(m,1H),6.62-6.74(m,1H),7.29-7.41(m,2H),7.41-7.61(m,1H),7.61-7.79(m,2H),7.80-7.85(m,1H),8.08-8.21(m,1H),8.43-8.53(m,1H),8.72-8.79(m,1H),8.83-8.94(m,1H),11.20-11.39(m,1H),12.75-13.38(m,1H)。 Compound 626: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.06 (m, 3H), 1.29-1.43 (m, 1H), 1.64-1.76 (m, 1H), 1.83-1.96 (m, 1H) ,2.00-2.19(m,1H),2.20-2.31(m,1H),2.77-3.28(m,1H),3.45-4.08(m,1H),5.15-5.67(m,1H),6.62-6.74( m,1H),7.29-7.41(m,2H),7.41-7.61(m,1H),7.61-7.79(m,2H),7.80-7.85(m,1H),8.08-8.21(m,1H), 8.43-8.53(m,1H), 8.72-8.79(m,1H), 8.83-8.94(m,1H), 11.20-11.39(m,1H), 12.75-13.38(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值432.2；實測值433.2；Rt=2.311min。LCMS (ESI): [M+H] + m/z: calculated 432.2; found 433.2; Rt=2.311 min.

RT(己烷-IPA-MeOH，50-25-25，12ml/min)=10.3252min。RT (Hexane-IPA-MeOH, 50-25-25, 12 ml/min) = 10.3252 min.

化合物627： 1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.06(m,3H),1.31-1.41(m,1H),1.65-1.75(m,1H),1.83-1.95(m,1H),2.01-2.19(m,1H),2.20-2.30(m,1H),2.76-3.28(m,1H),3.44-4.07(m,1H),5.14-5.65(m,1H),6.65-6.73(m,1H),7.32-7.43(m,2H),7.48-7.62(m,1H),7.62-7.76(m,1H),7.75-7.86(m,2H),8.08-8.22(m,1H),8.41-8.54(m,1H),8.66-8.81(m,1H),8.84-8.98(m,1H),11.15-11.40(m,1H),12.79-13.30(m,1H)。 Compound 627: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.01-1.06 (m, 3H), 1.31-1.41 (m, 1H), 1.65-1.75 (m, 1H), 1.83-1.95 (m, 1H) ,2.01-2.19(m,1H),2.20-2.30(m,1H),2.76-3.28(m,1H),3.44-4.07(m,1H),5.14-5.65(m,1H),6.65-6.73( m,1H),7.32-7.43(m,2H),7.48-7.62(m,1H),7.62-7.76(m,1H),7.75-7.86(m,2H),8.08-8.22(m,1H), 8.41-8.54(m,1H), 8.66-8.81(m,1H), 8.84-8.98(m,1H), 11.15-11.40(m,1H), 12.79-13.30(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值432.2；實測值433.2；Rt=2.316min。LCMS (ESI): [M+H] + m/z: calculated 432.2; found 433.2; Rt=2.316 min.

RT(己烷-IPA-MeOH，50-25-25，12ml/min)=6.410min。RT (Hexane-IPA-MeOH, 50-25-25, 12 ml/min) = 6.410 min.

實例106. 5-(2-(2-(3-羥基-4-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物554)之合成Example 106. 5-(2-(2-(3-Hydroxy-4-methylphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of (Compound 554)

Figure 110128222-A0202-12-1090-126
Figure 110128222-A0202-12-1090-126

向2-甲基-5-[(2S,5R )-5-甲基-2-哌啶基]苯酚(299.37mg，1.46mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(358.18mg，1.15mmol，Et3 N) 及TEA(1.03g，10.21mmol，1.42mL)於DMF(5mL)中之溶液中分批添加HATU(609.92mg，1.60mmol)。將混合物在25℃下攪拌2h。將反應混合物提交用於HPLC(20-20-70% 0-1-6min 0.1%NH3 -MeOH，流速：30ml/min(裝載泵4ml/min MeOH)，目標質量396，管柱：YMC Triart C18 100x20mm，5um)，以得到5-[[2-[(2S,5R )-2-(3-羥基-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(48mg，121.08μmol，8.30%產率)。產物含有6%順式異構物。To 2-methyl-5-[( 2S,5R )-5-methyl-2-piperidinyl]phenol (299.37 mg, 1.46 mmol, HCl), 2-[(5-aminocarbamoyl-3- Pyridyl)amino]-2-oxoacetic acid (358.18 mg, 1.15 mmol, Et3N ) and TEA (1.03 g, 10.21 mmol, 1.42 mL) in DMF (5 mL) was added portionwise HATU ( 609.92 mg, 1.60 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was submitted for HPLC (20-20-70% 0-1-6 min 0.1% NH3 -MeOH, flow rate: 30 ml/min (loading pump 4 ml/min MeOH), target mass 396, column: YMC Triart C18 100x20mm, 5um) to give 5-[[2-[( 2S,5R )-2-(3-hydroxy-4-methylphenyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (48 mg, 121.08 μmol, 8.30% yield). The product contained 6% cis isomer.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94-1.07(m,3H),1.25-1.35(m,1H),1.66-1.73(m,1H),1.79-1.91(m,1H),1.92-2.04(m,1H),2.04-2.09(m,4H),2.78-3.24(m,1H),3.48-4.06(m,1H),5.04-5.56(m,1H),6.61-6.69(m,1H),6.70-6.82(m,1H),7.00-7.08(m,1H),7.52-7.65(m,1H),8.07-8.23(m,1H),8.38-8.54(m,1H),8.67-8.80(m,1H),8.82-8.96(m,1H),9.16-9.30(m,1H),11.01-11.37(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.94-1.07(m,3H), 1.25-1.35(m,1H), 1.66-1.73(m,1H), 1.79-1.91(m,1H) ,1.92-2.04(m,1H),2.04-2.09(m,4H),2.78-3.24(m,1H),3.48-4.06(m,1H),5.04-5.56(m,1H),6.61-6.69( m,1H),6.70-6.82(m,1H),7.00-7.08(m,1H),7.52-7.65(m,1H),8.07-8.23(m,1H),8.38-8.54(m,1H), 8.67-8.80(m,1H), 8.82-8.96(m,1H), 9.16-9.30(m,1H), 11.01-11.37(m,1H).

LCMS(ESI)：[M]+ m/z：計算值396.4；實測值397.2；Rt=2.351min。LCMS (ESI): [M] + m/z: calculated 396.4; found 397.2; Rt=2.351 min.

實例107. 5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物883)及5-[[2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物897)之合成Example 107. 5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (Compound 883) and 5-[[2-[(2R,5S)-2-(1H-indazol-4-yl)-5-methyl-1-piperidine [Synthesis of]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 897)

Figure 110128222-A0202-12-1091-127
Figure 110128222-A0202-12-1091-127

步驟1：5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Synthesis of Amino]Pyridine-3-Carboxyamide

向4-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(475mg，1.32mmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(275.77mg，1.12mmol，HCl)及三乙胺(667.07mg，6.59mmol，918.83μL)於二甲基甲醯胺(4mL)中之經攪拌之混合物中添加HATU(551.45mg，1.45mmol)。將所得反應混合物在20℃下攪拌4h。然後， 使其經歷HPLC(30-30-60% 0-1-6min H2 O/MeOH/0.1% NH4OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(100mg，246.04μmol，18.66%產率)。To 4-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (475 mg, 1.32 mmol, 2HCl), 2-[(5-aminocarbamoyl-3-pyridyl )amino]-2-oxoacetic acid (275.77 mg, 1.12 mmol, HCl) and triethylamine (667.07 mg, 6.59 mmol, 918.83 μL) a stirred mixture in dimethylformamide (4 mL) To this was added HATU (551.45 mg, 1.45 mmol). The resulting reaction mixture was stirred at 20 °C for 4 h. It was then subjected to HPLC (30-30-60% 0-1-6 min H2O /MeOH/0.1% NH4OH, flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 5-[[ 2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]pyridine-3- Formamide (100 mg, 246.04 μmol, 18.66% yield).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=2.098min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=2.098 min.

步驟2：5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物883 )及5-[[2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物897 )之合成Step 2: 5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoethanoyl] Amino]pyridine-3-carboxamide (Compound 883 ) and 5-[[2-[(2R,5S)-2-(1H-indazol-4-yl)-5-methyl-1-piperidine [Synthesis of]-2-oxyacetyl]amino]pyridine-3-carboxamide (compound 897 )

藉由掌性HPLC(管柱：Chiralpak IA-I(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25，流速：12mL/min；5次注入，2mg/注入V=3,5L，時間5,5h.)將5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(10mg，24.60μmol)分成鏡像異構物，得到：化合物883 5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(3.5mg，8.61μmol，70.00%產率)(其中保留時間=35.174min)及化合物897 5-[[2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(3mg，7.38μmol，60.00%產率)(其中保留時間=42.954min)。By chiral HPLC (column: Chiralpak IA-I (250*20mm, 5mkm); mobile phase: Hexane-IPA-MeOH 50-25-25, flow rate: 12mL/min; 5 injections, 2mg/injection V =3,5L, time 5,5h.) 5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (10 mg, 24.60 μmol) split into enantiomers to give: compound 883 5-[[2-[(2S,5R)-2- (1H-Indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (3.5 mg, 8.61 μmol, 70.00 % yield) (wherein retention time=35.174 min) and compound 897 5-[[2-[(2R,5S)-2-(1H-indazol-4-yl)-5-methyl-1-piperidine yl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (3 mg, 7.38 μmol, 60.00% yield) (wherein retention time = 42.954 min).

化合物883： LCMS(ESI)：[M+H]+ m/z：計算值406.4；實測值407.4；Rt=3.303min。 Compound 883: LCMS (ESI): [M+H] + m/z: calcd 406.4; found 407.4; Rt=3.303 min.

RT(己烷-IPA-MeOH，50-25-25，12ml/min)=25.1832min。RT (Hexane-IPA-MeOH, 50-25-25, 12 ml/min) = 25.1832 min.

化合物897： LCMS(ESI)：[M+H]+ m/z：計算值406.4；實測值407.4；Rt=3.287min。 Compound 897: LCMS (ESI): [M+H] + m/z: calcd 406.4; found 407.4; Rt=3.287 min.

RT(己烷-IPA-MeOH，50-25-25，12ml/min)=35.4262min。RT (Hexane-IPA-MeOH, 50-25-25, 12 ml/min) = 35.4262 min.

實例108. 5-[[2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物918)及5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-Example 108. 5-[[2-[(2R,5S)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-2-methoxypyridine-3-carboxamide (Compound 918) and 5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5- 甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物926)之合成Synthesis of Methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (Compound 926)

Figure 110128222-A0202-12-1093-128
Figure 110128222-A0202-12-1093-128

步驟1：5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Synthesis of Amino]-2-methoxypyridine-3-carboxamide

向4-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(475mg，1.32mmol，2HCl)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(315.35mg，1.32mmol)及三乙胺(667.07mg，6.59mmol，918.83μL)於二甲基甲醯胺(4mL)中之經攪拌之混合物中添加HATU(551.45mg，1.45mmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(20-20-50% 0-1-6min H2 O/MeCN/0.1% NH4OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(135mg，309.30μmol，23.46%產率)。To 4-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (475 mg, 1.32 mmol, 2HCl), 2-[(5-aminocarbamoyl-6-methoxy (315.35 mg, 1.32 mmol) and triethylamine (667.07 mg, 6.59 mmol, 918.83 μL) in dimethylformamide (4 mL) To the stirred mixture was added HATU (551.45 mg, 1.45 mmol). The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (20-20-50% 0-1-6 min H2O /MeCN/0.1% NH4OH, flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 5-[[ 2-[(2S,5R)-2-(1H-Indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]-2-methyl Oxypyridine-3-carboxamide (135 mg, 309.30 μmol, 23.46% yield).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.0；Rt=2.420min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.0; Rt=2.420 min.

步驟2：5-[[2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基-吡啶-3-甲醯胺(化合物918 )及5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物926 )之合成Step 2: 5-[[2-[(2R,5S)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoethanoyl] Amino]-2-methoxy-pyridine-3-carboxamide ( compound 918 ) and 5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5- Synthesis of methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 926 )

藉由掌性HPLC(管柱：Chiralpak IB(250 * 30mm，5mkm)；流動相： CO2-MeOH，60-40；流速：80mL/min；管柱溫度：40℃；波長：215nm.)將5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(135mg，309.30μmol)分成鏡像異構物，得到：化合物926 5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(25mg，57.28μmol，37.04%產率)(其中保留時間=7.46min)及化合物918 5-[[2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(24mg，54.99μmol，35.56%產率)(其中保留時間=9.87min)。5 was separated by chiral HPLC (column: Chiralpak IB (250*30mm, 5mkm); mobile phase: CO2-MeOH, 60-40; flow rate: 80mL/min; column temperature: 40°C; wavelength: 215nm.). -[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]- 2-Methoxypyridine-3-carboxamide (135 mg, 309.30 μmol) was split into enantiomers to give: Compound 926 5-[[2-[(2S,5R)-2-(1H-indazole-4 -yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (25 mg, 57.28 μmol, 37.04% yield rate) (wherein retention time=7.46min) and compound 918 5-[[2-[(2R,5S)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (24 mg, 54.99 μmol, 35.56% yield) (wherein retention time = 9.87 min).

化合物918： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.03(m,3H),1.34(m,1H), 1.87(m,2H),2.18(m,2H),3.46(m,2H),3.92(m,3H),5.74(m,1H),7.07(m,1H),7.32(m,1H),7.45(d,1H),7.71(m,2H),8.07(m,1H),8.46(m,2H),10.98(m,1H),13.12(s,1H) Compound 918: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.03 (m, 3H), 1.34 (m, 1H), 1.87 (m, 2H), 2.18 (m, 2H), 3.46 (m, 2H), 3.92(m, 3H), 5.74(m, 1H), 7.07(m, 1H), 7.32(m, 1H), 7.45(d, 1H), 7.71(m, 2H), 8.07(m, 1H) ),8.46(m,2H),10.98(m,1H),13.12(s,1H)

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=2.431min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=2.431 min.

RT(CO2 -MeOH，60-40，80ml/min)=5.8212min。RT ( CO2 -MeOH, 60-40, 80 ml/min) = 5.8212 min.

化合物926： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.86(m,2H),2.22(m,2H),3.38(m,1H),3.92(m,4H),5.75(m,1H),7.04(m,1H),7.32(t,1H),7.45(d,1H),7.71(m,2H),8.07(m,1H),8.45(m,2H),10.99(m,1H),13.12(s,1H) Compound 926: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.02 (m, 3H), 1.34 (m, 1H), 1.86 (m, 2H), 2.22 (m, 2H), 3.38 (m, 1H), 3.92(m, 4H), 5.75(m, 1H), 7.04(m, 1H), 7.32(t, 1H), 7.45(d, 1H), 7.71(m, 2H), 8.07(m, 1H) ), 8.45(m, 2H), 10.99(m, 1H), 13.12(s, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=2.455min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=2.455 min.

RT(CO2 -MeOH，60-40，80ml/min)=6.9102min。RT ( CO2 -MeOH, 60-40, 80 ml/min) = 6.9102 min.

實例109. 5-(2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物746及化合物751)之合成Example 109. 5-(2-(5-Methyl-2-(3-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxyacetamido) nicotine Synthesis of Alkaline Amide (Compound 746 and Compound 751)

Figure 110128222-A0202-12-1094-129
Figure 110128222-A0202-12-1094-129

步驟1：5-(2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(3-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinum Synthesis of Alkaline Amide

將DIPEA(412.47mg，3.19mmol，555.89μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(190.72mg，776.48μmol，HCl)及6-(5-甲基-2-哌啶基)異吲哚啉-1-酮(0.21g，911.84μmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(381.38mg，1.00mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH為溶析液混合物)，以得到5-[[2-[5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.14g，332.19μmol，36.43%產率)。DIPEA (412.47 mg, 3.19 mmol, 555.89 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (190.72 mg, 776.48 μmol, HCl) and 6-(5-methyl-2-piperidinyl)isoindolin-1-one (0.21 g, 911.84 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (381.38 mg, 1.00 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH as eluent mixture) to give 5-[[2-[5-methyl-2-(3- Pendant oxyisoindolin-5-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.14 g, 332.19 μmol, 36.43% yield ).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02(d,3H),1.36(m,1H),1.68(m,1H),1.89(m,1H),2.08(m,1H),2.28(m,1H),2.72(m,1H),3.56(m,1H),3.96(m,1H),4.34(s,2H),5.56(m,1H),7.62(m,3H),8.21(m,1H),8.49(m,1H),8.62(m,1H),8.78(m,1H),8.96(m,1H),11.32(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.02(d,3H), 1.36(m,1H), 1.68(m,1H), 1.89(m,1H), 2.08(m,1H), 2.28(m, 1H), 2.72(m, 1H), 3.56(m, 1H), 3.96(m, 1H), 4.34(s, 2H), 5.56(m, 1H), 7.62(m, 3H), 8.21 (m, 1H), 8.49 (m, 1H), 8.62 (m, 1H), 8.78 (m, 1H), 8.96 (m, 1H), 11.32 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.882min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.882 min.

步驟2：掌性分離(化合物751 及化合物746 )Step 2: Chiral separation ( compound 751 and compound 746 )

藉由掌性HPLC(管柱：AS(250*20，10mkm)，以CO2 -MeOH，60-40，50ml/min補充流速-15ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物751 5-[[2-[(2R,5S )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(68.43mg，162.37μmol，48.88%產率)及化合物746 5-[[2-[(2S,5R )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(65.37mg，155.11μmol，46.69%產率)。The mirror isomers were separated by chiral HPLC (column: AS (250*20, 10mkm) with CO2 -MeOH, 60-40, 50ml/min supplemental flow - 15ml/min as mobile phase) to give two An individual enantiomer compound 751 5-[[2-[( 2R,5S )-5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl ]-2-oxyethanoyl]amino]pyridine-3-carboxamide (68.43 mg, 162.37 μmol, 48.88% yield) and compound 746 5-[[2-[( 2S,5R )-5 -Methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (65.37 mg, 155.11 μmol, 46.69% yield).

化合物751 於分析條件下(管柱：AS-H，CO2 -MeOH，60-40，2ml/min為流動相)之保留時間為5.80min且化合物746 之保留時間為3.93min。The retention time of compound 751 under analytical conditions (column: AS-H, CO 2 -MeOH, 60-40, 2 ml/min as mobile phase) was 5.80 min and the retention time of compound 746 was 3.93 min.

化合物751：保留時間：5.80minCompound 751: retention time: 5.80min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.06(m,3H),1.27-1.40(m,1H),1.60 -1.70(m,1H),1.83-1.95(m,1H),2.07-2.21(m,1H),2.21-2.33(m,1H),2.77-3.26(m,1H),3.45-4.11(m,1H),4.28-4.38(m,2H),5.22-5.71(m,1H),7.52-7.64(m,4H),8.07-8.19(m,1H),8.39-8.51(m,1H),8.52-8.57(m,1H),8.71-8.80(m,1H),8.81-8.93(m,1H),11.21-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.06(m,3H), 1.27-1.40(m,1H), 1.60-1.70(m,1H), 1.83-1.95(m,1H) ,2.07-2.21(m,1H),2.21-2.33(m,1H),2.77-3.26(m,1H),3.45-4.11(m,1H),4.28-4.38(m,2H),5.22-5.71( m,1H),7.52-7.64(m,4H),8.07-8.19(m,1H),8.39-8.51(m,1H),8.52-8.57(m,1H),8.71-8.80(m,1H), 8.81-8.93 (m, 1H), 11.21-11.39 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=0.812min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=0.812 min.

化合物746：保留時間：3.93minCompound 746: retention time: 3.93min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.29-1.41(m,1H),1.63-1.70(m,1H),1.83-1.93(m,1H),2.08-2.21(m,1H),2.22-2.29(m,1H),2.78-3.26(m,1H),3.48-4.09(m,1H),4.31-4.41(m,2H),5.22-5.72(m,1H),7.52-7.64(m,4H),8.08-8.20(m,1H),8.38-8.52(m,1H),8.51-8.60(m,1H),8.69-8.80(m,1H),8.81-8.93(m,1H),11.19-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.29-1.41(m,1H), 1.63-1.70(m,1H), 1.83-1.93(m,1H) ,2.08-2.21(m,1H),2.22-2.29(m,1H),2.78-3.26(m,1H),3.48-4.09(m,1H),4.31-4.41(m,2H),5.22-5.72( m,1H),7.52-7.64(m,4H),8.08-8.20(m,1H),8.38-8.52(m,1H),8.51-8.60(m,1H),8.69-8.80(m,1H), 8.81-8.93 (m, 1H), 11.19-11.39 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=0.812min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=0.812 min.

實例110. 2-甲氧基-5-(2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物759)之合成Example 110. 2-Methoxy-5-(2-(5-methyl-2-(3-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxygen Synthesis of acetamido)nicotinamide (compound 759)

Figure 110128222-A0202-12-1096-130
Figure 110128222-A0202-12-1096-130

將DIPEA(284.78mg，2.20mmol，383.80μL)添加到相應2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.3g，881.38μmol，Et3 N)及6-(5-甲基-2-哌啶基)異吲哚啉-1-酮(202.99mg，881.38μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(368.64mg，969.52μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5 mkm管柱且以H2 O-MeOH為溶析液混合物)，以得到2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(164.5mg，364.36μmol，41.34%產率)。DIPEA (284.78 mg, 2.20 mmol, 383.80 μL) was added to the corresponding 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid (0.3 g , 881.38 μmol, Et3N ) and 6-(5-methyl-2-piperidinyl)isoindolin-1-one (202.99 mg, 881.38 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (368.64 mg, 969.52 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (Waters Sunfire C18 20*100 5 mkm column with H 2 O-MeOH as eluent mixture) to give 2-methoxy-5-[[2-[( 2S, 5R )-5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (164.5 mg, 364.36 μmol, 41.34% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.03(m,3H),1.28-1.41(m,1H),1.60-1.71(m,1H),1.81-1.93(m,1H),2.05-2.20(m,1H),2.20-2.32(m,1H),2.74-3.27(m,1H),3.48-4.04(m,4H),4.32-4.35(m,2H),5.20-5.69(m,1H),7.51-7.60(m,3H),7.64-7.78(m,2H),8.37-8.47(m,1H),8.48-8.58(m,2H),10.99-11.10(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.03(m,3H), 1.28-1.41(m,1H), 1.60-1.71(m,1H), 1.81-1.93(m,1H) ,2.05-2.20(m,1H),2.20-2.32(m,1H),2.74-3.27(m,1H),3.48-4.04(m,4H),4.32-4.35(m,2H),5.20-5.69( m, 1H), 7.51-7.60 (m, 3H), 7.64-7.78 (m, 2H), 8.37-8.47 (m, 1H), 8.48-8.58 (m, 2H), 10.99-11.10 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值451.2；實測值452.2；Rt=2.197min。LCMS (ESI): [M] + m/z: calculated 451.2; found 452.2; Rt=2.197 min.

實例111.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物700及化合物695)之合成Example 111. N- (6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(3-oxyisoindolin-5-yl)piperidine- Synthesis of 1-yl)-2-oxoacetamide (Compound 700 and Compound 695)

Figure 110128222-A0202-12-1097-131
Figure 110128222-A0202-12-1097-131

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(3-oxyisoindolin-5-yl)piperidine- Synthesis of 1-yl)-2-oxyacetamide

將DIPEA(617.79mg，4.78mmol，832.60μL)添加到相應2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(0.25g，1.20mmol)及6-(5-甲基-2-哌啶基)異吲哚啉-1-酮(275.22mg，1.20mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(499.82mg，1.31mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH+NH3 為溶析液混合物)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.37g，877.84μmol， 73.46%產率)。DIPEA (617.79 mg, 4.78 mmol, 832.60 μL) was added to the corresponding 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (0.25 g, 1.20 mmol) ) and 6-(5-methyl-2-piperidinyl)isoindolin-1-one (275.22 mg, 1.20 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (499.82 mg, 1.31 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH+ NH3 as eluent mixture) to give N- (6-amino-5-ethyl-3 -pyridyl)-2-[5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyacetamide (0.37 g, 877.84 μmol, 73.46% yield).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.852min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.852 min.

步驟2：掌性分離(化合物700 及化合物695 )Step 2: Chiral separation ( compound 700 and compound 695 )

藉由掌性HPLC(管柱：IC-II，以己烷-IPA-MeOH，60-20-20，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物700 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(118.61mg，281.41μmol，32.06%產率)及化合物695 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(113.03mg，268.17μmol，30.55%產率)。The enantiomers were separated by chiral HPLC (column: IC-II with hexane-IPA-MeOH, 60-20-20, 12 ml/min as mobile phase) to give two separate enantiomers Compound 700 N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(3-oxyisoindoline-5- (118.61 mg, 281.41 μmol, 32.06% yield) and compound 695 N- (6-amino-5-ethyl-3-pyridyl) )-2-[( 2S,5R )-5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyacetamide ( 113.03 mg, 268.17 μmol, 30.55% yield).

化合物700 於分析條件下(管柱：IC，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為50.38min且化合物695 之保留時間為37.16min。The retention time of compound 700 under analytical conditions (column: IC, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 50.38 min and the retention time of compound 695 was 37.16 min.

化合物700：保留時間：50.38minCompound 700: retention time: 50.38min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.07(m,6H),1.36(m,1H),1.65(m,1H),1.87(m,1H),2.08(m,1H),2.33(m,3H),2.97(m,1H),3.76(m,1H),4.33(m,2H),5.61(m,3H),7.56(m,4H),8.01(m,1H),8.54(s,1H),10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.07(m, 6H), 1.36(m, 1H), 1.65(m, 1H), 1.87(m, 1H), 2.08(m, 1H), 2.33(m, 3H), 2.97(m, 1H), 3.76(m, 1H), 4.33(m, 2H), 5.61(m, 3H), 7.56(m, 4H), 8.01(m, 1H), 8.54 (s, 1H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.789min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.789 min.

化合物695：保留時間：37.16minCompound 695: retention time: 37.16min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.07(m,6H),1.36(m,1H),1.65(m,1H),1.87(m,1H),2.08(m,1H),2.33(m,3H),2.97(m,1H),3.76(m,1H),4.33(m,2H),5.61(m,3H),7.56(m,4H),8.01(m,1H),8.54(m,1H),10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.07(m, 6H), 1.36(m, 1H), 1.65(m, 1H), 1.87(m, 1H), 2.08(m, 1H), 2.33(m, 3H), 2.97(m, 1H), 3.76(m, 1H), 4.33(m, 2H), 5.61(m, 3H), 7.56(m, 4H), 8.01(m, 1H), 8.54 (m, 1H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.793min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.793 min.

實例112. 5-(2-(2-(3-氯-4,5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物834及化合物846)之合成Example 112. 5-(2-(2-(3-Chloro-4,5-difluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotine Synthesis of amides (compound 834 and compound 846)

Figure 110128222-A0202-12-1099-132
Figure 110128222-A0202-12-1099-132

步驟1：5-(2-(2-(3-氯-4.5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(2-(3-Chloro-4.5-difluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide synthesis

向(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基哌啶(200mg，814.02μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(199.94mg，814.02μmol，HCl)及TEA(247.11mg，2.44mmol，340.37μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(340.46mg，895.42μmol)。將所得反應混合物在20℃下攪拌5h。然後，使其經歷HPLC(40-90% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到5-[[2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(192mg，439.52μmol，53.99%產率)。To ( 2R,5S )-2-(3-chloro-4,5-difluorophenyl)-5-methylpiperidine (200 mg, 814.02 μmol), 2-[(5-aminocarbamoyl-3- Pyridinyl)amino]-2-oxoacetic acid (199.94 mg, 814.02 μmol, HCl) and TEA (247.11 mg, 2.44 mmol, 340.37 μL) in DMF (3 mL) were added HATU (340.46 μL) mg, 895.42 μmol). The resulting reaction mixture was stirred at 20 °C for 5 h. It was then subjected to HPLC (40-90% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 5-[[2- [( 2R,5S )-2-(3-Chloro-4,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (192 mg, 439.52 μmol, 53.99% yield).

LCMS(ESI)：[M]+ m/z：計算值436.2；實測值437.2；Rt=2.972min。LCMS (ESI): [M] + m/z: calculated 436.2; found 437.2; Rt=2.972 min.

步驟2：掌性分離(化合物834 及化合物846 )Step 2: Chiral separation ( compound 834 and compound 846 )

藉由掌性HPLC(管柱：Chiralpak AD-H-I(250 * 20mm，5mkm)；流動相：CO2 -MeOH 50-50；流速：40mL/min)將5-[[2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(192mg，439.52μmol)分成鏡像異構物，得到：5-[[2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(55mg，125.90μmol，57.29%產率)(其中保留時間=6.3min)(化合物846 )及5-[[2-[(2S,5R )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(68mg，155.66μmol，70.83%產率)(其中保留時間=8.98min)(化合物834 )。5-[[2-[( 2R,5S was separated by chiral HPLC (column: Chiralpak AD-HI (250*20 mm, 5 mkm); mobile phase: CO2 -MeOH 50-50; flow rate: 40 mL/min). )-2-(3-Chloro-4,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (192 mg, 439.52 μmol) split into the enantiomers to give: 5-[[2-[( 2R,5S )-2-(3-chloro-4,5-difluorophenyl)-5-methyl-1 -Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (55 mg, 125.90 μmol, 57.29% yield) (wherein retention time=6.3 min) (compound 846 ) and 5 -[[2-[( 2S,5R )-2-(3-Chloro-4,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (68 mg, 155.66 μmol, 70.83% yield) (wherein retention time=8.98 min) (compound 834 ).

化合物834 於分析條件下(管柱：AD-H，CO2 -MeOH，50-50，2ml/min 為流動相)之保留時間為8.34min且化合物846 之保留時間為5.93min。The retention time of compound 834 under analytical conditions (column: AD-H, CO 2 -MeOH, 50-50, 2 ml/min as mobile phase) was 8.34 min and the retention time of compound 846 was 5.93 min.

化合物834：保留時間：8.34minCompound 834: retention time: 8.34min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.93-1.06(m,3H),1.24-1.40(m,1H),1.58-1.68(m,1H),1.78-1.96(m,1H),1.96-2.12(m,1H),2.12-2.25(m,1H),2.77-3.28(m,1H),3.44-4.03(m,1H),5.12-5.52(m,1H),7.31-7.48(m,2H),7.55-7.65(m,1H),8.09-8.21(m,1H),8.41-8.51(m,1H),8.71-8.80(m,1H),8.80-8.93(m,1H),11.20-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.93-1.06(m,3H), 1.24-1.40(m,1H), 1.58-1.68(m,1H), 1.78-1.96(m,1H) ,1.96-2.12(m,1H),2.12-2.25(m,1H),2.77-3.28(m,1H),3.44-4.03(m,1H),5.12-5.52(m,1H),7.31-7.48( m,2H),7.55-7.65(m,1H),8.09-8.21(m,1H),8.41-8.51(m,1H),8.71-8.80(m,1H),8.80-8.93(m,1H), 11.20-11.34 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值436.2；實測值437.2；Rt=1.277min。LCMS (ESI): [M] + m/z: calculated 436.2; found 437.2; Rt=1.277 min.

化合物846：保留時間：5.93minCompound 846: retention time: 5.93min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.05(m,3H),1.23-1.37(m,1H),1.58-1.68(m,1H),1.81-1.93(m,1H),1.97-2.11(m,1H),2.11-2.25(m,1H),2.77-3.29(m,1H),3.44-4.04(m,1H),5.10-5.52(m,1H),7.30-7.46(m,2H),7.55-7.65(m,1H),8.10-8.20(m,1H),8.42-8.51(m,1H),8.71-8.79(m,1H),8.80-8.91(m,1H),11.16-11.33(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.05(m,3H), 1.23-1.37(m,1H), 1.58-1.68(m,1H), 1.81-1.93(m,1H) ,1.97-2.11(m,1H),2.11-2.25(m,1H),2.77-3.29(m,1H),3.44-4.04(m,1H),5.10-5.52(m,1H),7.30-7.46( m,2H),7.55-7.65(m,1H),8.10-8.20(m,1H),8.42-8.51(m,1H),8.71-8.79(m,1H),8.80-8.91(m,1H), 11.16-11.33 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值436.2；實測值437.2；Rt=1.284min。LCMS (ESI): [M] + m/z: calculated 436.2; found 437.2; Rt=1.284 min.

實例113. 5-(2-(2-(3-氯-5-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物646及化合物653)之合成Example 113. 5-(2-(2-(3-Chloro-5-(trifluoromethyl)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamido) Synthesis of Nicotinamide (Compound 646 and Compound 653)

Figure 110128222-A0202-12-1100-133
Figure 110128222-A0202-12-1100-133

步驟1：5-(2-(2-(3-氯-5-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(2-(3-Chloro-5-(trifluoromethyl)phenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido) Synthesis of Nicotinamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(279.38mg，900.21μmol)、(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基哌啶(250mg，900.21μmol)、 HATU(342.29mg，900.21μmol)及TEA(91.09mg，900.21μmol，125.47μL)混合於DMSO(2mL)中且在20℃下攪拌3h。使反應混合物經歷HPLC 2-10min 45-60%水/ACN(裝載泵4ml ACN)管柱：TRIART 100*20，5微米。獲得5-[[2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(240mg，511.88μmol，56.86%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (279.38 mg, 900.21 μmol), ( 2R,5S )-2-[3-chloro-5- (Trifluoromethyl)phenyl]-5-methylpiperidine (250 mg, 900.21 μmol), HATU (342.29 mg, 900.21 μmol) and TEA (91.09 mg, 900.21 μmol, 125.47 μL) were mixed in DMSO (2 mL) and stirred at 20 °C for 3 h. The reaction mixture was subjected to HPLC 2-10 min 45-60% water/ACN (loading pump 4 ml ACN) column: TRIART 100*20, 5 microns. 5-[[2-[( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide (240 mg, 511.88 μmol, 56.86% yield).

LCMS(ESI)：[M]+ m/z：計算值468.2；實測值469.2；Rt=3.311min。LCMS (ESI): [M] + m/z: calculated 468.2; found 469.2; Rt=3.311 min.

步驟2：掌性分離(化合物653 及化合物646 )Step 2: Chiral separation ( Compound 653 and Compound 646 )

將外消旋5-[[2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(240mg，511.88μmol)使用(Chiralpak IA-II 250*20，5mkm管柱；以己烷-IPA-MeOH，80-10-10為流動相；流速12mL/min；注入體積：900mkl)分離；得到5-[[2-[(2S,5R )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(82mg，174.89μmol，68.33%產率)及5-[[2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(86mg，183.43μmol，71.67%產率)。化合物653 於分析條件下(管柱：IA，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為13.53min且化合物646 之保留時間為20.36min。The racemic 5-[[2-[( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (240 mg, 511.88 μmol) was used (Chiralpak IA-II 250*20, 5 mkm column; with hexane-IPA-MeOH, 80-10-10 is mobile phase; flow rate 12mL/min; injection volume: 900mkl) separation; obtain 5-[[2-[( 2S,5R )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5 -Methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (82 mg, 174.89 μmol, 68.33% yield) and 5-[[2-[( 2R,5S )-2-[3-Chloro-5-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (86 mg, 183.43 μmol, 71.67% yield). The retention time of compound 653 under analytical conditions (column: IA, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 13.53 min and the retention time of compound 646 was 20.36 min.

化合物653：保留時間：13.53min 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.32(m,1H),1.62(m,1H),1.91(m,1H),2.18(m,3H),3.78(m,1H),5.41(m,1H),7.59(m,2H),7.68(m,1H),7.77(m,1H),8.14(m,1H),8.46(m,1H),8.80(m,2H),11.30(m,1H)。 Compound 653: Retention time: 13.53 min 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.01 (m, 3H), 1.32 (m, 1H), 1.62 (m, 1H), 1.91 (m, 1H) ,2.18(m,3H),3.78(m,1H),5.41(m,1H),7.59(m,2H),7.68(m,1H),7.77(m,1H),8.14(m,1H), 8.46 (m, 1H), 8.80 (m, 2H), 11.30 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值468.2；實測值469.2；Rt=3.312min。LCMS (ESI): [M] + m/z: calculated 468.2; found 469.2; Rt=3.312 min.

化合物646：保留時間：20.36min 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.33(m,1H),1.61(m,1H),1.91(m,1H),2.19(m,3H),3.78(m,1H),5.41(m,1H),7.63(m,3H),7.77(m,1H),8.14(m,1H),8.46(m,1H),8.80(m,2H),11.29(m, 1H)。 Compound 646: Retention time: 20.36 min 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.61 (m, 1H), 1.91 (m, 1H) ,2.19(m,3H),3.78(m,1H),5.41(m,1H),7.63(m,3H),7.77(m,1H),8.14(m,1H),8.46(m,1H), 8.80 (m, 2H), 11.29 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值468.2；實測值469.2；Rt=3.313min。LCMS (ESI): [M] + m/z: calculated 468.2; found 469.2; Rt=3.313 min.

實例114. 5-(2-(2-(3-氯-5-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1084、化合物615、化合物625及化合物624)之合成Example 114. 5-(2-(2-(3-Chloro-5-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide ( Synthesis of compound 1084, compound 615, compound 625 and compound 624)

Figure 110128222-A0202-12-1102-134
Figure 110128222-A0202-12-1102-134

在輕微加熱下，將(2R,5S )-2-(3-氯-5-氟苯基)-5-甲基哌啶(0.3g，1.32mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(323.60mg，1.32mmol，HCl)及DIPEA(340.55mg，2.63mmol，458.97μL)溶解於DMF(8mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(500.95mg，1.32mmol)。反應完成之後，藉由HPLC(23% 0.5-6.5min水-MeCN；流速：30ml/min；(裝載泵4ml/min MeCN)；目標質量380；管柱：SunFireC18 100x19mm 5um(L))純化混合物且藉由掌性層析(IA(250*30，5mkm)，己烷-IPA-MeOH，70-15-15，20ml/min)分離鏡像異構物，以得到5-[[2-[(2R,5S )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(83mg，198.16μmol，15.04%產率)、5-[[2-[(2S,5R )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(87mg，207.71μmol，15.77%產率)、5-[[2-[(2R,5R )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(10mg，23.88μmol，1.81%產率)及5-[[2-[(2S,5S )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(10mg，23.88μmol，1.81%產率)。( 2R,5S )-2-(3-chloro-5-fluorophenyl)-5-methylpiperidine (0.3 g, 1.32 mmol), 2-[(5-aminocarbamoyl -3-Pyridinyl)amino]-2-side oxyacetic acid (323.60 mg, 1.32 mmol, HCl) and DIPEA (340.55 mg, 2.63 mmol, 458.97 μL) were dissolved in DMF (8 mL). With vigorous stirring and occasional heating, HATU (500.95 mg, 1.32 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC (23% 0.5-6.5 min water-MeCN; flow rate: 30 ml/min; (loading pump 4 ml/min MeCN); target mass 380; column: SunFire C18 100x19 mm 5um (L)) and The enantiomers were separated by chiral chromatography (IA (250*30, 5mkm), hexane-IPA-MeOH, 70-15-15, 20ml/min) to give 5-[[2-[( 2R ,5S )-2-(3-Chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( 83 mg, 198.16 μmol, 15.04% yield), 5-[[2-[( 2S,5R )-2-(3-chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (87 mg, 207.71 μmol, 15.77% yield), 5-[[2-[( 2R,5R )-2-(3-chloro) -5-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (10 mg, 23.88 μmol, 1.81% yield) and 5-[[2-[( 2S,5S )-2-(3-chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (10 mg, 23.88 μmol, 1.81% yield).

化合物1084 於分析條件下(管柱：IC，以CO2 -MeOH，70-30，3ml/min為流動相)之保留時間為9.30min，化合物615 之保留時間為10.08min，化合物625 之保留時間為7.53min且化合物624 之保留時間為6.97min。The retention time of compound 1084 under analytical conditions (column: IC, with CO 2 -MeOH, 70-30, 3 ml/min as mobile phase) was 9.30 min, the retention time of compound 615 was 10.08 min, and the retention time of compound 625 was 7.53 min and the retention time for compound 624 was 6.97 min.

化合物1084：保留時間：9.30minCompound 1084: retention time: 9.30min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.01(m,3H),1.26-1.39(m,1H),1.53-1.67(m,1H),1.78-1.95(m,1H),2.01-2.13(m,1H),2.15-2.26(m,1H),2.74-3.28(m,1H),3.47-4.04(m,1H),5.11-5.65(m,1H),7.12-7.20(m,1H),7.20-7.26(m,1H),7.30-7.39(m,1H),7.56-7.65(m,1H),8.11-8.20(m,1H),8.41-8.52(m,1H),8.69-8.81(m,1H),8.81-8.96(m,1H),11.11-11.46(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.01(m,3H), 1.26-1.39(m,1H), 1.53-1.67(m,1H), 1.78-1.95(m,1H) ,2.01-2.13(m,1H),2.15-2.26(m,1H),2.74-3.28(m,1H),3.47-4.04(m,1H),5.11-5.65(m,1H),7.12-7.20( m,1H),7.20-7.26(m,1H),7.30-7.39(m,1H),7.56-7.65(m,1H),8.11-8.20(m,1H),8.41-8.52(m,1H), 8.69-8.81(m,1H), 8.81-8.96(m,1H), 11.11-11.46(m,1H).

LCMS(ESI)：[M]+ m/z：計算值418.2；實測值419.2；Rt=2.922min。LCMS (ESI): [M] + m/z: calculated 418.2; found 419.2; Rt=2.922 min.

化合物615：保留時間：10.08minCompound 615: retention time: 10.08min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.25-1.39(m,1H),1.58-1.66(m,1H),1.83-1.94(m,1H),2.02-2.13(m,1H),2.15-2.29(m,1H),2.78-3.28(m,1H),3.47-4.09(m,1H),5.14-5.58(m,1H),7.09-7.20(m,1H),7.20-7.26(m,1H),7.30-7.40(m,1H),7.55-7.67(m,1H),8.10-8.22(m,1H),8.39-8.54(m,1H),8.69-8.80(m,1H),8.80-8.96(m,1H),11.19-11.43(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.03(m,3H), 1.25-1.39(m,1H), 1.58-1.66(m,1H), 1.83-1.94(m,1H) ,2.02-2.13(m,1H),2.15-2.29(m,1H),2.78-3.28(m,1H),3.47-4.09(m,1H),5.14-5.58(m,1H),7.09-7.20( m,1H),7.20-7.26(m,1H),7.30-7.40(m,1H),7.55-7.67(m,1H),8.10-8.22(m,1H),8.39-8.54(m,1H), 8.69-8.80 (m, 1H), 8.80-8.96 (m, 1H), 11.19-11.43 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值418.2；實測值419.2；Rt=2.921min。LCMS (ESI): [M] + m/z: calculated 418.2; found 419.2; Rt=2.921 min.

化合物625：保留時間：7.53minCompound 625: retention time: 7.53min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.73-0.82(m,3H),0.98-1.05(m,1H),1.60-1.76(m,2H),1.79-1.96(m,1H),2.11-2.18(m,0.4H),2.57-2.60(m,1.6H),3.63-4.28(m,1H),5.15-5.67(m,1H),7.13-7.19(m,1H),7.19-7.24(m,1H),7.32-7.41(m,1H),7.58-7.65(m,1H),8.10-8.22(m,1H),8.41-8.56(m,1H),8.70-8.80(m,1H),8.80-8.96(m,1H),11.27-11.36(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.73-0.82(m,3H),0.98-1.05(m,1H),1.60-1.76(m,2H),1.79-1.96(m,1H) ,2.11-2.18(m,0.4H),2.57-2.60(m,1.6H),3.63-4.28(m,1H),5.15-5.67(m,1H),7.13-7.19(m,1H),7.19- 7.24(m,1H),7.32-7.41(m,1H),7.58-7.65(m,1H),8.10-8.22(m,1H),8.41-8.56(m,1H),8.70-8.80(m,1H ), 8.80-8.96 (m, 1H), 11.27-11.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值418.2；實測值419.2；Rt=2.981min。LCMS (ESI): [M] + m/z: calculated 418.2; found 419.2; Rt=2.981 min.

化合物624：保留時間：6.97minCompound 624: retention time: 6.97min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.66-0.86(m,3H),0.94-1.09(m,1H),1.55-1.77(m,2H),1.80-1.98(m,1H),2.11-2.19(m,0.4H),2.53-2.61(m,1.6H),3.62-4.29(m,1H),5.14-5.68(m,1H),7.13-7.19(m,1H),7.19-7.26(m,1H),7.32-7.40 (m,1H),7.54-7.66(m,1H),8.09-8.20(m,1H),8.43-8.55(m,1H),8.72-8.80(m,1H),8.80-8.94(m,1H),11.28-11.44(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.66-0.86(m,3H), 0.94-1.09(m,1H), 1.55-1.77(m,2H), 1.80-1.98(m,1H) ,2.11-2.19(m,0.4H),2.53-2.61(m,1.6H),3.62-4.29(m,1H),5.14-5.68(m,1H),7.13-7.19(m,1H),7.19- 7.26(m,1H),7.32-7.40(m,1H),7.54-7.66(m,1H),8.09-8.20(m,1H),8.43-8.55(m,1H),8.72-8.80(m,1H ), 8.80-8.94 (m, 1H), 11.28-11.44 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值418.2；實測值419.2；Rt=2.979min。LCMS (ESI): [M] + m/z: calculated 418.2; found 419.2; Rt=2.979 min.

實例115. 5-(2-(2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物683及化合物706)之合成Example 115. 5-(2-(2-(3,4-Difluorophenyl)-4,4-difluoro-5-methylpiperidin-1-yl)-2-oxoacetamido ) Synthesis of Nicotinamide (Compound 683 and Compound 706)

Figure 110128222-A0202-12-1104-135
Figure 110128222-A0202-12-1104-135

步驟1：5-(2-(2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(2-(3,4-Difluorophenyl)-4,4-difluoro-5-methylpiperidin-1-yl)-2-oxyacetamido ) Synthesis of Nicotinamide

向(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶(0.3g，1.21mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(298.04mg，1.21mmol，HCl)及TEA(613.94mg，6.07mmol，845.65μL)之溶液中分批添加HATU(507.52mg，1.33mmol)。將所得混合物在25℃下攪拌3h且藉由HPLC(30-70% 0-5min水-MeOH，流速30ml/min(裝載泵4ml/min MeOH)，管柱：SunFireC18 100*19mm 5um)純化，以獲得5-[[2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(160mg，364.98μmol，30.08%產率)。此化合物不經H-NMR即用於掌性拆分。To ( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidine (0.3 g, 1.21 mmol), 2-[(5-aminocarbamide HATU (507.52 mg, 1.33 μL) was added portionwise to a solution of yl-3-pyridyl)amino]-2-oxoacetic acid (298.04 mg, 1.21 mmol, HCl) and TEA (613.94 mg, 6.07 mmol, 845.65 μL). mmol). The resulting mixture was stirred at 25°C for 3h and purified by HPLC (30-70% 0-5min water-MeOH, flow rate 30ml/min (loading pump 4ml/min MeOH), column: SunFire C18 100*19mm 5um) to give 5-[[2-[( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (160 mg, 364.98 μmol, 30.08% yield). This compound was used for chiral resolution without H-NMR.

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=2.684min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=2.684 min.

步驟2：掌性分離(化合物683 及化合物706 )Step 2: Chiral separation ( compound 683 and compound 706 )

對5-[[2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(160mg，364.98μmol)進行掌性分離(樣品資訊：IA-I(250*.0,5mkm)，己烷-IPA-MeOH，50-25-25，14ml/min)，以獲得5-[[2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基] 吡啶-3-甲醯胺(73mg，166.52μmol，91.25%產率)及5-[[2-[(2R,5R )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(75mg，171.09μmol，93.75%產率)。p-5-[[2-[( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxygen chiral separation (sample information: IA-I (250*.0,5mkm), hexane-IPA-MeOH, 50- 25-25, 14ml/min) to obtain 5-[[2-[( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methyl-1 -Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (73 mg, 166.52 μmol, 91.25% yield) and 5-[[2-[( 2R,5R )- 2-(3,4-Difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (75 mg, 171.09 μmol, 93.75% yield).

化合物683 於分析條件下(管柱：AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為28.60min且化合物706 之保留時間為16.55min。The retention time of compound 683 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 28.60 min and the retention time of compound 706 was 16.55 min .

化合物683：保留時間：28.60minCompound 683: retention time: 28.60min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(m,3H),2.20(m,2H),2.86(m,1H),3.45(m,1H),4.07(m,1H),5.69(m,1H),7.17(m,1H),7.43(m,2H),7.60(m,1H),8.18(m,1H),8.48(m,1H),8.82(m,2H),11.36(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.08(m, 3H), 2.20(m, 2H), 2.86(m, 1H), 3.45(m, 1H), 4.07(m, 1H), 5.69(m, 1H), 7.17(m, 1H), 7.43(m, 2H), 7.60(m, 1H), 8.18(m, 1H), 8.48(m, 1H), 8.82(m, 2H), 11.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=2.800min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=2.800 min.

化合物706：保留時間：16.55minCompound 706: retention time: 16.55min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(m,3H),2.27(m,2H),2.93(m,1H),3.45(m,1H),4.08(m,1H),5.69(m,1H),7.17(m,1H),7.44(m,2H),7.60(m,1H),8.15(m,1H),8.48(m,1H),8.82(m,2H),11.28(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.08(m, 3H), 2.27(m, 2H), 2.93(m, 1H), 3.45(m, 1H), 4.08(m, 1H), 5.69(m, 1H), 7.17(m, 1H), 7.44(m, 2H), 7.60(m, 1H), 8.15(m, 1H), 8.48(m, 1H), 8.82(m, 2H), 11.28 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=2.796min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=2.796 min.

實例116.N -(6-胺基-5-乙基吡啶-3-基)-2-(2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物721及化合物728)之合成Example 116. N- (6-Amino-5-ethylpyridin-3-yl)-2-(2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperin Synthesis of pyridin-1-yl)-2-oxoacetamide (compound 721 and compound 728)

Figure 110128222-A0202-12-1105-136
Figure 110128222-A0202-12-1105-136

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidine Synthesis of pyridin-1-yl)-2-oxoacetamide

向(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶(0.25g，1.01mmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(296.16mg，1.42mmol) 及TEA(511.62mg，5.06mmol，704.71μL)之溶液中分批添加HATU(499.83mg，1.31mmol)。將所得混合物在40℃下攪拌3h且藉由HPLC(0-5min 40-80%水-MeOH(NH3 0.1%)，流速30ml/min(裝載泵4ml/min MeOH(NH3 0.1%))管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)純化，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(190mg，433.38μmol，42.86%產率)。此化合物不經H-NMR即用於掌性拆分。To ( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidine (0.25 g, 1.01 mmol), 2-[(6-amino- To a solution of 5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (296.16 mg, 1.42 mmol) and TEA (511.62 mg, 5.06 mmol, 704.71 μL) was added HATU (499.83 mg, 1.31 mmol). The resulting mixture was stirred at 40° C. for 3 h and quenched by HPLC (0-5 min 40-80% water-MeOH ( NH3 0.1%), flow rate 30 ml/min (loading pump 4 ml/min MeOH ( NH3 0.1%)) tube Column: YMC-Actus Triart C18 100*20mml.DS-5um) purification to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5S )-2-( 3,4-Difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyacetamide (190 mg, 433.38 μmol, 42.86% yield). This compound was used for chiral resolution without H-NMR.

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=2.475min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=2.475 min.

步驟2：掌性分離(化合物721 及化合物728 )Step 2: Chiral separation ( compound 721 and compound 728 )

對N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(190mg，433.38μmol)進行掌性分離(注入體積：900mkl樣品資訊：AD-H I(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，13ml/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(73mg，166.51μmol，76.84%產率)及N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5R )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(74mg，168.79μmol，77.89%產率)。p- N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5 -Methyl-1-piperidinyl]-2-oxyacetamide (190mg, 433.38μmol) for chiral separation (injection volume: 900mkl Sample information: AD-HI (250*20, 5mkm), hexane alkane-IPA-MeOH, 50-25-25, 13 ml/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5S )-2-( 3,4-Difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyacetamide (73 mg, 166.51 μmol, 76.84% yield) and N -(6-Amino-5-ethyl-3-pyridyl)-2-[( 2R,5R )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methyl yl-1-piperidinyl]-2-oxoacetamide (74 mg, 168.79 μmol, 77.89% yield).

化合物721 於分析條件下(管柱：AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為31.65min且化合物728 之保留時間為18.67min。The retention time of compound 721 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 31.65 min and the retention time of compound 728 was 18.67 min .

化合物721：保留時間：31.65minCompound 721: retention time: 31.65min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(m,6H),2.18(m,1H),2.39(m,2H),2.93(m,2H),3.41(m,1H),3.96(m,1H),5.69(m,3H),7.15(m,1H),7.43(m,3H),8.03(m,1H),10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.08(m, 6H), 2.18(m, 1H), 2.39(m, 2H), 2.93(m, 2H), 3.41(m, 1H), 3.96 (m, 1H), 5.69 (m, 3H), 7.15 (m, 1H), 7.43 (m, 3H), 8.03 (m, 1H), 10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.208min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.208 min.

化合物728：保留時間：18.67minCompound 728: retention time: 18.67min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.09(m,6H),2.18(m,1H),2.40(m,2H), 2.92(m,2H),3.41(m,1H),3.97(m,1H),5.69(m,3H),7.15(m,1H),7.43(m,3H),8.03(m,1H),10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.09(m, 6H), 2.18(m, 1H), 2.40(m, 2H), 2.92(m, 2H), 3.41(m, 1H), 3.97 (m, 1H), 5.69 (m, 3H), 7.15 (m, 1H), 7.43 (m, 3H), 8.03 (m, 1H), 10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.205min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.205 min.

實例117. 5-(2-(2-(3-氯-4-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物655、化合物647)之合成Example 117. 5-(2-(2-(3-Chloro-4-(trifluoromethyl)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamido) Synthesis of Nicotinamide (Compound 655, Compound 647)

Figure 110128222-A0202-12-1107-137
Figure 110128222-A0202-12-1107-137

步驟1：5-(2-(2-(3-氯-4-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(2-(3-Chloro-4-(trifluoromethyl)phenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido) Synthesis of Nicotinamide

向(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基哌啶(0.9g，3.24mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(955.19mg，3.89mmol，HCl)及DIPEA(1.05g，8.10mmol，1.41mL)於DMSO(5mL)中之經攪拌之溶液中添加HATU(1.48g，3.89mmol)。將所得反應混合物在20℃下攪拌13h。完成之後，將反應混合物提交至反相HPLC(管柱：SunFire 19*100mm，5mkl；MeOH為溶析液混合物)，以得到呈淡黃色固體之5-[[2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1g，213.29μmol，6.58%產率)。To ( 2R,5S )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methylpiperidine (0.9 g, 3.24 mmol), 2-[(5-aminocarbamoyl To a stirred solution of -3-pyridyl)amino]-2-pendoxoacetic acid (955.19 mg, 3.89 mmol, HCl) and DIPEA (1.05 g, 8.10 mmol, 1.41 mL) in DMSO (5 mL) was added HATU (1.48 g, 3.89 mmol). The resulting reaction mixture was stirred at 20 °C for 13 h. After completion, the reaction mixture was submitted to reverse phase HPLC (column: SunFire 19*100mm, 5mkl; MeOH was the eluent mixture) to give 5-[[2-[( 2R,5S )- as a pale yellow solid 2-[3-Chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.1 g, 213.29 μmol, 6.58% yield).

LCMS(ESI)：[M]+ m/z：計算值468.2；實測值469.2；Rt=1.202min。LCMS (ESI): [M] + m/z: calculated 468.2; found 469.2; Rt=1.202 min.

步驟2：掌性分離(化合物655 及化合物647 )Step 2: Chiral separation ( Compound 655 and Compound 647 )

將5-[[2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1g，213.29μmol)提交至掌性分離(IA-II(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)，以得到5-[[2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺 基]吡啶-3-甲醯胺(0.038g，81.05μmol，38.00%產率)及5-[[2-[(2S,5R )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.039g，83.18μmol，39.00%產率)。化合物655 於分析條件下(管柱：IC，以CO2 -MeOH，60-40，2.5ml/min為流動相)之保留時間為5.15min且化合物647 之保留時間為4.04min。5-[[2-[( 2R,5S )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carbamoylamine (0.1 g, 213.29 μmol) was submitted to chiral separation (IA-II (250*20, 5 mkm), hexane-IPA-MeOH, 60-20-20 , 12ml/min) to give 5-[[2-[( 2R,5S )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.038 g, 81.05 μmol, 38.00% yield) and 5-[[2-[( 2S,5R )-2-[ 3-Chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.039g , 83.18 μmol, 39.00% yield). The retention time of compound 655 under analytical conditions (column: IC, with CO2 -MeOH, 60-40, 2.5 ml/min as mobile phase) was 5.15 min and the retention time of compound 647 was 4.04 min.

化合物655：保留時間：5.15minCompound 655: retention time: 5.15min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.31(m,1H),1.63(m,1H),1.90(m,1H),2.15(m,2H),2.82(m,1H),3.78(m,1H),5.42(m,1H),7.49(m,1H),7.63(m,2H),7.86(m,1H),8.14(m,1H),8.46(m,1H),8.76(m,1H),8.86(m,1H),11.27(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.31(m, 1H), 1.63(m, 1H), 1.90(m, 1H), 2.15(m, 2H), 2.82(m, 1H), 3.78(m, 1H), 5.42(m, 1H), 7.49(m, 1H), 7.63(m, 2H), 7.86(m, 1H), 8.14(m, 1H), 8.46 (m, 1H), 8.76 (m, 1H), 8.86 (m, 1H), 11.27 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值468.2；實測值469.2；Rt=3.227min。LCMS (ESI): [M] + m/z: calculated 468.2; found 469.2; Rt=3.227 min.

化合物647：保留時間：4.04minCompound 647: retention time: 4.04min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.31(m,1H),1.63(m,1H),1.90(m,1H),2.17(m,2H),2.83(m,1H),3.70(m,1H),5.42(d,1H),7.50(m,1H),7.63(m,2H),7.86(m,1H),8.13(d,1H),8.46(m,1H),8.76(m,1H),8.86(m,1H),11.27(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.31(m, 1H), 1.63(m, 1H), 1.90(m, 1H), 2.17(m, 2H), 2.83(m, 1H), 3.70(m, 1H), 5.42(d, 1H), 7.50(m, 1H), 7.63(m, 2H), 7.86(m, 1H), 8.13(d, 1H), 8.46 (m, 1H), 8.76 (m, 1H), 8.86 (m, 1H), 11.27 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值468.2；實測值469.2；Rt=3.226min。LCMS (ESI): [M] + m/z: calculated 468.2; found 469.2; Rt=3.226 min.

實例118.N -(5,6-二甲基吡啶-3-基)-2-(5-甲基-2-(3-(甲基磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物648)之合成Example 118. N- (5,6-Lutidine-3-yl)-2-(5-methyl-2-(3-(methylsulfonyl)phenyl)piperidin-1-yl) - Synthesis of 2-oxoacetamide (Compound 648)

Figure 110128222-A0202-12-1108-138
Figure 110128222-A0202-12-1108-138

在25℃下，在0.5h內，向(2R,5S )-5-甲基-2-(3-甲基磺醯基苯基)哌啶 (250.00mg，986.74μmol)、2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(291.46mg，986.74μmol)及TEA(998.48mg，9.87mmol，1.38mL)於DMF(5mL)中之正攪拌溶液中小批量添加HATU(412.71mg，1.09mmol)。將所得反應混合物在25℃下攪拌18h。藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um，流動相：40-54% 0-5min 0.1% NH3 -MeOH，流速：30ml/min(裝載泵4ml/min MeOH))純化粗反應混合物，以得到化合物648 N -(5,6-二甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(180mg，419.06μmol，42.47%產率)。To ( 2R,5S )-5-methyl-2-(3-methylsulfonylphenyl)piperidine (250.00 mg, 986.74 μmol), 2-[(5 ,6-Dimethyl-3-pyridyl)amino]-2-oxoacetic acid (291.46 mg, 986.74 μmol) and TEA (998.48 mg, 9.87 mmol, 1.38 mL) in DMF (5 mL) under positive stirring To the solution was added HATU (412.71 mg, 1.09 mmol) in small portions. The resulting reaction mixture was stirred at 25 °C for 18 h. The crude reaction was purified by reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um, mobile phase: 40-54% 0-5min 0.1% NH3 -MeOH, flow rate: 30ml/min (load pump 4ml/min MeOH)) mixture to give compound 648 N- (5,6-dimethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(3-methylsulfonylphenyl) -1-Piperidinyl]-2-oxoacetamide (180 mg, 419.06 μmol, 42.47% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(dd,3H),1.34(m,1H),1.64(m,1H),1.89(d,1H),2.07(m,1H),2.20(m,4H),2.34(m,4H),3.21(m,3H),3.77(m,1H),5.43(m,1H),7.66(m,2H),7.82(m,3H),8.43(m,1H),10.96(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(dd,3H), 1.34(m,1H), 1.64(m,1H), 1.89(d,1H), 2.07(m,1H), 2.20(m, 4H), 2.34(m, 4H), 3.21(m, 3H), 3.77(m, 1H), 5.43(m, 1H), 7.66(m, 2H), 7.82(m, 3H), 8.43 (m, 1H), 10.96 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值429.4；實測值430.2；Rt=1.980min。LCMS (ESI): [M] + m/z: calculated 429.4; found 430.2; Rt=1.980 min.

實例119. 5-(2-(5-甲基-2-(3-(N -甲基胺磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物666)之合成Example 119. 5-(2-(5-Methyl-2-(3-( N -methylaminosulfonyl)phenyl)piperidin-1-yl)-2-oxyacetamido) Synthesis of Nicotinamide (Compound 666)

Figure 110128222-A0202-12-1109-139
Figure 110128222-A0202-12-1109-139

向N -甲基-3-[(2S,5R )-5-甲基-2-哌啶基]苯磺醯胺(535mg，1.99mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(489.64mg，1.99mmol，HCl)及TEA(605.16mg，5.98mmol，833.56μL)於DMF(4mL)中之經攪拌之混合物中添加HATU(833.78mg，2.19mmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；0-5min 10-60%水-MeOH(NH3 0.1%)，流速30ml/min)，得到5-[[2-[(2S,5R )-5-甲基-2-[3-(甲 基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(237mg，515.76μmol，25.87%產率)。To N -methyl-3-[( 2S,5R )-5-methyl-2-piperidinyl]benzenesulfonamide (535 mg, 1.99 mmol), 2-[(5-aminocarbamoyl-3- Pyridinyl)amino]-2-oxoacetic acid (489.64 mg, 1.99 mmol, HCl) and TEA (605.16 mg, 5.98 mmol, 833.56 μL) in DMF (4 mL) was added HATU (833.78 μL) mg, 2.19 mmol). The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 0-5min 10-60% water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give 5-[[2 -[( 2S,5R )-5-methyl-2-[3-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide (237 mg, 515.76 μmol, 25.87% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.36(m,1H),1.65(m,1H),1.90(m,1H),2.16(m,2H),2.38(m,3H),2.99(m,1H),3.80(m,1H),5.46(m,1H),7.46(m,1H),7.56(m,1H),7.63(m,2H),7.69(m,2H),8.16(m,1H),8.47(m,1H),8.75(m,1H),8.86(m,1H),11.26(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(m, 3H), 1.36(m, 1H), 1.65(m, 1H), 1.90(m, 1H), 2.16(m, 2H), 2.38(m, 3H), 2.99(m, 1H), 3.80(m, 1H), 5.46(m, 1H), 7.46(m, 1H), 7.56(m, 1H), 7.63(m, 2H), 7.69 (m, 2H), 8.16 (m, 1H), 8.47 (m, 1H), 8.75 (m, 1H), 8.86 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值459.4；實測值460.2；Rt=2.036min。LCMS (ESI): [M] + m/z: calculated 459.4; found 460.2; Rt=2.036 min.

實例120. 5-(2-(5-甲基-2-(2-(甲胺基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物862及化合物877)之合成Example 120. 5-(2-(5-Methyl-2-(2-(methylamino)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-pendant oxyacetyl Synthesis of amino)nicotinamide (compound 862 and compound 877)

Figure 110128222-A0202-12-1110-140
Figure 110128222-A0202-12-1110-140

步驟1：5-(2-(5-甲基-2-(2-(甲胺基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(2-(methylamino)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-pendoxoacetone Synthesis of Amino)nicotinamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(281.91mg，1.15mmol，HCl)及N -甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑-2-胺(0.3g，1.15mmol)混合於DMF(20mL)。將反應懸浮液冷卻至0℃且添加HATU(523.68mg，1.38mmol)，隨後添加TEA(348.42mg，3.44mmol，479.91μL)，且在環境溫度下攪拌12h。將反應混合物在真空中蒸發且藉由製備型(50-50-55% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml)純化0.36g所獲得之粗產物，以得到產物5-[[2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.15g，331.47μmol，28.88%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (281.91 mg, 1.15 mmol, HCl) and N -methyl-5-(5-methyl- 2-Piperidinyl)-1,3-benzothiazol-2-amine (0.3 g, 1.15 mmol) was mixed with DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (523.68 mg, 1.38 mmol) was added followed by TEA (348.42 mg, 3.44 mmol, 479.91 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and 0.36 g of the obtained crude product was purified by prep (50-50-55% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml) to give The product 5-[[2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl] was obtained -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.15 g, 331.47 μmol, 28.88% yield).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=1.875min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=1.875 min.

步驟2：掌性分離(化合物862 及化合物877 )Step 2: Chiral separation ( compound 862 and compound 877 )

使5-[[2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.15g，331.47μmol)經歷掌性HPLC純化(管柱：IA-II(250*20,5mkm)，溶析液：己烷-IPA-MeOH，70-15-15，流速：15mL/min)，以得到兩種單獨的鏡像異構物化合物877 5-[[2-[(2S,5R )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.02767g，61.15μmol，18.45%產率)及化合物862 5-[[2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.03257g，71.97μmol，21.71%產率)。Make 5-[[2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.15 g, 331.47 μmol) was purified by chiral HPLC (column: IA-II (250*20,5 mkm), eluent: Hexane-IPA-MeOH, 70-15-15, flow rate: 15 mL/min) to give two separate enantiomers Compound 877 5-[[2-[( 2S,5R )-5-methyl- 2-[2-(Methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.02767 g, 61.15 μmol, 18.45% yield) and compound 862 5-[[2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzo Thiazol-5-yl]-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (0.03257 g, 71.97 μmol, 21.71% yield).

化合物862 於分析條件下(管柱：IA-3，以己烷-IPA-MeOH，50-25-25，0.15ml/min為流動相)之保留時間為7.95min且化合物877 之保留時間為12.36min。The retention time of compound 862 under analytical conditions (column: IA-3, with hexane-IPA-MeOH, 50-25-25, 0.15 ml/min as mobile phase) was 7.95 min and the retention time of compound 877 was 12.36 min.

化合物862：保留時間：7.95minCompound 862: retention time: 7.95min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.06(m,3H),1.26-1.40(m,1H),1.63-1.77(m,1H),1.81-1.94(m,1H),1.98-2.19(m,1H),2.20-2.31(m,1H),2.78-2.84(m,0.4H),2.89-2.96(m,3H),3.22-3.28(m,0.6H),3.44-4.04(m,1H),5.15-5.66(m,1H),6.91-7.05(m,1H),7.28-7.40(m,1H),7.53-7.62(m,1H),7.62-7.71(m,1H),7.81-7.98(m,1H),8.03-8.25(m,1H),8.41-8.55(m,1H),8.69-8.79(m,1H),8.83-8.94(m,1H),11.11-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.06(m,3H), 1.26-1.40(m,1H), 1.63-1.77(m,1H), 1.81-1.94(m,1H) ,1.98-2.19(m,1H),2.20-2.31(m,1H),2.78-2.84(m,0.4H),2.89-2.96(m,3H),3.22-3.28(m,0.6H),3.44- 4.04(m,1H),5.15-5.66(m,1H),6.91-7.05(m,1H),7.28-7.40(m,1H),7.53-7.62(m,1H),7.62-7.71(m,1H) ),7.81-7.98(m,1H),8.03-8.25(m,1H),8.41-8.55(m,1H),8.69-8.79(m,1H),8.83-8.94(m,1H),11.11-11.39 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=1.960min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=1.960 min.

化合物877：保留時間：12.36minCompound 877: retention time: 12.36min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.06(m,3H),1.30-1.40(m,1H),1.65-1.77(m,1H),1.81-1.93(m,1H),1.98-2.18(m,1H),2.19-2.31(m,1H),2.79-2.82(m,0.3H),2.88-2.93(m,3H),3.25-3.28(m,0.7H),3.44-4.03(m,1H),5.15-5.67(m,1H),6.94-7.03(m,1H),7.29-7.40(m,1H),7.54-7.62(m,1H),7.62-7.70(m, 1H),7.89-7.94(m,1H),8.09-8.22(m,1H),8.42-8.51(m,1H),8.69-8.80(m,1H),8.82-8.94(m,1H),10.97-11.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.06(m,3H), 1.30-1.40(m,1H), 1.65-1.77(m,1H), 1.81-1.93(m,1H) ,1.98-2.18(m,1H),2.19-2.31(m,1H),2.79-2.82(m,0.3H),2.88-2.93(m,3H),3.25-3.28(m,0.7H),3.44- 4.03(m,1H),5.15-5.67(m,1H),6.94-7.03(m,1H),7.29-7.40(m,1H),7.54-7.62(m,1H),7.62-7.70(m,1H ),7.89-7.94(m,1H),8.09-8.22(m,1H),8.42-8.51(m,1H),8.69-8.80(m,1H),8.82-8.94(m,1H),10.97-11.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=1.961min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=1.961 min.

實例121. 2-甲氧基-5-(2-(5-甲基-2-(2-(甲胺基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物863及化合物875)之合成Example 121. 2-Methoxy-5-(2-(5-methyl-2-(2-(methylamino)benzo[d]thiazol-5-yl)piperidin-1-yl)-2 -Synthesis of pendant oxyacetamido)nicotinamide (compound 863 and compound 875)

Figure 110128222-A0202-12-1112-141
Figure 110128222-A0202-12-1112-141

步驟1：2-甲氧基-5-(2-(5-甲基2-(2-(甲胺基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 2-Methoxy-5-(2-(5-methyl 2-(2-(methylamino)benzo[d]thiazol-5-yl)piperidin-1-yl)-2- Synthesis of pendant oxyacetamido)nicotinamide

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(201.31mg，841.67μmol)及N -甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑-2-胺(0.22g，841.67μmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(384.03mg，1.01mmol)，隨後添加TEA(170.34mg，1.68mmol，234.62μL)，且在環境溫度下攪拌12h。將反應混合物在真空中蒸發且藉由製備型(55-75% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min)純化0.5g所獲得之粗產物，以得到產物2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.155g，321.21μmol，38.16%產率)。2-[(5-Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (201.31 mg, 841.67 μmol) and N -methyl-5-(5 -Methyl-2-piperidinyl)-1,3-benzothiazol-2-amine (0.22 g, 841.67 μmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (384.03 mg, 1.01 mmol) was added followed by TEA (170.34 mg, 1.68 mmol, 234.62 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and 0.5 g of the obtained crude product was purified by preparative (55-75% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min) to give The product 2-methoxy-5-[[2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.155 g, 321.21 μmol, 38.16% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.11(d,3H),1.42(m,1H),2.12(m,4H),2.98(m,3H),3.32(m,1H),3.52(m,1H),3.98(m,3H),5.55(m,1H),7.02(m,1H),7.46(m,1H),7.82(m,3H),7.96(m,1H),8.56(m,2H),11.12(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.11(d,3H), 1.42(m,1H), 2.12(m,4H), 2.98(m,3H), 3.32(m,1H), 3.52(m,1H),3.98(m,3H),5.55(m,1H),7.02(m,1H),7.46(m,1H),7.82(m,3H),7.96(m,1H),8.56 (m, 2H), 11.12 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值482.2；實測值483.2；Rt=2.409min。LCMS (ESI): [M] + m/z: calculated 482.2; found 483.2; Rt=2.409 min.

步驟2：掌性分離(化合物863 及化合物875 )Step 2: Chiral separation ( compound 863 and compound 875 )

使2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5- 基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.155g，321.21μmol)經歷掌性HPLC純化(管柱：IA-II(250*20,5mkm)，溶析液：己烷-IPA-MeOH，50-25-25，流速：12mL/min)，以得到兩種單獨的鏡像異構物化合物863 2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.05441g，112.75μmol，35.10%產率)及化合物875 2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0451g，93.46μmol，29.10%產率)。2-methoxy-5-[[2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1 -Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (0.155 g, 321.21 μmol) was subjected to chiral HPLC purification (column: IA-II (250*20,5mkm) ), eluent: hexane-IPA-MeOH, 50-25-25, flow rate: 12 mL/min) to obtain two separate enantiomer compounds 863 2-methoxy-5-[[2- [( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-pendoxetylacetone (0.05441 g, 112.75 μmol, 35.10% yield) and compound 875 2-methoxy-5-[[2-[( 2S,5R )-5-methyl -2-[2-(Methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (0.0451 g, 93.46 μmol, 29.10% yield).

化合物863 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為63.81min且化合物875 之保留時間為38.60min。The retention time of compound 863 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 63.81 min and the retention time of compound 875 was 38.60 min.

化合物863：保留時間：63.81minCompound 863: retention time: 63.81min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.27-1.37(m,1H),1.65-1.74(m,1H),1.79-1.92(m,1H),1.99-2.17(m,1H),2.20-2.30(m,1H),2.77-2.81(m,0.3H),2.89-2.92(m,3H),3.24-3.28(m,0.7H),3.42-3.49(m,0.7H),3.89-3.96(m,3H),3.99-4.04(m,0.3H),5.13-5.74(m,1H),6.90-7.04(m,1H),7.29-7.38(m,1H),7.58-7.68(m,1H),7.68-7.78(m,2H),7.87-7.95(m,1H),8.33-8.48(m,1H),8.49-8.59(m,1H),10.93-11.21(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,3H), 1.27-1.37(m,1H), 1.65-1.74(m,1H), 1.79-1.92(m,1H) ,1.99-2.17(m,1H),2.20-2.30(m,1H),2.77-2.81(m,0.3H),2.89-2.92(m,3H),3.24-3.28(m,0.7H),3.42- 3.49(m, 0.7H), 3.89-3.96(m, 3H), 3.99-4.04(m, 0.3H), 5.13-5.74(m, 1H), 6.90-7.04(m, 1H), 7.29-7.38(m ,1H),7.58-7.68(m,1H),7.68-7.78(m,2H),7.87-7.95(m,1H),8.33-8.48(m,1H),8.49-8.59(m,1H),10.93 -11.21 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值482.2；實測值483.2；Rt=1.749min。LCMS (ESI): [M] + m/z: calculated 482.2; found 483.2; Rt=1.749 min.

化合物875：保留時間：38.60minCompound 875: retention time: 38.60min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.10(m,3H),1.27-1.42(m,1H),1.64-1.76(m,1H),1.81-1.93(m,1H),2.01-2.20(m,1H),2.20-2.33(m,1H),2.76-2.83(m,0.3H),2.88-2.97(m,3H),3.24-3.28(m,0.7H),3.43-3.47(m,0.7H),3.88-3.98(m,3H),3.98-4.03(m,0.3H),5.11-5.65(m,1H),6.91-7.04(m,1H),7.27-7.38(m,1H),7.59-7.67(m,1H),7.66-7.77(m,2H),7.84-7.96(m,1H),8.37-8.49(m,1H),8.49-8.60(m,1H),10.89-11.25(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.10(m,3H), 1.27-1.42(m,1H), 1.64-1.76(m,1H), 1.81-1.93(m,1H) ,2.01-2.20(m,1H),2.20-2.33(m,1H),2.76-2.83(m,0.3H),2.88-2.97(m,3H),3.24-3.28(m,0.7H),3.43- 3.47(m, 0.7H), 3.88-3.98(m, 3H), 3.98-4.03(m, 0.3H), 5.11-5.65(m, 1H), 6.91-7.04(m, 1H), 7.27-7.38(m ,1H),7.59-7.67(m,1H),7.66-7.77(m,2H),7.84-7.96(m,1H),8.37-8.49(m,1H),8.49-8.60(m,1H),10.89 -11.25(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值482.2；實測值483.2；Rt=1.743min。LCMS (ESI): [M] + m/z: calculated 482.2; found 483.2; Rt=1.743 min.

實例122.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(2-(甲胺基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物896及化合物884)之合成Example 122. N- (6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2-(methylamino)benzo[ d ]thiazol-5-yl) ) Piperidin-1-yl)-2-oxoacetamide (Compound 896 and Compound 884) Synthesis

Figure 110128222-A0202-12-1114-142
Figure 110128222-A0202-12-1114-142

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(2-(甲胺基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(2-(methylamino)benzo[d]thiazol-5-yl) ) Synthesis of piperidin-1-yl)-2-side oxyacetamide

將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(230.50mg，1.10mmol)及N -甲基 -5-(5-甲基-2-哌啶基)-1,3-苯并噻唑-2-胺(0.32g，1.22mmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(465.50mg，1.22mmol)，隨後添加TEA(247.76mg，2.45mmol，341.27μL)，且在環境溫度下攪拌12h。將反應混合物在真空中蒸發且藉由製備型(60-60-70% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min)純化0.61g所獲得之粗產物，以得到產物N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.18g，397.73μmol，32.49%產率)。2-[(6-Amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (230.50 mg, 1.10 mmol) and N - methyl -5-(5-methyl) -2-Piperidinyl)-1,3-benzothiazol-2-amine (0.32 g, 1.22 mmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (465.50 mg, 1.22 mmol) was added followed by TEA (247.76 mg, 2.45 mmol, 341.27 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and 0.61 g of the obtained crude product was purified by preparative (60-60-70% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min) , to obtain the product N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1, 3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (0.18 g, 397.73 μmol, 32.49% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.18(m,6H),1.36(m,1H),2.12(m,3H),2.48(m,2H),2.98(m,2H),3.12(m,2H),3.36(m,2H),4.12(m,1H),5.62(m,2H),7.02(m,1H),7.51(m,2H),7.68(m,1H),8.06(m,2H),10.58(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.18(m, 6H), 1.36(m, 1H), 2.12(m, 3H), 2.48(m, 2H), 2.98(m, 2H), 3.12(m, 2H), 3.36(m, 2H), 4.12(m, 1H), 5.62(m, 2H), 7.02(m, 1H), 7.51(m, 2H), 7.68(m, 1H), 8.06 (m, 2H), 10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=1.983min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=1.983 min.

步驟2：掌性分離(化合物896 及化合物884 )Step 2: Chiral separation ( compound 896 and compound 884 )

使N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.18g，397.73μmol)經歷掌性HPLC純化(管柱：IA-II(250*20,5mkm)，溶析液：己烷-IPA-MeOH，60-20-20，流速： 12mL/min)，以得到兩種單獨的鏡像異構物化合物884 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.026g，57.45μmol，14.44%產率)及化合物896 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(30.20mg，66.73μmol，16.78%產率)。make N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzene Thiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (0.18 g, 397.73 μmol) was purified by chiral HPLC (column: IA-II (250*20,5 mkm), Eluent: Hexane-IPA-MeOH, 60-20-20, flow rate: 12 mL/min) to give two separate enantiomer compounds 884 N- (6-amino-5-ethyl-3 -pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]- 2-Pendant oxyacetamide (0.026 g, 57.45 μmol, 14.44% yield) and compound 896 N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S ) -5-Methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (30.20 mg, 66.73 μmol, 16.78% yield).

化合物896 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為24.85min且化合物884 之保留時間為43.94min。The retention time of compound 896 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 24.85 min and the retention time of compound 884 was 43.94 min.

化合物896：保留時間：24.85minCompound 896: retention time: 24.85min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(m,6H),1.34(m,1H),1.70(m,1H),1.86(m,1H),2.01(m,1H),2.14(m,1H),2.24(m,1H),2.38(m,2H),2.92(m,3H),3.43(m,1H),5.63(m,3H),6.98(m,1H),7.34(d,1H),7.48(d,1H),7.64(m,1H),7.92(m,1H),8.03(d,1H),10.54(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03(m, 6H), 1.34(m, 1H), 1.70(m, 1H), 1.86(m, 1H), 2.01(m, 1H), 2.14(m, 1H), 2.24(m, 1H), 2.38(m, 2H), 2.92(m, 3H), 3.43(m, 1H), 5.63(m, 3H), 6.98(m, 1H), 7.34 (d, 1H), 7.48 (d, 1H), 7.64 (m, 1H), 7.92 (m, 1H), 8.03 (d, 1H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=2.047min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=2.047 min.

化合物884：保留時間：43.94minCompound 884: retention time: 43.94min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(m,6H),1.32(m,1H),1.71(m,1H),1.87(m,1H),2.01(d,1H),2.18(m,1H),2.38(m,3H),2.92(s,3H),3.43(m,1H),5.62(m,3H),6.98(dd,1H),7.34(d,1H),7.48(d,1H),7.64(m,1H),7.92(m,1H),8.03(d,1H),10.53(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03(m, 6H), 1.32(m, 1H), 1.71(m, 1H), 1.87(m, 1H), 2.01(d, 1H), 2.18(m,1H),2.38(m,3H),2.92(s,3H),3.43(m,1H),5.62(m,3H),6.98(dd,1H),7.34(d,1H),7.48 (d, 1H), 7.64 (m, 1H), 7.92 (m, 1H), 8.03 (d, 1H), 10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=2.051min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=2.051 min.

實例123.N -(5,6-二甲基吡啶-3-基)-2-(5-甲基-2-(2-(甲胺基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物828)之合成Example 123. N- (5,6-Lutidine-3-yl)-2-(5-methyl-2-(2-(methylamino)benzo[ d ]thiazol-5-yl)piperidine Synthesis of pyridin-1-yl)-2-oxoacetamide (compound 828)

Figure 110128222-A0202-12-1116-143
Figure 110128222-A0202-12-1116-143

在室溫下將HATU(436.40mg，1.15mmol)分批添加到2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(339.01mg，1.15mmol)、N -甲基-5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(300mg，1.15mmol)及TEA(696.83mg，6.89mmol，959.83μL)於DMF(13mL)中之懸浮液中。將澄清溶液在周圍溫度下攪拌18h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以40-55% 0-5min H2 O/MeCN/0.1% NH4 OH，流速：30ml/min為流動相)，以得到化合物828 N -(5,6-二甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(293mg，669.63μmol，58.34%產率)。HATU (436.40 mg, 1.15 mmol) was added portionwise to 2-[(5,6-dimethyl-3-pyridinyl)amino]-2-oxoacetic acid (339.01 mg, 1.15 mmol) at room temperature ), N -methyl-5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-amine (300 mg, 1.15 mmol) and TEA (696.83 mg) , 6.89 mmol, 959.83 μL) in DMF (13 mL). The clear solution was stirred at ambient temperature for 18 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase with 40-55% 0-5min H2O /MeCN/0.1% NH4OH , flow rate: 30ml/min) to give compounds 828 N- (5,6-Dimethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazole -5-yl]-1-piperidinyl]-2-oxoacetamide (293 mg, 669.63 μmol, 58.34% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.70-1.03(m,3H),1.11-1.36(m,1H),1.64-1.73(m,1H),1.79-1.92(m,1H),2.12-2.19(m,2H),2.20-2.27(m,3H),2.31-2.37(m,3H),2.78-3.26(m,4H),3.38-4.24(m,1H),5.07-6.70(m,1H),6.92-7.02(m,1H),7.28-7.39(m,1H),7.58-7.66(m,1H),7.72-7.86(m,1H),7.86-7.97(m,1H),8.36-8.53(m,1H),10.85-11.03(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.70-1.03(m,3H), 1.11-1.36(m,1H), 1.64-1.73(m,1H), 1.79-1.92(m,1H) ,2.12-2.19(m,2H),2.20-2.27(m,3H),2.31-2.37(m,3H),2.78-3.26(m,4H),3.38-4.24(m,1H),5.07-6.70( m,1H),6.92-7.02(m,1H),7.28-7.39(m,1H),7.58-7.66(m,1H),7.72-7.86(m,1H),7.86-7.97(m,1H), 8.36-8.53 (m, 1H), 10.85-11.03 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=1.992min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=1.992 min.

實例124. 5-[[2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物704)及5-[[2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物686)之合成Example 124. 5-[[2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carbamoylamine (Compound 704) and 5-[[2-[(2R,5S)-2-(5-acetamido-2-thienyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 686)

Figure 110128222-A0202-12-1117-144
Figure 110128222-A0202-12-1117-144

步驟1：5-[[2-[2-(5-乙醯胺基-2-噻吩基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(5-Acetamido-2-thienyl]-5-methyl-1-piperidinyl]-2-oxyacetamido]amino] Synthesis of pyridine-3-carboxamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(627.34mg，2.55mmol，HCl)及N-[5-(5-甲基-2-哌啶基)-2-噻吩基]乙醯胺(0.9g，2.55mmol，CF3 COOH)混合於DMF(15mL)中。將反應懸浮液冷卻至20℃且添加HATU(971.15mg，2.55mmol)，隨後添加TEA(1.29g，12.77mmol，1.78mL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且倒入到水(100ml)中且用EtOAc(2* 30ml)萃取。將經合併之有機萃取物用水(2* 30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，且藉由製備型(25-75% 0-5min水-甲醇，流速30ml/min)純化0.45g所獲得之粗產物，以得到產物5-[[2-[2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.100g，232.83μmol，9.12%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (627.34 mg, 2.55 mmol, HCl) and N-[5-(5-methyl-2- Piperidinyl)-2-thienyl]acetamide (0.9 g, 2.55 mmol, CF3COOH ) was mixed in DMF (15 mL). The reaction suspension was cooled to 20°C and HATU (971.15 mg, 2.55 mmol) was added followed by TEA (1.29 g, 12.77 mmol, 1.78 mL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and poured into water (100ml) and extracted with EtOAc (2 * 30ml). The combined organic extracts were washed with water (2 * 30ml), dried over sodium sulfate and evaporated in vacuo, and purified by prep (25-75% 0-5min water-methanol, flow rate 30ml/min) 0.45g The crude product obtained to give the product 5-[[2-[2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-pendoxoethyl Acyl]amino]pyridine-3-carboxamide (0.100 g, 232.83 μmol, 9.12% yield).

LCMS(ESI)：[M+H]+ m/z：計算值429.1；實測值430.0；Rt=1.948min。LCMS (ESI): [M+H] + m/z: calculated 429.1; found 430.0; Rt=1.948 min.

步驟2：5-[[2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物704 )及5-[[2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物686 )之合成Step 2: 5-[[2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carbamoylamine ( Compound 704 ) and 5-[[2-[(2R,5S)-2-(5-acetamido-2-thienyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 686 )

藉由掌性HPLC(管柱：OJ-H(250* 20，5mkm))，以己烷-IPA-MeOH，70-15-15，14ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物704 5-[[2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(37.20mg，86.61μmol，37.20%產率)及化合物686 5-[[2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0461g，107.34μmol，46.10%產率)。The enantiomers were separated by chiral HPLC (column: OJ-H (250 * 20, 5mkm) with hexane-IPA-MeOH, 70-15-15, 14ml/min as mobile phase) to give Two separate enantiomers Compound 704 5-[[2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (37.20 mg, 86.61 μmol, 37.20% yield) and compound 686 5-[[2-[(2R,5S)-2- (5-Acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amino]pyridine-3-carboxamide (0.0461 g, 107.34 g μmol, 46.10% yield).

化合物686： RT(IA，己烷-IPA-MeOH，70-15-15，0.6mL/min)=30.346min。 Compound 686: RT (IA, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 30.346 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.78(m,3H),1.30(m,2H),1.68(m,2H),1.88(m,1H),2.02(m,3H),2.21(m,1H),3.90(m,1H),5.53(m,1H),6.47(m,1H),6.69(m,1H),7.58(m,1H),8.15(m,1H),8.49(m,1H),8.81(m,2H),11.05(s,1H),11.23(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.78(m, 3H), 1.30(m, 2H), 1.68(m, 2H), 1.88(m, 1H), 2.02(m, 3H), 2.21(m,1H),3.90(m,1H),5.53(m,1H),6.47(m,1H),6.69(m,1H),7.58(m,1H),8.15(m,1H),8.49 (m, 1H), 8.81 (m, 2H), 11.05 (s, 1H), 11.23 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值429.2；實測值430.2；Rt=1.042min。LCMS (ESI): [M+H] + m/z: calculated 429.2; found 430.2; Rt=1.042 min.

化合物704： RT(IA，己烷-IPA-MeOH，70-15-15，0.6mL/min)=26.867min。 Compound 704: RT (IA, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 26.867 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.79(dd,3H),1.31(m,1H),1.68(m,2H),1.89(m,1H),2.01(m,3H),2.20(m,1H),2.72(m,1H),3.89(m,1H),5.53(m,1H),6.47(m,1H),6.69(m,1H),7.59(d,1H),8.15(d,1H),8.49(m,1H),8.75(m,1H),8.87(m,1H),11.05(s,1H),11.23(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.79(dd,3H), 1.31(m,1H), 1.68(m,2H), 1.89(m,1H), 2.01(m,3H), 2.20(m, 1H), 2.72(m, 1H), 3.89(m, 1H), 5.53(m, 1H), 6.47(m, 1H), 6.69(m, 1H), 7.59(d, 1H), 8.15 (d, 1H), 8.49 (m, 1H), 8.75 (m, 1H), 8.87 (m, 1H), 11.05 (s, 1H), 11.23 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值429.2；實測值430.2；Rt=1.041min。LCMS (ESI): [M+H] + m/z: calculated 429.2; found 430.2; Rt=1.041 min.

實例125. 5-(2-(2-(5-胺甲醯基噻吩-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物796及化合物792)之合成Example 125. 5-(2-(2-(5-Aminocarbamoylthiophen-2-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of Amines (Compound 796 and Compound 792)

Figure 110128222-A0202-12-1118-145
Figure 110128222-A0202-12-1118-145

步驟1：5-(2-(2-(5-胺甲醯基噻吩-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(2-(5-Aminocarbamoylthiophen-2-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of Amines

向5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(185mg，824.71μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(202.56mg，824.71μmol，HCl)及TEA(250.36mg，2.47mmol，344.84μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(344.94mg，907.18μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；20-40% 1-6 min水-MeOH(NH3 0.1%)，流速30ml/min)，得到5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(127mg，305.68μmol，37.07%產率)。To 5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (185 mg, 824.71 μmol), 2-[(5-aminocarbamoyl-3-pyridyl )amino]-2-oxoacetic acid (202.56 mg, 824.71 μmol, HCl) and TEA (250.36 mg, 2.47 mmol, 344.84 μL) in DMF (3 mL) to a stirred mixture of HATU (344.94 mg, 907.18 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um; 20-40% 1-6 min water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give 5- [[2-[( 2S,5R )-2-(5-Aminocarbamoyl-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (127 mg, 305.68 μmol, 37.07% yield).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.784min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.784 min.

步驟2：掌性分離(化合物796 及化合物792 )Step 2: Chiral separation ( compound 796 and compound 792 )

藉由掌性HPLC將5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1- 哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(59mg，142.01μmol)分成鏡像異構物(CHIRALPAC IB 250*20mm，5mkm；己烷-IPA-MeOH，70-15-15，流速：15ml/min，10mg/注入，6次注入)，得到：5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(24mg，57.77μmol，81.36%產率)(其中保留時間=27.71min)(化合物792 )及5-[[2-[(2R,5S )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(26mg，62.58μmol，88.14%產率)(其中保留時間=46.89min)(化合物796 )。5-[[2-[( 2S,5R )-2-(5-aminocarboxy-2-thienyl)-5-methyl-1-piperidinyl]-2-side was separated by chiral HPLC Oxyacetyl]amino]pyridine-3-carboxamide (59 mg, 142.01 μmol) split into enantiomers (CHIRALPAC IB 250*20 mm, 5 mkm; hexane-IPA-MeOH, 70-15-15, flow rate : 15 ml/min, 10 mg/injection, 6 injections) to give: 5-[[2-[( 2S,5R )-2-(5-aminocarbamoyl-2-thienyl)-5-methyl- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (24 mg, 57.77 μmol, 81.36% yield) (wherein retention time = 27.71 min) ( compound 792 ) and 5-[[2-[( 2R,5S )-2-(5-aminocarbamoyl-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (26 mg, 62.58 μmol, 88.14% yield) (wherein retention time = 46.89 min) ( compound 796 ).

化合物796 於分析條件下(管柱：IB，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為55.18min且化合物792 之保留時間為30.99min。The retention time of compound 796 under analytical conditions (column: IB, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 55.18 min and the retention time of compound 792 was 30.99 min.

化合物796：保留時間：55.18minCompound 796: retention time: 55.18min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.37-1.47(m,1H),1.76-1.86(m,1H),1.86-1.97(m,1H),1.99-2.04(m,1H),2.06-2.22(m,1H),2.88-2.93(m,0.4H),3.32-3.36(m,0.6H),3.44-4.09(m,1H),5.43-5.85(m,1H),7.01(s,1H),7.25-7.40(m,1H),7.55-7.67(m,2H),7.84-7.97(m,1H),8.10-8.20(m,1H),8.45-8.51(m,1H),8.71-8.91(m,2H),11.09-11.46(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,3H), 1.37-1.47(m,1H), 1.76-1.86(m,1H), 1.86-1.97(m,1H) ,1.99-2.04(m,1H),2.06-2.22(m,1H),2.88-2.93(m,0.4H),3.32-3.36(m,0.6H),3.44-4.09(m,1H),5.43- 5.85(m, 1H), 7.01(s, 1H), 7.25-7.40(m, 1H), 7.55-7.67(m, 2H), 7.84-7.97(m, 1H), 8.10-8.20(m, 1H), 8.45-8.51 (m, 1H), 8.71-8.91 (m, 2H), 11.09-11.46 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.699min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.699 min.

化合物792：保留時間：30.99minCompound 792: retention time: 30.99min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.01(m,3H),1.37-1.45(m,1H),1.77 -1.85(m,1H),1.87-1.98(m,1H),1.99-2.04(m,1H),2.06-2.21(m,1H),2.88-2.93(m,0.4H),3.32-3.35(m,0.6H),3.46-4.07(m,1H),5.43-5.87(m,1H),7.01(s,1H),7.27-7.40(m,1H),7.55-7.66(m,2H),7.86-7.97(m,1H),8.11-8.21(m,1H),8.44-8.52(m,1H),8.72-8.83(m,1H),8.83-8.91(m,1H),11.09-11.37(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.01(m,3H), 1.37-1.45(m,1H), 1.77-1.85(m,1H), 1.87-1.98(m,1H) ,1.99-2.04(m,1H),2.06-2.21(m,1H),2.88-2.93(m,0.4H),3.32-3.35(m,0.6H),3.46-4.07(m,1H),5.43- 5.87(m,1H),7.01(s,1H),7.27-7.40(m,1H),7.55-7.66(m,2H),7.86-7.97(m,1H),8.11-8.21(m,1H), 8.44-8.52(m,1H), 8.72-8.83(m,1H), 8.83-8.91(m,1H), 11.09-11.37(m,1H).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.699min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.699 min.

實例126. 5-(2-(2-(5-胺甲醯基噻吩-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物844及化合物837)之合成Example 126. 5-(2-(2-(5-Aminocarbamoylthiophen-2-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-2- Synthesis of Methoxynicotinamide (Compound 844 and Compound 837)

Figure 110128222-A0202-12-1120-146
Figure 110128222-A0202-12-1120-146

步驟1：5-(2-(2-(5-胺甲醯基噻吩-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺之合成Step 1: 5-(2-(2-(5-Aminocarbamoylthiophen-2-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-2- Synthesis of Methoxynicotinamide

向5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(190mg，847.00μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(202.59mg，847.00μmol)及TEA(171.42mg，1.69mmol，236.11μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(354.26mg，931.70μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(20-60% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(164mg，368.13μmol，43.46%產率)。To 5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (190 mg, 847.00 μmol), 2-[(5-aminocarbamoyl-6-methoxy To a stirred mixture of TEA (171.42 mg, 1.69 mmol, 236.11 μL) in DMF (3 mL) was added HATU (354.26 mg, 931.70 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. It was then subjected to HPLC (20-60% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 5-[[2- [( 2S,5R )-2-(5-Aminocarbamoyl-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2- Methoxypyridine-3-carboxamide (164 mg, 368.13 μmol, 43.46% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm) 1 H NMR (500MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值445.2；實測值446.2；Rt=2.187min。LCMS (ESI): [M] + m/z: calculated 445.2; found 446.2; Rt=2.187 min.

步驟2：掌性分離(化合物844 及化合物837 )Step 2: Chiral separation ( compound 844 and compound 837 )

藉由掌性HPLC(管柱：Chiralpak IA(250 x 20mm，5mkm)；流動相： 己烷-IPA-MeOH，50-25-25，流速：12mL/min；管柱溫度：24℃)將5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(164mg，368.13μmol)分成鏡像異構物，得到：5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(40mg，89.79μmol，48.78%產率)(其中保留時間=45.11min)(化合物844 )及5-[[2-[(2R,5S )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(40mg，89.79μmol，48.78%產率)(其中保留時間=77.66min)(化合物837 )。5 was separated by chiral HPLC (column: Chiralpak IA (250 x 20 mm, 5 mkm); mobile phase: hexane-IPA-MeOH, 50-25-25, flow rate: 12 mL/min; column temperature: 24°C). -[[2-[( 2S,5R )-2-(5-aminocarbamoyl-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]-2-methoxypyridine-3-carboxamide (164 mg, 368.13 μmol) split into the enantiomers to give: 5-[[2-[( 2S,5R )-2-(5-aminocarbamide yl-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (40 mg, 89.79 μmol , 48.78% yield) (wherein retention time=45.11 min) ( compound 844 ) and 5-[[2-[( 2R,5S )-2-(5-aminocarboxy-2-thienyl)-5- Methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (40 mg, 89.79 μmol, 48.78% yield) (wherein retention time = 77.66 min) ( compound 837 ).

化合物844 於分析條件下(管柱：IA，以己烷-IPA-MeOH，40-30-30，0.6ml/min為流動相)之保留時間為30.58min且化合物837 之保留時間為49.18min。The retention time of compound 844 under analytical conditions (column: IA, with hexane-IPA-MeOH, 40-30-30, 0.6 ml/min as mobile phase) was 30.58 min and the retention time of compound 837 was 49.18 min.

化合物844：保留時間：30.58minCompound 844: retention time: 30.58min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.00(m,3H),1.37-1.45(m,1H),1.75-1.84(m,1H),1.85-1.96(m,1H),1.98-2.04(m,1H),2.07-2.21(m,1H),2.88(d,1H),3.44-4.06(m,4H),5.43-5.81(m,1H),6.98-7.02(m,1H),7.29-7.35(m,1H),7.59-7.64(m,1H),7.68-7.76(m,2H),7.86-7.94(m,1H),8.42-8.49(m,1H),8.51-8.55(m,1H),10.99-11.04(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.00(m,3H), 1.37-1.45(m,1H), 1.75-1.84(m,1H), 1.85-1.96(m,1H) ,1.98-2.04(m,1H),2.07-2.21(m,1H),2.88(d,1H),3.44-4.06(m,4H),5.43-5.81(m,1H),6.98-7.02(m, 1H), 7.29-7.35(m, 1H), 7.59-7.64(m, 1H), 7.68-7.76(m, 2H), 7.86-7.94(m, 1H), 8.42-8.49(m, 1H), 8.51- 8.55 (m, 1H), 10.99-11.04 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值445.2；實測值446.2；Rt=1.016min。LCMS (ESI): [M] + m/z: calculated 445.2; found 446.2; Rt=1.016 min.

化合物837：保留時間：49.18minCompound 837: retention time: 49.18min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.00(m,3H),1.36-1.45(m,1H),1.76-1.94(m,2H),1.95-2.03(m,1H),2.05-2.19(m,1H),2.85-3.27(m,1H),3.44-4.07(m,4H),5.40-5.82(m,1H),6.93-7.06(m,1H),7.24-7.40(m,1H),7.55-7.67(m,1H),7.67-7.78(m,2H),7.83-7.97(m,1H),8.42-8.49(m,1H),8.51-8.56(m,1H),10.97-11.06(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.00(m,3H), 1.36-1.45(m,1H), 1.76-1.94(m,2H), 1.95-2.03(m,1H) ,2.05-2.19(m,1H),2.85-3.27(m,1H),3.44-4.07(m,4H),5.40-5.82(m,1H),6.93-7.06(m,1H),7.24-7.40( m,1H),7.55-7.67(m,1H),7.67-7.78(m,2H),7.83-7.97(m,1H),8.42-8.49(m,1H),8.51-8.56(m,1H), 10.97-11.06 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值445.2；實測值446.2；Rt=1.017min。LCMS (ESI): [M] + m/z: calculated 445.2; found 446.2; Rt=1.017 min.

實例127. 5-(1-(2-((6-胺基-5-乙基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)噻吩-2-甲醯胺(化合物845及化合物838)之合成Example 127. 5-(1-(2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxyethanoyl)-5-methylpiperidine-2 Synthesis of -yl)thiophene-2-carboxamide (Compound 845 and Compound 838)

Figure 110128222-A0202-12-1122-147
Figure 110128222-A0202-12-1122-147

步驟1：5-(1-(2-((6-胺基-5-乙基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)噻吩-2-甲醯胺之合成Step 1: 5-(1-(2-((6-Amino-5-ethylpyridin-3-yl)amino)-2-oxyacetyl)-5-methylpiperidine-2 Synthesis of -yl)thiophene-2-formamide

向5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(190mg，847.00μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(177.19mg，847.00μmol)及TEA(171.42mg，1.69mmol，236.11μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(354.26mg，931.70μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(25-50% 0-5min H2 O/ACN/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到5-[(2S,5R )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(147mg，353.78μmol，41.77%產率)。To 5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (190 mg, 847.00 μmol), 2-[(6-amino-5-ethyl-3 -Pyridinyl)amino]-2-pendoxoacetic acid (177.19 mg, 847.00 μmol) and TEA (171.42 mg, 1.69 mmol, 236.11 μL) in DMF (3 mL) was added HATU (354.26 mg) to a stirred mixture , 931.70 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. It was then subjected to HPLC (25-50% 0-5 min H2O /ACN/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 5-[( 2S, 5R )-1-[2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl] Thiophene-2-carboxamide (147 mg, 353.78 μmol, 41.77% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm) 1 H NMR (500MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.753min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.753 min.

步驟2：掌性分離(化合物845 及化合物838 )Step 2: Chiral separation ( compound 845 and compound 838 )

藉由掌性HPLC(管柱：Chiralpak IA(250*20，5mkm)，流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min。24℃)將5-[(2S,5R )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(147mg，353.78μmol)分成鏡像異構物，得到：5-[(2R,5S )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(60mg，144.40 μmol，81.63%產率)(其中保留時間=32.2min)(化合物845 )及5-[(2S,5R )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(68mg，163.66μmol，92.52%產率)(其中保留時間=43.5min)(化合物838 )。5-[( 2S ,5R )-1-[2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl ]thiophene-2-carboxamide (147 mg, 353.78 μmol) split into the enantiomers to give: 5-[( 2R,5S )-1-[2-[(6-amino-5-ethyl-3- Pyridinyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl]thiophene-2-carboxamide (60 mg, 144.40 μmol, 81.63% yield) (wherein retention time =32.2min) (Compound 845 ) and 5-[( 2S,5R )-1-[2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-side oxyethyl Acyl]-5-methyl-2-piperidinyl]thiophene-2-carboxamide (68 mg, 163.66 μmol, 92.52% yield) (wherein retention time = 43.5 min) (compound 838 ).

化合物845 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為35.87min且化合物838 之保留時間為54.27min。The retention time of compound 845 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 35.87 min and the retention time of compound 838 was 54.27 min.

化合物845：保留時間：35.87minCompound 845: retention time: 35.87min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.11(m,6H),1.34-1.44(m,1H),1.73-1.96(m,2H),1.96-2.17(m,2H),2.36-2.42(m,2H),2.82-3.28(m,1H),3.38-4.04(m,1H),5.38-5.83(m,3H),6.94-7.03(m,1H),7.23-7.39(m,1H),7.42-7.52(m,1H),7.58-7.65(m,1H),7.80-7.95(m,1H),7.95-8.06(m,1H),10.42-10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.11(m, 6H), 1.34-1.44(m, 1H), 1.73-1.96(m, 2H), 1.96-2.17(m, 2H) ,2.36-2.42(m,2H),2.82-3.28(m,1H),3.38-4.04(m,1H),5.38-5.83(m,3H),6.94-7.03(m,1H),7.23-7.39( m, 1H), 7.42-7.52 (m, 1H), 7.58-7.65 (m, 1H), 7.80-7.95 (m, 1H), 7.95-8.06 (m, 1H), 10.42-10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=0.915min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=0.915 min.

化合物838：保留時間：54.27minCompound 838: retention time: 54.27min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.01(m,3H),1.06-1.12(m,3H),1.34-1.44(m,1H),1.74-1.85(m,1H),1.85-1.96(m,1H),2.00-2.19(m,2H),2.33-2.36(m,1H),2.38-2.40(m,1H),3.29(s,1H),3.42-4.06(m,1H),5.39-5.80(m,3H),6.94-7.02(m,1H),7.32(s,1H),7.45-7.51(m,1H),7.59-7.65(m,1H),7.90(s,1H),7.97-8.06(m,1H),10.45-10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.01(m,3H), 1.06-1.12(m,3H), 1.34-1.44(m,1H), 1.74-1.85(m,1H) ,1.85-1.96(m,1H),2.00-2.19(m,2H),2.33-2.36(m,1H),2.38-2.40(m,1H),3.29(s,1H),3.42-4.06(m, 1H), 5.39-5.80(m, 3H), 6.94-7.02(m, 1H), 7.32(s, 1H), 7.45-7.51(m, 1H), 7.59-7.65(m, 1H), 7.90(s, 1H), 7.97-8.06 (m, 1H), 10.45-10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=0.916min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=0.916 min.

實例128. 2-甲氧基-5-(2-(5-甲基-2-(5-(甲基胺甲醯基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物833及化合物843)之合成Example 128. 2-Methoxy-5-(2-(5-methyl-2-(5-(methylaminocarboxy)thiophen-2-yl)piperidin-1-yl)-2-side Synthesis of oxyacetamido)nicotinamide (compound 833 and compound 843)

Figure 110128222-A0202-12-1124-148
Figure 110128222-A0202-12-1124-148

步驟1：2-甲氧基-5-(2-(5-甲基-2-(5-(甲基胺甲醯基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 2-Methoxy-5-(2-(5-methyl-2-(5-(methylaminocarboxy)thiophen-2-yl)piperidin-1-yl)-2-side Synthesis of oxyacetamido)nicotinamide

向N -甲基-5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(186mg，780.37μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(186.65mg，780.37μmol)及TEA(157.93mg，1.56mmol，217.54μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(326.39mg，858.41μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(30-50% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(185mg，402.60μmol，51.59%產率)。To N -methyl-5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (186 mg, 780.37 μmol), 2-[(5-aminocarbamoyl Stirring of -6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid (186.65 mg, 780.37 μmol) and TEA (157.93 mg, 1.56 mmol, 217.54 μL) in DMF (3 mL) To this mixture was added HATU (326.39 mg, 858.41 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. It was then subjected to HPLC (30-50% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 2-methoxy- 5-[[2-[( 2S,5R )-5-methyl-2-[5-(methylaminocarboxy)-2-thienyl]-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (185 mg, 402.60 μmol, 51.59% yield).

LCMS(ESI)：[M]+ m/z：計算值459.2；實測值460.2；Rt=2.264min。LCMS (ESI): [M] + m/z: calculated 459.2; found 460.2; Rt=2.264 min.

步驟2：掌性分離(化合物833 及化合物843 )Step 2: Chiral separation ( compound 833 and compound 843 )

藉由掌性HPLC(管柱：Chiralpak IA(250 x 20mm，5mkm)；流動相：己烷-IPA-MeOH，60-20-20，流速：12mL/min；管柱溫度：24℃)將2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(185mg，402.60μmol)分成鏡像異構物，得到：2-甲氧基 -5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(81mg，176.27μmol，87.57%產率)(其中保留時間=55.00min)(化合物843 )及2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(83mg，180.62μmol，89.73%產率)(其中保留時間=74.84min)(化合物833 )。2 was separated by chiral HPLC (column: Chiralpak IA (250 x 20 mm, 5 mkm); mobile phase: hexane-IPA-MeOH, 60-20-20, flow rate: 12 mL/min; column temperature: 24°C). -Methoxy-5-[[2-[( 2S,5R )-5-methyl-2-[5-(methylaminocarboxy)-2-thienyl]-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (185 mg, 402.60 μmol) split into enantiomers to give: 2-methoxy-5-[[2-[( 2S,5R )-5-methyl-2-[5-(methylaminocarbamoyl)-2-thienyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Formamide (81 mg, 176.27 μmol, 87.57% yield) (wherein retention time=55.00 min) ( compound 843 ) and 2-methoxy-5-[[2-[( 2R,5S )-5-methyl -2-[5-(Methylaminocarboxy)-2-thienyl]-1-piperidinyl]-2-oxyacetoxy]amino]pyridine-3-carboamide (83 mg, 180.62 μmol, 89.73% yield) (wherein retention time=74.84 min) ( compound 833 ).

化合物833 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為46.47min且化合物843 之保留時間為34.75min。The retention time of compound 833 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 46.47 min and the retention time of compound 843 was 34.75 min.

化合物833：保留時間：46.47minCompound 833: retention time: 46.47min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.02(m,3H),1.36-1.44(m,1H),1.72-1.85(m,1H),1.86-1.97(m,1H),1.98-2.04(m,1H),2.06-2.19(m,1H),2.69-2.74(m,3H),2.84-3.29(m,1H),3.44-4.07(m,4H),5.43-5.80(m,1H),6.97-7.04(m,1H),7.54-7.61(m,1H),7.68-7.77(m,2H),8.34-8.42(m,1H),8.44-8.49(m,1H),8.52-8.56(m,1H),10.95-11.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.02(m,3H), 1.36-1.44(m,1H), 1.72-1.85(m,1H), 1.86-1.97(m,1H) ,1.98-2.04(m,1H),2.06-2.19(m,1H),2.69-2.74(m,3H),2.84-3.29(m,1H),3.44-4.07(m,4H),5.43-5.80( m,1H),6.97-7.04(m,1H),7.54-7.61(m,1H),7.68-7.77(m,2H),8.34-8.42(m,1H),8.44-8.49(m,1H), 8.52-8.56 (m, 1H), 10.95-11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值459.2；實測值460.2；Rt=0.958min。LCMS (ESI): [M] + m/z: calculated 459.2; found 460.2; Rt=0.958 min.

化合物843：保留時間：34.75minCompound 843: retention time: 34.75min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.01(m,3H),1.37-1.44(m,1H),1.72-1.95(m,2H),1.96-2.04(m,1H),2.08-2.22(m,1H),2.67-2.76(m,3H),2.84-3.29(m,1H),3.45-4.05(m,4H),5.41-5.81(m,1H),6.96-7.03(m,1H),7.53-7.60(m,1H),7.67-7.77(m,2H),8.32-8.43(m,1H),8.43-8.49(m,1H),8.51-8.55(m,1H),11.00-11.05(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.01(m,3H), 1.37-1.44(m,1H), 1.72-1.95(m,2H), 1.96-2.04(m,1H) ,2.08-2.22(m,1H),2.67-2.76(m,3H),2.84-3.29(m,1H),3.45-4.05(m,4H),5.41-5.81(m,1H),6.96-7.03( m,1H),7.53-7.60(m,1H),7.67-7.77(m,2H),8.32-8.43(m,1H),8.43-8.49(m,1H),8.51-8.55(m,1H), 11.00-11.05 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值459.2；實測值460.2；Rt=0.958min。LCMS (ESI): [M] + m/z: calculated 459.2; found 460.2; Rt=0.958 min.

實例129. 5-(1-(2-((6-胺基-5-乙基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)-N -甲基噻吩-2-甲醯胺(化合物840及化合物835)之合成Example 129. 5-(1-(2-((6-amino-5-ethylpyridin-3-yl)amino)-2-oxyethanoyl)-5-methylpiperidine-2 Synthesis of -yl) -N -methylthiophene-2-carboxamide (Compound 840 and Compound 835)

Figure 110128222-A0202-12-1126-149
Figure 110128222-A0202-12-1126-149

步驟1：5-(1-(2-((6-胺基-5-乙基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)-N-甲基噻吩-2-甲醯胺之合成Step 1: 5-(1-(2-((6-Amino-5-ethylpyridin-3-yl)amino)-2-oxyacetyl)-5-methylpiperidine-2 -Synthesis of -N-methylthiophene-2-formamide

向N -甲基-5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(186mg，780.37μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(163.26mg，780.37μmol)及TEA(157.93mg，1.56mmol，217.54μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(326.39mg，858.41μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(20-45% 0-5min H2 O/ACN/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到5-[(2S,5R )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基-噻吩-2-甲醯胺(145mg，337.57μmol，43.26%產率)。To N -methyl-5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (186 mg, 780.37 μmol), 2-[(6-amino-5 -Ethyl-3-pyridyl)amino]-2-pendoxoacetic acid (163.26 mg, 780.37 μmol) and TEA (157.93 mg, 1.56 mmol, 217.54 μL) in a stirred mixture of DMF (3 mL) HATU (326.39 mg, 858.41 μmol) was added. The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (20-45% 0-5min H2O /ACN/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 5-[( 2S, 5R )-1-[2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl] - N -Methyl-thiophene-2-carboxamide (145 mg, 337.57 μmol, 43.26% yield).

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.942min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.942 min.

步驟2：掌性分離(化合物840 及化合物835 )Step 2: Chiral separation ( compound 840 and compound 835 )

藉由掌性HPLC(管柱：Chiralpak AD-H(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：11mL/min；管柱溫度：20℃)將5-[(2S,5R )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基 -噻吩-2-甲醯胺(145mg，337.57μmol)分成鏡像異構物，得到：5-[(2S,5R )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基 -噻吩-2-甲醯胺(76mg，176.94μmol，52.41%產率)(其中保留時間=30.25min)(化合物835 )及5-[(2R,5S )-1-[2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基-噻吩-2-甲醯胺(88mg，204.87μmol，60.69%產率)(其中保留時間=64.89min)(化合物840 )。By chiral HPLC (column: Chiralpak AD-H (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 11 mL/min; column temperature: 20°C) 5-[( 2S,5R )-1-[2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl -2-Piperidinyl] -N - methyl -thiophene-2-carboxamide (145 mg, 337.57 μmol) split into the enantiomers to give: 5-[( 2S,5R )-1-[2-[( 6-Amino-5-ethyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl] -N - methyl -thiophene-2- Formamide (76 mg, 176.94 μmol, 52.41% yield) (wherein retention time=30.25 min) ( compound 835 ) and 5-[( 2R,5S )-1-[2-[(6-amino-5- Ethyl-3-pyridinyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl] -N -methyl-thiophene-2-carboxamide (88 mg, 204.87 μmol, 60.69% yield) (wherein retention time=64.89 min) ( compound 840 ).

化合物840 於分析條件下(管柱：AD-H，己烷-IPA-MeOH，40-30-30，0.6ml/min為流動相)之保留時間為50.87min且化合物835 之保留時間為25.71min。The retention time of compound 840 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 40-30-30, 0.6 ml/min as mobile phase) was 50.87 min and the retention time of compound 835 was 25.71 min .

化合物840：保留時間：50.87minCompound 840: retention time: 50.87min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.01(m,3H),1.07-1.12(m,3H),1.35-1.44(m,1H),1.73-1.84(m,1H),1.86-2.04(m,2H),2.05-2.18(m,1H),2.36-2.41(m,2H),2.69-2.74(m,3H),2.82-3.28(m,1H),3.41-4.06(m,1H),5.41-5.78(m,3H),6.95-7.03(m,1H),7.44-7.50(m,1H),7.53-7.59(m,1H),7.99-8.05(m,1H),8.34-8.40(m,1H),10.46-10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.01(m,3H), 1.07-1.12(m,3H), 1.35-1.44(m,1H), 1.73-1.84(m,1H) ,1.86-2.04(m,2H),2.05-2.18(m,1H),2.36-2.41(m,2H),2.69-2.74(m,3H),2.82-3.28(m,1H),3.41-4.06( m,1H),5.41-5.78(m,3H),6.95-7.03(m,1H),7.44-7.50(m,1H),7.53-7.59(m,1H),7.99-8.05(m,1H), 8.34-8.40 (m, 1H), 10.46-10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.753min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.753 min.

化合物835：保留時間：25.71minCompound 835: retention time: 25.71min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.01(m,3H),1.06-1.12(m,3H),1.34-1.44(m,1H),1.74-1.84(m,1H),1.86-2.03(m,2H),2.04-2.17(m,1H),2.36-2.41(m,2H),2.69-2.75(m,3H),2.82-3.28(m,1H),3.33-4.06(m,1H),5.39-5.81(m,3H),6.95-7.03(m,1H),7.45-7.52(m,1H),7.53-7.60(m,1H),8.01-8.05(m,1H),8.34-8.39(m,1H),10.47-10.52(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.01(m,3H), 1.06-1.12(m,3H), 1.34-1.44(m,1H), 1.74-1.84(m,1H) ,1.86-2.03(m,2H),2.04-2.17(m,1H),2.36-2.41(m,2H),2.69-2.75(m,3H),2.82-3.28(m,1H),3.33-4.06( m,1H),5.39-5.81(m,3H),6.95-7.03(m,1H),7.45-7.52(m,1H),7.53-7.60(m,1H),8.01-8.05(m,1H), 8.34-8.39 (m, 1H), 10.47-10.52 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=0.975min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=0.975min.

實例130. 5-(2-(5-甲基-2-(5-(甲基胺甲醯基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物839及化合物829)之合成Example 130. 5-(2-(5-Methyl-2-(5-(methylaminocarboxy)thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido ) Synthesis of Nicotinamide (Compound 839 and Compound 829)

Figure 110128222-A0202-12-1127-150
Figure 110128222-A0202-12-1127-150

步驟1：5-(2-(5-甲基-2-(5-(甲基胺甲醯基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(5-(methylaminocarboxy)thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido ) Synthesis of Nicotinamide

向N -甲基-5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(186mg，780.37 μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(191.67mg，780.37μmol，HCl)及TEA(236.90mg，2.34mmol，326.30μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(326.39mg，858.41μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(20-45% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(195mg，454.02μmol，58.18%產率)。To N -methyl-5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (186 mg, 780.37 μmol), 2-[(5-aminocarbamoyl -3-Pyridinyl)amino]-2-side oxyacetic acid (191.67 mg, 780.37 μmol, HCl) and TEA (236.90 mg, 2.34 mmol, 326.30 μL) in DMF (3 mL) were added to a stirred mixture HATU (326.39 mg, 858.41 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. It was then subjected to HPLC (20-45% 0-5min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give 5-[[2- [( 2S,5R )-5-methyl-2-[5-(methylaminocarbamoyl)-2-thienyl]-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (195 mg, 454.02 μmol, 58.18% yield).

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.898min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.898 min.

步驟2：掌性分離(化合物839 及化合物829 )Step 2: Chiral separation ( compound 839 and compound 829 )

藉由掌性HPLC(管柱：Chiralpak IA(250*20，5mkm)，流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min，管柱溫度24℃)將5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(195mg，454.02μmol)分成鏡像異構物，得到：5-[[2-[(2R,5S )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(45mg，104.77μmol，46.15%產率)(其中保留時間=27.9min)(化合物839 )及5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(48mg，111.76μmol，49.23%產率)(其中保留時間=35.6min)(化合物829 )。The 5- [[2-[( 2S,5R )-5-methyl-2-[5-(methylaminocarboxy)-2-thienyl]-1-piperidinyl]-2-side oxyacetyl yl]amino]pyridine-3-carboxamide (195 mg, 454.02 μmol) split into the enantiomers to give: 5-[[2-[( 2R,5S )-5-methyl-2-[5-( Methylaminocarboxy)-2-thienyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carbamoylamine (45 mg, 104.77 μmol, 46.15% yield ) (wherein retention time=27.9min) ( compound 839 ) and 5-[[2-[( 2S,5R )-5-methyl-2-[5-(methylaminocarboxy)-2-thienyl ]-1-piperidinyl]-2-oxyacetoxy]amino]pyridine-3-carboxamide (48 mg, 111.76 μmol, 49.23% yield) (wherein retention time = 35.6 min) ( Compound 829 ).

化合物839 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為20.57min且化合物829 之保留時間為25.04min。The retention time of compound 839 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 20.57 min and the retention time of compound 829 was 25.04 min.

化合物839：保留時間：20.57minCompound 839: retention time: 20.57min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.92-1.06(m,3H),1.36-1.46(m,1H),1.74-1.97(m,2H),2.00-2.21(m,2H),2.69-2.76(m,3H),2.85-3.28(m,1H),3.45-4.08(m,1H),5.42-5.82(m,1H),6.95-7.05(m,1H),7.53-7.64(m,2H),8.10-8.19(m, 1H),8.35-8.43(m,1H),8.45-8.52(m,1H),8.73-8.79(m,1H),8.87-8.91(m,1H),11.20-11.30(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.92-1.06(m,3H), 1.36-1.46(m,1H), 1.74-1.97(m,2H), 2.00-2.21(m,2H) ,2.69-2.76(m,3H),2.85-3.28(m,1H),3.45-4.08(m,1H),5.42-5.82(m,1H),6.95-7.05(m,1H),7.53-7.64( m,2H),8.10-8.19(m,1H),8.35-8.43(m,1H),8.45-8.52(m,1H),8.73-8.79(m,1H),8.87-8.91(m,1H), 11.20-11.30 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.000min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.000 min.

化合物829：保留時間：25.04minCompound 829: retention time: 25.04min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.01(m,3H),1.37-1.45(m,1H),1.74-1.91(m,2H),1.91-2.02(m,1H),2.07-2.18(m,1H),2.66-2.77(m,3H),2.87-3.29(m,1H),3.33-4.08(m,1H),5.42-5.83(m,1H),6.98-7.08(m,1H),7.50-7.66(m,2H),8.07-8.21(m,1H),8.32-8.44(m,1H),8.44-8.51(m,1H),8.68-8.81(m,1H),8.83-8.93(m,1H),11.18-11.30(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.01(m,3H), 1.37-1.45(m,1H), 1.74-1.91(m,2H), 1.91-2.02(m,1H) ,2.07-2.18(m,1H),2.66-2.77(m,3H),2.87-3.29(m,1H),3.33-4.08(m,1H),5.42-5.83(m,1H),6.98-7.08( m,1H),7.50-7.66(m,2H),8.07-8.21(m,1H),8.32-8.44(m,1H),8.44-8.51(m,1H),8.68-8.81(m,1H), 8.83-8.93 (m, 1H), 11.18-11.30 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=0.999min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=0.999 min.

實例131. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物579)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物589)之合成Example 131. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl -1-Piperidinyl]-2-oxyacetamide (Compound 579) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S) - Synthesis of 2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 589)

Figure 110128222-A0202-12-1129-151
Figure 110128222-A0202-12-1129-151

步驟1：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1 -Piperidinyl]-2-Side Oxyacetamide Synthesis

向2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(0.5g，2.39mmol)、5-[(2R,5S)-5-甲基-2-哌啶基]-1H-吲唑(321.60mg，1.49mmol)及三乙胺(906.93mg，8.96mmol，1.25mL)於DMF(5.0mL)中之溶液中分批添加HATU (681.57mg，1.79mmol)。將所得混合物在50℃下攪拌3h且使其經歷HPLC(40-40-80% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量406，管柱：YMC Triart C18 100* 20mm，5um)，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.2g，492.03μmol，32.94%產率)。此化合物不經HNMR即用於掌性拆分。To 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (0.5 g, 2.39 mmol), 5-[(2R,5S)-5-methyl To a solution of yl-2-piperidinyl]-1H-indazole (321.60 mg, 1.49 mmol) and triethylamine (906.93 mg, 8.96 mmol, 1.25 mL) in DMF (5.0 mL) was added HATU (681.57 g mg, 1.79 mmol). The resulting mixture was stirred at 50 °C for 3 h and subjected to HPLC (40-40-80% 0-1-5 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 406 , column: YMC Triart C18 100 * 20mm, 5um) to give N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indium Azol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (0.2 g, 492.03 μmol, 32.94% yield). This compound was used for chiral resolution without HNMR.

步驟2：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之掌性分離Step 2: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1 Chiral separation of -piperidinyl]-2-oxoacetamide

對N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.2g，492.03μmol)進行掌性分離(樣品資訊：IC-I(250* 20，5mkm)，己烷-IPA-MeOH，50-25-25，流速12ml/min)，以獲得化合物579 rel-2-((2R,5S)-2-(1H-吲唑-5-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺(92mg，226.33μmol，92.00%產率)及化合物589 rel-2-((2R,5S)-2-(1H-吲唑-5-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺(88mg，216.49μmol，88.00%產率)。p-N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidine Chiral separation of pyridyl]-2-oxyacetamide (0.2 g, 492.03 μmol) (sample info: IC-I (250 * 20, 5 mkm), Hexane-IPA-MeOH, 50-25-25 , flow rate 12ml/min) to obtain compound 579 rel-2-((2R,5S)-2-(1H-indazol-5-yl)-5-methylpiperidin-1-yl)-N-( 6-Amino-5-ethylpyridin-3-yl)-2-oxyacetamide (92 mg, 226.33 μmol, 92.00% yield) and compound 589 rel-2-((2R,5S)-2 -(1H-Indazol-5-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5-ethylpyridin-3-yl)-2-side oxyacetyl Amine (88 mg, 216.49 μmol, 88.00% yield).

化合物579： RT(IB，己烷-IPA-MeOH，50-25-25，0.6ml/min)=9.16min。 Compound 579: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 9.16 min.

1 H NMR(600MHz,DMSO-d6 )δ 1.00-1.04(m,4H),1.05-1.14(m,3H),1.29-1.38(m,1H),1.71-1.80(m,1H),1.80-1.89(m,1H),2.03-2.16(m,1H),2.22-2.30(m,1H),2.38-2.41(m,1H),2.72-3.24(m,1H),3.43-4.03(m,1H),5.20-5.60(m,1H),5.61-5.71(m,2H),7.25-7.38(m,1H),7.41-7.50(m,1H),7.51-7.56(m,1H),7.66-7.73(m,1H),7.95-8.03(m,1H),8.03-8.09(m,1H),10.43-10.58(m,1H),13.01(s,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.00-1.04(m,4H), 1.05-1.14(m,3H), 1.29-1.38(m,1H), 1.71-1.80(m,1H), 1.80- 1.89(m,1H), 2.03-2.16(m,1H), 2.22-2.30(m,1H), 2.38-2.41(m,1H), 2.72-3.24(m,1H), 3.43-4.03(m,1H) ),5.20-5.60(m,1H),5.61-5.71(m,2H),7.25-7.38(m,1H),7.41-7.50(m,1H),7.51-7.56(m,1H),7.66-7.73 (m, 1H), 7.95-8.03 (m, 1H), 8.03-8.09 (m, 1H), 10.43-10.58 (m, 1H), 13.01 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=3.684min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=3.684 min.

化合物589： RT(IB，己烷-IPA-MeOH，50-25-25，0.6ml/min)=12.20min。 Compound 589: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 12.20 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.97-1.14(m,6H),1.28-1.42(m,1H),1.68-1.80 (m,1H),1.80-1.92(m,1H),2.00-2.21(m,1H),2.23-2.30(m,1H),2.31-2.35(m,1H),2.37-2.41(m,1H),2.71-3.26(m,1H),3.40-4.04(m,1H),5.18-5.60(m,1H),5.61-5.74(m,2H),7.23-7.38(m,1H),7.38-7.57(m,2H),7.65-7.73(m,1H),7.95-8.09(m,2H),10.44-10.57(m,1H),13.01(s,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ 0.97-1.14 (m, 6H), 1.28-1.42 (m, 1H), 1.68-1.80 (m, 1H), 1.80-1.92 (m, 1H), 2.00- 2.21(m,1H), 2.23-2.30(m,1H), 2.31-2.35(m,1H), 2.37-2.41(m,1H), 2.71-3.26(m,1H), 3.40-4.04(m,1H) ), 5.18-5.60(m, 1H), 5.61-5.74(m, 2H), 7.23-7.38(m, 1H), 7.38-7.57(m, 2H), 7.65-7.73(m, 1H), 7.95-8.09 (m, 2H), 10.44-10.57 (m, 1H), 13.01 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=1.957min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=1.957 min.

實例132. 5-[[2-[(2S,SR)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物495)、5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物587)及5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物588)之合成Example 132. 5-[[2-[(2S,SR)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide (compound 495), 5-[[2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl yl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 587) and 5-[[2-[(2R,5S)-2-(1 Synthesis of ,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 588)

Figure 110128222-A0202-12-1131-152
Figure 110128222-A0202-12-1131-152

步驟1.5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物495 )之合成Step 1. 5-[[2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl Synthesis of ]amino]pyridine-3-carboxamide ( compound 495 )

在室溫下將HATU(654.60mg，1.72mmol)分批添加到2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(422.86mg，1.72mmol，HCl)、5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(400mg，1.72mmol)及TEA(1.05g，10.33mmol，1.44mL)於DMF(10mL)中之懸浮液中。將澄清溶液在25℃下攪拌32h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以30-60% 0-5min 0.1% NH3 -甲醇，流速：30ml/min為流動相)，以得到化 合物495 5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(290mg，684.79μmol，39.78%產率)。HATU (654.60 mg, 1.72 mmol) was added portionwise to 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-pendoxoacetic acid (422.86 mg, 1.72 mmol, HCl), 5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (400 mg, 1.72 mmol) and TEA (1.05 g, 10.33 mmol, 1.44 mL) in DMF (10 mL) in suspension. The clear solution was stirred at 25 °C for 32 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; with 30-60% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min as mobile phase) to give compound 495 5- [[2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (290 mg, 684.79 μmol, 39.78% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.09(m,3H),1.31-1.44(m,1H),1.67-1.77(m,1H),1.81-1.97(m,1H),2.07-2.24(m,1H),2.29-2.36(m,1H),2.81-3.29(m,1H),3.46-4.12(m,1H),5.28-5.79(m,1H),7.42-7.52(m,1H),7.52-7.65(m,1H),8.01-8.06(m,1H),8.09-8.24(m,2H),8.35-8.54(m,1H),8.69-8.79(m,1H),8.81-8.93(m,1H),9.35-9.43(m,1H),11.05-11.46(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.09(m,3H), 1.31-1.44(m,1H), 1.67-1.77(m,1H), 1.81-1.97(m,1H), 2.07- 2.24(m,1H), 2.29-2.36(m,1H), 2.81-3.29(m,1H), 3.46-4.12(m,1H), 5.28-5.79(m,1H), 7.42-7.52(m,1H) ),7.52-7.65(m,1H),8.01-8.06(m,1H),8.09-8.24(m,2H),8.35-8.54(m,1H),8.69-8.79(m,1H),8.81-8.93 (m, 1H), 9.35-9.43 (m, 1H), 11.05-11.46 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值242.0；Rt=2.322min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 242.0; Rt=2.322 min.

步驟2.5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物587 )及5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物588 )之合成Step 2. 5-[[2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide ( compound 587 ) and 5-[[2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carbamoylamine ( Compound 588 )

使用(Chiralpak IA-I(250 * 20mm,5mkm)管柱；以己烷-IPA-MeOH 40-30-30為流動相；流速：12mL/min；2pins，60mg/1pin)對5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(125.6mg，296.59μmol)進行掌性分離，得到呈黃色固體之化合物587 5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(52.93mg，124.99μmol，42.14%產率)(RT(IA，己烷-IPA-MeOH，40-30-30，0.6ml/min)=44.85min)及呈米色固體之化合物588 5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50.51mg，119.27μmol，40.21%產率)(RT(IA，己烷-IPA-MeOH，40-30-30，0.6ml/min=72.39min)。5-[[2 -[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]pyridine- Chiral separation of 3-formamide (125.6 mg, 296.59 μmol) afforded compound 587 as a yellow solid 5-[[2-[(2S,5R)-2-(1,3-benzothiazole-5- (52.93 mg, 124.99 μmol, 42.14% yield) (RT(IA) , hexane-IPA-MeOH, 40-30-30, 0.6ml/min)=44.85min) and compound 588 as a beige solid 5-[[2-[(2R,5S)-2-(1,3- Benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (50.51 mg, 119.27 μmol, 40.21% yield rate) (RT(IA, Hexane-IPA-MeOH, 40-30-30, 0.6 ml/min=72.39 min).

化合物587： 1H NMR(600MHz,DMSO-d 6 )δ 1.00-1.09(m,3H),1.32-1.45(m,1H),1.68-1.76(m,1H),1.83-1.98(m,1H),2.05-2.32(m,1H),2.32-2.37(m,1H),2.80-3.27(m,1H),3.48-4.08(m,1H),5.30-5.76(m,1H),7.42-7.53(m,1H),7.53 -7.66(m,1H),8.00-8.05(m,1H),8.08-8.23(m,2H),8.39-8.52(m,1H),8.69-8.79(m,1H),8.80-8.93(m,1H),9.36-9.41(m,1H),11.15-11.40(m,1H)。 Compound 587: 1H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.09 (m, 3H), 1.32-1.45 (m, 1H), 1.68-1.76 (m, 1H), 1.83-1.98 (m, 1H), 2.05-2.32(m, 1H), 2.32-2.37(m, 1H), 2.80-3.27(m, 1H), 3.48-4.08(m, 1H), 5.30-5.76(m, 1H), 7.42-7.53(m ,1H),7.53 -7.66(m,1H),8.00-8.05(m,1H),8.08-8.23(m,2H),8.39-8.52(m,1H),8.69-8.79(m,1H),8.80 -8.93(m, 1H), 9.36-9.41(m, 1H), 11.15-11.40(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值242.2；Rt=2.381min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 242.2; Rt=2.381 min.

化合物588： 1H NMR(600MHz,DMSO-d 6 )δ 1.00-1.09(m,3H),1.32-1.45(m,1H),1.68-1.76(m,1H),1.83-1.98(m,1H),2.05-2.32(m,1H),2.32-2.37(m,1H),2.80-3.27(m,1H),3.48-4.08(m,1H),5.30-5.76(m,1H),7.42-7.53(m,1H),7.53-7.66(m,1H),8.00-8.05(m,1H),8.08-8.23(m,2H),8.39-8.52(m,1H),8.69-8.79(m,1H),8.80-8.93(m,1H),9.36-9.41(m,1H),11.15-11.40(m,1H)。 Compound 588: 1H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.09 (m, 3H), 1.32-1.45 (m, 1H), 1.68-1.76 (m, 1H), 1.83-1.98 (m, 1H), 2.05-2.32(m, 1H), 2.32-2.37(m, 1H), 2.80-3.27(m, 1H), 3.48-4.08(m, 1H), 5.30-5.76(m, 1H), 7.42-7.53(m ,1H),7.53-7.66(m,1H),8.00-8.05(m,1H),8.08-8.23(m,2H),8.39-8.52(m,1H),8.69-8.79(m,1H),8.80 -8.93(m, 1H), 9.36-9.41(m, 1H), 11.15-11.40(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值242.2；Rt=2.380min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 242.2; Rt=2.380 min.

實例133. rel-5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物603)及rel-5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物602)之合成Example 133. rel-5-[[2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-2-methoxypyridine-3-carboxamide (Compound 603) and rel-5-[[2-[(2R,5S)-2-(1,3-benzoyl) Synthesis of thiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (compound 602)

Figure 110128222-A0202-12-1133-153
Figure 110128222-A0202-12-1133-153

步驟1：5-[[2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(1,3-Benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Synthesis of -2-methoxypyridine-3-carboxamide

在室溫下將HATU(490.95mg，1.29mmol)分批添加到2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(439.49mg，1.29mmol，C6H15N)、5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(300mg，1.29mmol)及TEA(783.93mg，7.75mmol，1.08mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；以0-5min 20-70%水-甲醇(NH3 0.1%)，流速：30ml/min為 流動相)，以得到5-[[2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(214mg，471.87μmol，36.55%產率)。HATU (490.95 mg, 1.29 mmol) was added portionwise to 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid ( 439.49 mg, 1.29 mmol, C6H15N), 5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (300 mg, 1.29 mmol) and TEA (783.93 mg, 7.75 mmol, 1.08 mL) in suspension in DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 0-5min 20-70% water-methanol ( NH3 0.1%), flow rate: 30ml/min as mobile phase) , to give 5-[[2-[2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] -2-Methoxypyridine-3-carboxamide (214 mg, 471.87 μmol, 36.55% yield).

LCMS(ESI)：[M+H]+ m/z：計算值453.2；實測值454.2；Rt=2.724min。LCMS (ESI): [M+H] + m/z: calculated 453.2; found 454.2; Rt=2.724 min.

步驟2：rel-5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物603 )及rel-5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物602 )之合成Step 2: rel-5-[[2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-2-methoxypyridine-3-carboxamide ( Compound 603 ) and rel-5-[[2-[(2R,5S)-2-(1,3-benzoyl) Synthesis of Thiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( Compound 602 )

藉由掌性HPLC(管柱：IC-I(250*20，5mkm)，以己烷-IPA-MeOH，50-25-25，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物603 5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(44mg，97.02μmol，41.12%產率)(保留時間=69.1min)及化合物602 5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(62mg，136.71μmol，57.94%產率)(保留時間=96.6min)。The enantiomers were separated by chiral HPLC (column: IC-I (250*20, 5mkm) with hexane-IPA-MeOH, 50-25-25, 12ml/min as mobile phase) to give two An individual enantiomer compound 603 5-[[2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (44 mg, 97.02 μmol, 41.12% yield) (retention time=69.1 min) and compound 602 5-[[ 2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]- 2-Methoxypyridine-3-carboxamide (62 mg, 136.71 μmol, 57.94% yield) (retention time = 96.6 min).

化合物603： RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=49.073min。 Compound 603: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 49.073 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.05(m,3H),1.32-1.42(m,1H),1.68-1.76(m,1H),1.83-1.94(m,1H),2.07-2.22(m,1H),2.28-2.35(m,1H),2.80-3.26(m,1H),3.51-4.10(m,4H),5.28-5.77(m,1H),7.39-7.53(m,1H),7.66-7.80(m,2H),7.97-8.07(m,1H),8.12-8.20(m,1H),8.39-8.59(m,2H),9.36-9.41(m,1H),11.01-11.17(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.01-1.05(m,3H), 1.32-1.42(m,1H), 1.68-1.76(m,1H), 1.83-1.94(m,1H), 2.07- 2.22(m,1H),2.28-2.35(m,1H),2.80-3.26(m,1H),3.51-4.10(m,4H),5.28-5.77(m,1H),7.39-7.53(m,1H) ),7.66-7.80(m,2H),7.97-8.07(m,1H),8.12-8.20(m,1H),8.39-8.59(m,2H),9.36-9.41(m,1H),11.01-11.17 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值453.1；實測值454.2；Rt=4.695min。LCMS (ESI): [M+H] + m/z: calculated 453.1; found 454.2; Rt=4.695 min.

化合物602： RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=67.435min。 Compound 602: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 67.435 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.06(m,3H),1.32-1.40(m,1H),1.69-1.75(m,1H),1.83-1.93(m,1H),2.08-2.23(m,1H),2.29-2.35(m,1H),2.77-3.28(m, 1H),3.50-4.09(m,4H),5.26-5.75(m,1H),7.41-7.51(m,1H),7.65-7.78(m,2H),8.00-8.04(m,1H),8.14-8.20(m,1H),8.38-8.57(m,2H),9.35-9.44(m,1H),10.98-11.21(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.01-1.06(m,3H), 1.32-1.40(m,1H), 1.69-1.75(m,1H), 1.83-1.93(m,1H), 2.08- 2.23(m, 1H), 2.29-2.35(m, 1H), 2.77-3.28(m, 1H), 3.50-4.09(m, 4H), 5.26-5.75(m, 1H), 7.41-7.51(m, 1H) ),7.65-7.78(m,2H),8.00-8.04(m,1H),8.14-8.20(m,1H),8.38-8.57(m,2H),9.35-9.44(m,1H),10.98-11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值453.1；實測值454.0；Rt=4.695min。LCMS (ESI): [M+H] + m/z: calculated 453.1; found 454.0; Rt=4.695 min.

實例134. 2-甲氧基-5-[[2-[5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1077)之合成Example 134. 2-Methoxy-5-[[2-[5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl] Synthesis of -2-oxyacetoxy]amino]pyridine-3-carboxamide (compound 1077)

Figure 110128222-A0202-12-1135-154
Figure 110128222-A0202-12-1135-154

步驟1：2-甲氧基-5-[[2-[5-甲基-2-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-[5-methyl-2-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5 -Synthesis of -naphthyridin-2-yl]-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide

向2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(100mg，0.418mmol，TEA)、6-(5-甲基-2-哌啶基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(300mg，0.803mmol)、HATU(250mg，0.658mmol)於DMF(8mL)中之溶液中添加DIEA(300μL，1.72mmol)。將混合物在20℃下攪拌6小時。在減壓下濃縮所得混合物。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~100%，然後EtOAc/MeOH，其中MeOH為0~5%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之2-甲氧基-5-[[2-[5-甲基-2-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(160mg，64.4%產率)。To 2-[(5-aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (100 mg, 0.418 mmol, TEA), 6-(5-methyl- 2-Piperidinyl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one (300 mg, 0.803 mmol), HATU (250 mg, 0.658 mmol) in DMF To the solution in (8 mL) was added DIEA (300 μL, 1.72 mmol). The mixture was stirred at 20°C for 6 hours. The resulting mixture was concentrated under reduced pressure. by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-100% EtOAc, then EtOAc/MeOH with 0-5% MeOH, flow rate = 30 mL/min , 254 nm), the residue was purified to give 2-methoxy-5-[[2-[5-methyl-2-[6-oxy-5-(2-trimethyl as a yellow oil Silylethoxymethyl)-1,5-naphthyridin-2-yl]-1-piperidinyl]-2-oxyethoxymethyl]amino]pyridine-3-carboxamide (160 mg, 64.4% yield).

步驟2：2-甲氧基-5-[[2-[5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1077 )之合成Step 2: 2-Methoxy-5-[[2-[5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide ( compound 1077 )

向2-甲氧基-5-[[2-[5-甲基-2-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(160mg，0.269 mmol)於DCM(2mL)中之溶液中添加TFA(800μL，0.010mol)。將混合物在20℃下攪拌12小時。在減壓下濃縮所得混合物。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Welch Xtimate C18 150×25mm×5μm；流動相A：具有0.225% FA(v%)之H2 O；流動相B：MeCN；梯度：在9.5min內16%至46% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm、254nm)純化殘餘物，以得到呈白色固體之2-甲氧基-5-[[2-[5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(35mg，28.0%)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 11.58(br s,1 H),10.72(br s,1 H),8.42-8.69(m,2 H),7.90(d,J =9.8Hz,1 H),7.72(br d,J =8.5Hz,1 H),7.50(br s,3 H),6.72(d,J =9.8Hz,1 H),5.29-5.81(m,1 H),3.88-4.16(m,4 H),2.43(br d,J =10.8Hz,1 H),1.73-2.23(m,4 H),1.37(br d,J =9.8Hz,1 H),1.07(br d,J =7.0Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值465.2，實測值465.1；HPLC：在254nm下為98.73%。To 2-methoxy-5-[[2-[5-methyl-2-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthalene To a solution of pyridin-2-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (160 mg, 0.269 mmol) in DCM (2 mL) was added TFA (800 μL, 0.010 mol). The mixture was stirred at 20°C for 12 hours. The resulting mixture was concentrated under reduced pressure. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Welch Xtimate C18 150 x 25 mm x 5 μm; mobile phase A: with 0.225% FA (v%) of H 2 O; mobile phase B: MeCN; gradient: 16% to 46% B in 9.5min, hold 100% B for 2min; flow rate: 25mL/min; column temperature: 30°C; wavelength: 220nm, 254nm) The residue was purified to give 2-methoxy-5-[[2-[5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl) as a white solid -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (35 mg, 28.0%). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 11.58(br s, 1 H), 10.72(br s, 1 H), 8.42-8.69(m, 2 H), 7.90(d, J =9.8Hz, 1 H), 7.72(br d, J = 8.5Hz, 1 H), 7.50(br s, 3 H), 6.72(d, J =9.8Hz, 1 H), 5.29-5.81(m, 1 H), 3.88-4.16(m, 4 H), 2.43(br d, J =10.8Hz, 1 H), 1.73-2.23(m, 4 H), 1.37(br d, J =9.8Hz, 1 H), 1.07( br d, J = 7.0 Hz, 3H); LCMS (ESI) [M+H] + m/z: calcd 465.2, found 465.1; HPLC: 98.73% at 254 nm.

實例135. 5-[[2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(化合物79)之合成Example 135. 5-[[2-Oxy-2-[( 1S , 4S , 5R )-4-(2-thienyl)-3-azabicyclo[3.2.1]octane-3- Synthesis of Acetyl] Acetyl] Amino] Pyridine-3-Carboxyamide (Compound 79)

Figure 110128222-A0202-12-1136-155
Figure 110128222-A0202-12-1136-155

將(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛烷(300.00mg，1.55mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(Et3 N鹽，324.60mg，1.05mmol)、HATU(619.59mg，1.63mmol)及三乙胺(785.20mg，7.76mmol，1.08mL)於DMF(3mL)中之懸浮液在40℃下攪拌12小時。12小時之後，在真空中濃縮反應混合物且使粗產物經歷反相HPLC純化(溶析液：40-40-60%，0-1-6min 0.1% NH3 -甲醇，流速：30mL/min；裝載泵：4mL/min，甲醇；管柱：YMC Actus Triart C18 100 x 20mm，5um)，以獲得呈白色固體之產物5-[[2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]吡啶-3-甲醯胺(化合物79 ，56mg，145.66μmol，9.39%產率)。(1 S ,4 S ,5 R )-4-(2-thienyl)-3-azabicyclo[3.2.1]octane (300.00 mg, 1.55 mmol), 2-[(5-aminocarboxylate yl-3-pyridyl)amino]-2-oxoacetic acid ( Et3N salt, 324.60 mg, 1.05 mmol), HATU (619.59 mg, 1.63 mmol) and triethylamine (785.20 mg, 7.76 mmol, 1.08 mL) in DMF (3 mL) was stirred at 40 °C for 12 h. After 12 hours, the reaction mixture was concentrated in vacuo and the crude product was subjected to reverse phase HPLC purification (eluent: 40-40-60%, 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 mL/min; loading Pump: 4 mL/min, methanol; column: YMC Actus Triart C18 100 x 20 mm, 5 um) to obtain the product 5-[[2-oxy-2-[( 1S , 4S ,5 as a white solid R )-4-(2-thienyl)-3-azabicyclo[3.2.1]oct-3-yl]acetyl]amino]pyridine-3-carboxamide (compound 79 , 56 mg, 145.66 μmol , 9.39% yield).

注意：獲得呈單一非鏡像異構物之標題化合物。結構藉由2D NMR證實為反式。Note: The title compound was obtained as a single diastereoisomer. The structure was confirmed in trans by 2D NMR.

LCMS(ESI)：[M+H]+ m/z：計算值384.1；實測值385.0；Rt=1.121min。LCMS (ESI): [M+H] + m/z: calculated 384.1; found 385.0; Rt=1.121 min.

實例136. 5-[[2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物170)之合成Example 136. 5-[[2-[2-(4,4-Difluorocyclohexyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Synthesis of compound 170)

Figure 110128222-A0202-12-1137-156
Figure 110128222-A0202-12-1137-156

將2-(4,4-二氟環己基)哌啶(0.2g，983.91μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(305.35mg，983.91μmol，Et3 N鹽)及三乙胺(995.62mg，9.84mmol，1.37mL)於DMF(3mL)中之混合物在25℃下攪拌20分鐘。20分鐘之後，添加HATU(561.17mg，1.48mmol)。將所得反應混合物在25℃下攪拌隔夜。在完成之後，將水(20mL)添加到反應混合物中且用乙酸乙酯(2 x 25mL)萃取。將經合併之有機相用水(3 x 20mL)、鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下乾燥。使粗產物經歷反相HPLC純化(溶析液：20-60%，1.3-11min，0.1% NH3 -甲醇；流速：30mL/min；管柱：XBridge C18 100 x 20mm，5um)，以獲得呈淡黃色固體之5-[[2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物170 ，50.3mg，127.53μmol，12.96%產率)。2-(4,4-Difluorocyclohexyl)piperidine (0.2 g, 983.91 μmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid ( A mixture of 305.35 mg, 983.91 μmol, Et3N salt) and triethylamine (995.62 mg, 9.84 mmol, 1.37 mL) in DMF (3 mL) was stirred at 25 °C for 20 min. After 20 minutes, HATU (561.17 mg, 1.48 mmol) was added. The resulting reaction mixture was stirred at 25°C overnight. After completion, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water (3 x 20 mL), brine, dried over Na2SO4 , filtered and dried under reduced pressure. The crude product was subjected to reverse phase HPLC purification (eluent: 20-60%, 1.3-11 min, 0.1% NH3 -methanol; flow rate: 30 mL/min; column: XBridge C18 100 x 20 mm, 5 um) to obtain a 5-[[2-[2-(4,4-difluorocyclohexyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide as pale yellow solid (Compound 170 , 50.3 mg, 127.53 μmol, 12.96% yield).

化合物170 ：1 H NMR(CDCl3 400MHz)：δ(ppm)1.34(m,3H),1.83(m,14H),2.95(m,1H),4.55(m,2H),7.24(s,1H),8.56(m,1H),8.78(m,1H),8.97(m,1H)。 Compound 170 : 1 H NMR (CDCl 3 400MHz): δ (ppm) 1.34 (m, 3H), 1.83 (m, 14H), 2.95 (m, 1H), 4.55 (m, 2H), 7.24 (s, 1H) , 8.56 (m, 1H), 8.78 (m, 1H), 8.97 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.2；Rt=2.927min。LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.2; Rt=2.927 min.

實例137. 5-[[2-[(2S ,5R )-2-異丙基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物176)之合成Example 137. 5-[[2-[( 2S , 5R )-2-isopropyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide (Compound 176)

Figure 110128222-A0202-12-1138-157
Figure 110128222-A0202-12-1138-157

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.23g，1.10mmol)及2-異丙基-5-甲基哌啶(195.42mg，1.10mmol，HCl)於DME(10mL)中之經攪拌之溶液中添加DIPEA(497.42mg，3.85mmol，670.38μL)。將所得混合物攪拌5分鐘。5分鐘之後，添加HATU(439.02mg，1.15mmol)於DME(2mL)中之溶液。將所得反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液且藉由HPLC純化粗產物且冷凍乾燥，以得到呈白色固體之5-[[2-[(2S ,5R )-2-異丙基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物176 ，50.9mg，153.13μmol，13.93%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.23 g, 1.10 mmol) and 2-isopropyl-5-methylpiperidine (195.42 mg , 1.10 mmol, HCl) in DME (10 mL) was added DIPEA (497.42 mg, 3.85 mmol, 670.38 μL) to a stirred solution. The resulting mixture was stirred for 5 minutes. After 5 minutes, a solution of HATU (439.02 mg, 1.15 mmol) in DME (2 mL) was added. The resulting reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure and the crude product was purified by HPLC and lyophilized to give 5-[[2-[( 2S , 5R )-2-isopropyl-5 as a white solid -Methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 176 , 50.9 mg, 153.13 μmol, 13.93% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.89(m,9H),1.30(m,1H),1.64(m,1H),1.89(m,3H),2.21(m,1H),2.90(m,1H),3.42(m,1H),4.04(m,1H),7.61(s,1H),8.17(s,1H),8.49(m,1H),8.77(s,1H),8.89(m,1H),11.08(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.89 (m, 9H), 1.30 (m, 1H), 1.64 (m, 1H), 1.89 (m, 3H), 2.21 (m, 1H) ,2.90(m,1H),3.42(m,1H),4.04(m,1H),7.61(s,1H),8.17(s,1H),8.49(m,1H),8.77(s,1H), 8.89 (m, 1H), 11.08 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值332.2；實測值333.4；Rt=2.739min。LCMS (ESI): [M+H] + m/z: calculated 332.2; found 333.4; Rt=2.739 min.

實例138. 5-[[2-(2-異丙基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物100)之合成Example 138. Synthesis of 5-[[2-(2-isopropyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 100)

Figure 110128222-A0202-12-1139-158
Figure 110128222-A0202-12-1139-158

在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.3g，966.66μmol，Et3 N鹽)、TATU(342.46mg，1.06mmol)及三乙胺(195.63mg，1.93mmol，269.47μL)一起混合於無水CH3 CN(25mL)中且將所得混合物攪拌15分鐘。15分鐘之後，添加2-異丙基哌啶(135.28mg，826.47μmol，鹽酸鹽)，且將所得混合物在21℃下攪拌隔夜。將所得混合物蒸發至乾且使其經歷HPLC純化(溶析液：2-7min，15-30% CH3 CN，流速：30mL/min；管柱：SunFire C18 100*19mm，5um)，以獲得呈灰白色固體之5-[[2-(2-異丙基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物100 ，52.9mg，166.16μmol，17.19%產率)。At 21 °C, 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.3 g, 966.66 μmol, Et 3 N salt), TATU (342.46 mg, 1.06 mmol) and triethylamine (195.63 mg, 1.93 mmol, 269.47 μL) were mixed together in dry CH3CN (25 mL) and the resulting mixture was stirred for 15 min. After 15 minutes, 2-isopropylpiperidine (135.28 mg, 826.47 μmol, hydrochloride) was added, and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was evaporated to dryness and subjected to HPLC purification (eluent: 2-7 min, 15-30% CH3CN , flow rate: 30 mL/min; column: SunFire C18 100*19 mm, 5 um) to obtain a 5-[[2-(2-Isopropyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 100 , 52.9 mg, 166.16 mg) as an off-white solid μmol, 17.19% yield).

1H NMR(DMSO-d 6 ,400MMHz)：δ(ppm)0.89(m,6H),1.58(m,5H),1.85(m,1H),2.20(m,1H),2.99(m,1H),3.49(m,1H),4.14(m,1H),7.63(s,1H),8.18(s,1H),8.50(s,1H),8.78(s,1H),8.89(d,1H),11.10(m,1H)。1H NMR (DMSO- d 6 , 400MMHz): δ(ppm) 0.89(m, 6H), 1.58(m, 5H), 1.85(m, 1H), 2.20(m, 1H), 2.99(m, 1H), 3.49(m, 1H), 4.14(m, 1H), 7.63(s, 1H), 8.18(s, 1H), 8.50(s, 1H), 8.78(s, 1H), 8.89(d, 1H), 11.10 (m, 1H).

LCMS(ESI)：[M+Boc]+ m/z：計算值318.2；實測值319.2；Rt=0.983min。LCMS (ESI): [M+Boc] + m/z: calculated 318.2; found 319.2; Rt=0.983 min.

實例139. 5-[[2-[(2R ,5S )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155)、5-[[2-[(2S,5R)-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,5S)-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物216及化合物211)之合成Example 139. 5-[[2-[( 2R ,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2- oxyethanoyl ]amino]pyridine- 3-Carboxamide (Compound 155), 5-[[2-[(2S,5R)-2-cyclobutyl-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carbamide and 5-[[2-[(2R,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2-oxyethanoyl Synthesis of ]amino]pyridine-3-carboxamide (Compound 216 and Compound 211)

Figure 110128222-A0202-12-1139-159
Figure 110128222-A0202-12-1139-159

步驟1：5-[[2-[(2R,5S)-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155 )之合成Step 1: 5-[[2-[(2R,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Synthesis of formamide ( compound 155 )

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.23g，1.10mmol)及2-環丁基-5-甲基哌啶(168.54mg，1.10mmol)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(355.30mg，2.75mmol，478.84μL)。將所得混合物攪拌5分鐘。5分鐘之後，添加HATU(439.02mg，1.15mmol)於DMF(2mL)中之溶液。將所得反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液且藉由HPLC純化粗產物且冷凍乾燥，以得到呈白色固體之外消旋 -5-[[2-[(2R ,5S )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155 ，20.4mg，59.23μmol，5.39%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.23 g, 1.10 mmol) and 2-cyclobutyl-5-methylpiperidine (168.54 mg , 1.10 mmol) in DMF (10 mL) was added DIPEA (355.30 mg, 2.75 mmol, 478.84 μL) to a stirred solution. The resulting mixture was stirred for 5 minutes. After 5 minutes, a solution of HATU (439.02 mg, 1.15 mmol) in DMF (2 mL) was added. The resulting reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure and the crude product was purified by HPLC and lyophilized to give rac -5-[[2-[( 2R , 5S )-2-ring as a white solid Butyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 155 , 20.4 mg, 59.23 μmol, 5.39% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.95(dd,3H),1.32(m,2H),1.80(m,9H),2.93(m,2H),3.81(m,1H),4.24(m,1H),7.62(m,1H),8.18(m,1H),8.50(m,1H),8.78(m,1H),8.90(m,1H),11.09(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.95 (dd, 3H), 1.32 (m, 2H), 1.80 (m, 9H), 2.93 (m, 2H), 3.81 (m, 1H) , 4.24(m, 1H), 7.62(m, 1H), 8.18(m, 1H), 8.50(m, 1H), 8.78(m, 1H), 8.90(m, 1H), 11.09(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.4；Rt=2.876min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.4; Rt=2.876 min.

步驟2：5-[[2-[(2S,5R)-2-環丁基-5-申基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,5S)-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物216 及化合物211 )之掌性分離Step 2: 5-[[2-[(2S,5R)-2-Cyclobutyl-5-senyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3- Formamide and 5-[[2-[(2R,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 - Chiral separation of formamide ( compound 216 and compound 211 )

使外消旋 -5-[[2-[(2R ,5S )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155 )經歷掌性層析(管柱：IA-II 250*20mm，5um，溶析液：己烷-IPA-MeOH，70-15-15，流速：12mL/min)，以得到呈白色固體之5-[[2-[(2R ,5S )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物211 )及5-[[2-[(2S ,5R )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物216 )。make rac -5-[[2-[( 2R ,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2- oxyethanoyl ]amino] Pyridine-3-carboxamide (compound 155 ) was subjected to chiral chromatography (column: IA-II 250*20mm, 5um, eluent: hexane-IPA-MeOH, 70-15-15, flow rate: 12mL/ min) to give 5-[[2-[(2 R ,5 S )-2-cyclobutyl-5-methyl-1-piperidinyl]-2-pendant oxyacetyl as a white solid ]amino]pyridine-3-carboxamide ( compound 211 ) and 5-[[2-[( 2S , 5R )-2-cyclobutyl-5-methyl-1-piperidinyl]-2- Pendant oxyacetoxy]amino]pyridine-3-carboxamide ( compound 216 ).

化合物216： LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=4.427 min。 Compound 216: LCMS (ESI): [M+H] + m/z: calcd 344.2; found 345.2; Rt=4.427 min.

掌性HPLC：Rt=31.56min(管柱：IA；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=31.56 min (column: IA; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

1H NMR(氯仿-d,400MHz)：δ(ppm)0.99(m,3H),1.38(m,2H),1.83(m,10H),3.04(m,2H),4.29(m,1H),4.75(m,1H),6.35(s,1H),6.70(s,1H),8.70(m,1H),8.91(m,1H),9.10(m,1H),10.05(m,1H)1H NMR (chloroform-d, 400MHz): δ (ppm) 0.99 (m, 3H), 1.38 (m, 2H), 1.83 (m, 10H), 3.04 (m, 2H), 4.29 (m, 1H), 4.75 (m,1H),6.35(s,1H),6.70(s,1H),8.70(m,1H),8.91(m,1H),9.10(m,1H),10.05(m,1H)

化合物211： LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=4.425min。 Compound 211: LCMS (ESI): [M+H] + m/z: calcd 344.2; found 345.2; Rt=4.425 min.

掌性HPLC：Rt=22.02min(管柱：IA；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=22.02 min (column: IA; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

1H NMR(氯仿-d,400MHz)：δ(ppm)0.99(m,3H),1.38(m,2H),1.83(m,10H),3.04(m,2H),4.29(m,1H),4.75(m,1H),6.35(s,1H),6.70(s,1H),8.70(m,1H),8.91(m,1H),9.10(m,1H),10.05(m,1H)1H NMR (chloroform-d, 400MHz): δ (ppm) 0.99 (m, 3H), 1.38 (m, 2H), 1.83 (m, 10H), 3.04 (m, 2H), 4.29 (m, 1H), 4.75 (m,1H),6.35(s,1H),6.70(s,1H),8.70(m,1H),8.91(m,1H),9.10(m,1H),10.05(m,1H)

實例140. 5-[[2-(2-環丁基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物103)之合成Example 140. Synthesis of 5-[[2-(2-Cyclobutyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 103)

Figure 110128222-A0202-12-1141-160
Figure 110128222-A0202-12-1141-160

在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.3g，966.66μmol，Et3 N鹽)、TATU(311.33mg，966.66μmol)及三乙胺(97.82mg，966.66μmol，134.73μL)混合於無水CH3 CN(25mL)且將所得混合物攪拌15分鐘。15分鐘之後，添加2-環丁基哌啶(148.05mg，1.06mmol)，且將所得混合物在21℃下攪拌隔夜。將所得混合物蒸發至乾且使其經歷HPLC純化(溶析液：2-7min，15 -30% CH3 CN；流速：30mL/min；管柱：SunFire C18 100*19mm，5μM)，以獲得呈灰白色固體之5-[[2-(2-環丁基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物103 ，91.3mg，276.35μmol，28.59%產率)。At 21 °C, 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.3 g, 966.66 μmol, Et 3 N salt), TATU (311.33 mg, 966.66 μmol) and triethylamine (97.82 mg, 966.66 μmol, 134.73 μL) were mixed in anhydrous CH 3 CN (25 mL) and the resulting mixture was stirred for 15 min. After 15 minutes, 2-cyclobutylpiperidine (148.05 mg, 1.06 mmol) was added, and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was evaporated to dryness and subjected to HPLC purification (eluent: 2-7 min, 15-30% CH3CN ; flow rate: 30 mL/min; column: SunFire C18 100*19 mm, 5 μM) to obtain a 5-[[2-(2-Cyclobutyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 103 , 91.3 mg, 276.35 mg) as an off-white solid μmol, 28.59% yield).

1H NMR(CDCl3 ,400MHz)：δ(ppm)1.92(m,13H),3.00(m,2H),4.89(m,1H),6.27(m,2H),8.73(d,1H),8.98(m,2H),9.72(s,1H)。1H NMR (CDCl 3 , 400MHz): δ(ppm) 1.92(m, 13H), 3.00(m, 2H), 4.89(m, 1H), 6.27(m, 2H), 8.73(d, 1H), 8.98( m, 2H), 9.72 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值330.2；實測值331.2；Rt=2.637min。LCMS (ESI): [M+H] + m/z: calculated 330.2; found 331.2; Rt=2.637 min.

實例141. 5-[[2-[(2S ,5R )-2-(4,4-二氟環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,5S )-2-(4,4-二氟環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物486及化合物320)之合成Example 141. 5-[[2-[( 2S , 5R )-2-(4,4-difluorocyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide and 5-[[2-[( 2R , 5S )-2-(4,4-difluorocyclohexyl)-5-methyl-1-piperidinyl] Synthesis of -2-Oxyacetyl]amino]pyridine-3-carboxamide (Compound 486 and Compound 320)

Figure 110128222-A0202-12-1142-161
Figure 110128222-A0202-12-1142-161

將2-(4,4-二氟環己基)-5-甲基哌啶(370mg，1.70mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(418.22mg，1.70mmol，鹽酸鹽)及三乙胺(1.72g，17.03mmol，2.37mL)於DMF(5mL)中之混合物在25℃下攪拌20分鐘。20分鐘之後，在30分鐘內小批量添加HATU(712.17mg，1.87mmol)。將所得反應混合物在25℃下攪拌12小時。完成之後，使粗反應混合物經歷反相HPLC純化(溶析液：35-40%，0-5min，0.1% NH3 -甲醇；流速：30mL/min；管柱：YMC Triart C18 100 x 20mm，5um)，以得到120mg外消旋產物(藉由LCMS為100%純度)，其藉由掌性HPLC(溶析液：己烷-IPA-MeOH，60-20-20；流速：12mL/min；管柱：AD-H-III(250 x 20mm,5um)進一步純化，以得到呈白色固體之5-[[2-[(2S ,5R )-2-(4,4-二氟環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物486 ，62.1mg，152.04μmol，8.93%產率)及5-[[2-[(2R ,5S )-2-(4,4- 二氟環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物320 ，62mg，151.80μmol，8.91%產率)。2-(4,4-Difluorocyclohexyl)-5-methylpiperidine (370 mg, 1.70 mmol), 2-[(5-aminocarboxy-3-pyridyl)amino]-2-side A mixture of oxyacetic acid (418.22 mg, 1.70 mmol, hydrochloride) and triethylamine (1.72 g, 17.03 mmol, 2.37 mL) in DMF (5 mL) was stirred at 25 °C for 20 min. After 20 minutes, HATU (712.17 mg, 1.87 mmol) was added in small batches over 30 minutes. The resulting reaction mixture was stirred at 25°C for 12 hours. After completion, the crude reaction mixture was subjected to reverse phase HPLC purification (eluent: 35-40%, 0-5 min, 0.1% NH3 -methanol; flow rate: 30 mL/min; column: YMC Triart C18 100 x 20 mm, 5 um ) to give 120 mg of racemic product (100% pure by LCMS) by chiral HPLC (eluent: hexane-IPA-MeOH, 60-20-20; flow rate: 12 mL/min; tube Column: AD-H-III (250 x 20mm, 5um) was further purified to give 5-[[2-[( 2S , 5R )-2-(4,4-difluorocyclohexyl) as a white solid -5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (compound 486 , 62.1 mg, 152.04 μmol, 8.93% yield) and 5- [[2-[(2 R ,5 S )-2-(4,4-difluorocyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (Compound 320 , 62 mg, 151.80 μmol, 8.91% yield).

化合物486：Compound 486:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.91-0.99(m,3H),1.10-1.23(m,2H),1.25-1.34(m,1H),1.53-1.73(m,3H),1.73-1.90(m,5H),1.90-2.11(m,4H),2.90-3.27(m,1H),3.53-4.18(m,1H),7.59(s,1H),8.15(s,1H),8.42-8.51(m,1H),8.70-8.80(m,1H),8.84-8.89(m,1H),11.01-11.10(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.91-0.99 (m, 3H), 1.10-1.23 (m, 2H), 1.25-1.34 (m, 1H), 1.53-1.73 (m, 3H) ), 1.73-1.90(m, 5H), 1.90-2.11(m, 4H), 2.90-3.27(m, 1H), 3.53-4.18(m, 1H), 7.59(s, 1H), 8.15(s, 1H) ), 8.42-8.51(m, 1H), 8.70-8.80(m, 1H), 8.84-8.89(m, 1H), 11.01-11.10(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值408.2；實測值409.2；Rt=3.077min。LCMS (ESI): [M+H] + m/z: calculated 408.2; found 409.2; Rt=3.077 min.

掌性HPLC：Rt=10.737min(溶析液：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min；管柱：AD-H)。Chiral HPLC: Rt=10.737 min (eluent: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min; column: AD-H).

化合物320：Compound 320:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.93-0.99(m,3H),1.08-1.23(m,2H),1.24-1.34(m,1H),1.56-1.73(m,3H),1.73-1.89(m,5H),1.91-2.13(m,4H),2.89-3.28(m,1H),3.52-4.17(m,1H),7.59(s,1H),8.15(s,1H),8.42-8.49(m,1H),8.70-8.79(m,1H),8.84-8.91(m,1H),11.00-11.11(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.93-0.99 (m, 3H), 1.08-1.23 (m, 2H), 1.24-1.34 (m, 1H), 1.56-1.73 (m, 3H) ), 1.73-1.89(m, 5H), 1.91-2.13(m, 4H), 2.89-3.28(m, 1H), 3.52-4.17(m, 1H), 7.59(s, 1H), 8.15(s, 1H) ), 8.42-8.49(m, 1H), 8.70-8.79(m, 1H), 8.84-8.91(m, 1H), 11.00-11.11(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值408.2；實測值409.2；Rt=3.090min。LCMS (ESI): [M+H] + m/z: calculated 408.2; found 409.2; Rt=3.090 min.

掌性HPLC：Rt=28.151min(溶析液：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min；管柱：AD-H)。Chiral HPLC: Rt=28.151 min (eluent: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min; column: AD-H).

實例142. 5-(2-(2-環戊基-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物172)之合成Example 142. Synthesis of 5-(2-(2-cyclopentyl-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 172)

Figure 110128222-A0202-12-1143-162
Figure 110128222-A0202-12-1143-162

將2-環戊基-5-甲基哌啶(200.00mg，1.20mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(371.03mg，1.20mmol)、三乙胺(1.21g，11.96mmol，1.67mL)混合於DMF(5mL)中，然後添加HATU(681.86mg，1.79mmol)。將所得混合物在25℃下攪拌12h。將混合物在減壓下蒸發且藉由HPLC(30-40%水-MeCN，10min，流速30ml/min)純化，以獲得5-[[2-[(2R,5S )-2-環戊基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(45.1mg，125.83μmol，10.52%產率)，E/Z=1/9。2-Cyclopentyl-5-methylpiperidine (200.00 mg, 1.20 mmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (371.03 mg , 1.20 mmol), triethylamine (1.21 g, 11.96 mmol, 1.67 mL) were mixed in DMF (5 mL), then HATU (681.86 mg, 1.79 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The mixture was evaporated under reduced pressure and purified by HPLC (30-40% water-MeCN, 10 min, flow rate 30 ml/min) to obtain 5-[[2-[( 2R,5S )-2-cyclopentyl- 5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (45.1 mg, 125.83 μmol, 10.52% yield), E/Z=1/ 9.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.97(m,3H),1.24(m,3H),1.64(m,9H),1.94(m,3H),3.53(m,1H),4.14(m,1H),7.63(s,1H),8.18(s,1H),8.50(m,1H),8.78(s,1H),8.90(s,1H),11.09(s,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.97(m, 3H), 1.24(m, 3H), 1.64(m, 9H), 1.94(m, 3H), 3.53(m, 1H), 4.14(m, 1H), 7.63(s, 1H), 8.18(s, 1H), 8.50(m, 1H), 8.78(s, 1H), 8.90(s, 1H), 11.09(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值358.4；實測值359.2；Rt=1.249min。LCMS (ESI): [M] + m/z: calculated 358.4; found 359.2; Rt=1.249 min.

實例143. 5-(2-(2-環戊基-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物306、化合物298、化合物295、化合物312)之合成Example 143. 5-(2-(2-Cyclopentyl-5-methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (Compound 306 , compound 298, compound 295, compound 312) synthesis

Figure 110128222-A0202-12-1144-163
Figure 110128222-A0202-12-1144-163

步驟1：5-(2-(2-環戊基-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺之合成Step 1: Synthesis of 5-(2-(2-cyclopentyl-5-methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide

在21℃下，將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.5g，1.47mmol，Et3 N)、TATU(567.73mg，1.76mmol)及TEA(148.65mg，1.47mmol，204.75μL)混合於無水DMF(15mL)中且將所得混合物攪拌15min。向其 中添加2-環戊基-5-甲基哌啶(245.75mg，1.47mmol)，且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-100% 2-7min；水-MeOH+NH3 ；30ml/min；裝載泵4ml/min水；管柱XBridge 19*100mm)。獲得呈白色固體之5-[[2-(2-環戊基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(189mg，486.54μmol，33.12%產率)。At 21 °C, 2-[(5-aminocarbamoyl-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (0.5 g, 1.47 mmol, Et 3 N), TATU (567.73 mg, 1.76 mmol) and TEA (148.65 mg, 1.47 mmol, 204.75 μL) were mixed in dry DMF (15 mL) and the resulting mixture was stirred for 15 min. To this was added 2-cyclopentyl-5-methylpiperidine (245.75 mg, 1.47 mmol), and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-100% 2-7 min; water-MeOH+ NH3 ; 30 ml/min; loading pump 4 ml/min water; column XBridge 19*100 mm). 5-[[2-(2-Cyclopentyl-5-methyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-methoxypyridine- 3-Carboxamide (189 mg, 486.54 μmol, 33.12% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.97(d,3H),1.57(m,11H),2.05(m,2H),2.44(m,1H),3.40(m,1H),4.22(s,3H),4.56(m,2H),6.24(m,1H),7.75(m,1H),8.71(m,1H),8.86(s,1H),9.70(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.97(d,3H), 1.57(m,11H), 2.05(m,2H), 2.44(m,1H), 3.40(m,1H), 4.22( s, 3H), 4.56 (m, 2H), 6.24 (m, 1H), 7.75 (m, 1H), 8.71 (m, 1H), 8.86 (s, 1H), 9.70 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.4；實測值389.2；Rt=3.704min。LCMS (ESI): [M] + m/z: calculated 388.4; found 389.2; Rt=3.704 min.

步驟2：掌性分離(化合物306、化合物298、化合物295 及化合物312 )Step 2: Chiral separation ( Compound 306, Compound 298, Compound 295 and Compound 312 )

將5-[[2-(2-環戊基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(180mg，463.37μmol)使用(Chiralpak IC 250*20，5mkm管柱；以己烷-IPA-MeOH，70-15-15為流動相；流速12mL/min；注入體積：900mkl，及Chiralpak IA 250*30，5mkm管柱；以己烷-IPA-MeOH，70-15-15為流動相；流速27mL/min；注入體積：900mkl)分離；得到呈白色固體之化合物306 5-[[2-[(2S,5R )-2-環戊基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(60.96mg，156.93μmol，33.87%產率)(RT(IB，己烷-IPA-MeOH，90-5-5，0.6ml/min)=43.14min)、呈白色固體之化合物298 5-[[2-[(2R,5S )-2-環戊基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(75.83mg，195.21μmol，42.13%產率)(RT(IB，己烷-IPA-MeOH，90-5-5，0.6ml/min)=29.19min)、呈白色固體之化合物295 5-[[2-[(2S,5S )-2-環戊基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(12.95mg，33.34μmol，7.19%產率)(RT(IB，己烷-IPA-MeOH，90-5-5，0.6ml/min)=27.47min)及呈白色固體之化合物 312 5-[[2-[(2R,5R )-2-環戊基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(10.81mg，27.83μmol，6.01%產率)(RT(IB，己烷-IPA-MeOH，90-5-5，0.6ml/min)=39.37min)。5-[[2-(2-Cyclopentyl-5-methyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxylate Amine (180 mg, 463.37 μmol) was used (Chiralpak IC 250*20, 5 mkm column; hexane-IPA-MeOH, 70-15-15 as mobile phase; flow rate 12 mL/min; injection volume: 900 mkl, and Chiralpak IA 250 *30, 5mkm column; with hexane-IPA-MeOH, 70-15-15 as mobile phase; flow rate 27mL/min; injection volume: 900mkl) separation; obtain compound 306 as white solid 5-[[2-[ ( 2S,5R )-2-cyclopentyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( 60.96 mg, 156.93 μmol, 33.87% yield) (RT(IB, hexane-IPA-MeOH, 90-5-5, 0.6 ml/min)=43.14 min), compound 298 as a white solid 5-[[2 -[( 2R,5S )-2-cyclopentyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxylate Amine (75.83 mg, 195.21 μmol, 42.13% yield) (RT(IB, hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 29.19 min), compound 295 as a white solid 5-[ [2-[( 2S,5S )-2-cyclopentyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3- Formamide (12.95 mg, 33.34 μmol, 7.19% yield) (RT(IB, hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 27.47 min) and compound 312 5 as a white solid -[[2-[( 2R,5R )-2-cyclopentyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine- 3-Carboxamide (10.81 mg, 27.83 μmol, 6.01% yield) (RT (IB, Hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 39.37 min).

化合物306：保留時間：43.14minCompound 306: retention time: 43.14min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.91-1.00(m,3H),1.02-1.23(m,2H),1.27-1.35(m,1H),1.42-1.78(m,8H),1.87-2.00(m,2H),2.93-3.26(m,1H),3.36-3.60(m,2H),3.95(s,3H),4.00-4.27(m,1H),7.74(s,2H),8.41-8.48(m,1H),8.52-8.58(m,1H),10.81-10.90(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.91-1.00(m,3H), 1.02-1.23(m,2H), 1.27-1.35(m,1H), 1.42-1.78(m,8H) ,1.87-2.00(m,2H),2.93-3.26(m,1H),3.36-3.60(m,2H),3.95(s,3H),4.00-4.27(m,1H),7.74(s,2H) , 8.41-8.48(m, 1H), 8.52-8.58(m, 1H), 10.81-10.90(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=3.520min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=3.520 min.

化合物298：保留時間：29.19minCompound 298: retention time: 29.19min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.92-0.98(m,3H),1.00-1.08(m,1H),1.12-1.28(m,2H),1.28-1.36(m,1H),1.45-1.77(m,8H),1.87-1.98(m,2H),2.96-3.19(m,1H),3.42-3.59(m,1H),3.95(s,3H),4.00-4.25(m,1H),7.74(s,2H),8.41-8.48(m,1H),8.53-8.57(m,1H),10.82-10.89(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.92-0.98(m,3H), 1.00-1.08(m,1H), 1.12-1.28(m,2H), 1.28-1.36(m,1H) ,1.45-1.77(m,8H),1.87-1.98(m,2H),2.96-3.19(m,1H),3.42-3.59(m,1H),3.95(s,3H),4.00-4.25(m, 1H), 7.74(s, 2H), 8.41-8.48(m, 1H), 8.53-8.57(m, 1H), 10.82-10.89(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=3.513min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=3.513 min.

化合物295：保留時間：27.47minCompound 295: retention time: 27.47min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.78-0.93(m,3H),1.01-1.23(m,2H),1.29-1.40(m,1H),1.48-1.75(m,10H),2.41-2.44(m,1H),2.78-3.19(m,1H),3.49-3.56(m,1H),3.92-3.98(m,3H),4.15-4.29(m,1H),7.70-7.80(m,2H),8.43-8.49(m,1H),8.51-8.57(m,1H),10.79-10.96(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.78-0.93(m, 3H), 1.01-1.23(m, 2H), 1.29-1.40(m, 1H), 1.48-1.75(m, 10H) ,2.41-2.44(m,1H),2.78-3.19(m,1H),3.49-3.56(m,1H),3.92-3.98(m,3H),4.15-4.29(m,1H),7.70-7.80( m, 2H), 8.43-8.49 (m, 1H), 8.51-8.57 (m, 1H), 10.79-10.96 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=3.556min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=3.556 min.

化合物312：保留時間：39.37minCompound 312: retention time: 39.37min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.81-0.92(m,3H),1.00-1.26(m,3H),1.32-1.41(m,1H),1.49-1.61(m,7H),1.64-1.79(m,3H),2.41-2.44(m,1H),2.79-2.86 (m,0.5H),3.50-3.53(m,0.5H),3.95-3.98(m,3H),4.12-4.25(m,1H),7.72-7.79(m,2H),8.43-8.49(m,1H),8.49-8.57(m,1H),10.81-10.93(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.81-0.92(m,3H), 1.00-1.26(m,3H), 1.32-1.41(m,1H), 1.49-1.61(m,7H) ,1.64-1.79(m,3H),2.41-2.44(m,1H),2.79-2.86(m,0.5H),3.50-3.53(m,0.5H),3.95-3.98(m,3H),4.12- 4.25(m,1H), 7.72-7.79(m,2H), 8.43-8.49(m,1H), 8.49-8.57(m,1H), 10.81-10.93(m,1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=3.556min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=3.556 min.

實例144. 5-(2-(4-羥基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物185)之合成Example 144. Synthesis of 5-(2-(4-Hydroxy-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 185)

Figure 110128222-A0202-12-1147-164
Figure 110128222-A0202-12-1147-164

將DIPEA(145.76mg，1.13mmol，196.44μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.1g，322.22μmol，Et3 N)及(2S,4R )-2-苯基哌啶-4-醇(57.11mg，267.24μmol，HCl)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(134.77mg，354.44μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到純的5-[[2-[(2R,4S )-4-羥基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(61.2mg，166.13μmol，51.56%產率)。DIPEA (145.76 mg, 1.13 mmol, 196.44 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.1 g, 322.22 μmol, Et 3 N) and ( 2S,4R )-2-phenylpiperidin-4-ol (57.11 mg, 267.24 μmol, HCl) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (134.77 mg, 354.44 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure 5-[[2-[( 2R,4S )-4-hydroxy-2-phenyl-1-piperidinyl]-2-oxoacetyl] Amino]pyridine-3-carboxamide (61.2 mg, 166.13 μmol, 51.56% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.54(m,1H),1.89(m,1H),2.07(m,1H),2.37(m,1H),3.49(m,1H),3.83(m,2H),4.46(m,1H),5.29(m,1H),7.29(m,5H),7.57(m,1H),8.13(m,1H),8.44(m,1H),8.80(m,2H),11.14(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.54(m,1H), 1.89(m,1H), 2.07(m,1H), 2.37(m,1H), 3.49(m,1H), 3.83(m, 2H), 4.46(m, 1H), 5.29(m, 1H), 7.29(m, 5H), 7.57(m, 1H), 8.13(m, 1H), 8.44(m, 1H), 8.80 (m, 2H), 11.14 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值368.4；實測值369.2；Rt=1.828min。LCMS (ESI): [M] + m/z: calculated 368.4; found 369.2; Rt=1.828 min.

實例145. 外消旋-5-[[2-[(2R,4R,5R)-4-羥基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物459)、外消旋-5-[[2-[(2R,4S,5R)-4-羥基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物470)之合成Example 145. Racemic-5-[[2-[(2R,4R,5R)-4-hydroxy-5-methyl-2-phenyl-1-piperidinyl]-2-pendoxetylacetamide yl]amino]pyridine-3-carboxamide (Compound 459), rac-5-[[2-[(2R,4S,5R)-4-hydroxy-5-methyl-2-phenyl- Synthesis of 1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carboxamide (Compound 470)

Figure 110128222-A0202-12-1148-165
Figure 110128222-A0202-12-1148-165

將(2R,5R)-5-甲基-2-苯基哌啶-4-醇(0.1g，522.82μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(162.26mg，522.82μmol，NEt3)、TEA(529.05mg，5.23mmol，728.71μL)及HATU(298.19mg，784.24μmol)溶解於DMF(5mL)中且在20℃下攪拌3h。將反應混合物用水稀釋且用乙酸乙酯萃取三次，然後將有機層用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在40℃下蒸發，以得到粗產物，其藉由HPLC(0-80% MeCN/水，2-10min，流速30ml/min(裝載泵4ml/min MeCN)管柱：SunFire 100*19 5mM)進行純化，以得到5-[[2-[(2R,4R,5R)-4-羥基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.034g，88.91μmol，17.01%產率)化合物459 及5-[[2-[(2R,4S,5R)-4-羥基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.017g，44.45μmol，8.50%產率)化合物470 。The (2R,5R)-5-methyl-2-phenylpiperidin-4-ol (0.1 g, 522.82 μmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]- 2-Pendoxacetic acid (162.26 mg, 522.82 μmol, NEt3), TEA (529.05 mg, 5.23 mmol, 728.71 μL) and HATU (298.19 mg, 784.24 μmol) were dissolved in DMF (5 mL) and stirred at 20 °C for 3 h . The reaction mixture was diluted with water and extracted three times with ethyl acetate, then the organic layer was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and evaporated at 40° C. to give crude product, which was obtained by HPLC (0-80% MeCN/water, 2-10 min, flow rate 30 ml/min (load pump 4 ml/min) MeCN) column: SunFire 100*19 5mM) for purification to give 5-[[2-[(2R,4R,5R)-4-hydroxy-5-methyl-2-phenyl-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.034 g, 88.91 μmol, 17.01% yield) compound 459 and 5-[[2-[(2R,4S,5R) -4-Hydroxy-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.017 g, 44.45 μmol, 8.50% yield) compound 470 .

化合物470：Compound 470:

1 H NMR(600MHz,DMSO)δ 0.88-0.95(m,3H),1.78-1.99(m,2H),2.32-2.38(m,1H),2.67-3.21(m,1H),3.56-4.22(m,2H),4.75-4.82(m,1H),5.25-5.81(m,1H),7.23-7.31(m,2H),7.31-7.42(m,3H),7.54-7.66(m,1H),8.08-8.22(m,1H),8.43-8.53(m,1H),8.71-8.80(m,1H),8.82-8.95(m,1H),11.19-11.33(m,1H)。 1 H NMR(600MHz,DMSO)δ 0.88-0.95(m,3H),1.78-1.99(m,2H),2.32-2.38(m,1H),2.67-3.21(m,1H),3.56-4.22(m ,2H),4.75-4.82(m,1H),5.25-5.81(m,1H),7.23-7.31(m,2H),7.31-7.42(m,3H),7.54-7.66(m,1H),8.08 -8.22(m,1H), 8.43-8.53(m,1H), 8.71-8.80(m,1H), 8.82-8.95(m,1H), 11.19-11.33(m,1H).

LCMS(ESI)：[M+1]+ m/z：計算值382.2；實測值383.2；Rt=2.221minLCMS(ESI): [M+1] + m/z: Calculated 382.2; Measured 383.2; Rt=2.221min

化合物459：Compound 459:

1 H NMR(600MHz,DMSO)δ 0.99(d,3H),1.67-1.73(m,1H),2.10-2.19(m,2H),3.48-3.52(m,1H),3.71-3.91(m,1H),4.61-4.69(m,1H),5.13-5.38(m,1H),7.09-7.28(m,2H),7.29-7.36(m,4H),7.51-7.64(m,1H),8.07-8.19(m,1H),8.26-8.52 (m,1H),8.68-8.77(m,1H),8.77-8.94(m,1H),10.87-11.24(m,1H)。 1 H NMR(600MHz, DMSO)δ 0.99(d,3H), 1.67-1.73(m,1H), 2.10-2.19(m,2H), 3.48-3.52(m,1H), 3.71-3.91(m,1H) ),4.61-4.69(m,1H),5.13-5.38(m,1H),7.09-7.28(m,2H),7.29-7.36(m,4H),7.51-7.64(m,1H),8.07-8.19 (m, 1H), 8.26-8.52 (m, 1H), 8.68-8.77 (m, 1H), 8.77-8.94 (m, 1H), 10.87-11.24 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值382.2：實測值383.2；Rt=2.221minLCMS(ESI): [M+1] + m/z: Calculated 382.2: Measured 383.2; Rt=2.221min

實例146. 5-[[2-[(4aR,8aS)-5,5-二甲基-1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物193)及5-[[2-[(4aS,8aR)-5,5-二甲基-1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物197)之合成Example 146. 5-[[2-[(4aR,8aS)-5,5-dimethyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 193) and 5-[[2-[(4aS,8aR)-5,5-dimethyl-1,3, Synthesis of 4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 197)

Figure 110128222-A0202-12-1149-166
Figure 110128222-A0202-12-1149-166

步驟1：5-[[2-[(4aS,8aR)-5,5-二甲基1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(4aS,8aR)-5,5-dimethyl 1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]- Synthesis of 2-Pendant Oxyacetyl] Amino] Pyridine-3-Carboxyamide

向(4aS,8aR)-5,5-二甲基-2,3,4,4a,6,7,8,8a-八氫-1H-異喹啉(239.95mg，1.43mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(300mg，1.43mmol，三乙胺)、DIPEA(556.11mg，4.30mmol，749.48μL)於DMF(5mL)中之溶液中分批添加EDC(329.95mg，1.72mmol)。將所得溶液在25℃下攪拌16h。然後，將溶劑蒸發且使殘餘物經歷HPLC(35-70% 0-5min 0.1% NH3 -甲醇，流速：30ml/min)，以得到5-[[2-[(4aS,8aR)-5,5-二甲基-1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(87mg，242.72μmol，16.92%產率)。To (4aS,8aR)-5,5-dimethyl-2,3,4,4a,6,7,8,8a-octahydro-1H-isoquinoline (239.95 mg, 1.43 mmol), 2-[ (5-Aminocarbamoyl-3-pyridinyl)amino]-2-side oxyacetic acid (300 mg, 1.43 mmol, triethylamine), DIPEA (556.11 mg, 4.30 mmol, 749.48 μL) in DMF (5 mL) To the solution was added EDC (329.95 mg, 1.72 mmol) in portions. The resulting solution was stirred at 25 °C for 16 h. Then, the solvent was evaporated and the residue was subjected to HPLC (35-70% 0-5 min 0.1% NH3 -methanol, flow rate: 30 ml/min) to give 5-[[2-[(4aS,8aR)-5, 5-Dimethyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (87 mg, 242.72 μmol, 16.92% yield).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=3.392min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=3.392 min.

步驟2：5-[[2-[(4aR,8aS)-5,5-二甲基-1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物193 )及5-[[2-[(4aS,8aR)-5,5-二甲基Step 2: 5-[[2-[(4aR,8aS)-5,5-dimethyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( Compound 193 ) and 5-[[2-[(4aS,8aR)-5,5-dimethyl -1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物197 )之合成-1,3,4,4a,6,7,8,8a-Octahydroisoquinolin-2-yl]-2-oxyacetyl]amino]pyridine-3-carboxamide ( Compound 197 ) synthesis

藉由掌性層析(OD-H(250* 30，5mkm)，己烷-IPA-MeOH，70-15-15，30ml/min)分離5-[[2-[(4aS,8aR)-5,5-二甲基-1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(87mg，242.72μmol)，以得到5-[[2-[(4aR,8aS)-5,5-二甲基-1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(37mg，103.23μmol，42.53%產率)(RT=12.56min)及5-[[2-[(4aS,8aR)-5,5-二甲基-1,3,4,4a,6,7,8,8a-八氫異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(36mg，100.44μmol，41.38%產率)(RT=19.56min)。5-[[2-[(4aS,8aR)-5 was isolated by chiral chromatography (OD-H (250 * 30, 5mkm), hexane-IPA-MeOH, 70-15-15, 30ml/min) ,5-Dimethyl-1,3,4,4a,6,7,8,8a-Octahydroisoquinolin-2-yl]-2-oxyethanoyl]amino]pyridine-3- Formamide (87 mg, 242.72 μmol) to give 5-[[2-[(4aR,8aS)-5,5-dimethyl-1,3,4,4a,6,7,8,8a-octa Hydroisoquinolin-2-yl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (37 mg, 103.23 μmol, 42.53% yield) (RT=12.56 min) and 5-[ [2-[(4aS,8aR)-5,5-dimethyl-1,3,4,4a,6,7,8,8a-octahydroisoquinolin-2-yl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide (36 mg, 100.44 μmol, 41.38% yield) (RT=19.56 min).

化合物193：Compound 193:

RT(OD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=12.56min。RT (OD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 12.56 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.82(m,6H),0.91(d,1H),1.04(m,2H),1.18(m,2H),1.36(m,3H),1.57(m,1H),1.70(m,1H),2.30(m,1H),2.65(m,1H),2.88(m,1H),3.74(m,1H),4.31(m,1H),7.60(s,1H),8.15(s,1H),8.47(m,1H),8.75(s,1H),8.85(s,1H),11.09(s,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.82 (m, 6H), 0.91 (d, 1H), 1.04 (m, 2H), 1.18 (m, 2H), 1.36 (m, 3H), 1.57 ( m, 1H), 1.70(m, 1H), 2.30(m, 1H), 2.65(m, 1H), 2.88(m, 1H), 3.74(m, 1H), 4.31(m, 1H), 7.60(s , 1H), 8.15(s, 1H), 8.47(m, 1H), 8.75(s, 1H), 8.85(s, 1H), 11.09(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=3.175min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=3.175 min.

化合物197：Compound 197:

RT(OD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=19.56min。RT (OD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 19.56 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.80(m,6H),1.03(m,2H),1.18(m,2H),1.38(m,4H),1.70(m,1H),2.30(m,1H),2.64(m,1H),2.88(m,1H),3.74(m,1H),4.31(m,1H),7.59(s,1H),8.14(s,1H),8.47(m,1H),8.75(s,1H),8.84(s,1H),11.09(s,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.80 (m, 6H), 1.03 (m, 2H), 1.18 (m, 2H), 1.38 (m, 4H), 1.70 (m, 1H), 2.30 ( m, 1H), 2.64(m, 1H), 2.88(m, 1H), 3.74(m, 1H), 4.31(m, 1H), 7.59(s, 1H), 8.14(s, 1H), 8.47(m , 1H), 8.75(s, 1H), 8.84(s, 1H), 11.09(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=3.175min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=3.175 min.

實例147. 5-[[2-[(2R ,4S )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶Example 147. 5-[[2-[( 2R , 4S )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -Carboxamide and 5-[[2-[( 2S , 4R )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-甲醯胺(化合物353及化合物352)之合成-Synthesis of 3-formamide (compound 353 and compound 352)

Figure 110128222-A0202-12-1151-167
Figure 110128222-A0202-12-1151-167

步驟1：5-[[2-[(2S,4R)-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,4R)-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Synthesis of Amide

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.2g，814.27μmol，鹽酸鹽)及(2S ,4R )-2-苯基哌啶-4-甲腈(151.66mg，680.96μmol，鹽酸鹽)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(578.81mg，4.48mmol，780.07μL)。將所得反應混合物攪拌5分鐘。5分鐘之後，添加HATU(340.57mg，895.69μmol)。將所得反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液。藉由HPLC純化所獲得之粗產物，以得到呈淡黃色固體之純的5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.15g，397.46μmol，48.81%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.2 g, 814.27 μmol, hydrochloride) and (2S, 4R )-2-benzene DIPEA (578.81 mg, 4.48 mmol, 780.07 μL) was added to a stirred solution of ylpiperidine-4-carbonitrile (151.66 mg, 680.96 μmol, hydrochloride) in DMF (10 mL). The resulting reaction mixture was stirred for 5 minutes. After 5 minutes, HATU (340.57 mg, 895.69 μmol) was added. The resulting reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure. The crude product obtained was purified by HPLC to give pure 5-[[2-[( 2S , 4R )-4-cyano-2-phenyl-1-piperidinyl] as a pale yellow solid -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.15 g, 397.46 μmol, 48.81% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值377.2；實測值378.4；Rt=2.314min。LCMS (ESI): [M+Boc] + m/z: calculated 377.2; found 378.4; Rt=2.314 min.

步驟2：5-[[2-[(2R,4S)-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S,4R)-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物353 及化合物352 )之掌性分離Step 2: 5-[[2-[(2R,4S)-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide and 5-[[2-[(2S,4R)-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Chiral separation of amides (compound 353 and compound 352 )

使5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.15g)經歷掌性HPLC(管柱：IB(250*20,5um)；溶析液：己烷-IPA-MeOH，50-25-25；流速：13mL/min)，以獲得呈淡黃色固體之5-[[2-[(2R ,4S )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物353 ，48.8mg)及5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物352 ，57.1mg)。5-[[2-[( 2S , 4R )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (0.15 g) was subjected to chiral HPLC (column: IB (250*20,5um); eluent: hexane-IPA-MeOH, 50-25-25; flow rate: 13 mL/min) to obtain a 5-[[2-[(2 R ,4 S )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- as a pale yellow solid 3-Carboxamide ( compound 353 , 48.8 mg) and 5-[[2-[( 2S , 4R )-4-cyano-2-phenyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide ( compound 352 , 57.1 mg).

化合物353： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.84-1.90(m,1H),1.98-2.06(m,1H),2.20-2.29(m,1H),2.59-2.71(m,1H),3.05-3.23(m,1H),3.34-3.50(m,1H),3.88-4.44(m,1H),5.30-5.62(m,1H),7.22-7.29(m,1H),7.31-7.40(m,4H),7.51-7.65(m,1H),8.09-8.21(m,1H),8.34-8.56(m,1H),8.71-8.95(m,2H),11.06-11.32(m,1H)。 Compound 353: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 1.84-1.90 (m, 1H), 1.98-2.06 (m, 1H), 2.20-2.29 (m, 1H), 2.59-2.71 ( m,1H),3.05-3.23(m,1H),3.34-3.50(m,1H),3.88-4.44(m,1H),5.30-5.62(m,1H),7.22-7.29(m,1H), 7.31-7.40(m, 4H), 7.51-7.65(m, 1H), 8.09-8.21(m, 1H), 8.34-8.56(m, 1H), 8.71-8.95(m, 2H), 11.06-11.32(m , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值377.2；實測值378.2；Rt=3.903min。LCMS (ESI): [M+H] + m/z: calculated 377.2; found 378.2; Rt=3.903 min.

掌性HPLC：Rt=14.44min(管柱：IB；溶析液：己烷-IPA-MeOH，50-25-25；流速：0.15mL/min)。Chiral HPLC: Rt=14.44 min (column: IB; eluent: hexane-IPA-MeOH, 50-25-25; flow rate: 0.15 mL/min).

化合物352： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.83-2.04(m,2H),2.20-2.25(m,1H),2.59-2.72(m,1H),3.04-3.24(m,1H),3.32-3.52(m,1H),3.87-4.46(m,1H),5.31-5.58(m,1H),7.21-7.28(m,1H),7.31-7.38(m,4H),7.51-7.65(m,1H),8.06-8.21(m,1H),8.36-8.55(m,1H),8.71-8.93(m,2H),11.07-11.31(m,1H)。 Compound 352: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 1.83-2.04 (m, 2H), 2.20-2.25 (m, 1H), 2.59-2.72 (m, 1H), 3.04-3.24 ( m,1H),3.32-3.52(m,1H),3.87-4.46(m,1H),5.31-5.58(m,1H),7.21-7.28(m,1H),7.31-7.38(m,4H), 7.51-7.65(m,1H), 8.06-8.21(m,1H), 8.36-8.55(m,1H), 8.71-8.93(m,2H), 11.07-11.31(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值377.2；實測值378.2；Rt=3.897min。LCMS (ESI): [M+H] + m/z: calculated 377.2; found 378.2; Rt=3.897 min.

掌性HPLC：Rt=8.97min(管柱：IB；溶析液：己烷-IPA-MeOH，50-25-25；流速：0.15mL/min)。Chiral HPLC: Rt = 8.97 min (column: IB; eluent: hexane-IPA-MeOH, 50-25-25; flow rate: 0.15 mL/min).

實例148. 5-[[2-[(2S ,4aR,8aR )-2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H -喹啉-1-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,4aS,8aS )-2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H -喹啉-1-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物245及化合物236)之合成Example 148. 5-[[2-[( 2S ,4aR, 8aR )-2-methyl-3,4,4a,5,6,7,8,8a-octahydro- 2H -quinoline- 1-yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide and 5-[[2-[(2 R ,4aS,8a S )-2-methyl-3,4 ,4a,5,6,7,8,8a-Octahydro- 2H -quinolin-1-yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 245 and Synthesis of compound 236)

Figure 110128222-A0202-12-1152-168
Figure 110128222-A0202-12-1152-168

步驟1：5-[[2-(2-甲基-3,4,4a,5,6,7,8,8a-八氫2H-喹啉-1-基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-(2-Methyl-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl)-2-pendoxetylacetone Synthesis of amino]pyridine-3-carboxamide

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.5g，1.61mmol， Et3 N鹽)及2-甲基-1,2,3,4,4a,5,6,7,8,8a-十氫喹啉(305.67mg，1.61mmol，鹽酸鹽)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(728.78mg，5.64mmol，982.18μL)。將所得反應混合物攪拌5分鐘。5分鐘之後，添加HATU(673.85mg，1.77mmol)。將反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液。藉由管柱層析純化所獲得之粗產物，以獲得呈淡黃色固體之5-[[2-(2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H -喹啉-1-基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.18g，522.64μmol，32.44%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.5 g, 1.61 mmol, Et 3 N salt) and 2-methyl-1,2,3 To a stirred solution of ,4,4a,5,6,7,8,8a-decahydroquinoline (305.67 mg, 1.61 mmol, hydrochloride) in DMF (10 mL) was added DIPEA (728.78 mg, 5.64 mmol) , 982.18 μL). The resulting reaction mixture was stirred for 5 minutes. After 5 minutes, HATU (673.85 mg, 1.77 mmol) was added. The reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 5-[[2-(2-methyl-3,4,4a,5,6,7,8,8a-octahydro as a pale yellow solid -2H-Quinolin-1-yl)-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.18 g, 522.64 μmol, 32.44% yield).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=1.180min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.2; Rt=1.180 min.

5-[[2-[(2S,4aR,8aR)-2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H-喹啉-1-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,4aS,8aS)-2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H-喹啉-1-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物245 及化合物236 )之掌性分離5-[[2-[(2S,4aR,8aR)-2-methyl-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2 -Pendant oxyacetyl]amino]pyridine-3-carboxamide and 5-[[2-[(2R,4aS,8aS)-2-methyl-3,4,4a,5,6,7 Chiral separation of ,8,8a-octahydro-2H-quinolin-1-yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 245 and compound 236 )

使5-[[2-(2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H -喹啉-1-基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.18g)經歷掌性HPLC(管柱：Chiralpak IA(250 * 20mm，5um)；溶析液：己烷-IPA-MeOH,80-10-10；流速：12mL/min)，以獲得呈白色固體之5-[[2-[(2S ,4aR ,8aR )-2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H -喹啉-1-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物245 ，10mg)及5-[[2-[(2R ,4aS ,8aS )-2-甲基-3,4,4a,5,6,7,8,8a-八氫-2H -喹啉-1-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物236 ，9.6mg)。5-[[2-(2-Methyl-3,4,4a,5,6,7,8,8a-octahydro- 2H -quinolin-1-yl)-2-pendoxetylacetone yl]amino]pyridine-3-carboxamide (0.18g) was subjected to chiral HPLC (column: Chiralpak IA (250*20mm, 5um); eluent: Hexane-IPA-MeOH, 80-10-10 ; flow rate: 12 mL/min) to obtain 5-[[2-[( 2S , 4aR , 8aR )-2-methyl-3,4,4a,5,6,7,8 as a white solid ,8a-Octahydro- 2H -quinolin-1-yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 245 , 10mg) and 5-[[2-[ (2 R ,4a S ,8a S )-2-methyl-3,4,4a,5,6,7,8,8a-octahydro- 2H -quinolin-1-yl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide ( compound 236 , 9.6 mg).

化合物236： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.96-1.18(m,1H),1.20-1.30(m,5H),1.30-1.40(m,1H),1.40-1.55(m,1H),1.55-1.66(m,4H),1.68-1.77(m,2H),1.78-1.87(m,1H),1.90-2.03(m,1H),3.61-4.00(m,1H),4.28-4.58(m,1H),7.58-7.65(m,1H),8.09-8.19(m,1H),8.43-8.50(m,1H),8.72-8.78(m,1H),8.80-8.86(m,1H),11.00-11.11(m,1H)。 Compound 236: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 0.96-1.18 (m, 1H), 1.20-1.30 (m, 5H), 1.30-1.40 (m, 1H), 1.40-1.55 ( m,1H),1.55-1.66(m,4H),1.68-1.77(m,2H),1.78-1.87(m,1H),1.90-2.03(m,1H),3.61-4.00(m,1H), 4.28-4.58(m, 1H), 7.58-7.65(m, 1H), 8.09-8.19(m, 1H), 8.43-8.50(m, 1H), 8.72-8.78(m, 1H), 8.80-8.86(m , 1H), 11.00-11.11 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=3.080min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.2; Rt=3.080 min.

掌性HPLC：Rt=21.02min(管柱：IA；溶析液：己烷-IPA-MeOH，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=21.02 min (column: IA; eluent: hexane-IPA-MeOH, 70-15-15; flow rate: 0.6 mL/min).

化合物245： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.95-1.18(m,1H),1.20-1.30(m,5H),1.31-1.43(m,1H),1.44-1.56(m,1H),1.56-1.66(m,4H),1.68-1.77(m,2H),1.78-1.89(m,1H),1.93-2.05(m,1H),3.59-4.03(m,1H),4.24-4.58(m,1H),7.54-7.66(m,1H),8.11-8.20(m,1H),8.41-8.49(m,1H),8.71-8.79(m,1H),8.81-8.87(m,1H),10.99-11.12(m,1H)。 Compound 245: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 0.95-1.18 (m, 1H), 1.20-1.30 (m, 5H), 1.31-1.43 (m, 1H), 1.44-1.56 ( m,1H),1.56-1.66(m,4H),1.68-1.77(m,2H),1.78-1.89(m,1H),1.93-2.05(m,1H),3.59-4.03(m,1H), 4.24-4.58(m, 1H), 7.54-7.66(m, 1H), 8.11-8.20(m, 1H), 8.41-8.49(m, 1H), 8.71-8.79(m, 1H), 8.81-8.87(m , 1H), 10.99-11.12 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=2.560min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.2; Rt=2.560 min.

掌性HPLC：Rt=17.37min(管柱：IA；溶析液：己烷-IPA-MeOH，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=17.37 min (column: IA; eluent: hexane-IPA-MeOH, 70-15-15; flow rate: 0.6 mL/min).

實例149. 5-[[2-[2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物501)之合成Example 149. 5-[[2-[2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2-methyl Synthesis of Oxypyridine-3-Carboxamide (Compound 501)

Figure 110128222-A0202-12-1154-169
Figure 110128222-A0202-12-1154-169

在25℃下，向2-(苯并噻吩-3-基)-5-甲基哌啶(0.3g，1.30mmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(441.36mg，1.30mmol，Et3 N)及N,N-二異丙基乙胺(837.95mg，6.48mmol，1.13mL)於DMF(6mL)中之經攪拌之溶液中添加HATU(591.65mg，1.56mmol)。將所得反應混合物在同一溫度下攪拌16h。粗反應混合物之LCMS分析指示在RT=1.353min處31.88%所要產物質量曲線下面積。藉由製備型HPLC(管柱：SunFireC18 100* 19mm 5um，流動相： 30-30-70% 0-1-5min水-乙腈，流速：30mL/min，裝載泵4mL/min乙腈)純化粗反應混合物，以得到產物呈灰白色固體之化合物501 5-[[2-[2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(200mg，441.96μmol，34.08%產率)。To 2-(benzothiophen-3-yl)-5-methylpiperidine (0.3 g, 1.30 mmol), 2-[(5-aminocarbamoyl-6-methoxy-3 at 25°C -Pyridinyl)amino]-2-oxoacetic acid (441.36 mg, 1.30 mmol, Et3N ) and N,N-diisopropylethylamine (837.95 mg, 6.48 mmol, 1.13 mL) in DMF (6 mL) ) was added to the stirred solution in HATU (591.65 mg, 1.56 mmol). The resulting reaction mixture was stirred at the same temperature for 16 h. LCMS analysis of the crude reaction mixture indicated 31.88% area under the curve for the mass of the desired product at RT=1.353 min. The crude reaction mixture was purified by preparative HPLC (column: SunFire C18 100 * 19mm 5um, mobile phase: 30-30-70% 0-1-5 min water-acetonitrile, flow rate: 30 mL/min, loading pump 4 mL/min acetonitrile) , to give compound 501 as an off-white solid 5-[[2-[2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-2-methoxypyridine-3-carboxamide (200 mg, 441.96 μmol, 34.08% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.94-1.08(m,3H),1.33-1.57(m,1H),1.91-1.99(m,1H),2.00-2.13(m,2H),2.13-2.30(m,1H),3.35-3.48(m,1H),3.48-3.65(m,1H),3.91-4.05(m,3H),5.51-6.00(m,1H),7.28-7.41(m,2H),7.67-7.74(m,2H),7.75-7.81(m,1H),7.81-7.90(m,1H),7.92-8.02(m,1H),8.34-8.46(m,1H),8.45-8.58(m,1H),10.86-11.12(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.94-1.08(m,3H), 1.33-1.57(m,1H), 1.91-1.99(m,1H), 2.00-2.13(m,2H), 2.13- 2.30(m, 1H), 3.35-3.48(m, 1H), 3.48-3.65(m, 1H), 3.91-4.05(m, 3H), 5.51-6.00(m, 1H), 7.28-7.41(m, 2H ),7.67-7.74(m,2H),7.75-7.81(m,1H),7.81-7.90(m,1H),7.92-8.02(m,1H),8.34-8.46(m,1H),8.45-8.58 (m, 1H), 10.86-11.12 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值452.1；實測值453.4；Rt=3.392min。LCMS (ESI): [M+H] + m/z: calculated 452.1; found 453.4; Rt=3.392 min.

實例150. 5-[[2-[(2R,5S)-2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物466)及5-[[2-[(2S,5R)-2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物463)之合成Example 150. 5-[[2-[(2R,5S)-2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (Compound 466) and 5-[[2-[(2S,5R)-2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide (compound 463)

Figure 110128222-A0202-12-1155-170
Figure 110128222-A0202-12-1155-170

步驟1：5-[[2-[2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基.乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(Benzothiophen-3-yl)-5-methyl-1-piperidinyl]-2-oxy.acetyl]amino]pyridine-3 -Synthesis of formamide

在25℃下，向2-(苯并噻吩-3-基)-5-甲基哌啶(0.3g，1.30mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(318.50mg，1.30mmol，HCl)及N,N-二 異丙基乙基胺(837.95mg，6.48mmol，1.13mL)於DMF(6mL)中之經攪拌之溶液中添加HATU(591.65mg，1.56mmol)。將所得反應混合物在25℃下攪拌16h。粗反應混合物之LCMS指示在RT=1.25min處55.77%所要產物質量曲線下面積。藉由製備型HPLC(管柱：SunFireC18 100* 19mm 5um，流動相：30-30-65% 0-1-5min水-乙腈，流速：30mL/min，裝載泵4mL/min乙腈)純化粗反應混合物，以得到呈灰白色固體之5-[[2-[2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(400mg，946.75μmol，73.01%產率)。To 2-(benzothiophen-3-yl)-5-methylpiperidine (0.3 g, 1.30 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino at 25 °C A stirred solution of ]-2-oxoacetic acid (318.50 mg, 1.30 mmol, HCl) and N,N-diisopropylethylamine (837.95 mg, 6.48 mmol, 1.13 mL) in DMF (6 mL) To this was added HATU (591.65 mg, 1.56 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. LCMS of the crude reaction mixture indicated 55.77% area under the curve for the mass of the desired product at RT=1.25 min. The crude reaction mixture was purified by preparative HPLC (column: SunFire C18 100 * 19mm 5um, mobile phase: 30-30-65% 0-1-5 min water-acetonitrile, flow rate: 30 mL/min, loading pump 4 mL/min acetonitrile) , to give 5-[[2-[2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] as an off-white solid Pyridine-3-carboxamide (400 mg, 946.75 μmol, 73.01% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.04(m,3H),1.42(m,1H),2.12(m,4H),3.40(m,1H),3.56(m,2H),6.00(m,1H),7.33(m,1H),7.40(s,1H),7.83(m,1H),7.94(m,1H),8.01(m,1H),8.18(m,1H),8.51(m,1H),8.79(s,1H),8.91(m,1H),11.28(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.04(m, 3H), 1.42(m, 1H), 2.12(m, 4H), 3.40(m, 1H), 3.56(m, 2H), 6.00(m ,1H),7.33(m,1H),7.40(s,1H),7.83(m,1H),7.94(m,1H),8.01(m,1H),8.18(m,1H),8.51(m, 1H), 8.79 (s, 1H), 8.91 (m, 1H), 11.28 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值422.1；實測值423.2；Rt=3.45min。LCMS (ESI): [M+H] + m/z: calculated 422.1; found 423.2; Rt=3.45 min.

步驟2：5-[[2-[(2R,5S)-2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物466 )及5-[[2-[(2S,5R)-2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物463 )之合成Step 2: 5-[[2-[(2R,5S)-2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (Compound 466 ) and 5-[[2-[(2S,5R)-2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide ( compound 463 )

將外消旋5-[[2-[(2S,5R)-2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(130mg，307.69μmol)提交至製備型掌性HPLC(管柱：IB-I(250* 20，5mkm)，流動相：己烷-IPA-MeOH，70-15-15，流速：12mL/min)，以得到呈白色固體之純產物(化合物466 )5-[[2-[(2R,5S)-2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(68.5mg，162.13μmol，52.69%產率)(RT=28.469min)及雜質級分(RT=18.587min)，其藉由製備型掌性HPLC(管柱：IA-II(250* 20，5mkm)，流動相：己烷-IPA-MeOH，50-25-25，流速：10mL/min)進一步純化，以獲得呈白色固體之純產物(化合物463 )5-[[2-[(2S,5R)-2-(苯并噻吩-3-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶 -3-甲醯胺(49.8mg，117.87μmol，38.31%產率)(RT=26.354min)。The racemic 5-[[2-[(2S,5R)-2-(benzothiophen-3-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (130 mg, 307.69 μmol) was submitted to preparative chiral HPLC (column: IB-I (250 * 20, 5 mkm), mobile phase: hexane-IPA-MeOH, 70- 15-15, flow rate: 12 mL/min) to give pure product (compound 466 )5-[[2-[(2R,5S)-2-(benzothiophen-3-yl)-5- as a white solid Methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (68.5mg, 162.13μmol, 52.69% yield) (RT=28.469min) and impurity grade fraction (RT=18.587 min) by preparative chiral HPLC (column: IA-II (250 * 20, 5mkm), mobile phase: hexane-IPA-MeOH, 50-25-25, flow rate: 10 mL /min) was further purified to obtain pure product ( compound 463 )5-[[2-[(2S,5R)-2-(benzothiophen-3-yl)-5-methyl-1- as a white solid Piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (49.8 mg, 117.87 μmol, 38.31% yield) (RT=26.354 min).

化合物466： RT(IA，Hex-IPA-MeOH，50-25-25，0.6mL/min)=19.058min。 Compound 466: RT (IA, Hex-IPA-MeOH, 50-25-25, 0.6 mL/min) = 19.058 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.04(m,3H),1.36-1.47(m,1H),1.91-2.01(m,1H),2.05-2.15(m,2H),2.15-2.32(m,1H),3.33-3.45(m,1H),3.50-4.06(m,1H),5.50-5.97(m,1H),7.24-7.41(m,2H),7.52-7.63(m,1H),7.70-7.87(m,2H),7.90-8.02(m,1H),8.06-8.19(m,1H),8.34-8.50(m,1H),8.69-8.91(m,2H),11.01-11.39(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.97-1.04(m,3H), 1.36-1.47(m,1H), 1.91-2.01(m,1H), 2.05-2.15(m,2H), 2.15- 2.32(m,1H),3.33-3.45(m,1H),3.50-4.06(m,1H),5.50-5.97(m,1H),7.24-7.41(m,2H),7.52-7.63(m,1H) ),7.70-7.87(m,2H),7.90-8.02(m,1H),8.06-8.19(m,1H),8.34-8.50(m,1H),8.69-8.91(m,2H),11.01-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值422.1；實測值423.0；Rt=3.309min。LCMS (ESI): [M+H] + m/z: calculated 422.1; found 423.0; Rt=3.309 min.

化合物463： RT(IA，Hex-IPA-MeOH，50-25-25，0.6mL/min)=23.854min。 Compound 463: RT (IA, Hex-IPA-MeOH, 50-25-25, 0.6 mL/min) = 23.854 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.98-1.06(m,3H),1.37-1.46(m,1H),1.93-2.01(m,1H),2.05-2.14(m,2H),2.14-2.31(m,1H),3.33-3.43(m,1H),3.52-4.04(m,1H),5.52-5.94(m,1H),7.28-7.41(m,2H),7.53-7.62(m,1H),7.69-7.88(m,2H),7.90-8.01(m,1H),8.07-8.19(m,1H),8.34-8.52(m,1H),8.68-8.91(m,2H),11.01-11.34(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.98-1.06(m,3H), 1.37-1.46(m,1H), 1.93-2.01(m,1H), 2.05-2.14(m,2H), 2.14- 2.31(m,1H), 3.33-3.43(m,1H), 3.52-4.04(m,1H), 5.52-5.94(m,1H), 7.28-7.41(m,2H), 7.53-7.62(m,1H) ),7.69-7.88(m,2H),7.90-8.01(m,1H),8.07-8.19(m,1H),8.34-8.52(m,1H),8.68-8.91(m,2H),11.01-11.34 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值422.1；實測值423.0；Rt=3.310min。LCMS (ESI): [M+H] + m/z: calculated 422.1; found 423.0; Rt=3.310 min.

實例151. 5-(2-(八氫異喹啉-2(1H )-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物429)之合成Example 151. Synthesis of 5-(2-(Octahydroisoquinolin-2( 1H )-yl)-2-oxyacetamido)nicotinamide (Compound 429)

Figure 110128222-A0202-12-1157-171
Figure 110128222-A0202-12-1157-171

將DIPEA(123.14mg，952.77μmol，165.96μL)添加到相應(4aS,8aS )-1,2,3,4,4a,5,6,7,8,8a-十氫異喹啉(37.2mg，211.73μmol，HCl)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(57.20mg，232.90μmol，HCl)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(96.61mg，254.07 μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH+NH3 為溶析液混合物)，以得到5-[[2-[(4aS,8aS )-3,4,4a,5,6,7,8,8a-八氫-1H -異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(51.4mg，155.58μmol，73.48%產率)。DIPEA (123.14 mg, 952.77 μmol, 165.96 μL) was added to the corresponding ( 4aS,8aS )-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline (37.2 mg, 211.73 μmol, HCl) and a solution of 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (57.20 mg, 232.90 μmol, HCl) in DMF (5 mL) . The resulting mixture was stirred for 5 min, then HATU (96.61 mg, 254.07 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH+ NH3 as eluent mixture) to give 5-[[2-[( 4aS,8aS )-3,4,4a ,5,6,7,8,8a-Octahydro- 1H -isoquinolin-2-yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (51.4 mg, 155.58 μmol , 73.48% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.17-1.33(m,2H),1.33-1.42(m,3H),1.43-1.52(m,2H),1.52-1.62(m,2H),1.63-1.81(m,2H),1.84-1.95(m,1H),2.92-3.25(m,2H),3.52-3.73(m,1H),3.77-4.11(m,1H),7.47-7.76(s,1H),8.08-8.24(s,1H),8.38-8.58(m,1H),8.69-8.81(m,1H),8.82-8.94(m,1H),10.57-11.17(br s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.17-1.33(m,2H), 1.33-1.42(m,3H), 1.43-1.52(m,2H), 1.52-1.62(m,2H) ,1.63-1.81(m,2H),1.84-1.95(m,1H),2.92-3.25(m,2H),3.52-3.73(m,1H),3.77-4.11(m,1H),7.47-7.76( s,1H),8.08-8.24(s,1H),8.38-8.58(m,1H),8.69-8.81(m,1H),8.82-8.94(m,1H),10.57-11.17(br s,1H) .

LCMS(ESI)：[M]+ m/z：計算值330.4；實測值331.2；Rt=2.719min。LCMS (ESI): [M] + m/z: calculated 330.4; found 331.2; Rt=2.719 min.

實例152. 5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物530)、5-[[2-[(2R,5S)-2-](1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物520)、5-[[2-[(2R,5S)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物529)及5-[[2-[(2S,5R)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物531)之合成Example 152. 5-[[2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide (Compound 530), 5-[[2-[(2R,5S)-2-](1R,3R)-3-hydroxycyclohexyl]-5-methyl yl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 520), 5-[[2-[(2R,5S)-2-[( 1R,3S)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 529) and 5- [[2-[(2S,5R)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide (Compound 531)

Figure 110128222-A0202-12-1159-172
Figure 110128222-A0202-12-1159-172

步驟1：5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S,5R)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide and 5-[[2-[(2S,5R)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl-1- Synthesis of piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide

在25℃下，將3-(5-甲基-2-哌啶基)環己醇(400.00mg，2.03mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(497.92mg，2.03mmol，HCl)及三乙胺(2.05g，20.27mmol，2.83mL)於DMF(6mL)中之混合物攪拌0.25h，然後在0.5h內小批量添加HATU(847.88mg，2.23mmol)。將反應混合物在25℃下攪拌12h，提交至反相HPLC(管柱：YMC-Triart C18 100* 20mm 5um，流動相：20-55% 0-5min 0.1%NH3 -甲醇，流速：30ml/min)，得到呈黃色膠狀物之5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(161mg，414.46μmol，20.44%產率)及5-[[2-[(2S,5R)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(257mg，661.59μmol，32.64%產率)。3-(5-Methyl-2-piperidinyl)cyclohexanol (400.00 mg, 2.03 mmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino] at 25°C - A mixture of 2-oxoacetic acid (497.92 mg, 2.03 mmol, HCl) and triethylamine (2.05 g, 20.27 mmol, 2.83 mL) in DMF (6 mL) was stirred for 0.25 h, then added in small batches over 0.5 h HATU (847.88 mg, 2.23 mmol). The reaction mixture was stirred at 25°C for 12h and submitted to reverse phase HPLC (column: YMC-Triart C18 100 * 20mm 5um, mobile phase: 20-55% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min ) to give 5-[[2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (161 mg, 414.46 μmol, 20.44% yield) and 5-[[2-[(2S,5R)-2-[(1S, 3R)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (257 mg, 661.59 μmol, 32.64% yield Rate).

第1級分：Tier 1:

1 H NMR(400MHz,DMSO-d6 )δ 0.9(m,2H),1.01(m,3H),1.31(m,2H),1.65(m,4H),1.98(m,5H),2.87(m,1H),3.61(m,1H),4.12(m,3H),4.56(m,1H),7.62(s,1H),8.18(s,1H),8.51(m,1H),8.78(s,1H),8.90(m,1H),11.05(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.9 (m, 2H), 1.01 (m, 3H), 1.31 (m, 2H), 1.65 (m, 4H), 1.98 (m, 5H), 2.87 (m ,1H),3.61(m,1H),4.12(m,3H),4.56(m,1H),7.62(s,1H),8.18(s,1H),8.51(m,1H),8.78(s, 1H), 8.90 (m, 1H), 11.05 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=2.317min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=2.317 min.

第2級分：Tier 2:

1 H NMR(400MHz,DMSO-d6 )δ 0.9(m,2H),1.00(m,3H),1.31(m,2H),1.82(m,10H),3.61(m,1H),4.09(m,3H),4.52(m,1H),7.62(s,1H),8.18(s,1H),8.51(m,1H),8.78(s,1H),8.90(m,1H),11.05(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.9(m, 2H), 1.00(m, 3H), 1.31(m, 2H), 1.82(m, 10H), 3.61(m, 1H), 4.09(m ,3H),4.52(m,1H),7.62(s,1H),8.18(s,1H),8.51(m,1H),8.78(s,1H),8.90(m,1H),11.05(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=2.636min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=2.636 min.

步驟2：5-[[2-[(2S.5R)-2-[(1S.3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物530 )及5-[[2-[(2R,5S)-2-[(1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物520 )之合成Step 2: 5-[[2-[(2S.5R)-2-[(1S.3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide ( Compound 530 ) and 5-[[2-[(2R,5S)-2-[(1R,3R)-3-hydroxycyclohexyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 520 )

將外消旋5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(161mg，414.46μmol)提交至製備型掌性HPLC(管柱：Chiralpak IC-I(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min；管柱溫度：23℃；波長：205nm.)，以得到呈白色固體之化合物530 5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(62.7mg，161.41μmol，38.94%產率)(R.T.=25.85min)及化合物520 5-[[2-[(2R,5S)-2-[(1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(62.7mg，161.41μmol，38.94%產率)(R.T.=49.50min)。The racemic 5-[[2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carbamoylamine (161 mg, 414.46 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IC-I (250*20 mm, 5 mkm); mobile phase: Hexane-IPA -MeOH, 50-25-25; flow rate: 12 mL/min; column temperature: 23°C; wavelength: 205 nm.) to give compound 530 as a white solid 5-[[2-[(2S,5R)-2 -[(1S,3S)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (62.7 mg, 161.41 μmol, 38.94% yield) (RT=25.85 min) and compound 520 5-[[2-[(2R,5S)-2-[(1R,3R)-3-hydroxycyclohexyl]-5-methyl -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (62.7 mg, 161.41 μmol, 38.94% yield) (RT=49.50 min).

化合物530： RT(IC-3，己烷-IPA-MeOH，50-25-25，0.15mL/min)=11.276min。 Compound 530: RT (IC-3, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 11.276 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.58-0.81(m,2H),0.92-0.98(m,3H),1.13-1.31(m,2H),1.41-1.53(m,1H),1.53-1.69(m,3H),1.69-2.04(m,6H),2.83-3.26(m, 1H),3.32-3.53(m,2H),3.92-4.19(m,1H),4.43-4.56(m,1H),7.59(s,1H),8.14(s,1H),8.42-8.51(m,1H),8.71-8.79(m,1H),8.82-8.90(m,1H),10.95-11.15(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.58-0.81(m, 2H), 0.92-0.98(m, 3H), 1.13-1.31(m, 2H), 1.41-1.53(m, 1H), 1.53- 1.69(m,3H),1.69-2.04(m,6H),2.83-3.26(m,1H),3.32-3.53(m,2H),3.92-4.19(m,1H),4.43-4.56(m,1H) ),7.59(s,1H),8.14(s,1H),8.42-8.51(m,1H),8.71-8.79(m,1H),8.82-8.90(m,1H),10.95-11.15(m,1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=3.610min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=3.610 min.

化合物520： RT(IC-3，己烷-IPA-MeOH，50-25-25，0.15mL/min)=21.019min。 Compound 520: RT (IC-3, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 21.019 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.59-0.79(m,2H),0.93-1.02(m,3H),1.13-1.30(m,2H),1.40-1.53(m,1H),1.52-1.68(m,3H),1.68-2.01(m,6H),2.85-3.26(m,1H),3.32-3.53(m,2H),3.95-4.17(m,1H),4.43-4.57(m,1H),7.53-7.62(m,1H),8.09-8.19(m,1H),8.43-8.50(m,1H),8.70-8.78(m,1H),8.83-8.91(m,1H),10.92-11.13(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.59-0.79(m, 2H), 0.93-1.02(m, 3H), 1.13-1.30(m, 2H), 1.40-1.53(m, 1H), 1.52- 1.68(m,3H),1.68-2.01(m,6H),2.85-3.26(m,1H),3.32-3.53(m,2H),3.95-4.17(m,1H),4.43-4.57(m,1H) ),7.53-7.62(m,1H),8.09-8.19(m,1H),8.43-8.50(m,1H),8.70-8.78(m,1H),8.83-8.91(m,1H),10.92-11.13 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=3.615min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=3.615 min.

步驟3：5-[[2-[(2R,5S)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物529 )及5-[[2-[(2S,5R)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物531 )之合成Step 3: 5-[[2-[(2R,5S)-2-[(1R,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide ( compound 529 ) and 5-[[2-[(2S,5R)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 531 )

首先使用製備型掌性HPLC(管柱：Chiralpak IA-II(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min)將外消旋5-[[2-[(2S,5R)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(257mg，661.59μmol)與其他雜質純化，然後使用製備型掌性HPLC(管柱：Chiralpak IC-I(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min)分離成鏡像異構物，以得到呈白色固體之化合物529 5-[[2-[(2R,5S)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(78mg，200.79μmol，30.35%產率)(R.T.=35.628min)及化合物531 5-[[2-[(2S,5R)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(76mg，195.64μmol，29.57%產率)(R.T.=53.630min)。Racemic 5 was first subjected to preparative chiral HPLC (column: Chiralpak IA-II (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12mL/min) -[[2-[(2S,5R)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxoacetyl]amine yl]pyridine-3-carboxamide (257 mg, 661.59 μmol) and other impurities were then purified using preparative chiral HPLC (column: Chiralpak IC-I (250*20 mm, 5 mkm); mobile phase: Hexane-IPA -MeOH, 50-25-25; flow rate: 12 mL/min) separated into enantiomers to give compound 529 as a white solid 5-[[2-[(2R,5S)-2-[(1R,3S )-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (78 mg, 200.79 μmol, 30.35% yield ) (RT=35.628min) and compound 531 5-[[2-[(2S,5R)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (76 mg, 195.64 μmol, 29.57% yield) (RT=53.630 min).

化合物529： RT(IC-3，己烷-IPA-MeOH，50-25-25，0.15mL/min)=14.944min。 Compound 529: RT (IC-3, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 14.944 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.58-0.78(m,2H),0.92-0.98(m,3H),1.17-1.30(m,2H),1.54-1.75(m,5H),1.75-2.00(m,5H),2.84-3.27(m,1H),3.34-3.57(m,2H),3.99-4.15(m,1H),4.43-4.54(m,1H),7.59(s,1H),8.15(s,1H),8.41-8.55(m,1H),8.69-8.79(m,1H),8.84-8.92(m,1H),10.92-11.20(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.58-0.78(m, 2H), 0.92-0.98(m, 3H), 1.17-1.30(m, 2H), 1.54-1.75(m, 5H), 1.75- 2.00(m, 5H), 2.84-3.27(m, 1H), 3.34-3.57(m, 2H), 3.99-4.15(m, 1H), 4.43-4.54(m, 1H), 7.59(s, 1H), 8.15(s, 1H), 8.41-8.55(m, 1H), 8.69-8.79(m, 1H), 8.84-8.92(m, 1H), 10.92-11.20(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=4.009min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=4.009 min.

化合物531： RT(IC-3，己烷-IPA-MeOH，50-25-25，0.15mL/min)=23.569min。 Compound 531: RT (IC-3, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 23.569 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.57-0.78(m,2H),0.92-0.98(m,3H),1.17-1.30(m,2H),1.52-1.75(m,5H),1.75-2.01(m,5H),2.84-3.24(m,1H),3.33-3.57(m,2H),3.98-4.15(m,1H),4.42-4.52(m,1H),7.59(s,1H),8.15(s,1H),8.42-8.52(m,1H),8.73-8.78(m,1H),8.86-8.91(m,1H),10.92-11.19(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.57-0.78(m, 2H), 0.92-0.98(m, 3H), 1.17-1.30(m, 2H), 1.52-1.75(m, 5H), 1.75- 2.01(m, 5H), 2.84-3.24(m, 1H), 3.33-3.57(m, 2H), 3.98-4.15(m, 1H), 4.42-4.52(m, 1H), 7.59(s, 1H), 8.15(s, 1H), 8.42-8.52(m, 1H), 8.73-8.78(m, 1H), 8.86-8.91(m, 1H), 10.92-11.19(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=4.013min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=4.013 min.

實例153. 5-(2-(2-(3-溴苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物601)之合成Example 153. Of 5-(2-(2-(3-bromophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 601) synthesis

Figure 110128222-A0202-12-1162-173
Figure 110128222-A0202-12-1162-173

向(2S,5R )-2-(3-溴苯基)-5-甲基哌啶(374.58mg，1.29mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(400mg，1.29mmol，Et3 N)及TEA(1.30g，12.89mmol，1.80mL)於DMF(3mL)中之溶液中分批添加HATU(539.08mg，1.42mmol)。將混合物在25℃下攪拌1.5h。然後藉由反相HPLC(50-50-90% 0-1-5min 0.2% FA-MeOH，流速：30ml/min(裝載泵4ml/min MeCN)，目標質量445，管柱：YMC Triart C18 100x20mm，5um)純化反應混合物，以得到呈2種 級分之5-[[2-[(2S,5R )-2-(3-溴苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(153mg，343.58μmol，26.66%產率)：第1級分：55mg(100% LCMS)；第2級分：98mg(97% LCMS)。To ( 2S,5R )-2-(3-bromophenyl)-5-methylpiperidine (374.58 mg, 1.29 mmol, HCl), 2-[(5-aminocarbamoyl-3-pyridyl)amine To a solution of DMF ( 3 mL) was added HATU (539.08 mg, 1.42 mmol) in portions ). The mixture was stirred at 25 °C for 1.5 h. Then by reverse phase HPLC (50-50-90% 0-1-5min 0.2% FA-MeOH, flow rate: 30ml/min (load pump 4ml/min MeCN), target mass 445, column: YMC Triart C18 100x20mm, 5um) purification of the reaction mixture to give 5-[[2-[( 2S,5R )-2-(3-bromophenyl)-5-methyl-1-piperidinyl]-2 in 2 fractions -Pendant oxyacetyl]amino]pyridine-3-carbamide (153 mg, 343.58 μmol, 26.66% yield): Fraction 1: 55 mg (100% LCMS); Fraction 2: 98 mg (97 % LCMS).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.27-1.36(m,1H),1.59-1.68(m,1H),1.82-1.94(m,1H),1.99-2.14(m,1H),2.15-2.25(m,1H),2.75-3.26(m,1H),3.47-4.06(m,1H),5.10-5.60(m,1H),7.31-7.37(m,2H),7.43-7.50(m,2H),7.55-7.67(m,1H),8.09-8.21(m,1H),8.44-8.52(m,1H),8.70-8.80(m,1H),8.80-8.95(m,1H),11.11-11.42(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,3H), 1.27-1.36(m,1H), 1.59-1.68(m,1H), 1.82-1.94(m,1H) ,1.99-2.14(m,1H),2.15-2.25(m,1H),2.75-3.26(m,1H),3.47-4.06(m,1H),5.10-5.60(m,1H),7.31-7.37( m,2H),7.43-7.50(m,2H),7.55-7.67(m,1H),8.09-8.21(m,1H),8.44-8.52(m,1H),8.70-8.80(m,1H), 8.80-8.95 (m, 1H), 11.11-11.42 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值445.4；實測值446.2；Rt=3.051min。LCMS (ESI): [M] + m/z: calculated 445.4; found 446.2; Rt=3.051 min.

實例154. 5-(2-(2-(5-氯吡啶-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物791)之合成Example 154. 5-(2-(2-(5-Chloropyridin-3-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 791) synthesis

Figure 110128222-A0202-12-1163-174
Figure 110128222-A0202-12-1163-174

在輕微加熱下，將3-氯-5-[(2R,5S )-5-甲基-2-哌啶基]吡啶(0.17g，806.82μmol)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(168.75mg，687.06μmol，HCl)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(368.13mg，968.19μmol)。反應完成(藉由反應混合物之LCMS推測)之後，藉由HPLC(14% 0.5-6.5min水-MeCN；流速30ml/min；(裝載泵4ml/min MecN)；目標質量575；管柱SunFireC18 100x19mm 5um(L))純化混合物，以得到呈順式/反式異構物之比率不同之2種級分的5-[[2-[(2R,5S )-2-(5-氯-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.3g，746.55μmol，92.53%產率)：第1級分3：97(200mg)；第2級分20：80(100mg)(藉由HNMR及LCMS推測)。3-Chloro-5-[( 2R,5S )-5-methyl-2-piperidinyl]pyridine (0.17 g, 806.82 μmol) and 2-[(5-aminocarbamoyl- 3-Pyridinyl)amino]-2-side oxyacetic acid (168.75 mg, 687.06 μmol, HCl) was dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (368.13 mg, 968.19 μmol) was added in small batches. After completion of the reaction (presumed by LCMS of the reaction mixture), by HPLC (14% 0.5-6.5min water-MeCN; flow rate 30ml/min; (loading pump 4ml/min MecN); target mass 575; column SunFire C18 100x19mm 5um (L)) Purification of the mixture to give 5-[[2-[( 2R,5S )-2-(5-chloro-3-pyridine in 2 fractions with different ratios of cis/trans isomers (0.3 g, 746.55 μmol, 92.53% yield): stage 1 Fraction 3:97 (200 mg); Fraction 2 20:80 (100 mg) (presumed by HNMR and LCMS).

化合物791： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.10(m,3H),1.26-1.41(m,1H),1.61-1.71(m,1H),1.84-1.95(m,1H),2.04-2.14(m,1H),2.19-2.31(m,1H),2.80-3.29(m,1H),3.36-4.08(m,1H),5.24-5.62(m,1H),7.56-7.67(m,1H),7.80-7.88(m,1H),8.09-8.22(m,1H),8.40-8.50(m,1H),8.50-8.60(m,2H),8.71-8.80(m,1H),8.80-8.92(m,1H),11.15-11.34(m,1H)。 Compound 791: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.95-1.10 (m, 3H), 1.26-1.41 (m, 1H), 1.61-1.71 (m, 1H), 1.84-1.95 (m) ,1H),2.04-2.14(m,1H),2.19-2.31(m,1H),2.80-3.29(m,1H),3.36-4.08(m,1H),5.24-5.62(m,1H),7.56 -7.67(m,1H),7.80-7.88(m,1H),8.09-8.22(m,1H),8.40-8.50(m,1H),8.50-8.60(m,2H),8.71-8.80(m, 1H), 8.80-8.92 (m, 1H), 11.15-11.34 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值401.2；實測值402.2；Rt=2.211min。LCMS (ESI): [M] + m/z: calculated 401.2; found 402.2; Rt=2.211 min.

實例155. 5-[[2-[(2R,5S)-5-甲基-2-[5-(甲胺基)-2-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物907)之合成Example 155. 5-[[2-[(2R,5S)-5-methyl-2-[5-(methylamino)-2-pyridyl]-1-piperidinyl]-2-side oxy Synthesis of Acetyl]amino]pyridine-3-carbamoylamine (Compound 907)

Figure 110128222-A0202-12-1164-175
Figure 110128222-A0202-12-1164-175

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(10.77mg，43.84μmol，HCl)及N-甲基-6-(5-甲基-2-哌啶基)吡啶-3-胺(0.009g，43.84μmol)混合於DMF(2mL)中。將反應懸浮液冷卻至20℃且添加HATU(18.34mg，48.22μmol)，隨後添加TEA(13.31mg，131.52μmol，18.33μL)，且在環境溫度下攪拌5h。將反應混合物在真空中蒸發且藉由製備型(25-60% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30ml/min)純化所獲得之粗產物0.06g，以得到產物5-[[2-[(2R,5S)-5-甲基-2-[5-(甲胺基)-2-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0035g，8.83μmol，20.14%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (10.77 mg, 43.84 μmol, HCl) and N-methyl-6-(5-methyl- 2-Piperidinyl)pyridin-3-amine (0.009 g, 43.84 μmol) was mixed in DMF (2 mL). The reaction suspension was cooled to 20°C and HATU (18.34 mg, 48.22 μmol) was added followed by TEA (13.31 mg, 131.52 μmol, 18.33 μL) and stirred at ambient temperature for 5 h. The reaction mixture was evaporated in vacuo and the obtained crude product 0.06 g was purified by prep (25-60% 0-5 min H2O /MeOH/0.1% NH4OH, flow rate: 30 ml/min) to give the product 5- [[2-[(2R,5S)-5-Methyl-2-[5-(methylamino)-2-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (0.0035 g, 8.83 μmol, 20.14% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.30(m,1H),1.72(m,1H),1.86(m,2H),2.36(m,2H),2.68(m,3H),2.77(m,1H),3.81(m,1H),5.26(m,1H),5.83(m,1H),6.88(m,1H),7.08(m,1H),7.56(m,1H),7.90(m,1H),8.12(m,1H),8.45(m,1H),8.72(m,1H),8.84(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.30(m, 1H), 1.72(m, 1H), 1.86(m, 2H), 2.36(m, 2H), 2.68(m, 3H), 2.77(m, 1H), 3.81(m, 1H), 5.26(m, 1H), 5.83(m, 1H), 6.88(m, 1H), 7.08(m, 1H), 7.56 (m, 1H), 7.90 (m, 1H), 8.12 (m, 1H), 8.45 (m, 1H), 8.72 (m, 1H), 8.84 (m, 1H)

LCMS(ESI)：[M+1]+ m/z：計算值396.2；實測值397.2；Rt=1.457min。LCMS (ESI): [M+1] + m/z: calculated 396.2; found 397.2; Rt=1.457 min.

實例156. 5-[[2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物533)及5-[[2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物532)之合成Example 156. 5-[[2-[(2R,5S)-2-(2-methoxy-4-pyridinyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone yl]amino]pyridine-3-carboxamide (Compound 533) and 5-[[2-[(2S,5R)-2-(2-methoxy-4-pyridyl)-5-methyl- Synthesis of 1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 532)

Figure 110128222-A0202-12-1165-176
Figure 110128222-A0202-12-1165-176

步驟1：5-[[2-[2-(2-甲氧基-4-吡啶基)-5-甲基1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(2-Methoxy-4-pyridinyl)-5-methyl1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide

將DIPEA(701.72mg，5.43mmol，945.71μL)添加到相應2-甲氧基-4-(5-甲基-2-哌啶基)吡啶(0.28g，1.36mmol)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(333.39mg，1.36mmol，HCl)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(448.65mg，1.18mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到純的5-[[2-[2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基1-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.33g，830.34μmol，61.17%產率)。DIPEA (701.72 mg, 5.43 mmol, 945.71 μL) was added to the corresponding 2-methoxy-4-(5-methyl-2-piperidinyl)pyridine (0.28 g, 1.36 mmol) and 2-[(5- Aminocarboxy-3-pyridyl)amino]-2-pendoxoacetic acid (333.39 mg, 1.36 mmol, HCl) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (448.65 mg, 1.18 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure 5-[[2-[2-(2-methoxy-4-pyridinyl)-5-methyl-1-piperidinyl 1-2-oxo Acetyl]amino]pyridine-3-carboxamide (0.33 g, 830.34 μmol, 61.17% yield).

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值398.2；Rt=2.593min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 398.2; Rt=2.593 min.

步驟2：5-[[2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物533 )及5-[[2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物532 )之合成Step 2: 5-[[2-[(2R,5S)-2-(2-methoxy-4-pyridinyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone ( Compound 533 ) and 5-[[2-[(2S,5R)-2-(2-methoxy-4-pyridyl)-5-methyl- Synthesis of 1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide ( compound 532 )

使用(Chiralpak IC 250* 20mm 5mkm管柱，以IPA-MeOH，50-50為流 動相，流速12mL/min)對5-[[2-[2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(330.0mg，830.34μmol)進行掌性分離，得到化合物532 5-[[2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(162.88mg，49.36%產率)及化合物533 5-[[2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(141.67mg，42.93%產率)。Use (Chiralpak IC 250 * 20mm 5mkm column, with IPA-MeOH, 50-50 as mobile phase, flow rate 12mL/min) for 5-[[2-[2-(2-methoxy-4-pyridyl) Chiral separation of -5-methyl-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (330.0 mg, 830.34 μmol) afforded compound 532 5-[ [2-[(2S,5R)-2-(2-Methoxy-4-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine -3-Carboxamide (162.88 mg, 49.36% yield) and compound 533 5-[[2-[(2R,5S)-2-(2-methoxy-4-pyridyl)-5-methyl -1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carboxamide (141.67 mg, 42.93% yield).

化合物532 (IC，MeOH-IPA，50-50，0.6mL/min)之保留時間=18.87minRetention time of compound 532 (IC, MeOH-IPA, 50-50, 0.6mL/min)=18.87min

化合物533 (IC，MeOH-IPA，50-50，0.6mL/min)之保留時間=35.96minRetention time of compound 533 (IC, MeOH-IPA, 50-50, 0.6mL/min)=35.96min

化合物533： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.01(m,3H),1.29-1.42(m,1H),1.51-1.61(m,1H),1.80-1.94(m,1H),1.97-2.14(m,1H),2.13-2.24(m,1H),2.74-3.25(m,1H),3.45-3.54(m,0.7H),3.80-3.88(m,3H),4.00-4.09(m,0.3H),5.06-5.69(m,1H),6.70-6.78(m,1H),6.91-6.97(m,1H),7.50-7.67(m,1H),8.05-8.21(m,2H),8.40-8.54(m,1H),8.69-8.80(m,1H),8.81-8.96(m,1H),11.18-11.35(m,1H)。 Compound 533: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.01 (m, 3H), 1.29-1.42 (m, 1H), 1.51-1.61 (m, 1H), 1.80-1.94 (m, 1H) ,1.97-2.14(m,1H),2.13-2.24(m,1H),2.74-3.25(m,1H),3.45-3.54(m,0.7H),3.80-3.88(m,3H),4.00-4.09 (m,0.3H),5.06-5.69(m,1H),6.70-6.78(m,1H),6.91-6.97(m,1H),7.50-7.67(m,1H),8.05-8.21(m,2H) ), 8.40-8.54(m, 1H), 8.69-8.80(m, 1H), 8.81-8.96(m, 1H), 11.18-11.35(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值398.2；Rt=0.895min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 398.2; Rt=0.895 min.

RT(IC，IPA-MeOH，50-50，12ml/min)=35.9532minRT(IC, IPA-MeOH, 50-50, 12ml/min)=35.9532min

化合物532： 1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.01(m,3H),1.29-1.36(m,1H),1.54-1.60(m,1H),1.75-1.97(m,1H),1.97-2.13(m,1H),2.13-2.23(m,1H),2.75-3.23(m,1H),3.47-3.50(m,0.7H),3.82-3.85(m,3H),4.02-4.06(m,0.3H),5.12-5.50(m,1H),6.71-6.73(m,1H),6.92-6.95(m,1H),7.56-7.63(m,1H),8.11-8.17(m,2H),8.43-8.50(m,1H),8.71-8.78(m,1H),8.83-8.90(m,1H),11.20-11.30(m,1H)。 Compound 532: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.01 (m, 3H), 1.29-1.36 (m, 1H), 1.54-1.60 (m, 1H), 1.75-1.97 (m, 1H) ,1.97-2.13(m,1H),2.13-2.23(m,1H),2.75-3.23(m,1H),3.47-3.50(m,0.7H),3.82-3.85(m,3H),4.02-4.06 (m,0.3H),5.12-5.50(m,1H),6.71-6.73(m,1H),6.92-6.95(m,1H),7.56-7.63(m,1H),8.11-8.17(m,2H) ), 8.43-8.50(m, 1H), 8.71-8.78(m, 1H), 8.83-8.90(m, 1H), 11.20-11.30(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值398.2；Rt=4.140min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 398.2; Rt=4.140 min.

RT(IC，IPA-MeOH，50-50，12ml/min)=18.8732min。RT (IC, IPA-MeOH, 50-50, 12 ml/min) = 18.8732 min.

實例157. 5-[[2-[(2R,5S)-5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物638)及5-[[2-[(2R,5S)-5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物611)之合成Example 157. 5-[[2-[(2R,5S)-5-methyl-2-(7-methyl-1H-indazol-5-yl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (Compound 638) and 5-[[2-[(2R,5S)-5-methyl-2-(7-methyl-1H-indazole Synthesis of -5-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 611)

Figure 110128222-A0202-12-1167-177
Figure 110128222-A0202-12-1167-177

步驟1：5-[[2-[5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[5-Methyl-2-(7-methyl-1H-indazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of base]pyridine-3-carboxamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(638.46mg，3.05mmol)及7-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑(0.7g，3.05mmol)混合於DMF(25mL)中。將反應懸浮液冷卻至0℃且添加HATU(1.16g，3.05mmol)，隨後添加TEA(926.65mg，9.16mmol，1.28mL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且倒入水(100ml)中且用EtOAc(2x30ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發且藉由製備型(30-80% 1-6min水-甲醇(NH3 0.1%)，流速30ml/min)純化所獲得之粗產物0.82g，以得到產物5-[[2-[5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.042g，99.89μmol，3.27%產率)。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (638.46 mg, 3.05 mmol) and 7-methyl-5-(5-methyl-2- piperidinyl)-lH-indazole (0.7 g, 3.05 mmol) was mixed in DMF (25 mL). The reaction suspension was cooled to 0 °C and HATU (1.16 g, 3.05 mmol) was added followed by TEA (926.65 mg, 9.16 mmol, 1.28 mL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and poured into water (100ml) and extracted with EtOAc (2x30ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo and washed by prep (30-80% 1-6 min water-methanol ( NH3 0.1%), flow rate 30ml/ min) 0.82 g of the obtained crude product was purified to obtain the product 5-[[2-[5-methyl-2-(7-methyl-1H-indazol-5-yl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.042 g, 99.89 μmol, 3.27% yield).

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=1.124min。LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=1.124 min.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物638 )及5-[[2-[(2R,5S)-5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物611 )之合成Step 2: 5-[[2-[(2R,5S)-5-methyl-2-(7-methyl-1H-indazol-5-yl)-1-piperidinyl]-2-oxo Acetyl]amino]pyridine-3-carboxamide ( Compound 638 ) and 5-[[2-[(2R,5S)-5-methyl-2-(7-methyl-1H-indazole Synthesis of -5-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 611 )

使5-[[2-[5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.03g，71.35μmol)經歷掌性HPLC純化(管柱：IC-II(250*20，5um)，溶析液：以己烷-IPA-MeOH，60-20-20為流動相，流速：12 mL/min)，以得到兩種單獨的鏡像異構物化合物611 5-[[2-[(2R,5S)-5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.007g，16.65μmol，23.33%產率)及化合物638 5-[[2-[(2R,5S)-5-甲基-2-(7-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.007g，16.65μmol，23.33%產率)。make 5-[[2-[5-methyl-2-(7-methyl-1H-indazol-5-yl)-1-piperidinyl]-2-oxyacetoxy]amino] Pyridine-3-carboxamide (0.03g, 71.35μmol) was purified by chiral HPLC (column: IC-II (250*20, 5um), eluent: hexane-IPA-MeOH, 60-20- 20 is the mobile phase, flow rate: 12 mL/min) to obtain two separate enantiomer compounds 611 5-[[2-[(2R,5S)-5-methyl-2-(7-methyl) -1H-Indazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.007 g, 16.65 μmol, 23.33% yield) and Compound 638 5-[[2-[(2R,5S)-5-methyl-2-(7-methyl-1H-indazol-5-yl)-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide (0.007 g, 16.65 μmol, 23.33% yield).

化合物638： 1 H NMR(500MHz,DMSO-d 6 )δ 1.00-1.06(m,3H),1.33-1.42(m,1H),1.75-1.91(m,2H),1.98-2.11(m,1H),2.11-2.25(m,1H),2.41-2.45(m,3H),2.79-3.24(m,1H),3.46-4.05(m,1H),5.19-5.70(m,1H),7.05-7.16(m,1H),7.48-7.68(m,2H),7.99-8.08(m,1H),8.09-8.22(m,1H),8.41-8.56(m,1H),8.70-8.79(m,1H),8.79-8.99(m,1H),11.16-11.38(m,1H),13.06-13.17(m,1H)。 Compound 638: 1 H NMR (500 MHz, DMSO- d 6 ) δ 1.00-1.06 (m, 3H), 1.33-1.42 (m, 1H), 1.75-1.91 (m, 2H), 1.98-2.11 (m, 1H) ,2.11-2.25(m,1H),2.41-2.45(m,3H),2.79-3.24(m,1H),3.46-4.05(m,1H),5.19-5.70(m,1H),7.05-7.16( m,1H),7.48-7.68(m,2H),7.99-8.08(m,1H),8.09-8.22(m,1H),8.41-8.56(m,1H),8.70-8.79(m,1H), 8.79-8.99(m,1H), 11.16-11.38(m,1H), 13.06-13.17(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值420.5；實測值421.4；Rt=3.923min。LCMS (ESI): [M+H] + m/z: calculated 420.5; found 421.4; Rt=3.923 min.

RT(己烷-IPA-MeOH，60-20-20，12ml/min)=52.9202min。RT (Hexane-IPA-MeOH, 60-20-20, 12 ml/min) = 52.9202 min.

化合物611： 1 H NMR(500MHz,DMSO-d 6 )δ 0.97-1.10(m,3H),1.30-1.44(m,1H),1.72-1.92(m,2H),2.04-2.19(m,1H),2.23-2.30(m,1H),2.40-2.47(m,3H),2.81-3.28(m,1H),3.46-4.08(m,1H),5.10-5.73(m,1H),7.04-7.17(m,1H),7.49-7.55(m,1H),7.55-7.69(m,1H),7.99-8.08(m,1H),8.09-8.21(m,1H),8.41-8.57(m,1H),8.70-8.80(m,1H),8.80-8.96(m,1H),11.10-11.46(m,1H),13.01-13.27(m,1H)。 Compound 611: 1 H NMR (500 MHz, DMSO- d 6 ) δ 0.97-1.10 (m, 3H), 1.30-1.44 (m, 1H), 1.72-1.92 (m, 2H), 2.04-2.19 (m, 1H) ,2.23-2.30(m,1H),2.40-2.47(m,3H),2.81-3.28(m,1H),3.46-4.08(m,1H),5.10-5.73(m,1H),7.04-7.17( m,1H),7.49-7.55(m,1H),7.55-7.69(m,1H),7.99-8.08(m,1H),8.09-8.21(m,1H),8.41-8.57(m,1H), 8.70-8.80(m,1H), 8.80-8.96(m,1H), 11.10-11.46(m,1H), 13.01-13.27(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值420.5；實測值421.4；Rt=3.926min。LCMS (ESI): [M+H] + m/z: calculated 420.5; found 421.4; Rt=3.926 min.

RT(己烷-IPA-MeOH，60-20-20，12ml/min)=34.8442min。RT (Hexane-IPA-MeOH, 60-20-20, 12 ml/min) = 34.8442 min.

實例158. 5-[[2-[(2R,5S)-2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物637)及5-[[2-[(2S,5R)-2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物612)之合成Example 158. 5-[[2-[(2R,5S)-2-(4-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (Compound 637) and 5-[[2-[(2S,5R)-2-(4-fluoro-1H-indazol-5-yl)-5 Synthesis of -Methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 612)

Figure 110128222-A0202-12-1169-178
Figure 110128222-A0202-12-1169-178

步驟1：5-[[2-[2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(4-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide

將4-氟-5-(5-甲基-2-哌啶基)-1H-吲唑(0.3g，1.29mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(315.86mg，1.29mmol，HCl)及三乙胺(1.30g，12.86mmol，1.79mL)一起混合於DMF(5mL)中。將HATU(733.46mg，1.93mmol)添加到前一混合物中且將所得混合物攪拌隔夜。在真空中濃縮反應混合物且藉由HPLC(2-10min 50-60% MeOH/H2 O，30ml/min(裝載泵4ml MeOH，管柱：SunFire 100*19mm，5微米)純化殘餘物，以獲得5-[[2-[2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0866g，204.04μmol，15.87%產率)。4-Fluoro-5-(5-methyl-2-piperidinyl)-1H-indazole (0.3 g, 1.29 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino ]-2-Pendoxoacetic acid (315.86 mg, 1.29 mmol, HCl) and triethylamine (1.30 g, 12.86 mmol, 1.79 mL) were mixed together in DMF (5 mL). HATU (733.46 mg, 1.93 mmol) was added to the previous mixture and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 50-60% MeOH/ H2O , 30 ml/min (loading pump 4 ml MeOH, column: SunFire 100*19 mm, 5 microns) to obtain 5-[[2-[2-(4-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (0.0866 g, 204.04 μmol, 15.87% yield).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=1.066min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=1.066 min.

步驟2：5-[[2-[(2R,5S)-2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物637 )及5-[[2-[(2S,5R)-2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物612 )之合成Step 2: 5-[[2-[(2R,5S)-2-(4-fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide ( compound 637 ) and 5-[[2-[(2S,5R)-2-(4-fluoro-1H-indazol-5-yl)-5 Synthesis of -Methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 612 )

對5-[[2-[2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0886g，208.75μmol)進行掌性分離(管柱：Chiralpak IC(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min；管柱溫度：24℃；波長：205nm.，以獲得：p-5-[[2-[2-(4-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide (0.0886g, 208.75μmol) for chiral separation (column: Chiralpak IC (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12mL /min; column temperature: 24°C; wavelength: 205nm. to obtain:

保留時間=54.05min：5-[[2-[(2R,5S)-2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.04274g，100.70μmol，48.24%產率)Retention time = 54.05 min: 5-[[2-[(2R,5S)-2-(4-fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.04274 g, 100.70 μmol, 48.24% yield)

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.03(m,3H),1.16-1.36(m,1H),1.83-1.94 (m,1H),1.98-2.20(m,3H),3.53-3.98(m,2H),5.45-5.58(m,1H),7.23-7.39(m,2H),7.51-7.65(m,1H),7.98-8.20(m,2H),8.27-8.54(m,1H),8.58-8.91(m,2H),10.70-11.39(m,1H),13.11-13.52(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ 1.00-1.03 (m, 3H), 1.16-1.36 (m, 1H), 1.83-1.94 (m, 1H), 1.98-2.20 (m, 3H), 3.53- 3.98(m,2H),5.45-5.58(m,1H),7.23-7.39(m,2H),7.51-7.65(m,1H),7.98-8.20(m,2H),8.27-8.54(m,1H ), 8.58-8.91 (m, 2H), 10.70-11.39 (m, 1H), 13.11-13.52 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.4；實測值425.2；Rt=4.117min。LCMS (ESI): [M+H] + m/z: calculated 424.4; found 425.2; Rt=4.117 min.

保留時間=26.80min：5-[[2-[(2S,5R)-2-(4-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(43.61mg，102.75μmol，49.22%產率)Retention time = 26.80 min: 5-[[2-[(2S,5R)-2-(4-fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (43.61 mg, 102.75 μmol, 49.22% yield)

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.01(m,3H),1.18-1.41(m,1H),1.82-2.02(m,3H),2.04-2.13(m,1H),3.56-3.91(m,2H),5.45-5.56(m,1H),7.22-7.38(m,2H),7.48-7.64(m,1H),8.00-8.17(m,2H),8.26-8.48(m,1H),8.61-8.92(m,2H),10.75-11.33(m,1H),13.12-13.46(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.01 (m, 3H), 1.18-1.41 (m, 1H), 1.82-2.02 (m, 3H), 2.04-2.13 (m, 1H), 3.56- 3.91(m, 2H), 5.45-5.56(m, 1H), 7.22-7.38(m, 2H), 7.48-7.64(m, 1H), 8.00-8.17(m, 2H), 8.26-8.48(m, 1H ), 8.61-8.92 (m, 2H), 10.75-11.33 (m, 1H), 13.12-13.46 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.4；實測值425.2；Rt=4.115min。LCMS (ESI): [M+H] + m/z: calculated 424.4; found 425.2; Rt=4.115 min.

實例159. 5-[[2-[(2R,5S)-2-(4-氟-3-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物540)之合成Example 159. 5-[[2-[(2R,5S)-2-(4-fluoro-3-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-pendant oxyacetyl Synthesis of ]amino]pyridine-3-carboxamide (Compound 540)

Figure 110128222-A0202-12-1170-179
Figure 110128222-A0202-12-1170-179

在25℃下，向2-氟-5-[(2R,5S)-5-甲基-2-哌啶基]苯酚(500mg，1.72mmol，HBr)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(423.23mg，1.72mmol，HCl)及三乙胺(1.74g，17.23mmol，2.40mL)於DMF(20mL)中之經攪拌之溶液中小批量添加HATU(1.31g，3.45mmol)。將所得反應混合物在25℃下攪拌16h，然後在真空中濃縮至大約5ml且提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um，流動相30-30-60% 0-1-6min 0.2%甲酸-甲醇，流速：30ml/min)，以得到呈白色固體之化合物540 5-[[2-[(2R,5S)-2-(4-氟-3-羥基苯基)-5-甲基-1-哌 啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(128mg，319.68μmol，18.55%產率)。To 2-fluoro-5-[(2R,5S)-5-methyl-2-piperidinyl]phenol (500 mg, 1.72 mmol, HBr), 2-[(5-aminocarboxylate at 25°C A stirred solution of -3-pyridyl)amino]-2-oxoacetic acid (423.23 mg, 1.72 mmol, HCl) and triethylamine (1.74 g, 17.23 mmol, 2.40 mL) in DMF (20 mL) HATU (1.31 g, 3.45 mmol) was added in small to medium batches. The resulting reaction mixture was stirred at 25°C for 16h, then concentrated in vacuo to approximately 5ml and submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um, mobile phase 30-30-60% 0-1-6min 0.2 % formic acid-methanol, flow rate: 30ml/min) to obtain compound 540 as a white solid 5-[[2-[(2R,5S)-2-(4-fluoro-3-hydroxyphenyl)-5-methan (128 mg, 319.68 μmol, 18.55% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.93-1.07(m,3H),1.25-1.38(m,1H),1.62-1.73(m,1H),1.81-2.14(m,3H),2.74-3.24(m,1H),3.44-4.04(m,1H),5.06-5.52(m,1H),6.67-6.78(m,1H),6.84-6.97(m,1H),7.04-7.16(m,1H),7.54-7.63(m,1H),8.08-8.20(m,1H),8.42-8.50(m,1H),8.71-8.79(m,1H),8.83-8.92(m,1H),9.75-9.92(m,1H),11.13-11.31(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.93-1.07(m,3H), 1.25-1.38(m,1H), 1.62-1.73(m,1H), 1.81-2.14(m,3H), 2.74- 3.24(m,1H),3.44-4.04(m,1H),5.06-5.52(m,1H),6.67-6.78(m,1H),6.84-6.97(m,1H),7.04-7.16(m,1H) ),7.54-7.63(m,1H),8.08-8.20(m,1H),8.42-8.50(m,1H),8.71-8.79(m,1H),8.83-8.92(m,1H),9.75-9.92 (m, 1H), 11.13-11.31 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值400.4；實測值401.2；Rt=2.299min。LCMS (ESI): [M+H] + m/z: calculated 400.4; found 401.2; Rt=2.299 min.

實例160. 2-[(2R,5S)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(化合物958)及2-[(2S,5R)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(化合物948)之合成Example 160. 2-[(2R,5S)-2-(3-amino-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-N-(5,6-di Methyl-3-pyridyl)-2-oxyacetamide (compound 958) and 2-[(2S,5R)-2-(3-amino-1H-indazol-5-yl)-5 Synthesis of -Methyl-1-piperidinyl]-N-(5,6-dimethyl-3-pyridyl)-2-oxoacetamide (Compound 948)

Figure 110128222-A0202-12-1171-180
Figure 110128222-A0202-12-1171-180

步驟1：2-[(2R,5S)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-I-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺之合成Step 1: 2-[(2R,5S)-2-(3-amino-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-N-(5,6-di Synthesis of methyl-3-pyridyl)-2-oxoacetamide

將2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(177.07mg，599.47μmol，C6H15N)及5-(5-甲基-2-哌啶基)-1H-吲唑-3-胺(0.21g，911.82μmol)混合於DMF(15mL)中。將反應懸浮液冷卻至0℃且添加HATU(381.37mg，1.00mmol)，隨後添加TEA(276.80mg，2.74mmol，381.27μL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且藉由製備型(40-70% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30ml/min)純化0.31g所獲得之粗產物，以得到產物2-[(2R,5S)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(22.60mg，55.60μmol，6.10%產率)。2-[(5,6-Dimethyl-3-pyridyl)amino]-2-oxoacetic acid (177.07mg, 599.47μmol, C6H15N) and 5-(5-methyl-2-piperidine yl)-1H-indazol-3-amine (0.21 g, 911.82 μmol) was mixed in DMF (15 mL). The reaction suspension was cooled to 0°C and HATU (381.37 mg, 1.00 mmol) was added followed by TEA (276.80 mg, 2.74 mmol, 381.27 μL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and 0.31 g of the obtained crude product was purified by prep (40-70% 0-5 min H2O /MeOH/0.1% NH4OH, flow rate: 30 ml/min) to give the product 2- [(2R,5S)-2-(3-Amino-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-N-(5,6-dimethyl-3- Pyridyl)-2-oxoacetamide (22.60 mg, 55.60 μmol, 6.10% yield).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.0；Rt=1.599min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.0; Rt=1.599 min.

步驟2：2-[(2R,5S)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(化合物958 )及2-[(2S,5R)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(化合物948 )之合成Step 2: 2-[(2R,5S)-2-(3-amino-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-N-(5,6-di Methyl-3-pyridyl)-2-oxyacetamide ( compound 958 ) and 2-[(2S,5R)-2-(3-amino-1H-indazol-5-yl)-5 Synthesis of -Methyl-1-piperidinyl]-N-(5,6-dimethyl-3-pyridyl)-2-oxoacetamide ( Compound 948 )

使2-[(2R,5S)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(0.0456g，112.18μmol)經歷掌性HPLC純化(管柱：IA-II(250*20,5mkm)，溶析液：己烷-IPA-MeOH，60-20-20，流速：12mL/min)，以得到兩種單獨的鏡像異構物化合物958 2-[(2R,5S)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(0.01055g，25.95μmol，23.14%產率)及化合物948 2-[(2S,5R)-2-(3-胺基-1H-吲唑-5-基)-5-甲基-1-哌啶基]-N-(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(0.01676g，41.23μmol，36.75%產率)make 2-[(2R,5S)-2-(3-amino-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-N-(5,6-dimethyl -3-Pyridinyl)-2-oxoacetamide (0.0456 g, 112.18 μmol) was purified by chiral HPLC (column: IA-II (250*20,5 mkm), eluent: hexane-IPA -MeOH, 60-20-20, flow rate: 12 mL/min) to give two separate enantiomers Compound 958 2-[(2R,5S)-2-(3-amino-1H-indazole- 5-yl)-5-methyl-1-piperidinyl]-N-(5,6-dimethyl-3-pyridyl)-2-oxoacetamide (0.01055 g, 25.95 μmol, 23.14 % yield) and compound 948 2-[(2S,5R)-2-(3-amino-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-N-(5 ,6-Dimethyl-3-pyridyl)-2-oxoacetamide (0.01676 g, 41.23 μmol, 36.75% yield)

化合物958： 1 H NMR(600MHz,DMSO-d 6 )δ 0.97-1.06(m,3H),1.30-1.40(m,1H),1.79-1.93(m,2H),2.01-2.28(m,5H),2.31-2.37(m,3H),2.75-3.24(m,1H),3.41-4.02(m,1H),5.13-5.69(m,3H),7.09-7.20(m,1H),7.20-7.26(m,1H),7.68(s,1H),7.73-7.85(m,1H),8.37-8.55(m,1H),10.82-10.92(m,1H),11.28-11.36(m,1H)。 Compound 958: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.97-1.06 (m, 3H), 1.30-1.40 (m, 1H), 1.79-1.93 (m, 2H), 2.01-2.28 (m, 5H) ,2.31-2.37(m,3H),2.75-3.24(m,1H),3.41-4.02(m,1H),5.13-5.69(m,3H),7.09-7.20(m,1H),7.20-7.26( m, 1H), 7.68 (s, 1H), 7.73-7.85 (m, 1H), 8.37-8.55 (m, 1H), 10.82-10.92 (m, 1H), 11.28-11.36 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=0.762min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=0.762 min.

RT(己烷-IPA-MeOH，80-10-10，0.6ml/min)=31.4212min。RT (Hexane-IPA-MeOH, 80-10-10, 0.6 ml/min) = 31.4212 min.

化合物948： 1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.05(m,3H),1.30-1.38(m,1H),1.82-1.93(m,2H),2.00-2.12(m,1H),2.13-2.27(m,5H),2.30-2.36(m,3H),2.78-3.19(m,1H),3.41-4.02(m,1H),5.14-5.30(m,2H),7.10-7.20(m,1H),7.20-7.26(m,1H),7.68(s,1H),7.73-7.85(m,1H),8.38-8.52(m,1H),10.82-10.91(m,1H),11.29-11.35(m,1H)。 Compound 948: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.05 (m, 3H), 1.30-1.38 (m, 1H), 1.82-1.93 (m, 2H), 2.00-2.12 (m, 1H) ,2.13-2.27(m,5H),2.30-2.36(m,3H),2.78-3.19(m,1H),3.41-4.02(m,1H),5.14-5.30(m,2H),7.10-7.20( m,1H),7.20-7.26(m,1H),7.68(s,1H),7.73-7.85(m,1H),8.38-8.52(m,1H),10.82-10.91(m,1H),11.29- 11.35 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=0.692min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=0.692 min.

RT(己烷-IPA-MeOH，80-10-10，0.6ml/min)=36.6272min。RT (Hexane-IPA-MeOH, 80-10-10, 0.6 ml/min) = 36.6272 min.

實例161. N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物649)之合成Example 161. N-(5,6-Dimethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(4-methylsulfonylphenyl)-1- Synthesis of piperidinyl]-2-oxoacetamide (compound 649)

Figure 110128222-A0202-12-1173-181
Figure 110128222-A0202-12-1173-181

在25℃下，在0.5h內，向(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)哌啶(250mg，986.74μmol)、2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(291.46mg，986.74μmol，N(C2H5)3)及三乙胺(998.48mg，9.87mmol，1.38mL)於DMF(5mL)中之正攪拌溶液中小批量添加HATU(412.71mg，1.09mmol)。將所得反應混合物在25℃下攪拌18h。藉由反相HPLC(管柱：SunFireC18 100x19mm 5um，流動相：15-40% 0-5min水-甲醇+FA，流速：30ml/min(裝載泵4ml/min甲醇))純化粗反應混合物，以得到化合物649 N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(87mg，202.55μmol，20.53%產率)。To (2R,5S)-5-methyl-2-(4-methylsulfonylphenyl)piperidine (250 mg, 986.74 μmol), 2-[(5, 6-Dimethyl-3-pyridyl)amino]-2-oxoacetic acid (291.46 mg, 986.74 μmol, N(C2H5)3) and triethylamine (998.48 mg, 9.87 mmol, 1.38 mL) in DMF To the stirring solution in (5 mL) was added HATU (412.71 mg, 1.09 mmol) in small portions. The resulting reaction mixture was stirred at 25 °C for 18 h. The crude reaction mixture was purified by reverse phase HPLC (column: SunFire C18 100x19mm 5um, mobile phase: 15-40% 0-5min water-methanol+FA, flow rate: 30ml/min (loading pump 4ml/min methanol)) to give Compound 649 N-(5,6-Dimethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(4-methylsulfonylphenyl)-1-piperidine Peridyl]-2-Pendant oxyacetamide (87 mg, 202.55 μmol, 20.53% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(dd,3H),1.33(m,1H),1.63(m,1H),1.88(m,1H),2.06(m,1H),2.21(m,4H),2.36(m,4H),3.20(m,3H),3.76(m,1H),5.41(m,1H),7.60(m,2H),7.81(m,1H),7.92(m,2H),8.48(m,1H),10.97(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(dd,3H), 1.33(m,1H), 1.63(m,1H), 1.88(m,1H), 2.06(m,1H), 2.21(m, 4H), 2.36(m, 4H), 3.20(m, 3H), 3.76(m, 1H), 5.41(m, 1H), 7.60(m, 2H), 7.81(m, 1H), 7.92 (m, 2H), 8.48 (m, 1H), 10.97 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值429.2；實測值430.2；Rt=1.962min。LCMS (ESI): [M+H] + m/z: calculated 429.2; found 430.2; Rt=1.962 min.

實例162. 外消旋5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物651)、5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物725)及5-[[2-[(2R,5S)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶Example 162. Racemic 5-[[2-[(2S,5R)-5-methyl-2-(4-sulfamonophenyl)-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carboxamide (Compound 651), 5-[[2-[(2S,5R)-5-methyl-2-(4-sulfamoylphenyl)-1 -Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (Compound 725) and 5-[[2-[(2R,5S)-5-methyl-2- (4-Sulfamonophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-甲醯胺(化合物724)之合成-Synthesis of 3-formamide (compound 724)

Figure 110128222-A0202-12-1174-182
Figure 110128222-A0202-12-1174-182

步驟1：5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基-乙醯基]胺基]吡啶-3-甲醯胺(化合物651 )之合成Step 1: 5-[[2-[(2S,5R)-5-methyl-2-(4-aminosulfonylphenyl)-1-piperidinyl]-2-pendoxyl-acetylene Synthesis of ]amino]pyridine-3-carboxamide ( Compound 651 )

向4-(5-甲基-2-哌啶基)苯磺醯胺(350mg，1.20mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(295.61mg，1.20mmol，HCl)及三乙胺(608.93mg，6.02mmol，838.75μL)於二甲基甲醯胺(4mL)中之經攪拌之混合物中添加HATU(503.38mg，1.32mmol)。將所得反應混合物在20℃下攪拌5h。然後，使其經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；10-10-40% 0-2-6min 0.1% NH3 -甲醇，流速：30ml/min-第1次運行，及30-30-65% 0-1-5min 0.2%FA-甲醇，流速：30ml/min；第2次運行)，得到5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(57mg，127.95μmol，10.63%產率)。To 4-(5-methyl-2-piperidinyl)benzenesulfonamide (350 mg, 1.20 mmol, HCl), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2- To a stirred mixture of oxoacetic acid (295.61 mg, 1.20 mmol, HCl) and triethylamine (608.93 mg, 6.02 mmol, 838.75 μL) in dimethylformamide (4 mL) was added HATU (503.38 mg, 1.32 mmol). The resulting reaction mixture was stirred at 20 °C for 5 h. It was then subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; 10-10-40% 0-2-6min 0.1% NH3 -methanol, flow rate: 30ml/min-1st run, and 30-30 -65% 0-1-5min 0.2%FA-methanol, flow rate: 30ml/min; 2nd run) to give 5-[[2-[(2S,5R)-5-methyl-2-(4- Sulfamonophenyl)-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (57 mg, 127.95 μmol, 10.63% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(dd,3H),1.35(m,1H),1.62(m,1H),1.93(m,1H),2.19(m,3H),3.79(m,1H),5.42(m,1H),7.32(m,2H),7.52(m,2H),7.59(m,1H),7.82(m,2H),8.14(m,1H),8.47(m,1H),8.76(m,1H),8.90(m,1H),11.23(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(dd,3H), 1.35(m,1H), 1.62(m,1H), 1.93(m,1H), 2.19(m,3H), 3.79(m, 1H), 5.42(m, 1H), 7.32(m, 2H), 7.52(m, 2H), 7.59(m, 1H), 7.82(m, 2H), 8.14(m, 1H), 8.47 (m, 1H), 8.76 (m, 1H), 8.90 (m, 1H), 11.23 (m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值445.2；實測值446.2；Rt=1.855min。LCMS (ESI): [M+H] + m/z: calculated 445.2; found 446.2; Rt=1.855 min.

步驟2：5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺Step 2: 5-[[2-[(2S,5R)-5-methyl-2-(4-aminosulfonylphenyl)-1-piperidinyl]-2-oxyethanoyl] amine 基]吡啶-3-甲醯胺(化合物725 )及5-[[2-[(2R,5S)-5-申基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物724 )之合成yl]pyridine-3-carboxamide ( compound 725 ) and 5-[[2-[(2R,5S)-5-heptyl-2-(4-aminosulfonylphenyl)-1-piperidinyl Synthesis of ]-2-oxyacetyl]amino]pyridine-3-carboxamide ( compound 724 )

使用(IB(250*20，5mkm)Chiralpak管柱，以己烷-IPA-MeOH，70-15-15為流動相，流速12ml/min)對5-[[2-[(2R,5S)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(47.0mg，105.50μmol)進行掌性分離，得到呈米色固體之化合物724 5-[[2-[(2R,5S)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(22.43mg，50.35μmol，47.72%產率)(RT=58.148min)及呈米色固體之化合物725 5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(20.4mg，45.79μmol，43.40%產率)(RT=39.671min)。5-[[2-[(2R,5S)- 5-Methyl-2-(4-Sulfamonoylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (47.0 mg, 105.50 μmol ) for chiral separation to give compound 724 as a beige solid 5-[[2-[(2R,5S)-5-methyl-2-(4-aminosulfonylphenyl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (22.43 mg, 50.35 μmol, 47.72% yield) (RT=58.148 min) and compound 725 as a beige solid 5-[[2 -[(2S,5R)-5-methyl-2-(4-aminosulfonylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (20.4 mg, 45.79 μmol, 43.40% yield) (RT=39.671 min).

化合物724：(IB，己烷-IPA-MeOH，70-15-15，0.6ml/min)=72.148minCompound 724: (IB, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 72.148 min

化合物725 ：(IB，己烷-IPA-MeOH，70-15-15，0.6ml/min)=51.595min Compound 725 : (IB, Hexane-IPA-MeOH, 70-15-15, 0.6ml/min)=51.595min

化合物725： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.64(m,1H),1.89(m,1H),2.17(m,2H),2.77(m,1H),3.79(m,1H),5.42(m,1H),7.32(m,2H),7.55(m,3H),7.82(m,2H),8.14(m,1H),8.47(m,1H),8.75(m,1H),8.87(m,1H),11.24(m,1H) Compound 725: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.02 (m, 3H), 1.34 (m, 1H), 1.64 (m, 1H), 1.89 (m, 1H), 2.17 (m, 2H), 2.77(m, 1H), 3.79(m, 1H), 5.42(m, 1H), 7.32(m, 2H), 7.55(m, 3H), 7.82(m, 2H), 8.14(m, 1H) ),8.47(m,1H),8.75(m,1H),8.87(m,1H),11.24(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值445.2；實測值446.2；Rt=0.785min。LCMS (ESI): [M+H] + m/z: calculated 445.2; found 446.2; Rt=0.785 min.

RT(己烷-IPA-MeOH，70-15-15，0.6ml/min)=51.622min。RT (Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 51.622 min.

化合物724： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.34(m,1H),1.61(m,1H),1.89(m,1H),2.17(m,2H),2.79(m,1H),3.79(m,1H),5.42(m,1H),7.32(m,2H),7.54(m,3H),7.82(m,2H),8.14(m,1H),8.47(m,1H),8.77(m,1H),8.87(m,1H),11.22(m,1H) Compound 724: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.00 (m, 3H), 1.34 (m, 1H), 1.61 (m, 1H), 1.89 (m, 1H), 2.17 (m, 2H), 2.79(m, 1H), 3.79(m, 1H), 5.42(m, 1H), 7.32(m, 2H), 7.54(m, 3H), 7.82(m, 2H), 8.14(m, 1H) ),8.47(m,1H),8.77(m,1H),8.87(m,1H),11.22(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值445.2；實測值446.2；Rt=0.785min。LCMS (ESI): [M+H] + m/z: calculated 445.2; found 446.2; Rt=0.785 min.

RT(己烷-IPA-MeOH，70-15-15，0.6ml/min)=72.1842min。RT (Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 72.1842 min.

實例163. 外消旋5-[[2-[(2S,SR)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物652)、5-[[2-[(2R,5S)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物722)及5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物723)之合成Example 163. Racemic 5-[[2-[(2S,SR)-5-methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 652), 5-[[2-[(2R,5S)-5-methyl-2-[4-(methylaminesulfone Acyl)phenyl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 722) and 5-[[2-[(2S,5R) -5-Methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Synthesis of compound 723)

Figure 110128222-A0202-12-1176-183
Figure 110128222-A0202-12-1176-183

步驟1：外消旋5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物652 )之合成Step 1: Racemic 5-[[2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2- Synthesis of pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 652 )

向N-甲基-4-(5-甲基-2-哌啶基)苯磺醯胺(370mg，1.38mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(338.63mg，1.38mmol，HCl)及三乙胺(697.54mg，6.89mmol，960.80μL)於二甲基甲醯胺(4mL)中之經攪拌之混合物中添加HATU(576.63mg，1.52mmol)。將所得反應混合物在20℃下攪拌5h。然後，使其經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；10-10-60% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min)，得到5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(130mg，282.91 μmol，20.52%產率)。To N-methyl-4-(5-methyl-2-piperidinyl)benzenesulfonamide (370 mg, 1.38 mmol, HCl), 2-[(5-aminocarbamoyl-3-pyridinyl)amine To a stirred mixture of triethylamine (697.54 mg, 6.89 mmol, 960.80 μL) in dimethylformamide (4 mL) was added HATU (576.63 mg, 1.52 mmol). The resulting reaction mixture was stirred at 20 °C for 5 h. Then, it was subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; 10-10-60% 0-1-6min 0.1% NH3 -methanol, flow rate: 30ml/min) to give 5-[[2-[ (2S,5R)-5-Methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 - Formamide (130 mg, 282.91 μmol, 20.52% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.64(m,1H),1.89(m,1H),2.20(m,3H),2.37(m,3H),3.78(m,1H),5.60(m,1H),7.42(m,1H),7.56(m,3H),7.77(m,2H),8.13(m,1H),8.45(m,1H),8.74(m,1H),8.86(m,1H),11.22(s,1H) 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 1.02 (m, 3H), 1.34 (m, 1H), 1.64 (m, 1H), 1.89 (m, 1H), 2.20 (m, 3H), 2.37(m, 3H), 3.78(m, 1H), 5.60(m, 1H), 7.42(m, 1H), 7.56(m, 3H), 7.77(m, 2H), 8.13(m, 1H), 8.45 (m, 1H), 8.74 (m, 1H), 8.86 (m, 1H), 11.22 (s, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值459.2；實測值460.2；Rt=2.096min。LCMS (ESI): [M+H] + m/z: calculated 459.2; found 460.2; Rt=2.096 min.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物722 )及5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物723 )之合成Step 2: 5-[[2-[(2R,5S)-5-methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide ( Compound 722 ) and 5-[[2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl) Synthesis of Phenyl]-1-Piperidinyl]-2-Pendant Oxyacetyl] Amino] Pyridine-3-Carboxamide ( Compound 723 )

藉由掌性HPLC(管柱：Chiralpak IA II(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 40-30-30；流速：12mL/min；m=0.12g，2次注入，60mg/注入，V=2,5L，時間=3h.)將5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(120.00mg，261.14μmol)分成鏡像異構物，得到：5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(33mg，71.81μmol，55.00%產率)(其中保留時間=19.304min)(化合物723 )及5-[[2-[(2R,5S)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(30mg，65.29μmol，50.00%產率)(其中保留時間=42.724min)(化合物722 )By chiral HPLC (column: Chiralpak IA II (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH 40-30-30; flow rate: 12mL/min; m=0.12g, 2 injections, 60mg/injection, V=2,5L, time=3h.) 5-[[2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl)phenyl] -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (120.00 mg, 261.14 μmol) split into the enantiomers to give: 5-[[2-[( 2S,5R)-5-methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Formamide (33 mg, 71.81 μmol, 55.00% yield) (wherein retention time=19.304 min) ( compound 723 ) and 5-[[2-[(2R,5S)-5-methyl-2-[4- (Methylaminosulfonyl)phenyl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (30 mg, 65.29 μmol, 50.00% yield) ( Wherein retention time=42.724min) ( compound 722 )

化合物722： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.64(m,1H),1.89(m,1H),2.10(m,1H),2.23(m,1H),2.38(m,3H),2.77(m,1H),3.69(m,1H),5.43(m,1H),7.42(m,1H),7.56(m,3H),7.77(m,2H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.86(m,1H),11.25(m,1H) Compound 722: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.02 (m, 3H), 1.34 (m, 1H), 1.64 (m, 1H), 1.89 (m, 1H), 2.10 (m, 1H), 2.23(m, 1H), 2.38(m, 3H), 2.77(m, 1H), 3.69(m, 1H), 5.43(m, 1H), 7.42(m, 1H), 7.56(m, 3H) ), 7.77(m, 2H), 8.14(m, 1H), 8.46(m, 1H), 8.75(m, 1H), 8.86(m, 1H), 11.25(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值459.2；實測值460.2；Rt=2.059min。LCMS (ESI): [M+H] + m/z: calculated 459.2; found 460.2; Rt=2.059 min.

RT(IPA-MeOH，50-50，0.6ml/min)=18.2272min。RT (IPA-MeOH, 50-50, 0.6 ml/min) = 18.2272 min.

化合物723： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.64(m,1H),1.89(m,1H),2.15(m,2H),2.38(m,3H),2.91(m,1H),3.78(m,1H),5.43(m,1H),7.42(m,1H),7.56(m,3H),7.77(m,2H),8.14(m,1H),8.46(d,1H),8.75(m,1H),8.87(m,1H),11.23(m,1H) Compound 723: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.02 (m, 3H), 1.34 (m, 1H), 1.64 (m, 1H), 1.89 (m, 1H), 2.15 (m, 2H), 2.38(m, 3H), 2.91(m, 1H), 3.78(m, 1H), 5.43(m, 1H), 7.42(m, 1H), 7.56(m, 3H), 7.77(m, 2H) ), 8.14(m, 1H), 8.46(d, 1H), 8.75(m, 1H), 8.87(m, 1H), 11.23(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值459.2；實測值460.2；Rt=2.059min。LCMS (ESI): [M+H] + m/z: calculated 459.2; found 460.2; Rt=2.059 min.

RT(IPA-MeOH，50-50，0.6ml/min)=11.0232min。RT (IPA-MeOH, 50-50, 0.6 ml/min) = 11.0232 min.

實例164. 5-[[2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物836)之合成Example 164. 5-[[2-[(2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side oxy Synthesis of Acetyl]amino]pyridine-3-carbamoylamine (Compound 836)

Figure 110128222-A0202-12-1178-184
Figure 110128222-A0202-12-1178-184

在輕微加熱下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(203.76mg，974.21μmol)、(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基哌啶(223.33mg，974.21μmol)及dipea(377.73mg，2.92mmol，509.07μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(444.51mg，1.17mmol)。反應完成之後，藉由HPLC純化混合物，以得到5-[[2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(35mg，83.26μmol，8.55%產率)2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (203.76 mg, 974.21 μmol), (2S,5S)-3,3- Difluoro-2-(4-fluorophenyl)-5-methylpiperidine (223.33 mg, 974.21 μmol) and dipea (377.73 mg, 2.92 mmol, 509.07 μL) were dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (444.51 mg, 1.17 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC to obtain 5-[[2-[(2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidine Peridyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (35 mg, 83.26 μmol, 8.55% yield)

HPLC條件：(23% 0.5-6.5min水-乙腈；流速30ml/min；(裝載泵4ml/min乙腈)；目標質量420；管柱SunFireC18 100x19mm 5um(L))HPLC conditions: (23% 0.5-6.5min water-acetonitrile; flow rate 30ml/min; (loading pump 4ml/min acetonitrile); target mass 420; column SunFireC18 100x19mm 5um (L))

1 H NMR(600MHz,DMSO-d 6 )δ 1.04-1.09(m,3H),1.90-2.01(m,1H),2.20-2.27(m,1H),2.37-2.46(m,1H),3.38-3.54(m,1H),3.58-4.05(m,1H),5.58-5.78(m,1H),7.15-7.29(m,2H),7.44-7.53(m,2H),7.60(s,1H),8.15(s,1H),8.47(s,1H), 8.77(s,1H),8.80-8.91(m,1H),11.11-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.04-1.09(m,3H), 1.90-2.01(m,1H), 2.20-2.27(m,1H), 2.37-2.46(m,1H), 3.38- 3.54(m, 1H), 3.58-4.05(m, 1H), 5.58-5.78(m, 1H), 7.15-7.29(m, 2H), 7.44-7.53(m, 2H), 7.60(s, 1H), 8.15(s, 1H), 8.47(s, 1H), 8.77(s, 1H), 8.80-8.91(m, 1H), 11.11-11.34(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=2.607min。LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=2.607 min.

實例165. 5-[[2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物898)及5-[[2-[(2R,3S,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物879)之合成Example 165. 5-[[2-[(2R,3R,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendantoxyethyl Acrylo]amino]pyridine-3-carboxamide (Compound 898) and 5-[[2-[(2R,3S,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 879)

Figure 110128222-A0202-12-1179-185
Figure 110128222-A0202-12-1179-185

在輕微加熱下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(203.76mg，974.21μmol)、(2S,5S)-3-氟-2-(4-氟苯基)-5-甲基哌啶(205.80mg，974.21μmol)及dipea(377.73mg，2.92mmol，509.07μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(444.51mg，1.17mmol)。反應完成之後，藉由HPLC純化混合物，以得到5-[[2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(130mg，323.07μmol，33.16%產率)及第二異構物，將第二異構物再純化(16-18% 0.5-7min水-乙腈+NH3 ；流速30ml/min(裝載泵4ml/min乙腈)；目標質量200；管柱XBridge 100x19mm 5um)，以得到5-[[2-[(2R,3S,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(15mg，37.28μmol，3.83%產率)2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (203.76 mg, 974.21 μmol), (2S,5S)-3-fluoro- 2-(4-Fluorophenyl)-5-methylpiperidine (205.80 mg, 974.21 μmol) and dipea (377.73 mg, 2.92 mmol, 509.07 μL) were dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (444.51 mg, 1.17 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC to give 5-[[2-[(2R,3R,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidine (130 mg, 323.07 μmol, 33.16% yield) and the second isomer, which was repurified (16 -18% 0.5-7min water-acetonitrile+ NH3 ; flow rate 30ml/min (load pump 4ml/min acetonitrile); target mass 200; column XBridge 100x19mm 5um) to give 5-[[2-[(2R,3S ,5R)-3-Fluoro-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( 15 mg, 37.28 μmol, 3.83% yield)

HPLC條件：19-23% 0.5-6min水-乙腈；流速30ml/min；(裝載泵4ml/min乙腈)；目標質量402；管柱SunFireC18 100x19mm 5um(L))HPLC conditions: 19-23% 0.5-6min water-acetonitrile; flow rate 30ml/min; (loading pump 4ml/min acetonitrile); target mass 402; column SunFireC18 100x19mm 5um (L))

化合物879： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.07(m,3H),1.73(m,1H),1.89(m,2H),3.36(m,1H),3.71(m,1H),5.59(m,2H),7.23(m,2H),7.42(m,2H),7.58 (m,1H),8.14(m,1H),8.49(m,1H),8.75(m,1H),8.87(m,1H),11.28(m,1H) Compound 879: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.07 (m, 3H), 1.73 (m, 1H), 1.89 (m, 2H), 3.36 (m, 1H), 3.71 (m, 1H), 5.59(m, 2H), 7.23(m, 2H), 7.42(m, 2H), 7.58(m, 1H), 8.14(m, 1H), 8.49(m, 1H), 8.75(m, 1H) ),8.87(m,1H),11.28(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值403.2；Rt=2.565min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 403.2; Rt=2.565 min.

化合物898： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.03(d,3H),1.36(m,1H),2.20(m,2H),3.63(m,2H),5.34(m,2H),7.20(m,2H),7.36(m,2H),7.59(m,1H),8.13(m,1H),8.40(m,1H),8.79(m,2H),11.09(m,1H)。 Compound 898: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.03 (d, 3H), 1.36 (m, 1H), 2.20 (m, 2H), 3.63 (m, 2H), 5.34 (m, 2H), 7.20(m, 2H), 7.36(m, 2H), 7.59(m, 1H), 8.13(m, 1H), 8.40(m, 1H), 8.79(m, 2H), 11.09(m, 1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值403.0；Rt=2。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 403.0; Rt=2.

實例166. 5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物970)及5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物942)之合成Example 166. 5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (Compound 970) and 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)-1-piperidine Synthesis of [methyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 942)

Figure 110128222-A0202-12-1180-186
Figure 110128222-A0202-12-1180-186

步驟1.5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基].-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺Step 1. 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)-1-piperidinyl].-2-oxoacetyl]amine yl]pyridine-3-carboxamide

在25℃下，在1.5h時段內，將HATU(702.48mg，1.85mmol)小批量添加到(2R,5S)-5-甲基-2-(1H-吡唑-4-基)哌啶(400mg，1.68mmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(474.41mg，1.93mmol，HCl)及三乙胺(1.36g，13.44mmol，1.87mL)於DMF(6mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：10-50% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30ml/min(裝載泵4ml/min甲醇)，以得到呈淡黃色膠狀物之5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(173mg，485.44μmol， 28.90%產率)，將其直接提交至製備型掌性HPLC。HATU (702.48 mg, 1.85 mmol) was added to (2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)piperidine (2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)piperidine ( 400 mg, 1.68 mmol, 2HCl), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (474.41 mg, 1.93 mmol, HCl) and triethylamine (1.36 g , 13.44 mmol, 1.87 mL) in a stirred mixture of DMF (6 mL). The resulting mixture was stirred at 25°C for 18h and then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 10-50% 0-5min H2O /MeOH/0.1% NH4OH, flow rate: 30ml /min (load pump 4ml/min methanol) to give 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl) as a pale yellow gum -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (173 mg, 485.44 μmol, 28.90% yield), which was submitted directly to preparative chiral HPLC.

LCMS(ESI)：[M+1]+ m/z：計算值356.2；實測值357.2；Rt=1.525min。LCMS (ESI): [M+1] + m/z: calculated 356.2; found 357.2; Rt=1.525 min.

步驟2.5-[[2-[(2S,5R)-5-甲基-2-(1H吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物970 )及5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶：基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物942 )之合成Step 2. 5-[[2-[(2S,5R)-5-Methyl-2-(1Hpyrazol-4-yl)-1-piperidinyl]-2-oxyethanoyl]amino] Pyridin-3-carboxamide ( Compound 970 ) and 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)-1-piperidin:yl] Synthesis of -2-oxyacetoxy]amino]pyridine-3-carboxamide ( compound 942 )

將外消旋5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(173mg，485.44μmol)提交至製備型掌性HPLC(管柱：Chiralpak AD-H-III(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 60-20-20；流速：12mL/min)，以得到化合物970 5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(73mg，204.84μmol，42.20%產率)(R.T.=23.439min)及化合物942 5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(72mg，202.03μmol，41.62%產率)(R.T.=32.685min)。The racemic 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-side oxyacetyl ]amino]pyridine-3-carboxamide (173 mg, 485.44 μmol) was submitted to preparative chiral HPLC (column: Chiralpak AD-H-III (250*20 mm, 5 mkm); mobile phase: hexane-IPA- MeOH 60-20-20; flow rate: 12 mL/min) to give compound 970 5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazol-4-yl)-1 -Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (73 mg, 204.84 μmol, 42.20% yield) (RT=23.439 min) and compound 942 5-[[2 -[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (72 mg, 202.03 μmol, 41.62% yield) (RT=32.685 min).

化合物970 1H NMR(600MHz,DMSO-d 6 )δ 0.96-1.01(m,3H),1.30-1.43(m,1H),1.74-1.89(m,2H),1.90-2.02(m,2H),2.79-3.27(m,1H),3.34-3.97(m,1H),5.02-5.63(m,1H),7.35-7.77(m,3H),8.10-8.21(m,1H),8.43-8.52(m,1H),8.72-8.79(m,1H),8.84-8.91(m,1H),11.08-11.21(m,1H),12.77(s,1H)。 Compound 970 1H NMR (600MHz, DMSO - d6 )δ 0.96-1.01(m,3H), 1.30-1.43(m,1H), 1.74-1.89(m,2H), 1.90-2.02(m,2H), 2.79 -3.27(m, 1H), 3.34-3.97(m, 1H), 5.02-5.63(m, 1H), 7.35-7.77(m, 3H), 8.10-8.21(m, 1H), 8.43-8.52(m, 1H), 8.72-8.79 (m, 1H), 8.84-8.91 (m, 1H), 11.08-11.21 (m, 1H), 12.77 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值356.2；實測值357.4；Rt=1.589min。LCMS (ESI): [M+1] + m/z: calculated 356.2; found 357.4; Rt=1.589 min.

化合物942 1H NMR(600MHz,DMSO-d 6 )δ 0.96-1.01(m,3H),1.30-1.43(m,1H),1.74-1.89(m,2H),1.90-2.02(m,2H),2.79-3.27(m,1H),3.34-3.97(m,1H),5.02-5.63(m,1H),7.35-7.77(m,3H),8.10-8.21(m,1H),8.43-8.52(m,1H),8.72-8.79(m,1H),8.84-8.91(m,1H),11.08-11.21(m,1H),12.77(s,1H)。 Compound 942 1H NMR (600MHz, DMSO - d6 )δ 0.96-1.01(m,3H), 1.30-1.43(m,1H), 1.74-1.89(m,2H), 1.90-2.02(m,2H), 2.79 -3.27(m, 1H), 3.34-3.97(m, 1H), 5.02-5.63(m, 1H), 7.35-7.77(m, 3H), 8.10-8.21(m, 1H), 8.43-8.52(m, 1H), 8.72-8.79 (m, 1H), 8.84-8.91 (m, 1H), 11.08-11.21 (m, 1H), 12.77 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值356.2；實測值357.2；Rt=1.584min。LCMS (ESI): [M+1] + m/z: calculated 356.2; found 357.2; Rt=1.584 min.

實例167. 5-[[2-[(2S,5R)-2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯Example 167. 5-[[2-[(2S,5R)-2-(5-amino-2-pyridinyl)-5-methyl-1-piperidinyl]-2-oxoacetyl 基]胺基]吡啶-3-甲醯胺(化合物607)及5-[[2-[(2R,5S)-2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物594)之合成yl]amino]pyridine-3-carboxamide (Compound 607) and 5-[[2-[(2R,5S)-2-(5-amino-2-pyridyl)-5-methyl-1 Synthesis of -piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 594)

Figure 110128222-A0202-12-1182-187
Figure 110128222-A0202-12-1182-187

步驟1. 第三丁基(2R,5S)-5-甲基-2-[1-(1H-吡唑-3-基)吡唑-4-基]哌啶Step 1. Tert-butyl(2R,5S)-5-methyl-2-[1-(1H-pyrazol-3-yl)pyrazol-4-yl]piperidine

將DIPEA(260.15mg，2.01mmol，350.60μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(120.29mg，489.73μmol，HCl)及6-(5-甲基-2-哌啶基)吡啶-3-胺(0.11g，575.10μmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(240.54mg，632.61μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到純的5-[[2-[2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(69.4mg，181.48μmol，31.56%產率)及順式雜質。DIPEA (260.15 mg, 2.01 mmol, 350.60 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (120.29 mg, 489.73 μmol, HCl) and 6-(5-methyl-2-piperidinyl)pyridin-3-amine (0.11 g, 575.10 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (240.54 mg, 632.61 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure 5-[[2-[2-(5-amino-2-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide (69.4 mg, 181.48 μmol, 31.56% yield) and cis impurity.

LCMS(ESI)：[M+1]+ m/z：計算值382.2；實測值383.2；Rt=1.322min。LCMS (ESI): [M+1] + m/z: calculated 382.2; found 383.2; Rt=1.322 min.

步驟2.5-[[2-[(2S,5R)-2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物607 )及5-[[2-[(2R,5S)-2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物594 )之合成Step 2. 5-[[2-[(2S,5R)-2-(5-amino-2-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide ( Compound 607 ) and 5-[[2-[(2R,5S)-2-(5-amino-2-pyridyl)-5-methyl-1-piperidine [Synthesis of]-2-oxoacetyl]amino]pyridine-3-carboxamide ( Compound 594 )

】在以下條件下分離外消旋物：OJ-H(250*30，5mkm)，己烷-IPA-MeOH，50-25-25，13ml/min，RT(化合物607 )=10.557min，RT(化合物594 )=20.873min。自69mg外消旋物獲得17.8mg(化合物607 )及4.96mg(化合物594 )鏡像異構物。] The racemate was isolated under the following conditions: OJ-H (250*30, 5mkm), hexane-IPA-MeOH, 50-25-25, 13ml/min, RT( compound 607 )=10.557min, RT( Compound 594 ) = 20.873 min. From 69 mg of the racemate, 17.8 mg ( compound 607 ) and 4.96 mg ( compound 594 ) of the enantiomer were obtained.

在以下條件下記錄分析資料：儀器：反相及梯度：己烷-IPA-MeOH，60-20-20，0.6ml/min，管柱：OD-HAnalytical data were recorded under the following conditions: Instrument: Reversed Phase and Gradient: Hexane-IPA-MeOH, 60-20-20, 0.6 ml/min, Column: OD-H

化合物594 於分析條件下之保留時間為20.10minThe retention time of compound 594 under analytical conditions is 20.10 min

化合物607 於分析條件下之保留時間為35.91minThe retention time of compound 607 under analytical conditions is 35.91 min

化合物594： 1 H NMR(600MHz,DMSO-d 6 )δ 0.68-0.83(m,3H),1.02-1.18(m,1H),1.37-1.67(m,2H),1.67-1.85(m,1H),2.11-2.36(m,1H),2.66-3.28(m,1H),3.57-4.22(m,1H),5.00-5.57(m,3H),6.88-7.10(m,2H),7.53-7.63(m,1H),7.87-7.95(m,1H),8.08-8.19(m,1H),8.44-8.54(m,1H),8.70-8.79(m,1H),8.79-8.91(m,1H),11.09-11.37(m,1H)。 Compound 594: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.68-0.83 (m, 3H), 1.02-1.18 (m, 1H), 1.37-1.67 (m, 2H), 1.67-1.85 (m, 1H) ,2.11-2.36(m,1H),2.66-3.28(m,1H),3.57-4.22(m,1H),5.00-5.57(m,3H),6.88-7.10(m,2H),7.53-7.63( m,1H),7.87-7.95(m,1H),8.08-8.19(m,1H),8.44-8.54(m,1H),8.70-8.79(m,1H),8.79-8.91(m,1H), 11.09-11.37 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值382.4；實測值383.2；Rt=3,825min。LCMS (ESI): [M+1] + m/z: calculated 382.4; found 383.2; Rt=3,825 min.

化合物607： 1 H NMR(600MHz,DMSO-d 6 )δ 0.69-0.84(m,3H),1.07-1.15(m,1H),1.52-1.68(m,2H),1.68-1.84(m,1H),2.15-2.21(m,0.5H),2.58-2.73(m,1.5H),3.57-4.22(m,1H),5.01-5.55(m,3H),6.88-7.08(m,2H),7.51-7.66(m,1H),7.86-7.93(m,1H),8.09-8.19(m,1H),8.43-8.55(m,1H),8.67-8.79(m,1H),8.79-8.94(m,1H),11.05-11.28(m,1H)。 Compound 607: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.69-0.84 (m, 3H), 1.07-1.15 (m, 1H), 1.52-1.68 (m, 2H), 1.68-1.84 (m, 1H) ,2.15-2.21(m,0.5H),2.58-2.73(m,1.5H),3.57-4.22(m,1H),5.01-5.55(m,3H),6.88-7.08(m,2H),7.51- 7.66(m,1H),7.86-7.93(m,1H),8.09-8.19(m,1H),8.43-8.55(m,1H),8.67-8.79(m,1H),8.79-8.94(m,1H) ), 11.05-11.28 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值382.4；實測值383.2；Rt=3,742min。LCMS (ESI): [M+1] + m/z: calculated 382.4; found 383.2; Rt=3,742 min.

實例168. 5-[[2-[5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,5R)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物584)、5-[[2-[(2R,5S)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物590)及5-[[2-[(2S,5R)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物578)之合成Example 168. 5-[[2-[5-Methyl-2-(2-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide and 5-[[2-[(2R,5R)-5-methyl-2-(2-pyridinyl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 -Carboxamide (Compound 584), 5-[[2-[(2R,5S)-5-methyl-2-(2-pyridyl)-1-piperidinyl]-2-side oxyacetamide yl]amino]pyridine-3-carboxamide (Compound 590) and 5-[[2-[(2S,5R)-5-methyl-2-(2-pyridyl)-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide (compound 578)

Figure 110128222-A0202-12-1183-188
Figure 110128222-A0202-12-1183-188

步驟1.5-[[2-[5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯Step 1. 5-[[2-[5-Methyl-2-(2-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate 胺及5-[[2-[(2R,5R)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物584 )之合成Amines and 5-[[2-[(2R,5R)-5-methyl-2-(2-pyridyl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine- Synthesis of 3-formamide ( compound 584 )

添加2-(5-甲基-2-哌啶基)吡啶(0.5g，2.35mmol，HCl)溶解於DMF(8mL)及三乙胺(2.38g，23.51mmol，3.28mL)，隨後添加2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(491.63mg，2.00mmol，HCl)。然後逐滴添加HATU(1.34g，3.53mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得5-[[2-[5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1135g，308.93μmol，13.14%產率)及5-[[2-[(2R,5R)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(86.47mg，235.36μmol，53.05%產率)2-(5-Methyl-2-piperidinyl)pyridine (0.5 g, 2.35 mmol, HCl) dissolved in DMF (8 mL) and triethylamine (2.38 g, 23.51 mmol, 3.28 mL) was added, followed by 2- [(5-Aminocarboxy-3-pyridyl)amino]-2-pendoxoacetic acid (491.63 mg, 2.00 mmol, HCl). HATU (1.34 g, 3.53 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC to give 5-[[2-[5-methyl-2-(2-pyridinyl)-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide (0.1135 g, 308.93 μmol, 13.14% yield) and 5-[[2-[(2R,5R)-5-methyl-2-(2- Pyridinyl)-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (86.47 mg, 235.36 μmol, 53.05% yield)

LCMS(ESI)：[M+1]+ m/z：計算值367.2；實測值368.2；Rt=1.758min。(反式)化合物584 LCMS (ESI): [M+1] + m/z: calculated 367.2; found 368.2; Rt=1.758 min. (trans) Compound 584

1 H NMR(600MHz,DMSO-d 6 )δ 0.72-0.83(m,3H),0.98-1.08(m,1H),1.59-1.73(m,2H),1.78-1.95(m,1H),2.25-2.30(m,0H),2.63-2.80(m,2H),3.66-4.28(m,1H),5.45(dd,1H),7.25-7.31(m,1H),7.31-7.43(m,1H),7.54-7.65(m,1H),7.77-7.89(m,1H),8.09-8.21(m,1H),8.42-8.54(m,1H),8.54-8.62(m,1H),8.69-8.80(m,1H),8.80-8.94(m,1H),11.11-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.72-0.83(m,3H), 0.98-1.08(m,1H), 1.59-1.73(m,2H), 1.78-1.95(m,1H), 2.25- 2.30(m,0H),2.63-2.80(m,2H),3.66-4.28(m,1H),5.45(dd,1H),7.25-7.31(m,1H),7.31-7.43(m,1H), 7.54-7.65(m, 1H), 7.77-7.89(m, 1H), 8.09-8.21(m, 1H), 8.42-8.54(m, 1H), 8.54-8.62(m, 1H), 8.69-8.80(m , 1H), 8.80-8.94 (m, 1H), 11.11-11.39 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值367.2；實測值368.2；Rt=1.876min。(順式)LCMS (ESI): [M+1] + m/z: calculated 367.2; found 368.2; Rt=1.876 min. (cis)

步驟2.5-[[2-[(2R,5S)-5-申基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物590 )及5-[[2-[(2S,5R)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物578 )之合成Step 2. 5-[[2-[(2R,5S)-5-Senyl-2-(2-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -Carboxamide ( Compound 590 ) and 5-[[2-[(2S,5R)-5-methyl-2-(2-pyridyl)-1-piperidinyl]-2-side oxyacetamide Synthesis of yl]amino]pyridine-3-carboxamide ( compound 578 )

對5-[[2-[5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1135g，308.93μmol)進行掌性分離(管柱：YMC CHIRAL ART Cellulose-SC 250*20,5己烷-IPA-MeOH，50-25-25，13ml/min，保留時間(化合 物578 )=19.244min且保留時間(化合物578 )=29.63min)，以獲得5-[[2-[(2S,5R)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.047g，127.93μmol，41.41%產率)及5-[[2-[(2R,5S)-5-甲基-2-(2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.046g，125.20μmol，40.53%產率)p-5-[[2-[5-Methyl-2-(2-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.1135 g, 308.93 μmol) for chiral separation (column: YMC CHIRAL ART Cellulose-SC 250*20,5 hexane-IPA-MeOH, 50-25-25, 13 ml/min, retention time ( compound 578 )=19.244 min and retention time ( compound 578 )=29.63 min) to obtain 5-[[2-[(2S,5R)-5-methyl-2-(2-pyridyl)-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carbamide (0.047 g, 127.93 μmol, 41.41% yield) and 5-[[2-[(2R,5S)-5-methyl-2 -(2-Pyridinyl)-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (0.046 g, 125.20 μmol, 40.53% yield)

化合物590：Compound 590:

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.04(m,3H),1.29-1.37(m,1H),1.58-1.65(m,1H),1.83-1.94(m,1H),1.94-2.04(m,1H),2.04-2.14(m,1H),2.85-3.40(m,1H),3.51-4.08(m,1H),5.21-5.61(m,1H),7.23-7.44(m,2H),7.49-7.64(m,1H),7.74-7.87(m,1H),8.05-8.22(m,1H),8.39-8.52(m,1H),8.53-8.61(m,1H),8.68-8.79(m,1H),8.79-8.93(m,1H),11.05-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.01-1.04(m,3H), 1.29-1.37(m,1H), 1.58-1.65(m,1H), 1.83-1.94(m,1H), 1.94- 2.04(m, 1H), 2.04-2.14(m, 1H), 2.85-3.40(m, 1H), 3.51-4.08(m, 1H), 5.21-5.61(m, 1H), 7.23-7.44(m, 2H ),7.49-7.64(m,1H),7.74-7.87(m,1H),8.05-8.22(m,1H),8.39-8.52(m,1H),8.53-8.61(m,1H),8.68-8.79 (m, 1H), 8.79-8.93 (m, 1H), 11.05-11.34 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值367.2；實測值368.2；Rt=1.758min。LCMS (ESI): [M+1] + m/z: calculated 367.2; found 368.2; Rt=1.758 min.

化合物578：Compound 578:

1 H NMR(600MHz,DMSO-d 6 )δ 1.02-1.05(m,3H),1.26-1.38(m,1H),1.56-1.69(m,1H),1.81-1.95(m,1H),1.95-2.13(m,1H),2.41-2.44(m,1H),2.85-3.39(m,1H),3.44-4.14(m,1H),5.21-5.61(m,1H),7.22-7.31(m,1H),7.31-7.46(m,1H),7.51-7.65(m,1H),7.75-7.87(m,1H),8.05-8.20(m,1H),8.42-8.50(m,1H),8.53-8.61(m,1H),8.69-8.80(m,1H),8.81-8.92(m,1H),11.07-11.28(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.02-1.05(m,3H), 1.26-1.38(m,1H), 1.56-1.69(m,1H), 1.81-1.95(m,1H), 1.95- 2.13(m,1H), 2.41-2.44(m,1H), 2.85-3.39(m,1H), 3.44-4.14(m,1H), 5.21-5.61(m,1H), 7.22-7.31(m,1H) ),7.31-7.46(m,1H),7.51-7.65(m,1H),7.75-7.87(m,1H),8.05-8.20(m,1H),8.42-8.50(m,1H),8.53-8.61 (m, 1H), 8.69-8.80 (m, 1H), 8.81-8.92 (m, 1H), 11.07-11.28 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值367.2；實測值368.2；Rt=1.758min。LCMS (ESI): [M+1] + m/z: calculated 367.2; found 368.2; Rt=1.758 min.

實例169. 5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物718)及5-1[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物731)之合成Example 169. 5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide (Compound 718) and 5-1[2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5 Synthesis of -Methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 731)

Figure 110128222-A0202-12-1186-189
Figure 110128222-A0202-12-1186-189

步驟1：外消旋-5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2 -Synthesis of pendant oxyacetyl]amino]pyridine-3-carboxamide

將(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基哌啶(0.6g，2.62mmol)、TEA(2.65g，26.17mmol，3.65mL)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(642.87mg，2.62mmol，HCl)溶解於(26mL)中且一次性添加HATU(1.49g，3.93mmol)，將所得混合物在20℃下攪拌3h。將反應混合物倒入到水中且將水相用EA萃取(3次)，然後將經合併之有機相用鹽水洗滌(3次)，經Na2 SO4 乾燥且在真空下濃縮。藉由反相HPLC(2-10min 50-60% ACN/H2 O 30ml/min(裝載泵4ml ACN)管柱：SunFire 100*19mm，5微米)純化粗產物。該反應為成功的。分離呈棕色固體之所要產物(5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.205g，487.65μmol，18.63%產率))。(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methylpiperidine (0.6 g, 2.62 mmol), TEA (2.65 g, 26.17 mmol, 3.65 mL) and 2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-pendoxoacetic acid (642.87 mg, 2.62 mmol, HCl) was dissolved in (26 mL) and HATU (1.49 g, 3.93 mmol) and the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water and the aqueous phase was extracted with EA (3 times), then the combined organic phases were washed with brine (3 times), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by reverse phase HPLC (2-10 min 50-60% ACN/ H2O 30 ml/min (loading pump 4 ml ACN) column: SunFire 100*19 mm, 5 microns). The reaction was successful. The desired product (5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetoxy]amino]pyridine-3-carboxamide (0.205 g, 487.65 μmol, 18.63% yield)).

LCMS(ESI)：[M+1]+ m/z：計算值420.2；實測值421.2；Rt=1.146min。LCMS (ESI): [M+1] + m/z: calculated 420.2; found 421.2; Rt=1.146 min.

步驟2：5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物718 )及5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物731 )之掌性分離Step 2: 5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide ( Compound 718 ) and 5-[[2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5 Chiral isolation of -methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide ( compound 731 )

使用(管柱：Chiralcel OJ-H(250*20，5mkm)，己烷-IPA-MeOH， 50-25-25，12ml/min)進行掌性分離，以得到5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯 基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.083g，197.44μmol，40.49%產率)化合物731 (保留時間為16.022min(Chiralcel OJ-3(150*2.1，3mkm)，己烷-IPA-MeOH，50-25-25，0.15ml/min)及5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.085g，202.20μmol，41.46%產率)化合物718 (保留時間為10.577min(Chiralcel OJ-3(150*2.1，3mkm)，己烷-IPA-MeOH，50-25-25，0.15ml/min)。Chiral separation was performed using (column: Chiralcel OJ-H (250*20, 5mkm), hexane-IPA-MeOH, 50-25-25, 12ml/min) to give 5-[[2-[(2R ,5R)-4,4-Difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (0.083 g, 197.44 μmol, 40.49% yield) compound 731 (retention time 16.022 min (Chiralcel OJ-3 (150*2.1, 3 mkm), hexane-IPA-MeOH, 50-25-25, 0.15 ml) /min) and 5-[[2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (0.085g, 202.20 μmol, 41.46% yield) compound 718 (retention time 10.577 min (Chiralcel OJ-3 (150*2.1, 3mkm), hexanes) -IPA-MeOH, 50-25-25, 0.15 ml/min).

化合物718 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(m,3H),2.20(m,1H),2.84(m,1H),3.05(d,1H),3.44(m,1H),3.99(m,1H),5.69(m,1H),7.19(m,2H),7.36(m,2H),7.59(m,1H),8.14(m,1H),8.47(m,1H),8.76(m,1H),8.87(m,1H),11.27(m,1H) Compound 718 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.08 (m, 3H), 2.20 (m, 1H), 2.84 (m, 1H), 3.05 (d, 1H), 3.44 (m, 1H) ), 3.99(m, 1H), 5.69(m, 1H), 7.19(m, 2H), 7.36(m, 2H), 7.59(m, 1H), 8.14(m, 1H), 8.47(m, 1H) ,8.76(m,1H),8.87(m,1H),11.27(m,1H)

LCMS(ESI)：[M+1]+ m/z：計算值420.2；實測值421.2；Rt=2.034min。LCMS (ESI): [M+1] + m/z: calculated 420.2; found 421.2; Rt=2.034 min.

化合物731 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(m,3H),2.20(m,1H),2.84(m,1H),3.05(d,1H),3.44(m,1H),3.99(m,1H),5.69(m,1H),7.19(m,2H),7.36(m,2H),7.59(m,1H),8.14(m,1H),8.47(m,1H),8.76(m,1H),8.87(m,1H),11.27(m,1H) Compound 731 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.08 (m, 3H), 2.20 (m, 1H), 2.84 (m, 1H), 3.05 (d, 1H), 3.44 (m, 1H) ), 3.99(m, 1H), 5.69(m, 1H), 7.19(m, 2H), 7.36(m, 2H), 7.59(m, 1H), 8.14(m, 1H), 8.47(m, 1H) ,8.76(m,1H),8.87(m,1H),11.27(m,1H)

LCMS(ESI)：[M+1]+ m/z：計算值420.2；實測值421.2；Rt=2.034min。LCMS (ESI): [M+1] + m/z: calculated 420.2; found 421.2; Rt=2.034 min.

實例170. 5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物1047)及5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基1-2-甲氧基吡啶-3-甲醯胺(化合物1068)之合成Example 170. 5-[[2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-2-methoxypyridine-3-carboxamide (Compound 1047) and 5-[[2-[(2R,5R)-4,4-difluoro-2-(4- Synthesis of Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino 1-2-methoxypyridine-3-carboxamide (Compound 1068)

Figure 110128222-A0202-12-1188-190
Figure 110128222-A0202-12-1188-190

步驟1：5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Synthesis of Acetyl] Amino]-2-methoxypyridine-3-carboxamide

將(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基哌啶(0.4g，1.74mmol)、TEA(1.77g，17.45mmol，2.43mL)及2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(417.35mg，1.74mmol)溶解於DMF(18mL)中且一次性添加HATU(995.19mg，2.62mmol)，將所得混合物在20℃下攪拌3h。將反應混合物倒入到水中且將水相用EA萃取(3次)，然後將經合併之有機相用鹽水洗滌(3次)，經Na2 SO4 乾燥且在真空下濃縮。藉由反相HPLC(2-10min 10-50%甲醇，30ml/min(裝載泵4ml甲醇)管柱：SunFire 100*19mm，5微米)純化粗產物。該反應為成功的。分離呈淡黃色固體之所要產物5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.151g，335.25μmol，19.21%產率)。Combine (2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methylpiperidine (0.4 g, 1.74 mmol), TEA (1.77 g, 17.45 mmol, 2.43 mL) and 2-[(5-Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-pendoxoacetic acid (417.35 mg, 1.74 mmol) was dissolved in DMF (18 mL) and added in one portion HATU (995.19 mg, 2.62 mmol), the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water and the aqueous phase was extracted with EA (3 times), then the combined organic phases were washed with brine (3 times), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by reverse phase HPLC (2-10 min 10-50% methanol, 30 ml/min (loading pump 4 ml methanol) column: SunFire 100*19 mm, 5 microns). The reaction was successful. The desired product 5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (0.151 g, 335.25 μmol, 19.21% yield).

LCMS(ESI)：[M+1]+ m/z：計算值450.2；實測值451.2；Rt=1.340min。LCMS (ESI): [M+1] + m/z: calculated 450.2; found 451.2; Rt=1.340 min.

步驟2.5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物1047 )及5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物1068 )之分離Step 2. 5-[[2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone yl]amino]-2-methoxypyridine-3-carboxamide ( Compound 1047 ) and 5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorobenzene yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 1068 )

使用(管柱：Chiralcel OJ-H(250*20，5mkm)，IPA-MeOH，50-50，12ml/min)進行掌性分離，以得到5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1- 哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.068g，150.97μmol，45.03%產率)(保留時間為32.799min)及5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.063g，139.87μmol，41.72%產率)(保留時間為10.884min)。Chiral separation was performed using (column: Chiralcel OJ-H (250*20, 5mkm), IPA-MeOH, 50-50, 12ml/min) to give 5-[[2-[(2S,5S)-4 ,4-Difluoro-2-(4-fluorophenyl)-5-methyl-1- piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (0.068 g, 150.97 μmol, 45.03% yield) (retention time 32.799 min) and 5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]-2-methoxypyridine-3-carboxamide (0.063 g, 139.87 μmol, 41.72% yield) (retention time 10.884 min).

化合物1068 1H NMR(600MHz,DMSO-d 6 )δ 1.08(d,3H),2.12-2.28(m,1H),2.40-2.46(m,1H),2.79-2.89(m,1H),2.99-3.07(m,0.3H),3.41-3.50(m,0.7H),3.79-3.91(m,0.7H),3.90-3.99(m,3H),4.23-4.34(m,0.3H),5.52-6.01(m,1H),7.13-7.27(m,2H),7.33-7.41(m,2H),7.66-7.81(m,2H),8.41-8.62(m,2H),10.76-11.27(m,1H)。 Compound 1068 1H NMR (600MHz, DMSO - d6 )δ 1.08(d,3H), 2.12-2.28(m,1H), 2.40-2.46(m,1H), 2.79-2.89(m,1H), 2.99-3.07 (m,0.3H),3.41-3.50(m,0.7H),3.79-3.91(m,0.7H),3.90-3.99(m,3H),4.23-4.34(m,0.3H),5.52-6.01( m, 1H), 7.13-7.27 (m, 2H), 7.33-7.41 (m, 2H), 7.66-7.81 (m, 2H), 8.41-8.62 (m, 2H), 10.76-11.27 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值450.2；實測值451.2；Rt=3.147min。LCMS (ESI): [M+1] + m/z: calculated 450.2; found 451.2; Rt=3.147 min.

化合物1047 1H NMR(600MHz,DMSO-d 6 )δ 1.08(d,3H),2.12-2.28(m,1H),2.40-2.46(m,1H),2.79-2.89(m,1H),2.99-3.07(m,0.3H),3.41-3.50(m,0.7H),3.79-3.91(m,0.7H),3.90-3.99(m,3H),4.23-4.34(m,0.3H),5.52-6.01(m,1H),7.13-7.27(m,2H),7.33-7.41(m,2H),7.66-7.81(m,2H),8.41-8.62(m,2H),10.76-11.27(m,1H)。 Compound 1047 1H NMR (600MHz, DMSO - d6 )δ 1.08(d,3H), 2.12-2.28(m,1H), 2.40-2.46(m,1H), 2.79-2.89(m,1H), 2.99-3.07 (m,0.3H),3.41-3.50(m,0.7H),3.79-3.91(m,0.7H),3.90-3.99(m,3H),4.23-4.34(m,0.3H),5.52-6.01( m, 1H), 7.13-7.27 (m, 2H), 7.33-7.41 (m, 2H), 7.66-7.81 (m, 2H), 8.41-8.62 (m, 2H), 10.76-11.27 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值450.2：實測值451.2；Rt=3.147min。LCMS (ESI): [M+1] + m/z: calculated 450.2: found 451.2; Rt=3.147 min.

實例171. 5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物787)及5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物778)之合成Example 171. 5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 787) and 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazolo Synthesis of [4,3-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 778)

Figure 110128222-A0202-12-1189-191
Figure 110128222-A0202-12-1189-191

步驟1.外消旋-5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-Step 1. Racemic-5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidine pyridyl]-2- 側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Synthesis of Pendant Oxyacetyl] Amino] Pyridine-3-Carboxamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(241.77mg，1.16mmol)及5-(5-甲基-2-哌啶基)-1H-吡唑并[4,3-b]吡啶(0.25g，1.16mmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(439.51mg，1.16mmol)，隨後添加TEA(116.97mg，1.16mmol，161.11μL)，且在周圍溫度下攪拌12h。在真空中蒸發反應混合物且藉由製備型(25-45% 1-6min水-甲醇(NH3 0.1%)，流速30ml/min)純化所獲得之0.48g粗產物，以得到產物5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.14g，343.62μmol，29.73%產率)。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (241.77 mg, 1.16 mmol) and 5-(5-methyl-2-piperidinyl)- 1H-Pyrazolo[4,3-b]pyridine (0.25 g, 1.16 mmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (439.51 mg, 1.16 mmol) was added followed by TEA (116.97 mg, 1.16 mmol, 161.11 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and the obtained 0.48 g of crude product was purified by preparative (25-45% 1-6 min water-methanol ( NH3 0.1%), flow rate 30 ml/min) to give the product 5-[[ 2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2-pendoxetylacetone yl]amino]pyridine-3-carboxamide (0.14 g, 343.62 μmol, 29.73% yield).

LCMS(ESI)：[M+1]+ m/z：計算值407.2；實測值408.2；Rt=1.756min。LCMS (ESI): [M+1] + m/z: calculated 407.2; found 408.2; Rt=1.756 min.

步驟2.5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物787 )及5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物778 )之分離Step 2. 5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 787 ) and 5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4] Isolation of ,3-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 778 )

使5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(187.70mg，460.70μmol)經歷掌性HPLC分離(管柱：IC-II(250*20，5um)，溶析液：己烷-IPA-MeOH，60-20-20，流速：12mL/min)，以得到兩種單獨的鏡像異構物化合物778 5-[[2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.056g，137.45μmol，29.83%產率)及化合物787 5-[[2-[(2S,5R)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(61.63mg，151.27μmol，32.83%產率)5-[[2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (187.70 mg, 460.70 μmol) was separated by chiral HPLC (column: IC-II (250*20, 5um), eluent: hexane -IPA-MeOH, 60-20-20, flow rate: 12 mL/min) to give two separate enantiomers Compound 778 5-[[2-[(2R,5S)-5-methyl-2- (1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.056 g, 137.45 μmol, 29.83% yield) and compound 787 5-[[2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl) -1-Piperidinyl]-2-Oxyacetyl]amino]pyridine-3-carboxamide (61.63 mg, 151.27 μmol, 32.83% yield)

化合物778 RT(AD-H，CO2-MeOH，60-40，2.0ml/min)=11.035minCompound 778 RT (AD-H, CO2-MeOH, 60-40, 2.0ml/min)=11.035min

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.10(m,3H),1.33-1.41(m,1H),1.73-1.85 (m,1H),1.85-1.98(m,1H),1.99-2.15(m,1H),2.50-2.55(m,1H),2.88-2.95(m,0.4H),3.34-3.42(m,0.6H),3.50-4.13(m,1H),5.28-5.82(m,1H),7.28-7.50(m,1H),7.53-7.65(m,1H),8.00-8.07(m,1H),8.08-8.19(m,1H),8.22-8.31(m,1H),8.42-8.53(m,1H),8.69-8.79(m,1H),8.81-8.93(m,1H),11.07-11.37(m,1H),13.30(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ 1.01-1.10 (m, 3H), 1.33-1.41 (m, 1H), 1.73-1.85 (m, 1H), 1.85-1.98 (m, 1H), 1.99- 2.15(m, 1H), 2.50-2.55(m, 1H), 2.88-2.95(m, 0.4H), 3.34-3.42(m, 0.6H), 3.50-4.13(m, 1H), 5.28-5.82(m ,1H),7.28-7.50(m,1H),7.53-7.65(m,1H),8.00-8.07(m,1H),8.08-8.19(m,1H),8.22-8.31(m,1H),8.42 -8.53(m,1H), 8.69-8.79(m,1H), 8.81-8.93(m,1H), 11.07-11.37(m,1H), 13.30(br s,1H).

LCMS(ESI)：[M+H]+ m/z：計算值408.2；實測值415.2；Rt=1.558min。LCMS (ESI): [M+H] + m/z: calculated 408.2; found 415.2; Rt=1.558 min.

化合物787 RT(AD-H，CO2-MeOH，60-40，2.0ml/min)=7.7minCompound 787 RT (AD-H, CO2-MeOH, 60-40, 2.0ml/min)=7.7min

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.10(m,3H),1.33-1.41(m,1H),1.73-1.85(m,1H),1.85-1.98(m,1H),1.99-2.15(m,1H),2.50-2.55(m,1H),2.88-2.95(m,0.4H),3.34-3.42(m,0.6H),3.50-4.13(m,1H),5.28-5.82(m,1H),7.28-7.50(m,1H),7.53-7.65(m,1H),8.00-8.07(m,1H),8.08-8.19(m,1H),8.22-8.31(m,1H),8.42-8.53(m,1H),8.69-8.79(m,1H),8.81-8.93(m,1H),11.07-11.37(m,1H),13.30(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.01-1.10(m,3H), 1.33-1.41(m,1H), 1.73-1.85(m,1H), 1.85-1.98(m,1H), 1.99- 2.15(m, 1H), 2.50-2.55(m, 1H), 2.88-2.95(m, 0.4H), 3.34-3.42(m, 0.6H), 3.50-4.13(m, 1H), 5.28-5.82(m ,1H),7.28-7.50(m,1H),7.53-7.65(m,1H),8.00-8.07(m,1H),8.08-8.19(m,1H),8.22-8.31(m,1H),8.42 -8.53(m,1H), 8.69-8.79(m,1H), 8.81-8.93(m,1H), 11.07-11.37(m,1H), 13.30(br s,1H).

LCMS(ESI)：[M+H]+ m/z：計算值408.2；實測值415.2；Rt=1.558min。LCMS (ESI): [M+H] + m/z: calculated 408.2; found 415.2; Rt=1.558 min.

實例172. 5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物490)及5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物491)之合成Example 172. 5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (Compound 490) and 5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidine Synthesis of [methyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 491)

Figure 110128222-A0202-12-1191-192
Figure 110128222-A0202-12-1191-192

步驟1.5-[[2-[2-(3，5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基.乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1. 5-[[2-[2-(3,5-Dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxy.acetyl]amino]pyridine-3- Synthesis of formamide

在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(508.43mg，1.64mmol，Et3N)、HATU(622.92mg，1.64mmol)及三乙胺(165.78mg，1.64 mmol，228.34μL)混合於無水DMF(5mL)中且將所得混合物攪拌5h。向其中添加2-(3,5-二氯苯基)-5-甲基哌啶(0.4g，1.64mmol)，且將所得混合物在21℃下攪拌隔夜將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-100% 2-7min；水-r1+nh3 30ml/min；裝載泵r1+h3 4ml/min；管柱YMC-Actus triat 19*100mm)。獲得兩種級分之5-[[2-[2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(347.9mg，799.21μmol，48.78%產率)：233.7mg(90.57%反式)及114.2mg(80.33%反式)。At 21 °C, 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (508.43 mg, 1.64 mmol, Et3N), HATU (622.92 mg, 1.64 mmol) were combined and triethylamine (165.78mg, 1.64 mmol, 228.34 μL) in dry DMF (5 mL) and the resulting mixture was stirred for 5 h. To this was added 2-(3,5-dichlorophenyl)-5-methylpiperidine (0.4 g, 1.64 mmol), and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, washed with EtOAc Extracted 3 times, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-100% 2-7min; water-r1+nh3 30ml/min; loading pump r1+h3 4ml/min; column YMC-Actus triat 19*100mm). Two fractions of 5-[[2-[2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] Pyridine-3-carboxamide (347.9 mg, 799.21 μmol, 48.78% yield): 233.7 mg (90.57% trans) and 114.2 mg (80.33% trans).

LCMS(ESI)：[M+1]+ m/z：計算值435.1；實測值436.0；Rt=1.222min。LCMS (ESI): [M+1] + m/z: calculated 435.1; found 436.0; Rt=1.222 min.

步驟2.5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物490 及5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物491 )之分離Step 2. 5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide ( compound 490 and 5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]- Isolation of 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 491 )

在以下條件下進行掌性分離：IA-II(250*20,5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min,RT(化合物491 )=29.063min，RT(化合物490 )=19.574minThe chiral separation was performed under the following conditions: IA-II (250*20,5mkm), Hexane-IPA-MeOH, 70-15-15, 12ml/min, RT( Compound 491 )=29.063min, RT( Compound 490 )=19.574min

5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺化合物490 (85.97mg，197.49μmol，36.79%產率)之RT=20.8502min(IA，己烷-IPA-MeOH，70-15-15，0.6ml/min)5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide compound 490 (85.97 mg, 197.49 μmol, 36.79% yield) RT=20.8502 min (IA, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min)

5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺化合物491 (92.28mg，211.99μmol，39.49%產率)之RT=31.7442min(IA，己烷-IPA-MeOH，70-15-15，0.6ml/min)5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide compound 491 (92.28 mg, 211.99 μmol, 39.49% yield) RT=31.7442 min (IA, hexane-IPA-MeOH, 70-15-15, 0.6 ml/min)

化合物490： 1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.04(m,3H),1.23-1.38(m,1H),1.56-1.68(m,1H),1.84-1.95(m,1H),1.98-2.14(m,1H),2.14-2.29(m,1H),2.76-3.27(m,1H),3.47-4.07(m,1H),5.12-5.56(m,1H),7.30-7.38(m,2H),7.49 -7.55(m,1H),7.56-7.65(m,1H),8.04-8.20(m,1H),8.41-8.54(m,1H),8.72-8.80(m,1H),8.80-8.91(m,1H),11.23-11.44(m,1H)。 Compound 490: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.96-1.04 (m, 3H), 1.23-1.38 (m, 1H), 1.56-1.68 (m, 1H), 1.84-1.95 (m, 1H) ,1.98-2.14(m,1H),2.14-2.29(m,1H),2.76-3.27(m,1H),3.47-4.07(m,1H),5.12-5.56(m,1H),7.30-7.38( m,2H),7.49-7.55(m,1H),7.56-7.65(m,1H),8.04-8.20(m,1H),8.41-8.54(m,1H),8.72-8.80(m,1H), 8.80-8.91 (m, 1H), 11.23-11.44 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值434.2；實測值345.2；Rt=3.594min。LCMS (ESI): [M+H] + m/z: calculated 434.2; found 345.2; Rt=3.594 min.

化合物491： 1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.04(m,3H),1.23-1.38(m,1H),1.56-1.68(m,1H),1.84-1.95(m,1H),1.98-2.14(m,1H),2.14-2.29(m,1H),2.76-3.27(m,1H),3.47-4.07(m,1H),5.12-5.56(m,1H),7.30-7.38(m,2H),7.49-7.55(m,1H),7.56-7.65(m,1H),8.04-8.20(m,1H),8.41-8.54(m,1H),8.72-8.80(m,1H),8.80-8.91(m,1H),11.23-11.44(m,1H)。 Compound 491: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.96-1.04 (m, 3H), 1.23-1.38 (m, 1H), 1.56-1.68 (m, 1H), 1.84-1.95 (m, 1H) ,1.98-2.14(m,1H),2.14-2.29(m,1H),2.76-3.27(m,1H),3.47-4.07(m,1H),5.12-5.56(m,1H),7.30-7.38( m,2H),7.49-7.55(m,1H),7.56-7.65(m,1H),8.04-8.20(m,1H),8.41-8.54(m,1H),8.72-8.80(m,1H), 8.80-8.91 (m, 1H), 11.23-11.44 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值434.2；實測值345.2；Rt=3.594min。LCMS (ESI): [M+H] + m/z: calculated 434.2; found 345.2; Rt=3.594 min.

實例173. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物966)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物951)之合成Example 173. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide (Compound 966) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-( Synthesis of 3,5-Dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 951)

Figure 110128222-A0202-12-1193-193
Figure 110128222-A0202-12-1193-193

步驟1.N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1 -Piperidinyl]-2-Side Oxyacetamide Synthesis

在21℃下，將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(0.2g，956.01μmol)、HATU(363.51mg，956.01μmol)及三乙胺(106.41mg，1.05mmol，146.57μL)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加(2S,5R)-2-(3,5-二氯苯基)-5-甲基哌啶(233.42mg，956.01μmol)，且將所得混 合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-75% 0.5-6min水-乙腈；流速30ml/min(裝載泵4ml/min；乙腈)；管柱SunFire 100x19mm 5um(R))。獲得呈米色固體之三種級分之N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(258.3mg，593.32μmol，62.06%產率)：第1級分-41.1mg(藉由LCMS為100%)；第2級分-109.3mg(93.46%反式、6.54%順式)；第3級分-107.9mg(84.79%反式、13.83%順式)。At 21 °C, 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (0.2 g, 956.01 μmol), HATU (363.51 mg, 956.01 μmol) were combined ) and triethylamine (106.41 mg, 1.05 mmol, 146.57 μL) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added (2S,5R)-2-(3,5-dichlorophenyl)-5-methylpiperidine (233.42 mg, 956.01 μmol), and the resulting mixture was mixed. The mixture was stirred at 21°C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-75% 0.5-6 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min; acetonitrile); column SunFire 100x19 mm 5um(R)). Three fractions of N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)- 5-Methyl-1-piperidinyl]-2-oxyacetamide (258.3 mg, 593.32 μmol, 62.06% yield): Fraction 1 - 41.1 mg (100% by LCMS); Fraction 2 - 109.3 mg (93.46% trans, 6.54% cis); Fraction 3 - 107.9 mg (84.79% trans, 13.83% cis).

LCMS(ESI)：[M]+ m/z：計算值434.2；實測值435.2；Rt=2.909min。LCMS (ESI): [M] + m/z: calculated 434.2; found 435.2; Rt=2.909 min.

步驟2.N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(3，5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物966 )及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物951 )之合成Step 2. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide ( Compound 966 ) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-( Synthesis of 3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 951 )

在以下條件下分離鏡像異構物：CHIRALPAC AD-H 250*20,5己烷-IPA-MeOH，50-25-25，12ml/min。RT(化合物966 )=13.308min，RT(化合物951 )=25.111minThe enantiomers were separated under the following conditions: CHIRALPAC AD-H 250*20,5 Hexane-IPA-MeOH, 50-25-25, 12 ml/min. RT( Compound 966 )=13.308min, RT( Compound 951 )=25.111min

N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(39.37mg，90.43μmol，26.18%產率)之RT=7.7182min(Chiralpak AD-3(150*2.1，3mkm)，己烷-IPA-MeOH，50-25-25，0.15ml/min)N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidine [methyl]-2-oxyacetamide (39.37 mg, 90.43 μmol, 26.18% yield) RT=7.7182 min (Chiralpak AD-3 (150*2.1, 3 mkm), hexane-IPA-MeOH, 50- 25-25, 0.15ml/min)

N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(53.66mg，123.26μmol，35.68%產率)之RT=15.6142min(Chiralpak AD-3(150*2.1，3mkm)，己烷-IPA-MeOH，50-25-25，0.15ml/min)N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidine [methyl]-2-oxyacetamide (53.66 mg, 123.26 μmol, 35.68% yield) RT=15.6142 min (Chiralpak AD-3 (150*2.1, 3 mkm), hexane-IPA-MeOH, 50- 25-25, 0.15ml/min)

化合物951： 1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.02(m,3H),1.06-1.13(m,3H),1.23-1.36(m,1H),1.56-1.65(m,1H),1.82-1.93(m,1H),1.96-2.10(m,1H),2.11-2.24(m,1H),2.39(q,2H),2.70-3.28(m,1H),3.44-4.04(m,1H),5.09-5.54 (m,1H),5.56-5.68(m,2H),7.26-7.39(m,2H),7.39-7.55(m,2H),7.90-8.10(m,1H),10.48-10.64(m,1H)。 Compound 951: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.96-1.02 (m, 3H), 1.06-1.13 (m, 3H), 1.23-1.36 (m, 1H), 1.56-1.65 (m, 1H) ,1.82-1.93(m,1H),1.96-2.10(m,1H),2.11-2.24(m,1H),2.39(q,2H),2.70-3.28(m,1H),3.44-4.04(m, 1H),5.09-5.54(m,1H),5.56-5.68(m,2H),7.26-7.39(m,2H),7.39-7.55(m,2H),7.90-8.10(m,1H),10.48- 10.64 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值434.2；實測值435.2；Rt=2.936min。LCMS (ESI): [M+1] + m/z: calculated 434.2; found 435.2; Rt=2.936 min.

化合物966： 1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.02(m,3H),1.06-1.13(m,3H),1.23-1.36(m,1H),1.56-1.65(m,1H),1.82-1.93(m,1H),1.96-2.10(m,1H),2.11-2.24(m,1H),2.39(q,2H),2.70-3.28(m,1H),3.44-4.04(m,1H),5.09-5.54(m,1H),5.56-5.68(m,2H),7.26-7.39(m,2H),7.39-7.55(m,2H),7.90-8.10(m,1H),10.48-10.64(m,1H)。 Compound 966: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.96-1.02 (m, 3H), 1.06-1.13 (m, 3H), 1.23-1.36 (m, 1H), 1.56-1.65 (m, 1H) ,1.82-1.93(m,1H),1.96-2.10(m,1H),2.11-2.24(m,1H),2.39(q,2H),2.70-3.28(m,1H),3.44-4.04(m, 1H), 5.09-5.54(m, 1H), 5.56-5.68(m, 2H), 7.26-7.39(m, 2H), 7.39-7.55(m, 2H), 7.90-8.10(m, 1H), 10.48- 10.64 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值434.2；實測值435.2；Rt=2.936min。LCMS (ESI): [M+1] + m/z: calculated 434.2; found 435.2; Rt=2.936 min.

實例174. 5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物945)及5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物965)之合成Example 174. 5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-2-methoxypyridine-3-carboxamide (Compound 945) and 5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (compound 965)

Figure 110128222-A0202-12-1195-194
Figure 110128222-A0202-12-1195-194

步驟1.5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1. 5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of ]-2-methoxypyridine-3-carboxamide

在21℃下，將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.2g，836.17μmol)、HATU(317.94mg，836.17μmol)及三乙胺(93.07mg，919.79μmol，128.20μL)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中 添加(2S,5R)-2-(3,5-二氯苯基)-5-甲基哌啶(204.16mg，836.17μmol)，且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(45-70% 0.5-6min水-乙腈；流速30ml/min(裝載泵4ml/min；乙腈)；管柱SunFire 100x19mm 5um(R))。獲得呈白色固體之三種級分：第1級分-76.5mg(100%)；第2級分-89.8mg(89.71%反式、10.29%順式)；第3級分-95.8mg(82.39%反式、17.61%順式)。At 21°C, 2-[(5-aminocarbamoyl-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (0.2 g, 836.17 μmol), HATU (317.94 mg , 836.17 μmol) and triethylamine (93.07 mg, 919.79 μmol, 128.20 μL) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. to it (2S,5R)-2-(3,5-dichlorophenyl)-5-methylpiperidine (204.16 mg, 836.17 μmol) was added, and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (45-70% 0.5-6 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min; acetonitrile); column SunFire 100x19 mm 5um(R)). Three fractions were obtained as white solids: Fraction 1 - 76.5 mg (100%); Fraction 2 - 89.8 mg (89.71% trans, 10.29% cis); Fraction 3 - 95.8 mg (82.39%) trans, 17.61% cis).

LCMS(ESI)：[M+1]+ m/z：計算值464.2；實測值465.2；Rt=3.489min。LCMS (ESI): [M+1] + m/z: calculated 464.2; found 465.2; Rt=3.489 min.

步驟2.5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物945 )及5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物965 )之分離Step 2. 5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-2-methoxypyridine-3-carboxamide ( compound 945 ) and 5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl- Isolation of 1-piperidinyl]-2-oxoacetyl]amino]-2-methoxypyridine-3-carboxamide ( compound 965 )

在以下條件下分離鏡像異構物：Chiralpak IC 250*20，5-II己烷-IPA-MeOH，60-20-20，15ml/minEnantiomers were separated under the following conditions: Chiralpak IC 250*20, 5-II Hexane-IPA-MeOH, 60-20-20, 15ml/min

製備型：CHIRALPAK-IC(250*20mm，5mkm)己烷-IPAMeOH，60-20-20，15ml/minPreparation: CHIRALPAK-IC (250*20mm, 5mkm) Hexane-IPAMeOH, 60-20-20, 15ml/min

5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺化合物965 (74.22mg，159.50μmol，44.63%產率)之RT=17.005min5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] RT = 17.005 min for -2-methoxypyridine-3-carboxamide compound 965 (74.22 mg, 159.50 μmol, 44.63% yield)

5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺化合物945 (77.71mg，167.00μmol，46.73%產率)之RT=23.346min5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] RT = 23.346 min for -2-methoxypyridine-3-carboxamide compound 945 (77.71 mg, 167.00 μmol, 46.73% yield)

5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺化合物945 (74.22mg，159.50μmol，44.63%產率)之RT=21.185min(Chiralpak IC-3(150*2.1，3mkm)，己烷-IPA-MeOH，70-15-15，0.15ml/min)5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] RT= 21.185 min (Chiralpak IC-3 (150*2.1, 3mkm), hexane-IPA- MeOH, 70-15-15, 0.15ml/min)

5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧 基吡啶-3-甲醯胺化合物965 (77.71mg，167.00μmol，46.73%產率)之RT=15,456min(Chiralpak IC-3(150*2.1，3mkm)，己烷-IPA-MeOH，70-15-15，0.15ml/min)5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] RT= 15,456 min (Chiralpak IC-3 (150*2.1, 3mkm), hexane-IPA- MeOH, 70-15-15, 0.15ml/min)

化合物945： 1H NMR(600MHz,DMSO-d 6 )δ 0.97-1.02(m,3H),1.23-1.37(m,1H),1.56-1.67(m,1H),1.82-1.94(m,1H),1.95-2.24(m,2H),2.59-3.11(m,1H),3.48-4.04(m,4H),5.14-5.52(m,1H),7.29-7.38(m,2H),7.48-7.55(m,1H),7.66-7.78(m,2H),8.40-8.58(m,2H),10.99-11.18(m,1H)。 Compound 945: 1H NMR (600 MHz, DMSO- d 6 ) δ 0.97-1.02 (m, 3H), 1.23-1.37 (m, 1H), 1.56-1.67 (m, 1H), 1.82-1.94 (m, 1H), 1.95-2.24(m, 2H), 2.59-3.11(m, 1H), 3.48-4.04(m, 4H), 5.14-5.52(m, 1H), 7.29-7.38(m, 2H), 7.48-7.55(m , 1H), 7.66-7.78 (m, 2H), 8.40-8.58 (m, 2H), 10.99-11.18 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值464.2；實測值465.2；Rt=3.591min。LCMS (ESI): [M+1] + m/z: calculated 464.2; found 465.2; Rt=3.591 min.

化合物965： 1H NMR(600MHz,DMSO-d 6 )δ 0.97-1.02(m,3H),1.23-1.37(m,1H),1.56-1.67(m,1H),1.82-1.94(m,1H),1.95-2.24(m,2H),2.59-3.11(m,1H),3.48-4.04(m,4H),5.14-5.52(m,1H),7.29-7.38(m,2H),7.48-7.55(m,1H),7.66-7.78(m,2H),8.40-8.58(m,2H),10.99-11.18(m,1H)。 Compound 965: 1H NMR (600 MHz, DMSO- d 6 ) δ 0.97-1.02 (m, 3H), 1.23-1.37 (m, 1H), 1.56-1.67 (m, 1H), 1.82-1.94 (m, 1H), 1.95-2.24(m, 2H), 2.59-3.11(m, 1H), 3.48-4.04(m, 4H), 5.14-5.52(m, 1H), 7.29-7.38(m, 2H), 7.48-7.55(m , 1H), 7.66-7.78 (m, 2H), 8.40-8.58 (m, 2H), 10.99-11.18 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值464.2；實測值465.2；Rt=3.591min。LCMS (ESI): [M+1] + m/z: calculated 464.2; found 465.2; Rt=3.591 min.

實例175. 外消旋-5-(2-((2R,5S)-5-甲基-2-(2-側氧基-1,2-二氫喹啉-6-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物670)、rel--5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物804)及rel-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺Example 175. Racemic-5-(2-((2R,5S)-5-methyl-2-(2-oxy-1,2-dihydroquinolin-6-yl)piperidine-1 -yl)-2-side oxyacetamido) nicotinamide (Compound 670), rel--5-[[2-[(2S,5R)-5-methyl-2-(2-side Oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-side oxyethanoyl]amino]pyridine-3-carboxamide (compound 804) and rel-5-[[ 2-[(2R,5S)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide

(化合物809)之合成Synthesis of (Compound 809)

Figure 110128222-A0202-12-1198-195
Figure 110128222-A0202-12-1198-195

步驟1：外消旋-5-(2-((2R,5S)-5-甲基-2-(2-側氧基-1,2-二氫喹啉-6-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物670 )之合成Step 1: Racemic-5-(2-((2R,5S)-5-methyl-2-(2-oxy-1,2-dihydroquinolin-6-yl)piperidin-1 Synthesis of -yl)-2-side oxyacetamido)nicotinamide ( compound 670 )

將6-(5-甲基-2-哌啶基)-1H-喹啉-2-酮(0.25g，1.03mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(253.41mg，1.03mmol，HCl)及三乙胺(1.04g，10.32mmol，1.44mL)一起混合於DMF(5mL)中。向其中添加HATU(588.43mg，1.55mmol)，且將所得混合物攪拌18h。在真空中濃縮反應混合物且藉由HPLC(2-10min 50-60% MeOH/H2 O，30mL/min(裝載泵4mL MeOH)，管柱：SunFire 100*19mm，5微米)純化殘餘物，以獲得5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2025g，467.17μmol，45.28%產率)。6-(5-Methyl-2-piperidinyl)-1H-quinolin-2-one (0.25 g, 1.03 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino ]-2-Pendoxoacetic acid (253.41 mg, 1.03 mmol, HCl) and triethylamine (1.04 g, 10.32 mmol, 1.44 mL) were mixed together in DMF (5 mL). To this was added HATU (588.43 mg, 1.55 mmol), and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 50-60% MeOH/ H2O , 30 mL/min (loading pump 4 mL MeOH), column: SunFire 100*19 mm, 5 microns) to give 5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (0.2025 g, 467.17 μmol, 45.28% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.03(m,3H),1.35(m,1H),1.73(m,1H),1.88(m,1H),2.19(m,2H),2.82(m,1H),3.74(m,1H),5.40(m,1H),6.47(m,1H),7.30(m,1H),7.45(m,1H),7.61(m,2H),7.87(m,1H),8.14(m,1H),8.47(m,1H),8.80(m,2H),11.21(m,1H),11.70(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 1.03 (m, 3H), 1.35 (m, 1H), 1.73 (m, 1H), 1.88 (m, 1H), 2.19 (m, 2H), 2.82(m,1H),3.74(m,1H),5.40(m,1H),6.47(m,1H),7.30(m,1H),7.45(m,1H),7.61(m,2H),7.87 (m, 1H), 8.14 (m, 1H), 8.47 (m, 1H), 8.80 (m, 2H), 11.21 (m, 1H), 11.70 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值433.2；實測值434.0；Rt=1.879min。LCMS (ESI): [M+H] + m/z: calculated 433.2; found 434.0; Rt=1.879 min.

步驟2：rel-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物804 )及rel-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基Step 2: rel-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 804 ) and rel-5-[[2-[(2R,5S)-5-methyl-2-(2-oxygen base -1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物809 )之合成Synthesis of -1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 809 )

藉由掌性層析(OJ-H，CO2-MeOH，70-30，3.0ml/min)分離非鏡像異構物之混合物，以獲得化合物804 rel-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(36.05mg，83.17μmol，23.02%產率)及化合物809 rel-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(37.44mg，86.37μmol，23.91%產率)。The mixture of diastereomers was separated by chiral chromatography (OJ-H, CO2-MeOH, 70-30, 3.0 ml/min) to obtain compound 804 rel-5-[[2-[(2S,5R )-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-methyl Amide (36.05 mg, 83.17 μmol, 23.02% yield) and compound 809 rel-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-1H-quinoline -6-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (37.44 mg, 86.37 μmol, 23.91% yield).

化合物804： RT(OJ-H，CO2 -MeOH，70-30，3.0mL/min)=2.726min。 Compound 804: RT (OJ-H, CO2 -MeOH, 70-30, 3.0 mL/min) = 2.726 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.99-1.07(m,3H),1.28-1.44(m,1H),1.66-1.77(m,1H),1.81-1.95(m,1H),2.01-2.16(m,1H),2.20-2.31(m,1H),2.78-3.23(m,1H),3.45-4.05(m,1H),5.15-5.67(m,1H),6.42-6.50(m,1H),7.26-7.36(m,1H),7.40-7.52(m,1H),7.54-7.68(m,2H),7.82-7.96(m,1H),8.05-8.24(m,1H),8.40-8.56(m,1H),8.68-8.79(m,1H),8.79-8.96(m,1H),10.92-11.49(m,1H),11.51-11.89(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.99-1.07 (m, 3H), 1.28-1.44 (m, 1H), 1.66-1.77 (m, 1H), 1.81-1.95 (m, 1H), 2.01 -2.16(m, 1H), 2.20-2.31(m, 1H), 2.78-3.23(m, 1H), 3.45-4.05(m, 1H), 5.15-5.67(m, 1H), 6.42-6.50(m, 1H), 7.26-7.36(m, 1H), 7.40-7.52(m, 1H), 7.54-7.68(m, 2H), 7.82-7.96(m, 1H), 8.05-8.24(m, 1H), 8.40- 8.56(m,1H), 8.68-8.79(m,1H), 8.79-8.96(m,1H), 10.92-11.49(m,1H), 11.51-11.89(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值433.2；實測值434.2；Rt=1.005min。LCMS (ESI): [M+H] + m/z: calculated 433.2; found 434.2; Rt=1.005 min.

化合物809： RT(OJ-H，CO2 -MeOH，70-30，3.0mL/min)=4.383min。 Compound 809: RT (OJ-H, CO2 -MeOH, 70-30, 3.0 mL/min) = 4.383 min.

1 H NMR(dmso,600MHz)：δ(ppm)1.00-1.09(m,3H),1.30-1.42(m,1H),1.67-1.79(m,1H),1.82-1.95(m,1H),2.01-2.19(m,1H),2.20-2.29(m,1H),2.78-3.23(m,1H),3.44-4.02(m,1H),5.11-5.70(m,1H),6.41-6.56(m,1H),7.25-7.37(m,1H),7.39-7.52(m,1H),7.53-7.67(m,2H),7.84-7.93(m,1H),8.08-8.23(m,1H),8.39-8.54(m,1H),8.69-8.79(m,1H),8.79-8.98(m,1H),11.11-11.52(m,1H),11.52-11.92(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 1.00-1.09 (m, 3H), 1.30-1.42 (m, 1H), 1.67-1.79 (m, 1H), 1.82-1.95 (m, 1H), 2.01 -2.19(m, 1H), 2.20-2.29(m, 1H), 2.78-3.23(m, 1H), 3.44-4.02(m, 1H), 5.11-5.70(m, 1H), 6.41-6.56(m, 1H), 7.25-7.37(m, 1H), 7.39-7.52(m, 1H), 7.53-7.67(m, 2H), 7.84-7.93(m, 1H), 8.08-8.23(m, 1H), 8.39- 8.54(m,1H), 8.69-8.79(m,1H), 8.79-8.98(m,1H), 11.11-11.52(m,1H), 11.52-11.92(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值433.2；實測值434.2；Rt=1.917min。LCMS (ESI): [M+H] + m/z: calculated 433.2; found 434.2; Rt=1.917 min.

實例176. rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物810)及rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物807)之合成Example 176. rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1- Piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 810) and rel-2-methoxy-5-[[2-[(2R,5S)- 5-Methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide Synthesis of (Compound 807)

Figure 110128222-A0202-12-1200-196
Figure 110128222-A0202-12-1200-196

步驟1：外消旋-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)- Synthesis of 1-Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide

將6-(5-甲基-2-哌啶基)-1H-喹啉-2-酮(0.3g，1.24mmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(296.12mg，1.24mmol)、三乙胺(626.39mg，6.19mmol，862.80μL)混合於DMF(10mL)中，然後添加HATU(706.12mg，1.86mmol)。將所得混合物在25℃下攪拌12h。將溶劑蒸發且將所得混合物與於甲醇(10ml)中之SiliaMetS® DMT(50mg)一起攪拌。將混合物過濾且在減壓下蒸發。藉由HPLC(2-10min 40-45%甲醇/H2 O，30mL/min)純化所得粗材料，以獲得外消旋-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(138.6mg，299.04μmol，24.15%產率)。6-(5-Methyl-2-piperidinyl)-1H-quinolin-2-one (0.3 g, 1.24 mmol), 2-[(5-aminocarbamoyl-6-methoxy-3 -Pyridinyl)amino]-2-oxoacetic acid (296.12 mg, 1.24 mmol), triethylamine (626.39 mg, 6.19 mmol, 862.80 μL) were mixed in DMF (10 mL), followed by the addition of HATU (706.12 mg, 1.86 mmol). The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the resulting mixture was stirred with SiliaMetS® DMT (50 mg) in methanol (10 ml). The mixture was filtered and evaporated under reduced pressure. The resulting crude material was purified by HPLC (2-10 min 40-45% methanol/ H2O , 30 mL/min) to obtain rac-2-methoxy-5-[[2-[(2S,5R) -5-Methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxy Amine (138.6 mg, 299.04 μmol, 24.15% yield).

LCMS(ESI)：[M+H]+ m/z：計算值463.2；實測值464.1；Rt=1.087min。LCMS (ESI): [M+H] + m/z: calculated 463.2; found 464.1; Rt=1.087 min.

步驟2：rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶Step 2: rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1- piperidine 基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物810 )及rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物807 )之合成yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 810 ) and rel-2-methoxy-5-[[2-[(2R,5S)-5- Methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 807 ) synthesis

藉由掌性層析(IA-II(250*20，5mkm)，IPA-MeOH，50-50，12mL/min)分離非鏡像異構物之混合物，以獲得(化合物807) rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(38.31mg，82.66μmol，27.64%產率)及(化合物810) rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(37.06mg，79.96μmol，26.74%產率)The mixture of diastereomers was separated by chiral chromatography (IA-II (250*20, 5mkm), IPA-MeOH, 50-50, 12mL/min) to obtain (compound 807) rel-2-methan Oxy-5-[[2-[(2R,5S)-5-methyl-2-(2-side oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (38.31 mg, 82.66 μmol, 27.64% yield) and (compound 810) rel-2-methoxy-5-[[2-[(2S ,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 -formamide (37.06 mg, 79.96 μmol, 26.74% yield)

製備型 ： Preparation :

化合物807 之RT(IA-II(250*20，5mkm)，IPA-MeOH，50-50，12ml/min)=41.297min。RT for compound 807 (IA-II (250*20, 5mkm), IPA-MeOH, 50-50, 12ml/min)=41.297min.

化合物810 之RT(IA-II(250*20，5mkm)，IPA-MeOH，50-50，12ml/min)=31.249min。RT for compound 810 (IA-II (250*20, 5mkm), IPA-MeOH, 50-50, 12ml/min)=31.249min.

化合物810： RT(IC，IPA-MeOH，50-50，0.6mL/min)=24.885min。 Compound 810: RT (IC, IPA-MeOH, 50-50, 0.6 mL/min) = 24.885 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.98-1.09(m,3H),1.30-1.44(m,1H),1.63-1.76(m,1H),1.81-1.93(m,1H),2.02-2.18(m,1H),2.19-2.28(m,1H),2.77-3.24(m,1H),3.45-3.50(m,0.6H),3.88-3.96(m,3H),3.97-4.02(m,0.4H),5.11-5.72(m,1H),6.40-6.54(m,1H),7.21-7.36(m,1H),7.37-7.50(m,1H),7.57-7.64(m,1H),7.65-7.77(m,2H),7.82-7.93(m,1H),8.37-8.59(m,2H),10.91-11.11(m,1H),11.66-11.76(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.98-1.09 (m, 3H), 1.30-1.44 (m, 1H), 1.63-1.76 (m, 1H), 1.81-1.93 (m, 1H), 2.02 -2.18(m, 1H), 2.19-2.28(m, 1H), 2.77-3.24(m, 1H), 3.45-3.50(m, 0.6H), 3.88-3.96(m, 3H), 3.97-4.02(m ,0.4H),5.11-5.72(m,1H),6.40-6.54(m,1H),7.21-7.36(m,1H),7.37-7.50(m,1H),7.57-7.64(m,1H), 7.65-7.77(m,2H), 7.82-7.93(m,1H), 8.37-8.59(m,2H), 10.91-11.11(m,1H), 11.66-11.76(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值463.2；實測值464.2；Rt=2.401min。LCMS (ESI): [M+H] + m/z: calculated 463.2; found 464.2; Rt=2.401 min.

化合物807： RT(IC，IPA-MeOH，50-50，0.6mL/min)=32.686min。 Compound 807: RT (IC, IPA-MeOH, 50-50, 0.6 mL/min) = 32.686 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.97-1.04(m,3H),1.27-1.38(m,1H),1.66- 1.75(m,1H),1.81-1.94(m,1H),2.01-2.17(m,1H),2.20-2.31(m,1H),2.80-3.23(m,1H),3.46-3.53(m,1H),3.89-3.96(m,3H),5.15-5.67(m,1H),6.40-6.52(m,1H),7.23-7.36(m,1H),7.39-7.50(m,1H),7.57-7.62(m,1H),7.66-7.77(m,2H),7.83-7.91(m,1H),8.40-8.59(m,2H),10.92-11.14(m,1H),11.60-11.77(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.97-1.04 (m, 3H), 1.27-1.38 (m, 1H), 1.66-1.75 (m, 1H), 1.81-1.94 (m, 1H), 2.01 -2.17(m, 1H), 2.20-2.31(m, 1H), 2.80-3.23(m, 1H), 3.46-3.53(m, 1H), 3.89-3.96(m, 3H), 5.15-5.67(m, 1H), 6.40-6.52(m, 1H), 7.23-7.36(m, 1H), 7.39-7.50(m, 1H), 7.57-7.62(m, 1H), 7.66-7.77(m, 2H), 7.83- 7.91 (m, 1H), 8.40-8.59 (m, 2H), 10.92-11.14 (m, 1H), 11.60-11.77 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值463.2；實測值464.0；Rt=2.401min。LCMS (ESI): [M+H] + m/z: calculated 463.2; found 464.0; Rt=2.401 min.

實例177. rel-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物892)及rel-5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物885)之合成Example 177. rel-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (Compound 892) and rel-5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidine Synthesis of [methyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 885)

Figure 110128222-A0202-12-1202-197
Figure 110128222-A0202-12-1202-197

步驟1：5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Synthesis of Amide

將6-(5-甲基-2-哌啶基)異喹啉(0.3g，1.33mmol)溶解於DMF中且添加三乙胺(1.34g，13.26mmol，1.85mL)，隨後添加2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(325.59mg，1.33mmol，HCl)。然後逐滴添加HATU(756.04mg，1.99mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.11g，263.50μmol，19.88%產率)。6-(5-Methyl-2-piperidinyl)isoquinoline (0.3 g, 1.33 mmol) was dissolved in DMF and triethylamine (1.34 g, 13.26 mmol, 1.85 mL) was added followed by 2-[ (5-Aminocarbamoyl-3-pyridinyl)amino]-2-pendoxoacetic acid (325.59 mg, 1.33 mmol, HCl). HATU (756.04 mg, 1.99 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC to obtain 5-[[2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (0.11 g, 263.50 μmol, 19.88% yield).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=0.681min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=0.681 min.

步驟2：rel-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物892 )及rel-5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物885 )之合成Step 2: rel-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide ( compound 892 ) and rel-5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidine [Synthesis of]-2-oxyacetyl]amino]pyridine-3-carboxamide ( compound 885 )

對外消旋-5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基] 胺基]吡啶-3-甲醯胺(0.11g，263.50μmol)進行掌性分離(管柱：Chiralpak AD-H(250*20mm，5m)；流動相：己烷-IPA-MeOH，70-15-15；流速：12mL/min；管柱溫度：24℃；波長：205nm、210nm、254nm保留時間(異構物A)=41.75min)，以獲得化合物892 5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.05085g，121.81μmol，46.23%產率)及化合物885 5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.04934g，118.19μmol，44.85%產率)。Racemic-5-[[2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Formamide (0.11 g, 263.50 μmol) for chiral separation (column: Chiralpak AD-H (250*20 mm, 5 m); mobile phase: hexane-IPA-MeOH, 70-15-15; flow rate: 12 mL/ min; column temperature: 24°C; wavelength: 205nm, 210nm, 254nm retention time (isomer A)=41.75min) to obtain compound 892 5-[[2-[(2S,5R)-2-(6 -Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.05085 g, 121.81 μmol, 46.23% yield) and compound 885 5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (0.04934 g, 118.19 μmol, 44.85% yield).

化合物892： RT(AD-H，Hex-IPA-MeOH，50-25-25，0.6mL/min)=23.254min。 Compound 892: RT (AD-H, Hex-IPA-MeOH, 50-25-25, 0.6 mL/min) = 23.254 min.

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.06(t,3H),1.39(m,1H),1.73(m,1H),1.89(m,1H),2.18(m,1H),2.39(m,2H),3.83(dd,1H),5.58(m,1H),7.66(m,2H),7.83(m,1H),7.92(m,1H),8.15(m,2H),8.49(m,2H),8.75(m,1H),8.87(m,1H),9.28(m,1H),11.29(m,1H)。 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.06(t, 3H), 1.39(m, 1H), 1.73(m, 1H), 1.89(m, 1H), 2.18(m, 1H), 2.39(m,2H),3.83(dd,1H),5.58(m,1H),7.66(m,2H),7.83(m,1H),7.92(m,1H),8.15(m,2H),8.49 (m, 2H), 8.75 (m, 1H), 8.87 (m, 1H), 9.28 (m, 1H), 11.29 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=0.854min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=0.854 min.

化合物885： RT(AD-H，Hex-IPA-MeOH，50-25-25，0.6mL/min)=34.603min。 Compound 885: RT (AD-H, Hex-IPA-MeOH, 50-25-25, 0.6 mL/min) = 34.603 min.

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.06(m,3H),1.39(m,1H),1.79(m,2H),2.25(m,3H),3.83(dd,1H),5.58(m,1H),7.66(m,2H),7.82(t,1H),7.92(d,1H),8.15(m,2H),8.49(m,2H),8.76(m,1H),8.87(m,1H),9.28(m,1H),11.29(m,1H)。 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.06(m, 3H), 1.39(m, 1H), 1.79(m, 2H), 2.25(m, 3H), 3.83(dd, 1H), 5.58(m, 1H), 7.66(m, 2H), 7.82(t, 1H), 7.92(d, 1H), 8.15(m, 2H), 8.49(m, 2H), 8.76(m, 1H), 8.87 (m, 1H), 9.28 (m, 1H), 11.29 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=0.855min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=0.855 min.

實例178. rel-5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物914)及rel-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物933)之合成Example 178. rel-5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-2-methoxypyridine-3-carboxamide (Compound 914) and rel-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (compound 933)

Figure 110128222-A0202-12-1204-198
Figure 110128222-A0202-12-1204-198

步驟1：5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxy Synthesis of pyridine-3-carboxamide

將6-(5-甲基-2-哌啶基)異喹啉(0.44g，1.94mmol)溶解於DMF(10mL)中且添加三乙胺(1.97g，19.44mmol，2.71mL)，隨後添加2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(465.02mg，1.94mmol)。然後逐滴添加HATU(1.11g，2.92mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.12g，268.17μmol，13.79%產率)。6-(5-Methyl-2-piperidinyl)isoquinoline (0.44 g, 1.94 mmol) was dissolved in DMF (10 mL) and triethylamine (1.97 g, 19.44 mmol, 2.71 mL) was added followed by 2-[(5-Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-pendoxoacetic acid (465.02 mg, 1.94 mmol). HATU (1.11 g, 2.92 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC to obtain 5-[[2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (0.12 g, 268.17 μmol, 13.79% yield).

LCMS(ESI)：[M+H]+ m/z：計算值447.2；實測值448.0；Rt=0.954min。LCMS (ESI): [M+H] + m/z: calculated 447.2; found 448.0; Rt=0.954 min.

步驟2：rel-5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物914 )及rel-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物933 )之合成Step 2: rel-5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-2-methoxypyridine-3-carboxamide ( Compound 914 ) and rel-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide ( compound 933 )

對5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.12g，268.17μmol)進行掌性分離(管柱：Chiralpak IB(250*30mm，5mkm)；以CO2 -MeOH，65-35為流動相，90mL/min；管柱溫度：40℃；波長：215nm。保留時間(異構物A)=8.55min；保留時間(異構物B)=9.23min)，以獲得化合物933 rel-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.04984g，111.38μmol，41.53%產率)及化合物914 5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(56.12mg，125.41μmol，46.77%產率)。p-5-[[2-[2-(6-Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine -3-Carboxamide (0.12g, 268.17μmol) for chiral separation (column: Chiralpak IB (250*30mm, 5mkm); CO 2 -MeOH, 65-35 as mobile phase, 90mL/min; column Temperature: 40°C; Wavelength: 215 nm. Retention time (Isomer A)=8.55 min; Retention time (Isomer B)=9.23 min) to obtain compound 933 rel-5-[[2-[(2S, 5R)-2-(6-Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxylate Amine (0.04984 g, 111.38 μmol, 41.53% yield) and compound 914 5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (56.12 mg, 125.41 μmol, 46.77% yield).

化合物933： RT(IB，CO2-MeOH，60-40，2.0mL/min)=6.159min。 Compound 933: RT (IB, CO2-MeOH, 60-40, 2.0 mL/min) = 6.159 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.04(m,3H),1.37(m,1H),1.72(m,1H),1.90(m,1H),2.19(m,1H),2.37(m,1H),2.84(m,1H),3.92(m,4H),5.56(d,1H),7.66(m,3H),7.81(m,1H),7.90(m,1H),8.13(m,1H),8.51(m,3H),9.27(m,1H),11.07(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.04(m, 3H), 1.37(m, 1H), 1.72(m, 1H), 1.90(m, 1H), 2.19(m, 1H), 2.37(m, 1H), 2.84(m, 1H), 3.92(m, 4H), 5.56(d, 1H), 7.66(m, 3H), 7.81(m, 1H), 7.90(m, 1H), 8.13 (m, 1H), 8.51 (m, 3H), 9.27 (m, 1H), 11.07 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值447.2；實測值448.2；Rt=0.964min。LCMS (ESI): [M+H] + m/z: calculated 447.2; found 448.2; Rt=0.964 min.

化合物914： RT(IB，CO2-MeOH，60-40，2.0mL/min)=6.890min。 Compound 914: RT (IB, CO2-MeOH, 60-40, 2.0 mL/min) = 6.890 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.38(m,1H),1.72(m,1H),1.90(m,1H),2.20(m,1H),2.37(m,1H),2.84(m,1H),3.92(m,4H),5.56(d,1H),7.61(d,1H),7.68(m,1H),7.74(m,1H),7.81(m,1H),7.90(m,1H),8.13(dd,1H),8.50(m,3H),9.27(m,1H),11.07(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.02(m, 3H), 1.38(m, 1H), 1.72(m, 1H), 1.90(m, 1H), 2.20(m, 1H), 2.37(m, 1H), 2.84(m, 1H), 3.92(m, 4H), 5.56(d, 1H), 7.61(d, 1H), 7.68(m, 1H), 7.74(m, 1H), 7.81 (m, 1H), 7.90 (m, 1H), 8.13 (dd, 1H), 8.50 (m, 3H), 9.27 (m, 1H), 11.07 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值447.2；實測值448.2；Rt=0.962min。LCMS (ESI): [M+H] + m/z: calculated 447.2; found 448.2; Rt=0.962 min.

實例179. rel-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物645)及rel-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物654)之合成Example 179. rel-5-[[2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide (Compound 645) and rel-5-[[2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl )-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 654) synthesis

Figure 110128222-A0202-12-1205-199
Figure 110128222-A0202-12-1205-199

步驟1：5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[5-Methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Synthesis of 3-formamide

將DIPEA(631.43mg，4.89mmol，850.98μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.3g，1.22mmol，HCl)及2-甲基-5-(5-甲基-2-哌啶基)吡啶(232.41mg，1.22mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(510.85mg，1.34mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire 100*19mm，5mkm管柱且以H2 O-MeOH為溶析液混合物)，以得到5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.23g，603.00μmol，49.37%產率)。DIPEA (631.43 mg, 4.89 mmol, 850.98 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.3 g, 1.22 mmol, HCl) and 2-methyl-5-(5-methyl-2-piperidinyl)pyridine (232.41 mg, 1.22 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (510.85 mg, 1.34 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire 100*19mm, 5mkm column with H2O -MeOH as eluent mixture) to give 5-[[2-[5-methyl-2-(6- Methyl-3-pyridyl)-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (0.23 g, 603.00 μmol, 49.37% yield).

LCMS(ESI)：[M+H]+ m/z：計算值381.4；實測值382.4；Rt=1.202min。LCMS (ESI): [M+H] + m/z: calculated 381.4; found 382.4; Rt=1.202 min.

步驟2：rel-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物645 )及rel-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物654 )之合成Step 2: rel-5-[[2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide ( Compound 645 ) and rel-5-[[2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl )-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 654 ) synthesis

使用(OJ-H I(250*20mm，5mkm)Chiralpak管柱且以己烷-IPA-MeOH，70-15-15為流動相，流速15mL/min)對5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(180.0mg，471.91μmol)進行掌性分離，得到化合物645 rel-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(79.97mg，43.89%產率)及化合物654 rel-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(94.9mg，52.72%產率)。Using (OJ-HI (250*20mm, 5mkm) Chiralpak column and hexane-IPA-MeOH, 70-15-15 as mobile phase, flow rate 15mL/min) for 5-[[2-[5-methan yl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (180.0 mg, 471.91 μmol) Chiral separation afforded compound 645 rel-5-[[2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (79.97 mg, 43.89% yield) and compound 654 rel-5-[[2-[(2S,5R)-5-methyl-2 -(6-Methyl-3-pyridinyl)-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (94.9 mg, 52.72% yield).

化合物645： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6mL/min)=23.503min。 Compound 645: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 23.503 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.65(m,1H),1.88(m,1H),2.07(m,1H),2.21(m,1H),2.38(m,3H),3.00(m,1H),3.73(m,1H),5.38(m,1H),7.25(m,1H),7.61(m,2H),8.17(m,1H),8.44(m,2H),8.75(m,1H),8.86(m,1H),11.21(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.02(m, 3H), 1.34(m, 1H), 1.65(m, 1H), 1.88(m, 1H), 2.07(m, 1H), 2.21(m, 1H), 2.38(m, 3H), 3.00(m, 1H), 3.73(m, 1H), 5.38(m, 1H), 7.25(m, 1H), 7.61(m, 2H), 8.17 (m, 1H), 8.44 (m, 2H), 8.75 (m, 1H), 8.86 (m, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=0.787min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=0.787 min.

化合物654： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6mL/min)=14.127min。 Compound 654: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 14.127 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.65(m,1H),1.89(m,1H),2.05(m,1H),2.20(m,1H),2.38(m,3H),2.99(m,1H),3.69(m,1H),5.38(m,1H),7.25(m,1H),7.60(m,2H),8.14(m,1H),8.44(m,2H),8.75(m,1H),8.86(m,1H),11.21(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.33(m, 1H), 1.65(m, 1H), 1.89(m, 1H), 2.05(m, 1H), 2.20(m, 1H), 2.38(m, 3H), 2.99(m, 1H), 3.69(m, 1H), 5.38(m, 1H), 7.25(m, 1H), 7.60(m, 2H), 8.14 (m, 1H), 8.44 (m, 2H), 8.75 (m, 1H), 8.86 (m, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=0.789min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=0.789 min.

實例180. rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物754)及rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物770)之合成Example 180. rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 754) and rel-2-methoxy-5-[[2-[(2R,5S)-5-methyl- Synthesis of 2-(6-Methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 770)

Figure 110128222-A0202-12-1207-200
Figure 110128222-A0202-12-1207-200

步驟1：2-甲氧基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-[5-methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]-2-oxyethanoyl Synthesis of ]amino]pyridine-3-carboxamide

將DIPEA(398.69mg，3.08mmol，537.32μL)添加到相應2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(0.3g，881.38μmol，Et3 N)及2-甲基-5-(5-甲基-2-哌啶基)吡啶(167.71mg，881.38μmol)於DMF(5mL)中之溶液中。 將所得混合物攪拌5min，隨後添加HATU(368.64mg，969.52μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeCN為溶析液混合物)，以得到2-甲氧基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.13g，315.95μmol，35.85%產率)。DIPEA (398.69 mg, 3.08 mmol, 537.32 μL) was added to the corresponding 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid (0.3 g , 881.38 μmol, Et3N ) and 2-methyl-5-(5-methyl-2-piperidinyl)pyridine (167.71 mg, 881.38 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (368.64 mg, 969.52 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeCN as eluent mixture) to give 2-methoxy-5-[[2-[5-methyl -2-(6-Methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.13 g, 315.95 μmol, 35.85% Yield).

1 H NMR(500MHz,DMSO-d6 )δ 0.94(s,3H),1.07(m,1H),1.44(m,1H),1.62(m,1H),2.01(m,2H),2.41(m,2H),3.09(s,3H),3.42(m,1H),4.01(s,3H),5.19(m,1H),7.22(m,1H),7.59(m,1H),7.72(m,2H),8.49(m,2H),8.56(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.94(s, 3H), 1.07(m, 1H), 1.44(m, 1H), 1.62(m, 1H), 2.01(m, 2H), 2.41(m ,2H),3.09(s,3H),3.42(m,1H),4.01(s,3H),5.19(m,1H),7.22(m,1H),7.59(m,1H),7.72(m, 2H), 8.49 (m, 2H), 8.56 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值412.0；Rt=1.467min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 412.0; Rt=1.467 min.

步驟5：rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物754 )及rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物770 )之合成Step 5: rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 754 ) and rel-2-methoxy-5-[[2-[(2R,5S)-5-methyl- Synthesis of 2-(6-Methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 770 )

對2-甲氧基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(130.0mg，315.95μmol)使用(Chiralpak IA(250*20mm，5mkm)且以己烷-IPA-MeOH，40-30-30為流動相，流速：12mL/min；管柱溫度：24℃；波長：205nm、266nm、308nm)，保留時間(異構物A)=35.04min；保留時間(異構物B)=46.12min)進行掌性分離，得到化合物754 rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(22.66mg，17.43%產率)及化合物770 2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(40.84mg，31.42%產率)。p-2-Methoxy-5-[[2-[5-methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (130.0 mg, 315.95 μmol) using (Chiralpak IA (250*20 mm, 5 mkm) and hexane-IPA-MeOH, 40-30-30 as mobile phase, flow rate: 12 mL/min ; column temperature: 24°C; wavelength: 205nm, 266nm, 308nm), retention time (isomer A)=35.04min; retention time (isomer B)=46.12min) for chiral separation to obtain compound 754 rel -2-Methoxy-5-[[2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carbamide (22.66 mg, 17.43% yield) and compound 770 2-methoxy-5-[[2-[(2R,5S)-5-methyl -2-(6-Methyl-3-pyridyl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (40.84 mg, 31.42% yield) .

化合物754： RT(IA，己烷-IPA-MeOH，40-30-30，0.6mL/min)=10.508min。 Compound 754: RT (IA, Hexane-IPA-MeOH, 40-30-30, 0.6 mL/min) = 10.508 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.93-1.08(m,3H),1.26-1.40(m,1H),1.56-1.74(m,1H),1.83-1.93(m,1H),1.98-2.15(m,1H),2.15-2.25(m,1H),2.41-2.45(m,3H),2.71-3.24(m,1H),3.44-4.02(m,4H),5.12-5.62(m,1H),7.19-7.32(m,1H),7.51-7.65(m,1H),7.65-7.77(m,2H),8.34-8.47(m,2H),8.47-8.58(m,1H),10.88-11.10(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.93-1.08(m,3H), 1.26-1.40(m,1H), 1.56-1.74(m,1H), 1.83-1.93(m,1H), 1.98- 2.15(m,1H), 2.15-2.25(m,1H), 2.41-2.45(m,3H), 2.71-3.24(m,1H), 3.44-4.02(m,4H), 5.12-5.62(m,1H) ),7.19-7.32(m,1H),7.51-7.65(m,1H),7.65-7.77(m,2H),8.34-8.47(m,2H),8.47-8.58(m,1H),10.88-11.10 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值412.2；Rt=0.862min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 412.2; Rt=0.862 min.

化合物770： RT(IA，己烷-IPA-MeOH，40-30-30，0.6mL/min)=72.637min。 Compound 770: RT (IA, Hexane-IPA-MeOH, 40-30-30, 0.6 mL/min) = 72.637 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.02-1.04(m,3H),1.27-1.38(m,1H),1.59-1.70(m,1H),1.80-1.93(m,1H),1.99-2.15(m,1H),2.15-2.25(m,1H),2.41-2.44(m,3H),2.72-3.24(m,1H),3.44-4.02(m,4H),5.13-5.60(m,1H),7.19-7.30(m,1H),7.54-7.65(m,1H),7.66-7.78(m,2H),8.37-8.47(m,2H),8.47-8.56(m,1H),10.94-11.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.02-1.04(m,3H), 1.27-1.38(m,1H), 1.59-1.70(m,1H), 1.80-1.93(m,1H), 1.99- 2.15(m,1H), 2.15-2.25(m,1H), 2.41-2.44(m,3H), 2.72-3.24(m,1H), 3.44-4.02(m,4H), 5.13-5.60(m,1H ),7.19-7.30(m,1H),7.54-7.65(m,1H),7.66-7.78(m,2H),8.37-8.47(m,2H),8.47-8.56(m,1H),10.94-11.08 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值412.2；Rt=0.862min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 412.2; Rt=0.862 min.

實例181. 5-[[2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物704)及5-[[2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物686)之合成Example 181. 5-[[2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carbamoylamine (Compound 704) and 5-[[2-[(2R,5S)-2-(5-acetamido-2-thienyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 686)

Figure 110128222-A0202-12-1209-201
Figure 110128222-A0202-12-1209-201

步驟1：5-[[2-[2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(5-Acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amino] Synthesis of pyridine-3-carboxamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(627.34mg，2.55mmol，HCl)及N-[5-(5-甲基-2-哌啶基)-2-噻吩基]乙醯胺(0.9g，2.55mmol， CF3 COOH)混合於DMF(15mL)中。將反應懸浮液冷卻至20℃且添加HATU(971.15mg，2.55mmol)，隨後添加TEA(1.29g，12.77mmol，1.78mL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且倒入到水(100ml)中且用EtOAc(2* 30ml)萃取。將經合併之有機萃取物用水(2* 30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，且藉由製備型(25-75% 0-5min水-甲醇，流速30ml/min)純化0.45g所獲得之粗產物，以得到產物5-[[2-[2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.100g，232.83μmol，9.12%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (627.34 mg, 2.55 mmol, HCl) and N-[5-(5-methyl-2- Piperidinyl)-2-thienyl]acetamide (0.9 g, 2.55 mmol, CF3COOH ) was mixed in DMF (15 mL). The reaction suspension was cooled to 20°C and HATU (971.15 mg, 2.55 mmol) was added followed by TEA (1.29 g, 12.77 mmol, 1.78 mL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and poured into water (100ml) and extracted with EtOAc (2 * 30ml). The combined organic extracts were washed with water (2 * 30ml), dried over sodium sulfate and evaporated in vacuo, and 0.45g purified by prep (25-75% 0-5min water-methanol, flow rate 30ml/min) The crude product obtained to give the product 5-[[2-[2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-pendoxoethyl Acyl]amino]pyridine-3-carboxamide (0.100 g, 232.83 μmol, 9.12% yield).

LCMS(ESI)：[M+H]+ m/z：計算值429.1；實測值430.0；Rt=1.948min。LCMS (ESI): [M+H] + m/z: calculated 429.1; found 430.0; Rt=1.948 min.

步驟2：5-[[2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物704 )及5-[[2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物686 )之合成Step 2: 5-[[2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carbamoylamine ( Compound 704 ) and 5-[[2-[(2R,5S)-2-(5-acetamido-2-thienyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 686 )

藉由掌性HPLC(管柱：OJ-H(250* 20，5mkm))，以己烷-IPA-MeOH，70-15-15，14ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物704 5-[[2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(37.20mg，86.61μmol，37.20%產率)及化合物686 5-[[2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0461g，107.34μmol，46.10%產率)。The enantiomers were separated by chiral HPLC (column: OJ-H (250 * 20, 5mkm) with hexane-IPA-MeOH, 70-15-15, 14ml/min as mobile phase) to give Two separate enantiomers Compound 704 5-[[2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (37.20 mg, 86.61 μmol, 37.20% yield) and compound 686 5-[[2-[(2R,5S)-2- (5-Acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amino]pyridine-3-carboxamide (0.0461 g, 107.34 g μmol, 46.10% yield).

化合物686： RT(IA，己烷-IPA-MeOH，70-15-15，0.6mL/min)=30.346min。 Compound 686: RT (IA, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 30.346 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.78(m,3H),1.30(m,2H),1.68(m,2H),1.88(m,1H),2.02(m,3H),2.21(m,1H),3.90(m,1H),5.53(m,1H),6.47(m,1H),6.69(m,1H),7.58(m,1H),8.15(m,1H),8.49(m,1H),8.81(m,2H),11.05(s,1H),11.23(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.78(m, 3H), 1.30(m, 2H), 1.68(m, 2H), 1.88(m, 1H), 2.02(m, 3H), 2.21(m,1H),3.90(m,1H),5.53(m,1H),6.47(m,1H),6.69(m,1H),7.58(m,1H),8.15(m,1H),8.49 (m, 1H), 8.81 (m, 2H), 11.05 (s, 1H), 11.23 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值429.2；實測值430.2；Rt=1.042min。LCMS (ESI): [M+H] + m/z: calculated 429.2; found 430.2; Rt=1.042 min.

化合物704： RT(IA，己烷-IPA-MeOH，70-15-15，0.6mL/min)=26.867min。 Compound 704: RT (IA, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 26.867 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.79(dd,3H),1.31(m,1H),1.68(m,2H),1.89(m,1H),2.01(m,3H),2.20(m,1H),2.72(m,1H),3.89(m,1H),5.53(m,1H),6.47(m,1H),6.69(m,1H),7.59(d,1H),8.15(d,1H),8.49(m,1H),8.75(m,1H),8.87(m,1H),11.05(s,1H),11.23(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.79(dd,3H), 1.31(m,1H), 1.68(m,2H), 1.89(m,1H), 2.01(m,3H), 2.20(m, 1H), 2.72(m, 1H), 3.89(m, 1H), 5.53(m, 1H), 6.47(m, 1H), 6.69(m, 1H), 7.59(d, 1H), 8.15 (d, 1H), 8.49 (m, 1H), 8.75 (m, 1H), 8.87 (m, 1H), 11.05 (s, 1H), 11.23 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值429.2；實測值430.2；Rt=1.041min。LCMS (ESI): [M+H] + m/z: calculated 429.2; found 430.2; Rt=1.041 min.

實例182. 5-(2-(2-(3,4-二氫-2H -苯并[b ][1,4 ]噁嗪-7-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物598及化合物605)之合成Example 182. 5-(2-(2-(3,4-Dihydro- 2H -benzo[ b ][ 1,4 ]oxazin-7-yl)-5-methylpiperidin-1-yl) Synthesis of -2-oxyacetamido)nicotinamide (Compound 598 and Compound 605)

Figure 110128222-A0202-12-1211-202
Figure 110128222-A0202-12-1211-202

步驟1：5-(2-(2-(3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(2-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5-methylpiperidin-1-yl) -2-Synthesis of oxyacetamido) nicotinamide

將7-(5-甲基-2-哌啶基)-3,4-二氫-2H -1,4-苯并噁嗪(0.68g，1.46mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(359.46mg，1.46mmol，HCl)、TEA(740.46mg，7.32mmol，1.02mL)混合於DMF(10mL)中，然後添加HATU(834.70mg，2.20mmol)。將所得混合物在25℃下攪拌13h。將混合物在減壓下蒸發，且使用HPLC(2-10min 50-60% MeOH/H2 0+NH3 ，30ml/min)純化，以獲得5-[[2-[(2S,5R )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(166.9mg，394.13μmol，26.93%產率)。7-(5-Methyl-2-piperidinyl)-3,4-dihydro- 2H -1,4-benzoxazine (0.68 g, 1.46 mmol), 2-[(5-aminocarboxylate (359.46 mg, 1.46 mmol, HCl), TEA (740.46 mg, 7.32 mmol, 1.02 mL) were mixed in DMF (10 mL), followed by the addition of HATU ( 834.70 mg, 2.20 mmol). The resulting mixture was stirred at 25 °C for 13 h. The mixture was evaporated under reduced pressure and purified using HPLC (2-10 min 50-60% MeOH/ H2O + NH3 , 30 ml/min) to obtain 5-[[2-[( 2S,5R )-2 -(3,4-Dihydro- 2H -1,4-benzoxazin-7-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide (166.9 mg, 394.13 μmol, 26.93% yield).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=1.029min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=1.029 min.

步驟2：掌性分離(化合物598 及化合物605 )Step 2: Chiral separation ( Compound 598 and Compound 605 )

藉由掌性層析(IA-II(250*20，5mkm)，己烷-IPA-MeOH，40-30-30，10ml/min)分離非鏡像異構物之混合物，以獲得5-[[2-[(2R,5S )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(58.99 mg，139.30μmol，35.34%產率)(RT=57.029)及5-[[2-[(2S,5R )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(48.14mg，113.68μmol，28.84%產率)(RT=32.475)。The mixture of diastereoisomers was separated by chiral chromatography (IA-II (250*20, 5mkm), hexane-IPA-MeOH, 40-30-30, 10ml/min) to obtain 5-[[ 2-[( 2R,5S )-2-(3,4-dihydro- 2H -1,4-benzoxazin-7-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (58.99 mg, 139.30 μmol, 35.34% yield) (RT=57.029) and 5-[[2-[( 2S,5R )-2-( 3,4-Dihydro- 2H -1,4-benzoxazin-7-yl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]pyridine-3 - Formamide (48.14 mg, 113.68 μmol, 28.84% yield) (RT=32.475).

化合物598 於分析條件下(管柱：IA，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為48.55min且化合物605 之保留時間為15.51min。The retention time of compound 598 under analytical conditions (column: IA, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 48.55 min and the retention time of compound 605 was 15.51 min.

化合物598：保留時間：48.55minCompound 598: retention time: 48.55min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.24-1.35(m,1H),1.65-1.78(m,1H),1.78-1.90(m,1H),1.91-2.06(m,1H),2.06-2.14(m,1H),2.77-3.26(m,3H),3.36-3.97(m,1H),4.05-4.17(m,2H),4.92-5.74(m,2H),6.49-6.60(m,2H),6.60-6.65(m,1H),7.47-7.63(m,1H),8.08-8.21(m,1H),8.42-8.51(m,1H),8.70-8.80(m,1H),8.81-8.95(m,1H),10.84-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.03(m,3H), 1.24-1.35(m,1H), 1.65-1.78(m,1H), 1.78-1.90(m,1H) ,1.91-2.06(m,1H),2.06-2.14(m,1H),2.77-3.26(m,3H),3.36-3.97(m,1H),4.05-4.17(m,2H),4.92-5.74( m,2H),6.49-6.60(m,2H),6.60-6.65(m,1H),7.47-7.63(m,1H),8.08-8.21(m,1H),8.42-8.51(m,1H), 8.70-8.80 (m, 1H), 8.81-8.95 (m, 1H), 10.84-11.39 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=2.289min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=2.289 min.

化合物605：保留時間：15.51minCompound 605: retention time: 15.51min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.03(m,3H),1.24-1.37(m,1H),1.65-1.76(m,1H),1.79-1.90(m,1H),1.93-2.06(m,1H),2.06-2.15(m,1H),2.75-3.24(m,3H),3.37-3.98(m,1H),4.05-4.12(m,2H),4.86-5.77(m,2H),6.49-6.60(m,2H),6.60-6.64(m,1H),7.45-7.65(m,1H),8.07-8.21(m,1H),8.38-8.51(m,1H),8.68-8.79(m,1H),8.83-8.93(m,1H),10.94-11.31(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.03(m,3H), 1.24-1.37(m,1H), 1.65-1.76(m,1H), 1.79-1.90(m,1H) ,1.93-2.06(m,1H),2.06-2.15(m,1H),2.75-3.24(m,3H),3.37-3.98(m,1H),4.05-4.12(m,2H),4.86-5.77( m,2H),6.49-6.60(m,2H),6.60-6.64(m,1H),7.45-7.65(m,1H),8.07-8.21(m,1H),8.38-8.51(m,1H), 8.68-8.79 (m, 1H), 8.83-8.93 (m, 1H), 10.94-11.31 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=2.290min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=2.290 min.

實例183. 5-(2-(2-(3,4-二氫-2H -苯并[b ][1,4 ]噁嗪-7-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物869)之合成Example 183. 5-(2-(2-(3,4-Dihydro- 2H -benzo[ b ][ 1,4 ]oxazin-7-yl)-5-methylpiperidin-1-yl) Synthesis of -2-oxyacetamido)-2-methoxynicotinamide (compound 869)

Figure 110128222-A0202-12-1213-203
Figure 110128222-A0202-12-1213-203

將7-[(2R,5S )-5-甲基-2-哌啶基]-3,4-二氫-2H -1,4-苯并噁嗪(0.2g，860.88μmol)、TEA(871.12mg，8.61mmol，1.20mL)及2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(205.91mg，860.88μmol)溶解於DMF(8.5mL)中且一次性添加HATU(491.00mg，1.29mmol)，將所得混合物在20℃下攪拌3h。將反應混合物倒入到水中且將水相用EtOAc萃取(3次)，然後將經合併之有機相用鹽水洗滌(3次)，經Na2 SO4 乾燥且在真空下濃縮。藉由反相HPLC(2-10min 10-25% MeCN/H2 O 30ml/min(裝載泵4ml MeCN)；管柱：SunFire 100*19mm,5毫米)純化粗產物，以得到呈白色固體之5-[[2-[(2R,5S )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.052g，114.67μmol，13.32%產率)。該反應為成功的。分離呈白色固體之所要產物5-[[2-[(2R,5S )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.052g，114.67μmol，13.32%產率)。7-[( 2R,5S )-5-methyl-2-piperidinyl]-3,4-dihydro- 2H -1,4-benzoxazine (0.2 g, 860.88 μmol), TEA (871.12 mg, 8.61 mmol, 1.20 mL) and 2-[(5-aminocarbamoyl-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (205.91 mg, 860.88 μmol) were dissolved in To DMF (8.5 mL) and HATU (491.00 mg, 1.29 mmol) was added in one portion, the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (3 times), then the combined organic phases were washed with brine (3 times), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by reverse phase HPLC (2-10 min 10-25% MeCN/ H2O 30 ml/min (loading pump 4 ml MeCN); column: SunFire 100*19 mm, 5 mm) to give 5 as a white solid -[[2-[( 2R,5S )-2-(3,4-dihydro- 2H -1,4-benzoxazin-7-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (0.052 g, 114.67 μmol, 13.32% yield). The reaction was successful. The desired product 5-[[2-[( 2R,5S )-2-(3,4-dihydro- 2H -1,4-benzoxazin-7-yl)-5-methyl was isolated as a white solid -1-Piperidinyl]-2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (0.052 g, 114.67 μmol, 13.32% yield).

化合物869： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94-1.03(m,3H),1.25-1.34(m,1H),1.62-1.75(m,1H),1.77-1.88(m,1H),1.90-2.04(m,1H),2.06-2.13(m,1H),2.74-3.20(m,1H),3.21-3.25(m,2H),3.36-3.40(m,1H),3.90-3.95(m,3H),4.05-4.13(m,2H),4.91-5.50(m,1H),5.69(s,1H),6.48-6.68(m,3H),7.66-7.79(m,2H),8.39-8.47(m,1H),8.48-8.60(m,1H),10.75-11.21(m,1H)。 Compound 869: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.94-1.03 (m, 3H), 1.25-1.34 (m, 1H), 1.62-1.75 (m, 1H), 1.77-1.88 (m ,1H),1.90-2.04(m,1H),2.06-2.13(m,1H),2.74-3.20(m,1H),3.21-3.25(m,2H),3.36-3.40(m,1H),3.90 -3.95(m,3H),4.05-4.13(m,2H),4.91-5.50(m,1H),5.69(s,1H),6.48-6.68(m,3H),7.66-7.79(m,2H) , 8.39-8.47 (m, 1H), 8.48-8.60 (m, 1H), 10.75-11.21 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.129min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.129 min.

實例184. 5-(2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺Example 184. 5-(2-(5-Methyl-2-(1-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxyacetamide 基)菸鹼醯胺(化合物741及化合物740)之合成Synthesis of base) nicotinamide (compound 741 and compound 740)

Figure 110128222-A0202-12-1214-204
Figure 110128222-A0202-12-1214-204

步驟1：5-(2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(1-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinum Synthesis of Alkaline Amide

將5-[(2R,5S )-5-甲基-2-哌啶基]異吲哚啉-1-酮(200.00mg，868.41μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(269.51mg，868.41μmol)、HATU(363.22mg，955.26μmol)及TEA(87.87mg，868.41μmol，121.04μL)混合於DMSO(4mL)中且在20℃下攪拌3h。使反應混合物經歷HPLC(2-10min 0-65% MeCN/水30ml/min(裝載泵4ml MeCN)管柱：YMC-ACTUS TRIART C18 100*20 5微米)，以得到5-[[2-[(2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(190mg，450.83μmol，51.91%產率)。5-[( 2R,5S )-5-methyl-2-piperidinyl]isoindolin-1-one (200.00 mg, 868.41 μmol), 2-[(5-aminocarbamoyl-3- Pyridyl)amino]-2-oxoacetic acid (269.51 mg, 868.41 μmol), HATU (363.22 mg, 955.26 μmol) and TEA (87.87 mg, 868.41 μmol, 121.04 μL) were mixed in DMSO (4 mL) and in Stir at 20°C for 3h. The reaction mixture was subjected to HPLC (2-10 min 0-65% MeCN/water 30 ml/min (loading pump 4 ml MeCN) column: YMC-ACTUS TRIART C18 100*20 5 microns) to give 5-[[2-[( 2R,5S )-5-methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 - Formamide (190 mg, 450.83 μmol, 51.91% yield).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.884min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.884 min.

步驟2：掌性分離(化合物741 及化合物740 )Step 2: Chiral separation ( compound 741 and compound 740 )

藉由掌性HPLC(AD(250*30，20mkm)，CO2-MeOH，55-45，90ml/min補充流速-30ml/min)將外消旋 -5-(2-((2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(190mg，450.83mmol)分成鏡像異構物。化合物741 於分析條件下(管柱：AD-H，CO2 -MeOH，50-50，2ml/min為流動相) 之保留時間為14.43min且化合物740 之保留時間為10.20min。 Racemic -5-(2-(( 2R,5S )- 5-Methyl-2-(1-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (190 mg, 450.83 mmol) Divided into mirror isomers. The retention time of compound 741 under analytical conditions (column: AD-H, CO 2 -MeOH, 50-50, 2 ml/min as mobile phase) was 14.43 min and the retention time of compound 740 was 10.20 min.

化合物741：保留時間：14.43minCompound 741: retention time: 14.43min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.35(m,1H),1.68(m,1H),1.89(m,1H),2.07(m,1H),2.20(m,1H),2.97(m,1H),3.69(m,1H),4.35(m,2H),5.46(m,1H),7.44(m,1H),7.53(m,1H),7.59(m,1H),7.67(m,1H),8.15(m,1H),8.48(m,2H),8.75(m,1H),8.87(m,1H),11.23(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.35(m, 1H), 1.68(m, 1H), 1.89(m, 1H), 2.07(m, 1H), 2.20(m, 1H), 2.97(m, 1H), 3.69(m, 1H), 4.35(m, 2H), 5.46(m, 1H), 7.44(m, 1H), 7.53(m, 1H), 7.59 (m, 1H), 7.67 (m, 1H), 8.15 (m, 1H), 8.48 (m, 2H), 8.75 (m, 1H), 8.87 (m, 1H), 11.23 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.981min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.981 min.

化合物740：保留時間：10.20minCompound 740: retention time: 10.20min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.35(m,1H),1.68(m,1H),1.96(m,2H),2.23(m,1H),2.83(m,1H),3.78(m,1H),4.35(m,2H),5.46(m,1H),7.57(m,4H),8.14(m,1H),8.48(m,2H),8.80(m,2H),11.23(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.35(m, 1H), 1.68(m, 1H), 1.96(m, 2H), 2.23(m, 1H), 2.83(m, 1H), 3.78(m, 1H), 4.35(m, 2H), 5.46(m, 1H), 7.57(m, 4H), 8.14(m, 1H), 8.48(m, 2H), 8.80 (m, 2H), 11.23 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=1.982min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=1.982 min.

實例185. 2-甲氧基-5-(2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物749及化合物750)之合成Example 185. 2-Methoxy-5-(2-(5-methyl-2-(1-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxygen Synthesis of acetamido)nicotinamide (compound 749 and compound 750)

Figure 110128222-A0202-12-1215-205
Figure 110128222-A0202-12-1215-205

步驟1：2-甲氧基-5-(2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 2-Methoxy-5-(2-(5-methyl-2-(1-oxyisoindolin-5-yl)piperidin-1-yl)-2-pentoxy Synthesis of Acetamino)nicotinamide

將5-[(2R,5S )-5-甲基-2-哌啶基]異吲哚啉-1-酮(200.00mg，868.41μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(295.59mg，868.41μmol)、HATU(363.22mg，955.26μmol)及TEA(87.87mg，868.41μmol，121.04μL)混合於DMSO(4mL)中且在20℃下攪拌3h。使反應混合物經歷HPLC(2-10min 45-60%水/MeOH+NH3 (裝載泵4ml MeOH+NH3 )管柱：TRIART 100*20 5微 米)。獲得2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(170mg，376.54μmol，43.36%產率)。5-[( 2R,5S )-5-methyl-2-piperidinyl]isoindolin-1-one (200.00 mg, 868.41 μmol), 2-[(5-aminocarbamoyl-6- Methoxy-3-pyridyl)amino]-2-oxoacetic acid (295.59 mg, 868.41 μmol), HATU (363.22 mg, 955.26 μmol) and TEA (87.87 mg, 868.41 μmol, 121.04 μL) were mixed in DMSO (4 mL) and stirred at 20 °C for 3 h. The reaction mixture was subjected to HPLC (2-10 min 45-60% water/MeOH+ NH3 (loading pump 4 ml MeOH+ NH3 ) column: TRIART 100*20 5 microns). 2-Methoxy-5-[[2-[( 2R,5S )-5-methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl]- 2-Pendant oxyacetoxy]amino]pyridine-3-carboxamide (170 mg, 376.54 μmol, 43.36% yield).

LCMS(ESI)：[M]+ m/z：計算值451.2；實測值452.2；Rt=2.251min。LCMS (ESI): [M] + m/z: calculated 451.2; found 452.2; Rt=2.251 min.

步驟2：掌性分離(化合物749 及化合物750 )Step 2: Chiral separation ( compound 749 and compound 750 )

藉由掌性HPLC(IA，IPA-MeOH，50-50，12ml/min)將外消旋 -2-甲氧基-5-(2-((2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(170mg，376.54mmol)分成鏡像異構物。 Racemic -2-methoxy-5-(2-(( 2R,5S )-5-methyl-2- (1-Pendant oxyisoindolin-5-yl)piperidin-1-yl)-2-pendantoxyacetamido)nicotinamide (170 mg, 376.54 mmol) separated into enantiomers.

化合物749 於分析條件下(管柱：IA，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為20.24min且化合物750 之保留時間為37.82min。The retention time of compound 749 under analytical conditions (column: IA, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 20.24 min and the retention time of compound 750 was 37.82 min.

化合物749：保留時間：20.24minCompound 749: retention time: 20.24min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.04(m,3H),1.26-1.41(m,1H),1.59-1.74(m,1H),1.81-1.94(m,1H),2.04-2.19(m,1H),2.19-2.32(m,1H),2.79-3.27(m,1H),3.47-3.56(m,0.6H),3.89-3.98(m,3H),4.00-4.06(m,0.4H),4.31-4.41(m,2H),5.24-5.70(m,1H),7.39-7.47(m,1H),7.49-7.56(m,1H),7.62-7.68(m,1H),7.68-7.78(m,2H),8.41-8.58(m,3H),10.87-11.15(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.04(m,3H), 1.26-1.41(m,1H), 1.59-1.74(m,1H), 1.81-1.94(m,1H) ,2.04-2.19(m,1H),2.19-2.32(m,1H),2.79-3.27(m,1H),3.47-3.56(m,0.6H),3.89-3.98(m,3H),4.00-4.06 (m,0.4H),4.31-4.41(m,2H),5.24-5.70(m,1H),7.39-7.47(m,1H),7.49-7.56(m,1H),7.62-7.68(m,1H) ), 7.68-7.78(m, 2H), 8.41-8.58(m, 3H), 10.87-11.15(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值451.2；實測值452.2；Rt=2.124min。LCMS (ESI): [M] + m/z: calculated 451.2; found 452.2; Rt=2.124 min.

化合物750：保留時間：37.82minCompound 750: retention time: 37.82min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.07(m,3H),1.30-1.42(m,1H),1.61-1.71(m,1H),1.82-1.95(m,1H),2.02-2.18(m,1H),2.20-2.31(m,1H),2.78-3.26(m,1H),3.46-3.56(m,0.7H),3.87-3.98(m,3H),4.01-4.05(m,0.3H),4.28-4.42(m,2H),5.25-5.71(m,1H),7.39-7.47(m,1H),7.49-7.55(m,1H),7.62-7.67(m,1H),7.68-7.79(m,2H),8.40-8.60(m,3H),11.01(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.07(m,3H), 1.30-1.42(m,1H), 1.61-1.71(m,1H), 1.82-1.95(m,1H) ,2.02-2.18(m,1H),2.20-2.31(m,1H),2.78-3.26(m,1H),3.46-3.56(m,0.7H),3.87-3.98(m,3H),4.01-4.05 (m,0.3H),4.28-4.42(m,2H),5.25-5.71(m,1H),7.39-7.47(m,1H),7.49-7.55(m,1H),7.62-7.67(m,1H) ), 7.68-7.79 (m, 2H), 8.40-8.60 (m, 3H), 11.01 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值451.2；實測值452.2；Rt=2.134min。LCMS (ESI): [M] + m/z: calculated 451.2; found 452.2; Rt=2.134 min.

實例186.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌Example 186. N- (6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1-oxyisoindolin-5-yl)piperidine 啶-1-基)-2-側氧基乙醯胺(化合物696及化合物699)之合成Synthesis of pyridin-1-yl)-2-oxoacetamide (Compound 696 and Compound 699)

Figure 110128222-A0202-12-1217-206
Figure 110128222-A0202-12-1217-206

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1-oxyisoindolin-5-yl)piperidine- Synthesis of 1-yl)-2-oxyacetamide

將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(472.35mg，2.26mmol)及TEA(1.76g，17.37mmol，2.42mL)溶解於DMF(12mL)中且冷卻至0℃，添加HATU(990.59mg，2.61mmol)且將混合物在0℃下攪拌15min。添加5-[(2S,5R)-5-甲基-2-哌啶基]異吲哚啉-1-酮(0.4g，1.74mmol)且將混合物升溫至室溫且攪拌3h。添加乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(2-10min 60-80% MeOH/H2 O 30ml/min(裝載泵4ml MeOH)管柱：SunFire 100*19mm，5微米)進行純化，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.049g，116.25μmol，6.69%產率)。2-[(6-Amino-5-ethyl-3-pyridinyl)amino]-2-oxoacetic acid (472.35 mg, 2.26 mmol) and TEA (1.76 g, 17.37 mmol, 2.42 mL) were dissolved In DMF (12 mL) and cooled to 0 °C, HATU (990.59 mg, 2.61 mmol) was added and the mixture was stirred at 0 °C for 15 min. 5-[(2S,5R)-5-methyl-2-piperidinyl]isoindolin-1-one (0.4 g, 1.74 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. Ethyl acetate was added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product, which was obtained by HPLC (2-10 min 60-80% MeOH/H 2 O 30 ml/min (load pump 4 ml) MeOH) column: SunFire 100*19mm, 5 microns) was purified to give N- (6-amino-5-ethyl-3-pyridinyl)-2-[( 2S,5R )-5-methyl - 2-(1-Pendant oxyisoindolin-5-yl)-1-piperidinyl]-2-pendant oxyacetamide (0.049 g, 116.25 μmol, 6.69% yield).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=0.967min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=0.967 min.

步驟2：掌性分離(化合物696 及化合物699 )Step 2: Chiral separation ( Compound 696 and Compound 699 )

使用管柱：Chiralpak IB(250*30mm，5mkm)；流動相：CO2 -MeOH 70-30流速：80mL/min進行掌性分離，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.016g，37.96μmol，32.65%產率)及N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(15.7mg，37.25μmol，32.04%產率)。Chiralpak IB (250*30mm, 5mkm) using column: mobile phase: CO2 -MeOH 70-30 flow rate: 80mL/min for chiral separation to give N- (6-amino-5-ethyl-3 -Pyridinyl)-2-[( 2S,5R )-5-methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyethyl Amide (0.016 g, 37.96 μmol, 32.65% yield) and N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2- (1-Pendant oxyisoindolin-5-yl)-1-piperidinyl]-2-pendant oxyacetamide (15.7 mg, 37.25 μmol, 32.04% yield).

化合物699 於分析條件下(管柱：IB，以CO2 -MeOH，70-30，2ml/min為流動相) 之保留時間為28.36min且化合物696 之保留時間為14.52min。The retention time of compound 699 under analytical conditions (column: IB, with CO 2 -MeOH, 70-30, 2 ml/min as mobile phase) was 28.36 min and the retention time of compound 696 was 14.52 min.

化合物699：保留時間：28.36minCompound 699: retention time: 28.36min

1 HNMR(600MHz,DMSO-d 6 )δ(ppm)1.06(m,6H),1.33(m,1H),1.65(m,1H),1.87(m,1H),2.06(m,1H),2.23(m,1H),2.36(m,1H),2.40(m,1H),2.77(m,1H),3.76(m,1H),4.35(m,2H),5.52(m,3H),7.46(m,3H),7.66(m,1H),8.01(m,1H),8.50(s,1H),10.50(m,1H)。 1 HNMR (600MHz, DMSO- d 6 )δ(ppm) 1.06(m, 6H), 1.33(m, 1H), 1.65(m, 1H), 1.87(m, 1H), 2.06(m, 1H), 2.23 (m,1H),2.36(m,1H),2.40(m,1H),2.77(m,1H),3.76(m,1H),4.35(m,2H),5.52(m,3H),7.46( m, 3H), 7.66 (m, 1H), 8.01 (m, 1H), 8.50 (s, 1H), 10.50 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=0.859min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=0.859 min.

化合物696：保留時間：14.52minCompound 696: retention time: 14.52min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.05(m,6H),1.34(m,1H),1.65(m,1H),1.87(m,1H),2.06(m,1H),2.24(m,1H),2.36(m,2H),2.78(m,1H),3.76(m,1H),4.35(m,2H),5.52(m,3H),7.46(m,3H),7.65(m,1H),8.02(m,1H),8.51(s,1H),10.51(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.05(m, 6H), 1.34(m, 1H), 1.65(m, 1H), 1.87(m, 1H), 2.06(m, 1H), 2.24(m,1H),2.36(m,2H),2.78(m,1H),3.76(m,1H),4.35(m,2H),5.52(m,3H),7.46(m,3H),7.65 (m, 1H), 8.02 (m, 1H), 8.51 (s, 1H), 10.51 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=0.864min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=0.864 min.

實例187. 5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物821及化合物817)之合成Example 187. 5-(2-(5-Methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of Amines (Compound 821 and Compound 817)

Figure 110128222-A0202-12-1218-207
Figure 110128222-A0202-12-1218-207

步驟1：5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of Amines

將DIPEA(331.50mg，2.56mmol，446.77μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.18g，732.84μmol，HCl)及5-[4-(5-甲基-2-哌啶基)苯基]噻唑(189.35mg，732.84μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(306.51mg，806.12μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN為溶析液混合物)，以得到5-[[2-[5-甲基-2-(4-噻唑-5-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.18g，400.42μmol，54.64%產率)。DIPEA (331.50 mg, 2.56 mmol, 446.77 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (0.18 g, 732.84 μmol, HCl) and 5-[4-(5-methyl-2-piperidinyl)phenyl]thiazole (189.35 mg, 732.84 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (306.51 mg, 806.12 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN as eluent mixture) to give 5-[[2-[5-methyl-2-(4-thiazole-5- (0.18 g, 400.42 μmol, 54.64% yield).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=2.576min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=2.576 min.

步驟6：掌性分離(化合物817 及化合物821 )Step 6: Chiral separation ( compound 817 and compound 821 )

藉由掌性HPLC(IC-II(250*20，5mkm)，IPA-MeOH，50-50，10ml/min)將5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(185mg，411.55mmol)分成鏡像異構物。5-(2-(5-Methyl-2-(4-(thiazole-5) was purified by chiral HPLC (IC-II (250*20, 5mkm), IPA-MeOH, 50-50, 10ml/min). -yl)phenyl)piperidin-1-yl)-2-oxoacetamido)nicotinamide (185 mg, 411.55 mmol) separated into enantiomers.

化合物817 於分析條件下(管柱：IC，以CO2 -MeOH，50-50，2ml/min為流動相)之保留時間為25.94min且化合物821 之保留時間為56.45min。The retention time of compound 817 under analytical conditions (column: IC, with CO2-MeOH, 50-50, 2 ml/min as mobile phase) was 25.94 min and that of compound 821 was 56.45 min.

化合物817：保留時間：25.94minCompound 817: retention time: 25.94min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.32-1.41(m,1H),1.63-1.73(m,1H),1.85-1.96(m,1H),2.04-2.17(m,1H),2.20-2.30(m,1H),2.77-3.26(m,1H),3.47-4.08(m,1H),5.15-5.69(m,1H),7.36-7.44(m,2H),7.55-7.63(m,1H),7.66-7.73(m,2H),8.10-8.20(m,1H),8.28-8.33(m,1H),8.45-8.52(m,1H),8.71-8.81(m,1H),8.82-8.93(m,1H),9.04-9.09(m,1H),11.21-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.32-1.41(m,1H), 1.63-1.73(m,1H), 1.85-1.96(m,1H) ,2.04-2.17(m,1H),2.20-2.30(m,1H),2.77-3.26(m,1H),3.47-4.08(m,1H),5.15-5.69(m,1H),7.36-7.44( m,2H),7.55-7.63(m,1H),7.66-7.73(m,2H),8.10-8.20(m,1H),8.28-8.33(m,1H),8.45-8.52(m,1H), 8.71-8.81 (m, 1H), 8.82-8.93 (m, 1H), 9.04-9.09 (m, 1H), 11.21-11.34 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=2.573min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=2.573 min.

化合物821：保留時間：56.45minCompound 821: retention time: 56.45min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.33-1.40(m,1H),1.64 -1.72(m,1H),1.84-1.94(m,1H),2.03-2.15(m,1H),2.22-2.32(m,1H),2.79-3.27(m,1H),3.47-4.08(m,1H),5.14-5.64(m,1H),7.35-7.45(m,2H),7.56-7.66(m,1H),7.66-7.77(m,2H),8.10-8.22(m,1H),8.25-8.35(m,1H),8.41-8.55(m,1H),8.71-8.81(m,1H),8.82-8.93(m,1H),9.02-9.11(m,1H),11.18-11.33(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.33-1.40(m,1H), 1.64-1.72(m,1H), 1.84-1.94(m,1H) ,2.03-2.15(m,1H),2.22-2.32(m,1H),2.79-3.27(m,1H),3.47-4.08(m,1H),5.14-5.64(m,1H),7.35-7.45( m,2H),7.56-7.66(m,1H),7.66-7.77(m,2H),8.10-8.22(m,1H),8.25-8.35(m,1H),8.41-8.55(m,1H), 8.71-8.81(m,1H), 8.82-8.93(m,1H), 9.02-9.11(m,1H), 11.18-11.33(m,1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=2.573min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=2.573 min.

實例188. 2-甲氧基-5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物830及化合物842)之合成Example 188. 2-Methoxy-5-(2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxoacetone Synthesis of amino)nicotinamide (compound 830 and compound 842)

Figure 110128222-A0202-12-1220-208
Figure 110128222-A0202-12-1220-208

步驟1：2-甲氧基-5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 2-Methoxy-5-(2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-pendoxetylacetone Synthesis of Amino)nicotinamide

將DIPEA(187.58mg，1.45mmol，252.80μL)添加到相應5-[4-(5-甲基-2-哌啶基)苯基]噻唑(0.15g，580.54μmol)及2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(138.86mg，580.54μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(242.81mg，638.59μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN為溶析液混合物)，以得到2-甲氧基-5-[[2-[5-甲基-2-(4-噻唑-5-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(187.1mg，390.16μmol，67.21%產率)。DIPEA (187.58 mg, 1.45 mmol, 252.80 μL) was added to the corresponding 5-[4-(5-methyl-2-piperidinyl)phenyl]thiazole (0.15 g, 580.54 μmol) and 2-[(5- A solution of aminocarbamoyl-6-methoxy-3-pyridinyl)amino]-2-pendoxoacetic acid (138.86 mg, 580.54 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (242.81 mg, 638.59 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN as eluent mixture) to give 2-methoxy-5-[[2-[5-methyl-2-( 4-Thiazol-5-ylphenyl)-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (187.1 mg, 390.16 μmol, 67.21% yield).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=2.929min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=2.929 min.

步驟2：掌性分離(化合物830 及化合物842 )Step 2: Chiral separation ( compound 830 and compound 842 )

藉由掌性HPLC(AS(250*20mm，5mkm)，CO2 -MeOH，55-45，50mL/min)將2-甲氧基-5-[[2-[5-甲基-2-(4-噻唑-5-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(187.1mg，390.16mmol)分成鏡像異構物。 2 -Methoxy-5-[[2-[5-methyl-2-( 4-Thiazol-5-ylphenyl)-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (187.1 mg, 390.16 mmol) separated into enantiomers.

化合物830 於分析條件下(管柱：AS-H，CO2 -MeOH，55-45，2ml/min為流動相)之保留時間為5.64min且化合物842 之保留時間為7.27min。The retention time of compound 830 under analytical conditions (column: AS-H, CO 2 -MeOH, 55-45, 2 ml/min as mobile phase) was 5.64 min and the retention time of compound 842 was 7.27 min.

化合物830：保留時間：5.64minCompound 830: retention time: 5.64min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.30-1.40(m,1H),1.63-1.71(m,1H),1.83-1.92(m,1H),2.03-2.15(m,1H),2.20-2.28(m,1H),2.77-3.27(m,1H),3.45-4.05(m,4H),5.15-5.62(m,1H),7.35-7.43(m,2H),7.65-7.72(m,3H),7.72-7.75(m,1H),8.26-8.33(m,1H),8.41-8.48(m,1H),8.48-8.58(m,1H),9.03-9.10(m,1H),10.98-11.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.30-1.40(m,1H), 1.63-1.71(m,1H), 1.83-1.92(m,1H) ,2.03-2.15(m,1H),2.20-2.28(m,1H),2.77-3.27(m,1H),3.45-4.05(m,4H),5.15-5.62(m,1H),7.35-7.43( m,2H),7.65-7.72(m,3H),7.72-7.75(m,1H),8.26-8.33(m,1H),8.41-8.48(m,1H),8.48-8.58(m,1H), 9.03-9.10 (m, 1H), 10.98-11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=1.299min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=1.299 min.

化合物842：保留時間：7.27minCompound 842: retention time: 7.27min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.04(m,3H),1.28-1.38(m,1H),1.59-1.72(m,1H),1.82-1.95(m,1H),2.00-2.15(m,1H),2.19-2.28(m,1H),2.76-3.26(m,1H),3.45-4.05(m,4H),5.15-5.63(m,1H),7.36-7.43(m,2H),7.65-7.76(m,4H),8.28-8.32(m,1H),8.40-8.48(m,1H),8.48-8.58(m,1H),9.03-9.08(m,1H),10.99-11.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.04(m,3H), 1.28-1.38(m,1H), 1.59-1.72(m,1H), 1.82-1.95(m,1H) ,2.00-2.15(m,1H),2.19-2.28(m,1H),2.76-3.26(m,1H),3.45-4.05(m,4H),5.15-5.63(m,1H),7.36-7.43( m,2H),7.65-7.76(m,4H),8.28-8.32(m,1H),8.40-8.48(m,1H),8.48-8.58(m,1H),9.03-9.08(m,1H), 10.99-11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=1.297min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=1.297 min.

實例189.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物827及化合物841)之合成Example 189. N- (6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidine-1- Synthesis of yl)-2-oxoacetamide (Compound 827 and Compound 841)

Figure 110128222-A0202-12-1222-209
Figure 110128222-A0202-12-1222-209

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidine-1- Synthesis of )-2-side oxyacetamide

將DIPEA(231.67mg，1.79mmol，312.23μL)添加到相應2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(0.15g，717.01μmol)及5-[4-(5-甲基-2-哌啶基)苯基]噻唑(185.26mg，717.01μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(299.89mg，788.71μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN為溶析液混合物)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(4-噻唑-5-基苯基)-1-哌啶基]-2-側氧基乙醯胺(140mg，311.41μmol，43.43%產率)。DIPEA (231.67 mg, 1.79 mmol, 312.23 μL) was added to the corresponding 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (0.15 g, 717.01 μmol ) and 5-[4-(5-methyl-2-piperidinyl)phenyl]thiazole (185.26 mg, 717.01 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (299.89 mg, 788.71 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN as eluent mixture) to give N- (6-amino-5-ethyl-3-pyridyl)-2- [5-Methyl-2-(4-thiazol-5-ylphenyl)-1-piperidinyl]-2-oxyacetamide (140 mg, 311.41 μmol, 43.43% yield).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=0.948min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=0.948 min.

步驟2：掌性分離(化合物841 及化合物827 )Step 2: Chiral separation ( compound 841 and compound 827 )

藉由掌性HPLC(OD-H(250*30mm，5mkm)，己烷-IPA-MeOH，75-15-15，28mL/min)將N -(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(4-噻唑-5-基苯基)-1-哌啶基]-2-側氧基乙醯胺(140mg，311.46mmol)分成鏡像異構物。 N- (6-amino-5-ethyl-3- Pyridyl)-2-[5-methyl-2-(4-thiazol-5-ylphenyl)-1-piperidinyl]-2-oxoacetamide (140 mg, 311.46 mmol) split into a mirror image structure.

化合物841 於分析條件下(管柱：IB，以CO2 -MeOH，70-30，2ml/min為流動相)之保留時間為17.44min且化合物827 之保留時間為13.86min。The retention time of compound 841 under analytical conditions (column: IB, with CO 2 -MeOH, 70-30, 2 ml/min as mobile phase) was 17.44 min and the retention time of compound 827 was 13.86 min.

化合物841：保留時間：17.44minCompound 841: retention time: 17.44min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.02(m,3H),1.04-1.13(m,3H),1.29-1.38(m,1H),1.59-1.71(m,1H),1.80-1.94(m,1H),1.97-2.14(m,1H),2.16-2.27 (m,1H),2.31-2.35(m,1H),2.38-2.41(m,1H),2.71-3.25(m,1H),3.42-4.06(m,1H),5.13-5.69(m,3H),7.32-7.51(m,3H),7.64-7.73(m,2H),7.97-8.09(m,1H),8.24-8.33(m,1H),9.04-9.79(m,1H),10.47-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.02(m,3H), 1.04-1.13(m,3H), 1.29-1.38(m,1H), 1.59-1.71(m,1H) ,1.80-1.94(m,1H),1.97-2.14(m,1H),2.16-2.27(m,1H),2.31-2.35(m,1H),2.38-2.41(m,1H),2.71-3.25( m,1H),3.42-4.06(m,1H),5.13-5.69(m,3H),7.32-7.51(m,3H),7.64-7.73(m,2H),7.97-8.09(m,1H), 8.24-8.33 (m, 1H), 9.04-9.79 (m, 1H), 10.47-10.57 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=1.082min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=1.082 min.

化合物827：保留時間：13.86minCompound 827: retention time: 13.86min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.02(m,3H),1.04-1.12(m,3H),1.26-1.40(m,1H),1.59-1.69(m,1H),1.81-1.92(m,1H),1.98-2.14(m,1H),2.16-2.29(m,1H),2.29-2.35(m,1H),2.38-2.41(m,1H),2.69-3.26(m,1H),3.42-4.04(m,1H),5.10-5.68(m,3H),7.31-7.52(m,3H),7.61-7.73(m,2H),7.95-8.07(m,1H),8.24-8.34(m,1H),9.06(s,1H),10.45-10.55(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.02(m,3H), 1.04-1.12(m,3H), 1.26-1.40(m,1H), 1.59-1.69(m,1H) ,1.81-1.92(m,1H),1.98-2.14(m,1H),2.16-2.29(m,1H),2.29-2.35(m,1H),2.38-2.41(m,1H),2.69-3.26( m,1H),3.42-4.04(m,1H),5.10-5.68(m,3H),7.31-7.52(m,3H),7.61-7.73(m,2H),7.95-8.07(m,1H), 8.24-8.34 (m, 1H), 9.06 (s, 1H), 10.45-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=1.088min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=1.088 min.

實例190. 乙酸4-(1-(2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)苯酯(化合物599及化合物604)之合成Example 190. Acetic Acid ) Synthesis of Phenyl Ester (Compound 599 and Compound 604)

Figure 110128222-A0202-12-1223-210
Figure 110128222-A0202-12-1223-210

步驟1：乙酸4-(1-(2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)苯酯之合成Step 1: Acetic acid 4-(1-(2-((5-aminocarboxypyridin-3-yl)amino)-2-oxyethanoyl)-5-methylpiperidin-2-yl ) Synthesis of Phenyl Ester

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(291.36mg，1.19mmol，HCl)及TEA(1.20g，11.86mmol，1.65mL)溶解於DMF(12mL)中且冷卻至0℃，添加HATU(676.55mg，1.78mmol)且將混合物在0℃下攪拌15min。添加乙酸[4-[(2S,5R )-5-甲基-2-哌啶基]苯]酯(0.32g，1.19mmol，HCl)且將混合物升溫至室溫且攪拌3h。添加10ml乙酸乙酯且將有機相用鹽水洗滌三次。將有機相 經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(2-10min 35-60% MeOH，30ml/min(裝載泵4ml MeOH)管柱：SunFire 100*19mm，5微米)進行純化，以得到乙酸[4-[(2S,5R )-1-[2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.101g，237.96μmol，20.06%產率)。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (291.36 mg, 1.19 mmol, HCl) and TEA (1.20 g, 11.86 mmol, 1.65 mL) were dissolved in In DMF (12 mL) and cooled to 0 °C, HATU (676.55 mg, 1.78 mmol) was added and the mixture was stirred at 0 °C for 15 min. [4-[( 2S,5R )-5-methyl-2-piperidinyl]phenyl]acetate (0.32 g, 1.19 mmol, HCl) was added and the mixture was warmed to room temperature and stirred for 3 h. 10 ml of ethyl acetate were added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product, which was obtained by HPLC (2-10 min 35-60% MeOH, 30 ml/min (load pump 4 ml MeOH) via tube Column: SunFire 100*19mm, 5 microns) was purified to give [4-[( 2S,5R )-1-[2-[(5-aminocarboxy-3-pyridinyl)amino]-2 acetate -Pendant oxyacetyl]-5-methyl-2-piperidinyl]phenyl]ester (0.101 g, 237.96 μmol, 20.06% yield).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=1.181min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=1.181 min.

步驟2：掌性分離(化合物604 及化合物599 )Step 2: Chiral separation ( Compound 604 and Compound 599 )

使用管柱：Chiralpak IB(250*20mm，5mkm)；流動相：己烷-IPA-MeOH 60-20-20；流速：13mL/min進行掌性分離，以得到乙酸[4-[(2S,5R )-1-[2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.051g，120.16μmol，51.00%產率)及乙酸[4-[(2R,5S )-1-[2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.048g，113.09μmol，48.00%產率)。Using column: Chiralpak IB (250*20mm, 5mkm); Mobile phase: Hexane-IPA-MeOH 60-20-20; Flow rate: 13 mL/min for chiral separation to give [4-[( 2S,5R acetic acid )-1-[2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl]phenyl]ester ( 0.051 g, 120.16 μmol, 51.00% yield) and [4-[( 2R,5S )-1-[2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetate Acetyl]-5-methyl-2-piperidinyl]phenyl]ester (0.048 g, 113.09 μmol, 48.00% yield).

化合物604 於分析條件下(管柱：IB，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為11.42min且化合物599 之保留時間為15.56min。The retention time of compound 604 under analytical conditions (column: IB, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 11.42 min and the retention time of compound 599 was 15.56 min.

化合物604：保留時間：11.42minCompound 604: retention time: 11.42min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.05(m,3H),1.29-1.39(m,1H),1.63-1.71(m,1H),1.83-1.94(m,1H),1.99-2.13(m,1H),2.13-2.23(m,1H),2.23-2.26(m,3H),2.72-3.23(m,1H),3.46-4.05(m,1H),5.13-5.60(m,1H),7.08-7.16(m,2H),7.30-7.41(m,2H),7.53-7.65(m,1H),8.09-8.20(m,1H),8.40-8.51(m,1H),8.67-8.80(m,1H),8.81-8.92(m,1H),11.17-11.30(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.05(m,3H), 1.29-1.39(m,1H), 1.63-1.71(m,1H), 1.83-1.94(m,1H) ,1.99-2.13(m,1H),2.13-2.23(m,1H),2.23-2.26(m,3H),2.72-3.23(m,1H),3.46-4.05(m,1H),5.13-5.60( m,1H),7.08-7.16(m,2H),7.30-7.41(m,2H),7.53-7.65(m,1H),8.09-8.20(m,1H),8.40-8.51(m,1H), 8.67-8.80 (m, 1H), 8.81-8.92 (m, 1H), 11.17-11.30 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=2.373min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=2.373 min.

化合物599：保留時間：15.56minCompound 599: retention time: 15.56min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.04(m,3H),1.25-1.41(m,1H),1.60-1.75(m,1H),1.79-1.97(m,1H),2.00-2.15(m,1H),2.15-2.23(m,1H),2.23-2.25 (m,3H),2.73-3.27(m,1H),3.45-4.06(m,1H),5.15-5.58(m,1H),7.10-7.16(m,2H),7.33-7.41(m,2H),7.53-7.65(m,1H),8.10-8.20(m,1H),8.39-8.50(m,1H),8.72-8.79(m,1H),8.83-8.91(m,1H),11.13-11.29(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.04(m,3H), 1.25-1.41(m,1H), 1.60-1.75(m,1H), 1.79-1.97(m,1H) ,2.00-2.15(m,1H),2.15-2.23(m,1H),2.23-2.25(m,3H),2.73-3.27(m,1H),3.45-4.06(m,1H),5.15-5.58( m,1H),7.10-7.16(m,2H),7.33-7.41(m,2H),7.53-7.65(m,1H),8.10-8.20(m,1H),8.39-8.50(m,1H), 8.72-8.79 (m, 1H), 8.83-8.91 (m, 1H), 11.13-11.29 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=2.372min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=2.372 min.

實例191. rel-5-[[2-[(2S,5R)-2-(7-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物663)及rel-5-[[2-[(2R,5S)-2-(7-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物680)之合成Example 191. rel-5-[[2-[(2S,5R)-2-(7-fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide (compound 663) and rel-5-[[2-[(2R,5S)-2-(7-fluoro-1H-indazole-5- Synthesis of )-5-methyl-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (Compound 680)

Figure 110128222-A0202-12-1225-211
Figure 110128222-A0202-12-1225-211

步驟1：外消旋-5-[[2-[2-(7-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-5-[[2-[2-(7-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetyl Synthesis of amino]pyridine-3-carboxamide

將7-氟-5-(5-甲基-2-哌啶基)-1H-吲唑(0.180g，771.59μmol)溶解於DMF(6mL)中且添加三乙胺(780.77mg，7.72mmol，1.08mL)，隨後添加2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(159.42mg，649.07μmol，HCl)。然後逐滴添加HATU(440.07mg，1.16mmol)且將反應混合物攪拌隔夜。在真空中濃縮反應混合物且藉由HPLC(2-10min 50-60%甲醇/H2 O 30mL/min(裝載泵4mL甲醇)管柱：SunFire 100*19mm，5微米)純化殘餘物，以獲得62.9mg。7-Fluoro-5-(5-methyl-2-piperidinyl)-1H-indazole (0.180 g, 771.59 μmol) was dissolved in DMF (6 mL) and triethylamine (780.77 mg, 7.72 mmol, 1.08 mL), followed by the addition of 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-pendoxoacetic acid (159.42 mg, 649.07 μmol, HCl). HATU (440.07 mg, 1.16 mmol) was then added dropwise and the reaction mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 50-60% methanol/ H2O 30 mL/min (loading pump 4 mL methanol) column: SunFire 100*19 mm, 5 microns) to obtain 62.9 mg.

LCMS(ESI)：[M+H]+ m/z：計算值424.1；實測值425.2；Rt=1.034min。LCMS (ESI): [M+H] + m/z: calculated 424.1; found 425.2; Rt=1.034 min.

步驟2：rel-5-[[2-[(2S,5R)-2-(7-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物663 )及rel-5-[[2-[(2R,5S)-2-(7-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲胺胺(化合物680 )之合成Step 2: rel-5-[[2-[(2S,5R)-2-(7-fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide ( compound 663 ) and rel-5-[[2-[(2R,5S)-2-(7-fluoro-1H-indazole-5- Synthesis of amine ( compound 680 )

對外消旋-5-[[2-[2-(7-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0629g，148.20μmol)進行掌性分離(管柱：Chiralpak AD-H(250*20mm，5mkm)；流動相：CO2-MeOH，50-50；流速：45mL/min；管柱溫度：40℃；波長：215nm。保留時間(異構物B)=6.48min)，以獲得化合物680 rel-5-[[2-[(2R,5S)-2-(7-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.022g，51.83μmol，34.98%產率)及Racemic-5-[[2-[2-(7-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (0.0629g, 148.20μmol) for chiral separation (column: Chiralpak AD-H (250*20mm, 5mkm); mobile phase: CO2-MeOH, 50-50; flow rate: 45mL /min; column temperature: 40°C; wavelength: 215nm. Retention time (isomer B)=6.48min) to obtain compound 680 rel-5-[[2-[(2R,5S)-2-(7 -Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.022 g, 51.83 μmol , 34.98% yield) and

化合物680： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.03(m,3H),1.35(m,1H),1.74(m,1H),1.88(m,1H),2.11(m,1H),2.27(m,1H),2.96(m,1H),3.75(m,1H),5.44(m,1H),7.17(m,1H),7.57(m,2H),8.14(m,2H),8.47(m,1H),8.75(m,1H),8.86(m,1H),11.26(m,1H),13.59(m,1H)。 Compound 680: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.03 (m, 3H), 1.35 (m, 1H), 1.74 (m, 1H), 1.88 (m, 1H), 2.11 (m, 1H), 2.27(m, 1H), 2.96(m, 1H), 3.75(m, 1H), 5.44(m, 1H), 7.17(m, 1H), 7.57(m, 2H), 8.14(m, 2H) ), 8.47(m, 1H), 8.75(m, 1H), 8.86(m, 1H), 11.26(m, 1H), 13.59(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.0；Rt=1.055min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.0; Rt=1.055 min.

化合物663： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.03(m,3H),1.35(m,1H),1.77(m,1H),1.89(m,1H),2.11(m,1H),2.27(m,1H),2.82(m,1H),3.75(m,1H),5.44(m,1H),7.17(m,1H),7.57(m,2H),8.12(m,1H),8.17(m,1H),8.47(m,1H),8.75(m,1H),8.86(m,1H),11.26(m,1H),13.59(m,1H)。 Compound 663: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.03 (m, 3H), 1.35 (m, 1H), 1.77 (m, 1H), 1.89 (m, 1H), 2.11 (m, 1H), 2.27(m, 1H), 2.82(m, 1H), 3.75(m, 1H), 5.44(m, 1H), 7.17(m, 1H), 7.57(m, 2H), 8.12(m, 1H) ), 8.17(m, 1H), 8.47(m, 1H), 8.75(m, 1H), 8.86(m, 1H), 11.26(m, 1H), 13.59(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=1.055min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=1.055 min.

實例192.外消旋 -5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基-1,3-二氫苯并咪唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物623)之合成Example 192. Racemic -5-[[2-[( 2R , 5S )-5-methyl-2-(2-oxy-1,3-dihydrobenzimidazol-5-yl) Synthesis of -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 623)

Figure 110128222-A0202-12-1227-212
Figure 110128222-A0202-12-1227-212

在室溫下，向外消旋 -5-[(2R ,5S )-5-甲基-2-哌啶基]-1,3-二氫苯并咪唑-2-酮(50.4mg，217.91μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(46.02mg，217.91μmol)及三乙胺(110.25mg，1.09mmol，151.86μL)於DMF(1mL)中之經攪拌之溶液中添加HATU(124.28mg，326.86μmol)。將所得反應混合物在同一溫度下攪拌12小時。12小時之後，在減壓下濃縮反應混合物。藉由HPLC純化所獲得之殘餘物，以得到呈白色固體之外消旋 -5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基-1,3-二氫苯并咪唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物623 ，23mg，54.45μmol，24.99%產率)。At room temperature, rac -5-[( 2R , 5S )-5-methyl-2-piperidinyl]-1,3-dihydrobenzimidazol-2-one (50.4 mg, 217.91 μmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (46.02 mg, 217.91 μmol) and triethylamine (110.25 mg, 1.09 mmol, 151.86 μL ) to a stirred solution in DMF (1 mL) was added HATU (124.28 mg, 326.86 μmol). The resulting reaction mixture was stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by HPLC to give rac -5-[[2-[( 2R ,5S)-5-methyl-2-(2- pendoxyloxy -1 as a white solid ,3-dihydrobenzimidazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 623 , 23mg, 54.45μmol, 24.99 %Yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.98-1.05(m,3H),1.28-1.38(m,1H),1.68-1.77(m,1H),1.81-1.94(m,1H),1.96-2.12(m,1H),2.13-2.24(m,1H),2.78-3.25(m,1H),3.43-4.04(m,1H),5.08-5.64(m,1H),6.83-6.96(m,3H),7.47-7.65(m,1H),8.04-8.19(m,1H),8.43-8.52(m,1H),8.69-8.81(m,1H),8.81-8.94(m,1H),10.53-10.62(m,2H),11.13-11.37(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.98-1.05 (m, 3H), 1.28-1.38 (m, 1H), 1.68-1.77 (m, 1H), 1.81-1.94 (m, 1H) ),1.96-2.12(m,1H),2.13-2.24(m,1H),2.78-3.25(m,1H),3.43-4.04(m,1H),5.08-5.64(m,1H),6.83-6.96 (m,3H),7.47-7.65(m,1H),8.04-8.19(m,1H),8.43-8.52(m,1H),8.69-8.81(m,1H),8.81-8.94(m,1H) , 10.53-10.62 (m, 2H), 11.13-11.37 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值422.2；實測值423.2；Rt=1.916min。LCMS (ESI): [M+H] + m/z: calculated 422.2; found 423.2; Rt=1.916 min.

實例193. 5-(2-(4-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物442)之合成Example 193. Synthesis of 5-(2-(4-Methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 442)

Figure 110128222-A0202-12-1228-213
Figure 110128222-A0202-12-1228-213

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(177.07mg，570.55μmol，Et3 N鹽)於DMF(2mL)中之經攪拌之溶液中添加HATU(216.94mg，570.55μmol)。將所得混合物在20℃下攪拌10分鐘。10分鐘之後，添加4-甲基-2-苯基哌啶(0.1g，570.55μmol)。將所得反應混合物在20℃下攪拌12小時。12小時之後，藉由HPLC(溶析液：0.5-6.5min,15-30%，水-乙腈；流速：30mL/min；裝載泵：4mL/min；乙腈；管柱：SunFire 19 x 100mm，5um)純化粗反應混合物，以獲得呈灰白色固體之5-(2-(4-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物442 ，0.0114g，31.11μmol，5.45%產率)。To a stirred solution of 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (177.07 mg, 570.55 μmol, Et3N salt) in DMF (2 mL) HATU (216.94 mg, 570.55 μmol) was added. The resulting mixture was stirred at 20°C for 10 minutes. After 10 minutes, 4-methyl-2-phenylpiperidine (0.1 g, 570.55 μmol) was added. The resulting reaction mixture was stirred at 20°C for 12 hours. After 12 hours, by HPLC (eluent: 0.5-6.5 min, 15-30%, water-acetonitrile; flow rate: 30 mL/min; loading pump: 4 mL/min; acetonitrile; column: SunFire 19 x 100 mm, 5 um ) purification of the crude reaction mixture to obtain 5-(2-(4-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide as an off-white solid ( Compound 442 , 0.0114 g, 31.11 μmol, 5.45% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.86(m,4H),1.27(m,1H),1.86(m,1H),2.07(m,2H),3.48(m,1H),5.18(m,1H),7.29(m,6H),7.62(m,1H),8.16(m,1H),8.52(m,1H),8.78(m,1H),8.92(m,1H),11.20(m,1H) 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.86 (m, 4H), 1.27 (m, 1H), 1.86 (m, 1H), 2.07 (m, 2H), 3.48 (m, 1H) ,5.18(m,1H),7.29(m,6H),7.62(m,1H),8.16(m,1H),8.52(m,1H),8.78(m,1H),8.92(m,1H), 11.20(m, 1H)

實例194. LCMS(ESI)：[M+H]Example 194. LCMS (ESI): [M+H] ++ m/z：計算值366.2；實測值367.0；Rt=2.951min。外消旋-5-[[2-[(2S ,4R )-4-乙基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物497)之合成m/z: Calculated value 366.2; Measured value 367.0; Rt=2.951min. Racemic-5-[[2-[( 2S , 4R )-4-ethyl-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine- Synthesis of 3-formamide (compound 497)

Figure 110128222-A0202-12-1228-214
Figure 110128222-A0202-12-1228-214

在輕微加熱下，在劇烈攪拌下，向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(331.48mg，1.58mmol，Et3 N鹽)、外消旋 -(2S ,4R )-4-乙基-2-苯基哌啶 (0.3g，1.58mmol)及DIPEA(614.47mg，4.75mmol，828.12μL)於DMF(6mL)中之正攪拌溶液中小批量添加HATU(723.12mg，1.90mmol)。完成之後，藉由反相HPLC(溶析液：0.5-6.5min，21%，水-乙腈；流速：30mL/min；裝載泵：4mL/min；管柱：SunFire 19 x 100mm，5um)純化粗反應混合物，以得到外消旋 -5-[[2-[(2S ,4R )-4-乙基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物497 ，0.35g，919.99μmol，58.05%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (331.48 mg, 1.58 mmol, Et3N salt), Rac- (2S,4R)-4-ethyl-2-phenylpiperidine (0.3 g, 1.58 mmol) and DIPEA ( 614.47 mg, 4.75 mmol, 828.12 μL) in DMF (6 mL) To the stirred solution was added HATU (723.12 mg, 1.90 mmol) in small portions. After completion, the crude was purified by reverse phase HPLC (eluent: 0.5-6.5 min, 21%, water-acetonitrile; flow rate: 30 mL/min; loading pump: 4 mL/min; column: SunFire 19 x 100 mm, 5 um) Reaction mixture to give rac -5-[[2-[( 2S , 4R )-4-ethyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide ( Compound 497 , 0.35 g, 919.99 μmol, 58.05% yield).

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)0.76-0.91(m,3H),1.14-1.42(m,3H),1.54-1.91(m,2H),1.97-2.19(m,2H),3.17-3.31(0.25H),3.42-3.56(m,0.75H),3.77-4.28(m,1H),5.11-5.18(m,1H),7.08-7.30(m,2H),7.30-7.39(m,3H),7.56-7.70(m,1H),8.08-8.24(m,1H),8.27-8.58(m,1H),8.63-8.99(m,2H),10.73-11.31(m,1H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 0.76-0.91 (m, 3H), 1.14-1.42 (m, 3H), 1.54-1.91 (m, 2H), 1.97-2.19 (m, 2H) ),3.17-3.31(0.25H),3.42-3.56(m,0.75H),3.77-4.28(m,1H),5.11-5.18(m,1H),7.08-7.30(m,2H),7.30-7.39 (m,3H),7.56-7.70(m,1H),8.08-8.24(m,1H),8.27-8.58(m,1H),8.63-8.99(m,2H),10.73-11.31(m,1H) .

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=3.236min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=3.236 min.

實例195.外消旋 -5-[[2-[(2R ,5S )-2-(3,5-二氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物560)之合成Example 195. Racemic -5-[[2-[( 2R , 5S )-2-(3,5-difluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl] Synthesis of -2-oxyacetyl]amino]pyridine-3-carboxamide (compound 560)

Figure 110128222-A0202-12-1229-215
Figure 110128222-A0202-12-1229-215

向外消旋 -2,6-二氟-4-[(2R ,5S )-5-甲基-2-哌啶基]苯酚(0.05g，220.02μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(55.22mg，264.03μmol，Et3 N鹽)及HATU(117.12mg，308.03μmol)於DMSO(1mL)中之經攪拌之溶液中添加DIPEA(56.87mg，440.04μmol，76.65μL)。將反應混合物在25℃下攪拌16小時。16小時之後，藉由反相HPLC(溶析液：2-10min，90%，MeOH/H2 O； 流速：30mL/min；裝載泵：4mL，MeOH；管柱：SunFireC18 100 x 19mm，5um)純化反應混合物，以獲得呈米色固體之外消旋 -5-[[2-[(2R ,5S )-2-(3,5-二氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物560 ，0.012g，28.68μmol，13.04%產率)。 Racemic -2,6-difluoro-4-[( 2R ,5S)-5-methyl-2-piperidinyl]phenol (0.05g, 220.02μmol ), 2-[(5-amine A stirred mixture of carboxyl-3-pyridyl)amino]-2-pendoxoacetic acid (55.22 mg, 264.03 μmol, Et3N salt) and HATU (117.12 mg, 308.03 μmol) in DMSO (1 mL) To the solution was added DIPEA (56.87 mg, 440.04 μmol, 76.65 μL). The reaction mixture was stirred at 25°C for 16 hours. After 16 hours, by reverse phase HPLC (eluent: 2-10 min, 90%, MeOH/ H2O ; flow rate: 30 mL/min; loading pump: 4 mL, MeOH; column: SunFire C18 100 x 19 mm, 5 um) The reaction mixture was purified to obtain rac -5-[[2-[( 2R , 5S )-2-(3,5-difluoro-4-hydroxyphenyl)-5-methyl as a beige solid -1-Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( Compound 560 , 0.012 g, 28.68 μmol, 13.04% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.97-1.02(m,3H),1.23-1.35(m,1H),1.58-1.74(m,1H),1.80-1.93(m,1H),1.94-2.10(m,1H),2.10-2.19(m,1H),2.75-3.24(m,1H),3.40-4.04(m,1H),4.98-5.53(m,1H),6.85-7.02(m,2H),7.51-7.65(m,1H),8.12-8.19(m,1H),8.40-8.52(m,1H),8.68-8.80(m,1H),8.80-8.91(m,1H),11.07-11.49(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.97-1.02 (m, 3H), 1.23-1.35 (m, 1H), 1.58-1.74 (m, 1H), 1.80-1.93 (m, 1H) ),1.94-2.10(m,1H),2.10-2.19(m,1H),2.75-3.24(m,1H),3.40-4.04(m,1H),4.98-5.53(m,1H),6.85-7.02 (m,2H),7.51-7.65(m,1H),8.12-8.19(m,1H),8.40-8.52(m,1H),8.68-8.80(m,1H),8.80-8.91(m,1H) , 11.07-11.49 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=2.057min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=2.057 min.

實例196. 外消旋-5-[[2-[(2S,5R)-5-甲基-2-(3-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物500)之合成Example 196. Racemic-5-[[2-[(2S,5R)-5-methyl-2-(3-methyl-1H-indazol-5-yl)-1-piperidinyl]- Synthesis of 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (Compound 500)

Figure 110128222-A0202-12-1230-216
Figure 110128222-A0202-12-1230-216

在室溫下，將HATU(411.20mg，1.08mmol)分批添加到2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(265.63mg，1.08mmol，HCl)、3-甲基-5-(5-甲基-2-哌啶基)-1H-吲唑(310mg，1.08mmol)及TEA(656.60mg，6.49mmol，904.40μL)於DMF(10mL)中之懸浮液中。將澄清溶液在25℃下攪拌32h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：SunFireC18 100x19mm 5um；以40-50% 0-6min水-甲醇+FA，流速：30ml/min為流動相)，以得到化合物500 外消旋-5-[[2-[(2S,5R)-5-甲基-2-(3-甲基-1H-吲唑-5-基)-1-哌啶基]-2-側氧基 乙醯基]胺基]吡啶-3-甲醯胺(150mg，356.75μmol，32.99%產率)。HATU (411.20 mg, 1.08 mmol) was added portionwise to 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-pendoxoacetic acid (265.63 mg, 1.08 mmol) at room temperature , HCl), 3-methyl-5-(5-methyl-2-piperidinyl)-1H-indazole (310 mg, 1.08 mmol) and TEA (656.60 mg, 6.49 mmol, 904.40 μL) in DMF (10 mL) ) in suspension. The clear solution was stirred at 25 °C for 32 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: SunFireC18 100x19mm 5um; with 40-50% 0-6min water-methanol+FA, flow rate: 30ml/min as mobile phase) to give compound 500 rac-5-[[ 2-[(2S,5R)-5-Methyl-2-(3-methyl-1H-indazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (150 mg, 356.75 μmol, 32.99% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.07(m,3H),1.30-1.42(m,1H),1.71-1.94(m,2H),1.95-2.25(m,1H),2.28-2.37(m,1H),2.42-2.46(m,3H),2.82-3.27(m,1H),3.36-4.08(m,1H),5.17-5.73(m,1H),7.24-7.36(m,1H),7.39-7.47(m,1H),7.53-7.67(m,2H),8.07-8.21(m,1H),8.42-8.54(m,1H),8.71-8.79(m,1H),8.79-8.95(m,1H),11.14-11.32(m,1H),12.54-12.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.01-1.07(m,3H), 1.30-1.42(m,1H), 1.71-1.94(m,2H), 1.95-2.25(m,1H), 2.28- 2.37(m,1H), 2.42-2.46(m,3H), 2.82-3.27(m,1H), 3.36-4.08(m,1H), 5.17-5.73(m,1H), 7.24-7.36(m,1H) ),7.39-7.47(m,1H),7.53-7.67(m,2H),8.07-8.21(m,1H),8.42-8.54(m,1H),8.71-8.79(m,1H),8.79-8.95 (m, 1H), 11.14-11.32 (m, 1H), 12.54-12.63 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=2.640minLCMS(ESI): [M+H] + m/z: Calculated 420.2; Measured 421.2; Rt=2.640min

實例197. rel-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物772)及rel-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物783)之合成Example 197. rel-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide (compound 772) and rel-5-[[2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl )-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 783) synthesis

Figure 110128222-A0202-12-1231-217
Figure 110128222-A0202-12-1231-217

步驟1：外消旋-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxygen Synthesis of Acetyl]amino]pyridine-3-carbamoylamine

向2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]噻唑(315.59mg，1.22mmol)、DIPEA(473.56mg，3.66mmol，638.22μL)及DIPEA(473.56mg，3.66mmol，638.22μL)於DMSO(4mL)中之經攪拌之溶液中添加HATU(557.30mg，1.47mmol)。將所得反應混合物在25℃下攪拌15h。完成之後，將反應混合物提交至反相HPLC， 以得到外消旋-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.12g，266.95μmol，21.86%產率)。To 2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]thiazole (315.59 mg, 1.22 mmol), DIPEA (473.56 mg, 3.66 mmol, 638.22 μL) and DIPEA ( To a stirred solution of 473.56 mg, 3.66 mmol, 638.22 μL) in DMSO (4 mL) was added HATU (557.30 mg, 1.47 mmol). The resulting reaction mixture was stirred at 25 °C for 15 h. After completion, the reaction mixture was submitted to reverse phase HPLC, to give racemic-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide (0.12 g, 266.95 μmol, 21.86% yield).

HPLC資料：2-10min 50-60% R1/H2 O，30ml/min(裝載泵4ml ACN)，管柱：HILIC，5微米HPLC profile: 2-10min 50-60% R1/ H2O , 30ml/min (loading pump 4ml ACN), column: HILIC, 5 micron

LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.2；Rt=1.171min。LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.2; Rt=1.171 min.

步驟2：rel-5-[[2-[((2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物772 )及rel-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物783 )之合成Step 2: rel-5-[[2-[((2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide ( Compound 772 ) and rel-5-[[2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylbenzene Synthesis of yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 783 )

將外消旋-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.12g，266.95μmol)提交至掌性分離，以得到呈白色固體之化合物772 rel-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.056g，124.58μmol，46.67%產率)及化合物783 rel-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.051g，113.45μmol，42.50%產率)。Racemic-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carboxamide (0.12 g, 266.95 μmol) was submitted to chiral isolation to give compound 772 rel-5-[[2-[(2R,5S)-5 as a white solid -Methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.056 g, 124.58 μmol , 46.67% yield) and compound 783 rel-5-[[[2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.051 g, 113.45 μmol, 42.50% yield).

層析資料：管柱：Chiralpak IC(250*20，5mkm)，流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min。24℃，波長：205nm、225nm，保留時間(異構物1(SR))化合物783 =35.4；保留時間(異構物2(RS)化合物772 )=109.9Chromatographic data: Column: Chiralpak IC (250*20, 5 mkm), mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12 mL/min. 24°C, wavelength: 205nm, 225nm, retention time (isomer 1(SR)) compound 783 = 35.4; retention time (isomer 2 (RS) compound 772 ) = 109.9

化合物772： RT(IB，己烷-IPA-MeOH，60-20-20，0.6mL/min)=24.123min。 Compound 772: RT (IB, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 24.123 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.05(m,3H),1.33-1.44(m,1H),1.65-1.73(m,1H),1.84-1.97(m,1H),2.07-2.18(m,1H),2.22-2.31(m,1H),2.81-3.27(m,1H),3.48-4.08(m,1H),5.20-5.66(m,1H),7.43-7.51(m,2H),7.55-7.64(m,1H),7.75-7.78(m,1H),7.87-7.93(m,1H),7.93-8.00(m,2H),8.11-8.22(m,1H),8.42-8.54(m,1H),8.70-8.81(m,1H),8.84-8.96(m,1H),11.09-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.99-1.05(m,3H), 1.33-1.44(m,1H), 1.65-1.73(m,1H), 1.84-1.97(m,1H), 2.07- 2.18(m, 1H), 2.22-2.31(m, 1H), 2.81-3.27(m, 1H), 3.48-4.08(m, 1H), 5.20-5.66(m, 1H), 7.43-7.51(m, 2H ),7.55-7.64(m,1H),7.75-7.78(m,1H),7.87-7.93(m,1H),7.93-8.00(m,2H),8.11-8.22(m,1H),8.42-8.54 (m, 1H), 8.70-8.81 (m, 1H), 8.84-8.96 (m, 1H), 11.09-11.34 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.2；Rt=2.715min。LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.2; Rt=2.715 min.

化合物783： RT(IB，己烷-IPA-MeOH，60-20-20，0.6mL/min)=20.994min。 Compound 783: RT (IB, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 20.994 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.06(m,3H),1.29-1.43(m,1H),1.59-1.76(m,1H),1.84-1.96(m,1H),2.04-2.19(m,1H),2.19-2.32(m,1H),2.78-3.27(m,1H),3.48-4.09(m,1H),5.20-5.69(m,1H),7.43-7.53(m,2H),7.54-7.64(m,1H),7.75-7.78(m,1H),7.89-7.92(m,1H),7.92-7.99(m,2H),8.08-8.21(m,1H),8.43-8.53(m,1H),8.69-8.81(m,1H),8.82-8.95(m,1H),11.15-11.43(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.99-1.06(m,3H), 1.29-1.43(m,1H), 1.59-1.76(m,1H), 1.84-1.96(m,1H), 2.04- 2.19(m, 1H), 2.19-2.32(m, 1H), 2.78-3.27(m, 1H), 3.48-4.09(m, 1H), 5.20-5.69(m, 1H), 7.43-7.53(m, 2H ),7.54-7.64(m,1H),7.75-7.78(m,1H),7.89-7.92(m,1H),7.92-7.99(m,2H),8.08-8.21(m,1H),8.43-8.53 (m, 1H), 8.69-8.81 (m, 1H), 8.82-8.95 (m, 1H), 11.15-11.43 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.2；Rt=2.734min。LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.2; Rt=2.734 min.

實例198. rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物811)及rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物799)之合成Example 198. rel-2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 811) and rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl- Synthesis of 2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 799)

Figure 110128222-A0202-12-1233-218
Figure 110128222-A0202-12-1233-218

步驟1：外消旋-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl Synthesis of ]-2-side oxyacetyl]amino]pyridine-3-carboxamide

向外消旋-2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]噻唑(0.15g，580.54μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(138.86mg，580.54 μmol，三乙胺)及DIPEA(150.06mg，1.16mmol，202.23μL)於DMSO(3mL)中之經攪拌之溶液中添加HATU(264.89mg，696.65μmol)。將所得反應混合物在25℃下攪拌14h。完成之後，將反應混合物提交至反相HPLC，以得到外消旋-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.085g，177.25μmol，30.53%產率)。Racemic-2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]thiazole (0.15 g, 580.54 μmol), 2-[(5-aminocarbamoyl -6-Methoxy-3-pyridyl)amino]-2-oxoacetic acid (138.86 mg, 580.54 μmol, triethylamine) and DIPEA (150.06 mg, 1.16 mmol, 202.23 μL) in DMSO (3 mL) was added HATU (264.89 mg, 696.65 μmol). The resulting reaction mixture was stirred at 25 °C for 14 h. After completion, the reaction mixture was submitted to reverse phase HPLC to give racemic-2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazole-2 -ylphenyl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.085 g, 177.25 μmol, 30.53% yield).

HPLC：2-10min 50-60% MeOH/H2 O；30mL/min(裝載泵4mL MeOH)，管柱：SunFire C18,5微米HPLC: 2-10 min 50-60% MeOH/ H2O ; 30 mL/min (loading pump 4 mL MeOH), column: SunFire C18, 5 micron

LCMS(ESI)：[M+H]+ m/z：計算值479.2；實測值480.2；Rt=1.316min。LCMS (ESI): [M+H] + m/z: calculated 479.2; found 480.2; Rt=1.316 min.

步驟2：rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物811 )及rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物799 )之合成Step 2: rel-2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 811 ) and rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl- Synthesis of 2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 799 )

將外消旋-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.085g，177.25μmol)提交至掌性分離，以得到化合物811 rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.034g，70.90μmol，40.00%產率)及化合物799 rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.034g，70.90μmol，40.00%產率)。Racemic-2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.085 g, 177.25 μmol) was submitted to chiral isolation to give compound 811 rel-2-methoxy-5-[[2- [(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (0.034 g, 70.90 μmol, 40.00% yield) and compound 799 rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(4-thiazole- 2-ylphenyl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.034 g, 70.90 μmol, 40.00% yield).

分離資料：Chiralpak IB 250*20，5-II己烷-IPA-MeOH，70-15-15，15mL/min；Rt1=23.43min；Rt2=30.94minIsolation data: Chiralpak IB 250*20, 5-II hexane-IPA-MeOH, 70-15-15, 15mL/min; Rt1=23.43min; Rt2=30.94min

化合物811： RT(IB，己烷-IPA-MeOH，50-25-25，0.6mL/min)=17.214min。 Compound 811: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 17.214 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.97-1.05(m,3H),1.31-1.41(m,1H),1.64-1.72(m,1H),1.83-1.94(m,1H),2.04-2.17(m,1H),2.19-2.29(m,1H),2.80-3.26(m,1H),3.46-3.54(m,0.6H),3.89-3.99(m,3H),4.01-4.07(m,0.4H),5.20-5.69 (m,1H),7.40-7.51(m,2H),7.66-7.76(m,2H),7.76-7.78(m,1H),7.88-7.92(m,1H),7.92-8.00(m,2H),8.36-8.68(m,2H),10.87-11.31(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.97-1.05 (m, 3H), 1.31-1.41 (m, 1H), 1.64-1.72 (m, 1H), 1.83-1.94 (m, 1H), 2.04 -2.17(m, 1H), 2.19-2.29(m, 1H), 2.80-3.26(m, 1H), 3.46-3.54(m, 0.6H), 3.89-3.99(m, 3H), 4.01-4.07(m ,0.4H),5.20-5.69(m,1H),7.40-7.51(m,2H),7.66-7.76(m,2H),7.76-7.78(m,1H),7.88-7.92(m,1H), 7.92-8.00 (m, 2H), 8.36-8.68 (m, 2H), 10.87-11.31 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值479.2；實測值480.2；Rt=2.983min。LCMS (ESI): [M+H] + m/z: calculated 479.2; found 480.2; Rt=2.983 min.

化合物799： RT(IB，己烷-IPA-MeOH，50-25-25，0.6mL/min)=13.684min。 Compound 799: RT (IB, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 13.684 min.

1 H NMR(dmso,600MHz)：δ(ppm)1.00-1.08(m,3H),1.31-1.43(m,1H),1.63-1.74(m,1H),1.81-1.94(m,1H),2.02-2.17(m,1H),2.20-2.29(m,1H),2.79-3.26(m,1H),3.47-3.54(m,0.6H),3.87-3.97(m,3H),4.01-4.06(m,0.4H),5.19-5.71(m,1H),7.41-7.50(m,2H),7.67-7.75(m,2H),7.76-7.79(m,1H),7.88-7.92(m,1H),7.92-8.00(m,2H),8.41-8.60(m,2H),10.87-11.23(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 1.00-1.08 (m, 3H), 1.31-1.43 (m, 1H), 1.63-1.74 (m, 1H), 1.81-1.94 (m, 1H), 2.02 -2.17(m, 1H), 2.20-2.29(m, 1H), 2.79-3.26(m, 1H), 3.47-3.54(m, 0.6H), 3.87-3.97(m, 3H), 4.01-4.06(m ,0.4H),5.19-5.71(m,1H),7.41-7.50(m,2H),7.67-7.75(m,2H),7.76-7.79(m,1H),7.88-7.92(m,1H), 7.92-8.00 (m, 2H), 8.41-8.60 (m, 2H), 10.87-11.23 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值479.2；實測值480.2；Rt=2.983min。LCMS (ESI): [M+H] + m/z: calculated 479.2; found 480.2; Rt=2.983 min.

實例199. 5-[[2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物880)及5-[[2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物937)之合成Example 199. 5-[[2-[(2R,5R)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2-pendant oxyethanoyl ]amino]pyridine-3-carboxamide (Compound 880) and 5-[[2-[(2R,5S)-5-methyl-2-(5-methyl-2-pyridyl)-1- Synthesis of piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 937)

Figure 110128222-A0202-12-1235-219
Figure 110128222-A0202-12-1235-219

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(195.72mg，630.64μmol，N(C2H5)3)、5-甲基-2-(5-甲基-2-哌啶基)吡啶(120mg，630.64μmol)、HATU(263.77mg，693.70μmol)及TEA(70.20mg，693.70μmol，96.69μL)混合於DMSO(2mL)中且在20℃下攪拌2h。使反應混合物經歷HPLC。2-[(5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (195.72 mg, 630.64 μmol, N(C2H5)3), 5-methyl-2-(5 -Methyl-2-piperidinyl)pyridine (120 mg, 630.64 μmol), HATU (263.77 mg, 693.70 μmol) and TEA (70.20 mg, 693.70 μmol, 96.69 μL) were mixed in DMSO (2 mL) and at 20°C Stir for 2h. The reaction mixture was subjected to HPLC.

HPLC資料：2-10min 20-45% MeCN/H2 O+TFA 30mL/min(裝載泵4mL MeCN)管柱：SunFire 100*19mm，5微米HPLC profile: 2-10min 20-45% MeCN/H 2 O+TFA 30mL/min (loading pump 4mL MeCN) Column: SunFire 100*19mm, 5 microns

獲得5-[[2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基] 吡啶-3-甲醯胺(96.7mg，253.52μmol，40.20%產率)(順式，淡棕色，固體)。藉由2D HNMR確認順式組態(化合物880 ，H2359620)5-[[2-[(2R,5R)-5-methyl-2-(5-methyl-2-pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amine was obtained yl]pyridine-3-carboxamide (96.7 mg, 253.52 μmol, 40.20% yield) (cis, light brown, solid). Confirmation of cis configuration by 2D HNMR ( compound 880 , H2359620)

獲得5-[[2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(44.7mg，117.19μmol，18.58%產率)(反式)。藉由2D HNMR確認反式組態(化合物937 ，H2359619)Obtained 5-[[2-[(2R,5S)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (44.7 mg, 117.19 μmol, 18.58% yield) (trans). Confirmation of trans configuration by 2D HNMR ( compound 937 , H2359619)

化合物880： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.76(dd,3H),1.03(m,1H),1.70(m,3H),2.27(m,3H),2.68(m,2H),3.96(dd,1H),5.40(m,1H),7.27(dd,1H),7.61(m,2H),8.14(d,1H),8.46(m,2H),8.75(dd,1H),8.86(dd,1H),11.21(m,1H)。 Compound 880: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 0.76 (dd, 3H), 1.03 (m, 1H), 1.70 (m, 3H), 2.27 (m, 3H), 2.68 (m, 2H), 3.96(dd, 1H), 5.40(m, 1H), 7.27(dd, 1H), 7.61(m, 2H), 8.14(d, 1H), 8.46(m, 2H), 8.75(dd, 1H) ), 8.86 (dd, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=1.971min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=1.971 min.

化合物937： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(t,3H),1.32(m,1H),1.61(m,1H),1.91(m,2H),2.27(m,3H),2.41(m,2H),2.86(m,1H),3.77(dd,1H),5.38(m,1H),7.29(dd,1H),7.59(m,1H),7.66(m,1H),8.14(m,1H),8.41(m,1H),8.47(m,1H),8.75(m,1H),8.87(m,1H),11.19(m,1H)。 Compound 937: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.02 (t, 3H), 1.32 (m, 1H), 1.61 (m, 1H), 1.91 (m, 2H), 2.27 (m, 3H), 2.41(m, 2H), 2.86(m, 1H), 3.77(dd, 1H), 5.38(m, 1H), 7.29(dd, 1H), 7.59(m, 1H), 7.66(m, 1H) ), 8.14(m, 1H), 8.41(m, 1H), 8.47(m, 1H), 8.75(m, 1H), 8.87(m, 1H), 11.19(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.0；Rt=1.831min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.0; Rt=1.831 min.

實例200. 2-甲氧基-5-[[2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物886)及2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物932)之合成Example 200. 2-Methoxy-5-[[2-[(2R,5R)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carbamide (compound 886) and 2-methoxy-5-[[2-[(2R,5S)-5-methyl-2-(5 Synthesis of -Methyl-2-pyridyl)-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 932)

Figure 110128222-A0202-12-1236-220
Figure 110128222-A0202-12-1236-220

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(214.65mg，630.64μmol，N(C2H5)3)、5-甲基-2-(5-甲基-2-哌啶基)吡啶(120mg，630.64 μmol)、HATU(263.77mg，693.70μmol)及TEA(70.20mg，693.70μmol，96.69μL)混合於DMSO(2mL)中且在20℃下攪拌2h。使反應混合物經歷HPLC。2-[(5-Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (214.65 mg, 630.64 μmol, N(C2H5)3), 5-methyl yl-2-(5-methyl-2-piperidinyl)pyridine (120 mg, 630.64 μmol), HATU (263.77 mg, 693.70 μmol) and TEA (70.20 mg, 693.70 μmol, 96.69 μL) were mixed in DMSO (2 mL) and stirred at 20° C. for 2 h. The reaction mixture was subjected to HPLC.

HPLC資料：2-10min 20-45% MeCN/H2 O+TFA 30mL/min(裝載泵4mL MeCN)管柱：SunFire 100*19mm，5微米HPLC profile: 2-10min 20-45% MeCN/H 2 O+TFA 30mL/min (loading pump 4mL MeCN) Column: SunFire 100*19mm, 5 microns

獲得2-甲氧基-5-[[2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(101.7mg，247.17μmol，39.19%產率)。藉由2D HNMR確認順式組態(化合物886 ，H2359596)2-Methoxy-5-[[2-[(2R,5R)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (101.7 mg, 247.17 μmol, 39.19% yield). Confirmation of cis configuration by 2D HNMR ( compound 886 , H2359596)

獲得2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(36.2mg，87.98μmol，13.95%產率)。藉2D HNMR確認反式組態(化合物932 ，H2359618)2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (36.2 mg, 87.98 μmol, 13.95% yield). Confirmation of trans configuration by 2D HNMR ( compound 932 , H2359618)

化合物886： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.75(dd,3H),1.02(m,1H),1.62(m,2H),1.79(m,1H),2.27(m,3H),2.69(m,2H),3.93(m,4H),5.40(m,1H),7.25(dd,1H),7.62(m,1H),7.71(m,2H),8.44(m,2H),8.53(dd,1H),11.01(m,1H)。 Compound 886: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 0.75 (dd, 3H), 1.02 (m, 1H), 1.62 (m, 2H), 1.79 (m, 1H), 2.27 (m, 3H), 2.69(m, 2H), 3.93(m, 4H), 5.40(m, 1H), 7.25(dd, 1H), 7.62(m, 1H), 7.71(m, 2H), 8.44(m, 2H ), 8.53 (dd, 1H), 11.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值412.2；Rt=2.337min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 412.2; Rt=2.337 min.

化合物932： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.31(m,1H),1.62(m,1H),1.95(m,2H),2.27(m,3H),2.41(m,1H),2.72(m,1H),3.78(m,4H),5.37(m,1H),7.27(m,1H),7.69(m,3H),8.48(m,3H),10.98(m,1H)。 Compound 932: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.01 (m, 3H), 1.31 (m, 1H), 1.62 (m, 1H), 1.95 (m, 2H), 2.27 (m, 3H), 2.41(m, 1H), 2.72(m, 1H), 3.78(m, 4H), 5.37(m, 1H), 7.27(m, 1H), 7.69(m, 3H), 8.48(m, 3H) ), 10.98 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值412.0；Rt=2.194min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 412.0; Rt=2.194 min.

實例201. rel-5-[[2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1029)及rel-5-[[2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1023)之合成Example 201. rel-5-[[2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1- Piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 1029) and rel-5-[[2-[(2R,5S)-5-methyl-2 -[2-(Trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carbamide Synthesis of (Compound 1023)

Figure 110128222-A0202-12-1238-221
Figure 110128222-A0202-12-1238-221

步驟1：外消旋-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl] Synthesis of -2-Oxyacetyl]amino]pyridine-3-carboxamide

將外消旋-2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(269.87mg，1.10mmol，HCl)及5-(5-甲基-2-哌啶基)-2-(三氟甲基)-1,3-苯并噻唑(0.33g，1.10mmol)混合於DMF(15mL)中。將反應懸浮液冷卻至0℃且添加HATU(459.55mg，1.21mmol)，隨後添加TEA(222.36mg，2.20mmol，306.29μL)，且在環境溫度下攪拌12h。將反應混合物在真空中蒸發且藉由製備型(60-80% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min)純化0.46g所獲得之粗產物，以得到產物外消旋-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.210g，427.28μmol，38.89%產率)。Racemic-2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (269.87 mg, 1.10 mmol, HCl) and 5-(5-methyl-2 -Piperidinyl)-2-(trifluoromethyl)-1,3-benzothiazole (0.33 g, 1.10 mmol) was mixed in DMF (15 mL). The reaction suspension was cooled to 0°C and HATU (459.55 mg, 1.21 mmol) was added followed by TEA (222.36 mg, 2.20 mmol, 306.29 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and 0.46 g of the obtained crude product was purified by preparative (60-80% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min) to give the product Racemic-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.210 g, 427.28 μmol, 38.89% yield).

LCMS(ESI)：[M+H]+ m/z：計算值491.2；實測值492.2；Rt=3.092min。LCMS (ESI): [M+H] + m/z: calculated 491.2; found 492.2; Rt=3.092 min.

步驟2：rel-5-[[2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1029 )及rel-5-[[2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1023 )之合成Step 2: rel-5-[[2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1- Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( Compound 1029 ) and rel-5-[[2-[(2R,5S)-5-methyl-2 -[2-(Trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carbamide Synthesis of ( Compound 1023 )

使外消旋-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.210g，427.28μmol)經歷掌性HPLC純化(管柱：ChiralArt YMC(250*20，5um)，溶析液：己烷-IPA-MeOH，50-25-25，流速：14mL/min)，以得到兩種單獨的鏡像異構物化合物1029 rel-5-[[2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0696g，141.61μmol，33.14%產率)及化合物1023 rel-5-[[2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0876g，178.24μmol，41.71%產率)。make rac-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.210 g, 427.28 μmol) was purified by chiral HPLC (column: ChiralArt YMC (250*20, 5um), eluent: hexane -IPA-MeOH, 50-25-25, flow rate: 14 mL/min) to give two separate enantiomers compound 1029 rel-5-[[2-[(2S,5R)-5-methyl- 2-[2-(Trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (0.0696 g, 141.61 μmol, 33.14% yield) and compound 1023 rel-5-[[2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl)-1, 3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.0876 g, 178.24 μmol, 41.71% yield).

化合物1029： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=18.399min。 Compound 1029: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 18.399 min.

LCMS(ESI)：[M+H]+ m/z：計算值491.2；實測值492.0；Rt=1.224min。LCMS (ESI): [M+H] + m/z: calculated 491.2; found 492.0; Rt=1.224 min.

化合物1023： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=34.083min。 Compound 1023: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 34.083 min.

LCMS(ESI)：[M+H]+ m/z：計算值491.2；實測值492.0；Rt=1.224min。LCMS (ESI): [M+H] + m/z: calculated 491.2; found 492.0; Rt=1.224 min.

實例202. rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1030)及rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1024)之合成Example 202. rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazole-5 -yl]-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 1030) and rel-2-methoxy-5-[[2-[ (2R,5S)-5-Methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyacetyl Synthesis of yl]amino]pyridine-3-carboxamide (compound 1024)

Figure 110128222-A0202-12-1239-222
Figure 110128222-A0202-12-1239-222

步驟1：外消旋-2-甲氧基-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-2-methoxy-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]- Synthesis of 1-Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(238.91mg，998.86μmol)及外消旋-5-(5-甲基-2-哌啶基)-2-(三氟甲基)-1,3-苯并噻唑(0.30g，998.86μmol)混合於DMF(15mL)。將反應懸浮液冷卻至0℃且添加HATU(417.78mg，1.10mmol)，隨後添加TEA(202.15mg，2.00mmol，278.44μL)，且在環境溫度下攪拌12h。將反應混合物在真空中蒸發且藉由製備型(55-90% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min)純化0.39g所獲得之粗產物，以得到產物外消旋-2-甲氧基-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1596g，306.03μmol，30.64%產率)。2-[(5-Aminocarbamoyl-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (238.91 mg, 998.86 μmol) and rac-5-(5- Methyl-2-piperidinyl)-2-(trifluoromethyl)-1,3-benzothiazole (0.30 g, 998.86 μmol) was mixed with DMF (15 mL). The reaction suspension was cooled to 0°C and HATU (417.78 mg, 1.10 mmol) was added followed by TEA (202.15 mg, 2.00 mmol, 278.44 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and 0.39 g of the obtained crude product was purified by prep (55-90% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min) to give the product Racemic-2-methoxy-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (0.1596 g, 306.03 μmol, 30.64% yield).

LCMS(ESI)：[M+H]+ m/z：計算值521.2；實測值522.2；Rt=3.608min。LCMS (ESI): [M+H] + m/z: calculated 521.2; found 522.2; Rt=3.608 min.

步驟2：rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1030 )及rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1024 )之合成Step 2: rel-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazole-5 -yl]-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 1030 ) and rel-2-methoxy-5-[[2-[ (2R,5S)-5-Methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyacetyl Synthesis of yl]amino]pyridine-3-carboxamide ( compound 1024 )

使外消旋-2-甲氧基-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1596g，306.03μmol)經歷掌性HPLC純化(管柱：ChiralPac IC(250*20，5um)，溶析液：己烷-IPA-MeOH，60-20-20，流速：15mL/min)，以得到兩種單獨的鏡像異構物化合物1030 rel-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0521g，99.90μmol，32.64%產率)及化合物1024 rel-2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0575g，110.26μmol，36.03%產率)。make rac-2-methoxy-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1- Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (0.1596 g, 306.03 μmol) was purified by chiral HPLC (column: ChiralPac IC (250*20, 5um), Eluent: Hexane-IPA-MeOH, 60-20-20, flow rate: 15 mL/min) to obtain two separate enantiomer compounds 1030 rel-2-methoxy-5-[[2- [(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide (0.0521 g, 99.90 μmol, 32.64% yield) and compound 1024 rel-2-methoxy-5-[[2-[(2R,5S)-5 -Methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- 3-Carboxamide (0.0575 g, 110.26 μmol, 36.03% yield).

化合物1030： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=19.034min。 Compound 1030: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 19.034 min.

LCMS(ESI)：[M+H]+ m/z：計算值521.0；實測值522.0；Rt=3.459min。LCMS (ESI): [M+H] + m/z: calculated 521.0; found 522.0; Rt=3.459 min.

化合物1024： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=29.406min。 Compound 1024: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 29.406 min.

LCMS(ESI)：[M+H]+ m/z：計算值521.0；實測值522.0；Rt=3.459min。LCMS (ESI): [M+H] + m/z: calculated 521.0; found 522.0; Rt=3.459 min.

實例203. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1027)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1022)之合成Example 203. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)- 1,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (Compound 1027) and rel-N-(6-amino-5-ethyl-3- Pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide (Compound 1022)

Figure 110128222-A0202-12-1241-223
Figure 110128222-A0202-12-1241-223

步驟1：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: Racemic-N-(6-amino-5-ethyl-3-pyridinyl)-2-[5-methyl-2-[2-(trifluoromethyl)-1,3- Synthesis of benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide

將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(208.96mg，998.86μmol)及外消旋-5-(5-甲基-2-哌啶基)-2-(三氟甲基)-1,3-苯并噻唑(0.3g，998.86μmol)混合於DMF(15mL)中。將反應懸浮液冷卻至0℃且添加HATU(417.78mg，1.10mmol)，隨後添加TEA(202.15mg，2.00mmol，278.44μL)，且在環境溫度下攪拌12h。將反應混合物在真空中蒸發且藉由製備型(65-85% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30mL/min)純化0.39g所獲得之粗產物， 以得到產物外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(227.20mg，462.23μmol，46.28%產率)。2-[(6-Amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (208.96 mg, 998.86 μmol) and rac-5-(5-methyl- 2-Piperidinyl)-2-(trifluoromethyl)-1,3-benzothiazole (0.3 g, 998.86 μmol) was mixed in DMF (15 mL). The reaction suspension was cooled to 0°C and HATU (417.78 mg, 1.10 mmol) was added followed by TEA (202.15 mg, 2.00 mmol, 278.44 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and 0.39 g of the obtained crude product was purified by preparative (65-85% 0-5 min H2O /MeOH/0.1% NH4OH, flow rate: 30 mL/min) to obtain product elimination Spin-N-(6-amino-5-ethyl-3-pyridyl)-2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazole-5 -yl]-1-piperidinyl]-2-oxoacetamide (227.20 mg, 462.23 μmol, 46.28% yield).

LCMS(ESI)：[M+H]+ m/z：計算值491.2；實測值492.2；Rt=2.992min。LCMS (ESI): [M+H] + m/z: calculated 491.2; found 492.2; Rt=2.992 min.

步驟2：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1027 )及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1022 )之合成Step 2: rel-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)- 1,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide ( Compound 1027 ) and rel-N-(6-amino-5-ethyl-3- Pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide ( Compound 1022 )

使外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(227.20mg，462.23μmol)經歷掌性HPLC純化(管柱：ChiralArt YMC(250*20，5um)，溶析液：己烷-IPA-MeOH，50-25-25，流速：14mL/min)，以得到兩種單獨的鏡像異構物化合物1027 rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.0675g，137.33μmol，29.71%產率)及化合物1022 rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.0795g，161.74μmol，34.99%產率)。make rac-N-(6-amino-5-ethyl-3-pyridyl)-2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzo Thiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (227.20 mg, 462.23 μmol) was purified by chiral HPLC (column: ChiralArt YMC (250*20, 5um), elution Liquid: Hexane-IPA-MeOH, 50-25-25, flow rate: 14 mL/min) to obtain two separate enantiomer compounds 1027 rel-N-(6-amino-5-ethyl-3 -Pyridinyl)-2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl] -2-Oxyacetamide (0.0675 g, 137.33 μmol, 29.71% yield) and compound 1022 rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R ,5S)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide ( 0.0795 g, 161.74 μmol, 34.99% yield).

化合物1027： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=12.813min。 Compound 1027: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 12.813 min.

LCMS(ESI)：[M+H]+ m/z：計算值491.0；實測值492.0；Rt=1.146min。LCMS (ESI): [M+H] + m/z: calculated 491.0; found 492.0; Rt=1.146 min.

化合物1022： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=20.716min。 Compound 1022: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 20.716 min.

LCMS(ESI)：[M+H]+ m/z：計算值491.0；實測值492.2；Rt=3.364min。LCMS (ESI): [M+H] + m/z: calculated 491.0; found 492.2; Rt=3.364 min.

實例204. 5-(2-(5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物868及化合物873)之合成Example 204. 5-(2-(5-Methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)piperidin-1-yl)-2-side oxyacetyl Synthesis of amino)nicotinamide (compound 868 and compound 873)

Figure 110128222-A0202-12-1243-224
Figure 110128222-A0202-12-1243-224

在輕微加熱下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(236.26mg，1.13mmol)、5-[(2R,5S )-5-甲基-2-哌啶基]-1H -噻吩并[3,2-c ]吡唑(0.25g，1.13mmol)及DIPEA(437.96mg，3.39mmol，590.24μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(515.40mg，1.36mmol)。反應完成之後，藉由HPLC(39% 0.5-6.5min水-MeOH；流速30ml/min(裝載泵4ml/min MeOH)；目標質量412；管柱SunFireC18 100x19mm 5um(R))純化混合物，以得到外消旋產物。在掌性HPLC(IA-I(250*20,5mkm)，己烷-IPA-MeOH,50-25-25,12ml/min)後，獲得5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(29mg，70.31μmol，6.22%產率)及5-[[2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(29mg，70.31μmol，6.22%產率)。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (236.26 mg, 1.13 mmol), 5-[( 2R,5S )-5 -Methyl-2-piperidinyl]-1H-thieno[ 3,2 -c ]pyrazole (0.25 g, 1.13 mmol) and DIPEA (437.96 mg, 3.39 mmol, 590.24 μL) were dissolved in DMSO (6 mL) . With vigorous stirring and occasional heating, HATU (515.40 mg, 1.36 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC (39% 0.5-6.5 min water-MeOH; flow rate 30 ml/min (loading pump 4 ml/min MeOH); target mass 412; column SunFire C18 100x19 mm 5um (R)) to obtain external racemic product. After chiral HPLC (IA-I (250*20,5mkm), hexane-IPA-MeOH, 50-25-25, 12ml/min), 5-[[2-[( 2S,5R )-5 was obtained -Methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide (29 mg, 70.31 μmol, 6.22% yield) and 5-[[2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazole-5 -yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (29 mg, 70.31 μmol, 6.22% yield).

化合物868 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為37.50min且化合物873 之保留時間為54.49min。The retention time of compound 868 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 37.50 min and the retention time of compound 873 was 54.49 min.

化合物868：保留時間：37.50minCompound 868: retention time: 37.50min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.03(m,3H),1.35-1.49(m,1H),1.82-2.01(m,2H),2.04-2.20(m,2H),2.96-3.02(m,0.4H),3.39-3.43(m,0.6H),3.45-4.14(m,1H),5.46-5.89(m,1H),6.98-7.20(m,1H),7.55-7.66(m,1H),7.68-8.02(m,1H),8.10-8.23(m,1H),8.44-8.52(m,1H),8.71-8.94(m,2H),11.19-11.32(m,1H),12.93-13.36(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.03(m,3H), 1.35-1.49(m,1H), 1.82-2.01(m,2H), 2.04-2.20(m,2H) ,2.96-3.02(m,0.4H),3.39-3.43(m,0.6H),3.45-4.14(m,1H),5.46-5.89(m,1H),6.98-7.20(m,1H),7.55- 7.66(m,1H),7.68-8.02(m,1H),8.10-8.23(m,1H),8.44-8.52(m,1H),8.71-8.94(m,2H),11.19-11.32(m,1H) ), 12.93-13.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=1.676min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=1.676 min.

化合物873：保留時間：54.49minCompound 873: retention time: 54.49min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.02(m,3H),1.39-1.48(m,1H),1.81-1.98(m,2H),2.05-2.24(m,2H),2.96-3.02(m,0.4H),3.37-3.43(m,0.6H),3.43-4.14(m,1H),5.43-5.91(m,1H),7.00-7.15(m,1H),7.54-7.65(m,1H),7.66-8.01(m,1H),8.11-8.21(m,1H),8.49(s,1H),8.70-8.94(m,2H),11.11-11.39(m,1H),12.79-13.38(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.02(m,3H), 1.39-1.48(m,1H), 1.81-1.98(m,2H), 2.05-2.24(m,2H) ,2.96-3.02(m,0.4H),3.37-3.43(m,0.6H),3.43-4.14(m,1H),5.43-5.91(m,1H),7.00-7.15(m,1H),7.54- 7.65(m,1H),7.66-8.01(m,1H),8.11-8.21(m,1H),8.49(s,1H),8.70-8.94(m,2H),11.11-11.39(m,1H), 12.79-13.38 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=1.700min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=1.700 min.

實例205. 2-甲氧基-5-(2-(5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1006及化合物952)之合成Example 205. 2-Methoxy-5-(2-(5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)piperidin-1-yl)-2 -Synthesis of pendant oxyacetamido)nicotinamide (compound 1006 and compound 952)

Figure 110128222-A0202-12-1244-225
Figure 110128222-A0202-12-1244-225

在輕微加熱下，將5-[(2R,5S )-5-甲基-2-哌啶基]-1H -噻吩并[3,2-c ]吡唑(300.79mg，1.36mmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(325.07mg，1.36mmol)及DIPEA(526.94mg，4.08mmol，710.16μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(620.11mg，1.63mmol)。反應完成之後，藉由HPLC(46% 0.5-6.5min水-MeOH；流速30ml/min(裝載泵4ml/min MeOH)；目標質量442；管柱SunFireC18 100x19mm 5um(R))純化混合物，以得到外消旋產物。在掌性HPLC(Chiral ART Cellulose-SC(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)之後，分離呈光學純形式但具有未知雜質之異構物2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(40mg，90.40μmol，6.65%產率)；藉由HPLC(18% 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min MeCN)；目 標質量442；管柱SunFireC18 100x19 mm 5um(R))純化，以得到純產物。分離具有相應順式雜質之異構物2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(53mg，119.78μmol，8.81%產率)且藉由掌性HPLC(Chiralcel OJ-H(250*20mm，5mkm)；流動相：IPA-MeOH，50-50，流速：10mL/min；管柱溫度：24℃；波長：205nm、254nm、306nm)，保留時間(異構物A)=21.24min；保留時間(異構物B)=29.74min)純化，以得到純產物2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(53mg，119.78μmol，8.81%產率)。5-[( 2R,5S )-5-methyl-2-piperidinyl]-1H-thieno[ 3,2 -c ]pyrazole (300.79 mg, 1.36 mmol), 2- [(5-Aminocarboxy-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (325.07 mg, 1.36 mmol) and DIPEA (526.94 mg, 4.08 mmol, 710.16 μL) were dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (620.11 mg, 1.63 mmol) was added in small batches. After the reaction was complete, the mixture was purified by HPLC (46% 0.5-6.5 min water-MeOH; flow rate 30 ml/min (loading pump 4 ml/min MeOH); target mass 442; column SunFire C18 100x19 mm 5um(R)) to obtain external racemic product. After chiral HPLC (Chiral ART Cellulose-SC (250*20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 12ml/min) isomers were isolated in optically pure form but with unknown impurities 2-Methoxy-5-[[2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidine [0.5-6.5 min water-MeCN; flow rate 30 ml /min (loading pump 4 ml/min MeCN); target mass 442; column SunFire C18 100x19 mm 5um(R)) purification to give pure product. Isolation of the isomer 2-methoxy-5-[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazole with the corresponding cis impurity -5-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (53 mg, 119.78 μmol, 8.81% yield) and analyzed by chiral HPLC ( Chiralcel OJ-H (250*20mm, 5mkm); mobile phase: IPA-MeOH, 50-50, flow rate: 10mL/min; column temperature: 24°C; wavelength: 205nm, 254nm, 306nm), retention time (isomerization Compound A) = 21.24 min; retention time (isomer B) = 29.74 min) purification to give pure product 2-methoxy-5-[[2-[( 2S,5R )-5-methyl-2 -( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (53 mg, 119.78 μmol, 8.81% yield).

化合物1006 於分析條件下(管柱：IC，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為74.26min且化合物952 之保留時間為31.77min。The retention time of compound 1006 under analytical conditions (column: IC, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 74.26 min and that of compound 952 was 31.77 min.

化合物1006：保留時間：74.26minCompound 1006: retention time: 74.26min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.06(m,3H),1.37-1.48(m,1H),1.84-1.99(m,2H),2.03-2.22(m,2H),2.94-3.01(m,0.4H),3.39-3.44(m,0.6H),3.47-3.52(m,0.6H),3.91-3.97(m,3H),4.03-4.08(m,0.4H),5.42-5.88(m,1H),7.00-7.10(m,1H),7.68-7.75(m,2H),7.80(br s,1H),8.44-8.50(m,1H),8.52-8.57(m,1H),11.01(br s,1H),13.06(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.06(m,3H), 1.37-1.48(m,1H), 1.84-1.99(m,2H), 2.03-2.22(m,2H) ,2.94-3.01(m,0.4H),3.39-3.44(m,0.6H),3.47-3.52(m,0.6H),3.91-3.97(m,3H),4.03-4.08(m,0.4H), 5.42-5.88(m, 1H), 7.00-7.10(m, 1H), 7.68-7.75(m, 2H), 7.80(br s, 1H), 8.44-8.50(m, 1H), 8.52-8.57(m, 1H), 11.01 (br s, 1H), 13.06 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值442.2；實測值443.2；Rt=2.428min。LCMS (ESI): [M] + m/z: calculated 442.2; found 443.2; Rt=2.428 min.

化合物952：保留時間：31.77minCompound 952: retention time: 31.77min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.02(m,3H),1.37-1.46(m,1H),1.82-1.98(m,2H),2.05-2.20(m,2H),2.92-3.42(m,1H),3.47-4.06(m,4H),5.45-5.86(m,1H),6.97-7.15(m,1H),7.63-8.04(m,3H),8.41-8.51(m,1H),8.51-8.57(m,1H),11.05(s,1H),12.93-13.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.02(m,3H), 1.37-1.46(m,1H), 1.82-1.98(m,2H), 2.05-2.20(m,2H) ,2.92-3.42(m,1H),3.47-4.06(m,4H),5.45-5.86(m,1H),6.97-7.15(m,1H),7.63-8.04(m,3H),8.41-8.51( m, 1H), 8.51-8.57 (m, 1H), 11.05 (s, 1H), 12.93-13.34 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值442.2；實測值443.2；Rt=2.430min。LCMS (ESI): [M] + m/z: calculated 442.2; found 443.2; Rt=2.430 min.

實例206. 5-(2-(5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯Example 206. 5-(2-(5-Methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)piperidin-1-yl)-2-pendant oxyacetyl 胺基)菸鹼醯胺(化合物971及化合物943)之合成Synthesis of amino)nicotinamide (compound 971 and compound 943)

Figure 110128222-A0202-12-1246-226
Figure 110128222-A0202-12-1246-226

在輕微加熱下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(284.26mg，1.36mmol)、5-[(2S,5R )-5-甲基-2-哌啶基]-2H -噻吩并[2,3-c ]吡唑(300.79mg，1.36mmol)及DIPEA(526.94mg，4.08mmol，710.16μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(620.11mg，1.63mmol)。反應完成之後，藉由HPLC(40-90% 0.5-6.5min水-MeOH；流速30ml/min；(裝載泵4ml/min MeOH)；目標質量498；管柱SunFireC18 100x19 mm 5um(L))及掌性HPLC(Chiralpak IA-II(250*30，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)純化混合物，以得到5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(55mg，133.34μmol，9.81%產率)、及5-[[2-[(2R,5S )-5-甲基-2-(1H -噻吩并[2,3-c]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(90mg，218.20μmol，16.06%產率)、及5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(55mg，133.34μmol，9.81%產率)。Under gentle heating, 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (284.26 mg, 1.36 mmol), 5-[( 2S,5R )-5 -Methyl-2-piperidinyl]-2H-thieno[ 2,3-c ]pyrazole ( 300.79 mg, 1.36 mmol) and DIPEA (526.94 mg, 4.08 mmol, 710.16 μL) were dissolved in DMSO (6 mL) . With vigorous stirring and occasional heating, HATU (620.11 mg, 1.63 mmol) was added in small batches. After completion of the reaction, it was analyzed by HPLC (40-90% 0.5-6.5 min water-MeOH; flow rate 30 ml/min; (loading pump 4 ml/min MeOH); target mass 498; column SunFire C18 100x19 mm 5um (L)) and palm The mixture was purified by HPLC (Chiralpak IA-II (250*30, 5mkm), hexane-IPA-MeOH, 50-25-25, 12ml/min) to give 5-[[2-[( 2S,5R )- 5-Methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Formamide (55 mg, 133.34 μmol, 9.81% yield), and 5-[[2-[( 2R,5S )-5-methyl-2-( 1H -thieno[2,3-c]pyrazole -5-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (90 mg, 218.20 μmol, 16.06% yield), and 5-[[2 -[( 2S,5R )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (55 mg, 133.34 μmol, 9.81% yield).

化合物971 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為81.55min且化合物943 之保留時間為41.81min。The retention time of compound 971 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 81.55 min and the retention time of compound 943 was 41.81 min.

化合物971：保留時間：81.55minCompound 971: retention time: 81.55min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(d,3H),1.41(m,1H),1.89(m,2H),2.17(m,2H),3.12(m,1H),4.02(m,1H),5.65(m,1H),6.95(s,1H),7.58(d,1H),7.94(bds,1H),8.13(d,1H),8.49(s,1H),8.77(s,1H),8.89(s,1H),11.23(bds,1H),13.29(bds, 1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(d,3H), 1.41(m,1H), 1.89(m,2H), 2.17(m,2H), 3.12(m,1H), 4.02(m, 1H), 5.65(m, 1H), 6.95(s, 1H), 7.58(d, 1H), 7.94(bds, 1H), 8.13(d, 1H), 8.49(s, 1H), 8.77 (s, 1H), 8.89 (s, 1H), 11.23 (bds, 1H), 13.29 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=2.028min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=2.028 min.

化合物943：保留時間：41.81minCompound 943: retention time: 41.81min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(d,3H),1.42(m,1H),1.95(m,2H),2.07(m,2H),3.12(m,1H),4.05(m,1H),5.65(m,1H),6.95(s,1H),7.60(d,1H),7.94(bds,1H),8.13(d,1H),8.49(s,1H),8.77(s,1H),8.89(s,1H),11.23(bds,1H),13.29(bds,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(d,3H), 1.42(m,1H), 1.95(m,2H), 2.07(m,2H), 3.12(m,1H), 4.05(m, 1H), 5.65(m, 1H), 6.95(s, 1H), 7.60(d, 1H), 7.94(bds, 1H), 8.13(d, 1H), 8.49(s, 1H), 8.77 (s, 1H), 8.89 (s, 1H), 11.23 (bds, 1H), 13.29 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=2.020min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=2.020 min.

實例207. 2-甲氧基-5-(2-(5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物950及化合物968)之合成Example 207. 2-Methoxy-5-(2-(5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)piperidin-1-yl)-2 -Synthesis of pendant oxyacetamido)nicotinamide (compound 950 and compound 968)

Figure 110128222-A0202-12-1247-227
Figure 110128222-A0202-12-1247-227

在輕微加熱下，將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(325.07mg，1.36mmol)、5-[(2S,5R )-5-甲基-2-哌啶基]-2H -噻吩并[2,3-c]吡唑(300.79mg，1.36mmol)及DIPEA(526.94mg，4.08mmol，710.16μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(620.11mg，1.63mmol)。反應完成之後，藉由HPLC(45-50% 0.5-6min水-MeOH；流速30ml/min(裝載泵4ml/min R1)；目標質量442；管柱SunFireC18 100x19mm 5um(R))純化混合物且使經純化之外消旋混合物經歷掌性HPLC(Chiralcel OD-H(250*30，5mkm)，己烷-IPA-MeOH，70-15-15,30ml/min)，以得到2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(210mg，474.59μmol，34.92%產率)、及2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-(1H - 噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(140mg，316.39μmol，23.28%產率)、及2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(210mg，474.59μmol，34.92%產率)。2-[(5-Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-pendoxoacetic acid (325.07 mg, 1.36 mmol), 5-[( 2S,5R )-5-methyl-2-piperidinyl]-2H-thieno[2,3-c]pyrazole ( 300.79 mg, 1.36 mmol) and DIPEA (526.94 mg, 4.08 mmol, 710.16 μL) were dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (620.11 mg, 1.63 mmol) was added in small batches. After the reaction was complete, the mixture was purified by HPLC (45-50% 0.5-6 min water-MeOH; flow rate 30 ml/min (loading pump 4 ml/min R1); target mass 442; column SunFire C18 100x19 mm 5um(R)) and passed through The racemic mixture was purified by chiral HPLC (Chiralcel OD-H (250*30, 5mkm), Hexane-IPA-MeOH, 70-15-15, 30ml/min) to give 2-methoxy-5 -[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[2,3-c]pyrazol-5-yl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (210 mg, 474.59 μmol, 34.92% yield), and 2-methoxy-5-[[2-[( 2R,5S )-5-methyl yl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (140 mg, 316.39 μmol, 23.28% yield), and 2-methoxy-5-[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxoacetoxy]amino]pyridine-3-carboxamide (210 mg, 474.59 μmol, 34.92% yield).

化合物950 於分析條件下(管柱：OD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為11.75min且化合物968 之保留時間為14.25min。The retention time of compound 950 under analytical conditions (column: OD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 11.75 min and the retention time of compound 968 was 14.25 min .

化合物950：保留時間：11.75minCompound 950: retention time: 11.75min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(d,3H),1.40(m,1H),1.89(m,2H),2.04(m,2H),3.12(m,1H),3.92(m,1H),3.94(s,3H),5.65(m,1H),6.95(s,1H),7.73(m,2H),7.93(m,1H),8.46(m,1H),8.55(s,1H),11.02(s,1H),13.30(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(d,3H), 1.40(m,1H), 1.89(m,2H), 2.04(m,2H), 3.12(m,1H), 3.92(m,1H),3.94(s,3H),5.65(m,1H),6.95(s,1H),7.73(m,2H),7.93(m,1H),8.46(m,1H),8.55 (s, 1H), 11.02 (s, 1H), 13.30 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=2.390min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=2.390 min.

化合物968：保留時間：14.25minCompound 968: retention time: 14.25min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(d,3H),1.42(m,1H),1.89(m,2H),2.05(m,2H),3.12(m,1H),3.86(m,1H),3.94(s,3H),5.65(m,1H),6.95(s,1H),7.73(m,2H),7.93(m,1H),8.46(m,1H),8.55(s,1H),11.02(s,1H),13.30(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(d,3H), 1.42(m,1H), 1.89(m,2H), 2.05(m,2H), 3.12(m,1H), 3.86(m,1H),3.94(s,3H),5.65(m,1H),6.95(s,1H),7.73(m,2H),7.93(m,1H),8.46(m,1H),8.55 (s, 1H), 11.02 (s, 1H), 13.30 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=2.394min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=2.394 min.

實例208. 5-(2-(5-甲基-2-(1H -吡唑-3-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物978及化合物1007)之合成Example 208. 5-(2-(5-Methyl-2-( 1H -pyrazol-3-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 978 and the synthesis of compound 1007)

Figure 110128222-A0202-12-1248-228
Figure 110128222-A0202-12-1248-228

步驟1：5-(2-(5-甲基-2-(1H-吡唑-3-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: Synthesis of 5-(2-(5-methyl-2-(1H-pyrazol-3-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide

在25℃下，在1h時段內，將HATU(702.48mg，1.85mmol)小批量添加到(2R,5S)-5-甲基-2-(1H -吡唑-3-基)哌啶(400mg，1.68mmol，2HCl)、2-[(5-胺 甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(474.41mg，1.93mmol，HCl)及TEA(1.36g，13.44mmol，1.87mL)於DMF(6mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：5-55% 0-5min H2 O/MeOH；流速：30ml/min(裝載泵4ml/min MeOH)，以得到呈淡黃色膠狀物之5-[[2-[(2R,5S )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(125mg，350.75μmol，20.88%產率)，將其直接提交至製備型掌性HPLC。HATU (702.48 mg, 1.85 mmol) was added in small batches to (2R,5S)-5-methyl-2-( 1H -pyrazol-3-yl)piperidine (400 mg) at 25°C over a period of 1 h , 1.68 mmol, 2HCl), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (474.41 mg, 1.93 mmol, HCl) and TEA (1.36 g, 13.44 mmol) , 1.87 mL) in a stirred mixture of DMF (6 mL). The resulting mixture was stirred at 25°C for 18h and then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 5-55% 0-5min H2O /MeOH; flow rate: 30ml/min (loading) pump 4 ml/min MeOH) to give 5-[[2-[( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)-1-piperidine as a pale yellow gum pyridyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (125 mg, 350.75 μmol, 20.88% yield), which was submitted directly to preparative chiral HPLC.

LCMS(ESI)：[M]+ m/z：計算值356.2；實測值357.2；Rt=1.694min。LCMS (ESI): [M] + m/z: calculated 356.2; found 357.2; Rt=1.694 min.

步驟2：掌性分離(化合物978 及化合物1007 )Step 2: chiral separation ( compound 978 and compound 1007 )

將外消旋5-[[2-[(2R,5S )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(125mg，350.75μmol)提交至製備型掌性HPLC(管柱：Chiralpak IC(250*20，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min，管柱溫度：20℃；波長：205nm、215nm)，以得到化合物1007 5-[[2-[(2S,5R )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(28mg，78.57μmol，22.40%產率)(RT=36.540min)及化合物978 5-[[2-[(2R,5S )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(32mg，89.79μmol，25.60%產率)(RT=58.232min)。The racemic 5-[[2-[( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (125 mg, 350.75 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IC (250*20, 5 mkm); mobile phase: hexane-IPA-MeOH, 60- 20-20; flow rate: 12ml/min, column temperature: 20°C; wavelength: 205nm, 215nm) to obtain compound 1007 5-[[2-[( 2S,5R )-5-methyl-2-( 1H -Pyrazol-3-yl)-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (28 mg, 78.57 μmol, 22.40% yield) (RT=36.540 min) and compound 978 5-[[2-[( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)-1-piperidinyl]-2-side oxyacetyl yl]amino]pyridine-3-carboxamide (32 mg, 89.79 μmol, 25.60% yield) (RT=58.232 min).

化合物978 於分析條件下(管柱：IC，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為31.91min且化合物1007 之保留時間為22.90min。The retention time of compound 978 under analytical conditions (column: IC, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 31.91 min and the retention time of compound 1007 was 22.90 min.

化合物978：保留時間：31.91minCompound 978: retention time: 31.91min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.69-0.95(m,3H),1.16-1.40(m,2H),1.54-1.69(m,1H),1.76-2.00(m,3H),2.03-2.12(m,1H),2.73-2.96(m,1H),3.42-3.62(m,1H),6.01-6.34(m,1H),7.24-7.62(m,2H),7.64-7.89(m,1H),8.13-8.20(m,1H),8.46-8.52(m,1H),8.71-8.79(m,1H),11.09-11.19(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.69-0.95(m,3H), 1.16-1.40(m,2H), 1.54-1.69(m,1H), 1.76-2.00(m,3H) ,2.03-2.12(m,1H),2.73-2.96(m,1H),3.42-3.62(m,1H),6.01-6.34(m,1H),7.24-7.62(m,2H),7.64-7.89( m, 1H), 8.13-8.20 (m, 1H), 8.46-8.52 (m, 1H), 8.71-8.79 (m, 1H), 11.09-11.19 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值356.2；實測值357.2；Rt=1.637min。LCMS (ESI): [M] + m/z: calculated 356.2; found 357.2; Rt=1.637 min.

化合物1007：保留時間：22.90minCompound 1007: retention time: 22.90min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.69-0.95(m,3H),1.16-1.40(m,2H),1.54-1.69(m,1H),1.76-2.00(m,3H),2.03-2.12(m,1H),2.73-2.96(m,1H),3.42-3.62(m,1H),6.01-6.34(m,1H),7.24-7.62(m,2H),7.64-7.89(m,1H),8.13-8.20(m,1H),8.46-8.52(m,1H),8.71-8.79(m,1H),11.09-11.19(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.69-0.95(m,3H), 1.16-1.40(m,2H), 1.54-1.69(m,1H), 1.76-2.00(m,3H) ,2.03-2.12(m,1H),2.73-2.96(m,1H),3.42-3.62(m,1H),6.01-6.34(m,1H),7.24-7.62(m,2H),7.64-7.89( m, 1H), 8.13-8.20 (m, 1H), 8.46-8.52 (m, 1H), 8.71-8.79 (m, 1H), 11.09-11.19 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值356.2；實測值357.2；Rt=1.638min。LCMS (ESI): [M] + m/z: calculated 356.2; found 357.2; Rt=1.638 min.

實例209. 2-(2-(1'H -[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-N -(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺(化合物931及化合物913)之合成Example 209. 2-(2-(1'H-[ 1,3' -bipyrazole]-3-yl)-5-methylpiperidin - 1-yl)-N-(6-amino-5 Synthesis of -ethylpyridin-3-yl)-2-oxoacetamide (Compound 931 and Compound 913)

Figure 110128222-A0202-12-1250-229
Figure 110128222-A0202-12-1250-229

步驟1：2-(2-(1'H-[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺之合成Step 1: 2-(2-(1'H-[1,3'-bipyrazole]-3-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5 Synthesis of -ethylpyridin-3-yl)-2-oxyacetamide

在25℃下，在1.5h時段內，將HATU(798.01mg，2.10mmol)小批量添加到(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]哌啶(650mg，1.91mmol，3HCl)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(399.15mg，1.91mmol)及TEA(1.5g，14.82mmol，2.07mL)於DMF(4.5mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um)，流動相：45-55% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，以得到230mg粗產物，其藉由反相HPLC(管柱：Chromatorex 18 SMB100-5T 100x19 mm 5um；流動相：20-70% 0-5min H2 O/MeOH；流速：30ml/min(裝載泵4ml/min MeOH))進行純化，以得到呈粉色膠狀物之N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑 -3-基]-1-哌啶基]-2-側氧基乙醯胺(64mg，151.49μmol，7.94%產率)，其直接用於下一步驟中。HATU (798.01 mg, 2.10 mmol) was added in small batches to ( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl) at 25°C over a period of 1.5 h Pyrazol-3-yl]piperidine (650 mg, 1.91 mmol, 3HCl), 2-[(6-amino-5-ethyl-3-pyridinyl)amino]-2-oxoacetic acid (399.15 mg , 1.91 mmol) and TEA (1.5 g, 14.82 mmol, 2.07 mL) in a stirred mixture of DMF (4.5 mL). The resulting mixture was stirred at 25°C for 18h, then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um), mobile phase: 45-55% 0-5 min H2O /MeOH/0.1% NH4OH , Flow rate: 30 ml/min (loading pump 4 ml/min MeOH) to give 230 mg of crude product by reverse phase HPLC (column: Chromatorex 18 SMB100-5T 100x19 mm 5um; mobile phase: 20-70% 0-5 min H 2 O/MeOH; flow rate: 30 ml/min (loading pump 4 ml/min MeOH)) was purified to give N- (6-amino-5-ethyl-3-pyridinyl)-2 as a pink gum -[( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl]-2-side oxyacetyl Amine (64 mg, 151.49 μmol, 7.94% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=1.017min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=1.017 min.

步驟2：掌性分離(化合物931 及化合物913 )Step 2: Chiral separation ( compound 931 and compound 913 )

將外消旋N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯胺(64mg，151.49μmol)提交至製備型掌性HPLC(管柱Chiralpak AD-H-II(250*20，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min；管柱溫度20℃；波長：230nm、225nm)，以得到化合物913 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯胺(21mg，49.71μmol，32.81%產率)(RT=26.645min)及化合物931 N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[1-(1H-吡唑 -3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯胺(22.6mg，53.49μmol，35.31%產率)(RT=36.187min)。The racemic N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[1-( 1H -pyrazole-3- yl)pyrazol-3-yl]-1-piperidinyl]-2-oxoacetamide (64 mg, 151.49 μmol) was submitted to preparative chiral HPLC (column Chiralpak AD-H-II (250* 20, 5mkm); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12ml/min; column temperature 20°C; wavelength: 230nm, 225nm) to obtain compound 913 N- (6-amine) yl-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl]- 1-Piperidinyl]-2-oxyacetamide (21 mg, 49.71 μmol, 32.81% yield) (RT=26.645 min) and compound 931 N- (6-amino-5-ethyl-3- Pyridyl)-2-[( 2S,5R )-5-methyl-2-[1-( 1H-pyrazol- 3-yl)pyrazol-3-yl]-1-piperidinyl]-2- Pendant oxyacetamide (22.6 mg, 53.49 μmol, 35.31% yield) (RT=36.187 min).

化合物931 於分析條件下(管柱：IC，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為46.80min且化合物913 之保留時間為37.45min。The retention time of compound 931 under analytical conditions (column: IC, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 46.80 min and the retention time of compound 913 was 37.45 min.

化合物931：保留時間：46.80minCompound 931: retention time: 46.80min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.06(m,6H),1.38(m,1H),1.89(m,3H),2.16(m,1H),2.38(m,2H),2.87(m,1H),3.65(m,1H),5.63(m,3H),6.40(m,2H),7.48(m,1H),7.78(d,1H),8.03(m,1H),8.17(m,1H),10.45(s,1H),12.78(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.06(m, 6H), 1.38(m, 1H), 1.89(m, 3H), 2.16(m, 1H), 2.38(m, 2H), 2.87(m,1H),3.65(m,1H),5.63(m,3H),6.40(m,2H),7.48(m,1H),7.78(d,1H),8.03(m,1H),8.17 (m, 1H), 10.45 (s, 1H), 12.78 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=1.947min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=1.947 min.

化合物913：保留時間：37.45minCompound 913: retention time: 37.45min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.07(m,6H),1.37(m,1H),1.85(m,1H),1.97(m,2H),2.17(m,1H),2.37(m,2H),2.86(m,1H),3.74(dd,1H),5.63(m,3H),6.40(m,2H),7.48(m,1H),7.78(d,1H),8.03(m,1H),8.17(dd,1H),10.45(s,1H), 12.78(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.07(m, 6H), 1.37(m, 1H), 1.85(m, 1H), 1.97(m, 2H), 2.17(m, 1H), 2.37(m, 2H), 2.86(m, 1H), 3.74(dd, 1H), 5.63(m, 3H), 6.40(m, 2H), 7.48(m, 1H), 7.78(d, 1H), 8.03 (m, 1H), 8.17 (dd, 1H), 10.45 (s, 1H), 12.78 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=1.931min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=1.931 min.

實例210. 5-(2-(2-(1'H -[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物894及化合物881)之合成Example 210. 5-(2-(2-(1'H-[ 1,3' -bipyrazol]-3-yl)-5-methylpiperidin-1-yl)-2-pendantoxyethyl Synthesis of amido)-2-methoxynicotinamide (compound 894 and compound 881)

Figure 110128222-A0202-12-1252-230
Figure 110128222-A0202-12-1252-230

步驟1：5-(2-(2-(1'H-[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺之合成Step 1: 5-(2-(2-(1'H-[1,3'-bipyrazol]-3-yl)-5-methylpiperidin-1-yl)-2-pendoxoethyl Synthesis of amide)-2-methoxynicotinamide

在25℃下，在1.5h時段內，將HATU(798.01mg，2.10mmol)小批量添加到(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]哌啶(650mg，1.91mmol，3HCl)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(456.35mg，1.91mmol)及TEA(1.5g，14.82mmol，2.07mL)於DMF(4.5mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um)，流動相：40-65% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，得到呈淡黃色膠狀物之2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(230mg，508.33μmol，26.64%產率)，其直接用於下一步驟中。HATU (798.01 mg, 2.10 mmol) was added in small batches to ( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl) at 25°C over a period of 1.5 h Pyrazol-3-yl]piperidine (650 mg, 1.91 mmol, 3HCl), 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (456.35 mg, 1.91 mmol) and TEA (1.5 g, 14.82 mmol, 2.07 mL) in a stirred mixture of DMF (4.5 mL). The resulting mixture was stirred at 25°C for 18h, then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um), mobile phase: 40-65% 0-5 min H2O /MeOH/0.1% NH4OH , Flow rate: 30ml/min (loading pump 4ml/min MeOH) to obtain 2-methoxy-5-[[[2-[( 2R,5S )-5-methyl-2-[1 as a pale yellow gum -( 1H -Pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (230 mg, 508.33 μmol , 26.64% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=2.399min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=2.399 min.

步驟2：掌性分離(化合物894 及化合物881 )Step 2: Chiral separation ( compound 894 and compound 881 )

將外消旋2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(230mg，508.33μmol)提交至製備型掌性HPLC(管柱：Chiralpak AD-H III(250*30mm，5mkm)；流動相：己 烷-IPA-MeOH，50-25-25；流速：12ml/min)，以得到化合物894 2-甲氧基-5-[[2-[(2S,5R )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(47.8mg，105.64μmol，20.78%產率)(RT=21.268min)及化合物881 2-甲氧基-5-[[2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(59.5mg，131.50μmol，25.87%產率)(RT=29.096min)。Racemic 2-methoxy-5-[[2-[( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl] -1-Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (230 mg, 508.33 μmol) was submitted to preparative chiral HPLC (column: Chiralpak AD-H III ( 250*30mm, 5mkm); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12ml/min) to obtain compound 894 2-methoxy-5-[[2-[( 2S, 5R )-5-methyl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (47.8 mg, 105.64 μmol, 20.78% yield) (RT=21.268 min) and compound 881 2-methoxy-5-[[2-[( 2R,5S )-5-methyl yl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (59.5 mg, 131.50 μmol, 25.87% yield) (RT=29.096 min).

化合物894 於分析條件下(管柱：AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為22.91min且化合物881 之保留時間為33.22min。The retention time of compound 894 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 22.91 min and the retention time of compound 881 was 33.22 min .

化合物894：保留時間：22.91minCompound 894: retention time: 22.91min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02(d,3H),1.39(m,1H),2.00(m,5H),3.78(m,4H),5.47(dd,1H),6.41(m,2H),7.76(m,3H),8.18(dd,1H),8.53(m,2H),11.01(s,1H),12.79(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.02(d,3H), 1.39(m,1H), 2.00(m,5H), 3.78(m,4H), 5.47(dd,1H), 6.41 (m, 2H), 7.76 (m, 3H), 8.18 (dd, 1H), 8.53 (m, 2H), 11.01 (s, 1H), 12.79 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=1.118min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=1.118 min.

化合物881：保留時間：33.22minCompound 881: retention time: 33.22min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02(d,3H),1.38(m,1H),1.86(m,1H),2.10(m,3H),3.78(m,5H),5.48(dd,1H),6.41(m,2H),7.76(m,3H),8.18(dd,1H),8.47(s,1H),8.54(m,1H),10.99(s,1H),12.80(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.02(d,3H), 1.38(m,1H), 1.86(m,1H), 2.10(m,3H), 3.78(m,5H), 5.48(dd,1H),6.41(m,2H),7.76(m,3H),8.18(dd,1H),8.47(s,1H),8.54(m,1H),10.99(s,1H),12.80 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值452.2；實測值453.2；Rt=1.120min。LCMS (ESI): [M] + m/z: calculated 452.2; found 453.2; Rt=1.120 min.

實例211. 5-(2-(2-(1'H -[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物899及化合物882)之合成Example 211. 5-(2-(2-(1'H-[ 1,3' -bipyrazol]-3-yl)-5-methylpiperidin-1-yl)-2-pendantoxyethyl Synthesis of amido)nicotinamide (compound 899 and compound 882)

Figure 110128222-A0202-12-1253-231
Figure 110128222-A0202-12-1253-231

步驟1：5-(2-(2-(1'H-[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸Step 1: 5-(2-(2-(1'H-[1,3'-bipyrazol]-3-yl)-5-methylpiperidin-1-yl)-2-pendoxoethyl amide) cigarette 鹼醯胺之合成Synthesis of Alkaline Amide

在25℃下，在1.5h時段內，將HATU(798.01mg，2.10mmol)小批量添加到(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]哌啶(650mg，1.91mmol，3HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(468.63mg，1.91mmol，HCl)及TEA(1.5g，14.82mmol，2.07mL)於DMF(4.5mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：25-50% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，以得到呈淡黃色膠狀物之5-[[2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(56mg，132.56μmol，6.95%產率)，其直接用於下一步驟中(將所有3種級分提交至製備型掌性HPLC)。HATU (798.01 mg, 2.10 mmol) was added in small batches to ( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl) at 25°C over a period of 1.5 h Pyrazol-3-yl]piperidine (650 mg, 1.91 mmol, 3HCl), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (468.63 mg, 1.91 mmol , HCl) and TEA (1.5 g, 14.82 mmol, 2.07 mL) in a stirred mixture of DMF (4.5 mL). The resulting mixture was stirred at 25°C for 18h and then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 25-50% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate : 30ml/min (loading pump 4ml/min MeOH) to give 5-[[2-[( 2R,5S )-5-methyl-2-[1-( 1H -pyrazole as a pale yellow gum -3-yl)pyrazol-3-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (56 mg, 132.56 μmol, 6.95% yield) , which was used directly in the next step (all 3 fractions were submitted to preparative chiral HPLC).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=2.060min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=2.060 min.

步驟2：掌性分離(化合物899 及化合物882 )Step 2: Chiral separation ( compound 899 and compound 882 )

將外消旋5-[[2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(56mg，132.56μmol)提交至製備型掌性HPLC(Chiralcel OJ-H-I(250*20，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min；管柱溫度：24℃；波長：205nm、215nm)，以得到化合物899 5-[[2-[(2S,5R )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(13.7mg，32.43μmol，24.46%產率)(RT=14.700min)及化合物882 5-[[2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(15.2mg，35.98μmol，27.14%產率)(RT=33.865min)。The racemic 5-[[2-[( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl ]-2-Oxyacetyl]amino]pyridine-3-carboxamide (56 mg, 132.56 μmol) was submitted to preparative chiral HPLC (Chiralcel OJ-HI (250*20, 5 mkm); mobile phase: Hexane-IPA-MeOH, 50-25-25; flow rate: 12 mL/min; column temperature: 24 °C; wavelength: 205 nm, 215 nm) to give compound 899 5-[[2-[( 2S,5R )- 5-Methyl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 -formamide (13.7 mg, 32.43 μmol, 24.46% yield) (RT=14.700 min) and compound 882 5-[[2-[( 2R,5S )-5-methyl-2-[1-( 1H -Pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (15.2 mg, 35.98 μmol, 27.14 % yield) (RT=33.865 min).

化合物899 於分析條件下(管柱：OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為11.87min且化合物882 之保留時間為33.79min。The retention time of compound 899 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 11.87 min and the retention time of compound 882 was 33.79 min .

化合物899：保留時間：11.87minCompound 899: retention time: 11.87min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(d,3H),1.40(m,1H),2.02(m,5H),3.68(m,1H),5.48(m,1H),6.40(m,1H),6.45(m,1H),7.60(d,1H),7.79(d,1H),8.17(m,2H),8.50(s,1H),8.76(m,1H),8.88(m,1H),11.22(s,1H),12.79(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03(d,3H), 1.40(m,1H), 2.02(m,5H), 3.68(m,1H), 5.48(m,1H), 6.40(m, 1H), 6.45(m, 1H), 7.60(d, 1H), 7.79(d, 1H), 8.17(m, 2H), 8.50(s, 1H), 8.76(m, 1H), 8.88 (m, 1H), 11.22 (s, 1H), 12.79 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=1.016min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=1.016 min.

化合物882：保留時間：33.79minCompound 882: retention time: 33.79min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(d,3H),1.38(m,1H),1.94(m,3H),2.18(m,2H),3.70(m,1H),5.48(dd,1H),6.40(m,1H),6.45(m,1H),7.59(dd,1H),7.79(m,1H),8.18(m,2H),8.50(s,1H),8.75(d,1H),8.88(d,1H),11.19(s,1H),12.80(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03(d,3H), 1.38(m,1H), 1.94(m,3H), 2.18(m,2H), 3.70(m,1H), 5.48(dd,1H),6.40(m,1H),6.45(m,1H),7.59(dd,1H),7.79(m,1H),8.18(m,2H),8.50(s,1H),8.75 (d, 1H), 8.88 (d, 1H), 11.19 (s, 1H), 12.80 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=1.016min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=1.016 min.

實例212. rel-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物946)及rel-5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物974)之合成Example 212. rel-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (compound 946) and rel-5-[[2-[(2R,5R)-4,4-difluoro-5-methyl Synthesis of yl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 974)

Figure 110128222-A0202-12-1255-232
Figure 110128222-A0202-12-1255-232

步驟1：外消旋-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: Racemic-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidine Synthesis of [methyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide

向5-[(2S,5S)-4,4-二氟-5-甲基-2-哌啶基]-2-甲基吡啶(0.35g，1.55mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(417.93mg，1.70mmol，HCl)及三乙胺(782.63mg，7.73mmol，1.08mL)之溶液中分批添加HATU(705.79mg，1.86mmol)。將所得混合物在25℃下攪拌12h且藉由HPLC(5-5-50% 0-1-5min H2 O/MeOH/0.1% NH4OH，流速：30mL/min(裝載泵4mL/min甲醇)目標質量 417.42管柱：YMC Triart C18 100x20mm，5um)純化，以獲得5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(170mg，407.27μmol，26.33%產率)。To 5-[(2S,5S)-4,4-difluoro-5-methyl-2-piperidinyl]-2-methylpyridine (0.35 g, 1.55 mmol), 2-[(5-aminomethane To a solution of acyl-3-pyridyl)amino]-2-oxoacetic acid (417.93 mg, 1.70 mmol, HCl) and triethylamine (782.63 mg, 7.73 mmol, 1.08 mL) was added HATU (705.79 mg, 1.86 mmol). The resulting mixture was stirred at 25 °C for 12 h and analyzed by HPLC (5-5-50% 0-1-5 min H2O /MeOH/0.1% NH4OH, flow rate: 30 mL/min (loading pump 4 mL/min methanol) target mass 417.42 Column: YMC Triart C18 100x20mm, 5um) purification to obtain 5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3- Pyridinyl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (170 mg, 407.27 μmol, 26.33% yield).

此化合物不經HNMR即用於掌性拆分。This compound was used for chiral resolution without HNMR.

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=1.295min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=1.295 min.

步驟2：rel-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物946 )及rel-5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物974 )之合成Step 2: rel-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 946 ) and rel-5-[[2-[(2R,5R)-4,4-difluoro-5-methyl Synthesis of base-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 974 )

對外消旋-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.17g，407.27μmol)進行掌性分離(樣品資訊：YMC Chiral Art(250*20mm，5mkm)，己烷-IPA-MeOH，40-30-30，12mL/min)，以獲得化合物946 rel-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(81mg，194.05μmol，95.29%產率)及化合物974 rel-5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(84mg，201.24μmol，98.82%產率)。Racemic-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]- 2-Oxyacetyl]amino]pyridine-3-carboxamide (0.17g, 407.27μmol) for chiral separation (sample information: YMC Chiral Art (250*20mm, 5mkm), hexane-IPA- MeOH, 40-30-30, 12 mL/min) to obtain compound 946 rel-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl) (81 mg, 194.05 μmol, 95.29% yield) and compound 974 rel- 5-[[2-[(2R,5R)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (84 mg, 201.24 μmol, 98.82% yield).

化合物946： RT(IC,CO2 -MeOH,60-40,0.6mL/min)=6.533min。 Compound 946: RT (IC, CO2 -MeOH, 60-40, 0.6 mL/min) = 6.533 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.05-1.15(m,3H),2.12-2.28(m,1H),2.37-2.45(m,4H),2.80-2.91(m,1H),3.01-3.47(m,1H),3.81-4.29(m,1H),5.57-5.88(m,1H),7.15-7.29(m,1H),7.54-7.66(m,2H),8.07-8.21(m,1H),8.37-8.52(m,2H),8.72-8.80(m,1H),8.80-8.95(m,1H),11.16-11.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.05-1.15(m,3H), 2.12-2.28(m,1H), 2.37-2.45(m,4H), 2.80-2.91(m,1H), 3.01- 3.47(m,1H),3.81-4.29(m,1H),5.57-5.88(m,1H),7.15-7.29(m,1H),7.54-7.66(m,2H),8.07-8.21(m,1H) ), 8.37-8.52(m, 2H), 8.72-8.80(m, 1H), 8.80-8.95(m, 1H), 11.16-11.39(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.4；Rt=1.332min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.4; Rt=1.332 min.

化合物974： RT(IC,CO2 -MeOH,60-40,0.6mL/min)=7.087min。 Compound 974: RT (IC, CO2 -MeOH, 60-40, 0.6 mL/min) = 7.087 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.05-1.13(m,3H),2.11-2.26(m,1H),2.37-2.45 (m,4H),2.79-2.90(m,1H),3.00-3.46(m,1H),3.79-4.29(m,1H),5.57-5.87(m,1H),7.16-7.28(m,1H),7.53-7.66(m,2H),8.08-8.21(m,1H),8.34-8.53(m,2H),8.70-8.80(m,1H),8.80-8.94(m,1H),11.15-11.38(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ 1.05-1.13 (m, 3H), 2.11-2.26 (m, 1H), 2.37-2.45 (m, 4H), 2.79-2.90 (m, 1H), 3.00- 3.46(m,1H),3.79-4.29(m,1H),5.57-5.87(m,1H),7.16-7.28(m,1H),7.53-7.66(m,2H),8.08-8.21(m,1H) ), 8.34-8.53(m, 2H), 8.70-8.80(m, 1H), 8.80-8.94(m, 1H), 11.15-11.38(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.4；Rt=1.338min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.4; Rt=1.338 min.

實例213. rel-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物936)及rel-5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物908)之合成Example 213. rel-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (compound 936) and rel-5-[[2-[(2R,5R)-4,4- Difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3 -Synthesis of carboxamide (compound 908)

Figure 110128222-A0202-12-1257-233
Figure 110128222-A0202-12-1257-233

步驟1：外消旋-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: Racemic-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidine [Synthesis of]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide

向5-[(2S,5S)-4,4-二氟-5-甲基-2-哌啶基]-2-甲基吡啶(0.35g，1.55mmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(406.98mg，1.70mmol)及三乙胺(782.63mg，7.73mmol，1.08mL)之溶液中分批添加HATU(705.79mg，1.86mmol).將所得混合物在25℃下攪拌12h且藉由HPLC(15-65% 0-5min H2 O/MeOH，流速：30mL/min(裝載泵4mL/min甲醇)目標質量447.45管柱：YMC Triart C18 100x20mm，5um)純化，以獲得5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.27g， 603.44μmol，39.01%產率)。To 5-[(2S,5S)-4,4-difluoro-5-methyl-2-piperidinyl]-2-methylpyridine (0.35 g, 1.55 mmol), 2-[(5-aminomethane Acyl-6-methoxy-3-pyridinyl)amino]-2-pendoxoacetic acid (406.98 mg, 1.70 mmol) and triethylamine (782.63 mg, 7.73 mmol, 1.08 mL) in portions in a solution HATU (705.79 mg, 1.86 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h and analyzed by HPLC (15-65% 0-5 min H2O /MeOH, flow rate: 30 mL/min (load pump 4 mL/min methanol) Target mass 447.45 column: YMC Triart C18 100x20mm, 5um) purification to obtain 5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl- 3-Pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (0.27 g, 603.44 μmol, 39.01% yield) .

此化合物不經HNMR即用於掌性拆分。This compound was used for chiral resolution without HNMR.

LCMS(ESI)：[M+H]+ m/z：計算值447.2；實測值448.2；Rt=1.747min。LCMS (ESI): [M+H] + m/z: calculated 447.2; found 448.2; Rt=1.747 min.

步驟2：rel-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物936 )及rel-5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物908 )之合成Step 2: rel-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide ( compound 936 ) and rel-5-[[2-[(2R,5R)-4,4- Difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3 -Synthesis of formamide ( compound 908 )

對外消旋-5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(0.27g，603.44μmol)進行掌性分離(Chiralpak IC-II(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)，以獲得5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(106mg，236.91μmol，78.52%產率)及5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(98mg，219.03μmol，72.59%產率)。Racemic-5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]- 2-Oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (0.27g, 603.44μmol) was chiral separation (Chiralpak IC-II (250*20, 5mkm), hexane alkane-IPA-MeOH, 50-25-25, 12 mL/min) to obtain 5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl) (106 mg, 236.91 μmol, 78.52% yield) ) and 5-[[2-[(2R,5R)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (98 mg, 219.03 μmol, 72.59% yield).

化合物936： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=23.904min。 Compound 936: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 23.904 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.06(d,3H),2.19(m,1H),2.42(m,4H),2.87(m,2H),3.62(dd,1H),3.91(m,3H),5.72(dd,1H),7.23(dd,1H),7.61(d,1H),7.72(m,2H),8.42(m,1H),8.49(m,2H),11.09(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.06(d,3H), 2.19(m,1H), 2.42(m,4H), 2.87(m,2H), 3.62(dd,1H), 3.91(m,3H),5.72(dd,1H),7.23(dd,1H),7.61(d,1H),7.72(m,2H),8.42(m,1H),8.49(m,2H),11.09 (m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值447.2；實測值448.4；Rt=1.648min。LCMS (ESI): [M+H] + m/z: calculated 447.2; found 448.4; Rt=1.648 min.

化合物908： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=39.401min。 Compound 908: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 39.401 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.08(d,3H),2.19(m,1H),2.42(m,4H),2.88(m,2H),3.62(dd,1H),3.93(m,3H),5.72(dd,1H),7.23(dd,1H),7.61(d,1H),7.72(m,2H),8.40(m,1H),8.49(m,2H),11.08(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.08(d,3H), 2.19(m,1H), 2.42(m,4H), 2.88(m,2H), 3.62(dd,1H), 3.93(m, 3H), 5.72(dd, 1H), 7.23(dd, 1H), 7.61(d, 1H), 7.72(m, 2H), 8.40(m, 1H), 8.49(m, 2H), 11.08 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值447.2；實測值448.4；Rt=1.650min。LCMS (ESI): [M+H] + m/z: calculated 447.2; found 448.4; Rt=1.650 min.

實例214. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物935)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物909)之合成Example 214. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6- Methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide (compound 935) and rel-N-(6-amino-5-ethyl-3-pyridyl)- 2-[(2R,5R)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 909)

Figure 110128222-A0202-12-1259-234
Figure 110128222-A0202-12-1259-234

步驟1：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: Racemic-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-( Synthesis of 6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide

向5-[(2S,5S)-4,4-二氟-5-甲基-2-哌啶基]-2-甲基吡啶(0.35g，1.55mmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(355.97mg，1.70mmol)及三乙胺(782.63mg，7.73mmol，1.08mL)之溶液中分批添加HATU(705.79mg，1.86mmol)。將所得混合物在25℃下攪拌12h且藉由HPLC(15-65% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30mL/min(裝載泵4mL/min甲醇)目標質量417.46管柱：YMC Triart C18 100x20mm，5um)，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(0.2g，479.10μmol，30.97%產率)。To 5-[(2S,5S)-4,4-difluoro-5-methyl-2-piperidinyl]-2-methylpyridine (0.35 g, 1.55 mmol), 2-[(6-amino HATU ( 705.79 mg, 1.86 mmol). The resulting mixture was stirred at 25 °C for 12 h and analyzed by HPLC (15-65% 0-5 min H2O /MeOH/0.1% NH4OH, flow rate: 30 mL/min (loading pump 4 mL/min methanol) target mass 417.46 column: YMC Triart C18 100x20mm, 5um) to obtain N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl- 2-(6-Methyl-3-pyridinyl)-1-piperidinyl]-2-oxyacetamide (0.2 g, 479.10 μmol, 30.97% yield).

此化合物不經HNMR即用於掌性拆分。This compound was used for chiral resolution without HNMR.

LCMS(ESI)：[M+H]+ m/z：計算值417.0；實測值418.0；Rt=1.282min。LCMS (ESI): [M+H] + m/z: calculated 417.0; found 418.0; Rt=1.282 min.

步驟2 rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物935 )及rel-N-(6-胺基-5-乙基-3-吡啶Step 2 rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl) ( Compound 935 ) and rel-N-(6-amino-5-ethyl-3-pyridine) 基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物909 )之合成base)-2-[(2R,5R)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-side oxy Synthesis of Acetamide ( Compound 909 )

對外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(0.2g，479.10μmol)進行掌性分離(YMC Chiral Art(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12mL/min)，以獲得rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(86mg，206.01μmol，86.00%產率)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(86mg，206.01μmol，86.00%產率)。Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl) Chiral separation (YMC Chiral Art (250*20, 5mkm), Hexane-IPA -MeOH, 60-20-20, 12 mL/min) to obtain rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-4,4- Difluoro-5-methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]-2-oxyacetamide (86 mg, 206.01 μmol, 86.00% yield) and rel -N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5R)-4,4-difluoro-5-methyl-2-(6-methyl-3 -Pyridinyl)-1-piperidinyl]-2-oxoacetamide (86 mg, 206.01 μmol, 86.00% yield).

化合物935：Compound 935:

RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=15.626min。RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 15.626 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.08(m,6H),2.18(m,1H),2.40(m,5H),2.57(m,2H),2.89(m,1H),3.59(m,1H),5.70(m,3H),7.24(m,1H),7.47(m,1H),7.60(m,1H),8.03(m,1H),8.39(s,1H),10.58(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.08(m, 6H), 2.18(m, 1H), 2.40(m, 5H), 2.57(m, 2H), 2.89(m, 1H), 3.59(m, 1H), 5.70(m, 3H), 7.24(m, 1H), 7.47(m, 1H), 7.60(m, 1H), 8.03(m, 1H), 8.39(s, 1H), 10.58 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=1.298min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=1.298 min.

化合物909：Compound 909:

RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=19.9458min。RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 19.9458 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.08(m,7H),2.19(m,1H),2.40(m,6H),2.91(m,1H),3.67(m,1H),5.71(m,3H),7.23(m,1H),7.51(m,2H),8.03(m,1H),8.39(s,1H),10.58(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.08(m, 7H), 2.19(m, 1H), 2.40(m, 6H), 2.91(m, 1H), 3.67(m, 1H), 5.71(m, 3H), 7.23(m, 1H), 7.51(m, 2H), 8.03(m, 1H), 8.39(s, 1H), 10.58(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=1.335min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=1.335 min.

實例215. 外消旋-2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物891)之合成Example 215. Racemic-2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1 Synthesis of ,8-naphthyridin-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 891)

Figure 110128222-A0202-12-1261-235
Figure 110128222-A0202-12-1261-235

將外消旋-6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-1,8-萘啶-2-酮(200mg，815.26μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(195.00mg，815.26μmol)、三乙胺(412.48mg，4.08mmol，568.16μL)混合於DMF(5mL)中，然後添加HATU(464.98mg，1.22mmol)。將所得混合物在24℃下攪拌12h。將溶劑蒸發且將所得混合物與於甲醇(10mL)中之SiliaMetS® DMT(50mg)一起攪拌。將混合物過濾且在減壓下蒸發。藉由HPLC(2-10min 50-100%甲醇/H2 O)純化所得粗材料，以獲得2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(51mg，109.33μmol，13.41%產率)。Racemic-6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-1,8-naphthyridin-2-one (200 mg, 815.26 μmol ), 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-oxyacetic acid (195.00 mg, 815.26 μmol), triethylamine (412.48 mg, 4.08 mmol, 568.16 μL) in DMF (5 mL), then HATU (464.98 mg, 1.22 mmol) was added. The resulting mixture was stirred at 24 °C for 12 h. The solvent was evaporated and the resulting mixture was stirred with SiliaMetS® DMT (50 mg) in methanol (10 mL). The mixture was filtered and evaporated under reduced pressure. The resulting crude material was purified by HPLC (2-10 min 50-100% methanol/ H2O ) to obtain 2-methoxy-5-[[2-[(2S,5R)-5-methyl-2- (7-Pendant oxy-6,8-dihydro-5H-1,8-naphthyridin-3-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3 - Formamide (51 mg, 109.33 μmol, 13.41% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.71(m,1H),1.89(m,1H),2.04(m,1H),2.18(m,1H),2.98(m,4H),3.45(m,1H),3.93(m,4H),5.32(m,1H),7.53(m,1H),7.72(m,2H),8.03(s,1H),8.49(m,2H),10.44(m,1H),11.01(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.33(m, 1H), 1.71(m, 1H), 1.89(m, 1H), 2.04(m, 1H), 2.18(m, 1H), 2.98(m, 4H), 3.45(m, 1H), 3.93(m, 4H), 5.32(m, 1H), 7.53(m, 1H), 7.72(m, 2H), 8.03 (s, 1H), 8.49 (m, 2H), 10.44 (m, 1H), 11.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值467.2；Rt=1.028min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 467.2; Rt=1.028 min.

實例216. 外消旋-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物888)之合成Example 216. Racemic-5-[[2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1,8-naphthyridine- Synthesis of 3-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 888)

Figure 110128222-A0202-12-1262-236
Figure 110128222-A0202-12-1262-236

將外消旋-6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-1,8-萘啶-2-酮(200mg，815.26μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(200.24mg，815.26μmol，HCl)、三乙胺(412.48mg，4.08mmol，568.16μL)混合於DMF(5mL)中，然後添加HATU(464.98mg，1.22mmol)。將所得混合物在25℃下攪拌12h。將溶劑蒸發且將所得混合物與於甲醇(10ml)中之SiliaMetS® DMT(50mg)一起攪拌。將混合物過濾且在減壓下蒸發。藉由HPLC(2-10min 50-100%甲醇/H2 O)純化所得粗材料，以獲得5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(126.9mg，290.75μmol，35.66%產率)。Racemic-6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-1,8-naphthyridin-2-one (200 mg, 815.26 μmol ), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (200.24mg, 815.26μmol, HCl), triethylamine (412.48mg, 4.08mmol, 568.16μL ) in DMF (5 mL), then HATU (464.98 mg, 1.22 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the resulting mixture was stirred with SiliaMetS® DMT (50 mg) in methanol (10 ml). The mixture was filtered and evaporated under reduced pressure. The resulting crude material was purified by HPLC (2-10 min 50-100% methanol/ H2O ) to obtain 5-[[2-[(2S,5R)-5-methyl-2-(7-pendoxyl -6,8-Dihydro-5H-1,8-naphthyridin-3-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (126.9 mg, 290.75 μmol, 35.66% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.70(m,1H),1.89(m,1H),2.05(m,1H),2.17(m,1H),2.87(m,4H),3.81(m,1H),5.32(m,1H),7.54(m,1H),7.59(m,1H),8.04(s,1H),8.15(m,1H),8.47(m,1H),8.75(m,1H),8.85(m,1H),10.44(m,1H),11.22(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.33(m, 1H), 1.70(m, 1H), 1.89(m, 1H), 2.05(m, 1H), 2.17(m, 1H), 2.87(m, 4H), 3.81(m, 1H), 5.32(m, 1H), 7.54(m, 1H), 7.59(m, 1H), 8.04(s, 1H), 8.15 (m, 1H), 8.47 (m, 1H), 8.75 (m, 1H), 8.85 (m, 1H), 10.44 (m, 1H), 11.22 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.0；Rt=0.930min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.0; Rt=0.930 min.

實例217. 5-(2-(2-(2-胺基苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物987及化合物1001)之合成Example 217. 5-(2-(2-(2-Aminobenzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido) Synthesis of Nicotinamide (Compound 987 and Compound 1001)

Figure 110128222-A0202-12-1262-237
Figure 110128222-A0202-12-1262-237

步驟1：5-(2-(2-(2-胺基苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)Step 1: 5-(2-(2-(2-Aminobenzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido) 菸鹼醯胺之合成Synthesis of Nicotinamide

在25℃下，在0.5h時段內，將HATU(169.09mg，444.70μmol)小批量添加到5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(100mg，404.27μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(114.19mg，464.91μmol，HCl)及TEA(204.54mg，2.02mmol，281.74μL)於DMF(4mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：10-60% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，以得到呈白色固體之5-[[2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(106mg，241.73μmol，59.79%產率)，將其直接提交至製備型掌性HPLC。HATU (169.09 mg, 444.70 μmol) was added in small batches to 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzene at 25 °C over a period of 0.5 h Thiazol-2-amine (100 mg, 404.27 μmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (114.19 mg, 464.91 μmol, HCl) and TEA (204.54 mg, 2.02 mmol, 281.74 μL) in a stirred mixture in DMF (4 mL). The resulting mixture was stirred at 25°C for 18h, then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 10-60% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate : 30 ml/min (loading pump 4 ml/min MeOH) to give 5-[[2-[( 2R,5S )-2-(2-amino-1,3-benzothiazole-5- as a white solid) (106 mg, 241.73 μmol, 59.79% yield), which was submitted directly to preparative chiral HPLC.

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.810min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.810 min.

步驟2：掌性分離(化合物987 及化合物1001 )Step 2: Chiral separation ( compound 987 and compound 1001 )

外消旋5-[[2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(106mg，241.73μmol)提交至製備型掌性HPLC(管柱：Chiralpak IA-I(250*20，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12ml/min；管柱溫度：24℃；波長：205nm、215nm、254nm)，以得到化合物1001 5-[[2-[(2S,5R )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(45mg，102.62μmol，42.45%產率)(RT=22.501min)及化合物987 5-[[2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(116mg，粗品)(RT=39.531min)。Racemic 5-[[2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carbamoylamine (106 mg, 241.73 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IA-I (250*20, 5 mkm); mobile phase: Hexane-IPA-MeOH, 50-25-25; flow rate: 12ml/min; column temperature: 24°C; wavelength: 205nm, 215nm, 254nm) to give compound 1001 5-[[2-[( 2S,5R )-2-(2-Amino-1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3 -formamide (45 mg, 102.62 μmol, 42.45% yield) (RT=22.501 min) and compound 987 5-[[2-[( 2R,5S )-2-(2-amino-1,3-benzene Thiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (116 mg, crude) (RT=39.531 min) .

化合物987 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為43.57min且化合物1001 之保留時間為23.68min。The retention time of compound 987 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 43.57 min and the retention time of compound 1001 was 23.68 min.

化合物987：保留時間：43.57minCompound 987: retention time: 43.57min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.06(m,3H),1.26-1.41(m,1H),1.67 -1.77(m,1H),1.82-1.94(m,1H),2.02-2.19(m,1H),2.19-2.28(m,1H),2.80-3.20(m,1H),3.44-4.04(m,1H),5.16-5.66(m,1H),6.92-7.03(m,1H),7.25-7.32(m,1H),7.42-7.47(m,2H),7.53-7.61(m,1H),7.61-7.66(m,1H),8.09-8.20(m,1H),8.42-8.53(m,1H),8.69-8.79(m,1H),8.82-8.94(m,1H),11.06-11.43(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.06(m,3H), 1.26-1.41(m,1H), 1.67-1.77(m,1H), 1.82-1.94(m,1H) ,2.02-2.19(m,1H),2.19-2.28(m,1H),2.80-3.20(m,1H),3.44-4.04(m,1H),5.16-5.66(m,1H),6.92-7.03( m,1H),7.25-7.32(m,1H),7.42-7.47(m,2H),7.53-7.61(m,1H),7.61-7.66(m,1H),8.09-8.20(m,1H), 8.42-8.53(m,1H), 8.69-8.79(m,1H), 8.82-8.94(m,1H), 11.06-11.43(m,1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.705min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.705 min.

化合物1001：保留時間：23.68minCompound 1001: retention time: 23.68min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.06(m,3H),1.26-1.41(m,1H),1.67-1.77(m,1H),1.82-1.94(m,1H),2.02-2.19(m,1H),2.19-2.28(m,1H),2.80-3.20(m,1H),3.44-4.04(m,1H),5.16-5.66(m,1H),6.92-7.03(m,1H),7.25-7.32(m,1H),7.42-7.47(m,2H),7.53-7.61(m,1H),7.61-7.66(m,1H),8.09-8.20(m,1H),8.42-8.53(m,1H),8.69-8.79(m,1H),8.82-8.94(m,1H),11.06-11.43(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.06(m,3H), 1.26-1.41(m,1H), 1.67-1.77(m,1H), 1.82-1.94(m,1H) ,2.02-2.19(m,1H),2.19-2.28(m,1H),2.80-3.20(m,1H),3.44-4.04(m,1H),5.16-5.66(m,1H),6.92-7.03( m,1H),7.25-7.32(m,1H),7.42-7.47(m,2H),7.53-7.61(m,1H),7.61-7.66(m,1H),8.09-8.20(m,1H), 8.42-8.53(m,1H), 8.69-8.79(m,1H), 8.82-8.94(m,1H), 11.06-11.43(m,1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.703min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.703 min.

實例218. 2-甲氧基-5-(2-(5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物954)之合成Example 218. 2-Methoxy-5-(2-(5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)piperidin-1-yl)-2 -Synthesis of pendant oxyacetamido)nicotinamide (compound 954)

Figure 110128222-A0202-12-1264-238
Figure 110128222-A0202-12-1264-238

在25℃下，在0.5h時段內，將HATU(169.09mg，444.70μmol)小批量添加到5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(100mg，404.27μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(111.20mg，464.91μmol)及TEA(163.63mg，1.62mmol，225.39μL)於DMF(4mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：15-65% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，以得到呈白色固體之化合物954 5-[[2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(123mg，262.52μmol，64.94%產率)。HATU (169.09 mg, 444.70 μmol) was added in small batches to 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzene at 25 °C over a period of 0.5 h Thiazol-2-amine (100 mg, 404.27 μmol), 2-[(5-aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (111.20 mg, 464.91 μmol) and TEA (163.63 mg, 1.62 mmol, 225.39 μL) in a stirred mixture of DMF (4 mL). The resulting mixture was stirred at 25°C for 18h and then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 15-65% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate : 30 ml/min (loading pump 4 ml/min MeOH) to give compound 954 as a white solid 5-[[2-[( 2R,5S )-2-(2-amino-1,3-benzothiazole- 5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (123 mg, 262.52 μmol, 64.94% Yield).

化合物954： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94-1.08(m,3H),1.27-1.39(m,1H),1.65-1.73(m,1H),1.81-1.91(m,1H),2.08-2.29(m,2H),2.75-3.02(m,1H),3.43-4.03(m,4H),5.14-5.64(m,1H),6.92-7.01(m,1H),7.24-7.32(m,1H),7.37-7.48(m,2H),7.58-7.65(m,1H),7.65-7.77(m,2H),8.38-8.47(m,1H),8.49-8.59(m,1H),11.06(s,1H)。 Compound 954: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.94-1.08 (m, 3H), 1.27-1.39 (m, 1H), 1.65-1.73 (m, 1H), 1.81-1.91 (m) ,1H),2.08-2.29(m,2H),2.75-3.02(m,1H),3.43-4.03(m,4H),5.14-5.64(m,1H),6.92-7.01(m,1H),7.24 -7.32(m,1H),7.37-7.48(m,2H),7.58-7.65(m,1H),7.65-7.77(m,2H),8.38-8.47(m,1H),8.49-8.59(m, 1H), 11.06(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值468.2；實測值469.2；Rt=2.106min。LCMS (ESI): [M] + m/z: calculated 468.2; found 469.2; Rt=2.106 min.

實例219. 2-(2-(2-胺基苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-N -(5,6-二甲基吡啶-3-基)-2-側氧基乙醯胺(化合物920)之合成Example 219. 2-(2-(2-Aminobenzo[ d ]thiazol-5-yl)-5-methylpiperidin - 1-yl)-N-(5,6-lutidine-3 Synthesis of -yl)-2-oxoacetamide (Compound 920)

Figure 110128222-A0202-12-1265-239
Figure 110128222-A0202-12-1265-239

在25℃下，在0.5h時段內，將HATU(169.09mg，444.70μmol)小批量添加到5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(100mg，404.27μmol)、2-[(5,6-二甲基-3-吡啶基)胺基]-2-側氧基乙酸(137.32mg，464.91μmol)及TEA(163.63mg，1.62mmol，225.39μL)於DMF(4mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：50-80% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，以得到呈白色固體之化合物920 2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(5,6-二甲基-3-吡啶基)-2-側氧基乙醯胺(70mg，165.28μmol，40.88%產率)。HATU (169.09 mg, 444.70 μmol) was added in small batches to 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzene at 25 °C over a period of 0.5 h Thiazol-2-amine (100 mg, 404.27 μmol), 2-[(5,6-dimethyl-3-pyridyl)amino]-2-oxoacetic acid (137.32 mg, 464.91 μmol) and TEA ( 163.63 mg, 1.62 mmol, 225.39 μL) in a stirred mixture of DMF (4 mL). The resulting mixture was stirred at 25°C for 18h and then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 50-80% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate : 30 ml/min (loading pump 4 ml/min MeOH) to give compound 920 as a white solid 2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl) -5-Methyl-1-piperidinyl]-N-(5,6- dimethyl -3-pyridyl)-2-oxyacetamide (70 mg, 165.28 μmol, 40.88% yield).

化合物920： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(dd,3H),1.33(m,1H),1.70(m,1H),1.86(m,1H),2.02(m,1H),2.20(m,4H),2.34(m,3H),2.95(m,1H),3.71(dd,1H),5.37(m,1H),6.96(dd,1H),7.27(m,1H),7.44(m,2H),7.62(m,1H),7.78(m,1H),8.46(m,1H),10.92(m,1H)。 Compound 920: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.01 (dd, 3H), 1.33 (m, 1H), 1.70 (m, 1H), 1.86 (m, 1H), 2.02 (m, 1H), 2.20(m, 4H), 2.34(m, 3H), 2.95(m, 1H), 3.71(dd, 1H), 5.37(m, 1H), 6.96(dd, 1H), 7.27(m, 1H) ), 7.44(m, 2H), 7.62(m, 1H), 7.78(m, 1H), 8.46(m, 1H), 10.92(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=1.861min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=1.861 min.

實例220.N -(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-胺基苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物984及化合物996)之合成Example 220. N- (6-Amino-5-ethylpyridin-3-yl)-2-(2-(2-aminobenzo[ d ]thiazol-5-yl)-5-methylpiperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 984 and Compound 996)

Figure 110128222-A0202-12-1266-240
Figure 110128222-A0202-12-1266-240

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-胺基苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-(2-aminobenzo[d]thiazol-5-yl)-5-methylpiperidine Synthesis of -1-yl)-2-oxyacetamide

在25℃下，在0.5h時段內，將HATU(169.09mg，444.70μmol)小批量添加到5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(100mg，404.27μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(97.26mg，464.91μmol)及TEA(163.63mg，1.62mmol，225.39μL)於DMF(4mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：20-70% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，以得到呈粉色膠狀物之2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(110mg，250.83μmol，62.04%產率)，將其直接提交至製備型掌性HPLC。HATU (169.09 mg, 444.70 μmol) was added in small batches to 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzene at 25 °C over a period of 0.5 h Thiazol-2-amine (100 mg, 404.27 μmol), 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (97.26 mg, 464.91 μmol) and In a stirred mixture of TEA (163.63 mg, 1.62 mmol, 225.39 [mu]L) in DMF (4 mL). The resulting mixture was stirred at 25°C for 18h, then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 20-70% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate : 30ml/min (loading pump 4ml/min MeOH) to give 2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl) as a pink gum -5-Methyl - 1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxyacetamide (110 mg, 250.83 μmol, 62.04% yield ), which were submitted directly to preparative chiral HPLC.

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.781min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.781 min.

步驟2：掌性分離(化合物984 及化合物996 )Step 2: Chiral separation ( compound 984 and compound 996 )

將外消旋2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(110mg，250.83μmol)提交至製備型掌性HPLC(管柱：Chiralpak IA-I(250*20，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12ml/min；管柱溫度：24℃；波長：205nm、215nm、254nm)，以得到第1粗級分(RT=30.983min)及化合物996 2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(46.8mg，106.72μmol，42.55%產率)(RT=48.378min)。藉由製備型掌性HPLC(管柱：Chiralpak IC-II(250*20，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min；管柱溫度：24℃；波長：205nm、215nm)純化第1粗級分，以得到化合物984 2-[(2S,5R )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(53mg，120.85μmol，48.18%產率)(RT=44.479min)。The racemic 2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl)-5-methyl - 1-piperidinyl]-N-(6 - Amino-5-ethyl-3-pyridyl)-2-oxoacetamide (110 mg, 250.83 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IA-I (250*20, 5 mkm) ); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12ml/min; column temperature: 24°C; wavelength: 205nm, 215nm, 254nm) to obtain the first crude fraction (RT= 30.983min) and compound 996 2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl)-5-methyl - 1-piperidinyl]-N- (6-Amino-5-ethyl-3-pyridyl)-2-oxoacetamide (46.8 mg, 106.72 μmol, 42.55% yield) (RT=48.378 min). By preparative chiral HPLC (column: Chiralpak IC-II (250*20, 5mkm); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12 ml/min; column temperature: 24 °C; wavelength: 205 nm, 215 nm) Purification of the 1st crude fraction to give compound 984 2-[( 2S,5R )-2-(2-amino-1,3-benzothiazol-5-yl)-5 -Methyl - 1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxyacetamide (53 mg, 120.85 μmol, 48.18% yield) ( RT=44.479min).

化合物996 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為64.84min且化合物984 之保留時間為34.41min。The retention time of compound 996 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 64.84 min and the retention time of compound 984 was 34.41 min.

化合物996：保留時間：64.84minCompound 996: retention time: 64.84min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.02(m,3H),1.05-1.14(m,3H),1.28-1.41(m,1H),1.65-1.76(m,1H),1.80-1.90(m,1H),1.98-2.15(m,1H),2.17-2.27(m,1H),2.35-2.42(m,2H),2.75-3.26(m,1H),3.45-4.03(m,1H),5.14-5.66(m,3H),6.91-7.00(m,1H),7.23-7.32(m,1H),7.41-7.54(m,3H),7.59-7.66(m,1H),7.96-8.07(m,1H),10.37-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.02(m,3H), 1.05-1.14(m,3H), 1.28-1.41(m,1H), 1.65-1.76(m,1H) ,1.80-1.90(m,1H),1.98-2.15(m,1H),2.17-2.27(m,1H),2.35-2.42(m,2H),2.75-3.26(m,1H),3.45-4.03( m,1H),5.14-5.66(m,3H),6.91-7.00(m,1H),7.23-7.32(m,1H),7.41-7.54(m,3H),7.59-7.66(m,1H), 7.96-8.07 (m, 1H), 10.37-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.700min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.700 min.

化合物984：保留時間：34.41minCompound 984: retention time: 34.41min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.05-1.15(m,3H),1.26 -1.39(m,1H),1.65-1.75(m,1H),1.80-1.92(m,1H),1.95-2.17(m,1H),2.17-2.28(m,1H),2.35-2.42(m,2H),2.73-3.24(m,1H),3.43-4.04(m,1H),5.15-5.67(m,3H),6.91-7.02(m,1H),7.24-7.31(m,1H),7.41-7.51(m,3H),7.59-7.64(m,1H),7.95-8.08(m,1H),10.43-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,3H), 1.05-1.15(m,3H), 1.26-1.39(m,1H), 1.65-1.75(m,1H) ,1.80-1.92(m,1H),1.95-2.17(m,1H),2.17-2.28(m,1H),2.35-2.42(m,2H),2.73-3.24(m,1H),3.43-4.04( m,1H),5.15-5.67(m,3H),6.91-7.02(m,1H),7.24-7.31(m,1H),7.41-7.51(m,3H),7.59-7.64(m,1H), 7.95-8.08 (m, 1H), 10.43-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.690min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.690 min.

實例221. 2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-噻唑-5-基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物514)及2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-噻唑-5-基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物516)之合成Example 221. 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-thiazol-5-yl-1-piperidinyl]-2-oxyethanoyl ]Amino]pyridine-3-carbamide (Compound 514) and 2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-thiazol-5-yl-1- Synthesis of piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 516)

Figure 110128222-A0202-12-1268-241
Figure 110128222-A0202-12-1268-241

步驟1：2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-噻唑-5-基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-[(2S,5R)-5-methyl-2-thiazol-5-yl-1-piperidinyl]-2-oxyethanoyl Synthesis of ]amino]pyridine-3-carboxamide

向5-[(2S,5R)-5-甲基-2-哌啶基]噻唑(0.25g，1.37mmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(466.81mg，1.37mmol，Et3N)及三乙胺(693.90mg，6.86mmol，955.78μL)之溶液中分批添加HATU(547.55mg，1.44mmol)。將所得混合物在25℃下攪拌3h且使其經歷HPLC：40-40-75% 0-1-5min水-甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量403，管柱：YMC Triart C18 100x20mm，5um)，以得到2-甲氧基-5-[[2-[(2S,5R)-5-甲基-2-噻唑-5-基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(150mg，371.79μmol，27.11%產率)。To 5-[(2S,5R)-5-methyl-2-piperidinyl]thiazole (0.25 g, 1.37 mmol), 2-[(5-aminocarboxy-6-methoxy-3-pyridine To a solution of triethylamine (693.90 mg, 6.86 mmol, 955.78 μL) was added HATU (547.55 mg, 1.44 mmol) in portions. The resulting mixture was stirred at 25°C for 3h and subjected to HPLC: 40-40-75% 0-1-5min water-methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 403, column : YMC Triart C18 100x20mm, 5um) to give 2-methoxy-5-[[2-[(2S,5R)-5-methyl-2-thiazol-5-yl-1-piperidinyl]- 2-Pendant oxyacetoxy]amino]pyridine-3-carboxamide (150 mg, 371.79 μmol, 27.11% yield).

此物質不經NMR-光譜即用於掌性拆分。This material was used for chiral resolution without NMR-spectroscopy.

LCMS(ESI)：[M+H]+ m/z：計算值403.1；實測值404.2；Rt=2.305min。LCMS (ESI): [M+H]+ m/z: calculated 403.1; found 404.2; Rt=2.305 min.

步驟2：2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-噻唑-5-基-1-哌啶基]-2-側氧基乙醯基]Step 2: 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-thiazol-5-yl-1-piperidinyl]-2-oxyethanoyl ] 胺基]吡啶-3-甲醯胺(化合物514 )及2-甲氧基-5-[[2-[(2S,5R)-5-甲基2-噻唑-5-基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物516 )之合成Amino]pyridine-3-carboxamide ( compound 514 ) and 2-methoxy-5-[[2-[(2S,5R)-5-methyl 2-thiazol-5-yl-1-piperidine [Synthesis of]-2-oxyacetyl]amino]pyridine-3-carboxamide ( Compound 516 )

在以下條件下分離鏡像異構物：管柱：Chiral ART纖維素-SC(250*20，5mkm)；流動相：IPA-MeOH，50-50，流速：10mL/min；管柱溫度：24℃；波長：218nm、246nm、302nm)，保留時間(化合物514 )=17.49min；保留時間(化合物516 )=34.43minThe enantiomers were separated under the following conditions: Column: Chiral ART cellulose-SC (250*20, 5mkm); Mobile phase: IPA-MeOH, 50-50, Flow rate: 10 mL/min; Column temperature: 24°C ; wavelength: 218nm, 246nm, 302nm), retention time ( compound 514 )=17.49min; retention time ( compound 516 )=34.43min

在以下條件下另外純化經分離之鏡像異構物：The isolated enantiomers were additionally purified under the following conditions:

管柱：Chiralcel OJ-H(250*20mm/5m)；流動相：己烷-IPA-MeOH，60-20-20；Column: Chiralcel OJ-H (250*20mm/5m); Mobile phase: Hexane-IPA-MeOH, 60-20-20;

流速：12mL/min；管柱溫度：24℃；波長：218nm、246nm、302nm)，Flow rate: 12mL/min; column temperature: 24°C; wavelength: 218nm, 246nm, 302nm),

保留時間(化合物514 )=41.12minRetention time (compound 514 )=41.12min

保留時間(化合物516 )=30.488minRetention time (compound 516 )=30.488min

化合物514： 1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.02(m,3H),1.38-1.48(m,1H),1.79-1.88(m,1H),1.88-1.98(m,1H),1.98-2.04(m,1H),2.04-2.29(m,1H),2.78-3.27(m,1H),3.43-3.50(m,0.7H),3.92-3.96(m,3H),4.02-4.05(m,0.3H),5.53-5.92(m,1H),7.69-7.78(m,2H),7.79-7.88(m,1H),8.43-8.50(m,1H),8.51-8.56(m,1H),9.02-9.09(m,1H),10.93-11.19(m,1H)。 Compound 514: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.96-1.02 (m, 3H), 1.38-1.48 (m, 1H), 1.79-1.88 (m, 1H), 1.88-1.98 (m, 1H) ,1.98-2.04(m,1H),2.04-2.29(m,1H),2.78-3.27(m,1H),3.43-3.50(m,0.7H),3.92-3.96(m,3H),4.02-4.05 (m,0.3H),5.53-5.92(m,1H),7.69-7.78(m,2H),7.79-7.88(m,1H),8.43-8.50(m,1H),8.51-8.56(m,1H) ), 9.02-9.09 (m, 1H), 10.93-11.19 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值403.5；實測值404.0；Rt=4.221min。LCMS (ESI): [M+H] + m/z: calculated 403.5; found 404.0; Rt=4.221 min.

RT(IPA-MeOH，50-50，10ml/min)=33.40min。RT (IPA-MeOH, 50-50, 10 ml/min) = 33.40 min.

化合物516： 1 H NMR(600MHz,DMSO-d 6 )δ 0.97-1.01(m,3H),1.37-1.47(m,1H),1.79-1.87(m,1H),1.88-1.97(m,1H),1.99-2.06(m,1H),2.09-2.24(m,1H),2.80-3.27(m,1H),3.44-3.50(m,0.7H),3.93-3.96(m,3H),4.02-4.06(m,0.3H),5.46-5.95(m,1H),7.69-7.77(m,2H),7.78-7.88(m,1H),8.41-8.51(m,1H),8.51-8.56(m,1H),9.03-9.08(m,1H),11.00-11.04(m,1H)。 Compound 516: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.97-1.01 (m, 3H), 1.37-1.47 (m, 1H), 1.79-1.87 (m, 1H), 1.88-1.97 (m, 1H) ,1.99-2.06(m,1H),2.09-2.24(m,1H),2.80-3.27(m,1H),3.44-3.50(m,0.7H),3.93-3.96(m,3H),4.02-4.06 (m,0.3H),5.46-5.95(m,1H),7.69-7.77(m,2H),7.78-7.88(m,1H),8.41-8.51(m,1H),8.51-8.56(m,1H) ), 9.03-9.08 (m, 1H), 11.00-11.04 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值403.5；實測值404.0；Rt=4.222min。LCMS (ESI): [M+H] + m/z: calculated 403.5; found 404.0; Rt=4.222 min.

RT(IPA-MeOH，50-50，10ml/min)=27.93min。RT (IPA-MeOH, 50-50, 10 ml/min) = 27.93 min.

實例222. 5-[[2-[(2R,5S)-5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1076)及5-[[2-[(2S,5R)-5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1079)之合成Example 222. 5-[[2-[(2R,5S)-5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl] -2-Oxyacetyl]amino]pyridine-3-carboxamide (Compound 1076) and 5-[[2-[(2S,5R)-5-methyl-2-(6-oxo Synthesis of yl-5H-1,5-naphthyridin-2-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 1079)

Figure 110128222-A0202-12-1270-242
Figure 110128222-A0202-12-1270-242

步驟1：5-[[2-[5-甲基-2-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[5-Methyl-2-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthyridine-2- [Synthesis of]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide

將6-(5-甲基-2-哌啶基)-1-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-酮(300mg，0.803mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(100mg，0.322mmol，Et3 N)、HATU(147mg，0.387mmol)及TEA(0.130mL，0.933mmol)於DMF(6mL)中之混合物在25℃下攪拌2小時。所得混合物藉由添加水(20mL)來淬滅且用DCM(100mL*3)萃取。將經合併之有機層用鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；25g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~50%，然後EtOAc/MeOH，其中MeOH為0~5%，流速=30mL/min，254nm)純化殘餘物，以得到呈白色固體之5-[[2-[5-甲基-2-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶-2-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(150mg，82.4%產率)。LCMS(ESI)[M+H]+ m/z：計算值565.3，實測值565.3。6-(5-Methyl-2-piperidinyl)-1-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-one (300 mg, 0.803 mmol), 2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (100 mg, 0.322 mmol, Et3N ), HATU (147 mg, 0.387 mmol) and TEA (0.130 mL, A mixture of 0.933 mmol) in DMF (6 mL) was stirred at 25°C for 2 hours. The resulting mixture was quenched by adding water (20 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. by flash chromatography ( ISCO® ; 25g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-50% EtOAc, then EtOAc/MeOH with 0-5% MeOH, flow rate = 30 mL/min , 254 nm), the residue was purified to give 5-[[2-[5-methyl-2-[6-oxy-5-(2-trimethylsilylethoxymethyl) as a white solid -1,5-Naphthyridin-2-yl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (150 mg, 82.4% yield). LCMS (ESI) [M+H] + m/z: calcd 565.3, found 565.3.

步驟2：5-[[2-[5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 2: 5-[[2-[5-Methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl]-2-oxy Synthesis of Acetyl] Amino] Pyridine-3-Carboxyamide

向5-[[2-[5-甲基-2-[6-側氧基-5-(2-三甲基矽基乙氧基甲基)-1,5-萘啶 -2-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(140mg，0.248mmol)於DCM(5mL)中之混合物中添加TFA(1mL，13.0mmol)。將所得混合物在20℃下攪拌1小時。將所得混合物用飽和NaHCO3 溶液調節至pH=8，然後將混合物在真空中濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，DCM/MeOH，其中MeOH為0~20%，流速=30mL/min，254nm)進行純化，以得到呈白色固體之5-[[2-[5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50mg，46.4%產率)。LCMS(ESI)[M+H]+ m/z：計算值435.2，實測值435.2；HPLC：在254nm下為90.34%。to 5-[[2-[5-methyl-2-[6-oxy-5-(2-trimethylsilylethoxymethyl)-1,5-naphthyridin-2-yl] TFA (1 mL, 13.0 mmol) was added to a mixture of -1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (140 mg, 0.248 mmol) in DCM (5 mL) . The resulting mixture was stirred at 20°C for 1 hour. The resulting mixture was adjusted to pH= 8 with saturated NaHCO solution, then the mixture was concentrated in vacuo to give the crude product, which was purified by flash chromatography ( ISCO® ; 12 g AgelaFlash® silica flash column, DCM/MeOH , wherein MeOH is 0~20%, flow rate=30mL/min, 254nm) for purification to obtain 5-[[2-[5-methyl-2-(6-oxy-5H-1 as a white solid ,5-Naphthyridin-2-yl)-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (50 mg, 46.4% yield). LCMS (ESI) [M+H] + m/z: calcd 435.2, found 435.2; HPLC: 90.34% at 254 nm.

步驟3：5-[[2-[(2R,5S)-5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1076 )及5-[[2-[(2S,5R)-5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1079 )之合成Step 3: 5-[[2-[(2R,5S)-5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl] -2-Oxyacetyl]amino]pyridine-3-carboxamide ( Compound 1076 ) and 5-[[2-[(2S,5R)-5-methyl-2-(6-oxo Synthesis of base-5H-1,5-naphthyridin-2-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 1079 )

將5-[[2-[5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50mg，0.115mmol)藉由SFC(儀器：Berger，Multigr AM-II；管柱：Daicel Chiralcel OJ-H 250mm×30mm×5μm；流動相：超臨界CO2 /MeOH(0.1% NH3 -H2 O，v%)=70/30；流速：70mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離，以得到 化合物1076 (峰3，保留時間=4.899min)及 化合物1079 (峰4，保留時間=6.996min)。5-[[2-[5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl]-2-oxyacetyl yl]amino]pyridine-3-carboxamide (50 mg, 0.115 mmol) by SFC (instrument: Berger, Multigr AM-II; column: Daicel Chiralcel OJ-H 250 mm × 30 mm × 5 μm; mobile phase: supercritical CO 2 /MeOH (0.1% NH 3 -H 2 O, v%) = 70/30; flow rate: 70 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature : 20°C; trimmer temperature: 25°C; wavelength: 220 nm) separation to obtain compound 1076 (peak 3, retention time=4.899 min) and compound 1079 (peak 4, retention time=6.996 min).

化合物1076：5-[[2-[(2R,5S)-5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(10.5mg，具有反式相對化學之單一未知鏡像異構物，峰3，保留時間=4.899min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 8.64-8.95(m,2H),8.40(br s,1H),7.88(d,J =9.8Hz,1H),7.71(br d,J =8.5Hz,2H),7.49(br s,2H),6.71(d,J =9.8Hz,1H),5.32-5.71(m,1H),2.44(br dd,J = 13.8,3.3Hz,1H),2.10(br s,1H),1.92(br s,1H),1.81(br t,J =12.7Hz,2H),1.36(br d,J =10.8Hz,2H),1.07(d,J =6.8Hz,4H)；LCMS(ESI)[M+H]+ m/z：計算值435.2，實測值435.1；HPLC：在254nm下為100%；97.5%ee。Compound 1076: 5-[[2-[(2R,5S)-5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (10.5 mg, single unknown enantiomer with trans relative chemistry, peak 3, retention time = 4.899 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 8.64-8.95 (m, 2H), 8.40 (br s, 1H), 7.88 (d, J =9.8Hz, 1H), 7.71 (br d, J =8.5 Hz, 2H), 7.49(br s, 2H), 6.71(d, J = 9.8Hz, 1H), 5.32-5.71(m, 1H), 2.44(br dd, J = 13.8, 3.3Hz, 1H), 2.10 (br s, 1H), 1.92(br s, 1H), 1.81(br t, J =12.7Hz, 2H), 1.36(br d, J =10.8Hz, 2H), 1.07(d, J =6.8Hz, 4H); LCMS (ESI) [M+H] + m/z: calcd 435.2, found 435.1; HPLC: 100% at 254 nm; 97.5% ee.

化合物1079：5-[[2-[(2S,5R)-5-甲基-2-(6-側氧基-5H-1,5-萘啶-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(10mg，具有反式相對化學之單一未知鏡像異構物，峰4，保留時間=6.996min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 8.61-8.94(m,2H),8.40(br s,1H),7.88(d,J =9.5Hz,1H),7.70(br d,J =8.5Hz,2H),7.49(br s,2H),6.70(d,J =9.8Hz,1H),5.34-5.68(m,1H),2.41(br d,J =3.0Hz,1H),1.99-2.20(m,1H),1.92(br s,1H),1.70-1.87(m,2H),1.36(br d,J =9.0Hz,2H),1.06(d,J =6.8Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值435.2，實測值435.1；HPLC：在254nm下為100%；100%ee。Compound 1079: 5-[[2-[(2S,5R)-5-methyl-2-(6-oxy-5H-1,5-naphthyridin-2-yl)-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (10 mg, single unknown enantiomer with trans relative chemistry, peak 4, retention time = 6.996 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 8.61-8.94 (m, 2H), 8.40 (br s, 1H), 7.88 (d, J =9.5Hz, 1H), 7.70 (br d, J =8.5 Hz, 2H), 7.49(br s, 2H), 6.70(d, J =9.8Hz, 1H), 5.34-5.68(m, 1H), 2.41(br d, J =3.0Hz, 1H), 1.99-2.20 (m,1H),1.92(br s,1H),1.70-1.87(m,2H),1.36(br d, J =9.0Hz,2H),1.06(d, J =6.8Hz,3H); LCMS( ESI) [M+H] + m/z: calcd 435.2, found 435.1; HPLC: 100% at 254 nm; 100% ee.

實例223. 5-(2-(6-(4-氟苯基)-5-氮雜螺[2.5]辛-5-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物776)之合成Example 223. 5-(2-(6-(4-Fluorophenyl)-5-azaspiro[2.5]oct-5-yl)-2-oxyacetamido)nicotinamide (compound 776) synthesis

Figure 110128222-A0202-12-1272-243
Figure 110128222-A0202-12-1272-243

在0℃下，向酸性2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸(36mg，0.17mmol)及6-(4-氟苯基)-5-氮雜螺[2.5]辛烷(35mg，0.17mmol)於DMF(1.00mL)中之經攪拌之溶液中添加HATU(65mg，0.17mmol)及三乙胺(52mg，71μL，0.51mmol)。將所得反應混合物在環境溫度下攪拌18小時。18小時之後，將反應混合物在減壓下濃縮且添加水。將水層用EtOAc(2x)萃取。將經合併之有機相用水(2x)洗滌，乾燥(Na2 SO4 )且在減壓下濃縮，以獲得粗產物。藉由矽膠管柱層析(5/5環己烷/乙酸乙酯至0/1)純化殘餘物，以得到呈白色固體之苯甲基5-(2-(6-(4-氟苯基)-5-氮雜螺[2.5]辛-5-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物776 )(14mg， 25%)。To acidic 2-((5-aminocarbamoylpyridin-3-yl)amino)-2-oxoacetic acid (36 mg, 0.17 mmol) and 6-(4-fluorophenyl)- To a stirred solution of 5-azaspiro[2.5]octane (35 mg, 0.17 mmol) in DMF (1.00 mL) was added HATU (65 mg, 0.17 mmol) and triethylamine (52 mg, 71 μL, 0.51 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure and water was added. The aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with water (2x), dried ( Na2SO4 ) and concentrated under reduced pressure to obtain crude product. The residue was purified by silica gel column chromatography (5/5 cyclohexane/ethyl acetate to 0/1) to give benzyl 5-(2-(6-(4-fluorophenyl) as a white solid )-5-azaspiro[2.5]oct-5-yl)-2-oxyacetamido)nicotinamide ( Compound 776 ) (14 mg, 25%).

1 H NMR(CD3 OD,400MHz)δ 8.96(d,J =2.4Hz,0.7H),8.90(d,J =2.4Hz,0.3H),8.79(d,J =1.9Hz,0.7H),8.76(d,J =1.9Hz,0.3H),8.62(t,J =2.2Hz,0.7H),8.58(t,J =2.2Hz,0.3H),7.48-7.36(m,2H),7.19-7.10(m,2H),5.90(app s,0.7H),5.52(app s,0.3H),3.63(d,J =13.7Hz,0.3H),3.52(d,J =13.7Hz,0.7H),3.17-3.08(m,1H),2.52-2.61(m,1H),2.32-2.01(m,2H),1.02-0.93(m,1H),0.70-0.59(m,1H),0.48-0.32(m,3H)。 1 H NMR (CD 3 OD, 400MHz) δ 8.96(d, J =2.4Hz, 0.7H), 8.90(d, J =2.4Hz, 0.3H), 8.79(d, J =1.9Hz, 0.7H), 8.76(d, J =1.9Hz,0.3H),8.62(t, J =2.2Hz,0.7H),8.58(t, J =2.2Hz,0.3H),7.48-7.36(m,2H),7.19- 7.10(m,2H),5.90(app s,0.7H),5.52(app s,0.3H),3.63(d, J =13.7Hz,0.3H),3.52(d, J =13.7Hz,0.7H) ,3.17-3.08(m,1H),2.52-2.61(m,1H),2.32-2.01(m,2H),1.02-0.93(m,1H),0.70-0.59(m,1H),0.48-0.32( m, 3H).

19 F NMR(CD3 OD,376MHz)δ -118.3,118.1. 19 F NMR (CD 3 OD, 376MHz) δ -118.3, 118.1.

實例224. 5-(2-(2-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1008)之合成Example 224. 5-(2-(2-(4-Fluorophenyl)-5-methylpiperidin-1-yl-2-d)-2-oxyacetamido)nicotinamide ( Synthesis of compound 1008)

Figure 110128222-A0202-12-1273-244
Figure 110128222-A0202-12-1273-244

在0℃下，向酸性2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸鹽酸鹽(108mg，0.51mmol)及2-(4-氟苯基)-5-甲基哌啶-2-d(100mg，0.51mmol)於DMF(0.2mL)中之經攪拌之溶液中添加HATU(196mg，0.51mmol)及三乙胺(215μL，1.54mmol)。將所得反應混合物在環境溫度下攪拌18小時。18小時之後，將反應混合物在減壓下濃縮且添加水。將水層用EtOAc(2x)萃取。將經合併之有機相用水(2x)洗滌，乾燥(Na2 SO4 )且在減壓下濃縮，以獲得粗產物。藉由矽膠管柱層析(CH2 Cl2 /MeOH 10/0至9/1)純化殘餘物，以得到呈白色固體之5-(2-(2-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1008 )(60mg，30%)To acidic 2-((5-aminocarbamoylpyridin-3-yl)amino)-2-oxoacetic acid hydrochloride (108 mg, 0.51 mmol) and 2-(4-fluorobenzene at 0 °C yl)-5-methylpiperidine-2-d (100 mg, 0.51 mmol) in DMF (0.2 mL) was added HATU (196 mg, 0.51 mmol) and triethylamine (215 μL, 1.54 mmol) to a stirred solution of . The resulting reaction mixture was stirred at ambient temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure and water was added. The aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with water (2x), dried ( Na2SO4 ) and concentrated under reduced pressure to obtain crude product. The residue was purified by silica gel column chromatography ( CH2Cl2 /MeOH 10/0 to 9/1) to give 5-( 2- (2-(4-fluorophenyl)-5- as a white solid) Methylpiperidin-1-yl-2-d)-2-oxyacetamido)nicotinamide ( Compound 1008 ) (60 mg, 30%)

1 H NMR(CDCl3 ,400MHz)9.93(s,1H),9.06-8.91(m,1H),8.75(s,1H),8.56(s,1H),7.24-7.11(m,2H),7.04-6.90(m,2H),6.56(s,1H),6.22(s,1H),4.41(d,J =13.2Hz, 0.7H),4.12(d,J =13.2Hz,0.3H)3.28(d,J =12.5Hz,1H),2.19-2.02(m,1H),1.98-1.84(m,1H),1.84-1.70(m,1H),1.05-0.95(m,3H) 1 H NMR (CDCl 3 , 400MHz) 9.93(s, 1H), 9.06-8.91(m, 1H), 8.75(s, 1H), 8.56(s, 1H), 7.24-7.11(m, 2H), 7.04- 6.90(m, 2H), 6.56(s, 1H), 6.22(s, 1H), 4.41(d, J =13.2Hz, 0.7H), 4.12(d, J =13.2Hz, 0.3H) 3.28(d, J =12.5Hz,1H),2.19-2.02(m,1H),1.98-1.84(m,1H),1.84-1.70(m,1H),1.05-0.95(m,3H)

19 F NMR(CDCl3 ,376MHz)δ -115.9,-115.8。 19 F NMR (CDCl 3 , 376 MHz) δ -115.9, -115.8.

實例225. 5-(2-(2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1004)之合成Example 225. 5-(2-(2-(4-Fluorophenyl-2,3,5,6-d4)-5-methylpiperidin-1-yl)-2-oxyacetamido ) Synthesis of Nicotinamide (Compound 1004)

Figure 110128222-A0202-12-1274-245
Figure 110128222-A0202-12-1274-245

在0℃下，向酸性2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸鹽酸鹽(62mg，0.25mmol)及2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶(50mg，0.25mmol)於DMF(4mL)中之經攪拌之溶液中添加HATU(96mg，0.25mmol)及三乙胺(140μL，1.0mmol)。將所得反應混合物在環境溫度下攪拌18小時。18小時之後，將反應混合物在減壓下濃縮且添加水。將水層用EtOAc(2x)萃取。將經合併之有機相用水(2x)洗滌，乾燥(Na2 SO4 )且在減壓下濃縮，以獲得粗產物。藉由矽膠管柱層析(環己烷/乙酸乙酯10/0至0/10)純化殘餘物，以得到呈白色固體之5-(2-(2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1004 )(60mg，30%)To acidic 2-((5-aminocarbamoylpyridin-3-yl)amino)-2-oxoacetic acid hydrochloride (62 mg, 0.25 mmol) and 2-(4-fluorobenzene at 0 °C To a stirred solution of yl-2,3,5,6-d4)-5-methylpiperidine (50 mg, 0.25 mmol) in DMF (4 mL) was added HATU (96 mg, 0.25 mmol) and triethylamine ( 140 μL, 1.0 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure and water was added. The aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with water (2x), dried ( Na2SO4 ) and concentrated under reduced pressure to obtain crude product. The residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate 10/0 to 0/10) to give 5-(2-(2-(4-fluorophenyl-2, 3,5,6-d4)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 1004 ) (60 mg, 30%)

1 H NMR(DMSO-d 6 ,400MHz)11.3(s,0.6H),11.2(m,0.4H),8.93(app d,0.6H),8.86(s,0.4H),8.81(s,0.6H),8.77(s,0.4H),8.52(s,0.6H),8.48(s,0.4H),8.20(s,0.6H),8.16(s,0.4H),7.65(s,0.6H),7.60(s,0.4H),5.59(s,0.6H),5.16(s,0.4H),3.48(d,J =13.6Hz),3.25(dd,J =3.2,13.7Hz,1H),2.82-2.75(m,1H)2.24-1.80(m,3.4H),1.75-1.62(m,1H),1.42-1.35(m,1H),1.10-1.01(m,3H) 1 H NMR(DMSO- d 6 , 400MHz) 11.3(s, 0.6H), 11.2(m, 0.4H), 8.93(app d, 0.6H), 8.86(s, 0.4H), 8.81(s, 0.6H) ), 8.77(s, 0.4H), 8.52(s, 0.6H), 8.48(s, 0.4H), 8.20(s, 0.6H), 8.16(s, 0.4H), 7.65(s, 0.6H), 7.60(s, 0.4H), 5.59(s, 0.6H), 5.16(s, 0.4H), 3.48(d, J =13.6Hz), 3.25(dd, J =3.2, 13.7Hz, 1H), 2.82- 2.75(m,1H)2.24-1.80(m,3.4H),1.75-1.62(m,1H),1.42-1.35(m,1H),1.10-1.01(m,3H)

19 F NMR(DMSO-d 6 ,376MHz)δ -116.9,-117.0。 19 F NMR (DMSO- d 6 , 376 MHz) δ -116.9, -117.0.

LRMS(APCI- )m/z(C20 H16 D4 FN4 O3 )：理論值387.2，實驗值387.3。LRMS (APCI − ) m/z (C 20 H 16 D 4 FN 4 O 3 ): theoretical 387.2, experimental 387.3.

實例226. 5-(2-(2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1010)之合成Example 226. 5-(2-(2-(4-Fluorophenyl-2,3,5,6-d4)-5-methylpiperidin-1-yl-2-d)-2-oxygen Synthesis of Acetamido)nicotinamide (Compound 1010)

Figure 110128222-A0202-12-1275-246
Figure 110128222-A0202-12-1275-246

在0℃下，向酸性2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸鹽酸鹽(108mg，0.51mmol)及2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-2-d(100mg，0.51mmol)於DMF(0.2mL)中之經攪拌之溶液中添加HATU(196mg，0.51mmol)及三乙胺(215μL，1.54mmol)。將所得反應混合物在環境溫度下攪拌18小時。18小時之後，將反應混合物在減壓下濃縮且添加水。將水層用EtOAc(2x)萃取。將經合併之有機相用水(2x)洗滌，乾燥(Na2 SO4 )且在減壓下濃縮，以獲得粗產物。藉由矽膠管柱層析(CH2 Cl2 /MeOH 10/0至9/1)純化殘餘物，以得到呈白色固體之5-(2-(2-(4-氟苯基-2,3,5,6-d4)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1010 )(60mg，30%)To acidic 2-((5-aminocarbamoylpyridin-3-yl)amino)-2-oxoacetic acid hydrochloride (108 mg, 0.51 mmol) and 2-(4-fluorobenzene at 0 °C To a stirred solution of yl-2,3,5,6-d4)-5-methylpiperidine-2-d (100 mg, 0.51 mmol) in DMF (0.2 mL) was added HATU (196 mg, 0.51 mmol) and triethylamine (215 μL, 1.54 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure and water was added. The aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with water (2x), dried ( Na2SO4 ) and concentrated under reduced pressure to obtain crude product. The residue was purified by silica gel column chromatography ( CH2Cl2 /MeOH 10/0 to 9/1) to give 5-( 2- (2-(4-fluorophenyl-2,3 as a white solid) ,5,6-d4)-5-methylpiperidin-1-yl-2-d)-2-oxyacetamido)nicotinamide (Compound 1010 ) (60mg, 30%)

1 H NMR(DMSO-d 6 ,400MHz)11.3(s,0.6H),11.2(m,0.4H),8.93(app d,0.6H),8.87(s,0.4H),8.81(app d,0.6H),8.77(app d,0.4H),8.52(s,0.6H),8.48(s,0.4H),8.20(s,0.6H),8.16(s,0.4H),7.64(s,0.6H),7.60(s,0.4H),4.04(d,J =13.2Hz,0.7H),4.12(d,J =13.0Hz,0.3H),3.25(d,J =3.4,14.3Hz,1H),2.81-2.75(m,1H)2.27-1.85(m,3.4H),1.75-1.62(m,1H),1.42-1.29(m,1H),1.10-1.01(m,3H) 1 H NMR (DMSO- d 6 , 400MHz) 11.3(s, 0.6H), 11.2(m, 0.4H), 8.93(app d, 0.6H), 8.87(s, 0.4H), 8.81(app d, 0.6 H), 8.77(app d, 0.4H), 8.52(s, 0.6H), 8.48(s, 0.4H), 8.20(s, 0.6H), 8.16(s, 0.4H), 7.64(s, 0.6H) ), 7.60(s, 0.4H), 4.04(d, J =13.2Hz, 0.7H), 4.12(d, J =13.0Hz, 0.3H), 3.25(d, J =3.4, 14.3Hz, 1H), 2.81-2.75(m,1H)2.27-1.85(m,3.4H),1.75-1.62(m,1H),1.42-1.29(m,1H),1.10-1.01(m,3H)

19 F NMR(DMSO-d 6 ,376MHz)δ -116.9,-117.0。 19 F NMR (DMSO- d 6 , 376 MHz) δ -116.9, -117.0.

LRMS(APCI+ )m/z(C20 H16 D5 FN4 O3 H)：理論值390.1，實驗值390.4。LRMS (APCI + ) m/z (C 20 H 16 D 5 FN 4 O 3 H): theoretical 390.1, found 390.4.

實例227. 5-(2-(5-甲基-2-(吡啶-4-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物539及化合物544)之合成Example 227. 5-(2-(5-Methyl-2-(pyridin-4-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 539 and Compounds 544) synthesis

Figure 110128222-A0202-12-1276-247
Figure 110128222-A0202-12-1276-247

在輕微加熱下，將4-[(2R,5S )-5-甲基-2-哌啶基]吡啶(0.3g，1.70mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(356.00mg，1.70mmol，TEA)及DIPEA(659.92mg，5.11mmol，889.38μL)溶解於DMF(6mL)中在劇烈攪拌及偶爾加熱下，小批量添加HATU(776.60mg，2.04mmol)。反應完成之後，藉由HPLC(0-25%，0.5-6.5min；30ml/min；水-MeCN(裝載泵4ml/min MeCN)；目標質量368；管柱SunFire 100*19mm 5um)純化混合物且藉由掌性HPLC(體系2.管柱：Chiralpak IA(250*20mm*5mm)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min；管柱溫度：24℃；波長：210nm、215nm、254nm)分離所獲得之外消旋混合物，以得到5-[[2-[(2R,5S )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(44mg，119.76μmol，7.04%產率)及5-[[2-[(2S,5R )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(43mg，117.04μmol，6.88%產率)。4-[( 2R,5S )-5-methyl-2-piperidinyl]pyridine (0.3 g, 1.70 mmol), 2-[(5-aminocarbamoyl-3-pyridyl )amino]-2-oxoacetic acid (356.00 mg, 1.70 mmol, TEA) and DIPEA (659.92 mg, 5.11 mmol, 889.38 μL) were dissolved in DMF (6 mL) and added in small batches with vigorous stirring and occasional heating HATU (776.60 mg, 2.04 mmol). After completion of the reaction, the mixture was purified by HPLC (0-25%, 0.5-6.5 min; 30 ml/min; water-MeCN (loading pump 4 ml/min MeCN); target mass 368; column SunFire 100*19mm 5um) and used By chiral HPLC (system 2. Column: Chiralpak IA (250*20mm*5mm); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12 mL/min; column temperature: 24°C; Wavelengths: 210 nm, 215 nm, 254 nm) to separate the obtained racemic mixture to give 5-[[2-[( 2R,5S )-5-methyl-2-(4-pyridyl)-1-piperidine (44 mg, 119.76 μmol, 7.04% yield) and 5-[[2-[( 2S,5R )-5-methyl yl-2-(4-pyridyl)-1-piperidinyl]-2-oxoethanoyl]amino]pyridine-3-carboxamide (43 mg, 117.04 μmol, 6.88% yield).

化合物539 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為38.74min且化合物544 之保留時間為31.88min。The retention time of compound 539 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 38.74 min and the retention time of compound 544 was 31.88 min.

化合物539：保留時間：38.74minCompound 539: retention time: 38.74min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.05(m,3H),1.28-1.40(m,1H),1.51-1.61(m,1H),1.80-1.94(m,1H),1.99-2.15(m,1H),2.15-2.25(m,1H),2.73-3.25(m,1H),3.46-4.12(m,1H),5.18-5.63(m,1H),7.27-7.39(m,2H),7.52-7.66(m,1H),8.09-8.21(m,1H),8.39-8.53(m,1H),8.53-8.63(m,2H),8.70-8.81(m,1H),8.81-8.93(m,1H),11.14-11.38(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.05(m,3H), 1.28-1.40(m,1H), 1.51-1.61(m,1H), 1.80-1.94(m,1H) ,1.99-2.15(m,1H),2.15-2.25(m,1H),2.73-3.25(m,1H),3.46-4.12(m,1H),5.18-5.63(m,1H),7.27-7.39( m,2H),7.52-7.66(m,1H),8.09-8.21(m,1H),8.39-8.53(m,1H),8.53-8.63(m,2H),8.70-8.81(m,1H), 8.81-8.93 (m, 1H), 11.14-11.38 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值367.2；實測值368.2；Rt=1.211min。LCMS (ESI): [M] + m/z: calculated 367.2; found 368.2; Rt=1.211 min.

化合物544：保留時間：31.88minCompound 544: retention time: 31.88min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.04(m,3H),1.29-1.39(m,1H),1.51-1.60(m,1H),1.82-1.93(m,1H),2.01-2.15(m,1H),2.17-2.24(m,1H),2.74-3.25(m,1H),3.46-4.10(m,1H),5.17-5.63(m,1H),7.28-7.37(m,2H),7.53-7.67(m,1H),8.09-8.21(m,1H),8.41-8.52(m,1H),8.53-8.61(m,2H),8.71-8.81(m,1H),8.82-8.93(m,1H),11.19-11.31(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.04(m,3H), 1.29-1.39(m,1H), 1.51-1.60(m,1H), 1.82-1.93(m,1H) ,2.01-2.15(m,1H),2.17-2.24(m,1H),2.74-3.25(m,1H),3.46-4.10(m,1H),5.17-5.63(m,1H),7.28-7.37( m,2H),7.53-7.67(m,1H),8.09-8.21(m,1H),8.41-8.52(m,1H),8.53-8.61(m,2H),8.71-8.81(m,1H), 8.82-8.93 (m, 1H), 11.19-11.31 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值367.2；實測值368.2；Rt=1.209min。LCMS (ESI): [M] + m/z: calculated 367.2; found 368.2; Rt=1.209 min.

實例228. 5-(2-(5-甲基-2-(3-胺磺醯基苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物661)之合成Example 228. 5-(2-(5-Methyl-2-(3-aminosulfonylphenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 661) synthesis

Figure 110128222-A0202-12-1277-248
Figure 110128222-A0202-12-1277-248

向3-[(2S,5R )-5-甲基-2-哌啶基]苯磺醯胺(490mg，1.93mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(473.19mg，1.93mmol，HCl)及TEA(584.83mg，5.78mmol，805.55uL)於DMF(4mL)中之經攪拌之混合物中添加HATU(805.76mg，2.12mmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；0-1-6min 5-5-50%水-CAN(NH3 0.1%)，流速30ml/min)，得到5-[[2-[(2S,5R )-5-甲基-2-(3-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(190mg，426.50umol，22.14%產率)。To 3-[( 2S,5R )-5-methyl-2-piperidinyl]benzenesulfonamide (490 mg, 1.93 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino ]-2-Pendoxoacetic acid (473.19 mg, 1.93 mmol, HCl) and TEA (584.83 mg, 5.78 mmol, 805.55 uL) in DMF (4 mL) to a stirred mixture of HATU (805.76 mg, 2.12 mmol) . The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 0-1-6min 5-5-50% water-CAN ( NH3 0.1%), flow rate 30ml/min) to give 5 -[[2-[( 2S,5R )-5-methyl-2-(3-aminosulfonylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide (190 mg, 426.50 umol, 22.14% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.36(m,1H),1.66(m,1H),1.91(m,1H),2.18(m,2H),3.01(m,1H),3.81(m,1H),5.46(m,1H),7.36(m,2H),7.55(m,3H),7.75(m,2H),8.14(m,1H),8.48(m,1H),8.75(m,1H),8.86(m,1H), 11.24(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.36(m, 1H), 1.66(m, 1H), 1.91(m, 1H), 2.18(m, 2H), 3.01(m, 1H), 3.81(m, 1H), 5.46(m, 1H), 7.36(m, 2H), 7.55(m, 3H), 7.75(m, 2H), 8.14(m, 1H), 8.48 (m, 1H), 8.75 (m, 1H), 8.86 (m, 1H), 11.24 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值445.4；實測值446.2；Rt=1.855min。LCMS (ESI): [M] + m/z: calculated 445.4; found 446.2; Rt=1.855 min.

實例229. 5-[[2-[(2R,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物75)、5-[[2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物88)、5-[[2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物71)及5-[[2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物82)之合成Example 229. 5-[[2-[(2R,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-methyl Amide (compound 75), 5-[[2-[(2R,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide (Compound 88), 5-[[2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide (Compound 71) and 5-[[2-[(2S,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-side oxy Synthesis of Acetyl]amino]pyridine-3-carbamoylamine (Compound 82)

Figure 110128222-A0202-12-1278-249
步驟1：5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基胺基]吡啶-3-甲醯胺之合成
Figure 110128222-A0202-12-1278-249
Step 1: Synthesis of 5-[[2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyethanoylamino]pyridine-3-carboxamide

將5-甲基-2-苯基哌啶(200mg，1.14mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(354.14mg，1.14mmol，N(Et)3 )及HATU(477.27mg，1.26mmol)混合於DMSO(4mL)中且在25℃下攪拌16h。使最終溶液經歷HPLC(03_MeCN 2-9min 20-45% MeCN，30ml/min管柱：SunFire C18 100* 195微米)，以得到5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(229mg，624.98μmol，54.77%產率)。5-Methyl-2-phenylpiperidine (200 mg, 1.14 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (354.14 mg, 1.14 mmol, N(Et) 3 ) and HATU (477.27 mg, 1.26 mmol) were mixed in DMSO (4 mL) and stirred at 25 °C for 16 h. The final solution was subjected to HPLC (03_MeCN 2-9min 20-45% MeCN, 30ml/min column: SunFire C18 100 * 195 microns) to give 5-[[2-(5-methyl-2-phenyl-1 -Piperidinyl)-2-side oxyacetyl]amino]pyridine-3-carboxamide (229 mg, 624.98 μmol, 54.77% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.02(d,3H),1.65(m,2H),2.10(m,2H),2.60(m, 1H),3.11(m,3H),3.26(m,1H),4.12(m,1H),5.36(m,1H),7.31(m,5H),7.54(d,1H),8.36(d,1H),8.50(m,1H),8.82(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.02(d, 3H), 1.65(m, 2H), 2.10(m, 2H), 2.60(m, 1H), 3.11(m, 3H), 3.26(m ,1H),4.12(m,1H),5.36(m,1H),7.31(m,5H),7.54(d,1H),8.36(d,1H),8.50(m,1H),8.82(m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值366.1；實測值367.2；Rt=1.199min。LCMS (ESI): [M+H] + m/z: calculated 366.1; found 367.2; Rt=1.199 min.

步驟2：5-[[2-[(2R,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物75 )、5-[[2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物88 )、5-[[2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物71 )及5-[[2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物82 )之合成Step 2: 5-[[2-[(2R,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide ( compound 75 ), 5-[[2-[(2R,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide ( Compound 88 ), 5-[[2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl] Amino]pyridine-3-carboxamide ( compound 71 ) and 5-[[2-[(2S,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-side oxy Synthesis of Acetyl]amino]pyridine-3-carbamoylamine ( Compound 82 )

使用(IA(250* 25，5mkm)管柱，以己烷-IPA-MeOH，70-15-15為流動相；流速12ml/min)對5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺進行掌性分離，得到化合物75 5-[[2-[(2R,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(19.9mg，12.54%；RT=29.173min)、化合物88 5-[[2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(56.2mg，35.41%；RT=78.286min)、化合物71 5-[[2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(49.2mg，31.0%；RT=40.746min)及化合物82 5-[[2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(14.2mg，8.95%；RT=34.172min)。5-[[2-(5- methyl -2- Chiral separation of phenyl-1-piperidinyl)-2-oxoacetyl]amino]pyridine-3-carboxamide afforded compound 75 5-[[2-[(2R,5R)- 5-Methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (19.9 mg, 12.54%; RT=29.173 min), compound 88 5-[[2-[(2R,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (56.2 mg, 35.41%; RT=78.286 min), Compound 71 5-[[2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide (49.2 mg, 31.0%; RT=40.746 min) and compound 82 5-[[2-[(2S,5S)-5-methyl-2-benzene (14.2 mg, 8.95%; RT=34.172 min).

化合物71： RT(IA(250* 25，5mkm)，己烷-IPA-MeOH，60-20-20，0.6ml/min)=19.56min。 Compound 71: RT (IA(250 * 25, 5mkm), Hexane-IPA-MeOH, 60-20-20, 0.6ml/min)=19.56min.

1 H NMR(500MHz,DMSO-d 6 )δ 1.05(m,3H),1.35(m,1H),1.69(m,1H),1.90(m,1H),2.23(m,1H),3.23(m,2H),3.77(m,1H),5.41(m,1H),7.35(m,5H),7.60(m,1H),8.16(m,1H),8.49(m,1H),8.78(m,1H),8.90(m,1H),11.24(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 1.05(m, 3H), 1.35(m, 1H), 1.69(m, 1H), 1.90(m, 1H), 2.23(m, 1H), 3.23(m ,2H),3.77(m,1H),5.41(m,1H),7.35(m,5H),7.60(m,1H),8.16(m,1H),8.49(m,1H),8.78(m, 1H), 8.90 (m, 1H), 11.24 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.361min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.361 min.

化合物82： RT(IA(250* 25，5mkm)，己烷-IPA-MeOH，60-20-20，0.6ml/min)= 16.02min。 Compound 82: RT (IA(250 * 25, 5mkm), Hexane-IPA-MeOH, 60-20-20, 0.6ml/min) = 16.02min.

1 H NMR(500MHz,DMSO-d 6 )δ 0.77(m,3H),1.07(m,1H),1.66(m,2H),1.92(m,1H),2.21(m,1H),2.59(m,1H),3.94(m,1H),5.44(m,1H),7.37(m,5H),7.61(m,1H),8.17(m,1H),8.50(m,1H),8.78(m,1H),8.89(m,1H),11.28(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.77(m, 3H), 1.07(m, 1H), 1.66(m, 2H), 1.92(m, 1H), 2.21(m, 1H), 2.59(m ,1H),3.94(m,1H),5.44(m,1H),7.37(m,5H),7.61(m,1H),8.17(m,1H),8.50(m,1H),8.78(m, 1H), 8.89 (m, 1H), 11.28 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.421min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.421 min.

化合物88： RT(IA(250* 25，5mkm)，己烷-IPA-MeOH，60-20-20，0.6ml/min)=38.93min。 Compound 88: RT (IA(250 * 25, 5mkm), Hexane-IPA-MeOH, 60-20-20, 0.6ml/min)=38.93min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.03(m,3H),1.34(m,1H),1.66(m,1H),1.85(m,1H),2.05(m,1H),2.21(m,1H),3.26(m,1H),3.75(m,1H),5.61(m,1H),7.27(m,1H),7.37(m,4H),7.59(m,1H),8.15(m,1H),8.48(m,1H),8.77(m,1H),8.89(m,1H),11.23(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.03(m, 3H), 1.34(m, 1H), 1.66(m, 1H), 1.85(m, 1H), 2.05(m, 1H), 2.21(m ,1H),3.26(m,1H),3.75(m,1H),5.61(m,1H),7.27(m,1H),7.37(m,4H),7.59(m,1H),8.15(m, 1H), 8.48 (m, 1H), 8.77 (m, 1H), 8.89 (m, 1H), 11.23 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.363min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.363 min.

化合物75： RT(IA(250* 25，5mkm)，己烷-IPA-MeOH，60-20-20，0.6ml/min)=14.26min。 Compound 75: RT (IA(250 * 25, 5mkm), Hexane-IPA-MeOH, 60-20-20, 0.6ml/min)=14.26min.

1 H NMR(500MHz,DMSO-d 6 )δ 0.77(m,3H),1.07(m,1H),1.69(m,2H),1.92(m,1H),2.23(m,1H),2.60(m,1H),3.94(m,1H),5.44(m,1H),7.36(m,5H),7.61(m,1H),8.17(m,1H),8.50(m,1H),8.78(m,1H),8.89(m,1H),11.28(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.77(m, 3H), 1.07(m, 1H), 1.69(m, 2H), 1.92(m, 1H), 2.23(m, 1H), 2.60(m ,1H),3.94(m,1H),5.44(m,1H),7.36(m,5H),7.61(m,1H),8.17(m,1H),8.50(m,1H),8.78(m, 1H), 8.89 (m, 1H), 11.28 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.421min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.421 min.

實例230.外消旋 -2-((2R,5S )-5-甲基-2-(萘-2-基)哌啶-1-基)-N -(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物83)之合成Example 230. Racemic -2-(( 2R,5S )-5-methyl-2-(naphthalen-2-yl)piperidin-1 - yl)-N-(5-methylpyridin-3-yl )-2-side oxyacetamide (compound 83) synthesis

Figure 110128222-A0202-12-1280-250
Figure 110128222-A0202-12-1280-250

將[2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]氧基鋰(412.94mg，2.22mmol)及HATU(843.73mg，2.22mmol)混合於DMF(3mL)中且將所得混合物在20℃下攪拌20min，隨後添加5-甲基-2-(2-萘基)哌啶(0.5g，2.22mmol)且將所得混合物在20℃下攪拌12h。使所得混合物經歷HPLC，以獲得2-[(2S,5R )-5-甲基-2-(2-萘基)-1-哌啶基]-N -(間甲苯基)-2-側氧基乙醯胺(0.029g，75.04μmol，3.38%產率)。[2-[(5-Methyl-3-pyridinyl)amino]-2-oxyethanoyl]oxylithium (412.94 mg, 2.22 mmol) and HATU (843.73 mg, 2.22 mmol) were mixed in DMF (3 mL) and the resulting mixture was stirred at 20 °C for 20 min, then 5-methyl-2-(2-naphthyl)piperidine (0.5 g, 2.22 mmol) was added and the resulting mixture was stirred at 20 °C for 12 h . The resulting mixture was subjected to HPLC to obtain 2-[( 2S,5R )-5-methyl-2-(2-naphthyl)-1-piperidinyl]-N-( m -tolyl)-2-oxygen Ethylacetamide (0.029 g, 75.04 μmol, 3.38% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.11(d,3H),1.43(m,1H),1.96(m,2H),2.31(m,5H),3.23(m,1H),4.55(m,1H),6.27(m,1H),7.42(m,3H),7.79(m,4H),8.00(m,1H),8.21(m,1H),8.48(m,1H),9.40(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.11(d,3H), 1.43(m,1H), 1.96(m,2H), 2.31(m,5H), 3.23(m,1H), 4.55( m, 1H), 6.27(m, 1H), 7.42(m, 3H), 7.79(m, 4H), 8.00(m, 1H), 8.21(m, 1H), 8.48(m, 1H), 9.40(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值386.5；實測值387.2；Rt=3.213min。LCMS (ESI): [M] + m/z: calculated 386.5; found 387.2; Rt=3.213 min.

實例231. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1170))及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1170)之合成Example 231. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-1,3-benzo Oxazol-5-yl)-1-piperidinyl]-2-oxoacetamide (enantiomer 1170)) and N-(6-amino-5-methyl-3-pyridyl) -2-[(2S,5S)-5-methyl-2-(2-methyl-1,3-benzoxazol-5-yl)-1-piperidinyl]-2-side oxyethyl Synthesis of amide (compound 1170)

Figure 110128222-A0202-12-1281-251
Figure 110128222-A0202-12-1281-251

步驟1：(3S)-3-甲基-6-(2-甲基-1,3-苯并噁唑-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: (3S)-3-Methyl-6-(2-methyl-1,3-benzoxazol-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid 3rd Synthesis of Butyl Ester

向圓底燒瓶中添加2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噁唑(100mg，0.386mmol)、(3S)-3-甲基-6-(三氟甲基磺醯基氧 基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(135mg，0.391mmol)、Pd(dppf)Cl2 -DCM(65mg，0.0796mmol)、Na2 CO3 (125mg，1.18mmol)、H2 O(0.5mL)及二噁烷(2mL)。將混合物除氣且用氮氣回填三次，然後在90℃、氮氣下攪拌12小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(20mL*3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(20mL*2)、鹽水(20mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；8g Agela Flash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~30%，流速：30mL/min)純化殘餘物，以得到呈白色膠狀物之(3S)-3-甲基-6-(2-甲基-1,3-苯并噁唑-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(100mg，78.9%產率)。LCMS(ESI)[M+H]+ m/z：計算值329.2，實測值329.1。To the round bottom flask was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3- Benzoxazole (100 mg, 0.386 mmol), (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid 3rd Butyl ester (135 mg, 0.391 mmol), Pd(dppf)Cl2 - DCM (65 mg, 0.0796 mmol), Na2CO3 (125 mg, 1.18 mmol), H2O (0.5 mL) and dioxane ( 2 mL). The mixture was degassed and backfilled with nitrogen three times, then stirred at 90°C under nitrogen for 12 hours. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (20 mL*2), brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 8g Agela Flash® silica flash column, petroleum ether/EtOAc, where EtOAc was 0-30%, flow rate: 30 mL/min) to give a white gum (3S)-3-methyl-6-(2-methyl-1,3-benzoxazol-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (100 mg, 78.9% yield). LCMS (ESI) [M+H]+ m/z: calculated 329.2, found 329.1.

步驟2：(5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (5S)-5-methyl-2-(2-methyl-1,3-benzoxazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester

向(3S)-3-甲基-6-(2-甲基-1,3-苯并噁唑-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(80mg，0.244mmol)於MeOH(5mL)中之溶液中添加Pd/C(10mg，具有50重量%水之10重量%Pd)。將混合物除氣且用氫氣回填3次。將混合物在20℃、氫氣氣氛下(在氣球中，約15psi)攪拌12小時。將所得混合物過濾且在減壓下濃縮，以得到呈黃色油狀物之(5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)哌啶-1-甲酸第三丁酯(70mg，87.0%產率)。LCMS(ESI)[M+H]+ m/z：計算值331.1，實測值331.1。To (3S)-3-methyl-6-(2-methyl-1,3-benzoxazol-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (80 mg, 0.244 mmol) in MeOH (5 mL) was added Pd/C (10 mg, 10 wt % Pd with 50 wt % water). The mixture was degassed and backfilled with hydrogen 3 times. The mixture was stirred at 20°C under a hydrogen atmosphere (in a balloon, about 15 psi) for 12 hours. The resulting mixture was filtered and concentrated under reduced pressure to give (5S)-5-methyl-2-(2-methyl-1,3-benzoxazol-5-yl)piperine as a yellow oil 3-butyl pyridine-1-carboxylate (70 mg, 87.0% yield). LCMS (ESI) [M+H] + m/z: calcd 331.1, found 331.1.

步驟3：2-甲基-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噁唑之合成Step 3: Synthesis of 2-methyl-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzoxazole

向(5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)哌啶-1-甲酸第三丁酯(70mg，0.212mmol)於DCM(3mL)中之溶液中添加TFA(0.5mL，6.49mmol)。將混合物在20℃下攪拌12小時。藉由添加飽和NaHCO3 水溶液(20mL)淬滅所得混合物且用DCM(50mL*3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色油狀物之2-甲基-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噁唑 (50mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值231.1，實測值231.1。To (5S)-5-methyl-2-(2-methyl-1,3-benzoxazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.212 mmol) in DCM ( To the solution in 3 mL) was added TFA (0.5 mL, 6.49 mmol). The mixture was stirred at 20°C for 12 hours. The resulting mixture was quenched by addition of saturated aqueous NaHCO 3 (20 mL) and extracted with DCM (50 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 2-methyl-5-[(5S)-5-methyl-2-piperidine as a yellow oil Peridyl]-1,3-benzoxazole (50 mg, crude). LCMS (ESI) [M+H] + m/z: calculated 231.1, found 231.1.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(5S)-5-methyl-2-(2-methyl-1,3-benzoxazole Synthesis of -5-yl)-1-piperidinyl]-2-oxoacetamide

向2-甲基-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噁唑(45mg，0.195mmol)於DMF(5mL)中之溶液中添加2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(45mg，0.231mmol)及HATU(80mg，0.210mmol)。然後，添加DIPEA(90mg，0.696mmol)且將混合物在20℃下攪拌12小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(20mL*3)萃取。將經合併之有機層用飽和NH4Cl水溶液(10mL*2)、鹽水(10mL*3)洗滌，經無水Na2SO4乾燥，過濾且在減壓下濃縮。藉由製備型TLC(二氧化矽，DCM/MeOH=10：1，254nm)純化殘餘物，以得到呈黃色油狀物之N-(6-胺基-5-甲基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(35mg，44.0%產率)。LCMS(ESI)[M+H]+ m/z：計算值408.2，實測值408.1。To a solution of 2-methyl-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzoxazole (45 mg, 0.195 mmol) in DMF (5 mL) was added 2 -[(6-Amino-5-methyl-3-pyridinyl)amino]-2-side oxyacetic acid (45 mg, 0.231 mmol) and HATU (80 mg, 0.210 mmol). Then, DIPEA (90 mg, 0.696 mmol) was added and the mixture was stirred at 20°C for 12 hours. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (10 mL*2), brine (10 mL*3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica, DCM/MeOH=10:1, 254 nm) to give N-(6-amino-5-methyl-3-pyridyl) as a yellow oil -2-[(5S)-5-methyl-2-(2-methyl-1,3-benzoxazol-5-yl)-1-piperidinyl]-2-oxoacetamide (35 mg, 44.0% yield). LCMS (ESI) [M+H]+ m/z: calculated 408.2, found 408.1.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1170))及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1170)之合成Step 5: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-1,3-benzo Oxazol-5-yl)-1-piperidinyl]-2-oxoacetamide (enantiomer 1170)) and N-(6-amino-5-methyl-3-pyridyl) -2-[(2S,5S)-5-methyl-2-(2-methyl-1,3-benzoxazol-5-yl)-1-piperidinyl]-2-side oxyethyl Synthesis of amide (compound 1170)

將N-(6-胺基-5-甲基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(30mg，73.6μmol)藉由掌性SFC(儀器：Thar80；管柱：Daicel Chiralcel OJ(250mm*30mm，10μm)；流動相：超臨界CO2/EtOH(0.1% NH3-H2O，v%)=65/35；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離，以得到鏡像異構化合物1170(峰1，保留時間=1.520min)及化合物1170(峰2，保留時間=1.641min)。N-(6-amino-5-methyl-3-pyridyl)-2-[(5S)-5-methyl-2-(2-methyl-1,3-benzoxazole-5 -yl)-1-piperidinyl]-2-oxyacetamide (30 mg, 73.6 μmol) by chiral SFC (instrument: Thar80; column: Daicel Chiralcel OJ (250 mm*30 mm, 10 μm); flow Phase: supercritical CO2/EtOH (0.1% NH3-H2O, v%) = 65/35; flow rate: 80 mL/min; column temperature: 38 °C; nozzle temperature: 100 bar; nozzle temperature: 60 °C; evaporator temperature : 20°C; trimmer temperature: 25°C; wavelength: 220 nm) were separated to obtain the mirror image isomer compound 1170 (peak 1, retention time=1.520 min) and compound 1170 (peak 2, retention time=1.641 min).

鏡像異構化合物1170：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(5mg，具有一個已知掌性中心之單一未知鏡像異構物，峰1，保留時間=1.520min，16.7%產率，黃色固體)。1H NMR(400MHz，甲醇-d4)δ ppm 7.87-8.02(1 H,m),7.43-7.58(3 H,m),7.23-7.36(1 H,m),5.39-5.82(1 H,m),3.71(1 H,dd,J=13.30,3.76Hz),2.46-2.64(4 H,m),2.02-2.27(3 H,m),1.86-1.99(1 H,m),1.62-1.82(2 H,m),0.69-0.82(5 H,m)；LCMS(ESI)[M+H]+ m/z：計算值408.2，實測值408.1；HPLC：在220nm下為98.32%，在254nm下為99.30%；>95%ee、99.8%de。Enantiomer 1170: N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-1,3 - benzoxazol-5-yl)-1-piperidinyl]-2-oxyacetamide (5 mg, single unknown enantiomer with one known chiral center, peak 1, retention time = 1.520 min, 16.7% yield, yellow solid). 1H NMR (400MHz, methanol-d4) δ ppm 7.87-8.02(1H,m), 7.43-7.58(3H,m), 7.23-7.36(1H,m), 5.39-5.82(1H,m) ,3.71(1 H,dd,J=13.30,3.76Hz),2.46-2.64(4 H,m),2.02-2.27(3 H,m),1.86-1.99(1 H,m),1.62-1.82( 2 H, m), 0.69-0.82 (5 H, m); LCMS (ESI) [M+H]+ m/z: calcd 408.2, found 408.1; HPLC: 98.32% at 220 nm, at 254 nm is 99.30%; >95%ee, 99.8%de.

化合物1170：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-(2-甲基-1,3-苯并噁唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(3mg，16.7%產率)，黃色固體。1H NMR(400MHz，甲醇-d4)δ ppm 7.88-8.12(1 H,m),7.53-7.67(3 H,m),7.39(1 H,br s),5.79(1 H,br s),4.07-3.72(1 H,m),2.61-2.65(3 H,m),2.30(2 H,br s),2.09-2.18(3 H,m),1.93(2 H,br d,J=12.30Hz),1.45(1 H,br d,J=12.30Hz),1.14(3 H,d,J=6.78Hz),0.89(1 H,br d,J=7.53Hz)；LCMS(ESI)[M+H]+ m/z：計算值408.2，實測值408.1；HPLC：在220nm下為92.86%，在254nm下為94.72%；>95%ee、93.0%de。Compound 1170: N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-5-methyl-2-(2-methyl-1,3-benzo Oxazol-5-yl)-1-piperidinyl]-2-oxyacetamide (3 mg, 16.7% yield), yellow solid. 1H NMR (400MHz, methanol-d4) δ ppm 7.88-8.12(1H,m), 7.53-7.67(3H,m), 7.39(1H,br s), 5.79(1H,br s), 4.07 -3.72(1 H,m),2.61-2.65(3 H,m),2.30(2 H,br s),2.09-2.18(3 H,m),1.93(2 H,br d,J=12.30Hz ),1.45(1 H,br d,J=12.30Hz),1.14(3 H,d,J=6.78Hz),0.89(1 H,br d,J=7.53Hz); LCMS(ESI)[M+ H]+ m/z: calculated 408.2, found 408.1; HPLC: 92.86% at 220 nm, 94.72% at 254 nm; >95% ee, 93.0% de.

實例232. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1166)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1166)之合成Example 232. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(3-methyl-1,2-benzo Thiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (Compound 1166) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R)-5-methyl-2-(3-methyl-1,2-benzothiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (santiomer Synthesis of compound 1166)

Figure 110128222-A0202-12-1285-252
Figure 110128222-A0202-12-1285-252

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(3-methyl-1,2-benzothiazol-5-yl) Synthesis of -1-Piperidinyl]-2-Pendant Oxyacetamide

向2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(59mg，0.302mmol)、3-甲基-5-(5-甲基-2-哌啶基)-1,2-苯并噻唑(75.0mg，0.304mmol)及DMF(2mL)中之混合物中添加HATU(118mg，0.310mmol)及DIPEA(117mg，0.903mmol)，然後將混合物在20℃下攪拌12小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(10mL*3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL*2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO®；12g AgelaFlash®二氧化矽急驟管柱，EtOAc/MeOH，其中MeOH為0~5%，流速：30mL/min，254nm)進行純化，以得到呈黃色油狀物之N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(52mg，40.6%產率)。LCMS(ESI)[M+H]+ m/z：計算值424.1，實測值424.1。To 2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (59 mg, 0.302 mmol), 3-methyl-5-(5-methyl- 2-Piperidinyl)-1,2-benzothiazole (75.0 mg, 0.304 mmol) and DMF (2 mL) were added HATU (118 mg, 0.310 mmol) and DIPEA (117 mg, 0.903 mmol) and the mixture was mixed Stir at 20°C for 12 hours. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product, which was purified by flash purification (ISCO®; 12 g AgelaFlash® silica flash column, EtOAc/MeOH with 0~5% MeOH, flow rate: 30 mL/min, 254 nm) to give N-(6 as a yellow oil -Amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(3-methyl-1,2-benzothiazol-5-yl)-1-piperidinyl] -2-Oxyacetamide (52 mg, 40.6% yield). LCMS (ESI) [M+H] + m/z: calcd 424.1, found 424.1.

步驟7：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1166)及N-(6-胺基-5-甲基-3-吡啶Step 7: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(3-methyl-1,2-benzo Thiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (Compound 1166) and N-(6-amino-5-methyl-3-pyridine 基)-2-[(2S,5R)-5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1166)之合成yl)-2-[(2S,5R)-5-methyl-2-(3-methyl-1,2-benzothiazol-5-yl)-1-piperidinyl]-2-side oxy Synthesis of Acetamide (Enantiomer Compound 1166)

將N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(50mg，0.118mmol)藉由掌性SFC(儀器：Thar800Q；Daicel Chiralpak IG(250mm*30mm，10μm)；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=60/40；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化，以得到化合物1166及鏡像異構化合物1166 。N-(6-amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(3-methyl-1,2-benzothiazol-5-yl)-1 -Piperidinyl]-2-oxyacetamide (50 mg, 0.118 mmol) by chiral SFC (instrument: Thar800Q; Daicel Chiralpak IG (250 mm*30 mm, 10 μm); mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=60/40; flow rate: 80 mL/min; column temperature: 38 °C; nozzle temperature: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; Dresser temperature: 25°C; wavelength: 220 nm) purification to give compound 1166 and enantiomer compound 1166 .

化合物1166 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(16mg，具有反式相對化學之單一未知鏡像異構物，峰3，保留時間=4.341min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.26(br s,1H),8.12(d,J =8.5Hz,1 H),8.02(br s,1 H),7.97(s,1 H),7.59(br d,J =8.5Hz,1 H),7.47(br s,1 H),5.62(br s,1 H),5.34(br s,2 H),3.55-3.87(m,1 H),3.05-3.09(m,1 H),2.66-2.75(m,3 H),2.16-2.35(m,2 H),2.01-2.08(m,3 H),1.96(br d,J =11.3Hz,1 H),1.75-1.87(m,1 H),1.34-1.43(m,1 H),1.08(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值424.1，實測值424.1；HPLC：在220nm下為100%，在254nm下為100%；100%ee。 Compound 1166 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(3-methyl-1,2-benzo Thiazol-5-yl)-1-piperidinyl]-2-oxyacetamide (16 mg, single unknown enantiomer with trans relative chemistry, peak 3, retention time = 4.341 min, white solid) . 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.26(br s, 1H), 8.12(d, J =8.5Hz, 1 H), 8.02(br s, 1 H), 7.97(s, 1 H) ,7.59(br d, J =8.5Hz,1 H),7.47(br s,1 H),5.62(br s,1 H),5.34(br s,2 H),3.55-3.87(m,1 H) ), 3.05-3.09(m, 1 H), 2.66-2.75(m, 3 H), 2.16-2.35(m, 2 H), 2.01-2.08(m, 3 H), 1.96(br d, J =11.3 Hz, 1 H), 1.75-1.87 (m, 1 H), 1.34-1.43 (m, 1 H), 1.08 (d, J = 7.0 Hz, 3 H); LCMS(ESI) [M+H] + m /z: Calculated 424.1, found 424.1; HPLC: 100% at 220 nm, 100% at 254 nm; 100% ee.

鏡像異構化合物1166 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(3-甲基-1,2-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(16mg，具有反式相對化學之單一未知鏡像異構物，峰4，保留時間=5.604min，白色固體)，1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.26(br s,1 H),8.12(d,J =8.5Hz,1 H),8.02(br s,1 H),7.97(s,1 H),7.59(br d,J =8.5Hz,1 H),7.47(br s,1 H),5.62(br s,1 H),5.34(br s,2 H),3.55-3.87(m,1 H),3.05-3.09(m,1 H),2.66-2.75(m,3 H),2.16-2.35(m,2 H),2.01-2.08(m,3 H),1.96(br d,J =11.3Hz,1 H),1.75-1.87(m,1 H),1.34-1.43(m,1 H), 1.08(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值424.1，實測值424.1；HPLC：在220nm下為100%，在254nm下為100%；100%ee。 Enantiomer 1166 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(3-methyl-1,2 - benzothiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (16 mg, single unknown enantiomer with trans relative chemistry, peak 4, retention time = 5.604 min, white solid), 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.26(br s, 1 H), 8.12(d, J =8.5Hz, 1 H), 8.02(br s, 1 H), 7.97( s, 1 H), 7.59(br d, J =8.5Hz, 1 H), 7.47(br s, 1 H), 5.62(br s, 1 H), 5.34(br s, 2 H), 3.55-3.87 (m, 1 H), 3.05-3.09 (m, 1 H), 2.66-2.75 (m, 3 H), 2.16-2.35 (m, 2 H), 2.01-2.08 (m, 3 H), 1.96 (br d, J =11.3Hz,1H),1.75-1.87(m,1H),1.34-1.43(m,1H), 1.08(d, J =7.0Hz,3H); LCMS(ESI)[M +H] + m/z: calculated 424.1, found 424.1; HPLC: 100% at 220 nm, 100% at 254 nm; 100% ee.

實例233. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1319)之合成Example 233. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide (compound 1319)

Figure 110128222-A0202-12-1287-253
Figure 110128222-A0202-12-1287-253

步驟1：3-環丙基吡啶-2-胺之合成Step 1: Synthesis of 3-Cyclopropylpyridin-2-amine

向3-溴吡啶-2-胺(50.0g，289mmol)於甲苯(500mL)及水(100mL)中之溶液中添加環丙基硼酸(32.3g，376mmol)、三環己基膦(8.10g，28.9mmol)、無水磷酸鉀(184g，867mmol)及乙酸鈀(II)(3.24g，14.5mmol)。將反應混合物抽真空，然後用Ar回填。將反應混合物在90℃下攪拌16h。將所獲得之混合物在真空中濃縮。將所獲得之物質用水稀釋且用MTBE(3 x 500mL)萃取。將經合併之有機層經硫酸鈉乾燥且在真空中濃縮至乾，以得到呈棕色油狀物之3-環丙基吡啶-2-胺(59.0g，粗品)。To a solution of 3-bromopyridin-2-amine (50.0 g, 289 mmol) in toluene (500 mL) and water (100 mL) were added cyclopropylboronic acid (32.3 g, 376 mmol), tricyclohexylphosphine (8.10 g, 28.9 mmol), anhydrous potassium phosphate (184 g, 867 mmol) and palladium(II) acetate (3.24 g, 14.5 mmol). The reaction mixture was evacuated and backfilled with Ar. The reaction mixture was stirred at 90 °C for 16 h. The obtained mixture was concentrated in vacuo. The obtained material was diluted with water and extracted with MTBE (3 x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to give 3-cyclopropylpyridin-2-amine (59.0 g, crude) as a brown oil.

LCMS(ESI)：[M+H]+ m/z：計算值135.1；實測值135.2；Rt=0.609。LCMS (ESI): [M+H] + m/z: calculated 135.1; found 135.2; Rt=0.609.

步驟2：5-溴-3-環丙基吡啶-2-胺之合成Step 2: Synthesis of 5-bromo-3-cyclopropylpyridin-2-amine

將NBS(50.9g，286mmol，24.2mL)分批添加到3-環丙基吡啶-2-胺(59.0g，286mmol)於無水DCM中之溶液。將反應混合物在室溫下攪拌3h。將所獲得之混合物用水洗滌。將水層用二氯甲烷萃取。將經合併之有機萃取物用鹽 水洗滌且經Na2 SO4 乾燥。在減壓下移除溶劑。藉由CC(Interchim；800g SiO2 ，氯仿/乙腈，其中乙腈為0~40%，流速=150mL/min,Rv=5-6CV)純化殘餘物，以得到呈棕色固體之5-溴-3-環丙基吡啶-2-胺(30.4g，143mmol，49.9%產率)。NBS (50.9 g, 286 mmol, 24.2 mL) was added portionwise to a solution of 3-cyclopropylpyridin-2-amine (59.0 g, 286 mmol) in dry DCM. The reaction mixture was stirred at room temperature for 3 h. The obtained mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4 . The solvent was removed under reduced pressure. The residue was purified by CC (Interchim; 800 g SiO 2 , chloroform/acetonitrile with 0-40% acetonitrile, flow rate=150 mL/min, Rv=5-6CV) to give 5-bromo-3- as a brown solid Cyclopropylpyridin-2-amine (30.4 g, 143 mmol, 49.9% yield).

LCMS(ESI)：[M+H]+ m/z：計算值213.01及215.01；實測值215.0；Rt=0.834。LCMS (ESI): [M+H] + m/z: calculated 213.01 and 215.01; found 215.0; Rt=0.834.

步驟3：5-(二苯亞甲基胺基)-3-環丙基吡啶-2-胺之合成Step 3: Synthesis of 5-(Dibenzylideneamino)-3-cyclopropylpyridin-2-amine

將5-溴-3-環丙基吡啶-2-胺(15.0g，70.4mmol)、二苯基甲亞胺(14.0g，77.4mmol，12.9mL)、碳酸銫(68.8g，211mmol)、XantPhos(2.04g，3.52mmol)及Pd2 (dba)3 (1.61g，1.76mmol)於二噁烷(250mL)中之混合物抽真空，然後用Ar回填。在90℃、Ar氣氛下將反應混合物攪拌12h。將反應混合物冷卻至室溫，用MTBE(250mL)稀釋，且過濾。將濾液在真空中濃縮，以得到呈棕色膠狀物之5-(二苯亞甲基胺基)-3-環丙基吡啶-2-胺(27.3g，粗品)。5-Bromo-3-cyclopropylpyridin-2-amine (15.0 g, 70.4 mmol), diphenylmethaneimine (14.0 g, 77.4 mmol, 12.9 mL), cesium carbonate (68.8 g, 211 mmol), XantPhos (2.04 g, 3.52 mmol) and Pd2(dba )3 ( 1.61 g, 1.76 mmol) in dioxane (250 mL) was evacuated and backfilled with Ar. The reaction mixture was stirred at 90 °C under Ar atmosphere for 12 h. The reaction mixture was cooled to room temperature, diluted with MTBE (250 mL), and filtered. The filtrate was concentrated in vacuo to give 5-(dibenzylideneamino)-3-cyclopropylpyridin-2-amine (27.3 g, crude) as a brown gum.

1H NMR(400MHz,CDCl3 )δ 0.26-0.27(m,2H),0.75-0.76(m,2H),1.46-1.47(m,1H),4.52(br,2H),6.62(m,1H),7.08(m,2H),7.29-7.41(m,6H),7.53(m,1H),7.69(m,2H)。1H NMR (400MHz, CDCl 3 )δ 0.26-0.27(m, 2H), 0.75-0.76(m, 2H), 1.46-1.47(m, 1H), 4.52(br, 2H), 6.62(m, 1H), 7.08 (m, 2H), 7.29-7.41 (m, 6H), 7.53 (m, 1H), 7.69 (m, 2H).

步驟4：3-環丙基吡啶-2,5-二胺之合成Step 4: Synthesis of 3-Cyclopropylpyridine-2,5-diamine

將36% w/w鹽酸水溶液(4.50g，123mmol，5.63mL)添加到5-(二苯亞甲基胺基)-3-環丙基吡啶-2-胺(15.0g，35.9mmol)於THF(150mL)及水(100mL)中之溶液中。將所得混合物在21℃下攪拌18h。將所獲得之混合物用水(20.0mL)稀釋且用MTBE(2x25.0mL)萃取。收集有機層且丟棄。將水層用固體K2 CO3 鹼化至pH

Figure 110128222-A0202-12-1288-359
10-11且用DCM(4x25.0mL)萃取。將經合併之有機層經K2 CO3 乾燥且在減壓下濃縮，以得到呈紅色油狀物之3-環丙基吡啶-2,5-二胺(5.30g，粗品)。36% w/w aqueous hydrochloric acid (4.50 g, 123 mmol, 5.63 mL) was added to 5-(dibenzylideneamino)-3-cyclopropylpyridin-2-amine (15.0 g, 35.9 mmol) in THF (150 mL) and water (100 mL). The resulting mixture was stirred at 21 °C for 18 h. The obtained mixture was diluted with water (20.0 mL) and extracted with MTBE (2 x 25.0 mL). The organic layer was collected and discarded. The aqueous layer was basified to pH with solid K2CO3
Figure 110128222-A0202-12-1288-359
10-11 and extracted with DCM (4x25.0 mL). The combined organic layers were dried over K2CO3 and concentrated under reduced pressure to give 3 -cyclopropylpyridine-2,5-diamine (5.30 g, crude) as a red oil.

LCMS(ESI)：[M+H]+ m/z：計算值150.11；實測值150.2；Rt=0.323。LCMS (ESI): [M+H] + m/z: calculated 150.11; found 150.2; Rt=0.323.

步驟5：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1319)之合成Step 5: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide (compound 1319)

在室溫下將3-環丙基吡啶-2,5-二胺(1.15g，2.31mmol)及HATU(923mg，2.43mmol)混合於無水DMF(10.0mL)中。將所得混合物攪拌15min。向其中添加2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙酸鋰(718mg，2.31mmol)，且在室溫下繼續攪拌隔夜。將所獲得之混合物倒入到水中且用EtOAc萃取3次。將經合併之有機層用水、鹽水洗滌且在真空中濃縮。使殘餘物經歷HPLC(0.5-6.5min 30-65%水-ACN；流速：30mL/min，管柱：Waters SunFire C18，100x19mm，5μm)。藉由掌性管柱(Chiral ART(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min，RT=34.231min)純化所獲得之物質(236.5mg)，以得到呈棕色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(168mg，385μmol，16.7%產率)。3-Cyclopropylpyridine-2,5-diamine (1.15 g, 2.31 mmol) and HATU (923 mg, 2.43 mmol) were mixed in dry DMF (10.0 mL) at room temperature. The resulting mixture was stirred for 15 min. To this was added lithium 2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetate (718 mg, 2.31 mmol) and continued stirring at room temperature overnight. The obtained mixture was poured into water and extracted 3 times with EtOAc. The combined organic layers were washed with water, brine and concentrated in vacuo. The residue was subjected to HPLC (0.5-6.5 min 30-65% water-ACN; flow rate: 30 mL/min, column: Waters SunFire C18, 100 x 19 mm, 5 μm). The material obtained (236.5 mg) was purified by chiral column (Chiral ART (250*20, 5 mkm), hexane-IPA-MeOH, 50-25-25, 12 ml/min, RT=34.231 min) to give to give N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)- as a brown solid 5-Methyl-1-piperidinyl]-2-oxoacetamide (168 mg, 385 μmol, 16.7% yield).

RT=58.171min(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)RT=58.171min (Chiralpak IC (250*4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)

1H NMR(600MHz,DMSO-d6 )δ 0.40-0.47(m,2H),0.83-0.89(m,2H),1.00-1.04(m,3H),1.32-1.40(m,2H),1.60-1.90(m,2H),2.05-2.37(m,2H),3.50(d,1H),4.05(d,1H),5.30-5.77(m,3H),7.28-7.50(m,2H),7.99-8.06(m,2H),8.15-8.18(m,1H),9.39(m,1H),10.55(m,1H)1H NMR (600MHz, DMSO-d 6 )δ 0.40-0.47 (m, 2H), 0.83-0.89 (m, 2H), 1.00-1.04 (m, 3H), 1.32-1.40 (m, 2H), 1.60-1.90 (m,2H),2.05-2.37(m,2H),3.50(d,1H),4.05(d,1H),5.30-5.77(m,3H),7.28-7.50(m,2H),7.99-8.06 (m,2H),8.15-8.18(m,1H),9.39(m,1H),10.55(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值436.2；Rt=2.536。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 436.2; Rt=2.536.

實例234. rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1313)及rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-S-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1313)之合成Example 234. rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-methyl-1,3 -Benzothiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (spiegelisomeric compound 1313) and rel-N-(6-amino-5-cyclopropyl-3) -Pyridinyl)-2-[(2R,5S)-S-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-side Synthesis of Oxyacetamide (Compound 1313)

Figure 110128222-A0202-12-1290-254
Figure 110128222-A0202-12-1290-254

步驟1：N-(6-胺基-5-環丙基-3-吡啶基)-2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺Step 1: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl )-1-Piperidinyl]-2-oxyacetamide

在室溫下將2-[(6-胺基-5-環丙基-3-吡啶基)胺基]-2-側氧基乙酸鋰鹽(2.10g，3.25mmol)及HATU(1.36g，3.57mmol)混合於無水DMF(25mL)中且將所得混合物攪拌15min。向其中添加2-甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(0.8g，3.25mmol)，且將所得混合物在室溫下攪拌2h。使所得混合物經歷HPLC (40-65 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；管柱SunFire 100x19mm 5um(R))。獲得呈米色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.3398g，755.84umol，23.28%產率)及13%順式雜質。2-[(6-Amino-5-cyclopropyl-3-pyridinyl)amino]-2-oxoacetate lithium salt (2.10 g, 3.25 mmol) and HATU (1.36 g, 3.57 mmol) in dry DMF (25 mL) and the resulting mixture was stirred for 15 min. To this was added 2-methyl-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (0.8 g, 3.25 mmol), and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was subjected to HPLC (40-65 0.5-6.5min water-acetonitrile; flow rate 30ml/min (load pump 4ml/min acetonitrile); column SunFire 100x19mm 5um(R)). N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[5-methyl-2-(2-methyl-1,3-benzothiazole-5 was obtained as a beige solid -yl)-1-piperidinyl]-2-side oxyacetamide (0.3398 g, 755.84 umol, 23.28% yield) and 13% cis impurity.

LCMS(ESI)：[M+1]+ m/z：計算值449.2；實測值450.2；Rt=2.663min。LCMS (ESI): [M+1] + m/z: calculated 449.2; found 450.2; Rt=2.663 min.

步驟2：rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1313)及rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1313)之合成Step 2: rel-N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(2-methyl-1,3 -Benzothiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (spiegelisomeric compound 1313) and rel-N-(6-amino-5-cyclopropyl-3) -Pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-side Synthesis of Oxyacetamide (Compound 1313)

藉由掌性層析(第1次運行：Chiralpak IC-III(250*20，5mkm)，IPA-MeOH，50-50，10ml/min，然後第2次運行：Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)分離非鏡像異構物之混合物，以獲得N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶 基]-2-側氧基乙醯胺(117.08mg，260.43umol，34.46%產率)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(110.18mg，245.08umol，32.42%產率)By chiral chromatography (1st run: Chiralpak IC-III (250*20, 5mkm), IPA-MeOH, 50-50, 10ml/min, then 2nd run: Chiralcel OD-H (250*20 , 5mkm), hexane-IPA-MeOH, 60-20-20, 12ml/min) to separate the mixture of diastereoisomers to obtain N-(6-amino-5-cyclopropyl-3-pyridyl) )-2-[(2R,5S)-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidine yl]-2-oxyacetamide (117.08 mg, 260.43 umol, 34.46% yield) and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S, 5R)-5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (110.18 mg, 245.08 umol , 32.42% yield)

分析型：Analytical:

化合物1313之RT(Chiralpak IC(250*4.6，5mkm)，IPA-MeOH，50-50，0.6ml/min)-26.667min；RT of compound 1313 (Chiralpak IC (250*4.6, 5mkm), IPA-MeOH, 50-50, 0.6ml/min)-26.667min;

鏡像異構化合物1313之RT(Chiralpak IC(250*4.6，5mkm)，IPA-MeOH，50-50，0,5ml/min)-16.52min。RT for Spiegelmer 1313 (Chiralpak IC (250*4.6, 5mkm), IPA-MeOH, 50-50, 0,5ml/min) - 16.52min.

製備型：Preparation:

安裝運行(自P2及其順式雜質之混合物分離P1)：Setup run (separation of P1 from a mixture of P2 and its cis-impurities):

化合物1313之RT(Chiralpak IC-III(250*20，5mkm)，IPA-MeOH，50-50，10ml/min)-34.014min；RT of compound 1313 (Chiralpak IC-III (250*20, 5mkm), IPA-MeOH, 50-50, 10ml/min)-34.014min;

鏡像異構化合物1313之RT(具有順式雜質)(Chiralpak IC-III(250*20，5mkm)，IPA-MeOH，50-50，10ml/min)-19.557min。RT for enantiomer 1313 (with cis impurity) (Chiralpak IC-III (250*20, 5mkm), IPA-MeOH, 50-50, 10ml/min) - 19.557min.

製備型，第二次運行(P2與順式雜質之分離)Preparative, second run (separation of P2 and cis impurity)

鏡像異構化合物1313之RT(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)=17.823min。RT for enantiomer 1313 (Chiralcel OD-H (250*20, 5mkm), Hexane-IPA-MeOH, 60-20-20, 12ml/min)=17.823min.

化合物1313：Compound 1313:

1 H NMR(600MHz,dmso)δ 0.40-0.47(m,2H),0.83-0.89(m,2H),1.00-1.04(m,3H),1.22-1.39(m,2H),1.61-1.89(m,2H),2.05-2.36(m,2H),2.78(s,3H),3.48(d,1H),4.03(d,1H),5.28-5.76(m,3H),7.28-7.40(m,2H),7.83-7.86(m,1H),7.99-8.06(m,2H),10.54(m,1H)。LCMS(ESI)：[M+1]+ m/z：計算值263.1；實測值264.2；Rt=2.800min。 1 H NMR(600MHz,dmso)δ 0.40-0.47(m,2H),0.83-0.89(m,2H),1.00-1.04(m,3H),1.22-1.39(m,2H),1.61-1.89(m ,2H),2.05-2.36(m,2H),2.78(s,3H),3.48(d,1H),4.03(d,1H),5.28-5.76(m,3H),7.28-7.40(m,2H ), 7.83-7.86 (m, 1H), 7.99-8.06 (m, 2H), 10.54 (m, 1H). LCMS (ESI): [M+1] + m/z: calculated 263.1; found 264.2; Rt=2.800 min.

LCMS(ESI)：[M+1]+ m/z：計算值449.2；實測值450.2；Rt=2.551min。LCMS (ESI): [M+1] + m/z: calculated 449.2; found 450.2; Rt=2.551 min.

鏡像異構化合物1313：Enantiomer compound 1313:

1 H NMR(600MHz,dmso)δ 0.40-0.47(m,2H),0.83-0.89(m,2H),1.00-1.04(m,3H),1.22-1.38(m,2H),1.60-1.89(m,2H),2.05-2.36(m,2H),2.78(s,3H),3.48(d,1H),4.03(d,1H),5.28-5.76(m,3H),7.28-7.39(m,2H),7.83-7.86(m,1H),7.99-8.06(m,2H),10.54(m,1H)。 1 H NMR(600MHz,dmso)δ 0.40-0.47(m,2H),0.83-0.89(m,2H),1.00-1.04(m,3H),1.22-1.38(m,2H),1.60-1.89(m ,2H),2.05-2.36(m,2H),2.78(s,3H),3.48(d,1H),4.03(d,1H),5.28-5.76(m,3H),7.28-7.39(m,2H) ), 7.83-7.86 (m, 1H), 7.99-8.06 (m, 2H), 10.54 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值449.2；實測值450.2；Rt=2.527min。LCMS (ESI): [M+1] + m/z: calculated 449.2; found 450.2; Rt=2.527 min.

實例235. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1361)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1251)之合成Example 235. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide (Compound 1361) and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2 Synthesis of -(1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1251)

Figure 110128222-A0202-12-1292-255
Figure 110128222-A0202-12-1292-255

步驟1：N-(6-胺基-5-環丙基-3-吡啶基)-2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-cyclopropyl-3-pyridinyl)-2-[2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl] -2-Synthesis of Pendant Oxyacetamide

在21℃下，將5-(5-甲基-2-哌啶基)-1H-吲唑(0.1g，464.48umol)、HATU(229.59mg，603.83umol)混合於無水DMF(5mL)中，且將所得混合物攪拌15min。向其中添加2-[(6-胺基-5-環丙基-3-吡啶基)胺基]-2-側氧基乙酸鈉(225.92mg，464.48umol)，且將所得混合物在21℃下攪拌隔夜。使所得混合物經歷HPLC(30-55 0.5-6.5min水-乙腈；流速30ml/min(裝載泵5ml/min乙腈)；管柱SunFire 100x19mm 5um(R))。獲得呈淡黃色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(57.1mg，136.44umol，29.38%產率)。5-(5-Methyl-2-piperidinyl)-1H-indazole (0.1 g, 464.48 umol), HATU (229.59 mg, 603.83 umol) were mixed in dry DMF (5 mL) at 21 °C, And the resulting mixture was stirred for 15 min. To this was added sodium 2-[(6-amino-5-cyclopropyl-3-pyridinyl)amino]-2-oxoacetate (225.92 mg, 464.48 umol), and the resulting mixture was heated at 21 °C Stir overnight. The resulting mixture was subjected to HPLC (30-55 0.5-6.5min water-acetonitrile; flow rate 30ml/min (load pump 5ml/min acetonitrile); column SunFire 100x19mm 5um(R)). N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[2-(1H-indazol-5-yl)-5-methyl-1-piperin was obtained as a pale yellow solid Peridyl]-2-Pendant oxyacetamide (57.1 mg, 136.44 umol, 29.38% yield).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.4；Rt=2.211min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.4; Rt=2.211 min.

步驟2：實例236. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1361)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[((2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1251)之合成Step 2: Example 236. N-(6-Amino-5-cyclopropyl-3-pyridinyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5- Methyl-1-piperidinyl]-2-oxoacetamide (Compound 1361) and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[((2R, Synthesis of 5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1251)

藉由掌性層析(管柱：Chiralpak IC-III(250*20mm，5mkm)；流動相：IPA-MeOH 50-50流速：10mL/min)分離非鏡像異構物之混合物，以獲得N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺化合物1361 (21.4mg，51.14umol，37.48%產率，具有5.4%順式雜質)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺化合物1251 (20.41mg，48.77umol，35.74%產率)The mixture of enantiomers was separated by chiral chromatography (column: Chiralpak IC-III (250*20mm, 5mkm); mobile phase: IPA-MeOH 50-50 flow rate: 10 mL/min) to obtain N- (6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl ]-2-Oxyacetamide compound 1361 (21.4 mg, 51.14 umol, 37.48% yield, with 5.4% cis impurity) and N-(6-amino-5-cyclopropyl-3-pyridyl )-2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide compound 1251 (20.41 mg, 48.77umol, 35.74% yield)

分析型：Analytical:

化合物1361之RT(Chiralpak IC(250*4.6，5mkm),IPA-MeOH，50-50，0,5ml/min)-11.4912min；RT of compound 1361 (Chiralpak IC (250*4.6, 5mkm), IPA-MeOH, 50-50, 0,5ml/min)-11.4912min;

化合物1251之RT(Chiralpak IC(250*4.6，5mkm)，IPA-MeOH，50-50，0,5ml/min)-24.8342min。RT for compound 1251 (Chiralpak IC (250*4.6, 5mkm), IPA-MeOH, 50-50, 0,5ml/min) - 24.8342min.

製備型：Preparation:

化合物1361之RT(Chiralpak IC-III(250*20，5mkm)，IPA-MeOH，50-50，10ml/min)-12.466min；RT of compound 1361 (Chiralpak IC-III (250*20, 5mkm), IPA-MeOH, 50-50, 10ml/min)-12.466min;

化合物1251之RT(Chiralpak IC-III(250*20，5mkm)，IPA-MeOH，50-50，10ml/min)-25.178min。RT for compound 1251 (Chiralpak IC-III (250*20, 5mkm), IPA-MeOH, 50-50, 10ml/min) - 25.178min.

化合物1361：Compound 1361:

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.44(m,2H),0.87(m,2H),1.02(m,3H),1.33(m,1H),1.76(m,3H),2.19(m,2H),2.76(m,1H),3.74(m,1H),5.72(m,3H),7.27(d,1H),7.36(m,1H),7.53(m,1H),7.69(m,1H),8.03(m,2H),10.50(s,1H), 13.00(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.44(m, 2H), 0.87(m, 2H), 1.02(m, 3H), 1.33(m, 1H), 1.76(m, 3H), 2.19(m, 2H), 2.76(m, 1H), 3.74(m, 1H), 5.72(m, 3H), 7.27(d, 1H), 7.36(m, 1H), 7.53(m, 1H), 7.69 (m, 1H), 8.03 (m, 2H), 10.50 (s, 1H), 13.00 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.843min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.843 min.

化合物1251：Compound 1251:

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.44(m,2H),0.87(m,2H),1.01(m,3H),1.35(m,1H),1.76(m,3H),2.19(m,2H),2.76(m,1H),3.74(dd,1H),5.72(m,3H),7.27(m,1H),7.37(m,1H),7.53(m,1H),7.69(m,1H),8.03(m,2H),10.49(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.44(m, 2H), 0.87(m, 2H), 1.01(m, 3H), 1.35(m, 1H), 1.76(m, 3H), 2.19(m, 2H), 2.76(m, 1H), 3.74(dd, 1H), 5.72(m, 3H), 7.27(m, 1H), 7.37(m, 1H), 7.53(m, 1H), 7.69 (m, 1H), 8.03 (m, 2H), 10.49 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.838min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.838 min.

實例236. 雙環哌啶化合物之文庫合成Example 236. Library Synthesis of Bicyclic Piperidine Compounds

Figure 110128222-A0202-12-1294-256
Figure 110128222-A0202-12-1294-256

將DIPEA(3.5當量)添加到2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸(1.1當量；反應物1)及相應胺(1.0當量；反應物2)於DMF(2.0mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(1.2當量)於DMF(1.0mL)中之溶液。將反應混合物在室溫下攪拌隔夜。在消耗所有起始材料(如藉由LCMS展示)之後，將所得混合物在減壓下濃縮。使殘餘物經歷HPLC(C18管柱且以MeOH-H2 O+0.1% NH3 為流動相，運行時間5min)，以得到純產物。DIPEA (3.5 equiv) was added to 2-((5-aminocarbamoylpyridin-3-yl)amino)-2-oxoacetic acid (1.1 equiv; reactant 1) and the corresponding amine (1.0 equiv; reaction Compound 2) in DMF (2.0 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (1.2 equiv.) in DMF (1.0 mL) was added. The reaction mixture was stirred at room temperature overnight. After consumption of all starting material (as shown by LCMS), the resulting mixture was concentrated under reduced pressure. The residue was subjected to HPLC (C18 column with MeOH- H2O +0.1% NH3 as mobile phase, run time 5 min) to give pure product.

5-[2-(1-苯甲基-十氫-1,6-萘啶-6-基)-2-側氧基乙醯胺基]吡啶-3-甲醯胺(化合物412 )之合成Synthesis of 5-[2-(1-benzyl-decahydro-1,6-naphthyridin-6-yl)-2-oxyacetamido]pyridine-3-carboxamide ( Compound 412 )

Figure 110128222-A0202-12-1294-257
Figure 110128222-A0202-12-1294-257

產率：31.0mg，43.44%Yield: 31.0 mg, 43.44%

1 H NMR(500MHz,DMSO)δ 1.34-1.49(m,2H),1.50-1.65(m,3H),1.88-2.09(m,2H),2.16-2.34(m,1H),2.44-2.47(m,1H),2.68-2.99(m,2H),3.04-3.16(m,1H),3.48-3.57(m,1H),3.59-3.83(m,2H),3.98-4.15(m,1H),7.20-7.27(m,1H),7.27-7.35(m,4H),7.62(s,1H),8.18(s,1H),8.47-8.55(m,1H),8.75-8.80(m,1H),8.85-8.92(m,1H),11.11(s,1H)。 1 H NMR (500MHz, DMSO)δ 1.34-1.49(m, 2H), 1.50-1.65(m, 3H), 1.88-2.09(m, 2H), 2.16-2.34(m, 1H), 2.44-2.47(m ,1H),2.68-2.99(m,2H),3.04-3.16(m,1H),3.48-3.57(m,1H),3.59-3.83(m,2H),3.98-4.15(m,1H),7.20 -7.27(m,1H),7.27-7.35(m,4H),7.62(s,1H),8.18(s,1H),8.47-8.55(m,1H),8.75-8.80(m,1H),8.85 -8.92(m, 1H), 11.11(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=0.759min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=0.759 min.

5-[2-(4a-羥基-十氫異喹啉-2-基)-2-側氧基乙醯胺基]吡啶-3-甲醯胺(化合物421 )之合成Synthesis of 5-[2-(4a-Hydroxy-decahydroisoquinolin-2-yl)-2-oxyacetamido]pyridine-3-carboxamide ( Compound 421 )

Figure 110128222-A0202-12-1295-258
Figure 110128222-A0202-12-1295-258

產率：21.8mg，30.16%Yield: 21.8 mg, 30.16%

1 H NMR(500MHz,DMSO)δ 1.16-1.29(m,3H),1.30-1.51(m,4H),1.53-1.64(m,4H),1.83-1.99(m,1H),3.12-3.27(m,1H),3.55-3.69(m,1H),3.77-4.11(m,1H),4.48-4.55(m,1H),7.62(s,1H),8.17(s,1H),8.47-8.54(m,1H),8.74-8.80(m,1H),8.87(dd,1H),11.08(s,1H)。 1 H NMR (500MHz, DMSO) δ 1.16-1.29(m, 3H), 1.30-1.51(m, 4H), 1.53-1.64(m, 4H), 1.83-1.99(m, 1H), 3.12-3.27(m ,1H),3.55-3.69(m,1H),3.77-4.11(m,1H),4.48-4.55(m,1H),7.62(s,1H),8.17(s,1H),8.47-8.54(m , 1H), 8.74-8.80 (m, 1H), 8.87 (dd, 1H), 11.08 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值346.2；實測值347.2；Rt=2.126min。LCMS (ESI): [M+H] + m/z: calculated 346.2; found 347.2; Rt=2.126 min.

5-[2-(6-羥基-十氫異喹啉-2-基)-2-側氧基乙醯胺基]吡啶-3-甲醯胺(化合物418 )之合成Synthesis of 5-[2-(6-Hydroxy-decahydroisoquinolin-2-yl)-2-oxoacetamido]pyridine-3-carboxamide ( Compound 418 )

Figure 110128222-A0202-12-1295-259
Figure 110128222-A0202-12-1295-259

產率：5.4mg，8.35%Yield: 5.4mg, 8.35%

LCMS(ESI)：[M+H]+ m/z：計算值346.2；實測值347.2；Rt=1.765min。LCMS (ESI): [M+H] + m/z: calculated 346.2; found 347.2; Rt=1.765 min.

5-{2-[6-(胺甲醯基甲基)-十氫異喹啉-2-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物420 )之合成of 5-{2-[6-(aminocarbamoylmethyl)-decahydroisoquinolin-2-yl]-2-oxyacetamido}pyridine-3-carbamoylamine ( Compound 420 ) synthesis

Figure 110128222-A0202-12-1296-260
Figure 110128222-A0202-12-1296-260

產率：19.9mg，28.46%Yield: 19.9 mg, 28.46%

1 H NMR(500MHz,DMSO)δ 0.87-1.02(m,1H),1.17-1.31(m,1H),1.33-1.56(m,4H),1.60-1.84(m,3H),1.86-1.95(m,1H),1.96-2.02(m,1H),2.07-2.26(m,1H),2.68-2.97(m,2H),3.09-3.26(m,1H),3.59-4.00(m,1H),4.11-4.48(m,1H),6.70(s,1H),7.11-7.30(m,1H),7.62(s,1H),8.17(s,1H),8.44-8.57(m,1H),8.73-8.81(m,1H),8.84-9.14(m,1H),11.10(br s,1H)。 1 H NMR (500MHz, DMSO)δ 0.87-1.02(m, 1H), 1.17-1.31(m, 1H), 1.33-1.56(m, 4H), 1.60-1.84(m, 3H), 1.86-1.95(m ,1H),1.96-2.02(m,1H),2.07-2.26(m,1H),2.68-2.97(m,2H),3.09-3.26(m,1H),3.59-4.00(m,1H),4.11 -4.48(m,1H),6.70(s,1H),7.11-7.30(m,1H),7.62(s,1H),8.17(s,1H),8.44-8.57(m,1H),8.73-8.81 (m, 1H), 8.84-9.14 (m, 1H), 11.10 (br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值387.2；實測值388.2；Rt=2.023min。LCMS (ESI): [M+H] + m/z: calculated 387.2; found 388.2; Rt=2.023 min.

外消旋-5-{2-[(1R,5S)-3-氧雜螺[雙環[3.1.0]己烷-2,3'-哌啶]-1'-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物124 )之合成Racemic-5-{2-[(1R,5S)-3-oxaspiro[bicyclo[3.1.0]hexane-2,3'-piperidin]-1'-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine ( Compound 124 )

Figure 110128222-A0202-12-1296-261
Figure 110128222-A0202-12-1296-261

藉由一般程序製備。產率：16.0mg，32.0%Prepared by general procedure. Yield: 16.0 mg, 32.0%

1 H NMR(500MHz,cdcl3)δ 0.52(m,2H),1.42(m,1H),1.80(m,4H),3.05(m,1H),3.40(m,1H),3.75(m,3H),4.10(m,1H),4.43(m,1H),5.96(m,2H),8.62(m,1H),8.86(m,2H),9.41(m,1H)。 1 H NMR (500MHz, cdcl3)δ 0.52(m, 2H), 1.42(m, 1H), 1.80(m, 4H), 3.05(m, 1H), 3.40(m, 1H), 3.75(m, 3H) , 4.10 (m, 1H), 4.43 (m, 1H), 5.96 (m, 2H), 8.62 (m, 1H), 8.86 (m, 2H), 9.41 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.4；Rt=2.275min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.4; Rt=2.275 min.

5-(2-{十氫-1H-環庚并[c]吡啶-2-基}-2-側氧基乙醯胺基)吡啶-3-甲醯胺(化合物133 )之合成Synthesis of 5-(2-{decahydro-1H-cyclohepta[c]pyridin-2-yl}-2-oxyacetamido)pyridine-3-carbamoylamine ( Compound 133 )

Figure 110128222-A0202-12-1297-262
Figure 110128222-A0202-12-1297-262

藉由一般程序製備。產率：18.1mg，51.71%Prepared by general procedure. Yield: 18.1 mg, 51.71%

1 H NMR(500MHz,DMSO-d 6 )δ 1.27(m,5H),1.52(m,3H),1.64(m,4H),1.76(m,1H),1.83(m,1H),1.92(m,1H),3.18(m,1H),3.49(m,1H),3.64(m,1H),7.61(s,1H),8.16(s,1H),8.50(m,1H),8.77(m,1H),8.86(m,1H),10.77(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 1.27(m, 5H), 1.52(m, 3H), 1.64(m, 4H), 1.76(m, 1H), 1.83(m, 1H), 1.92(m ,1H),3.18(m,1H),3.49(m,1H),3.64(m,1H),7.61(s,1H),8.16(s,1H),8.50(m,1H),8.77(m, 1H), 8.86 (m, 1H), 10.77 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.1；Rt=1.161min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.1; Rt=1.161 min.

5-[2-(5-環戊基-2-甲基哌啶-1-基)-2-側氧基乙醯胺基]吡啶-3-甲醯胺(化合物143 )之合成Synthesis of 5-[2-(5-cyclopentyl-2-methylpiperidin-1-yl)-2-oxyacetamido]pyridine-3-carboxamide ( Compound 143 )

Figure 110128222-A0202-12-1297-263
Figure 110128222-A0202-12-1297-263

藉由一般程序製備。產率：18.0mg，51.43%Prepared by general procedure. Yield: 18.0 mg, 51.43%

1 H NMR(500MHz,DMSO-d 6 )δ 0.97(m,2H),1.23(m,3H),1.35(m,2H),1.44(m,2H),1.56(m,3H),1.71(m,2H),1.88(m,3H),3.01(m,0.5H),3.45(m,1H),4.23(m,1.5H),7.61(s,1H),8.17(s,1H),8.49(s,1H),8.77(m,1H),8.87(m,1H),10.80(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.97(m, 2H), 1.23(m, 3H), 1.35(m, 2H), 1.44(m, 2H), 1.56(m, 3H), 1.71(m ,2H),1.88(m,3H),3.01(m,0.5H),3.45(m,1H),4.23(m,1.5H),7.61(s,1H),8.17(s,1H),8.49( s, 1H), 8.77 (m, 1H), 8.87 (m, 1H), 10.80 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.1；Rt=1.214min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.1; Rt=1.214 min.

5-(2-{3-氧雜螺[雙環[3.1.0]己烷-2,4'-哌啶]-1'-基}-2-側氧基乙醯胺基)吡啶-3-甲醯5-(2-{3-oxaspiro[bicyclo[3.1.0]hexane-2,4'-piperidin]-1'-yl}-2-oxyacetamido)pyridine-3- formazan 胺(化合物149 )之合成Synthesis of Amine ( Compound 149 )

Figure 110128222-A0202-12-1298-264
Figure 110128222-A0202-12-1298-264

藉由一般程序製備。產率：16.0mg，45.71%Prepared by general procedure. Yield: 16.0 mg, 45.71%

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.27(m,1H),0.45(m,1H),1.54(m,3H),1.63(m,3H),3.20(m,1H),3.35(m,1H),3.59(m,1H),3.68(m,2H),3.90(m,1H),7.59(s,1H),8.15(s,1H),8.47(s,1H),8.75(m,1H),8.85(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.27 (m, 1H), 0.45 (m, 1H), 1.54 (m, 3H), 1.63 (m, 3H), 3.20 (m, 1H), 3.35(m, 1H), 3.59(m, 1H), 3.68(m, 2H), 3.90(m, 1H), 7.59(s, 1H), 8.15(s, 1H), 8.47(s, 1H), 8.75 (m, 1H), 8.85 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.1；Rt=0.916min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.1; Rt=0.916 min.

5-[2-(2-甲基-十氫喹啉-1-基)-2-側氧基乙醯胺基]吡啶-3-甲醯胺(化合物144 )之合成Synthesis of 5-[2-(2-methyl-decahydroquinolin-1-yl)-2-oxoacetamido]pyridine-3-carboxamide ( Compound 144 )

Figure 110128222-A0202-12-1298-265
Figure 110128222-A0202-12-1298-265

藉由一般程序製備。產率：3.4mg，9.71%Prepared by general procedure. Yield: 3.4mg, 9.71%

1 H NMR(氯仿-d,600MHz)：δ(ppm)1.33(m,6H),1.48(m,1H),1.66(m,2H),1.73(m,2H),1.89(m,3H),2.01(m,3H),4.53(m,1H),4.75(m,1H),6.25(s,1H),6.86(s,1H),8.78(s,1H),8.98(s,1H),9.11(s,1H),10.02(s,1H)。 1 H NMR (chloroform-d, 600MHz): δ (ppm) 1.33 (m, 6H), 1.48 (m, 1H), 1.66 (m, 2H), 1.73 (m, 2H), 1.89 (m, 3H), 2.01(m,3H),4.53(m,1H),4.75(m,1H),6.25(s,1H),6.86(s,1H),8.78(s,1H),8.98(s,1H),9.11 (s, 1H), 10.02 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.1；Rt=1.141min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.1; Rt=1.141 min.

5-{2-[2-(2-羥基環戊基)哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物169 )之合成Synthesis of 5-{2-[2-(2-hydroxycyclopentyl)piperidin-1-yl]-2-oxyacetamido}pyridine-3-carboxamide ( Compound 169 )

Figure 110128222-A0202-12-1299-266
Figure 110128222-A0202-12-1299-266

藉由一般程序製備。產率：6.1mg，17.43%Prepared by general procedure. Yield: 6.1 mg, 17.43%

1 H NMR(氯仿-d,500MHz)：δ(ppm)1.31(m,1H),1.73(m,8H),2.05(m,2H),2.42(m,1H),3.01(m,1H),4.03(m,1H),4.52(m,1H),5.06(m,1H),8.63(s,1H),8.83(m,1H),8.89(m,1H),9.47(m,1H)。 1 H NMR (chloroform-d, 500MHz): δ (ppm) 1.31 (m, 1H), 1.73 (m, 8H), 2.05 (m, 2H), 2.42 (m, 1H), 3.01 (m, 1H), 4.03(m,1H), 4.52(m,1H), 5.06(m,1H), 8.63(s,1H), 8.83(m,1H), 8.89(m,1H), 9.47(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值360.2；實測值361.2；Rt=0.830min。LCMS (ESI): [M+H] + m/z: calculated 360.2; found 361.2; Rt=0.830 min.

5-(2-側氧基-2-{9-硫雜-2-氮雜螺[5.5]十一烷-2-基}乙醯胺基)吡啶-3-甲醯胺(化合物166 )之合成Of 5-(2-oxo-2-{9-thia-2-azaspiro[5.5]undecan-2-yl}acetamido)pyridine-3-carboxamide ( compound 166 ) synthesis

Figure 110128222-A0202-12-1299-267
Figure 110128222-A0202-12-1299-267

藉由一般程序製備。產率：10.2mg，29.14%Prepared by general procedure. Yield: 10.2 mg, 29.14%

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.53(m,6H),2.43(m,2H),2.66(m,2H),3.28(m,2H),3.43(m,4H),7.62(m,1H),8.17(m,1H),8.49(s,1H),8.77(s,1H),8.88(m,1H),10.47(s,1H) 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.53(m, 6H), 2.43(m, 2H), 2.66(m, 2H), 3.28(m, 2H), 3.43(m, 4H), 7.62(m, 1H), 8.17(m, 1H), 8.49(s, 1H), 8.77(s, 1H), 8.88(m, 1H), 10.47(s, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值362.2；實測值363.1；Rt=1.002min。LCMS (ESI): [M+H] + m/z: calculated 362.2; found 363.1; Rt=1.002 min.

5-[2-(5,5-二甲基-十氫異喹啉-2-基)-2-側氧基乙醯胺基]吡啶-3-甲醯胺(化合物141 )之合成Synthesis of 5-[2-(5,5-Dimethyl-decahydroisoquinolin-2-yl)-2-oxyacetamido]pyridine-3-carboxamide ( Compound 141 )

Figure 110128222-A0202-12-1300-268
Figure 110128222-A0202-12-1300-268

藉由一般程序製備。產率：14.5mg，41.43%Prepared by general procedure. Yield: 14.5 mg, 41.43%

1 H NMR(500MHz,DMSO-d 6 )δ 0.84(m,6H),1.01(m,2H),1.21(m,2H),1.37(m,1H),1.46(m,3H),1.69(m,1H),2.31(m,1H),2.87(m,2H),3.77(m,1H),4.34(m,1H),7.61(s,1H),8.16(s,1H),8.49(m,1H),8.77(s,1H),8.86(s,1H),10.70(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.84(m, 6H), 1.01(m, 2H), 1.21(m, 2H), 1.37(m, 1H), 1.46(m, 3H), 1.69(m ,1H),2.31(m,1H),2.87(m,2H),3.77(m,1H),4.34(m,1H),7.61(s,1H),8.16(s,1H),8.49(m, 1H), 8.77(s, 1H), 8.86(s, 1H), 10.70(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=1.289min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=1.289 min.

實例237. 螺哌啶化合物之文庫合成：Example 237. Library Synthesis of Spiropiperidine Compounds:

一般程序：General procedure:

Figure 110128222-A0202-12-1300-269
Figure 110128222-A0202-12-1300-269

將TEA(10.0當量)添加到2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸(1.1當量；反應物1)、相應胺(1.0當量；反應物2)及HATU(1.1當量)於DMF(3mL)中之溶液中。將反應混合物在25℃下攪拌12h，然後提交至反相HPLC(管柱：YMC-Triart C18 100x20mm 5um，流動相：0-20% 0-5min 0.1% NH3 -甲醇)，以得到粗產物。藉由反相HPLC(管柱：SunFireC18 100x19 mm5um，流動相：0-25% 0-5min水+甲醇+甲酸)再純化所獲得之固體，以得到目標產物。TEA (10.0 equiv) was added to 2-((5-aminocarbamoylpyridin-3-yl)amino)-2-oxoacetic acid (1.1 equiv; reactant 1), the corresponding amine (1.0 equiv; reaction Compound 2) and HATU (1.1 equiv) in DMF (3 mL). The reaction mixture was stirred at 25°C for 12h, then submitted to reverse phase HPLC (column: YMC-Triart C18 100x20mm 5um, mobile phase: 0-20% 0-5min 0.1% NH3 -methanol) to give crude product. The solid obtained was repurified by reverse phase HPLC (column: SunFire C18 100x19 mm5um, mobile phase: 0-25% 0-5 min water+methanol+formic acid) to obtain the desired product.

5-[[2-(3-氧雜-9-氮雜螺[5.5]十一烷-9-基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物191 )之合成5-[[2-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 191 ) synthesis

Figure 110128222-A0202-12-1301-270
Figure 110128222-A0202-12-1301-270

藉由一般程序製備。產率：28.0mg(12.55%)Prepared by general procedure. Yield: 28.0 mg (12.55%)

1 H NMR(CD3 OD,400MHz)：δ(ppm)1.58(m,4H),1.65(m,4H),3.67(m,8H),8.07(s,1H),8.58(m,1H),8.77(d,1H),8.93(d,1H) 1 H NMR (CD 3 OD, 400MHz): δ(ppm) 1.58(m, 4H), 1.65(m, 4H), 3.67(m, 8H), 8.07(s, 1H), 8.58(m, 1H), 8.77(d,1H),8.93(d,1H)

LCMS(ESI)：[M+H]+ m/z：計算值346.2；實測值347.2；Rt=2.062min。LCMS (ESI): [M+H] + m/z: calculated 346.2; found 347.2; Rt=2.062 min.

5-(2-(3,3-二氧橋-3-硫雜-9-氮雜螺[5.5]十一烷-9-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物195 )之合成5-(2-(3,3-Dioxo-3-thia-9-azaspiro[5.5]undecan-9-yl)-2-oxyacetamido)nicotinamide Synthesis of ( Compound 195 )

Figure 110128222-A0202-12-1301-271
Figure 110128222-A0202-12-1301-271

藉由一般程序製備。產率：44.0mg(26.75%)Prepared by general procedure. Yield: 44.0 mg (26.75%)

1 H NMR(dmso,600MHz)：δ(ppm)1.53(m,4H),1.89(m,4H),3.02(m,4H),3.43(m,2H),3.50(m,2H),7.59(s,1H),8.15(s,1H),8.47(s,1H),8.75(s,1H),8.85(s,1H),11.11(s,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 1.53 (m, 4H), 1.89 (m, 4H), 3.02 (m, 4H), 3.43 (m, 2H), 3.50 (m, 2H), 7.59 ( s, 1H), 8.15(s, 1H), 8.47(s, 1H), 8.75(s, 1H), 8.85(s, 1H), 11.11(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.2；Rt=1.565min。LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.2; Rt=1.565 min.

5-[[2-(3-氮雜螺[5.5]十一烷-3-基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物203 )之合成Synthesis of 5-[[2-(3-azaspiro[5.5]undecan-3-yl)-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 203 )

Figure 110128222-A0202-12-1301-272
Figure 110128222-A0202-12-1301-272

藉由一般程序製備。產率：53.0mg(29.20%)Prepared by general procedure. Yield: 53.0 mg (29.20%)

1 H NMR(400MHz,DMSO-d6 )δ 1.39(m,15H),3.43(m,4H),7.64(s,1H),8.49(s,1H),8.78(s,1H),8.86(s,1H),11.12(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.39(m, 15H), 3.43(m, 4H), 7.64(s, 1H), 8.49(s, 1H), 8.78(s, 1H), 8.86(s , 1H), 11.12(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=3.186min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.2; Rt=3.186 min.

實例238. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1314)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1293)之合成Example 238. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Peridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (Compound 1314) and N-(6-amino-5-methyl- 3-Pyridinyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl] Synthesis of -1-piperidinyl]-2-oxoacetamide (compound 1293)

Figure 110128222-A0202-12-1302-273
Figure 110128222-A0202-12-1302-273

步驟1：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑之合成Step 1: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole

Figure 110128222-A0202-12-1302-274
Figure 110128222-A0202-12-1302-274

將5-溴-1,3-苯并噻唑(500mg，2.34mmol)、KOAc(1.32g，4.67mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(900mg，3.54mmol)、環戊基(二苯基)燐烷；二氯鈀；鐵(171mg， 0.234mmol)及二噁烷(10mL)之混合物在100℃下攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL*3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL*2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~40%，流速：30mL/min，254nm)進行純化，以得到呈黃色固體之5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(500mg，82.0%產率)。5-Bromo-1,3-benzothiazole (500 mg, 2.34 mmol), KOAc (1.32 g, 4.67 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5 - Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (900 mg, 3.54 mmol), cyclopentyl ( A mixture of diphenyl)fenane; dichloropalladium; iron (171 mg, 0.234 mmol) and dioxane (10 mL) was stirred at 100°C for 12 hours. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (100 mL*2), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash (ISCO®; 24 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-40% EtOAc, flow rate: 30 mL/min, 254 nm) was purified to give 5-(4,1 as a yellow solid). 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (500 mg, 82.0% yield).

步驟2：6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(1,3-benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1303-275
Figure 110128222-A0202-12-1303-275

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(500mg，1.91mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(800mg，2.32mmol)、Na2 CO3 (660mg，6.23mmol)、Pd(dppf)Cl2 -DCM(160mg，0.196mmol)、二噁烷(10mL)及H2 O(3mL)之混合物在85℃下攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL*3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL*2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速：30mL/min，254nm)進行純化，以得到呈黃色油狀物之6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(528mg，83.4%產率)。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (500 mg, 1.91 mmol), 3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (800 mg, 2.32 mmol), Na 2 CO 3 (660 mg , 6.23 mmol), Pd(dppf)Cl 2 -DCM (160 mg, 0.196 mmol), dioxane (10 mL) and H 2 O (3 mL) were stirred at 85 °C for 12 h. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (100 mL*2), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash (ISCO®; 24g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-20% EtOAc, flow rate: 30 mL/min, 254 nm) was purified to give 6-( 1,3-Benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (528 mg, 83.4% yield).

步驟3：2-(1,3-苯并噻唑-5-基)-5-甲基哌旋-1-甲酸第三丁酯之合成Step 3: Synthesis of 3-butyl 2-(1,3-benzothiazol-5-yl)-5-methylpiperin-1-carboxylate

Figure 110128222-A0202-12-1304-276
Figure 110128222-A0202-12-1304-276

將6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(300mg，0.908mmol)、TFA(2.5mL，32.4mmol)及DCM(2mL)之混合物在20℃下攪拌1小時。然後，在減壓下濃縮混合物且將殘餘物溶解於MeOH(5mL)中，隨後添加NaBH4 (120mg，3.17mmol)。將混合物在0℃下攪拌30分鐘。添加Boc2 O(500mg，2.29mmol)、K2 CO3 (400mg，2.89mmol)及H2 O(2mL)且將混合物在20℃下攪拌2.5小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(50mL*3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL*2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速：30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(300mg，99.4%產率)。6-(1,3-benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (300 mg, 0.908 mmol), TFA (2.5 mL, 32.4 mmol) and DCM (2 mL) were stirred at 20 °C for 1 h. Then, the mixture was concentrated under reduced pressure and the residue was dissolved in MeOH ( 5 mL), followed by the addition of NaBH4 (120 mg, 3.17 mmol). The mixture was stirred at 0°C for 30 minutes. Boc 2 O (500 mg, 2.29 mmol), K 2 CO 3 (400 mg, 2.89 mmol) and H 2 O (2 mL) were added and the mixture was stirred at 20° C. for 2.5 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (10 mL*2), brine (10 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 24g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-20% EtOAc, flow rate: 30 mL/min, 254 nm) to give a yellow oil 2-(1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 99.4% yield).

步驟4：2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of 2-(2-bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1304-277
Figure 110128222-A0202-12-1304-277

向2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(300mg，0.902mol)、2-甲基丙-2-醇酸鈉(350mg，3.64mmol)及DMF(1mL)之混合物中添加CBr4 (333mg，1.00mmol)且將混合物在20℃下攪拌30分鐘。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(30mL*3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL*2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色油狀物之2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯 (350mg，94.3%產率)。To 2-(1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.902 mol), sodium 2-methylpropan-2-olate ( To a mixture of 350 mg, 3.64 mmol) and DMF (1 mL) was added CBr4 (333 mg, 1.00 mmol) and the mixture was stirred at 20 °C for 30 min. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 2- as a yellow oil (2-Bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (350 mg, 94.3% yield).

步驟5：3-甲基-6-[2-(1-甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 5: 3-Methyl-6-[2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]-3, Synthesis of 4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1305-278
Figure 110128222-A0202-12-1305-278

在微波下，將2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(350mg，0.851mmol)、1-甲基-1,2,3,6-四氫吡啶-4-硼酸頻吶醇酯(280mg，1.25mmol)、Pd(PPh3 )4 (105mg，90.9umol)、K2 CO3 (364.00mg，2.63mmol)、H2 O(3mL)及EtOH(10mL)之混合物在95℃下攪拌1.5小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(50mL*3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL*2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；12g AgelaFlash®二氧化矽急驟管柱，DCM/MeOH，其中MeOH為0~20%，流速：30mL/min，254nm)進行純化，以得到呈黃色固體之3-甲基-6-[2-(1-甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(250mg，69.0%產率)。Under microwave, 2-(2-bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.851 mmol), 1-methyl -1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (280 mg, 1.25 mmol), Pd(PPh 3 ) 4 (105 mg, 90.9 umol), K 2 CO 3 (364.00 mg, 2.63 mmol) ), H2O (3 mL) and EtOH (10 mL) were stirred at 95 °C for 1.5 h. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash layer purification (ISCO®; 12 g AgelaFlash® silica flash column, DCM/MeOH with 0~20% MeOH, flow rate: 30 mL/min, 254 nm) to give 3-methyl-6 as a yellow solid -[2-(1-Methyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H-pyridine- 3-Butyl 1-carboxylate (250 mg, 69.0% yield).

步驟6：5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯之合成Step 6: Synthesis of 5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1305-279
Figure 110128222-A0202-12-1305-279

在氫氣下(在氣球中，15psi)，將5-甲基-2-[2-(1-甲基-3,6-二氫-2H-吡 啶-4-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(250mg，0.585mmol)、Pd/C(170mg，具有50重量%水之10重量% Pd)於MeOH(5mL)中之混合物在20℃下攪拌12小時。將混合物過濾且在減壓下濃縮，以得到呈黃色油狀物之5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(120mg，47.8%產率)。Under hydrogen (in a balloon, 15 psi), 5-methyl-2-[2-(1-methyl-3,6-dihydro-2H-pyridine Perid-4-yl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.585 mmol), Pd/C (170 mg, 10 wt % with 50 wt % water) % Pd) in MeOH (5 mL) was stirred at 20 °C for 12 h. The mixture was filtered and concentrated under reduced pressure to give 5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazole-5 as a yellow oil -yl]piperidine-1-carboxylic acid tert-butyl ester (120 mg, 47.8% yield).

步驟7：2-(1-甲基-4-哌啶基)-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑之合成Step 7: Synthesis of 2-(1-Methyl-4-piperidinyl)-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole

Figure 110128222-A0202-12-1306-280
Figure 110128222-A0202-12-1306-280

將5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(120mg，0.279mmol)、TFA(1mL，13.0mmol)及DCM(2mL)之混合物在20℃下攪拌2小時。在減壓下濃縮混合物，以得到殘餘物，將其溶解於MeOH(約5mL)中且藉由Na2 CO3 固體中和至pH=7。在減壓下濃縮混合物，以得到殘餘物，將其用DCM(50mL)研磨。將混合物過濾且將濾液在減壓下濃縮，以得到呈黃色油狀物之2-(1-甲基-4-哌啶基)-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(90mg，97.8%產率)。5-Methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.279 mmol), TFA (1 mL, 13.0 mmol) and DCM (2 mL) was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue, which was dissolved in MeOH (about 5 mL) and neutralized to pH= 7 by Na2CO3 solid. The mixture was concentrated under reduced pressure to give a residue, which was triturated with DCM (50 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(1-methyl-4-piperidinyl)-5-(5-methyl-2-piperidinyl)- as a yellow oil 1,3-benzothiazole (90 mg, 97.8% yield).

步驟8：N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 8: N-(6-Amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-[2-(1-methyl-4-piperidinyl)-1, Synthesis of 3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide

Figure 110128222-A0202-12-1306-281
Figure 110128222-A0202-12-1306-281

向2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(55mg，0.22mmol)、2-(1-甲基-4-哌啶基)-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(90mg，0.273 mmol)、HATU(104mg，0.274mmol)及DMF(5mL)之混合物中添加DIPEA(0.3mL，1.72mmol)且將混合物在20℃下攪拌12小時。藉由急驟層析(管柱：SepaFlash® Sphercial C18，25g，40-60μm，120Å；MeCN/水(0.5v% NH3 -H2 O)，其中MeCN為0-45%，25mL/min，254nm)純化混合物，以得到呈黃色油狀物之N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(60mg，42.0%產率)。To 2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (55 mg, 0.22 mmol), 2-(1-methyl-4-piperidinyl )-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (90 mg, 0.273 mmol), HATU (104 mg, 0.274 mmol) and DMF (5 mL) was added DIPEA (0.3 mL, 1.72 mmol) and the mixture was stirred at 20 °C for 12 h. by flash chromatography (column: SepaFlash® Sphercial C18, 25g, 40-60μm, 120Å; MeCN/water (0.5v% NH3 - H2O ) with MeCN 0-45%, 25mL/min, 254nm ) purify the mixture to give N-(6-amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-[2-(1-methyl- 4-Piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (60 mg, 42.0% yield).

步驟9：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1314)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1293)之合成Step 9: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Peridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (Compound 1314) and N-(6-amino-5-methyl- 3-Pyridinyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl] Synthesis of -1-piperidinyl]-2-oxoacetamide (compound 1293)

Figure 110128222-A0202-12-1307-282
Figure 110128222-A0202-12-1307-282

將N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(45mg，88.8μmol)藉由掌性SFC分離(儀器：Thar800Q；管柱：Daicel Chiralpak IG(250mm*30mm，10μm)；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=50/50；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)來分離，以得到化合物1314 (峰2，保留時間=1.610min)及化合物1293 (峰3，保留時間=2.469min)。N-(6-amino-5-methyl-3-pyridyl)-2-[5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3- Benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (45 mg, 88.8 μmol) was separated by chiral SFC (instrument: Thar800Q; column: Daicel Chiralpak IG (250 mm* 30 mm, 10 μm); mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=50/50; flow rate: 80 mL/min; column temperature: 38 °C; nozzle temperature: 100 bar ; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) to separate to give compound 1314 (peak 2, retention time = 1.610 min) and compound 1293 (peak 3, retention time=2.469min).

化合物1314 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(15mg，具有反式相對化學之單一未知鏡像異構物，峰2，保留時間=1.610min，白色固體)。1 H NMR(400MHz, DMSO-d 6 )δ ppm 10.30(br s,1 H),8.03(br d,J =8.3Hz,2 H),7.90(s,1 H),7.50(brs,1 H),7.40(br d,J =8.0Hz,1 H),5.60(br s,1 H),5.37(br s,2 H),3.71(br s,1 H),2.89(br d,J =11.8Hz,2 H),2.23-2.34(m,5 H),2.08-2.20(m,6 H),2.06(s,3 H),1.84-1.96(m,3 H),1.71-1.83(m,1 H),1.38(br d,J =7.5Hz,1 H),1.07(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值507.2，實測值507.2；HPLC：在220nm下為100%，在254nm下為100%；100%ee Compound 1314 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Peridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (15 mg, single unknown enantiomer with trans relative chemistry, peak 2 , retention time = 1.610 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.30(br s, 1 H), 8.03(br d, J =8.3 Hz, 2 H), 7.90(s, 1 H), 7.50(br s, 1 H) ), 7.40(br d, J = 8.0Hz, 1 H), 5.60(br s, 1 H), 5.37(br s, 2 H), 3.71(br s, 1 H), 2.89(br d, J = 11.8Hz, 2 H), 2.23-2.34(m, 5 H), 2.08-2.20(m, 6 H), 2.06(s, 3 H), 1.84-1.96(m, 3 H), 1.71-1.83(m ,1 H),1.38(br d, J =7.5Hz,1 H),1.07(d, J =7.0Hz,3 H); LCMS(ESI)[M+H] + m/z: calculated 507.2, Found 507.2; HPLC: 100% at 220 nm, 100% at 254 nm; 100% ee

化合物1293 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(15mg，具有反式相對化學之單一未知鏡像異構物，峰3，保留時間=2.469min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.31(br s,1 H),8.04(br d,J =8.3Hz,2 H),7.90(s,1 H),7.50(br s,1 H),7.41(br d,J =8.3Hz,1 H),5.60(br s,1 H),5.37(br s,2 H),3.70-3.90(m,1 H),2.60(br t,J =11.0Hz,4 H),2.09-2.35(m,8 H),2.06(br s,3 H),1.90-2.02(m,4 H),1.71-1.83(m,1 H),1.37(br d,J =11.3Hz,1 H),1.07(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值507.2，實測值507.2；HPLC：在220nm下為100%，在254nm下為100%；100%ee。 Compound 1293 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Peridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (15 mg, single unknown enantiomer with trans relative chemistry, peak 3 , retention time = 2.469min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.31(br s, 1 H), 8.04(br d, J =8.3Hz, 2 H), 7.90(s, 1 H), 7.50(br s, 1 H), 7.41(br d, J =8.3Hz, 1 H), 5.60(br s, 1 H), 5.37(br s, 2 H), 3.70-3.90(m, 1 H), 2.60(br t, J =11.0Hz,4H),2.09-2.35(m,8H),2.06(br s,3H),1.90-2.02(m,4H),1.71-1.83(m,1H),1.37( br d, J =11.3 Hz, 1 H), 1.07 (d, J =7.0 Hz, 3 H); LCMS(ESI) [M+H] + m/z: calculated 507.2, found 507.2; HPLC: at 100% at 220nm, 100% at 254nm; 100% ee.

實例239. 5-(2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1281、化合物1281及化合物1197)之合成Example 239. 5-(2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)- Synthesis of 2-oxyacetamido)-2-methoxynicotinamide (Compound 1281, Compound 1281 and Compound 1197)

Figure 110128222-A0202-12-1308-283
Figure 110128222-A0202-12-1308-283

步驟1：5-(2-(2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1281)之合成Step 1: 5-(2-(2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)- Synthesis of 2-oxyacetamido)-2-methoxynicotinamide (Compound 1281)

Figure 110128222-A0202-12-1309-284
Figure 110128222-A0202-12-1309-284

藉由一般程序2製備。產率：19.8mg(5.73%)。Prepared by General Procedure 2. Yield: 19.8 mg (5.73%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-5min 40-90%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 40-90% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.06(m,3H),1.35(m,1H),1.70(m,1H),1.90(m,1H),2.09(m,2H),2.20(s,6H),2.29(m,2H),2.69(m,2H),3.22(m,2H),3.91-3.96(m,3H),5.71(m,1H),7.35(m,1H),7.65-7.74(m,2H),7.85(m,1H),7.98-8.05(m,1H),8.40-8.57(m,2H),11.10(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.06(m, 3H), 1.35(m, 1H), 1.70(m, 1H), 1.90(m, 1H), 2.09(m, 2H) ), 2.20(s, 6H), 2.29(m, 2H), 2.69(m, 2H), 3.22(m, 2H), 3.91-3.96(m, 3H), 5.71(m, 1H), 7.35(m, 1H), 7.65-7.74(m, 2H), 7.85(m, 1H), 7.98-8.05(m, 1H), 8.40-8.57(m, 2H), 11.10(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值524.2；實測值525.2；Rt=2.151min。LCMS (ESI): [M] + m/z: calculated 524.2; found 525.2; Rt=2.151 min.

步驟2：掌性分離(化合物1281及化合物1197)Step 2: Chiral separation (compound 1281 and compound 1197)

Figure 110128222-A0202-12-1309-285
Figure 110128222-A0202-12-1309-285

對外消旋5-(2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(290mg，552.77umol)進行掌性分離(管柱：Chirapak IC-III(250*20mm，5mkm)，IPA-MeOH，50-50，12ml/min)，以獲得5-[[2-[(2R,5S )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶 基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(140mg，266.85umol，96.55%產率)(RT=53.79min)及5-[[2-[(2S,5R )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(140mg，266.85umol，96.55%產率)(RT=27.78min)。Racemic 5-(2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)- 2-Oxyacetamido)-2-methoxynicotinamide (290mg, 552.77umol) for chiral separation (column: Chirapak IC-III (250*20mm, 5mkm), IPA-MeOH, 50-50, 12ml/min) to obtain 5-[[2-[( 2R,5S )-2-[2-[2-(dimethylamino)ethyl]-1,3-benzothiazole- 5-yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (140mg, 266.85umol, 96.55% Yield) (RT=53.79 min) and 5-[[2-[( 2S,5R )-2-[2-[2-(dimethylamino)ethyl]-1,3-benzothiazole-5 -yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (140mg, 266.85umol, 96.55% yield rate) (RT=27.78min).

化合物1197於分析條件下(管柱：IC，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為57.47min且化合物1197之保留時間為29.97min。The retention time of compound 1197 under analytical conditions (column: IC, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 57.47 min and the retention time of compound 1197 was 29.97 min.

化合物1281：Compound 1281:

保留時間：57.47minRetention time: 57.47min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.04(m,3H),1.35(m,1H),1.72(m,1H),1.88(m,1H),2.11(m,1H),2.20(d,6H),2.31(m,1H),2.69(m,3H),3.21(m,2H),3.50(m,1H),3.94(m,3H),5.50(m,1H),7.37(dd,1H),7.72(m,2H),7.86(d,1H),8.02(dd,1H),8.50(m,2H),11.07(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.04(m, 3H), 1.35(m, 1H), 1.72(m, 1H), 1.88(m, 1H), 2.11(m, 1H), 2.20(d, 6H), 2.31(m, 1H), 2.69(m, 3H), 3.21(m, 2H), 3.50(m, 1H), 3.94(m, 3H), 5.50(m, 1H), 7.37 (dd, 1H), 7.72 (m, 2H), 7.86 (d, 1H), 8.02 (dd, 1H), 8.50 (m, 2H), 11.07 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值524.2；實測值525.2；Rt=2.635min。LCMS (ESI): [M] + m/z: calculated 524.2; found 525.2; Rt=2.635 min.

化合物1197：Compound 1197:

保留時間：29.97minRetention time: 29.97min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.04(m,3H),1.37(m,1H),1.72(m,1H),1.88(m,1H),2.11(m,1H),2.20(m,6H),2.31(m,1H),2.69(m,3H),3.21(m,2H),3.95(m,4H),5.50(m,1H),7.37(dd,1H),7.73(m,2H),7.86(m,1H),8.02(dd,1H),8.52(m,2H),11.07(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.04(m, 3H), 1.37(m, 1H), 1.72(m, 1H), 1.88(m, 1H), 2.11(m, 1H), 2.20(m, 6H), 2.31(m, 1H), 2.69(m, 3H), 3.21(m, 2H), 3.95(m, 4H), 5.50(m, 1H), 7.37(dd, 1H), 7.73 (m, 2H), 7.86 (m, 1H), 8.02 (dd, 1H), 8.52 (m, 2H), 11.07 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值524.2；實測值525.2；Rt=2.632min。LCMS (ESI): [M] + m/z: calculated 524.2; found 525.2; Rt=2.632 min.

實例240. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(2S)-2,4-二甲基哌嗪-1-基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1099)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(2R)-2,4-二甲基哌嗪-1-基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1294)之合成Example 240. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[6-[(2S)-2,4-dimethylpiperazine -1-yl]-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 1099) and N-(6-amino-5-ethyl- 3-Pyridinyl)-2-[(2R,5S)-2-[6-[(2R)-2,4-dimethylpiperazin-1-yl]-3-pyridyl]-5-methyl Synthesis of -1-piperidinyl]-2-oxoacetamide (compound 1294)

Figure 110128222-A0202-12-1311-286
Figure 110128222-A0202-12-1311-286

掌性分離條件：Chiralpak IA，250*20mm，5mkm，IPA-MeOH，50-50，10mL/min，注入體積：200.000μl；管柱溫度：24℃；波長：205nm、264nm)，保留時間(異構物A)=34.968min；保留時間(異構物B)=51.008minPalm separation conditions: Chiralpak IA, 250*20mm, 5mkm, IPA-MeOH, 50-50, 10mL/min, injection volume: 200.000μl; column temperature: 24°C; wavelength: 205nm, 264nm), retention time (iso Construct A)=34.968min; retention time (isomer B)=51.008min

藉由掌性HPLC將N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-(2,4-二甲基哌嗪-1-基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(100mg，208.50umol)分成鏡像異構物，得到：化合物1099 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(2S)-2,4-二甲基哌嗪-1-基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(41mg，85.49umol，42.00%產率)(其中保留時間=28.721min(分析型)、34.968min(製備型))及化合物1294 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(2R)-2,4-二甲基哌嗪-1-基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(38mg，79.23umol，38.00%產率)(其中保留時間=40.733min(分析型)、51.008min(製備型))。N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[6-(2,4-dimethylpiperazine- 1-yl)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (100 mg, 208.50 umol) was separated into the enantiomers to give: compound 1099 N-( 6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[6-[(2S)-2,4-dimethylpiperazin-1-yl]- 3-Pyridinyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (41 mg, 85.49 umol, 42.00% yield) (wherein retention time = 28.721 min (analytical), 34.968 min (preparative)) and compound 1294 N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[6-[(2R)-2,4 -Dimethylpiperazin-1-yl]-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (38 mg, 79.23 umol, 38.00% yield) ( Wherein retention time=40.733min (analytical type), 51.008min (preparative type)).

化合物1294：Compound 1294:

產率：41.0mg(42.00%)Yield: 41.0 mg (42.00%)

RT(Chiralpak IA(250*20mm，5mkm)，IPA-MeOH，50-50，0.6mL/min)=38.669min。RT (Chiralpak IA (250*20mm, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=38.669min.

1 H NMR(500MHz,dmso)δ 0.96-1.03(m,3H),1.07-1.14(m,6H),1.26-1.38(m,1H),1.66-1.77(m,1H),1.81-2.00(m,3H),2.04-2.14(m,2H),2.17(s,3H),2.36-2.41(m,2H),2.65-2.72(m,1H),2.79-3.19(m,3H),3.36-3.99(m,2H),4.43(s, 1H),5.00-5.53(m,1H),5.58-5.67(m,2H),6.71-6.80(m,1H),7.38-7.54(m,2H),7.98-8.09(m,2H),10.42-10.52(m,1H)。 1 H NMR(500MHz,dmso)δ 0.96-1.03(m,3H),1.07-1.14(m,6H),1.26-1.38(m,1H),1.66-1.77(m,1H),1.81-2.00(m ,3H),2.04-2.14(m,2H),2.17(s,3H),2.36-2.41(m,2H),2.65-2.72(m,1H),2.79-3.19(m,3H),3.36-3.99 (m,2H),4.43(s,1H),5.00-5.53(m,1H),5.58-5.67(m,2H),6.71-6.80(m,1H),7.38-7.54(m,2H),7.98 -8.09(m, 2H), 10.42-10.52(m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值481.2；實測值481.2；Rt=0.736min。LCMS (ESI): [M+2H] + m/z: calculated 481.2; found 481.2; Rt=0.736 min.

化合物1099：Compound 1099:

產率：38.0mg(38.00%)Yield: 38.0 mg (38.00%)

RT(Chiralpak IA(250*20mm，5mkm)，IPA-MeOH，50-50，0.6mL/min)=28.704min。RT (Chiralpak IA (250*20mm, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=28.704min.

1 H NMR(500MHz,dmso)δ 0.97-1.03(m,3H),1.07-1.13(m,6H),1.27-1.37(m,1H),1.63-1.76(m,1H),1.78-2.02(m,3H),2.03-2.12(m,2H),2.17(s,3H),2.36-2.41(m,2H),2.65-3.23(m,4H),3.38-3.97(m,2H),4.43(s,1H),5.00-5.52(m,1H),5.56-5.67(m,2H),6.71-6.80(m,1H),7.38-7.54(m,2H),8.00-8.10(m,2H),10.44-10.54(m,1H)。 1 H NMR(500MHz,dmso)δ 0.97-1.03(m,3H),1.07-1.13(m,6H),1.27-1.37(m,1H),1.63-1.76(m,1H),1.78-2.02(m ,3H),2.03-2.12(m,2H),2.17(s,3H),2.36-2.41(m,2H),2.65-3.23(m,4H),3.38-3.97(m,2H),4.43(s ,1H),5.00-5.52(m,1H),5.56-5.67(m,2H),6.71-6.80(m,1H),7.38-7.54(m,2H),8.00-8.10(m,2H),10.44 -10.54 (m, 1H).

6LCMS(ESI)：[M+H]+ m/z：計算值481.2；實測值481.4；Rt=0.734min。6LCMS (ESI): [M+H] + m/z: calculated 481.2; found 481.4; Rt=0.734 min.

實例241. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(3-吡啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1310)之合成Example 241. N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(3-pyridyl)-1, Synthesis of 3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1310)

Figure 110128222-A0202-12-1312-287
Figure 110128222-A0202-12-1312-287

將N-(6-胺基-5-甲基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(3-吡啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(50mg，0.103mmol)藉由SFC(儀器：Berger，Multigr AM-II；管柱：Daicel Chiralcel OD-H 250mm×30mm×5μm；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=55/45；流速：80mL/min；管 柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(3-吡啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(44.4mg，具有反式相對化學之單一已知鏡像異構物，峰2，保留時間：8.370min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 9.27(br s,1H),8.70(br s,1H),8.26-8.57(m,2H),7.99-8.23(m,2H),7.39-7.88(m,3H),5.49-5.89(m,1H),3.77-4.13(m,1H),3.50(br s,1H),2.37(br s,2H),2.25(br s,2H),2.13(br s,1H),1.85-2.09(m,2H),1.50(br s,1H),1.15(br d,J =6.5Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值487.2，實測值487.3；HPLC：在254nm下為100%；100%ee、99.5%de。N-(6-amino-5-methyl-3-pyridyl)-2-[(5S)-5-methyl-2-[2-(3-pyridyl)-1,3-benzo Thiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (50 mg, 0.103 mmol) by SFC (instrument: Berger, Multigr AM-II; column: Daicel Chiralcel OD-H 250 mm ×30mm×5μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=55/45; flow rate: 80 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar ; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) purification to give N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,5S)-5-Methyl-2-[2-(3-pyridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-pendoxoethyl Amide (44.4 mg, single known enantiomer with trans relative chemistry, peak 2, retention time: 8.370 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 9.27 (br s, 1H), 8.70 (br s, 1H), 8.26-8.57 (m, 2H), 7.99-8.23 (m, 2H), 7.39-7.88 (m,3H),5.49-5.89(m,1H),3.77-4.13(m,1H),3.50(br s,1H),2.37(br s,2H),2.25(br s,2H),2.13( br s,1H),1.85-2.09(m,2H),1.50(br s,1H),1.15(br d, J =6.5Hz,3H); LCMS(ESI)[M+H] + m/z: Calculated 487.2, found 487.3; HPLC: 100% at 254 nm; 100% ee, 99.5% de.

實例242. rel-5-[[2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物1364)及rel-5-[[2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物1344)之合成Example 242. rel-5-[[2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidine Iridinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (Compound 1364) and rel-5-[[2-[(2R,4S,5R) -2-(1,3-Benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2- Synthesis of Methoxypyridine-3-Carboxamide (Compound 1344)

Figure 110128222-A0202-12-1314-288
Figure 110128222-A0202-12-1314-288

步驟1：外消旋-(6S,9S)-9-(1,3-苯并噻唑-5-基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷之合成Step 1: Racemic-(6S,9S)-9-(1,3-benzothiazol-5-yl)-6-methyl-1,4-dioxa-8-azaspiro[4.5] Synthesis of Decane

Figure 110128222-A0202-12-1314-289
Figure 110128222-A0202-12-1314-289

將2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-胺(6.67g，45.96mmol)溶解於甲苯(60mL)中且向其中添加1,3-苯并噻唑-5-甲醛(7.5g，45.96mmol)，隨後添加對甲苯磺酸單水合物(26.23g，137.87mmol，21.15mL)。將所得混合物加熱至回流且以迪安-斯塔克分離器回流隔夜。冷卻反應混合物且添加K2 CO3 水溶液(50 mL)。將所得混合物轉移至分離漏斗且分離有機層。用EtOAc(2x100mL)萃取水層，且將經合併之有機層經Na2 SO4 乾燥，過濾且濃縮。將殘餘物溶解於CHCl3 (200mL)中且將所得混合物用NaHSO4 水溶液(於10mL水中之1g，2*50mL)萃取。將經合併之水層用CHCl3 (2*100mL)洗滌，然後用K2 CO3 (20g)鹼化。將所得混合物用CHCl3 (2*100mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得(6S,9S)-9-(1,3-苯并噻唑-5-基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(4.63g，粗品)。2-(2-Methyl-1,3-dioxolan-2-yl)propan-1-amine (6.67 g, 45.96 mmol) was dissolved in toluene (60 mL) and 1,3- Benzothiazole-5-carbaldehyde (7.5 g, 45.96 mmol) followed by p-toluenesulfonic acid monohydrate (26.23 g, 137.87 mmol, 21.15 mL). The resulting mixture was heated to reflux and refluxed with a Dean-Stark separator overnight. The reaction mixture was cooled and aqueous K2CO3 ( 50 mL) was added. The resulting mixture was transferred to a separation funnel and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×100 mL), and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in CHCl3 (200 mL) and the resulting mixture was extracted with aqueous NaHSO4 (1 g in 10 mL water, 2*50 mL). The combined aqueous layers were washed with CHCl3 ( 2 *100 mL), then basified with K2CO3 ( 20 g). The resulting mixture was extracted with CHCl 3 (2*100 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to obtain (6S,9S)-9-(1,3-benzothiazole-5 -yl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane (4.63 g, crude).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0093(d,3H),1.70(m,4H),1.99(m,2H),2.84(m,1H),3.14(m,1H),4.01(m,3H),7.54(d,1H),7.91(d,1H),8.13(s,1H),9.00(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0093(d,3H), 1.70(m,4H), 1.99(m,2H), 2.84(m,1H), 3.14(m,1H), 4.01(m, 3H), 7.54(d, 1H), 7.91(d, 1H), 8.13(s, 1H), 9.00(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值291.2；實測值291.2；Rt=0.752min。LCMS (ESI): [M+H] + m/z: calculated 291.2; found 291.2; Rt=0.752 min.

步驟2：外消旋-(2S,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-4-酮之合成Step 2: Synthesis of Racemic-(2S,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidin-4-one

Figure 110128222-A0202-12-1315-290
Figure 110128222-A0202-12-1315-290

將(6S,9S)-9-(1,3-苯并噻唑-5-基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(7.53g，25.93mmol)溶解於6N HCl(300mL)中且將所得混合物在80℃下(在油浴中)加熱隔夜。將反應混合物冷卻且用K2 CO3 鹼化至pH=10。將所得混合物用DCM(2*200mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得(2S,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-4-酮(6.3g，粗品)。(6S,9S)-9-(1,3-benzothiazol-5-yl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane (7.53 g, 25.93 mmol) was dissolved in 6N HCl (300 mL) and the resulting mixture was heated at 80 °C (in an oil bath) overnight. The reaction mixture was cooled and basified to pH = 10 with K2CO3. The resulting mixture was extracted with DCM (2*200 mL) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to obtain (2S,5S)-2-(1,3-benzothiazole-5- yl)-5-methylpiperidin-4-one (6.3 g, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.08(d,3H),2.89(m,4H),3.53(m,1H),4.12(m,1H),7.50(d,1H),7.95(d,1H),8.16(s,1H),9.01(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.08(d,3H), 2.89(m,4H), 3.53(m,1H), 4.12(m,1H), 7.50(d,1H), 7.95( d, 1H), 8.16 (s, 1H), 9.01 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值247.0；實測值247.0；Rt=0.551min。LCMS (ESI): [M+H] + m/z: calculated 247.0; found 247.0; Rt=0.551 min.

步驟3：外消旋-(2S,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-4-醇之合成Step 3: Synthesis of Racemic-(2S,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidin-4-ol

Figure 110128222-A0202-12-1316-291
Figure 110128222-A0202-12-1316-291

將硼氫化鈉(635.80mg，16.81mmol，594.21uL)分批添加到(2S,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-4-酮(6.9g，28.01mmol)於甲醇中之溶液中。將所得懸浮液在室溫下攪拌1h。添加水(10mL)且將混合物用MTBE(2x10mL)萃取。將有機相經Na2 SO4乾燥，過濾且蒸發，以獲得(2S,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-4-醇(5.06g，粗品)。Sodium borohydride (635.80 mg, 16.81 mmol, 594.21 uL) was added portionwise to (2S,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidin-4-one (6.9 g, 28.01 mmol) in methanol. The resulting suspension was stirred at room temperature for 1 h. Water (10 mL) was added and the mixture was extracted with MTBE (2 x 10 mL). The organic phase was dried over Na2SO4 , filtered and evaporated to give (2S,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidin-4-ol (5.06 g ,Crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.69(m,4H),2.17(m,1H),2.49(m,1H),3.28(m,2H),3.85(m,1H),7.47(d,1H),7.89(d,1H),8.09(s,1H),8.95(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.69(m,4H), 2.17(m,1H), 2.49(m,1H), 3.28(m,2H), 3.85( m, 1H), 7.47 (d, 1H), 7.89 (d, 1H), 8.09 (s, 1H), 8.95 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值249.0；實測值249.0；Rt=0.463min。LCMS (ESI): [M+H] + m/z: calculated 249.0; found 249.0; Rt=0.463 min.

步驟4：外消旋-(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of racemic-(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1316-292
Figure 110128222-A0202-12-1316-292

將99%碳酸氫鈉(3.04g，36.24mmol，1.41mL)溶解於THF(15mL)及水(15mL)中，然後添加(2S,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-4-醇(3g，12.08mmol)。將反應混合物在室溫下攪拌5min，隨後添加二碳酸二-第三丁酯(2.90g，13.29mmol，3.05mL)。將反應混合物在室溫下攪拌隔夜。將反應混合物用EtOAc/水稀釋，分離有機相且將水層用EtOAc(2次)洗滌，將經合併之有機相用鹽水洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以得到(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯(4.4g，粗品)。99% sodium bicarbonate (3.04 g, 36.24 mmol, 1.41 mL) was dissolved in THF (15 mL) and water (15 mL), then (2S,5S)-2-(1,3-benzothiazole-5-) was added yl)-5-methylpiperidin-4-ol (3 g, 12.08 mmol). The reaction mixture was stirred at room temperature for 5 min, then di-tert-butyl dicarbonate (2.90 g, 13.29 mmol, 3.05 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc/water, the organic phase was separated and the aqueous layer was washed with EtOAc (2 times), the combined organic phases were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo to give (2S,5S)-2-(1,3-benzothiazol-5-yl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (4.4 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值349.2；實測值349.2；Rt=1.107min。LCMS (ESI): [M+H] + m/z: calculated 349.2; found 349.2; Rt=1.107 min.

步驟5：外消旋-(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Mixture of racemic-(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester synthesis

Figure 110128222-A0202-12-1317-293
Figure 110128222-A0202-12-1317-293

將氫化鈉(909.15mg，37.88mmol)添加到(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯(4.4g，12.63mmol)於DMF(44mL)中之溶液中且將混合物攪拌30分鐘。添加碘甲烷(5.38g，37.88mmol，2.36mL)且將混合物攪拌5h。添加水(10mL)且將混合物用乙醚(2×10mL)萃取。將經合併之有機級分用水(4×10mL)及鹽水洗滌，乾燥(MgSO4 )且將溶劑在減壓下蒸發，以得到標題化合物(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(4.23g，粗品)，其不經進一步純化即用於下一步驟中。Sodium hydride (909.15 mg, 37.88 mmol) was added to (2S,5S)-2-(1,3-benzothiazol-5-yl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid third A solution of butyl ester (4.4 g, 12.63 mmol) in DMF (44 mL) and the mixture was stirred for 30 min. Iodomethane (5.38 g, 37.88 mmol, 2.36 mL) was added and the mixture was stirred for 5 h. Water (10 mL) was added and the mixture was extracted with ether (2 x 10 mL). The combined organic fractions were washed with water (4 x 10 mL) and brine, dried ( MgSO4 ) and the solvent was evaporated under reduced pressure to give the title compound (2S,5S)-2-(1,3-benzol) Thiazol-5-yl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (4.23 g, crude) was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值363.2；實測值363.2；Rt=1.342min。LCMS (ESI): [M+H] + m/z: calculated 363.2; found 363.2; Rt=1.342 min.

步驟6：外消旋-5-[(2S,5S)-4-甲氧基-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 6: Synthesis of Racemic-5-[(2S,5S)-4-methoxy-5-methyl-2-piperidinyl]-1,3-benzothiazole

Figure 110128222-A0202-12-1317-294
Figure 110128222-A0202-12-1317-294

將(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(4.23g，11.67mmol)於二噁烷/HCl(5mL)中之溶液在室溫下攪拌2h。將所形成之沉澱過濾，用MTBE(2x 10mL)洗滌且在減壓下乾燥，以獲得5-[(2S,5S)-4-甲氧基-5-甲基-2-哌啶基]-1,3-苯并噻唑(2.98g，粗品，HCl)。(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (4.23 g, 11.67 mmol) The solution in dioxane/HCl (5 mL) was stirred at room temperature for 2 h. The resulting precipitate was filtered, washed with MTBE (2 x 10 mL) and dried under reduced pressure to obtain 5-[(2S,5S)-4-methoxy-5-methyl-2-piperidinyl]- 1,3-benzothiazole (2.98 g, crude, HCl).

LCMS(ESI)：[M+H]+ m/z：計算值263.0；實測值263.0；Rt=0.802minLCMS(ESI): [M+H] + m/z: Calculated 263.0; Measured 263.0; Rt=0.802min

步驟7：外消旋-5-[[2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 7: Racemic-5-[[2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1 Synthesis of -Piperidinyl]-2-side oxyacetyl]amino]-2-methoxypyridine-3-carboxamide

Figure 110128222-A0202-12-1318-295
Figure 110128222-A0202-12-1318-295

將5-[(2S,5S)-4-甲氧基-5-甲基-2-哌啶基]-1,3-苯并噻唑(0.2g，762.28umol)、2-[(5-胺甲醯基-2-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(182.33mg，762.28umol)、三乙胺(385.68mg，3.81mmol，531.24uL)混合於DMF(2mL)中，然後添加HATU(434.76mg，1.14mmol)。將所得混合物在25℃下攪拌12h。蒸發溶劑。藉由HPLC(2-10min 0-45% MeCN 30mL/min(裝載泵4mL MeCN；管柱：SunFire 100*19mm，5微米)純化所得粗產物，以獲得外消旋-5-[[2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(44.2mg，91.41umol，11.99%產率)5-[(2S,5S)-4-methoxy-5-methyl-2-piperidinyl]-1,3-benzothiazole (0.2g, 762.28umol), 2-[(5-amine Methyl-2-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (182.33 mg, 762.28 umol), triethylamine (385.68 mg, 3.81 mmol, 531.24 uL) were mixed in DMF ( 2 mL), then HATU (434.76 mg, 1.14 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. Evaporate the solvent. The resulting crude product was purified by HPLC (2-10 min 0-45% MeCN 30 mL/min (loading pump 4 mL MeCN; column: SunFire 100*19 mm, 5 microns) to obtain rac-5-[[2-[ (2S,4R,5S)-2-(1,3-Benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]-2-methoxypyridine-3-carboxamide (44.2 mg, 91.41 umol, 11.99% yield)

LCMS(ESI)：[M+H]+ m/z：計算值484.2；實測值484.2；Rt=1.013min。LCMS (ESI): [M+H] + m/z: calculated 484.2; found 484.2; Rt=1.013 min.

步驟8：rel-5-[[[2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物1364)及rel-5-[[2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(化合物1344)之合成Step 8: rel-5-[[[2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1- Piperidinyl]-2-side oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (Compound 1364) and rel-5-[[2-[(2R,4S,5R )-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-side oxyacetyl]amino]-2 - Synthesis of Methoxypyridine-3-Carboxamide (Compound 1344)

Figure 110128222-A0202-12-1318-296
Figure 110128222-A0202-12-1318-296

對外消旋-5-[[2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(44.20mg，91.41umol) 進行掌性分離(Chiralpak AD-HIII(250*20，5mkm)，IPA-MeOH，50-50，11mL/min)，以獲得化合物1344 rel-5-[[2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(12.84mg，26.55umol，29.05%產率)及化合物1364 rel-5-[[2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(14.14mg，29.24umol，31.99%產率)。Racemic-5-[[2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidine [methyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxamide (44.20mg, 91.41umol) Chiral separation (Chiralpak AD-HIII (250*20, 5mkm), IPA-MeOH, 50-50, 11 mL/min) was performed to obtain compound 1344 rel-5-[[2-[(2R,4S,5R) -2-(1,3-Benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2- Methoxypyridine-3-carboxamide (12.84 mg, 26.55 umol, 29.05% yield) and compound 1364 rel-5-[[2-[(2S,4R,5S)-2-(1,3-benzene Thiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methoxypyridine-3-carboxylate Amine (14.14 mg, 29.24 umol, 31.99% yield).

製備型：Preparation:

化合物1344之RT(Chiralpak AD-HIII(250*20，5mkm)，IPA-MeOH，50-50，11ml/min)=89.951RT of compound 1344 (Chiralpak AD-HIII (250*20, 5mkm), IPA-MeOH, 50-50, 11ml/min)=89.951

化合物1364之RT(Chiralpak AD-HIII(250*20，5mkm)，IPA-MeOH，50-50，11ml/min)=67.124RT of compound 1364 (Chiralpak AD-HIII (250*20, 5mkm), IPA-MeOH, 50-50, 11ml/min)=67.124

化合物1344 ： Compound 1344 :

產率：12.84mg(29.05%)Yield: 12.84 mg (29.05%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=15.273min。RT (Chiralcel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 15.273 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.04(d,3H),1.88(m,1H),2.28(m,1H),2.38(m,1H),3.06(m,3H),3.18(m,1H),3.59(m,1H),3.93(m,4H),5.44(m,1H),7.48(m,1H),7.71(m,2H),8.05(m,2H),8.42(m,2H),9.35(m,1H),10.95(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ(ppm) 1.04(d,3H), 1.88(m,1H), 2.28(m,1H), 2.38(m,1H), 3.06(m,3H) ,3.18(m,1H),3.59(m,1H),3.93(m,4H),5.44(m,1H),7.48(m,1H),7.71(m,2H),8.05(m,2H), 8.42 (m, 2H), 9.35 (m, 1H), 10.95 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值484.2；實測值484.2；Rt=2.873min。LCMS (ESI): [M+H] + m/z: calculated 484.2; found 484.2; Rt=2.873 min.

化合物1364：Compound 1364:

產率：14.14mg(31.99%)Yield: 14.14 mg (31.99%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=19.962min。RT (Chiralcel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 19.962 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.04(d,3H),1.88(m,1H),2.28(m,1H),2.38 (m,1H),3.06(m,3H),3.18(m,1H),3.58(m,1H),3.92(m,4H),5.44(m,1H),7.48(m,1H),7.71(m,2H),8.04(m,2H),8.42(m,2H),9.35(m,1H),10.95(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.04 (d, 3H), 1.88 (m, 1H), 2.28 (m, 1H), 2.38 (m, 1H), 3.06 (m, 3H) ,3.18(m,1H),3.58(m,1H),3.92(m,4H),5.44(m,1H),7.48(m,1H),7.71(m,2H),8.04(m,2H), 8.42 (m, 2H), 9.35 (m, 1H), 10.95 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值484.2；實測值484.2；Rt=2.873min。LCMS (ESI): [M+H] + m/z: calculated 484.2; found 484.2; Rt=2.873 min.

實例243. rel-5-[[2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1161)及rel-5-[[2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1221)之合成Example 243. rel-5-[[2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidine Iridinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (Compound 1161) and rel-5-[[2-[(2S,4R,5S)-2-(1, 3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 1221) synthesis

Figure 110128222-A0202-12-1320-297
Figure 110128222-A0202-12-1320-297

根據一般方法製備。Prepared according to general methods.

製備型：Preparation:

化合物1221之RT(ChirapakAS-H(250*20mm，5mkm)，己烷-IPA-MeOH，70-15-15，15mL/min)=28.857min。RT for compound 1221 (Chirapak AS-H (250*20 mm, 5 mkm), hexane-IPA-MeOH, 70-15-15, 15 mL/min) = 28.857 min.

化合物1161之RT(ChirapakAS-H(250*20mm，5mkm)，己烷-IPA-MeOH，70-15-15，15mL/min)=17.976min。RT for compound 1161 (Chirapak AS-H (250*20 mm, 5 mkm), hexane-IPA-MeOH, 70-15-15, 15 mL/min) = 17.976 min.

化合物1221：Compound 1221:

產率：7.87mg(32.66%)Yield: 7.87 mg (32.66%)

RT(Chiralpak AS-H(250*4.6，5mkm)，己烷-IPA-MeOH，70-15-15，0.6mL/min)=29.012min。RT (Chiralpak AS-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 29.012 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.05(d,3H),1.91(m,1H),2.28(m,2H),3.06(m,3H),3.19(m,1H),3.76(m,2H),5.44(m,1H),7.52(m,2H),8.07(m,3H),8.41 (m,1H),8.79(m,2H),9.34(m,1H),11.15(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.05 (d, 3H), 1.91 (m, 1H), 2.28 (m, 2H), 3.06 (m, 3H), 3.19 (m, 1H) ,3.76(m,2H),5.44(m,1H),7.52(m,2H),8.07(m,3H),8.41(m,1H),8.79(m,2H),9.34(m,1H), 11.15 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值454.2；實測值454.2；Rt=2.517min。LCMS (ESI): [M+H] + m/z: calculated 454.2; found 454.2; Rt=2.517 min.

化合物1161：Compound 1161:

產率：8.35mg(34.65%)Yield: 8.35 mg (34.65%)

RT(Chiralpak AS-H(250*4.6，5mkm)，己烷-IPA-MeOH，70-15-15，0.6mL/min)=19.651min。RT (Chiralpak AS-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 19.651 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.05(d,3H),1.93(m,1H),2.28(m,2H),3.06(m,3H),3.19(m,1H),3.76(m,2H),5.44(m,1H),7.52(m,2H),8.08(m,3H),8.41(m,1H),8.79(m,2H),9.35(m,1H),11.15(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.05 (d, 3H), 1.93 (m, 1H), 2.28 (m, 2H), 3.06 (m, 3H), 3.19 (m, 1H) ,3.76(m,2H),5.44(m,1H),7.52(m,2H),8.08(m,3H),8.41(m,1H),8.79(m,2H),9.35(m,1H), 11.15 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值454.2；實測值454.2；Rt=2.520min。LCMS (ESI): [M+H] + m/z: calculated 454.2; found 454.2; Rt=2.520 min.

實例244. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1138)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1286)之合成Example 244. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl) -4-Methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 1138) and rel-N-(6-amino-5-ethyl-3-pyridine) yl)-2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 1286)

步驟1：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: Racemic-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl) Synthesis of -4-methoxy-5-methyl-1-piperidinyl]-2-oxoacetamide

Figure 110128222-A0202-12-1321-298
Figure 110128222-A0202-12-1321-298

將5-[(2S,5S)-4-甲氧基-5-甲基-2-哌啶基]-1,3-苯并噻唑(246.00mg，937.61μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(196.15mg，937.61μmol)及三乙胺(474.38mg，4.69mmol，653.42μL)一起混合於DMF(3mL)中且向其中添加HATU(427.81mg，1.13mmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 45-55%甲醇+NH3 流速30mL/min(裝載泵4 mL甲醇)，管柱：SunFire 100*19mm，5微米)，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(44.1mg，97.23μmol，10.37%產率)、N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(33mg，72.76μmol，7.76%產率)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31.7mg，69.89μmol，7.45%產率)5-[(2S,5S)-4-methoxy-5-methyl-2-piperidinyl]-1,3-benzothiazole (246.00 mg, 937.61 μmol), 2-[(6-amine (196.15 mg, 937.61 μmol) and triethylamine (474.38 mg, 4.69 mmol, 653.42 μL) were mixed together in DMF (3 mL) and to it was added HATU (427.81 mg, 1.13 mmol). The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 45-55% methanol + NH 3 flow rate 30 mL/min (load pump 4 mL methanol), column: SunFire 100*19 mm, 5 microns) to obtain N-(6 -Amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl -1-Piperidinyl]-2-oxyacetamide (44.1 mg, 97.23 μmol, 10.37% yield), N-(6-amino-5-ethyl-3-pyridyl)-2- [(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide ( 33 mg, 72.76 μmol, 7.76% yield) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazole- 5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (31.7 mg, 69.89 μmol, 7.45% yield)

LCMS(ESI)：[M+H]+ m/z：計算值454.0；實測值454.0；Rt=0.964min。LCMS (ESI): [M+H] + m/z: calculated 454.0; found 454.0; Rt=0.964 min.

步驟2：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1138)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1286) 之合成Step 2: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl) -4-Methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 1138) and rel-N-(6-amino-5-ethyl-3-pyridine) yl)-2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 1286)

Figure 110128222-A0202-12-1322-299
Figure 110128222-A0202-12-1322-299

對外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(108.8mg，239.88μmol)(經合併之級分)進行掌性分離(Chiralcel OD-H(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min，保留時間(化合物1138)=12.331min，保留時間(化合物1286)=14.940min)，以獲得rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(34.1mg，75.18μmol，31.34%產率)(化合物1138)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(30.98mg，68.30μmol，28.47%產率)(化合物1286)Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4- Methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (108.8 mg, 239.88 μmol) (combined fractions) were chiral (Chiralcel OD-H (250*) 20mm, 5mkm), Hexane-IPA-MeOH, 50-25-25, 12mL/min, RT(Compound 1138)=12.331min, RT(Compound 1286)=14.940min) to obtain rel-N-( 6-Amino-5-ethyl-3-pyridyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5 -Methyl-1-piperidinyl]-2-oxyacetamide (34.1 mg, 75.18 μmol, 31.34% yield) (compound 1138) and rel-N-(6-amino-5-ethyl) -3-Pyridinyl)-2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl ]-2-Oxyacetamide (30.98 mg, 68.30 μmol, 28.47% yield) (Compound 1286)

化合物1138 ： Compound 1138 :

產率：34.1mg(31.34%)Yield: 34.1 mg (31.34%)

RT(Chiracel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=11.014min。RT (Chiracel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 11.014 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.05(m,6H),1.89(m,1H),2.26(m,2H),2.41(m,2H),3.05(m,3H),3.18(m,1H),3.64(m,2H),5.58(m,3H),7.49(m,2H),8.07(m,3H),9.37(s,1H),10.43(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.05 (m, 6H), 1.89 (m, 1H), 2.26 (m, 2H), 2.41 (m, 2H), 3.05 (m, 3H) , 3.18(m, 1H), 3.64(m, 2H), 5.58(m, 3H), 7.49(m, 2H), 8.07(m, 3H), 9.37(s, 1H), 10.43(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值454.0；實測值454.0；Rt=0.967min。LCMS (ESI): [M+H] + m/z: calculated 454.0; found 454.0; Rt=0.967 min.

化合物1286：Compound 1286:

產率：30.98mg(28.47%)Yield: 30.98 mg (28.47%)

RT(Chiracel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=13.123min。RT (Chiracel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 13.123 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.05(m,6H),1.89(m,1H),2.26(m,2H),2.41(m,2H),3.05(m,3H),3.18(m,1H),3.65(m,2H),5.58(m,3H),7.49(m,2H),8.07(m,3H),9.37(s,1H),10.43(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.05 (m, 6H), 1.89 (m, 1H), 2.26 (m, 2H), 2.41 (m, 2H), 3.05 (m, 3H) , 3.18(m, 1H), 3.65(m, 2H), 5.58(m, 3H), 7.49(m, 2H), 8.07(m, 3H), 9.37(s, 1H), 10.43(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值454.0；實測值454.0；Rt=0.967min。LCMS (ESI): [M+H] + m/z: calculated 454.0; found 454.0; Rt=0.967 min.

實例245. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1130)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1216)之合成Example 245. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl) -4-Methoxy-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1130) and rel-N-(6-amino-5-methyl-3-pyridine) yl)-2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 1216)

步驟1：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: Racemic-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl) Synthesis of -4-methoxy-5-methyl-1-piperidinyl]-2-oxoacetamide

Figure 110128222-A0202-12-1324-300
Figure 110128222-A0202-12-1324-300

將5-[(2S,5S)-4-甲氧基-5-甲基-2-哌啶基]-1,3-苯并噻唑(200mg，762.28μmol)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(148.78mg，762.28μmol)及三乙胺(385.68mg，3.81mmol，531.24μL)一起混合於DMF(3mL)中且向其中添加HATU(347.81mg，914.74μmol)。所得混合物在室溫下攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 30-45% MeOH 30mL/min(裝載泵4mL MeOH管柱：SunFire 100*19mm，5微米)，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(34.4mg，78.27μmol，10.27%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(20.7mg，47.10μmol，6.18%產率)5-[(2S,5S)-4-methoxy-5-methyl-2-piperidinyl]-1,3-benzothiazole (200 mg, 762.28 μmol), 2-[(6-amino -5-Methyl-3-pyridyl)amino]-2-oxoacetic acid (148.78 mg, 762.28 μmol) and triethylamine (385.68 mg, 3.81 mmol, 531.24 μL) were mixed together in DMF (3 mL) And HATU (347.81 mg, 914.74 μmol) was added thereto. The resulting mixture was stirred at room temperature overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 30-45% MeOH 30 mL/min (loading pump 4 mL MeOH column: SunFire 100*19 mm, 5 microns) to obtain N-(6-amino-5-methyl) yl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl] -2-Oxyacetamide (34.4 mg, 78.27 μmol, 10.27% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)- 2-(1,3-Benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (20.7 mg, 47.10 μmol, 6.18 %Yield)

LCMS(ESI)：[M+H]+ m/z：計算值440.1；實測值440.1；Rt=0.912min。LCMS (ESI): [M+H] + m/z: calculated 440.1; found 440.1; Rt=0.912 min.

步驟2：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑.5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1130)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-2-(1，3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1216 )之合成Step 2: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol.5-yl) -4-Methoxy-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1130) and rel-N-(6-amino-5-methyl-3-pyridine) yl)-2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 1216 )

Figure 110128222-A0202-12-1324-301
Figure 110128222-A0202-12-1324-301

對外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5- 基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(55.1mg，125.36μmol)進行掌性分離(Chiralpak IA(250*30mm，5mkm)，IPA-MeOH，50-50，20mL/min，Rt(化合物1130)=40.066min，Rt(化合物1216)=56.059min)，以獲得rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(14.26mg，32.44μmol，25.88%產率)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(14.09mg，32.06μmol，25.57%產率)。Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazole-5- (55.1 mg, 125.36 μmol) chiral separation (Chiralpak IA (250*30 mm, 5 mkm) , IPA-MeOH, 50-50, 20 mL/min, Rt(Compound 1130)=40.066min, Rt(Compound 1216)=56.059min) to obtain rel-N-(6-amino-5-methyl-3 -Pyridinyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]- 2-Oxyacetamide (14.26 mg, 32.44 μmol, 25.88% yield) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4S, 5R)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (14.09 mg, 32.06 g μmol, 25.57% yield).

化合物1130：Compound 1130:

產率：14.26mg(25.88%)Yield: 14.26 mg (25.88%)

RT(Chiralpak IA(250*4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=31.408min。RT (Chiralpak IA (250*4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=31.408min.

1 H NMR(600MHz,dmso)δ 1.00-1.10(m,3H),1.83-2.21(m,5H),2.22-2.35(m,1H),3.03-3.29(m,4H),3.34-4.10(m,2H),5.30-5.67(m,3H),7.21-7.54(m,2H),7.79-8.15(m,3H),9.32-9.39(m,1H),10.28-10.58(m,1H)。 1 H NMR (600MHz, dmso) δ 1.00-1.10 (m, 3H), 1.83-2.21 (m, 5H), 2.22-2.35 (m, 1H), 3.03-3.29 (m, 4H), 3.34-4.10 (m , 2H), 5.30-5.67(m, 3H), 7.21-7.54(m, 2H), 7.79-8.15(m, 3H), 9.32-9.39(m, 1H), 10.28-10.58(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值440.2；實測值440.2；Rt=2.399min。LCMS (ESI): [M+H] + m/z: calculated 440.2; found 440.2; Rt=2.399 min.

化合物1216：Compound 1216:

產率：14.09mg(25.57%)Yield: 14.09 mg (25.57%)

RT(Chiralpak IA(250*4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=51.749min。RT (Chiralpak IA (250*4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=51.749min.

1 H NMR(600MHz,dmso)δ 0.99-1.09(m,3H),1.84-2.18(m,5H),2.24-2.35(m,1H),3.01-3.28(m,4H),3.34-4.08(m,2H),5.29-5.73(m,3H),7.20-7.54(m,2H),7.80-8.16(m,3H),9.33-9.41(m,1H),10.28-10.64(m,1H)。 1 H NMR (600MHz, dmso)δ 0.99-1.09(m, 3H), 1.84-2.18(m, 5H), 2.24-2.35(m, 1H), 3.01-3.28(m, 4H), 3.34-4.08(m , 2H), 5.29-5.73(m, 3H), 7.20-7.54(m, 2H), 7.80-8.16(m, 3H), 9.33-9.41(m, 1H), 10.28-10.64(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值440.2；實測值440.2；Rt=2.395min。LCMS (ESI): [M+H] + m/z: calculated 440.2; found 440.2; Rt=2.395 min.

實例246. N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1223、化合物1121及化合物1229)之合成Example 246. N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)phenyl) Synthesis of piperidin-1-yl)-2-oxoacetamide (Compound 1223, Compound 1121 and Compound 1229)

Figure 110128222-A0202-12-1326-302
Figure 110128222-A0202-12-1326-302

步驟4：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1223)之合成Step 4: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)phenyl) Synthesis of piperidin-1-yl)-2-oxoacetamide (compound 1223)

Figure 110128222-A0202-12-1326-303
Figure 110128222-A0202-12-1326-303

將DIPEA(87.45mg，676.63umol，117.86uL)添加到相應2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(52.82mg，270.65umol)及1-甲基-4-[3-(5-甲基-2-哌啶基)苯基]哌嗪(74mg，270.65umol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(113.20mg，297.72umol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH+NH3 為溶析液混合物)，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(30.7mg，68.14umol，25.17%產率)。DIPEA (87.45 mg, 676.63 umol, 117.86 uL) was added to the corresponding 2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (52.82 mg, 270.65 umol) ) and 1-methyl-4-[3-(5-methyl-2-piperidinyl)phenyl]piperazine (74 mg, 270.65 umol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (113.20 mg, 297.72 umol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH+ NH3 as eluent mixture) to give N- (6-amino-5-methyl-3-pyridyl) -2-[( 2R,5S )-5-methyl-2-[3-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-side oxyacetyl Amine (30.7 mg, 68.14 umol, 25.17% yield).

化合物1223：Compound 1223:

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.25-1.38(m,1H),1.61 -1.76(m,1H),1.80-1.93(m,1H),1.96-2.03(m,3H),2.04-2.17(m,1H),2.17-2.23(m,4H),2.40-2.44(m,4H),2.72-2.76(m,0.4H),3.07-3.13(m,4H),3.22-3.26(m,0.6H),3.39-4.04(m,1H),5.07-5.55(m,1H),5.58-5.67(m,2H),6.68-6.79(m,1H),6.78-6.84(m,2H),7.15-7.24(m,1H),7.40-7.50(m,1H),7.94-8.06(m,1H),10.45-10.58(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96-1.03(m,3H), 1.25-1.38(m,1H), 1.61-1.76(m,1H), 1.80-1.93(m,1H) ,1.96-2.03(m,3H),2.04-2.17(m,1H),2.17-2.23(m,4H),2.40-2.44(m,4H),2.72-2.76(m,0.4H),3.07-3.13 (m,4H),3.22-3.26(m,0.6H),3.39-4.04(m,1H),5.07-5.55(m,1H),5.58-5.67(m,2H),6.68-6.79(m,1H) ), 6.78-6.84(m, 2H), 7.15-7.24(m, 1H), 7.40-7.50(m, 1H), 7.94-8.06(m, 1H), 10.45-10.58(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值450.2；實測值451.2；Rt=1.880min。LCMS (ESI): [M] + m/z: calculated 450.2; found 451.2; Rt=1.880 min.

步驟5：掌性分離(化合物1121及化合物1229)Step 5: Chiral separation (Compound 1121 and Compound 1229)

Figure 110128222-A0202-12-1327-304
Figure 110128222-A0202-12-1327-304

對外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(18.5mg，41.06μmol)進行掌性分離(管柱：Chiralpak AD-H(250-20mm-5m)；流動相：己烷-IPA-MeOH，40-30-30流速：12mL/min)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(8.66mg，19.22μmol，46.81%產率)(RT=25.5min)及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(8.29mg，18.40μmol，44.81%產率)(RT=47.1min)。Racemic N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[3-(4-methylpiperazine-1 -yl)phenyl]-1-piperidinyl]-2-oxoacetamide (18.5 mg, 41.06 μmol) for chiral separation (column: Chiralpak AD-H (250-20 mm-5 m); flow Phase: Hexane-IPA-MeOH, 40-30-30 Flow rate: 12 mL/min) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R ) -5-Methyl-2-[3-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxyacetamide (8.66 mg, 19.22 μmol, 46.81 % yield) (RT=25.5 min) and N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[3-( 4-Methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (8.29 mg, 18.40 μmol, 44.81% yield) (RT=47.1 min).

化合物1121：Compound 1121:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.00(m,3H),1.33-1.36(m,2H),1.64-1.90(m,3H),1.99-2.20(m,6H),2.42-2.43(m,2H),3.08-3.26(m,4H),3.41-4.01(m,3H),5.10-5.62(m,4H),6.70-6.82(m,3H),7.19-7.22(m,1H),7.44-7.49(m,1H),7.96-8.01(m,1H),10.48-10.51(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.00(m,3H), 1.33-1.36(m,2H), 1.64-1.90(m,3H), 1.99-2.20(m,6H) ,2.42-2.43(m,2H),3.08-3.26(m,4H),3.41-4.01(m,3H),5.10-5.62(m,4H),6.70-6.82(m,3H),7.19-7.22( m, 1H), 7.44-7.49 (m, 1H), 7.96-8.01 (m, 1H), 10.48-10.51 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值450.2；實測值451.2；Rt=1.934min。LCMS (ESI): [M] + m/z: calculated 450.2; found 451.2; Rt=1.934 min.

化合物1229：Compound 1229:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.00(m,3H),1.22-1.36(m,2H),1.62-1.90(m,3H),1.99-2.20(m,6H),2.42-2.43(m,2H),3.08-3.24(m,4H),3.41-4.01(m,3H),5.10-5.62(m,4H),6.70-6.82(m,3H),7.19-7.22(m,1H),7.44-7.49(d,1H),7.96-8.01(d,1H),10.48-10.51(d,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.00(m,3H), 1.22-1.36(m,2H), 1.62-1.90(m,3H), 1.99-2.20(m,6H) ,2.42-2.43(m,2H),3.08-3.24(m,4H),3.41-4.01(m,3H),5.10-5.62(m,4H),6.70-6.82(m,3H),7.19-7.22( m, 1H), 7.44-7.49 (d, 1H), 7.96-8.01 (d, 1H), 10.48-10.51 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值450.2；實測值451.2；Rt=1.603min。LCMS (ESI): [M] + m/z: calculated 450.2; found 451.2; Rt=1.603 min.

實例247. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物 1327)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5S)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物 1088)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物 1302)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R,5S)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物 1351)之合成 Example 247. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4R,5R)-4-isopropoxy-5-methyl-2-benzene base-1-piperidinyl]-2-oxyacetamide (compound 1327 ), rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4S ,5S)-4-isopropoxy-5-methyl-2-phenyl-1-piperidinyl]-2-side oxyacetamide (compound 1088 ), rel-N-(6-amino -5-Methyl-3-pyridyl)-2-[(2R,4S,5R)-4-isopropoxy-5-methyl-2-phenyl-1-piperidinyl]-2-side Oxyacetamide (Compound 1302 ) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4R,5S)-4-isopropoxy-5 Synthesis of -methyl-2-phenyl-1-piperidinyl]-2-oxoacetamide (compound 1351 )

Figure 110128222-A0202-12-1329-305
Figure 110128222-A0202-12-1329-305

步驟1：(6R,9R)-6-甲基-9-苯基-1,4-二氧雜-8-氮雜螺[4.5]癸烷之合成Step 1: Synthesis of (6R,9R)-6-methyl-9-phenyl-1,4-dioxa-8-azaspiro[4.5]decane

Figure 110128222-A0202-12-1329-306
Figure 110128222-A0202-12-1329-306

將2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-胺(2g，13.77mmol)溶解於苯(40mL)中且向其中添加苯甲醛(1.46g，13.77mmol，1.41mL)，隨後添加對甲苯磺酸單水合物(7.86g，41.32mmol，6.34mL)。將所得混合物加熱至回流且以迪安-斯塔克分離器回流隔夜。反應完成之後，蒸發苯。將殘餘物溶解於20mL水中，添加K2 CO3 至鹼性pH，將水相用CHCl3 (3*15mL)萃取。將經合併之有機層用NaHSO4 水溶液(於20mL水中之2g，2*20mL)萃取。將經合併之水層用K2 CO3 鹼化。將所得混合物用CHCl3 (3*20mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得(6R,9R)-6-甲基-9-苯基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(1.1g， 4.71mmol，34.23%產率)。2-(2-Methyl-1,3-dioxolan-2-yl)propan-1-amine (2 g, 13.77 mmol) was dissolved in benzene (40 mL) and to it was added benzaldehyde (1.46 g , 13.77 mmol, 1.41 mL), followed by the addition of p-toluenesulfonic acid monohydrate (7.86 g, 41.32 mmol, 6.34 mL). The resulting mixture was heated to reflux and refluxed with a Dean-Stark separator overnight. After the reaction was completed, the benzene was evaporated. The residue was dissolved in 20 mL of water, K2CO3 was added to basic pH, and the aqueous phase was extracted with CHCl3 ( 3 *15 mL). The combined organic layers were extracted with aqueous NaHSO4 (2 g in 20 mL water, 2*20 mL). The combined aqueous layers were basified with K2CO3. The resulting mixture was extracted with CHCl3 (3*20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to give (6R,9R)-6-methyl-9-phenyl-1,4-dioxa-8-azaspiro[4.5 ] Decane (1.1 g, 4.71 mmol, 34.23% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.64(m,2H),1.88(m,1H),1.89(m,1H),2.73(m,1H),3.03(m,1H),3.82(m,1H),3.98(m,4H),7.29-7.33(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d,3H), 1.64(m,2H), 1.88(m,1H), 1.89(m,1H), 2.73(m,1H), 3.03( m, 1H), 3.82 (m, 1H), 3.98 (m, 4H), 7.29-7.33 (m, 5H).

LCMS(ESI)：[M+H]+ m/z：計算值234.2；實測值234.2；Rt=0.803min。LCMS (ESI): [M+H] + m/z: calculated 234.2; found 234.2; Rt=0.803 min.

步驟2：(2R,5R)-5-甲基-2-苯基哌啶-4-酮之合成Step 2: Synthesis of (2R,5R)-5-methyl-2-phenylpiperidin-4-one

Figure 110128222-A0202-12-1330-307
Figure 110128222-A0202-12-1330-307

使(6R,9R)-6-甲基-9-苯基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(1g，4.29mmol)於6N HCl(10mL)中之混合物在80℃下攪拌15h。反應完成之後，將10mL水添加到混合物且將溶液用K2 CO3 鹼化至鹼性pH。將水層用CHCl3 (3*10mL)萃取，將經合併之有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得(2R,5R)-5-甲基-2-苯基哌啶-4-酮(0.76g，4.02mmol，93.69%產率)。A mixture of (6R,9R)-6-methyl-9-phenyl-1,4-dioxa-8-azaspiro[4.5]decane (1 g, 4.29 mmol) in 6N HCl (10 mL) Stir at 80°C for 15h. After the reaction was complete, 10 mL of water was added to the mixture and the solution was basified with K2CO3 to basic pH. The aqueous layer was extracted with CHCl 3 (3*10 mL), the combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain (2R,5R)-5-methyl-2-benzene ylpiperidin-4-one (0.76 g, 4.02 mmol, 93.69% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.08(d,3H),2.57(m,2H),2.70(m,2H),3.47(m,1H),3.95(m,1H),7.37(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.08(d,3H), 2.57(m,2H), 2.70(m,2H), 3.47(m,1H), 3.95(m,1H), 7.37( m, 5H).

LCMS(ESI)：[M+H]+ m/z：計算值190.2；實測值190.2；Rt=0.626min。LCMS (ESI): [M+H] + m/z: calculated 190.2; found 190.2; Rt=0.626 min.

步驟3：(2R,5R)-5-甲基-4-側氧基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of (2R,5R)-5-methyl-4-oxo-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1330-308
Figure 110128222-A0202-12-1330-308

向(2R,5R)-5-甲基-2-苯基哌啶-4-酮(0.76g，4.02mmol)於THF(15mL)中之混合物中一次性添加碳酸第三丁氧基羰基第三丁酯(876.43mg，4.02mmol，921.59uL)。使所得混合物在室溫下攪拌隔夜。反應完成之後，在減壓下蒸發THF，以得到(2R,5R)-5-甲基-4-側氧基-2-苯基哌啶-1-甲酸第三丁酯(1.1g，3.80 mmol，94.66%產率)。To a mixture of (2R,5R)-5-methyl-2-phenylpiperidin-4-one (0.76 g, 4.02 mmol) in THF (15 mL) was added tertiary butoxycarbonyl carbonate in one portion Butyl ester (876.43 mg, 4.02 mmol, 921.59 uL). The resulting mixture was stirred at room temperature overnight. After completion of the reaction, THF was evaporated under reduced pressure to give tert-butyl (2R,5R)-5-methyl-4-oxy-2-phenylpiperidine-1-carboxylate (1.1 g, 3.80 g mmol, 94.66% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.17(m,3H),1.43(s,9H),2.48(m,1H),2.94(m,2H),3.58(m,1H),3.81(m,1H),5.60(m,1H),7.22-7.32(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.17(m, 3H), 1.43(s, 9H), 2.48(m, 1H), 2.94(m, 2H), 3.58(m, 1H), 3.81( m, 1H), 5.60 (m, 1H), 7.22-7.32 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值190.2；實測值190.2；Rt=1.414min。LCMS (ESI): [M-Boc] + m/z: calculated 190.2; found 190.2; Rt=1.414 min.

步驟4：(2R,4S,5R)-4-羥基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of (2R,4S,5R)-4-hydroxy-5-methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1331-309
Figure 110128222-A0202-12-1331-309

將硼氫化鈉(143.81mg，3.80mmol，134.40uL)一次性添加到(2R,5R)-5-甲基-4-側氧基-2-苯基哌啶-1-甲酸第三丁酯(1.1g，3.80mmol)於MeOH(20mL)中之冰冷溶液中。使所得混合物在25℃下攪拌隔夜。反應完成之後，將MeOH蒸發至乾。將20mL水添加到殘餘物中且將混合物用K2 CO3 鹼化至鹼性pH，將水相用CHCl3 (3*15mL)萃取，將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下蒸發，以得到(2R,4S,5R)-4-羥基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯(0.9g，3.09mmol，81.25%產率)。Sodium borohydride (143.81 mg, 3.80 mmol, 134.40 uL) was added in one portion to tert-butyl (2R,5R)-5-methyl-4-oxy-2-phenylpiperidine-1-carboxylate ( 1.1 g, 3.80 mmol) in an ice-cold solution of MeOH (20 mL). The resulting mixture was stirred at 25°C overnight. After the reaction was complete, MeOH was evaporated to dryness. 20 mL of water was added to the residue and the mixture was basified with K2CO3 to basic pH, the aqueous phase was extracted with CHCl3 ( 3 *15 mL), the combined organic layers were dried over Na2SO4 , filtered and evaporated under reduced pressure to give tert-butyl (2R,4S,5R)-4-hydroxy-5-methyl-2-phenylpiperidine-1-carboxylate (0.9 g, 3.09 mmol, 81.25% yield). Rate).

LCMS(ESI)：[M-Boc]+ m/z：計算值192.2；實測值192.2；Rt=1.362min。LCMS (ESI): [M-Boc] + m/z: calculated 192.2; found 192.2; Rt=1.362 min.

步驟5：(2R,4S,5R)-4-甲氧基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of (2R,4S,5R)-4-methoxy-5-methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1331-310
Figure 110128222-A0202-12-1331-310

向(2R,4S,5R)-4-羥基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯(0.4g，1.37mmol)於DMF(10mL)中之混合物中分批添加於礦物油中之氫化鈉(油分散物)60%分散物(47.34mg，2.06mmol)，將所得混合物在室溫下攪拌20min且用冰冷卻至0℃。一次性添加碘甲烷(292.27mg，2.06mmol，128.19uL)且使反應物在室溫下攪拌48h。反應完成之後，將25mL水添加到混合物中。將水相用EtOAc(3*15 mL)萃取，將經合併之有機層用鹽水(3*10mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得(2R,4S,5R)-4-甲氧基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯(0.4g，1.31mmol，95.41%產率)。To a mixture of (2R,4S,5R)-4-hydroxy-5-methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.37 mmol) in DMF (10 mL) was batched Sodium hydride (oil dispersion) 60% dispersion in mineral oil (47.34 mg, 2.06 mmol) was added and the resulting mixture was stirred at room temperature for 20 min and cooled to 0 °C with ice. Iodomethane (292.27 mg, 2.06 mmol, 128.19 uL) was added in one portion and the reaction was allowed to stir at room temperature for 48 h. After the reaction was completed, 25 mL of water was added to the mixture. The aqueous phase was extracted with EtOAc (3*15 mL), the combined organic layers were washed with brine (3*10 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to obtain (2R,4S, 5R)-4-Methoxy-5-methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.31 mmol, 95.41% yield).

LCMS(ESI)：[M+H]+ m/z：計算值306.2；實測值306.2；Rt=1.428min。LCMS (ESI): [M+H] + m/z: calculated 306.2; found 306.2; Rt=1.428 min.

步驟6：(2R,4S,5R)-4-甲氧基-5-甲基-2-苯基哌啶之合成Step 6: Synthesis of (2R,4S,5R)-4-methoxy-5-methyl-2-phenylpiperidine

Figure 110128222-A0202-12-1332-311
Figure 110128222-A0202-12-1332-311

將(2R,4S,5R)-4-甲氧基-5-甲基-2-苯基哌啶-1-甲酸第三丁酯(0.41g，1.34mmol)溶解於二噁烷/HCl(10mL)中。使所得混合物在25℃下攪拌17h。反應完成之後，將溶劑蒸發至乾，以獲得(2R,4S,5R)-4-甲氧基-5-甲基-2-苯基哌啶(0.23g，951.37umol，70.87%產率，HCl)。(2R,4S,5R)-4-methoxy-5-methyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.41 g, 1.34 mmol) was dissolved in dioxane/HCl (10 mL) )middle. The resulting mixture was stirred at 25 °C for 17 h. After the reaction was completed, the solvent was evaporated to dryness to obtain (2R,4S,5R)-4-methoxy-5-methyl-2-phenylpiperidine (0.23 g, 951.37 umol, 70.87% yield, HCl ).

LCMS(ESI)：[M+H]+ m/z：計算值206.2；實測值206.2；Rt=0.842min。LCMS (ESI): [M+H] + m/z: calculated 206.2; found 206.2; Rt=0.842 min.

步驟7：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺之合成Step 7: Racemic-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,4S,5R)-4-isopropoxy-5-methyl-2 - Synthesis of Phenyl-1-Piperidinyl]-2-Pendant Oxyacetamide

Figure 110128222-A0202-12-1332-312
Figure 110128222-A0202-12-1332-312

向(2R,4S,5R)-4-異丙氧基-5-甲基-2-苯基哌啶(0.2g，741.26umol，HCl)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(144.68mg，741.26umol)及三乙胺(525.06mg，5.19mmol，723.22uL)於DMF(4mL)中之混合物中一次性添加HATU(338.22mg，889.52umol)。使所得混合物在室溫下攪拌19h。反應完成之後，將DMF蒸發，使殘餘物經歷HPLC(0-5min 30-80%水/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeOH)，管柱：YMC Triart C18 100 *20mm，5um)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.052g，126.67umol，17.09%產率)。To (2R,4S,5R)-4-isopropoxy-5-methyl-2-phenylpiperidine (0.2g, 741.26umol, HCl), 2-[(6-amino-5-methyl To a mixture of -3-pyridyl)amino]-2-side oxyacetic acid (144.68 mg, 741.26 umol) and triethylamine (525.06 mg, 5.19 mmol, 723.22 uL) in DMF (4 mL) was added HATU in one portion (338.22 mg, 889.52 umol). The resulting mixture was stirred at room temperature for 19 h. After the reaction was complete, DMF was evaporated and the residue was subjected to HPLC (0-5 min 30-80% water/MeOH/0.1% NH4OH , flow rate: 30 mL/min (loading pump 4 mL/min MeOH), column: YMC Triart C18 100*20mm, 5um) to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4S,5R)-4-isopropoxy-5-methyl yl-2-phenyl-1-piperidinyl]-2-oxoacetamide (0.052 g, 126.67 umol, 17.09% yield).

1 H NMR(500MHz,dmso)δ 0.62-1.05(m,9H),1.67-1.92(m,1H),1.94-2.05(m,3H),2.15(s,1H),2.67-3.14(m,1H),3.37-3.68(m,3H),3.69-4.20(m,1H),5.14-5.57(m,1H),5.58-5.80(m,2H),7.02-7.23(m,1H),7.24-7.32(m,3H),7.34-7.42(m,1H),7.43-7.53(m,1H),7.80-8.06(m,1H),10.18-10.60(m,1H)。 1 H NMR(500MHz, dmso)δ 0.62-1.05(m, 9H), 1.67-1.92(m, 1H), 1.94-2.05(m, 3H), 2.15(s, 1H), 2.67-3.14(m, 1H) ), 3.37-3.68(m, 3H), 3.69-4.20(m, 1H), 5.14-5.57(m, 1H), 5.58-5.80(m, 2H), 7.02-7.23(m, 1H), 7.24-7.32 (m, 3H), 7.34-7.42 (m, 1H), 7.43-7.53 (m, 1H), 7.80-8.06 (m, 1H), 10.18-10.60 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=2.297min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=2.297 min.

步驟8：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物1327)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5S)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物1088)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物1302)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R,5S)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物1351)之合成Step 8: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4R,5R)-4-isopropoxy-5-methyl-2-benzene yl-1-piperidinyl]-2-oxoacetamide (compound 1327), rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4S ,5S)-4-isopropoxy-5-methyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (compound 1088), rel-N-(6-amino) -5-Methyl-3-pyridyl)-2-[(2R,4S,5R)-4-isopropoxy-5-methyl-2-phenyl-1-piperidinyl]-2-side Oxyacetamide (Compound 1302) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4R,5S)-4-isopropoxy-5 Synthesis of -methyl-2-phenyl-1-piperidinyl]-2-oxoacetamide (compound 1351)

藉由掌性層析(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，90-5-5，12mL/min)分離非鏡像異構物之混合物，以獲得化合物1327 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.00422g，10.28μmol，8.12%產率)、化合物1088 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5S)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(3.39mg，8.26μmol，6.52%產率)、化合物1302 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S,5R)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.01669g，40.66μmol，32.10%產率)、化合物1351 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R,5S)-4-異丙氧基-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.01743g，42.46μmol，33.52%產率)。The mixture of diastereomers was separated by chiral chromatography (Chiralcel OD-H (250*20, 5mkm), hexane-IPA-MeOH, 90-5-5, 12mL/min) to obtain compound 1327 rel -N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,4R,5R)-4-isopropoxy-5-methyl-2-phenyl-1- Piperidinyl]-2-oxyacetamide (0.00422 g, 10.28 μmol, 8.12% yield), compound 1088 rel-N-(6-amino-5-methyl-3-pyridyl)-2 -[(2S,4S,5S)-4-isopropoxy-5-methyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (3.39 mg, 8.26 μmol, 6.52 % yield), compound 1302 rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4S,5R)-4-isopropoxy-5-methyl -2-Phenyl-1-piperidinyl]-2-oxyacetamide (0.01669 g, 40.66 μmol, 32.10% yield), compound 1351 rel-N-(6-amino-5-methyl) -3-Pyridinyl)-2-[(2S,4R,5S)-4-isopropoxy-5-methyl-2-phenyl-1-piperidinyl]-2-oxoacetamide (0.01743 g, 42.46 μmol, 33.52% yield).

製備型：Preparation:

化合物1088之RT(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，90-5-5，12mL/min)=33.950min。RT for compound 1088 (Chiralcel OD-H (250*20, 5mkm), Hexane-IPA-MeOH, 90-5-5, 12mL/min)=33.950min.

化合物1351之RT(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，90-5-5，12mL/min)=45.434min。RT for compound 1351 (Chiralcel OD-H (250*20, 5mkm), Hexane-IPA-MeOH, 90-5-5, 12mL/min)=45.434min.

化合物1302之RT(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，90-5-5，12mL/min)=57.493min。RT for compound 1302 (Chiralcel OD-H (250*20, 5 mkm), hexane-IPA-MeOH, 90-5-5, 12 mL/min) = 57.493 min.

化合物1327之RT(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，90-5-5，12mL/min)=79.390min。RT for compound 1327 (Chiralcel OD-H (250*20, 5mkm), Hexane-IPA-MeOH, 90-5-5, 12mL/min)=79.390min.

化合物1327：Compound 1327:

產率：4.22mg(8.12%)Yield: 4.22 mg (8.12%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=26.456min。RT (Chiralcel OD-H (250*4.6, 5mkm), Hexane-IPA-MeOH, 80-10-10, 0.6mL/min)=26.456min.

1 H NMR(dmso,600MHz)：δ(ppm)0.87-0.91(m,3H),1.00-1.04(m,6H),1.78-1.85(m,1H),1.92-1.99(m,1H),1.99-2.05(m,3H),2.05-2.11(m,1H),2.65-3.14(m,1H),3.45-3.61(m,2H),3.61-4.21(m,1H),5.23-5.89(m,3H),7.27-7.31(m,2H),7.35-7.37(m,1H),7.38-7.44(m,2H),7.47-7.55(m,1H),7.95-8.09(m,1H),10.50-10.67(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.87-0.91 (m, 3H), 1.00-1.04 (m, 6H), 1.78-1.85 (m, 1H), 1.92-1.99 (m, 1H), 1.99 -2.05(m, 3H), 2.05-2.11(m, 1H), 2.65-3.14(m, 1H), 3.45-3.61(m, 2H), 3.61-4.21(m, 1H), 5.23-5.89(m, 3H), 7.27-7.31(m, 2H), 7.35-7.37(m, 1H), 7.38-7.44(m, 2H), 7.47-7.55(m, 1H), 7.95-8.09(m, 1H), 10.50- 10.67 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=2.149min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=2.149 min.

化合物1088：Compound 1088:

產率：3.39mg(6.52%)Yield: 3.39 mg (6.52%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=14.072min。RT (Chiralcel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 80-10-10, 0.6 mL/min) = 14.072 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.87-0.91(m,3H),1.00-1.04(m,6H),1.78- 1.85(m,1H),1.92-1.99(m,1H),1.99-2.05(m,3H),2.05-2.10(m,1H),2.65-3.14(m,1H),3.45-3.61(m,2H),3.61-4.21(m,1H),5.23-5.88(m,3H),7.27-7.31(m,2H),7.35-7.38(m,1H),7.38-7.42(m,2H),7.47-7.55(m,1H),7.95-8.09(m,1H),10.50-10.67(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.87-0.91 (m, 3H), 1.00-1.04 (m, 6H), 1.78- 1.85 (m, 1H), 1.92-1.99 (m, 1H), 1.99 -2.05(m, 3H), 2.05-2.10(m, 1H), 2.65-3.14(m, 1H), 3.45-3.61(m, 2H), 3.61-4.21(m, 1H), 5.23-5.88(m, 3H), 7.27-7.31(m, 2H), 7.35-7.38(m, 1H), 7.38-7.42(m, 2H), 7.47-7.55(m, 1H), 7.95-8.09(m, 1H), 10.50- 10.67 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=2.147min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=2.147 min.

化合物1302：Compound 1302:

產率：16.69mg(32.10%)Yield: 16.69 mg (32.10%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=20.214min。RT (Chiralcel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 80-10-10, 0.6 mL/min) = 20.214 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.43-0.72(m,3H),0.88-0.97(m,3H),0.97-1.07(m,3H),1.64-1.81(m,1H),1.94-2.05(m,3H),2.09-2.27(m,2H),2.89-3.29(m,1H),3.36-3.57(m,2H),3.66-4.07(m,1H),5.15-5.43(m,1H),5.54-6.02(m,2H),7.11-7.22(m,1H),7.23-7.33(m,4H),7.33-7.54(m,1H),7.69-8.11(m,1H),9.67-10.69(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.43-0.72 (m, 3H), 0.88-0.97 (m, 3H), 0.97-1.07 (m, 3H), 1.64-1.81 (m, 1H), 1.94 -2.05(m, 3H), 2.09-2.27(m, 2H), 2.89-3.29(m, 1H), 3.36-3.57(m, 2H), 3.66-4.07(m, 1H), 5.15-5.43(m, 1H), 5.54-6.02(m, 2H), 7.11-7.22(m, 1H), 7.23-7.33(m, 4H), 7.33-7.54(m, 1H), 7.69-8.11(m, 1H), 9.67- 10.69 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=2.105min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=2.105 min.

化合物1351：Compound 1351:

產率：17.43mg(33.52%)Yield: 17.43 mg (33.52%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=17.795min。RT (Chiralcel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 80-10-10, 0.6 mL/min) = 17.795 min.

1 H NMR(dmso,600MHz)：δ(ppm)0.42-0.72(m,3H),0.87-0.98(m,3H),0.97-1.07(m,3H),1.64-1.81(m,1H),1.94-2.05(m,3H),2.09-2.26(m,2H),2.89-3.28(m,1H),3.36-3.57(m,2H),3.66-4.07(m,1H),5.16-5.43(m,1H),5.55-6.02(m,2H),7.11-7.22(m,1H),7.21-7.33(m,4H),7.33-7.54(m,1H),7.69-8.11(m,1H),9.67-10.69(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.42-0.72 (m, 3H), 0.87-0.98 (m, 3H), 0.97-1.07 (m, 3H), 1.64-1.81 (m, 1H), 1.94 -2.05(m, 3H), 2.09-2.26(m, 2H), 2.89-3.28(m, 1H), 3.36-3.57(m, 2H), 3.66-4.07(m, 1H), 5.16-5.43(m, 1H), 5.55-6.02(m, 2H), 7.11-7.22(m, 1H), 7.21-7.33(m, 4H), 7.33-7.54(m, 1H), 7.69-8.11(m, 1H), 9.67- 10.69 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=2.103min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=2.103 min.

實例248. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(4-(2-(二甲胺基)乙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1228)之合成Example 248. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(4-(2-(dimethylamino)ethyl)phenyl )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1228) Synthesis

Figure 110128222-A0202-12-1336-313
Figure 110128222-A0202-12-1336-313

步驟1：(S)-6-(4-(2-(二甲胺基)乙基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: (S)-6-(4-(2-(dimethylamino)ethyl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl Synthesis of Esters

Figure 110128222-A0202-12-1336-314
Figure 110128222-A0202-12-1336-314

將[4-[2-(二甲胺基)乙基]苯基]硼酸(8g，41.44mmol)及(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(21.47g，62.16mmol)一起混合於二噁烷(91.71mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(4.83mL)中之碳酸鈉(8.78g，82.88mmol，3.47mL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(1.52g，2.07mmol)。將反應混合物在氬氣、90℃下攪拌15h，然後冷卻且在真空中蒸發，將其倒入水(180ml)中且用EtOAc(2x150ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下14g粗產物，14g粗產物藉由矽膠管柱層析使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到(3S )-6-[4-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.5 g，10.16mmol，24.52%產率)。[4-[2-(Dimethylamino)ethyl]phenyl]boronic acid (8 g, 41.44 mmol) and ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)- 3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (21.47 g, 62.16 mmol) was mixed together in dioxane (91.71 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (8.78 g, 82.88 mmol, 3.47 mL) in water (4.83 mL) and [1,1'-bis(1,1'-bis(1,1'-bis) were added under argon. (Diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (1.52 g, 2.07 mmol). The reaction mixture was stirred under argon at 90°C for 15h, then cooled and evaporated in vacuo, poured into water (180ml) and extracted with EtOAc (2x150ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 14g of crude product which was subjected to silica gel column chromatography using a hexane/MTBE gradient (10- 100% MTBE) to give ( 3S )-6-[4-[2-(dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine- 3 -Butyl 1-carboxylate (3.5 g, 10.16 mmol, 24.52% yield).

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=1.163min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=1.163 min.

步驟2：(S)-N,N-二甲基-2-(4-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)乙胺之合成Step 2: Synthesis of (S)-N,N-dimethyl-2-(4-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)ethanamine

Figure 110128222-A0202-12-1337-315
Figure 110128222-A0202-12-1337-315

將(3S )-6-[4-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.50g，10.16mmol)於DCM(20mL)及99% TFA(20g，175.40mmol，13.51mL)中之溶液在0℃下攪拌5h，然後在真空中蒸發。將碎冰(50g)添加到殘餘物中且將pH用10%碳酸氫鈉水溶液調節至8。將所得混合物用MTBE(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到N,N -二甲基-2-[4-[(3S )-3-甲基-1,2,3,4-四氫吡啶-6-基]苯基]乙胺(2g，8.18mmol，80.55%產率)。( 3S )-6-[4-[2-(dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester ( A solution of 3.50 g, 10.16 mmol) in DCM (20 mL) and 99% TFA (20 g, 175.40 mmol, 13.51 mL) was stirred at 0 °C for 5 h, then evaporated in vacuo. Crushed ice (50 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate. The resulting mixture was extracted with MTBE (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N,N -dimethyl-2-[4-[( 3S )-3-methyl-1,2,3,4- Tetrahydropyridin-6-yl]phenyl]ethanamine (2 g, 8.18 mmol, 80.55% yield).

LCMS(ESI)：[M]+ m/z：計算值244.2；實測值245.2；Rt=0.584min。LCMS (ESI): [M] + m/z: calculated 244.2; found 245.2; Rt=0.584 min.

步驟3：N,N-二甲基-2-(4-((2R,5S)-5-甲基哌啶-2-基)苯基)乙胺之合成Step 3: Synthesis of N,N-dimethyl-2-(4-((2R,5S)-5-methylpiperidin-2-yl)phenyl)ethanamine

Figure 110128222-A0202-12-1337-316
Figure 110128222-A0202-12-1337-316

在0℃下，將硼氫化鈉(619.26mg，16.37mmol，576.59μL)一次性添加到N,N -二甲基-2-[4-[(3S )-3-甲基-1,2,3,4-四氫吡啶-6-基]苯基]乙胺(2.00g，8.18mmol)於MeOH(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌6h，然 後在真空中蒸發。將殘餘物用水(40mL)稀釋且用DCM(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到N,N -二甲基-2-[4-[(2R,5S )-5-甲基-2-哌啶基]苯基]乙胺(1.7g，6.90mmol，84.30%產率)。Sodium borohydride (619.26 mg, 16.37 mmol, 576.59 μL) was added in one portion to N,N -dimethyl-2-[4-[( 3S )-3-methyl-1,2,0 at 0 °C 3,4-Tetrahydropyridin-6-yl]phenyl]ethanamine (2.00 g, 8.18 mmol) in a stirred solution of MeOH (20 mL). The resulting mixture was stirred at 0 °C for 6 h, then evaporated in vacuo. The residue was diluted with water (40 mL) and extracted with DCM (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N,N -dimethyl-2-[4-[( 2R,5S )-5-methyl-2-piperidinyl] Phenyl]ethylamine (1.7 g, 6.90 mmol, 84.30% yield).

LCMS(ESI)：[M]+ m/z：計算值246.2；實測值247.2；Rt=0.556min。LCMS (ESI): [M] + m/z: calculated 246.2; found 247.2; Rt=0.556 min.

Figure 110128222-A0202-12-1338-317
Figure 110128222-A0202-12-1338-317

將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(339.63mg，1.62mmol)及N,N -二甲基-2-[4-[(2R,5S )-5-甲基-2-哌啶基]苯基]乙胺(0.32g，1.30mmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(617.28mg，1.62mmol)，隨後添加TEA(131.42mg，1.30mmol，181.02μL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且藉由製備型(50-50-75% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min)純化0.7g所獲得之粗產物，以得到產物N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[4-[2-(二甲胺基)乙基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.268g，612.46μmol，47.16%產率)。2-[(6-Amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (339.63 mg, 1.62 mmol) and N,N -dimethyl-2-[4 -[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]ethanamine (0.32 g, 1.30 mmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (617.28 mg, 1.62 mmol) was added followed by TEA (131.42 mg, 1.30 mmol, 181.02 μL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and 0.7 g of the obtained crude product was purified by prep (50-50-75% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min) , to give the product N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-[4-[2-(dimethylamino)ethyl]benzene yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (0.268 g, 612.46 μmol, 47.16% yield).

化合物1228：Compound 1228:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.71-1.36(m,6H),1.29-1.36(m,2H),1.65-1.89(m,2H),1.99-2.21(m,8H),2.35-2.39(m,2H),2.65-2.72(m,2H),3.19-3.21(m,1H),3.42-4.01(m,2H),5.11-5.64(m,3H),7.18-7.23(m,4H),7.45-7.50(d,1H),8.00-8.08(d,1H),10.46-10.54(d,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.71-1.36(m,6H), 1.29-1.36(m,2H), 1.65-1.89(m,2H), 1.99-2.21(m,8H) ,2.35-2.39(m,2H),2.65-2.72(m,2H),3.19-3.21(m,1H),3.42-4.01(m,2H),5.11-5.64(m,3H),7.18-7.23( m, 4H), 7.45-7.50 (d, 1H), 8.00-8.08 (d, 1H), 10.46-10.54 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=1.969min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=1.969 min.

實例249. N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(4-(吡啶-4-基)苯基)哌啶-1-Example 249. N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(4-(pyridin-4-yl)phenyl)piperidine-1- 基)-2-側氧基乙醯胺(化合物1233、化合物1322及化合物1358)之合成yl)-2-oxyacetamide (Compound 1233, Compound 1322 and Compound 1358) Synthesis

Figure 110128222-A0202-12-1339-318
Figure 110128222-A0202-12-1339-318

步驟1：2-(4-溴苯基)-N,N-二甲基乙胺之合成Step 1: Synthesis of 2-(4-bromophenyl)-N,N-dimethylethylamine

Figure 110128222-A0202-12-1339-319
Figure 110128222-A0202-12-1339-319

向2-(4-溴苯基)乙胺(5g，24.99mmol，3.88mL)於甲酸(30mL)中之溶液中添加用7-8% MeOH穩定之37% w/w甲醛水溶液(4.50g，149.94mmol，4.17mL)。在100℃下攪拌48h之後，將反應混合物蒸發且倒入到H2 O(200ml)中且將pH用10%碳酸氫鈉水溶液調節至9，用MTBE(50ml*2)萃取且將經合併之有機層用H2 O(40ml*2)洗滌，乾燥且濃縮，以得到產物2-(4-溴苯基)-N,N -二甲基乙胺(5.1g，22.36mmol，89.46%產率)。To a solution of 2-(4-bromophenyl)ethanamine (5 g, 24.99 mmol, 3.88 mL) in formic acid (30 mL) was added 37% w/w aqueous formaldehyde (4.50 g, stabilised with 7-8% MeOH) 149.94 mmol, 4.17 mL). After stirring at 100°C for 48h, the reaction mixture was evaporated and poured into H2O (200ml) and the pH was adjusted to 9 with 10% aqueous sodium bicarbonate, extracted with MTBE (50ml*2) and the combined The organic layer was washed with H2O (40 ml*2), dried and concentrated to give the product 2-(4-bromophenyl) -N,N -dimethylethylamine (5.1 g, 22.36 mmol, 89.46% yield ).

LCMS(ESI)：[M]+ m/z：計算值228.2；實測值229.2；Rt=0.622min。LCMS (ESI): [M] + m/z: calculated 228.2; found 229.2; Rt=0.622 min.

步驟2：N,N-二甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)乙胺之合成Step 2: N,N-Dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl ) Synthesis of ethylamine

Figure 110128222-A0202-12-1339-320
Figure 110128222-A0202-12-1339-320

將乙酸鉀(4.39g，44.71mmol，2.79mL)添加到2-(4-溴苯基)-N,N -二甲基乙胺(5.1g，22.36mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(7.38g，29.06mmol)於二噁烷(150mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加Pd(dppf)Cl2 *DCM(817.89mg，1.12mmol)。將所得混合物在100℃、惰性氣氛下攪拌12h，然後冷卻且在真空中蒸發，倒入到水(200ml)中且用DCM(2x100ml)萃取。將經合併之有機萃取物用水(150ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物N,N -二甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]乙胺(5.5g，19.99mmol，89.40%產率)。Potassium acetate (4.39 g, 44.71 mmol, 2.79 mL) was added to 2-(4-bromophenyl) -N,N -dimethylethylamine (5.1 g, 22.36 mmol) and 4,4,5,5- Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A solution of cyclopentane (7.38 g, 29.06 mmol) in dioxane (150 mL). The reaction flask was evacuated and refilled with argon 3 times. Pd(dppf)Cl2*DCM ( 817.89 mg, 1.12 mmol) was then added under argon flow. The resulting mixture was stirred at 100°C under inert atmosphere for 12h, then cooled and evaporated in vacuo, poured into water (200ml) and extracted with DCM (2x100ml). The combined organic extracts were washed with water (150 ml), dried over sodium sulfate and evaporated in vacuo to give the product N,N -dimethyl-2-[4-(4,4,5,5-tetramethyl] yl-1,3,2-dioxaborol-2-yl)phenyl]ethanamine (5.5 g, 19.99 mmol, 89.40% yield).

LCMS(ESI)：[M]+ m/z：計算值275.2；實測值276.2；Rt=0.974min。LCMS (ESI): [M] + m/z: calculated 275.2; found 276.2; Rt=0.974 min.

步驟3：6-(4-(2-(二甲胺基)乙基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: Synthesis of 6-(4-(2-(dimethylamino)ethyl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1340-321
Figure 110128222-A0202-12-1340-321

將N,N -二甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]乙胺(3g，10.90mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(8.28g，23.98mmol)一起混合於二噁烷(95mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(5mL)中之碳酸鈉(2.31g，21.80mmol，913.39uL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(398.83mg，545.07umol)。將反應混合物在氬氣、90℃下攪拌48h，然後冷卻且在真空中蒸發，將其倒入水(180ml)中且用EtOAc(2x150ml)萃取。將 經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下4g粗產物，4g粗產物藉由矽膠管柱層析使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到6-[4-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0.35g，1.02mmol，9.32%產率)。 N,N -dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl Amine (3 g, 10.90 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (8.28 g, 23.98 mmol) in dioxane (95 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (2.31 g, 21.80 mmol, 913.39 uL) in water (5 mL) and [1,1'-bis() were added under argon. Diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (398.83 mg, 545.07 umol). The reaction mixture was stirred under argon at 90°C for 48h, then cooled and evaporated in vacuo, poured into water (180ml) and extracted with EtOAc (2x150ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 4g of crude product which was subjected to silica gel column chromatography using a hexane/MTBE gradient (10- 100% MTBE) to give 6-[4-[2-(dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid Tributyl ester (0.35 g, 1.02 mmol, 9.32% yield).

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=1.139min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=1.139 min.

步驟4：N,N-二甲基-2-(4-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)乙胺之合成Step 4: Synthesis of N,N-dimethyl-2-(4-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)ethanamine

Figure 110128222-A0202-12-1341-322
Figure 110128222-A0202-12-1341-322

將6-[4-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(0.35g，1.02mmol)於DCM(20mL)及TFA(20g，175.41mmol，13.51mL)中之溶液在0℃下攪拌5h，然後在真空中蒸發。將碎冰(50g)添加到殘餘物中且將pH用10%碳酸氫鈉水溶液調節至8。將所得混合物用MTBE(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到N,N -二甲基-2-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]乙胺(0.248g，1.01mmol，99.89%產率)。6-[4-[2-(Dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (0.35 g, 1.02 mmol) in DCM (20 mL) and TFA (20 g, 175.41 mmol, 13.51 mL) was stirred at 0 °C for 5 h, then evaporated in vacuo. Crushed ice (50 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate. The resulting mixture was extracted with MTBE (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N,N -dimethyl-2-[4-(3-methyl-2,3,4,5-tetrahydropyridine- 6-yl)phenyl]ethanamine (0.248 g, 1.01 mmol, 99.89% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.01(d,3H),1.22(m,1H),1.38(m,1H),1.95(m,1H),2.29(s,6H),2.53(m,3H),2.82(m,3H),3.28(m,1H),3.93(m,1H),7.21(m,2H),7.70(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.01(d,3H), 1.22(m,1H), 1.38(m,1H), 1.95(m,1H), 2.29(s,6H), 2.53( m, 3H), 2.82 (m, 3H), 3.28 (m, 1H), 3.93 (m, 1H), 7.21 (m, 2H), 7.70 (m, 2H).

步驟5：N,N-二甲基-2-(4-(5-甲基哌啶-2-基)苯基)乙胺之合成Step 5: Synthesis of N,N-dimethyl-2-(4-(5-methylpiperidin-2-yl)phenyl)ethanamine

Figure 110128222-A0202-12-1342-323
Figure 110128222-A0202-12-1342-323

在0℃下，將硼氫化鈉(84.46mg，2.23mmol，78.94uL)一次性添加到N,N -二甲基-2-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]乙胺(0.248g，1.01mmol)於MeOH(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌5h，然後在真空中蒸發。將殘餘物用水(40mL)稀釋且用DCM(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到N,N -二甲基-2-[4-(5-甲基-2-哌啶基)苯基]乙胺(0.2g，811.72umol，79.99%產率)。At 0 °C, sodium borohydride (84.46 mg, 2.23 mmol, 78.94 uL) was added in one portion to N,N -dimethyl-2-[4-(3-methyl-2,3,4,5- In a stirred solution of tetrahydropyridin-6-yl)phenyl]ethanamine (0.248 g, 1.01 mmol) in MeOH (20 mL). The resulting mixture was stirred at 0 °C for 5 h, then evaporated in vacuo. The residue was diluted with water (40 mL) and extracted with DCM (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N,N -dimethyl-2-[4-(5-methyl-2-piperidinyl)phenyl]ethanamine ( 0.2 g, 811.72 umol, 79.99% yield).

LCMS(ESI)：[M]+ m/z：計算值246.2；實測值247.2；Rt=0.344min。LCMS (ESI): [M] + m/z: calculated 246.2; found 247.2; Rt=0.344 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(4-(吡啶-4-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1233)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(4-(pyridin-4-yl)phenyl)piperidine-1- Synthesis of yl)-2-oxoacetamide (Compound 1233)

將2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(158.43mg，811.72umol)及N,N -二甲基-2-[4-(5-甲基-2-哌啶基)苯基]乙胺(0.2g，811.72umol)混合於DMF(15mL)中。將反應懸浮液冷卻至20℃且添加HATU(339.50mg，892.89umol)，隨後添加TEA(328.55mg，3.25mmol，452.55uL)，且在環境溫度下攪拌7h。將反應混合物在真空中蒸發且藉由製備型(30-30-80% 0-1-6min H2 O/MeOH，流速：30ml/mi)純化0.5g所獲得之粗產物，以得到產物N -(6-胺基-5-甲基-3-吡啶基)-2-[2-[4-[2-(二甲胺基)乙基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.1175g，277.42umol，34.18%產率)。2-[(6-Amino-5-methyl-3-pyridinyl)amino]-2-oxoacetic acid (158.43 mg, 811.72 umol) and N,N -dimethyl-2-[4 -(5-Methyl-2-piperidinyl)phenyl]ethanamine (0.2 g, 811.72 umol) was mixed in DMF (15 mL). The reaction suspension was cooled to 20°C and HATU (339.50 mg, 892.89 umol) was added followed by TEA (328.55 mg, 3.25 mmol, 452.55 uL) and stirred at ambient temperature for 7 h. The reaction mixture was evaporated in vacuo and 0.5 g of the obtained crude product was purified by prep (30-30-80% 0-1-6 min H2O /MeOH, flow rate: 30 ml/mi) to give product N- (6-Amino-5-methyl-3-pyridyl)-2-[2-[4-[2-(dimethylamino)ethyl]phenyl]-5-methyl-1-piperidine yl]-2-oxoacetamide (0.1175 g, 277.42 umol, 34.18% yield).

化合物1233 ： Compound 1233 :

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96-1.05(m,3H),1.25-1.39(m,1H),1.58 -1.69(m,1H),1.80-1.91(m,1H),1.97-2.03(m,3H),2.05-2.13(m,1H),2.14-2.16(m,6H),2.17-2.28(m,1H),2.41-2.44(m,2H),2.65-2.70(m,2H),2.72-3.21(m,1H),3.39-4.04(m,1H),5.06-5.57(m,1H),5.58-5.72(m,2H),7.17-7.25(m,4H),7.42-7.54(m,1H),7.92-8.07(m,1H),10.42-10.55(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96-1.05(m,3H), 1.25-1.39(m,1H), 1.58-1.69(m,1H), 1.80-1.91(m,1H) ,1.97-2.03(m,3H),2.05-2.13(m,1H),2.14-2.16(m,6H),2.17-2.28(m,1H),2.41-2.44(m,2H),2.65-2.70( m, 2H), 2.72-3.21(m, 1H), 3.39-4.04(m, 1H), 5.06-5.57(m, 1H), 5.58-5.72(m, 2H), 7.17-7.25(m, 4H), 7.42-7.54 (m, 1H), 7.92-8.07 (m, 1H), 10.42-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=1.704min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=1.704 min.

步驟7：掌性分離(化合物1322及化合物1358)Step 7: Chiral separation (compound 1322 and compound 1358)

對外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[4-[2-(二甲胺基)乙基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0979g，231.14μmol)進行掌性分離(管柱：Chiralpak AD-H(250-20mm-5m)；流動相：IPA-MeOH，50-50流速：12mL/min)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[4-[2-(二甲胺基)乙基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.04862g，114.79μmol，49.66%產率)及N -(6-胺基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.05775g，124.60umol，50.22%產率)。Racemic N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[4-[2-(dimethylamino)ethyl]phenyl ]-5-methyl-1-piperidinyl]-2-oxoacetamide (0.0979 g, 231.14 μmol) for chiral separation (column: Chiralpak AD-H (250-20 mm-5 m); flow Phase: IPA-MeOH, 50-50 Flow rate: 12 mL/min) to obtain N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R,5S )-2-[4 -[2-(Dimethylamino)ethyl]phenyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (0.04862 g, 114.79 μmol, 49.66% yield) and N- (6-Amino-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazole-5- yl]-1-piperidinyl]-2-oxoacetamide (0.05775 g, 124.60 umol, 50.22% yield).

化合物1322於分析條件下(管柱：AD-H，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為52.72min且化合物1358之保留時間為36.60min。The retention time of compound 1322 under analytical conditions (column: AD-H, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 52.72 min and the retention time of compound 1358 was 36.60 min.

化合物1322：Compound 1322:

保留時間：52.72minRetention time: 52.72min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.2(m,3H),1.22-1.36(m,2H),1.63-1.88(m,2H),1.98-2.26(m,10H),2.37-2.44(m,2H),2.65-2.72(m,2H),3.18-3.21(m,1H),3.42-4.01(m,1H),5.10-5.62(m,3H),7.18-7.25(m,4H),7.44-7.49(d,1H),7.96-8.02(d,1H),10.46-10.49(d,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.2(m,3H), 1.22-1.36(m,2H), 1.63-1.88(m,2H), 1.98-2.26(m,10H) ,2.37-2.44(m,2H),2.65-2.72(m,2H),3.18-3.21(m,1H),3.42-4.01(m,1H),5.10-5.62(m,3H),7.18-7.25( m, 4H), 7.44-7.49 (d, 1H), 7.96-8.02 (d, 1H), 10.46-10.49 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=2.040min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=2.040 min.

化合物1358：Compound 1358:

保留時間：36.60minRetention time: 36.60min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.02(m,3H),1.22-1.36(m,2H),1.63-1.88(m,2H),1.98-2.26(m,10H),2.41-2.44(m,2H),2.65-2.71(m,2H)3.18-3.21(m,1H),3.42-4.01(m,1H),5.10-5.62(m,3H),7.18-7.25(m,4H),7.44-7.49(d,1H),7.96-8.02(d,1H),10.45-10.49(d,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.02(m,3H), 1.22-1.36(m,2H), 1.63-1.88(m,2H), 1.98-2.26(m,10H) ,2.41-2.44(m,2H),2.65-2.71(m,2H)3.18-3.21(m,1H),3.42-4.01(m,1H),5.10-5.62(m,3H),7.18-7.25(m , 4H), 7.44-7.49(d, 1H), 7.96-8.02(d, 1H), 10.45-10.49(d, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=2.051min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=2.051 min.

實例250. N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(1-甲基哌啶-4-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物 1149、化合物1253及化合物1291)之合成 Example 250. N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(1-methylpiperidin-4-yl)phenyl) Synthesis of piperidin-1-yl)-2-oxoacetamide (Compound 1149 , Compound 1253 and Compound 1291)

Figure 110128222-A0202-12-1344-324
Figure 110128222-A0202-12-1344-324

步驟1：5-甲基-2-(3-(1-甲基-1,2,3,6-四氫吡啶-4-基)苯基)哌啶-1-甲群第三丁酯之合成Step 1: 5-methyl-2-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)piperidine-1-methanthyl tert-butyl ester synthesis

將1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H-吡啶(314.89mg，1.41mmol)、2-(3-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(0.5g，1.41mmol)及碳酸鈉(448.75mg，4.23mmol，177.37uL)添加到水(5mL)及二噁烷(15mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 DCM(57.63mg，70.57umol)。將反應混合物在氬氣、70℃下攪拌16h，然後冷卻且過濾。將濾餅用二噁烷(2*20ml)洗滌且丟棄。將濾液在真空中蒸發，以得到呈黃色油狀物之5-甲基-2-[3-(1-甲基-3,6-二氫-2H-吡啶-4-基)苯基]哌啶-1-甲酸第三丁酯(0.45g，1.21mmol，86.05%產率)，其不經純化即用於下一步驟中。1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro-2H- Pyridine (314.89 mg, 1.41 mmol), tert-butyl 2-(3-bromophenyl)-5-methylpiperidine-1-carboxylate (0.5 g, 1.41 mmol) and sodium carbonate (448.75 mg, 4.23 mmol, 177.37 uL) was added to a mixture of water (5 mL) and dioxane (15 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf) Cl2DCM (57.63 mg, 70.57 umol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 16 h, then cooled and filtered. The filter cake was washed with dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 5-methyl-2-[3-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)phenyl]piperidine as a yellow oil 3-butyl pyridine-1-carboxylate (0.45 g, 1.21 mmol, 86.05% yield) was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值370.2；實測值371.2；Rt=1.094min。LCMS (ESI): [M] + m/z: calculated 370.2; found 371.2; Rt=1.094 min.

步驟2：5-甲基-2-(3-(1-甲基哌啶-4-基)苯基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 5-methyl-2-(3-(1-methylpiperidin-4-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

將5-甲基-2-[3-(1-甲基-3,6-二氫-2H-吡啶-4-基)苯基]哌啶-1-甲酸第三丁酯(0.45g，1.21mmol)溶解於MeOH(30mL)中且添加10%鈀/碳(129.25mg，1.21mmol)。將所得混合物抽真空，然後用H2回填，且將其在室溫下攪拌48h。然後將其蒸發，以得到5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]哌啶-1-甲酸第三丁酯(0.4g，1.07mmol，88.41%產率)。5-Methyl-2-[3-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.45 g, 1.21 mmol) was dissolved in MeOH (30 mL) and 10% palladium on carbon (129.25 mg, 1.21 mmol) was added. The resulting mixture was evacuated, then backfilled with H2, and it was stirred at room temperature for 48 h. It was then evaporated to give tert-butyl 5-methyl-2-[3-(1-methyl-4-piperidinyl)phenyl]piperidine-1-carboxylate (0.4 g, 1.07 mmol, 88.41 g %Yield).

LCMS(ESI)：[M]+ m/z：計算值372.2；實測值373.2；Rt=1.134min。LCMS (ESI): [M] + m/z: calculated 372.2; found 373.2; Rt=1.134 min.

步驟3：1-甲基-4-(3-(5-甲基哌啶-2-基)苯基)哌啶之合成Step 3: Synthesis of 1-methyl-4-(3-(5-methylpiperidin-2-yl)phenyl)piperidine

將5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]哌啶-1-甲酸第三丁酯(0.4g，1.07mmol)溶解於MeOH(20mL)中且添加二噁烷/HCl(1.07mmol，5mL)。然後將其蒸發且使其經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以水-MeOH+NH3 為溶析液混合物)，以得到1-甲基-4-[3-(5-甲基-2-哌啶基)苯基]哌啶(107.4mg，394.23umol，36.72%產率)。5-Methyl-2-[3-(1-methyl-4-piperidinyl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.07 mmol) was dissolved in MeOH (20 mL) And dioxane/HCl (1.07 mmol, 5 mL) was added. It was then evaporated and subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with water-MeOH+ NH3 as eluent mixture) to give 1-methyl-4-[3-(5-methan yl-2-piperidinyl)phenyl]piperidine (107.4 mg, 394.23 umol, 36.72% yield).

LCMS(ESI)：[M]+ m/z：計算值272.2；實測值273.2；Rt=1.334min。LCMS (ESI): [M] + m/z: calculated 272.2; found 273.2; Rt=1.334 min.

步驟4：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(1-甲基哌啶-4-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1149)之合成Step 4: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(1-methylpiperidin-4-yl)phenyl) Synthesis of piperidin-1-yl)-2-oxoacetamide (compound 1149)

將DIPEA(127.38mg，985.58umol，171.67uL)添加到相應2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(76.94mg，394.23umol)及1-甲基-4-[3-(5-甲基-2-哌啶基)苯基]哌啶(107.4mg，394.23umol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(164.89mg，433.66umol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH+NH3 為溶析液混合物)，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5- 甲基-2-[3-(1-甲基-4-哌啶基)苯基]-1-哌啶基]-2-側氧基乙醯胺(40.4mg，89.86umol，22.79%產率)。DIPEA (127.38 mg, 985.58 umol, 171.67 uL) was added to the corresponding 2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (76.94 mg, 394.23 umol) ) and 1-methyl-4-[3-(5-methyl-2-piperidinyl)phenyl]piperidine (107.4 mg, 394.23 umol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (164.89 mg, 433.66 umol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH+ NH3 as eluent mixture) to give N- (6-amino-5-methyl-3-pyridyl) -2-[( 2S,5R )-5-methyl-2-[3-(1-methyl-4-piperidinyl)phenyl]-1-piperidinyl]-2-side oxyacetyl Amine (40.4 mg, 89.86 umol, 22.79% yield).

化合物1149：Compound 1149:

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.82-1.02(m,3H),1.29-1.40(m,1H),1.61-1.71(m,4H),1.83-2.03(m,6H),2.17-2.26(m,4H),2.44(m,1H),2.70-3.22(m,4H),3.43-4.02(m,2H),5.12-5.62(m,3H),7.00-7.31(m,4H),7.44-7.50(m,1H),7.95-8.02(m,1H),10.50-10.55(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.82-1.02(m,3H), 1.29-1.40(m,1H), 1.61-1.71(m,4H), 1.83-2.03(m,6H) ,2.17-2.26(m,4H),2.44(m,1H),2.70-3.22(m,4H),3.43-4.02(m,2H),5.12-5.62(m,3H),7.00-7.31(m, 4H), 7.44-7.50 (m, 1H), 7.95-8.02 (m, 1H), 10.50-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=2.102min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=2.102 min.

步驟5：掌性分離(化合物1253及化合物1291)Step 5: Chiral separation (compound 1253 and compound 1291)

對外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]-1-哌啶基]-2-側氧基乙醯胺(34.6mg，76.96μmol)進行掌性分離(管柱：Chiralpak AD-H-V(250*20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25流速：12mL/min)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]-1-哌啶基]-2-側氧基乙醯胺(13.99mg，31.12μmol，40.43%產率)(RT=17.07min)及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]-1-哌啶基]-2-側氧基乙醯胺(12.8mg，28.47μmol，36.99%產率)(RT=22.83min)。Racemic N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-[3-(1-methyl-4-piperidine Chiral separation (column: Chiralpak AD-HV (250*20mm, 5mkm); flow Phase: Hexane-IPA-MeOH 50-25-25 Flow rate: 12 mL/min) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )- 5-Methyl-2-[3-(1-methyl-4-piperidinyl)phenyl]-1-piperidinyl]-2-oxyacetamide (13.99 mg, 31.12 μmol, 40.43% Yield) (RT=17.07 min) and N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[3-(1 -Methyl-4-piperidinyl)phenyl]-1-piperidinyl]-2-oxoacetamide (12.8 mg, 28.47 μmol, 36.99% yield) (RT=22.83 min).

化合物1253於分析條件下(管柱：AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為22.91min且化合物1291之保留時間為16.11min。The retention time of compound 1253 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 22.91 min and the retention time of compound 1291 was 16.11 min .

化合物1253：Compound 1253:

保留時間：22.91minRetention time: 22.91min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.04(m,3H),1.22-1.40(m,1H),1.60-1.73(m,5H),1.79-1.90(m,1H),1.90-2.06(m,6H),2.06-2.18(m,1H),2.20(s,3H),2.21-2.29(m,1H),2.69-2.74(m,0.4H),2.84-2.90(m,2H),3.19-3.23(m, 0.6H),3.41-4.03(m,1H),5.08-5.57(m,1H),5.57-5.67(m,2H),7.08-7.19(m,3H),7.26-7.33(m,1H),7.41-7.54(m,1H),7.92-8.06(m,1H),10.46-10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.04(m,3H), 1.22-1.40(m,1H), 1.60-1.73(m,5H), 1.79-1.90(m,1H) ,1.90-2.06(m,6H),2.06-2.18(m,1H),2.20(s,3H),2.21-2.29(m,1H),2.69-2.74(m,0.4H),2.84-2.90(m , 2H), 3.19-3.23(m, 0.6H), 3.41-4.03(m, 1H), 5.08-5.57(m, 1H), 5.57-5.67(m, 2H), 7.08-7.19(m, 3H), 7.26-7.33(m,1H), 7.41-7.54(m,1H), 7.92-8.06(m,1H), 10.46-10.54(m,1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=2.009min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=2.009 min.

化合物1291：Compound 1291:

保留時間：16.11minRetention time: 16.11min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.26-1.40(m,1H),1.60-1.73(m,5H),1.81-1.92(m,1H),1.94-2.04(m,5H),2.04-2.17(m,1H),2.20(s,3H),2.21-2.29(m,1H),2.42-2.45(m,1H),2.70-2.74(m,0.4H),2.83-2.90(m,2H),3.19-3.23(m,0.6H),3.41-4.06(m,1H),5.10-5.57(m,1H),5.57-5.65(m,2H),7.07-7.14(m,2H),7.14-7.21(m,1H),7.24-7.35(m,1H),7.42-7.52(m,1H),7.94-8.05(m,1H),10.41-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.05(m,3H), 1.26-1.40(m,1H), 1.60-1.73(m,5H), 1.81-1.92(m,1H) ,1.94-2.04(m,5H),2.04-2.17(m,1H),2.20(s,3H),2.21-2.29(m,1H),2.42-2.45(m,1H),2.70-2.74(m, 0.4H), 2.83-2.90(m, 2H), 3.19-3.23(m, 0.6H), 3.41-4.06(m, 1H), 5.10-5.57(m, 1H), 5.57-5.65(m, 2H), 7.07-7.14(m, 2H), 7.14-7.21(m, 1H), 7.24-7.35(m, 1H), 7.42-7.52(m, 1H), 7.94-8.05(m, 1H), 10.41-10.57(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=2.007min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=2.007 min.

實例251. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-(4-甲基哌嗪-1-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物 1230)之合成 Example 251. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(4-methylpiperazine-1 Synthesis of -yl)phenyl)piperidin-1-yl)-2-side oxyacetamide (compound 1230 )

Figure 110128222-A0202-12-1347-325
Figure 110128222-A0202-12-1347-325

將1-甲基-4-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]哌嗪(130mg，475.47μmol)溶解於DMF(5mL)中且添加TEA(481.13mg，4.75mmol，662.71μL)，隨後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(99.47mg，475.47μmol)。然後，逐滴添加HATU(271.18mg，713.20μmol)且將反應混合物攪拌隔 夜。次日，將其在真空中蒸發且藉由HPLC(2-10min 34-45%水/MeOH+NH3 ；30ml/min；裝載泵MeOH 4ml/min；管柱SunFire 19*100mm)純化，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(30.9mg，66.51μmol，13.99%產率)。1-Methyl-4-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]piperazine (130 mg, 475.47 μmol) was dissolved in DMF (5 mL) and TEA was added (481.13 mg, 4.75 mmol, 662.71 μL), followed by the addition of 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (99.47 mg, 475.47 μmol). Then, HATU (271.18 mg, 713.20 μmol) was added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC (2-10 min 34-45% water/MeOH+ NH3 ; 30 ml/min; loading pump MeOH 4 ml/min; column SunFire 19*100 mm) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[3-(4-methylpiperazin-1-yl) Phenyl]-1-piperidinyl]-2-oxoacetamide (30.9 mg, 66.51 μmol, 13.99% yield).

化合物1230：Compound 1230:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.04(m,3H),1.07-1.13(m,3H),1.26-1.38(m,1H),1.62-1.75(m,1H),1.80-1.92(m,1H),1.95-2.12(m,1H),2.15-2.22(m,4H),2.34-2.40(m,2H),2.40-2.44(m,4H),2.72-3.27(m,5H),3.41-4.05(m,1H),5.08-5.53(m,1H),5.57-5.67(m,2H),6.69-6.79(m,1H),6.79-6.85(m,2H),7.17-7.23(m,1H),7.43-7.53(m,1H),7.99-8.08(m,1H),10.49-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.04(m,3H), 1.07-1.13(m,3H), 1.26-1.38(m,1H), 1.62-1.75(m,1H) ,1.80-1.92(m,1H),1.95-2.12(m,1H),2.15-2.22(m,4H),2.34-2.40(m,2H),2.40-2.44(m,4H),2.72-3.27( m,5H),3.41-4.05(m,1H),5.08-5.53(m,1H),5.57-5.67(m,2H),6.69-6.79(m,1H),6.79-6.85(m,2H), 7.17-7.23(m,1H), 7.43-7.53(m,1H), 7.99-8.08(m,1H), 10.49-10.57(m,1H).

LCMS(ESI)：[M]+ m/z：計算值464.2；實測值465.2；Rt=0.806min。LCMS (ESI): [M] + m/z: calculated 464.2; found 465.2; Rt=0.806 min.

實例252.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-(4-甲基哌嗪-1-基)苯基)哌啶-1-基)-2-側氧基乙醯胺( 化合物1367)之合成 Example 252. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-(4-methylpiperazine-1 Synthesis of -yl)phenyl)piperidin-1-yl)-2-side oxyacetamide ( compound 1367 )

Figure 110128222-A0202-12-1348-326
Figure 110128222-A0202-12-1348-326

對N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]乙醯胺(75mg，161.43μmol)進行掌性分離(Chiralcel OJ-H-I(250*20mm，5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]乙醯胺(54mg，116.23μmol，72.00%產率)。p- N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3-(4-methyl) Piperazin-1-yl)phenyl]-1-piperidinyl]acetamide (75 mg, 161.43 μmol) was chiral (Chiralcel OJ-HI (250*20 mm, 5 mkm), hexane-IPA-MeOH, 70-15-15, 12ml/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl yl-2-[3-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]acetamide (54 mg, 116.23 μmol, 72.00% yield).

化合物1367於分析條件下(管柱：OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min 為流動相)8.51minCompound 1367 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) 8.51min

化合物1367：Compound 1367:

保留時間：8.51minRetention time: 8.51min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.07-1.16(m,3H),1.25-1.38(m,1H),1.59-1.76(m,1H),1.79-1.92(m,1H),1.95-2.15(m,1H),2.15-2.19(m,1H),2.20(s,3H),2.34-2.38(m,1H),2.40-2.45(m,5H),2.73-2.77(m,0.3H),3.03-3.14(m,4H),3.23-3.27(m,0.7H),3.43-4.04(m,1H),5.08-5.55(m,1H),5.58-5.66(m,2H),6.68-6.78(m,1H),6.79-6.84(m,2H),7.14-7.25(m,1H),7.41-7.54(m,1H),7.94-8.10(m,1H),10.44-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.03(m,3H), 1.07-1.16(m,3H), 1.25-1.38(m,1H), 1.59-1.76(m,1H) ,1.79-1.92(m,1H),1.95-2.15(m,1H),2.15-2.19(m,1H),2.20(s,3H),2.34-2.38(m,1H),2.40-2.45(m, 5H), 2.73-2.77(m, 0.3H), 3.03-3.14(m, 4H), 3.23-3.27(m, 0.7H), 3.43-4.04(m, 1H), 5.08-5.55(m, 1H), 5.58-5.66(m, 2H), 6.68-6.78(m, 1H), 6.79-6.84(m, 2H), 7.14-7.25(m, 1H), 7.41-7.54(m, 1H), 7.94-8.10(m , 1H), 10.44-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值464.2；實測值465.2；Rt=1.766min。LCMS (ESI): [M] + m/z: calculated 464.2; found 465.2; Rt=1.766 min.

實例253. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-氯-4-(2-(二甲胺基)乙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1402)之合成Example 253. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-chloro-4-(2-(dimethylamino)ethyl) Synthesis of phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1402)

Figure 110128222-A0202-12-1349-327
Figure 110128222-A0202-12-1349-327

步驟1：2-(4-溴-2-氯苯基)-N,N-二甲基乙胺之合成Step 1: Synthesis of 2-(4-bromo-2-chlorophenyl)-N,N-dimethylethylamine

Figure 110128222-A0202-12-1349-328
Figure 110128222-A0202-12-1349-328

向2-(4-溴-2-氯苯基)乙胺(1g，4.26mmol)於甲酸(30mL)中之溶液中添加用7-8% MeOH穩定之37% w/w甲醛水溶液(256.10mg，8.53mmol，236.47 μL)。在100℃下攪拌24h之後，將反應混合物蒸發且倒入到H2 O(200ml)中且將pH用10%碳酸氫鈉水溶液調節至9，用MTBE(50ml*2)萃取且將經合併之有機層用H2 O(40ml*2)洗滌，乾燥且濃縮，以得到產物2-(4-溴-2-氯苯基)-N,N -二甲基乙胺(0.6g，2.29mmol，53.59%產率)。To a solution of 2-(4-bromo-2-chlorophenyl)ethanamine (1 g, 4.26 mmol) in formic acid (30 mL) was added 37% w/w aqueous formaldehyde (256.10 mg) stabilized with 7-8% MeOH , 8.53 mmol, 236.47 μL). After stirring at 100°C for 24h, the reaction mixture was evaporated and poured into H2O (200ml) and the pH was adjusted to 9 with 10% aqueous sodium bicarbonate, extracted with MTBE (50ml*2) and the combined The organic layer was washed with H2O (40 ml*2), dried and concentrated to give the product 2-(4-bromo-2-chlorophenyl) -N,N -dimethylethylamine (0.6 g, 2.29 mmol, 53.59% yield).

LCMS(ESI)：[M]+ m/z：計算值262.2；實測值263.2；Rt=2.009min。LCMS (ESI): [M] + m/z: calculated 262.2; found 263.2; Rt=2.009 min.

步驟2：2-(2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)-N,N-二甲基乙胺之合成Step 2: 2-(2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)-N, Synthesis of N-dimethylethylamine

Figure 110128222-A0202-12-1350-329
Figure 110128222-A0202-12-1350-329

將乙酸鉀(3.59g，36.56mmol，2.29mL)添加到2-(4-溴-2-氯苯基)-N,N -二甲基乙胺(4.8g，18.28mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(5.57g，21.94mmol)於二噁烷(200mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加Pd(dppf)Cl2 *DCM(1.34g，1.83mmol)。將所得混合物在100℃、惰性氣氛下攪拌12h，然後冷卻且在真空中蒸發，倒入到水(300ml)中且用DCM(2x80ml)萃取。將經合併之有機萃取物用水(80ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物2-[2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-N,N -二甲基乙胺(7.2g，粗品)。Potassium acetate (3.59 g, 36.56 mmol, 2.29 mL) was added to 2-(4-bromo-2-chlorophenyl) -N,N -dimethylethylamine (4.8 g, 18.28 mmol) and 4,4, 5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-di A solution of oxaborolane (5.57 g, 21.94 mmol) in dioxane (200 mL). The reaction flask was evacuated and refilled with argon 3 times. Then Pd(dppf)Cl2*DCM (1.34 g , 1.83 mmol) was added under argon flow. The resulting mixture was stirred at 100°C under inert atmosphere for 12h, then cooled and evaporated in vacuo, poured into water (300ml) and extracted with DCM (2x80ml). The combined organic extracts were washed with water (80 ml), dried over sodium sulfate and evaporated in vacuo to give the product 2-[2-chloro-4-(4,4,5,5-tetramethyl-1 , 3,2-Dioxaborol-2-yl)phenyl] -N,N -dimethylethylamine (7.2 g, crude).

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=1.074min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=1.074 min.

步驟3：(S)-6-(3-氯-4-(2-(二甲胺基)乙基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(3-Chloro-4-(2-(dimethylamino)ethyl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)- Synthesis of tert-butyl formate

Figure 110128222-A0202-12-1351-330
Figure 110128222-A0202-12-1351-330

將2-[2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-N,N -二甲基乙胺(3g，9.69mmol)及(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.35g，9.69mmol)一起混合於二噁烷(90mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(10mL)中之碳酸鈉(2.05g，19.38mmol，811.14μL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(354.46mg，484.44μmol)。將反應混合物在氬氣、90℃下攪拌18h，然後冷卻且在真空中蒸發，將其倒入水(180ml)中且用EtOAc(2x150ml)萃取。將經合併之有機萃取物用水(2*40ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下4.2g粗產物，4.2g粗產物藉由矽膠管柱層析使用MTBE/MeOH梯度(10-100% MeOH)進行純化，以得到(3S )-6-[3-氯-4-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.1g，2.90mmol，29.96%產率)。2-[2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl] -N,N- Dimethylethylamine (3 g, 9.69 mmol) and ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid Tributyl ester (3.35 g, 9.69 mmol) was mixed together in dioxane (90 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (2.05 g, 19.38 mmol, 811.14 μL) in water (10 mL) and [1,1′-bis(1,1′-bis() were added under argon Diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (354.46 mg, 484.44 [mu]mol). The reaction mixture was stirred under argon at 90°C for 18h, then cooled and evaporated in vacuo, poured into water (180ml) and extracted with EtOAc (2x150ml). The combined organic extracts were washed with water (2*40ml), dried over sodium sulfate and evaporated in vacuo to leave 4.2g of crude product which was subjected to silica gel column chromatography using a MTBE/MeOH gradient (10 -100% MeOH) to give ( 3S )-6-[3-chloro-4-[2-(dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro - 3 -butyl 2H -pyridine-1-carboxylate (1.1 g, 2.90 mmol, 29.96% yield).

LCMS(ESI)：[M]+ m/z：計算值378.2；實測值379.2；Rt=1.110min。LCMS (ESI): [M] + m/z: calculated 378.2; found 379.2; Rt=1.110 min.

步驟4：(S)-2-(2-氯-4-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)-N,N-二甲基乙胺之合成Step 4: (S)-2-(2-Chloro-4-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)-N,N-dimethylethyl Synthesis of Amines

Figure 110128222-A0202-12-1351-331
Figure 110128222-A0202-12-1351-331

將(3S )-6-[3-氯-4-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶 -1-甲酸第三丁 酯(1.1g，2.90mmol)於DCM(10mL)及TFA(10g，87.70mmol，6.76mL)中之溶液在0℃下攪拌8h，然後在真空中蒸發。將碎冰(50g)添加到殘餘物中且將pH用10%碳酸氫鈉水溶液調節至8。將所得混合物用MTBE(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到2-[2-氯-4-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]-N,N -二甲基乙胺(0.3g，1.08mmol，37.07%產率)。( 3S )-6-[3-Chloro-4-[2-(dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid A solution of tributyl ester (1.1 g, 2.90 mmol) in DCM (10 mL) and TFA (10 g, 87.70 mmol, 6.76 mL) was stirred at 0 &lt;0&gt;C for 8 h, then evaporated in vacuo. Crushed ice (50 g) was added to the residue and the pH was adjusted to 8 with 10% aqueous sodium bicarbonate. The resulting mixture was extracted with MTBE (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-[2-chloro-4-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridine- 6-yl]phenyl] -N,N -dimethylethylamine (0.3 g, 1.08 mmol, 37.07% yield).

LCMS(ESI)：[M]+ m/z：計算值278.2；實測值279.2；Rt=0.669min。LCMS (ESI): [M] + m/z: calculated 278.2; found 279.2; Rt=0.669 min.

步驟5：2-(2-氯-4-((2R,5S)-5-甲基哌啶-2-基)苯基)-N,N-二甲基乙胺之合成Step 5: Synthesis of 2-(2-chloro-4-((2R,5S)-5-methylpiperidin-2-yl)phenyl)-N,N-dimethylethylamine

Figure 110128222-A0202-12-1352-332
Figure 110128222-A0202-12-1352-332

在0℃下，將硼氫化鈉(81.41mg，2.15mmol，75.80μL)一次性添加到2-[2-氯-4-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]-N,N -二甲基乙胺(0.3g，1.08mmol)於MeOH(10mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌5h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用DCM(2*20mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到2-[2-氯-4-[(2R,5S )-5-甲基-2-哌啶基]苯基]-N,N -二甲基乙胺(0.15g，534.12μmol，49.64%產率)。Sodium borohydride (81.41 mg, 2.15 mmol, 75.80 μL) was added in one portion to 2-[2-chloro-4-[( 3S )-3-methyl-2,3,4,5- at 0 °C Tetrahydropyridin-6-yl]phenyl] -N,N -dimethylethylamine (0.3 g, 1.08 mmol) in a stirred solution of MeOH (10 mL). The resulting mixture was stirred at 0 °C for 5 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with DCM (2*20 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-[2-chloro-4-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]- N,N -Dimethylethylamine (0.15 g, 534.12 μmol, 49.64% yield).

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=1.250min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=1.250 min.

將2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(139.67mg，667.65μmol)及2-[2-氯-4-[(2R,5S )-5-甲基-2-哌啶基]苯基]-N,N -二甲基乙胺(0.15g，534.12μmol)混合於DMF(10mL)中。將反應懸浮液冷卻至20℃且添加HATU(253.86mg，667.65μmol)，隨後添加TEA(162.14mg，1.60mmol，223.34μL)， 且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且藉由製備型(45-90% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min)純化0.5g所獲得之粗產物，以得到產物N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[3-氯-4-[2-(二甲胺基)乙基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0702g，148.72μmol，27.84%產率)。2-[(6-Amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (139.67 mg, 667.65 μmol) and 2-[2-chloro-4-[( 2R ,5S )-5-methyl-2-piperidinyl]phenyl] -N,N -dimethylethylamine (0.15 g, 534.12 μmol) was mixed in DMF (10 mL). The reaction suspension was cooled to 20°C and HATU (253.86 mg, 667.65 μmol) was added followed by TEA (162.14 mg, 1.60 mmol, 223.34 μL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and 0.5 g of the obtained crude product was purified by preparative (45-90% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min) to give the product N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-[3-chloro-4-[2-(dimethylamino)ethyl]benzene yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (0.0702 g, 148.72 μmol, 27.84% yield).

化合物1402：Compound 1402:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.03(m,3H),1.07-1.13(m,3H),1.25-1.37(m,1H),1.57-1.66(m,1H),1.80-1.93(m,1H),1.97-2.09(m,1H),2.12-2.21(m,8H),2.35-2.40(m,2H),2.42-2.45(m,1H),2.70-3.25(m,3H),3.41-4.04(m,1H),5.09-5.53(m,1H),5.59-5.70(m,2H),7.18-7.25(m,1H),7.27-7.39(m,2H),7.42-7.53(m,1H),7.94-8.09(m,1H),10.48-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.03(m,3H), 1.07-1.13(m,3H), 1.25-1.37(m,1H), 1.57-1.66(m,1H) ,1.80-1.93(m,1H),1.97-2.09(m,1H),2.12-2.21(m,8H),2.35-2.40(m,2H),2.42-2.45(m,1H),2.70-3.25( m,3H),3.41-4.04(m,1H),5.09-5.53(m,1H),5.59-5.70(m,2H),7.18-7.25(m,1H),7.27-7.39(m,2H), 7.42-7.53 (m, 1H), 7.94-8.09 (m, 1H), 10.48-10.60 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值472.2；實測值473.2；Rt=1.885min。LCMS (ESI): [M] + m/z: calculated 472.2; found 473.2; Rt=1.885min.

實例254. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S)-5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]-1-哌啶基]乙醯胺(化合物1363)之合成Example 254. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[(2R,5S)-5-methyl-2-[3-(1- Synthesis of methyl-4-piperidinyl)phenyl]-1-piperidinyl]acetamide (compound 1363)

Figure 110128222-A0202-12-1353-333
Figure 110128222-A0202-12-1353-333

對N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]-1-哌啶基]乙醯胺(54mg，116.48μmol)進行掌性分離(Chiralpak IA-III(250*20mm，5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(1-甲基-4-哌啶基)苯基]-1-哌啶基]乙醯胺(44mg，94.91μmol，81.48%產率)(RT=31.06min)。p- N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3-(1-methyl) -4-Piperidinyl)phenyl]-1-piperidinyl]acetamide (54 mg, 116.48 μmol) chiral separation (Chiralpak IA-III (250*20 mm, 5 mkm), hexane-IPA-MeOH, 70-15-15, 12ml/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl yl-2-[3-(1-methyl-4-piperidinyl)phenyl]-1-piperidinyl]acetamide (44 mg, 94.91 μmol, 81.48% yield) (RT=31.06 min).

化合物1363於分析條件下(管柱：IA，以己烷-IPA-MeOH，70-15-15，0.6ml/min 為流動相)之保留時間為33.82minCompound 1363 under analytical conditions (column: IA with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min is the mobile phase) with a retention time of 33.82 min

化合物1363：Compound 1363:

保留時間：33.82minRetention time: 33.82min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.06-1.13(m,3H),1.27-1.37(m,1H),1.60-1.71(m,5H),1.80-2.04(m,4H),2.07-2.27(m,5H),2.39-2.44(m,2H),2.70-3.21(m,3H),3.40-4.03(m,1H),5.11-5.58(m,1H),5.58-5.66(m,2H),7.09-7.19(m,3H),7.26-7.32(m,1H),7.42-7.52(m,1H),7.97-8.07(m,1H),10.49-10.55(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.03(m,3H), 1.06-1.13(m,3H), 1.27-1.37(m,1H), 1.60-1.71(m,5H) ,1.80-2.04(m,4H),2.07-2.27(m,5H),2.39-2.44(m,2H),2.70-3.21(m,3H),3.40-4.03(m,1H),5.11-5.58( m,1H),5.58-5.66(m,2H),7.09-7.19(m,3H),7.26-7.32(m,1H),7.42-7.52(m,1H),7.97-8.07(m,1H), 10.49-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值463.2；實測值464.2；Rt=2.081min。LCMS (ESI): [M] + m/z: calculated 463.2; found 464.2; Rt=2.081 min.

實例255.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-((1-甲基吡咯啶-2-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1362)之合成Example 255. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-((1-methylpyrrolidine- Synthesis of 2-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1362)

Figure 110128222-A0202-12-1354-334
Figure 110128222-A0202-12-1354-334

步驟1：(2R,5S)-5-甲基-2-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)哌啶-1-甲酸第三丁酯之合成Step 1: (2R,5S)-5-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) ) Synthesis of 3-butyl phenyl)piperidine-1-carboxylate

Figure 110128222-A0202-12-1354-335
Figure 110128222-A0202-12-1354-335

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸第三丁 酯(3.4g，9.60mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.68g，10.56mmol)及乙酸鉀(2.35g，23.99mmol，1.50mL)一起混合於二噁烷(40.00mL)中且將所得混合物抽真空且用氬氣回填三次。將Pd(dppf)Cl2 *DCM(391.86mg，479.85μmol)添加到先前混合物中且將所得混合物在100℃下加熱隔夜。將反應混合物在真空中濃縮且將水(25mL)添加到殘餘物中。將所得混合物用MTBE(2*40mL)萃取且將經合併之有機層用水(25mL)、鹽水(25mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-5-甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁 酯(3.5g，8.72mmol，90.87%產率)。( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (3.4 g, 9.60 mmol), 4,4,5,5-tetramethyl -2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (2.68 g, 10.56 mmol) and potassium acetate (2.35 g, 23.99 mmol, 1.50 mL) were mixed together in dioxane (40.00 mL) and the resulting mixture was evacuated and backfilled with argon three times. Pd(dppf)Cl2*DCM ( 391.86 mg, 479.85 μmol) was added to the previous mixture and the resulting mixture was heated at 100 °C overnight. The reaction mixture was concentrated in vacuo and water (25 mL) was added to the residue. The resulting mixture was extracted with MTBE (2*40 mL) and the combined organic layers were washed with water (25 mL), brine (25 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain ( 2R,5S ) -5-Methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]piperidine-1 - tert -butyl formate (3.5 g, 8.72 mmol, 90.87% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值301.2；實測值302.2；Rt=1.745min。LCMS (ESI): [M-Boc] + m/z: calculated 301.2; found 302.2; Rt=1.745 min.

步驟2：(2R,5S)-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-2-(3-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1355-336
Figure 110128222-A0202-12-1355-336

將(2R,5S )-5-甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁 酯(3.7g，9.22mmol)溶解於THF(50.73mL)中且在室溫下小心地逐滴添加35%過氧化氫(1.34g，13.83mmol，1.22mL，35%純度)。添加完成之後，將反應混合物攪拌1h且在室溫下逐滴添加氫氧化鈉珠之水溶液(590.01mg，14.75mmol，277.00μL)。添加完成之後，將反應混合物攪拌1h。將反應混合物用檸檬酸酸化且將所得混合物轉移至分離漏斗。分離有機層且將水層用MTBE(2*40mL)萃取。將經合併之有機層用亞硫酸鈉水溶液洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1- 甲酸第三丁 酯(3g，粗品)。( 2R,5S )-5-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene tert- butyl ]piperidine-1-carboxylate (3.7 g, 9.22 mmol) was dissolved in THF (50.73 mL) and 35% hydrogen peroxide (1.34 g, 13.83 mmol, 1.22 % hydrogen peroxide (1.34 g, 13.83 mmol, 1.22 mL) was carefully added dropwise at room temperature mL, 35% pure). After the addition was complete, the reaction mixture was stirred for 1 h and an aqueous solution of sodium hydroxide beads (590.01 mg, 14.75 mmol, 277.00 μL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred for 1 h. The reaction mixture was acidified with citric acid and the resulting mixture was transferred to a separation funnel. The organic layer was separated and the aqueous layer was extracted with MTBE (2*40 mL). The combined organic layers were washed with aqueous sodium sulfite, dried over Na2SO4 , filtered and concentrated in vacuo to give ( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine- 3 -Butyl 1-carboxylate (3 g, crude).

LCMS(ESI)：[M-Boc]+ m/z：計算值191.2；實測值192.2；Rt=1.482min。LCMS (ESI): [M-Boc] + m/z: calculated 191.2; found 192.2; Rt=1.482 min.

步驟3：(2R,5S)-5-甲基-2-(3-((外消旋-S)-1-甲基吡咯啶-2-基)甲氧基)苯基)哌啶-1-甲第第三丁酯之合成Step 3: (2R,5S)-5-methyl-2-(3-((rac-S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)piperidine-1 -Synthesis of methyl tertiary butyl ester

Figure 110128222-A0202-12-1356-337
Figure 110128222-A0202-12-1356-337

將(2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁 酯(0.75g，2.57mmol)溶解於DMF(10mL)中且向其中添加3-溴-1-甲基哌啶(1.33g，5.15mmol，HBr)，隨後添加碳酸銫(3.35g，10.30mmol)。將所得混合物在50℃下加熱隔夜。將反應混合物倒入到水(5mL)中且將所得混合物用EtOAc(3*20mL)萃取。將經合併之有機層用水(3*10mL)、鹽水(10mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (0.75 g, 2.57 mmol) was dissolved in DMF (10 mL) and to it was added 3 -Bromo-1-methylpiperidine (1.33 g, 5.15 mmol, HBr) followed by the addition of cesium carbonate (3.35 g, 10.30 mmol). The resulting mixture was heated at 50°C overnight. The reaction mixture was poured into water (5 mL) and the resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were washed with water (3*10 mL), brine (10 mL), dried over Na2SO4 , filtered and concentrated in vacuo.

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=1.063min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=1.063 min.

步驟4：(2R,5S)-5-甲基-2-(3-(((外消旋-S)-1-甲基吡咯啶-2-基)甲氧基)苯基)哌啶之合成Step 4: (2R,5S)-5-methyl-2-(3-(((rac-S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)piperidine synthesis

Figure 110128222-A0202-12-1356-338
Figure 110128222-A0202-12-1356-338

將(2R,5S )-5-甲基-2-[3-[[外消旋 -(2S )-1-甲基吡咯啶-2-基]甲氧基]苯基]哌啶-1-甲酸第三丁 酯(550.00mg，1.42mmol)溶解於DCM(5mL)中且向其中 添加TFA(3mL)。攪拌所得混合物1h。將反應混合物小心倒入NaHCO3 水溶液(3g於10mL水中)且將所得混合物用DCM(2*15mL)萃取。將經合併之有機層經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-5-甲基-2-[3-[[外消旋 -(2S )-1-甲基吡咯啶-2-基]甲氧基]苯基]哌啶(350mg，1.21mmol，85.73%產率)。( 2R,5S )-5-methyl-2-[3-[[ rac- ( 2S )-1-methylpyrrolidin-2-yl]methoxy]phenyl]piperidine-1- 3 -Butyl formate (550.00 mg, 1.42 mmol) was dissolved in DCM (5 mL) and TFA (3 mL) was added to it. The resulting mixture was stirred for 1 h. The reaction mixture was poured carefully into aqueous NaHCO 3 (3 g in 10 mL water) and the resulting mixture was extracted with DCM (2*15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain ( 2R,5S )-5-methyl-2-[3-[[ rac- ( 2S )-1-methyl Pyrrolidin-2-yl]methoxy]phenyl]piperidine (350 mg, 1.21 mmol, 85.73% yield).

LCMS(ESI)：[M]+ m/z：計算值288.2；實測值289.2；Rt=0.685min。LCMS (ESI): [M] + m/z: calculated 288.2; found 289.2; Rt=0.685min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-((1-甲基吡咯啶-2-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1362)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-((1-methylpyrrolidine- Synthesis of 2-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1362)

Figure 110128222-A0202-12-1357-339
Figure 110128222-A0202-12-1357-339

將(2R,5S )-5-甲基-2-[3-[[外消旋 -(2S )-1-甲基吡咯啶-2-基]甲氧基]苯基]哌啶(0.35g，1.21mmol)溶解於DMF(5mL)中且添加TEA(1.23g，12.13mmol，1.69mL)，隨後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(253.86mg，1.21mmol)。然後逐滴添加HATU(692.10mg，1.82mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC(2-10min 35-60% MeOH+NH3 30mL/min(裝載泵4mL MeOH+NH3 )管柱：SunFire 100*19mm，5微米)純化，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-[[外消旋 -(2S )-1-甲基吡咯啶-2-基]甲氧基]苯基]-1-哌啶基]乙醯胺(56.4mg，117.59μmol，9.69%產率)及N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-[[外消旋 -(2S )-1-甲基吡咯啶-2-基]甲氧基]苯基]-1-哌啶基]乙醯胺(84.6mg，176.39μmol，14.54%產率)。( 2R,5S )-5-methyl-2-[3-[[ rac- ( 2S )-1-methylpyrrolidin-2-yl]methoxy]phenyl]piperidine (0.35 g , 1.21 mmol) was dissolved in DMF (5 mL) and TEA (1.23 g, 12.13 mmol, 1.69 mL) was added followed by 2-[(6-amino-5-ethyl-3-pyridyl)amino]- 2-Pendoxoacetic acid (253.86 mg, 1.21 mmol). HATU (692.10 mg, 1.82 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC (2-10 min 35-60% MeOH+ NH3 30 mL/min (loading pump 4 mL MeOH+ NH3 ) column: SunFire 100*19 mm, 5 microns), to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-oxo-2-[( 2R,5S )-5-methyl-2-[3-[[ elimination Spin- ( 2S )-1-methylpyrrolidin-2-yl]methoxy]phenyl]-1-piperidinyl]acetamide (56.4 mg, 117.59 μmol, 9.69% yield) and N- ( 6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3-[[ rac- ( 2S ) -1-Methylpyrrolidin-2-yl]methoxy]phenyl]-1-piperidinyl]acetamide (84.6 mg, 176.39 μmol, 14.54% yield).

化合物1362： 1 H NMR(600MHz,dmso)δ 0.97-1.03(m,3H),1.06-1.13(m,3H), 1.27-1.36(m,1H),1.53-1.69(m,4H),1.77-2.24(m,6H),2.31-2.35(m,3H),2.38-2.42(m,2H),2.72-3.27(m,3H),3.78-4.03(m,2H),5.07-5.57(m,1H),5.57-5.68(m,2H),6.77-6.95(m,3H),7.24-7.32(m,1H),7.43-7.53(m,1H),7.98-8.09(m,1H),10.46-10.63(m,1H)。LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=0.878min。 Compound 1362: 1 H NMR (600 MHz, dmso) δ 0.97-1.03 (m, 3H), 1.06-1.13 (m, 3H), 1.27-1.36 (m, 1H), 1.53-1.69 (m, 4H), 1.77- 2.24(m, 6H), 2.31-2.35(m, 3H), 2.38-2.42(m, 2H), 2.72-3.27(m, 3H), 3.78-4.03(m, 2H), 5.07-5.57(m, 1H ), 5.57-5.68(m, 2H), 6.77-6.95(m, 3H), 7.24-7.32(m, 1H), 7.43-7.53(m, 1H), 7.98-8.09(m, 1H), 10.46-10.63 (m, 1H). LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=0.878 min.

實例256.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-(3-(二甲胺基)-1,1-二氟丙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1381)之合成Example 256. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-(3-(dimethylamino)-1,1- Synthesis of difluoropropyl)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1381)

Figure 110128222-A0202-12-1358-340
Figure 110128222-A0202-12-1358-340

步驟1：3-(3-溴苯基)-3,3-二氟-N,N-二甲基丙-1-胺之合成Step 1: Synthesis of 3-(3-bromophenyl)-3,3-difluoro-N,N-dimethylpropan-1-amine

Figure 110128222-A0202-12-1358-341
Figure 110128222-A0202-12-1358-341

將1-(3-溴苯基)-3-(二甲胺基)丙-1-酮(4g，15.62mmol)及HF(4mL)置於哈氏合金(Hastelloy)高壓釜中。將其冷卻至-196℃，抽真空且使SF4 (5.06g，46.85mmol)冷凝。將高壓釜在室溫下保持15h，釋放氣體產物且將反應混合物倒入到NaHCO3 /H2 O上。將產物用MTBE萃取，將經合併之萃取物用水洗滌，經Na2 SO4 乾燥且蒸發，以得到3-(3-溴苯基)-3,3-二氟-N,N -二甲基丙-1-胺(3.4g，12.22mmol，78.28%產率)。1-(3-Bromophenyl)-3-(dimethylamino)propan-1-one (4 g, 15.62 mmol) and HF (4 mL) were placed in a Hastelloy autoclave. It was cooled to -196 °C, evacuated and SF4 ( 5.06 g, 46.85 mmol) was condensed. The autoclave was kept at room temperature for 15 h, gaseous product was released and the reaction mixture was poured onto NaHCO3 / H2O . The product was extracted with MTBE, the combined extracts were washed with water, dried over Na2SO4 and evaporated to give 3-(3-bromophenyl)-3,3-difluoro- N,N -dimethyl Propan-1-amine (3.4 g, 12.22 mmol, 78.28% yield).

LCMS(ESI)：[M]+ m/z：計算值278.2；實測值279.2；Rt=0.851min。LCMS (ESI): [M] + m/z: calculated 278.2; found 279.2; Rt=0.851 min.

步驟2：3,3-二氟-N,N-二甲基-3-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙-1-胺之合成Step 2: 3,3-Difluoro-N,N-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of -2-yl)phenyl)propan-1-amine

Figure 110128222-A0202-12-1359-342
Figure 110128222-A0202-12-1359-342

將3-(3-溴苯基)-3,3-二氟-N,N -二甲基丙-1-胺(3.4g，12.22mmol)、雙(頻 哪醇)二硼(3.73g，14.67mmol)及乙酸鉀(3.60g，36.67mmol，2.29mL)於二噁烷(50mL)中之混合物用氬氣除氣10min。接著添加Pd(dppf)Cl2 *DCM(499.14mg，611.21μmol)且將反應混合物在90℃下加熱12h。將反應混合物冷卻至室溫，用DCM及水稀釋。將有機相分離且在減壓下濃縮。將粗產物用HCl/二噁烷溶液處理且再次濃縮。將殘餘物用MTBE處理且藉由過濾收集沉澱，以得到3,3-二氟-N,N -二甲基-3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-1-胺(1.55g，粗品，HCl)。3-(3-Bromophenyl)-3,3-difluoro- N,N -dimethylpropan-1-amine (3.4 g, 12.22 mmol), bis( pinacol)diboron (3.73 g, 14.67 mmol) and potassium acetate (3.60 g, 36.67 mmol, 2.29 mL) in dioxane (50 mL) were degassed with argon for 10 min. Then Pd(dppf)Cl2*DCM ( 499.14 mg, 611.21 μmol) was added and the reaction mixture was heated at 90 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with DCM and water. The organic phase was separated and concentrated under reduced pressure. The crude product was treated with HCl/dioxane solution and concentrated again. The residue was treated with MTBE and the precipitate was collected by filtration to give 3,3-difluoro- N,N -dimethyl-3-[3-(4,4,5,5-tetramethyl-1 , 3,2-Dioxaborol-2-yl)phenyl]propan-1-amine (1.55 g, crude, HCl).

LCMS(ESI)：[M]+ m/z：計算值325.2；實測值326.2；Rt=1.123min。LCMS (ESI): [M] + m/z: calculated 325.2; found 326.2; Rt=1.123 min.

步驟3：(S)-6-(3-(3-(二甲胺基)-1,1-二氟丙基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(3-(3-(dimethylamino)-1,1-difluoropropyl)phenyl)-3-methyl-3,4-dihydropyridine-1( Synthesis of 2H)-tert-butyl formate

Figure 110128222-A0202-12-1359-343
Figure 110128222-A0202-12-1359-343

將3,3-二氟-N,N -二甲基-3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-1-胺(1.55g，3.21mmol，HCl)及碳酸鈉(1.36g，12.86mmol，538.21 μL)混合於H2 O(10mL)及二噁烷(30mL)中且攪拌20min，然後在氬氣下添加(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.33g，3.86mmol)及Pd(dppf)Cl2 *DCM(262.29mg，321.43μmol)且在75℃下攪拌12h。將反應混合物用水稀釋且將所需產物用DCM萃取，經Na2 SO4 乾燥且在真空中濃縮。獲得(3S )-6-[3-[3-(二甲胺基)-1,1-二氟丙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.95g，粗品)。3,3-Difluoro- N,N -dimethyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl]propan-1-amine (1.55 g, 3.21 mmol, HCl) and sodium carbonate (1.36 g, 12.86 mmol, 538.21 μL) were mixed in H2O (10 mL) and dioxane (30 mL) and Stir for 20 min, then add ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester under argon (1.33 g, 3.86 mmol) and Pd(dppf)Cl2*DCM ( 262.29 mg, 321.43 μmol) and stirred at 75 °C for 12 h. The reaction mixture was diluted with water and the desired product was extracted with DCM, dried over Na2SO4 and concentrated in vacuo. ( 3S )-6-[3-[3-(dimethylamino)-1,1-difluoropropyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1 was obtained - tert -butyl formate (1.95 g, crude).

LCMS(ESI)：[M]+ m/z：計算值394.2；實測值395.2；Rt=1.236min。LCMS (ESI): [M] + m/z: calculated 394.2; found 395.2; Rt=1.236 min.

步驟4：(S)-3,3-二氟-N,N-二甲基-3-(3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)丙-1-胺之合成Step 4: (S)-3,3-Difluoro-N,N-dimethyl-3-(3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzene Synthesis of base)propan-1-amine

Figure 110128222-A0202-12-1360-344
Figure 110128222-A0202-12-1360-344

將(3S )-6-[3-[3-(二甲胺基)-1,1-二氟丙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.95g，2.17mmol)溶解於TFA(6.64g，58.23mmol，4.49mL)及DCM(20.93mL)之混合物中且攪拌1h。將反應混合物在真空中濃縮且將殘餘物用NaHCO3 溶液處理，隨後用DCM(2*50mL)萃取。然後，將水層再次用EtOAc處理，將有機相經Na2 SO4 乾燥且在減壓下濃縮，以得到3,3-二氟-N,N -二甲基-3-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]丙-1-胺(210g，粗品)，其不經純化即用於下一步驟中。( 3S )-6-[3-[3-(dimethylamino)-1,1-difluoropropyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1 - tert -butyl formate (1.95 g, 2.17 mmol) was dissolved in a mixture of TFA (6.64 g, 58.23 mmol, 4.49 mL) and DCM (20.93 mL) and stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was treated with NaHCO3 solution, followed by extraction with DCM (2*50 mL). Then, the aqueous layer was treated with EtOAc again, the organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to give 3,3-difluoro- N,N -dimethyl-3-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl]propan-1-amine (210 g, crude) was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值294.2；實測值295.2；Rt=0.645min。LCMS (ESI): [M] + m/z: calculated 294.2; found 295.2; Rt=0.645 min.

步驟5：3,3-二氟-N,N-二甲基-3-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)丙-1-胺之合成Step 5: 3,3-Difluoro-N,N-dimethyl-3-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)propan-1-amine synthesis

Figure 110128222-A0202-12-1361-345
Figure 110128222-A0202-12-1361-345

將3,3-二氟-N,N -二甲基-3-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]丙-1-胺(210mg，292.48μmol)溶解於MeOH(20mL)中且添加硼氫化鈉(22.13mg，584.95μmol，20.60μL)。攪拌12h之後，將反應混合物濃縮且不經任何純化即用於下一步驟中。3,3-二氟-N,N -二甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]丙-1-胺(250mg，粗品)。3,3-Difluoro- N,N -dimethyl-3-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl] Propan-1-amine (210 mg, 292.48 μmol) was dissolved in MeOH (20 mL) and sodium borohydride (22.13 mg, 584.95 μmol, 20.60 μL) was added. After stirring for 12 h, the reaction mixture was concentrated and used in the next step without any purification. 3,3-Difluoro- N,N -dimethyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]propan-1-amine (250 mg, crude ).

LCMS(ESI)：[M]+ m/z：計算值296.2；實測值297.2；Rt=0.244min。LCMS (ESI): [M] + m/z: calculated 296.2; found 297.2; Rt=0.244 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-(3-(二甲胺基)-1,1-二氟丙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1381)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-(3-(dimethylamino)-1,1- Synthesis of difluoropropyl)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1381)

將來自前一階段之粗產物3,3-二氟-N,N -二甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]丙-1-胺(250mg，337.38μmol)與TEA(400mg，3.95mmol，550.96μL)混合於DMSO(3.92mL)中，接著添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(70.58mg，337.38μmol)及HATU(179.60mg，472.34μmol)且攪拌隔夜。過濾RM且使其經歷HPLC(2-10min 0-55%水/MeOH+NH3 30mL/min；裝載泵4mL/min MeOH；管柱SunFire 19*100mm)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[3-(二甲胺基)-1,1-二氟丙基]苯基]-5-甲基-1-哌啶基]乙醯胺(29.8mg，61.12μmol，18.12%產率)。The crude product from the previous stage, 3,3-difluoro- N,N -dimethyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]propane- 1-amine (250 mg, 337.38 μmol) was mixed with TEA (400 mg, 3.95 mmol, 550.96 μL) in DMSO (3.92 mL) followed by the addition of 2-[(6-amino-5-ethyl-3-pyridyl) Amino]-2-pendoxoacetic acid (70.58 mg, 337.38 μmol) and HATU (179.60 mg, 472.34 μmol) and stirred overnight. The RM was filtered and subjected to HPLC (2-10 min 0-55% water/MeOH+ NH3 30 mL/min; loading pump 4 mL/min MeOH; column SunFire 19*100 mm) to give N- (6-amino- 5-Ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2-[3-[3-(dimethylamino)-1,1-difluoropropyl] Phenyl]-5-methyl-1-piperidinyl]acetamide (29.8 mg, 61.12 μmol, 18.12% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.73-1.04(m,3H),1.05-1.16(m,3H),1.25-1.41(m,1H),1.58-1.72(m,1H),1.80-1.96(m,1H),2.04-2.08(m,6H),2.08-2.20(m,1H),2.20-2.32(m,3H),2.34-2.43(m,4H),2.70-3.23(m,1H),3.46-4.05(m, 1H),5.14-5.75(m,3H),7.36-7.47(m,3H),7.47-7.58(m,2H),7.97-8.12(m,1H),10.49-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.73-1.04(m,3H), 1.05-1.16(m,3H), 1.25-1.41(m,1H), 1.58-1.72(m,1H) ,1.80-1.96(m,1H),2.04-2.08(m,6H),2.08-2.20(m,1H),2.20-2.32(m,3H),2.34-2.43(m,4H),2.70-3.23( m,1H),3.46-4.05(m,1H),5.14-5.75(m,3H),7.36-7.47(m,3H),7.47-7.58(m,2H),7.97-8.12(m,1H), 10.49-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值487.2；實測值488.2；Rt=1.923min。LCMS (ESI): [M] + m/z: calculated 487.2; found 488.2; Rt=1.923 min.

實例257.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-((2,6-二甲基吡啶-4-基)氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1297)之合成Example 257. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-((2,6-lutidine-4-yl )oxy)phenyl)-5-methylpiperidin-1-yl)-2-oxyacetamide (compound 1297) synthesis

Figure 110128222-A0202-12-1362-346
Figure 110128222-A0202-12-1362-346

步驟1：4-(3-溴苯氧基)-2,6-二甲基吡啶之合成Step 1: Synthesis of 4-(3-bromophenoxy)-2,6-lutidine

Figure 110128222-A0202-12-1362-348
Figure 110128222-A0202-12-1362-348

將3-溴苯酚(30g，173.40mmol)溶解於DMSO(400mL)中，隨後添加第三丁醇鉀(29.19g，260.10mmol)。將反應混合物在室溫下攪拌1h，然後添加4-氯-2,6-二甲基吡啶(36.83g，260.10mmol)。將反應混合物在160℃下攪拌16h。完成之後，將反應混合物用水(3L)稀釋且用乙酸乙酯萃取。將有機相乾燥，在減壓下濃縮且將殘餘物提交至急驟管柱層析(Interchim；330g SiO2 ，CHCl3 -MeCN0~100%，流速=100mL/min，cv=7.6)，以得到4-(3-溴苯氧基)-2,6-二甲基吡啶(12g，43.14mmol，24.88%產率)。3-Bromophenol (30 g, 173.40 mmol) was dissolved in DMSO (400 mL) followed by the addition of potassium tert-butoxide (29.19 g, 260.10 mmol). The reaction mixture was stirred at room temperature for 1 h, then 4-chloro-2,6-lutidine (36.83 g, 260.10 mmol) was added. The reaction mixture was stirred at 160 °C for 16 h. After completion, the reaction mixture was diluted with water (3 L) and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure and the residue was submitted to flash column chromatography (Interchim; 330 g SiO2 , CHCl3 -MeCN0~100%, flow rate=100 mL/min, cv=7.6) to give 4 -(3-Bromophenoxy)-2,6-lutidine (12 g, 43.14 mmol, 24.88% yield).

LCMS(ESI)：[M]+ m/z：計算值278.2；實測值279.2；Rt=0.870min。LCMS (ESI): [M] + m/z: calculated 278.2; found 279.2; Rt=0.870 min.

步驟2：2,6-二甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)吡Step 2: 2,6-Dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy base) pyridine 啶之合成Synthesis of pyridine

Figure 110128222-A0202-12-1363-349
Figure 110128222-A0202-12-1363-349

將4-(3-溴苯氧基)-2,6-二甲基吡啶(12g，43.14mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(13.2g，51.98mmol)、乙酸鉀(12.7g，129.40mmol，8.09mL)及Pd(dppf)Cl2 *DCM(1.76g，2.16mmol)混合於二噁烷(250mL)中且將反應混合物在惰性氣氛、85℃下攪拌17h。完成之後，透過SiO2 薄墊過濾反應混合物。將濾液用DCM稀釋，用水洗滌且濃縮。將殘餘物用己烷處理，過濾且在減壓下濃縮，以得到2,6-二甲基-4-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(12g，粗品)，其不經純化即用於下一步驟中。4-(3-Bromophenoxy)-2,6-lutidine (12 g, 43.14 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (13.2 g, 51.98 mmol), potassium acetate (12.7 g, 129.40 mmol, 8.09 mL) and Pd(dppf)Cl2*DCM (1.76 g , 2.16 mmol) were mixed in dioxane (250 mL) and the reaction mixture was stirred at 85 °C for 17 h under an inert atmosphere. After completion, the reaction mixture was filtered through a thin pad of SiO2 . The filtrate was diluted with DCM, washed with water and concentrated. The residue was treated with hexane, filtered and concentrated under reduced pressure to give 2,6-dimethyl-4-[3-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)phenoxy]pyridine (12 g, crude) was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值325.2；實測值326.2；Rt=1.186min。LCMS (ESI): [M] + m/z: calculated 325.2; found 326.2; Rt=1.186 min.

步驟3：(S)-6-(3-((2,6-二甲基吡啶-4-基)氧基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(3-((2,6-Lutidine-4-yl)oxy)phenyl)-3-methyl-3,4-dihydropyridine-1(2H )-Synthesis of tert-butyl formate

Figure 110128222-A0202-12-1363-350
Figure 110128222-A0202-12-1363-350

將2,6-二甲基-4-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(4g，12.30mmol)、(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(4.3g，12.45mmol)、碳酸鈉(3.9g，36.80mmol，1.54mL) 及Pd(dppf)Cl2 *DCM(0.5g，612.27μmol)在二噁烷(60mL)及水(20mL)之混合物中在惰性氣氛、85℃下攪拌15h。完成之後，將反應混合物冷卻，用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且將殘餘物提交至急驟管柱層析(Interchim；120g SiO2 ，己烷-EtOAc 0~100%，流速=70mL/min，cv=13.3)，以得到(3S)-6-[3-[(2,6-二甲基-4-吡啶基)氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3g，7.60mmol，61.83%產率)。2,6-Dimethyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy] Pyridine (4 g, 12.30 mmol), ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester ( 4.3 g, 12.45 mmol), sodium carbonate (3.9 g, 36.80 mmol, 1.54 mL) and Pd(dppf)Cl2*DCM (0.5 g , 612.27 μmol) in a mixture of dioxane (60 mL) and water (20 mL) Stir at 85 °C for 15 h in an inert atmosphere. After completion, the reaction mixture was cooled, diluted with water and extracted with DCM. The organic layer was separated, dried over Na 2 SO 4 and the residue was submitted to flash column chromatography (Interchim; 120 g SiO 2 , hexane-EtOAc 0~100%, flow rate=70 mL/min, cv=13.3), with to give (3S)-6-[3-[(2,6-dimethyl-4-pyridinyl)oxy]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1- 3 -butyl formate (3 g, 7.60 mmol, 61.83% yield).

LCMS(ESI)：[M]+ m/z：計算值394.2；實測值395.2；Rt=1.262min。LCMS (ESI): [M] + m/z: calculated 394.2; found 395.2; Rt=1.262 min.

步驟4：(S)-2,6-二甲基-4-(3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯氧基)吡啶之合成Step 4: Synthesis of (S)-2,6-dimethyl-4-(3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenoxy)pyridine

Figure 110128222-A0202-12-1364-351
Figure 110128222-A0202-12-1364-351

將(3S)-6-[3-[(2,6-二甲基-4-吡啶基)氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(0.7g，1.77mmol)溶解於TFA(1.48g，12.98mmol，1mL)及DCM(1mL)之混合物中。將反應混合物在室溫下攪拌0.5h且在真空中濃縮，以得到2,6-二甲基-4-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]吡啶(0.5g，粗品)，其不經純化及分析資料收集即直接用於下一步驟中。(3S)-6-[3-[(2,6-Dimethyl-4-pyridyl)oxy]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1- 3 -Butyl formate (0.7 g, 1.77 mmol) was dissolved in a mixture of TFA (1.48 g, 12.98 mmol, 1 mL) and DCM (1 mL). The reaction mixture was stirred at room temperature for 0.5 h and concentrated in vacuo to give 2,6-dimethyl-4-[3-[( 3S )-3-methyl-2,3,4,5-tetrakis Hydropyridin-6-yl]phenoxy]pyridine (0.5 g, crude) was used in the next step without purification and analytical data collection.

步驟5：2,6-二甲基-4-(3-((2R,5S)-5-甲基哌啶-2-基)苯氧基)吡啶之合成Step 5: Synthesis of 2,6-dimethyl-4-(3-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)pyridine

Figure 110128222-A0202-12-1364-352
Figure 110128222-A0202-12-1364-352

將2,6-二甲基-4-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]吡啶(0.5g，1.70mmol)溶解於MeOH(6mL)中，隨後分批添加硼氫化鈉(192.77mg，5.10mmol，179.49μL)。將反應混合物在室溫下攪拌15h且在真空中濃縮。將殘餘物溶解於DCM中，用水洗滌。將有機層經Na2 SO4 乾燥且在減壓下濃縮，以得到2,6-二甲基-4-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]吡啶(0.2g，粗品)，其不經純化即用於下一步驟中。2,6-Dimethyl-4-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenoxy]pyridine (0.5 g, 1.70 mmol) was dissolved in MeOH (6 mL), then sodium borohydride (192.77 mg, 5.10 mmol, 179.49 μL) was added portionwise. The reaction mixture was stirred at room temperature for 15 h and concentrated in vacuo. The residue was dissolved in DCM and washed with water. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give 2,6-dimethyl-4-[3-[( 2R,5S )-5-methyl-2-piperidinyl]benzene oxy]pyridine (0.2 g, crude), which was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值296.2；實測值297.2；Rt=0.710min。LCMS (ESI): [M] + m/z: calculated 296.2; found 297.2; Rt=0.710 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-((2,6-二甲基吡啶-4-基)氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1297)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-((2,6-lutidine-4-yl) )oxy)phenyl)-5-methylpiperidin-1-yl)-2-oxyacetamide (compound 1297) synthesis

向2,6-二甲基-4-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]吡啶(0.2g，674.75μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(155.27mg，742.23μmol)及DIPEA(348.83mg，2.70mmol，470.12μL)於DMSO(2mL)中之經攪拌之溶液中添加HATU(359.18mg，944.65μmol)。將所得反應混合物在25℃下攪拌4h。完成之後，將反應混合物提交至反相HPLC(2-10min 55-75% MeOH+NH3 流速30mL/min(裝載泵4mL/minTo 2,6-dimethyl-4-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]pyridine (0.2 g, 674.75 μmol), 2-[(6 -Amino-5-ethyl-3-pyridyl)amino]-2-side oxyacetic acid (155.27 mg, 742.23 μmol) and DIPEA (348.83 mg, 2.70 mmol, 470.12 μL) in DMSO (2 mL) To the stirred solution was added HATU (359.18 mg, 944.65 μmol). The resulting reaction mixture was stirred at 25 °C for 4 h. After completion, the reaction mixture was submitted to reverse phase HPLC (2-10 min 55-75% MeOH+NH flow rate 30 mL/min (load pump 4 mL/min)

MeOH)，管柱Sun Fire C18 100*19mm)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[(2,6-二甲基-4-吡啶基)氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(0.1g，205.09μmol，30.39%產率)。MeOH), column Sun Fire C18 100*19mm) to give N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2 -[3-[(2,6-Dimethyl-4-pyridyl)oxy]phenyl]-5-methyl-1-piperidinyl]acetamide (0.1 g, 205.09 μmol, 30.39% yield Rate).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.07-1.13(m,3H),1.29-1.38(m,1H),1.61-1.71(m,1H),1.83-1.94(m,1H),1.98-2.11(m,1H),2.16-2.26(m,1H),2.30-2.34(m,6H),2.36-2.41(m,2H),2.74-3.23(m,1H),3.44-4.05(m,1H),5.16-5.66(m,3H),6.55-6.60(m,2H),7.02(dd,1H),7.05-7.16(m,1H),7.18-7.29(m,1H),7.41-7.52(m,2H),7.97-8.06(m,1H),10.43-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.04(m,3H), 1.07-1.13(m,3H), 1.29-1.38(m,1H), 1.61-1.71(m,1H) ,1.83-1.94(m,1H),1.98-2.11(m,1H),2.16-2.26(m,1H),2.30-2.34(m,6H),2.36-2.41(m,2H),2.74-3.23( m,1H),3.44-4.05(m,1H),5.16-5.66(m,3H),6.55-6.60(m,2H),7.02(dd,1H),7.05-7.16(m,1H),7.18- 7.29 (m, 1H), 7.41-7.52 (m, 2H), 7.97-8.06 (m, 1H), 10.43-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值487.2；實測值488.2；Rt=2.203min。LCMS (ESI): [M] + m/z: calculated 487.2; found 488.2; Rt=2.203 min.

實例258.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-(吡啶-3-基氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1297)之合成Example 258. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-(pyridin-3-yloxy) Synthesis of Phenyl)piperidin-1-yl)-2-oxoacetamide (Compound 1297)

Figure 110128222-A0202-12-1366-353
Figure 110128222-A0202-12-1366-353

步驟1：3-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)吡啶之合成Step 1: Synthesis of 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy)pyridine

Figure 110128222-A0202-12-1366-354
Figure 110128222-A0202-12-1366-354

將3-碘吡啶(30g，146.34mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(32.21g，146.34mmol)、TMEDA(1.70g，14.63mmol，2.19mL)、碘化銅(I)(2.79g，14.63mmol，495.93μL)及碳酸銫(95.36g，292.69mmol)混合於DMSO(500mL)中。向反應混合物中裝入Ar且在130℃下攪拌24h。完成之後，將反應混合物用水(3L)稀釋且用乙酸乙酯萃取。將有機層用水洗滌若干次，分離，經Na2 SO4 乾燥且在減壓下濃縮。將殘餘物提交至急驟管柱層析(Interchim；120g SiO2 ，CHCl3 -MeCN 0~100%，流速=70mL/min，cv=16)，以得到3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(7g，粗品)。3-iodopyridine (30 g, 146.34 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol (32.21 g , 146.34 mmol), TMEDA (1.70 g, 14.63 mmol, 2.19 mL), copper(I) iodide (2.79 g, 14.63 mmol, 495.93 μL) and cesium carbonate (95.36 g, 292.69 mmol) were mixed in DMSO (500 mL) . Ar was charged to the reaction mixture and stirred at 130 °C for 24 h. After completion, the reaction mixture was diluted with water (3 L) and extracted with ethyl acetate. The organic layer was washed several times with water, separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was submitted to flash column chromatography (Interchim; 120 g SiO 2 , CHCl 3 -MeCN 0~100%, flow rate=70 mL/min, cv=16) to give 3-[3-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]pyridine (7 g, crude).

LCMS(ESI)：[M]+ m/z：計算值297.2；實測值298.2；Rt=1.437min。LCMS (ESI): [M] + m/z: calculated 297.2; found 298.2; Rt=1.437 min.

步驟2：(S)-3-甲基-6-(3-(吡啶-3-基氧基)苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯Step 2: (S)-3-Methyl-6-(3-(pyridin-3-yloxy)phenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 之合成synthesis

Figure 110128222-A0202-12-1367-355
Figure 110128222-A0202-12-1367-355

將3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(4g，13.46mmol)、(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(4.71g，13.63mmol)、碳酸鈉(4.27g，40.27mmol，1.69mL)及Pd(dppf)Cl2 *DCM(547.20mg，670.07μmol)在二噁烷(60mL)及水(20mL)之混合物中在惰性氣氛、85℃下攪拌16h。完成之後，將反應混合物冷卻，用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮，以得到(3S )-3-甲基-6-[3-(3-吡啶基氧基)苯基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(5g，粗品)，其不經純化即用於下一步驟中。3-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]pyridine (4 g, 13.46 mmol), ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (4.71 g, 13.63 mmol), carbonic acid Sodium (4.27 g, 40.27 mmol, 1.69 mL) and Pd(dppf)Cl2*DCM ( 547.20 mg, 670.07 μmol) in a mixture of dioxane (60 mL) and water (20 mL) were stirred at 85 °C under an inert atmosphere 16h. After completion, the reaction mixture was cooled, diluted with water and extracted with DCM. The organic layer was separated, dried over Na 2 SO 4 and concentrated under reduced pressure to give ( 3S )-3-methyl-6-[3-(3-pyridyloxy)phenyl]-3,4- Dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (5 g, crude) was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=1.578min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=1.578 min.

步驟3：(S)-3-(3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯氧基)吡啶之合成Step 3: Synthesis of (S)-3-(3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenoxy)pyridine

Figure 110128222-A0202-12-1367-356
Figure 110128222-A0202-12-1367-356

將(3S )-3-甲基-6-[3-(3-吡啶基氧基)苯基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1g，2.73mmol)溶解於TFA(2.22g，19.47mmol，1.5mL)及DCM(1.5mL)之混合物中。將反應混合物在室溫下攪拌0.5h且在真空中濃縮，以得到 3-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]吡啶(0.5g，粗品)，其不經純化及分析資料收集即直接用於下一步驟中。( 3S )-3-methyl-6-[3-(3-pyridyloxy)phenyl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (1 g, 2.73 mmol ) was dissolved in a mixture of TFA (2.22 g, 19.47 mmol, 1.5 mL) and DCM (1.5 mL). The reaction mixture was stirred at room temperature for 0.5 h and concentrated in vacuo to give 3-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]benzene oxy]pyridine (0.5 g, crude), which was used in the next step without purification and analytical data collection.

LCMS(ESI)：[M]+ m/z：計算值266.2；實測值267.2；Rt=min。LCMS (ESI): [M] + m/z: calculated 266.2; found 267.2; Rt=min.

步驟4：3-(3-((2R,5S)-5-甲基哌啶-2-基)苯氧基)吡啶之合成Step 4: Synthesis of 3-(3-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)pyridine

Figure 110128222-A0202-12-1368-357
Figure 110128222-A0202-12-1368-357

將3-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]吡啶(0.5g，1.88mmol)溶解於MeOH(5mL)中，隨後分批添加硼氫化鈉(142.04mg，3.75mmol，132.25μL)。將反應混合物在室溫下攪拌15h且在真空中濃縮。將殘餘物溶解於DCM中，用水洗滌。將有機層經Na2 SO4 乾燥且在減壓下濃縮，以得到3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]吡啶(0.5g，粗品)，其不經純化即用於下一步驟中。3-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenoxy]pyridine (0.5 g, 1.88 mmol) was dissolved in MeOH (5 mL) , followed by the portionwise addition of sodium borohydride (142.04 mg, 3.75 mmol, 132.25 μL). The reaction mixture was stirred at room temperature for 15 h and concentrated in vacuo. The residue was dissolved in DCM and washed with water. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give 3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]pyridine (0.5 g, crude product), which was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值268.2；實測值269.2；Rt=0.713min。LCMS (ESI): [M] + m/z: calculated 268.2; found 269.2; Rt=0.713 min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-(吡啶-3-基氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1297)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(pyridin-3-yloxy) Synthesis of Phenyl)piperidin-1-yl)-2-oxoacetamide (Compound 1297)

向3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]吡啶(0.5g，1.86mmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(428.77mg，2.05mmol)及DIPEA(722.41mg，5.59mmol，973.59μL)於DMSO(8.32mL)中之經攪拌之溶液中添加HATU(991.83mg，2.61mmol)。將所得反應混合物在25℃下攪拌4h。完成之後，將反應混合物提交至反相HPLC(2-10min 55-75% MeOH+NH3 流速30mL/min(裝載泵4mL/min MeOH)，管柱Sun Fire C18 100*19mm)，以得到N -(6-胺基-5- 乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(3-吡啶基氧基)苯基]-1-哌啶基]乙醯胺(0.023g，50.05μmol，2.69%產率)。To 3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]pyridine (0.5 g, 1.86 mmol), 2-[(6-amino-5-ethyl HATU was added to a stirred solution of -3-pyridyl)amino]-2-oxoacetic acid (428.77 mg, 2.05 mmol) and DIPEA (722.41 mg, 5.59 mmol, 973.59 μL) in DMSO (8.32 mL) (991.83 mg, 2.61 mmol). The resulting reaction mixture was stirred at 25 °C for 4 h. After completion, the reaction mixture was submitted to reverse phase HPLC (2-10min 55-75% MeOH+ NH3 flow rate 30mL/min (load pump 4mL/min MeOH), column Sun Fire C18 100*19mm) to obtain N- (6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3-(3-pyridyloxy) Phenyl]-1-piperidinyl]acetamide (0.023 g, 50.05 μmol, 2.69% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.06-1.12(m,3H),1.25-1.37(m,1H),1.60-1.73(m,1H),1.82-1.91(m,1H),1.96-2.12(m,1H),2.14-2.24(m,1H),2.37-2.43(m,2H),2.76-3.21(m,1H),3.46-4.08(m,1H),5.14-5.59(m,1H),5.60-5.69(m,2H),6.89-6.96(m,1H),7.03-7.11(m,1H),7.12-7.22(m,1H),7.36-7.52(m,4H),7.95-8.09(m,1H),8.29-8.41(m,2H),10.25(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.05(m,3H), 1.06-1.12(m,3H), 1.25-1.37(m,1H), 1.60-1.73(m,1H) ,1.82-1.91(m,1H),1.96-2.12(m,1H),2.14-2.24(m,1H),2.37-2.43(m,2H),2.76-3.21(m,1H),3.46-4.08( m,1H),5.14-5.59(m,1H),5.60-5.69(m,2H),6.89-6.96(m,1H),7.03-7.11(m,1H),7.12-7.22(m,1H), 7.36-7.52 (m, 4H), 7.95-8.09 (m, 1H), 8.29-8.41 (m, 2H), 10.25 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值459.2；實測值460.2；Rt=0.855min。LCMS (ESI): [M] + m/z: calculated 459.2; found 460.2; Rt=0.855min.

實例259.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-(3-(二甲胺基)丙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1393)之合成Example 259. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-(3-(dimethylamino)propyl)phenyl )-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1393) synthesis

Figure 110128222-A0202-12-1369-358
Figure 110128222-A0202-12-1369-358

步驟1：3-(3-溴苯基)-N,N-二甲基丙-1-胺之合成Step 1: Synthesis of 3-(3-bromophenyl)-N,N-dimethylpropan-1-amine

將氰基硼氫化鈉(13.22g，210.33mmol)分4批次添加到3-(3-溴苯基)丙-1-胺(5.27g，21.03mmol，HCl)及福馬林(12.34g，152.04mmol，11.39mL，37%純度)於MeOH(100.00mL)中之混合物中且攪拌隔夜。將反應混合物用NaHCO3 水溶液處理且將所要產物用300mL DCM萃取，經Na2 SO4 乾燥且在真空中濃縮，以得到3-(3-溴苯基)-N,N -二甲基丙-1-胺(3.4g，粗品)。Sodium cyanoborohydride (13.22 g, 210.33 mmol) was added in 4 portions to 3-(3-bromophenyl)propan-1-amine (5.27 g, 21.03 mmol, HCl) and formalin (12.34 g, 152.04 mmol, 11.39 mL, 37% purity) in MeOH (100.00 mL) and stirred overnight. The reaction mixture was treated with aqueous NaHCO 3 and the desired product was extracted with 300 mL of DCM, dried over Na 2 SO 4 and concentrated in vacuo to give 3-(3-bromophenyl) -N,N -dimethylpropane- 1-amine (3.4 g, crude).

LCMS(ESI)：[M]+ m/z：計算值242.2；實測值243.2；Rt=0.631min。LCMS (ESI): [M] + m/z: calculated 242.2; found 243.2; Rt=0.631 min.

步驟2：N,N-二甲基-3-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙Step 2: N,N-Dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl ) C -1-胺之合成-1-Amine Synthesis

將3-(3-溴苯基)-N,N -二甲基丙-1-胺(3.4g，14.04mmol)、雙(頻哪醇)二硼(4.64g，18.25mmol)及乙酸鉀(4.13g，42.12mmol，2.63mL)於二噁烷(49.66mL)中之混合物用氬氣除氣10min。接著添加Pd(dppf)Cl2 *DCM(573.30mg，702.03μmol)且將反應混合物在90℃下加熱12h。將反應混合物冷卻至室溫，用DCM稀釋。將有機相分離且在減壓下濃縮。將粗產物用HCl/二噁烷溶液(10% HCl)處理且再次濃縮。將殘餘物用MTBE處理且藉由過濾收集沉澱，以得到N,N -二甲基-3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-1-胺(2.67g，粗品，HCl)。3-(3-Bromophenyl) -N,N -dimethylpropan-1-amine (3.4 g, 14.04 mmol), bis(pinacol)diboron (4.64 g, 18.25 mmol) and potassium acetate ( A mixture of 4.13 g, 42.12 mmol, 2.63 mL) in dioxane (49.66 mL) was degassed with argon for 10 min. Then Pd(dppf)Cl2*DCM ( 573.30 mg, 702.03 μmol) was added and the reaction mixture was heated at 90 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with DCM. The organic phase was separated and concentrated under reduced pressure. The crude product was treated with HCl/dioxane solution (10% HCl) and concentrated again. The residue was treated with MTBE and the precipitate was collected by filtration to give N,N -dimethyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxa Borolin-2-yl)phenyl]propan-1-amine (2.67 g, crude, HCl).

LCMS(ESI)：[M]+ m/z：計算值289.2；實測值290.2；Rt=1.085min。LCMS (ESI): [M] + m/z: calculated 289.2; found 290.2; Rt=1.085min.

步驟3：(S)-6-(3-(3-(二甲胺基)丙基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(3-(3-(dimethylamino)propyl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl Synthesis of Esters

將N,N -二甲基-3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-1-胺(2.67g，6.15mmol，HCl)及碳酸鈉(2.61g，24.59mmol，1.03mL)混合於H2 O(10mL)及二噁烷(30mL)中且攪拌20min，然後在氬氣下添加(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(2.55g，7.38mmol)及Pd(dppf)Cl2 *DCM(501.73mg，614.87μmol)且在75℃下攪拌12h。將反應混合物用水稀釋且將所要產物用100mL DCM萃取，經Na2 SO4 乾燥且在真空中濃縮。獲得(3S )-6-[3-[3-(二甲胺基)丙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.2g，粗品)。 N,N -dimethyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]propane -1-amine (2.67 g, 6.15 mmol, HCl) and sodium carbonate (2.61 g, 24.59 mmol, 1.03 mL) were mixed in H2O (10 mL) and dioxane (30 mL) and stirred for 20 min, then under argon ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (2.55 g, 7.38 mmol) was added under and Pd(dppf)Cl2*DCM ( 501.73 mg, 614.87 μmol) and stirred at 75 °C for 12 h. The reaction mixture was diluted with water and the desired product was extracted with 100 mL of DCM, dried over Na2SO4 and concentrated in vacuo. ( 3S )-6-[3-[3-(dimethylamino)propyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester ( 3.2g, crude product).

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=1.226min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=1.226 min.

步驟4：(S)-N,N-二甲基-3-(3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)丙-1-胺之合成Step 4: (S)-N,N-Dimethyl-3-(3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)propan-1-amine synthesis

將(3S )-6-[3-[3-(二甲胺基)丙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.2g，3.79mmol)溶解於TFA(8g，70.16mmol，5.41mL)及DCM(20mL)之混合物中且攪拌1h。將反應混合物在真空中濃縮且將殘餘物用NaHCO3 溶液處理，隨後用DCM(2*50mL)萃取。然後，將水層再次用EtOAc處理，將有機相經Na2 SO4 乾燥且在減壓下濃縮，以得到N,N -二甲基-3-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]丙-1-胺(320mg，粗品)，其不經純化即用於下一步驟中。( 3S )-6-[3-[3-(dimethylamino)propyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester ( 3.2 g, 3.79 mmol) was dissolved in a mixture of TFA (8 g, 70.16 mmol, 5.41 mL) and DCM (20 mL) and stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was treated with NaHCO3 solution, followed by extraction with DCM (2*50 mL). Then, the aqueous layer was treated with EtOAc again, the organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to give N,N -dimethyl-3-[3-[( 3S )-3-methyl -2,3,4,5-Tetrahydropyridin-6-yl]phenyl]propan-1-amine (320 mg, crude), which was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值258.2；實測值259.2；Rt=0.613min。LCMS (ESI): [M] + m/z: calculated 258.2; found 259.2; Rt=0.613 min.

步驟5：N,N-二甲基-3-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)丙-1-胺之合成Step 5: Synthesis of N,N-dimethyl-3-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)propan-1-amine

將N,N -二甲基-3-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]丙-1-胺(320mg，850.52μmol)溶解於MeOH(20mL)中且添加硼氫化鈉(64.35mg，1.70mmol，59.92μL)。攪拌12h之後，將RM濃縮且不經純化即用於下一步驟中。獲得N,N -二甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]丙-1-胺(250mg，粗品)。 N,N -dimethyl-3-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl]propan-1-amine (320 mg , 850.52 μmol) was dissolved in MeOH (20 mL) and sodium borohydride (64.35 mg, 1.70 mmol, 59.92 μL) was added. After stirring for 12 h, the RM was concentrated and used in the next step without purification. N,N -Dimethyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]propan-1-amine (250 mg, crude) was obtained.

LCMS(ESI)：[M]+ m/z：計算值260.2；實測值261.2；Rt=0.203min。LCMS (ESI): [M] + m/z: calculated 260.2; found 261.2; Rt=0.203 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-(3-(二甲胺基)丙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1393)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-(3-(dimethylamino)propyl)phenyl )-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1393) synthesis

將來自前一階段之粗產物N,N -二甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]丙-1-胺(320mg，847.87μmol)與TEA(400mg，3.95mmol，550.96μL)混合於DMSO(4mL)中，接著添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(177.38mg，847.87μmol)及HATU(451.34mg，1.19mmol)且攪拌隔夜。過濾RM且使其經歷HPLC(2-10min 0-55%水/MeOH+NH3 30mL/min；裝載泵4mL/min MeOH；管柱SunFire 19*100mm)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[3-(二甲胺基)丙基]苯基]-5-甲基-1-哌啶基]乙醯胺(34.2mg，75.73μmol，8.93%產率)。The crude N,N -dimethyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]propan-1-amine from the previous stage (320 mg, 847.87 g μmol) was mixed with TEA (400 mg, 3.95 mmol, 550.96 μL) in DMSO (4 mL) followed by the addition of 2-[(6-amino-5-ethyl-3-pyridinyl)amino]-2-oxo acetic acid (177.38 mg, 847.87 μmol) and HATU (451.34 mg, 1.19 mmol) and stirred overnight. The RM was filtered and subjected to HPLC (2-10 min 0-55% water/MeOH+ NH3 30 mL/min; loading pump 4 mL/min MeOH; column SunFire 19*100 mm) to give N- (6-amino- 5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2-[3-[3-(dimethylamino)propyl]phenyl]-5-methyl yl-1-piperidinyl]acetamide (34.2 mg, 75.73 μmol, 8.93% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.75-1.03(m,3H),1.06-1.15(m,3H),1.28-1.39(m,1H),1.61-1.69(m,3H),1.79-1.93(m,1H),1.96-2.07(m,1H),2.07-2.11(m,6H),2.14-2.25(m,3H),2.35-2.42(m,2H),2.56-2.62(m,2H),2.72-3.23(m, 1H),3.44-4.05(m,1H),5.11-5.58(m,1H),5.59-5.67(m,2H),7.06-7.12(m,2H),7.12-7.18(m,1H),7.25-7.32(m,1H),7.43-7.54(m,1H),7.95-8.09(m,1H),10.47-10.58(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.75-1.03(m,3H), 1.06-1.15(m,3H), 1.28-1.39(m,1H), 1.61-1.69(m,3H) ,1.79-1.93(m,1H),1.96-2.07(m,1H),2.07-2.11(m,6H),2.14-2.25(m,3H),2.35-2.42(m,2H),2.56-2.62( m, 2H), 2.72-3.23(m, 1H), 3.44-4.05(m, 1H), 5.11-5.58(m, 1H), 5.59-5.67(m, 2H), 7.06-7.12(m, 2H), 7.12-7.18(m,1H), 7.25-7.32(m,1H), 7.43-7.54(m,1H), 7.95-8.09(m,1H), 10.47-10.58(m,1H).

LCMS(ESI)：[M]+ m/z：計算值451.2；實測值452.2；Rt=1.832min。LCMS (ESI): [M] + m/z: calculated 451.2; found 452.2; Rt=1.832 min.

實例260.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-(3-(二甲胺基)丙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1384)之合成Example 260. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-(3-(dimethylamino)propoxy)benzene Synthesis of )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1384)

Figure 110128222-A0202-12-1372-359
Figure 110128222-A0202-12-1372-359

步驟1：(2R,5S)-5-甲基-2-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)哌啶-1-甲酸第三丁酯之合成Step 1: (2R,5S)-5-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) ) Synthesis of 3-butyl phenyl)piperidine-1-carboxylate

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸第三丁 酯(3.4g，9.60mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.68g，10.56mmol)及乙酸鉀(2.35g，23.99mmol，1.50mL)一起混合於二噁烷(40.00mL)中且將所得混合物抽真空且用氬氣回填三次。將Pd(dppf)Cl2 *DCM(391.86mg，479.85μmol)添加到先前混合物中且將所得混合物在100℃下加熱隔夜。將反應混合物在真空中濃縮且將水(25mL)添加到殘餘物中。將所得混合物用MTBE(2*40mL)萃取且將經合併之有機層用水(25mL)、鹽水(25mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-5-甲基 -2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁 酯(3.5g，8.72mmol，90.87%產率)。( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (3.4 g, 9.60 mmol), 4,4,5,5-tetramethyl -2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (2.68 g, 10.56 mmol) and potassium acetate (2.35 g, 23.99 mmol, 1.50 mL) were mixed together in dioxane (40.00 mL) and the resulting mixture was evacuated and backfilled with argon three times. Pd(dppf)Cl2*DCM ( 391.86 mg, 479.85 μmol) was added to the previous mixture and the resulting mixture was heated at 100 °C overnight. The reaction mixture was concentrated in vacuo and water (25 mL) was added to the residue. The resulting mixture was extracted with MTBE (2*40 mL) and the combined organic layers were washed with water (25 mL), brine (25 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain ( 2R,5S ) -5-Methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]piperidine-1 - tert -butyl formate (3.5 g, 8.72 mmol, 90.87% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值301.2；實測值302.2；Rt=1.745min。LCMS (ESI): [M-Boc] + m/z: calculated 301.2; found 302.2; Rt=1.745 min.

步驟2：(2R,5S)-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-2-(3-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5S )-5-甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁 酯(3.7g，9.22mmol)溶解於THF(50.73mL)中且在室溫下小心地逐滴添加35%過氧化氫(1.34g，13.83mmol，1.22mL，35%純度)。添加完成之後，將反應混合物攪拌1h且在室溫下逐滴添加氫氧化鈉珠之水溶液(590.01mg，14.75mmol，277.00μL)。添加完成之後，將反應混合物攪拌1h。將反應混合物用檸檬酸酸化且將所得混合物轉移至分離漏斗。分離有機層且將水層用MTBE(2*40mL)萃取。將經合併之有機層用亞硫酸鈉水溶液洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁 酯(3g，粗品)。( 2R,5S )-5-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene tert- butyl ]piperidine-1-carboxylate (3.7 g, 9.22 mmol) was dissolved in THF (50.73 mL) and 35% hydrogen peroxide (1.34 g, 13.83 mmol, 1.22 % hydrogen peroxide (1.34 g, 13.83 mmol, 1.22 mL) was carefully added dropwise at room temperature mL, 35% pure). After the addition was complete, the reaction mixture was stirred for 1 h and an aqueous solution of sodium hydroxide beads (590.01 mg, 14.75 mmol, 277.00 μL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred for 1 h. The reaction mixture was acidified with citric acid and the resulting mixture was transferred to a separation funnel. The organic layer was separated and the aqueous layer was extracted with MTBE (2*40 mL). The combined organic layers were washed with aqueous sodium sulfite, dried over Na2SO4 , filtered and concentrated in vacuo to give ( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine- 3 -Butyl 1-carboxylate (3 g, crude).

LCMS(ESI)：[M-Boc]+ m/z：計算值191.2；實測值192.2；Rt=1.428min。LCMS (ESI): [M-Boc] + m/z: calculated 191.2; found 192.2; Rt=1.428 min.

步驟3：(2R,5S)-2-(3-(3-(二甲胺基)丙氧基)苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成 Step 3: Synthesis of (2R,5S)-2-(3-(3-(dimethylamino)propoxy)phenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁 酯(0.75g，2.57mmol)溶解於DMF(10mL)中且向其中添加3-溴-N,N -二甲基丙-1-胺(1.27g，5.15mmol，HBr)，隨後添加碳酸銫(3.35g，10.30mmol)。將所得混合物在50℃下加熱隔夜。將反應混合物倒入到水(5mL)中且將所得混合物用EtOAc(3*20mL)萃取。將經合併之有機層用水(3*10mL)、鹽水(10mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以得到產物。( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (0.75 g, 2.57 mmol) was dissolved in DMF (10 mL) and to it was added 3 -Bromo- N,N -dimethylpropan-1-amine (1.27 g, 5.15 mmol, HBr) followed by cesium carbonate (3.35 g, 10.30 mmol). The resulting mixture was heated at 50°C overnight. The reaction mixture was poured into water (5 mL) and the resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were washed with water (3*10 mL), brine (10 mL), dried over Na2SO4 , filtered and concentrated in vacuo to give the product.

LCMS(ESI)：[M]+ m/z：計算值376.2；實測值377.2；Rt=1.109min。LCMS (ESI): [M] + m/z: calculated 376.2; found 377.2; Rt=1.109 min.

步驟4：N,N-二甲基3-(3-((2R,5S)-5-甲基哌啶-2-基)苯氧基)丙-1-胺之合成Step 4: Synthesis of N,N-dimethyl 3-(3-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)propan-1-amine

將(2R,5S )-2-[3-[3-(二甲胺基)丙氧基]苯基]-5-甲基哌啶-1-甲酸第三丁 酯(350mg，929.54μmol)溶解於DCM(1.5mL)中且向其中添加TFA(1.5mL)。攪拌所得混合物1h。將反應混合物小心倒入NaHCO3 水溶液(3g於10mL水中)且將所得混合物用DCM(2*15mL)萃取。將經合併之有機層經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得N,N -二甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]丙-1-胺(250mg，粗品)。( 2R,5S )-2-[3-[3-(dimethylamino)propoxy]phenyl]-5-methylpiperidine-1-carboxylic acid tert- butyl ester (350 mg, 929.54 μmol) was dissolved in DCM (1.5 mL) and to this was added TFA (1.5 mL). The resulting mixture was stirred for 1 h. The reaction mixture was poured carefully into aqueous NaHCO 3 (3 g in 10 mL water) and the resulting mixture was extracted with DCM (2*15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give N,N -dimethyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl ]phenoxy]propan-1-amine (250 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值276.2；實測值277.2；Rt=0.581min。LCMS (ESI): [M] + m/z: calculated 276.2; found 277.2; Rt=0.581 min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-(3-(二甲胺基)丙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1384)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-(3-(dimethylamino)propoxy)benzene Synthesis of )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1384)

將N,N -二甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]丙-1-胺(250mg，904.43μmol)溶解於DMF(5mL)中且添加TEA(915.20mg，9.04mmol，1.26mL)，隨後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(189.21mg，904.43μmol)。然後逐滴添加HATU(515.84mg，1.36mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC(2-10min 0-55%水/MeOH+NH3 30mL/min；裝載泵4mL/min MeOH+NH3 ；管柱SunFire 19*100mm)純化，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[3-(二甲胺基)丙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(33.4mg，71.43μmol，7.90%產率)。 N,N -Dimethyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]propan-1-amine (250 mg, 904.43 μmol) was dissolved in DMF (5 mL) and TEA (915.20 mg, 9.04 mmol, 1.26 mL) was added, followed by 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid ( 189.21 mg, 904.43 μmol). HATU (515.84 mg, 1.36 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC (2-10 min 0-55% water/MeOH+ NH3 30 mL/min; loading pump 4 mL/min MeOH+ NH3 ; column SunFire 19*100 mm), to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2-[3-[3-(dimethylamino) Propoxy]phenyl]-5-methyl-1-piperidinyl]acetamide (33.4 mg, 71.43 μmol, 7.90% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.99-1.05(m,3H),1.07-1.13(m,3H),1.26-1.37(m,1H),1.60-1.72(m,1H),1.80-1.91(m,3H),1.97-2.09(m,1H),2.11-2.14(m,6H),2.15-2.25(m,1H),2.34-2.43(m,4H),2.72-3.23(m,1H),3.44-4.02(m,3H),5.11-5.55(m,1H),5.59-5.67(m,2H),6.78-6.95(m,3H),7.25-7.31(m,1H),7.43-7.53(m,1H),7.99-8.09(m,1H),10.41-10.62(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.99-1.05(m,3H), 1.07-1.13(m,3H), 1.26-1.37(m,1H), 1.60-1.72(m,1H) ,1.80-1.91(m,3H),1.97-2.09(m,1H),2.11-2.14(m,6H),2.15-2.25(m,1H),2.34-2.43(m,4H),2.72-3.23( m,1H),3.44-4.02(m,3H),5.11-5.55(m,1H),5.59-5.67(m,2H),6.78-6.95(m,3H),7.25-7.31(m,1H), 7.43-7.53 (m, 1H), 7.99-8.09 (m, 1H), 10.41-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值467.2；實測值468.2；Rt=0.779min。LCMS (ESI): [M] + m/z: calculated 467.2; found 468.2; Rt=0.779 min.

實例261.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-(2-(吡咯啶-1-基)Example 261. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-(2-(pyrrolidine-1- base) 乙氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1391)之合成Synthesis of ethoxy)phenyl)piperidin-1-yl)-2-oxyacetamide (compound 1391)

Figure 110128222-A0202-12-1375-360
Figure 110128222-A0202-12-1375-360

步驟1：(S)-3-甲基-6-(3-(2-(吡咯啶-1-基)乙氧基)苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: (S)-3-Methyl-6-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid Synthesis of tertiary butyl ester

將(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1g，2.90mmol)、1-[2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]乙基]吡咯啶(853.50mg，2.41mmol，HCl)及碳酸鈉(767.30mg，7.24mmol，303.04μL)一起混合於二噁烷(12mL)及水(4mL)之混合物中。將所得混合物抽真空且用氬氣回填三次，且向其中添加Pd(dppf)Cl2 *DCM(98.53mg，120.66μmol)。將所得混合物在90℃下加熱隔夜。將所得混合物冷卻且用水(40mL)稀釋。將所得混合物用EtOAc(2*45mL)萃取且將經合併之有機層用鹽水(40mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由管柱層析(梯度，於氯仿中之MeOH，0%至9%)純化殘餘物(1.12g粗產物)，以獲得(3S )-3-甲基-6-[3-(2-吡咯啶-1-基乙氧基)苯基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(0.534g，1.38mmol，57.25%產率)。( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (1 g, 2.90 mmol), 1-[2-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]ethyl]pyrrolidine ( 853.50 mg, 2.41 mmol, HCl) and sodium carbonate (767.30 mg, 7.24 mmol, 303.04 μL) were mixed together in a mixture of dioxane (12 mL) and water (4 mL). The resulting mixture was evacuated and backfilled with argon three times, and to it was added Pd(dppf)Cl2*DCM (98.53 mg , 120.66 μmol). The resulting mixture was heated at 90°C overnight. The resulting mixture was cooled and diluted with water (40 mL). The resulting mixture was extracted with EtOAc (2*45 mL) and the combined organic layers were washed with brine (40 mL), dried over Na2SO4 , filtered and concentrated in vacuo. The residue (1.12 g crude) was purified by column chromatography (gradient, MeOH in chloroform, 0% to 9%) to obtain ( 3S )-3-methyl-6-[3-(2- Pyrrolidin-1-ylethoxy)phenyl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (0.534 g, 1.38 mmol, 57.25% yield).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.210min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.210 min.

步驟2：(S)-3-甲基-6-(3-(2-(吡咯啶-1-基)乙氧基)苯基)-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of (S)-3-methyl-6-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-2,3,4,5-tetrahydropyridine

將(3S )-3-甲基-6-[3-(2-吡咯啶-1-基乙氧基)苯基]-3,4-二氫-2H -吡啶-1- 甲酸第三丁 酯(0.534g，1.38mmol)溶解於DCM(2mL)中且向其中添加TFA(2mL)。攪拌所得混合物1h。將反應混合物小心倒入NaHCO3 水溶液(3g於25mL水中)且將所得混合物用DCM(2*30mL)萃取。將經合併之有機層經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得(3S )-3-甲基-6-[3-(2-吡咯啶-1-基乙氧基)苯基]-2,3,4,5-四氫吡啶(333mg，1.16mmol，84.16%產率)。( 3S )-3-methyl-6-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (0.534 g, 1.38 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added to it. The resulting mixture was stirred for 1 h. The reaction mixture was carefully poured into aqueous NaHCO 3 (3 g in 25 mL of water) and the resulting mixture was extracted with DCM (2*30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain ( 3S )-3-methyl-6-[3-(2-pyrrolidin-1-ylethoxy)phenyl] - 2,3,4,5-Tetrahydropyridine (333 mg, 1.16 mmol, 84.16% yield).

LCMS(ESI)：[M]+ m/z：計算值286.2；實測值287.2；Rt=0.386min。LCMS (ESI): [M] + m/z: calculated 286.2; found 287.2; Rt=0.386 min.

步驟3：(2R,5S)-5-甲基-2-(3-(2-(吡咯啶-1-基)乙氧基)苯基)哌啶之合成Step 3: Synthesis of (2R,5S)-5-methyl-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)piperidine

將(3S )-3-甲基-6-[3-(2-吡咯啶-1-基乙氧基)苯基]-2,3,4,5-四氫吡啶(333mg，1.16mmol)溶解於MeOH(5mL)中且分批添加硼氫化鈉(87.97mg，2.33mmol，81.91μL)。將所得混合物攪拌隔夜。將水(10mL)添加到反應混合物中且在真空中濃縮所得混合物。將殘餘物用水(15mL)稀釋且將所得混合物用DCM(2*35mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-5-甲基-2-[3-(2-吡咯啶-1-基乙氧基)苯基]哌啶(235mg，814.77μmol，70.08%產率)。( 3S )-3-methyl-6-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-2,3,4,5-tetrahydropyridine (333 mg, 1.16 mmol) was dissolved In MeOH (5 mL) was added sodium borohydride (87.97 mg, 2.33 mmol, 81.91 μL) portionwise. The resulting mixture was stirred overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water (15 mL) and the resulting mixture was extracted with DCM (2*35 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain ( 2R,5S )-5-methyl-2-[3-(2-pyrrolidin-1-ylethoxy )phenyl]piperidine (235 mg, 814.77 μmol, 70.08% yield).

LCMS(ESI)：[M]+ m/z：計算值288.2；實測值289.2；Rt=0.548min。LCMS (ESI): [M] + m/z: calculated 288.2; found 289.2; Rt=0.548 min.

步驟4：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-(2-(吡咯啶-1-基)乙氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 4: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(2-(pyrrolidine-1- Synthesis of yl)ethoxy)phenyl)piperidin-1-yl)-2-side oxyacetamide

將(2R,5S )-5-甲基-2-[3-(2-吡咯啶-1-基乙氧基)苯基]哌啶(235.00mg，814.77μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(170.45mg，814.77μmol)及TEA(412.23mg，4.07mmol，567.81μL)一起混合於DMF(2mL)中且向其中添加HATU(371.76mg，977.72μmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 40-65% MeOH+NH3 ，30mL/min(裝載泵4mL MeOH+NH3 )管柱：SunFire 100*19mm，5微米)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(2-吡咯啶-1-基乙氧基)苯基]-1-哌啶基]乙 醯胺(87.7mg，182.86μmol，22.44%產率)及N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(2-吡咯啶-1-基乙氧基)苯基]-1-哌啶基]乙醯胺(49.4mg，103.00μmol，12.64%產率)。( 2R,5S )-5-methyl-2-[3-(2-pyrrolidin-1-ylethoxy)phenyl]piperidine (235.00 mg, 814.77 μmol), 2-[(6-amine (170.45 mg, 814.77 μmol) and TEA (412.23 mg, 4.07 mmol, 567.81 μL) were mixed together in DMF (2 mL) and To this was added HATU (371.76 mg, 977.72 μmol). The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 40-65% MeOH+ NH3 , 30 mL/min (load pump 4 mL MeOH+ NH3 ) Column: SunFire 100*19 mm, 5 microns) to obtain N- ( 6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3-(2-pyrrolidin-1-yl Ethoxy)phenyl]-1-piperidinyl]acetamide (87.7 mg, 182.86 μmol, 22.44% yield) and N- (6-amino-5-ethyl-3-pyridyl)-2 -Pendant oxy-2-[( 2R,5S )-5-methyl-2-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1-piperidinyl]acetamide (49.4 mg, 103.00 μmol, 12.64% yield).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=0.909min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=0.909 min.

步驟5：掌性分離(化合物1391)之合成Step 5: Synthesis of chiral separation (compound 1391)

對N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(2-吡咯啶-1-基乙氧基)苯基]-1-哌啶基]乙醯胺(49.4mg，103.00μmol)進行掌性分離(Chiralpak AS-H(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：10mL/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(2-吡咯啶-1-基乙氧基)苯基]-1-哌啶基]乙醯胺(34.53mg，72.00μmol，69.90%產率)(RT=8min)。p- N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3-(2-pyrrolidine -1-ylethoxy)phenyl]-1-piperidinyl]acetamide (49.4 mg, 103.00 μmol) for chiral separation (Chiralpak AS-H (250*20 mm, 5 mkm); mobile phase: hexane -IPA-MeOH, 50-25-25; flow rate: 10 mL/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R ,5S )-5-methyl-2-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1-piperidinyl]acetamide (34.53 mg, 72.00 μmol, 69.90% yield rate) (RT=8min).

化合物1391於分析條件下(管柱：AS-H，以己烷-IPA-MeOH，50-25-25，0.6mL/min為流動相)之保留時間為6.92minThe retention time of compound 1391 under analytical conditions (column: AS-H, hexane-IPA-MeOH, 50-25-25, 0.6 mL/min as mobile phase) was 6.92 min

化合物1391：保留時間：6.92minCompound 1391: retention time: 6.92min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.99-1.04(m,3H),1.05-1.13(m,3H),1.25-1.39(m,1H),1.62-1.71(m,5H),1.81-1.95(m,1H),1.96-2.13(m,1H),2.14-2.25(m,1H),2.35-2.45(m,3H),2.68-2.84(m,3H),3.20-3.27(m,1H),3.34-3.50(m,2H),3.96-4.36(m,3H),5.09-5.57(m,1H),5.57-5.69(m,2H),6.78-6.94(m,3H),7.23-7.33(m,1H),7.42-7.53(m,1H),7.97-8.09(m,1H),10.43-10.64(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.99-1.04(m,3H), 1.05-1.13(m,3H), 1.25-1.39(m,1H), 1.62-1.71(m,5H) ,1.81-1.95(m,1H),1.96-2.13(m,1H),2.14-2.25(m,1H),2.35-2.45(m,3H),2.68-2.84(m,3H),3.20-3.27( m,1H),3.34-3.50(m,2H),3.96-4.36(m,3H),5.09-5.57(m,1H),5.57-5.69(m,2H),6.78-6.94(m,3H), 7.23-7.33(m,1H), 7.42-7.53(m,1H), 7.97-8.09(m,1H), 10.43-10.64(m,1H).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=2.115min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=2.115 min.

實例262. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4S,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1157)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1284)、rel-N-(6-胺基-5-Example 262. rel-N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[racemic-(2R,4S,5S)-2-(1, 3-Benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (Compound 1157), rel-N-(6-amino-5-methyl) -3-Pyridinyl)-2-oxo-2-[racemic-(2R,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-isobutyl- 5-Methyl-1-piperidinyl]acetamide (Compound 1284), rel-N-(6-amino-5- 甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1210)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,4R,5R)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1190)之合成Methyl-3-pyridinyl)-2-oxo-2-[racemic-(2S,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-isobutyl yl-5-methyl-1-piperidinyl]acetamide (compound 1210) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2- [racemic-(2S,4R,5R)-2-(1,3-benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide ( Synthesis of compound 1190)

Figure 110128222-A0202-12-1378-361
Figure 110128222-A0202-12-1378-361

步驟1：2-甲氧基-5-甲基-4-(2-甲基丙-1-烯基)吡啶之合成Step 1: Synthesis of 2-methoxy-5-methyl-4-(2-methylprop-1-enyl)pyridine

將4-碘-2-甲氧基-5-甲基吡啶(3.54g，14.23mmol)、4,4,5,5-四甲基-2-(2-甲基丙-1-烯基)-1,3,2-二氧雜硼雜環戊烷(3.24g，17.79mmol)及碳酸鈉(3.77g，35.58mmol，1.49mL)一起混合於二噁烷(52.5mL)及水(17.5mL)之混合物中。將所得混合物抽真空且用氬氣回填三次.將Pd(dppf)Cl2 -CH2 Cl2 (581.04mg，711.51μmol)添加到前一混合物中且將所得混合物在90℃下(油浴)加熱隔夜。將反應混 合物在真空中濃縮，且將殘餘物以水(75mL)稀釋。將所得混合物用DCM(3*75mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由管柱層析(SiO2 ，以己烷-EtOAc為溶劑混合物)純化殘餘物，以獲得2-甲氧基-5-甲基-4-(2-甲基丙-1-烯基)吡啶(2.29g，12.92mmol，90.79%產率)。4-iodo-2-methoxy-5-methylpyridine (3.54 g, 14.23 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl) - 1,3,2-Dioxaborolane (3.24 g, 17.79 mmol) and sodium carbonate (3.77 g, 35.58 mmol, 1.49 mL) were mixed together in dioxane (52.5 mL) and water (17.5 mL) ) in the mixture. The resulting mixture was evacuated and backfilled with argon three times. Pd(dppf)Cl2- CH2Cl2 ( 581.04 mg , 711.51 μmol) was added to the previous mixture and the resulting mixture was heated at 90°C (oil bath) overnight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (75 mL). The resulting mixture was extracted with DCM (3*75 mL) and the combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography ( SiO2 with hexane-EtOAc as solvent mixture) to obtain 2-methoxy-5-methyl-4-(2-methylprop-1-enyl) Pyridine (2.29 g, 12.92 mmol, 90.79% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.63(s,3H),1.84(s,3H),2.02(s,3H),3.79(s,3H),6.11(m,1H),6.47(s,1H),7.86(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.63(s,3H), 1.84(s,3H), 2.02(s,3H), 3.79(s,3H), 6.11(m,1H), 6.47(s, 1H), 7.86(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值178.2；實測值178.2；Rt=1.122min。LCMS (ESI): [M+H] + m/z: calculated 178.2; found 178.2; Rt=1.122 min.

步驟2：4-異丁基-2-甲氧.基-5-甲基吡啶之合成Step 2: Synthesis of 4-isobutyl-2-methoxy.yl-5-methylpyridine

將2-甲氧基-5-甲基-4-(2-甲基丙-1-烯基)吡啶(2.29g，12.92mmol)溶解於MeOH(30mL)中且添加鈀(5%於碳上)Noblyst P1093(549.99mg，5.17mmol)。將所得混合物抽真空且用氫氣回填三次，且在週末內將所得混合物在1atm(氣球)下氫化。過濾出催化劑且將濾液在真空中濃縮，以獲得4-異丁基-2-甲氧基-5-甲基吡啶(2.13g，11.91mmol，92.18%產率)。2-Methoxy-5-methyl-4-(2-methylprop-1-enyl)pyridine (2.29 g, 12.92 mmol) was dissolved in MeOH (30 mL) and palladium (5% on carbon) was added ) Noblyst P1093 (549.99 mg, 5.17 mmol). The resulting mixture was evacuated and backfilled with hydrogen three times, and the resulting mixture was hydrogenated at 1 atm (balloon) over the weekend. The catalyst was filtered off and the filtrate was concentrated in vacuo to obtain 4-isobutyl-2-methoxy-5-methylpyridine (2.13 g, 11.91 mmol, 92.18% yield).

LCMS(ESI)：[M+H]+ m/z：計算值180.2；實測值180.2；Rt=1.327min。LCMS (ESI): [M+H] + m/z: calculated 180.2; found 180.2; Rt=1.327 min.

步驟3：4-異丁基-5-甲基吡啶-2-醇之合成Step 3: Synthesis of 4-isobutyl-5-methylpyridin-2-ol

將4-異丁基-2-甲氧基-5-甲基吡啶(1.88g，10.49mmol)溶解於48%HBr溶液(53mL)中且將所得混合物回流隔夜。將反應混合物冷卻且用Na2 CO3 中和。將所得混合物用氯仿(2*50mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得4-異丁基-5-甲基吡啶-2-醇(1.69g，10.20mmol，97.29%產率)。4-Isobutyl-2-methoxy-5-methylpyridine (1.88 g, 10.49 mmol) was dissolved in 48% HBr solution (53 mL) and the resulting mixture was refluxed overnight. The reaction mixture was cooled and neutralized with Na2CO3 . The resulting mixture was extracted with chloroform (2*50 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain 4-isobutyl-5-methylpyridin-2-ol ( 1.69 g, 10.20 mmol, 97.29% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.89(m,6H),1.79(m,1H),1.94(s,3H),2.26(m,2H),6.05(s,1H),7.08(s,1H),11.18(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.89(m, 6H), 1.79(m, 1H), 1.94(s, 3H), 2.26(m, 2H), 6.05(s, 1H), 7.08(s, 1H), 11.18(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值166.2；實測值166.2；Rt=1.104min。LCMS (ESI): [M+H] + m/z: calculated 166.2; found 166.2; Rt=1.104 min.

步驟4：4-異丁基-5-甲基哌啶-2-酮之合成Step 4: Synthesis of 4-isobutyl-5-methylpiperidin-2-one

將4-異丁基-5-甲基吡啶-2-醇(1.91g，11.57mmol)溶解於MeOH(20mL)中且向其中添加AcOH(7mL)。將Pd/C JM A402028-10(369.24mg，3.47mmol)添加到前一混合物中且將所得混合物在50atm、60℃下氫化隔夜。藉由等分試樣之NMR得到10%產物。將乾燥的487型鈀(10%於碳上)(738.49mg，6.94mmol)添加到反應混合物中且將所得混合物在50atm、60℃下氫化隔夜。藉由等分試樣之NMR得到80%產物。將乾燥的487型鈀(10%於碳上)(246.16mg，2.31mmol)添加到反應混合物中且在週末內將所得混合物在50atm、60℃下氫化。冷卻反應混合物且過濾。將濾液在真空中濃縮且將殘餘物溶解於CHCl3 中。將所得溶液用NaHCO3 水溶液洗滌且將有機層在真空中濃縮，以獲得4-異丁基-5-甲基哌啶-2-酮(1.80g，10.61mmol，91.74%產率)。4-Isobutyl-5-methylpyridin-2-ol (1.91 g, 11.57 mmol) was dissolved in MeOH (20 mL) and AcOH (7 mL) was added to it. Pd/C JM A402028-10 (369.24 mg, 3.47 mmol) was added to the previous mixture and the resulting mixture was hydrogenated at 50 atm, 60 °C overnight. 10% product was obtained by NMR of an aliquot. Dry palladium Form 487 (10% on carbon) (738.49 mg, 6.94 mmol) was added to the reaction mixture and the resulting mixture was hydrogenated at 50 atm, 60 °C overnight. 80% product was obtained by NMR of an aliquot. Dry palladium type 487 (10% on carbon) (246.16 mg, 2.31 mmol) was added to the reaction mixture and the resulting mixture was hydrogenated at 50 atm, 60 °C over the weekend. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in CHCl3 . The resulting solution was washed with aqueous NaHCO 3 and the organic layer was concentrated in vacuo to obtain 4-isobutyl-5-methylpiperidin-2-one (1.80 g, 10.61 mmol, 91.74% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.79-0.99(m,9H),0.99-1.10(m,2H),1.27-1.86(m,4H),2.12-2.21(m,1H),2.76-2.85(m,1H),3.09-3.19(m,1H),7.26-7.36(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.79-0.99(m, 9H), 0.99-1.10(m, 2H), 1.27-1.86(m, 4H), 2.12-2.21(m, 1H) , 2.76-2.85 (m, 1H), 3.09-3.19 (m, 1H), 7.26-7.36 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值170.2；實測值170.2；Rt=1.179min。LCMS (ESI): [M+H] + m/z: calculated 170.2; found 170.2; Rt=1.179 min.

步驟5：4-異丁基-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of 3-butyl 4-isobutyl-5-methyl-2-oxypiperidine-1-carboxylate

將4-異丁基-5-甲基哌啶-2-酮(1.80g，10.61mmol)及DMAP(129.63mg，1.06mmol)溶解於MeCN(35mL)中且添加二碳酸二-第三丁酯(2.66g，12.20mmol，2.80mL)。將所得混合物攪拌隔夜。在真空中濃縮反應混合物且將殘餘物溶解於氯仿(75mL)中。將所得溶液用NaHSO4 溶液(2*40mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得4-異丁基-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2.77g，10.28mmol，96.91%產率)。4-Isobutyl-5-methylpiperidin-2-one (1.80 g, 10.61 mmol) and DMAP (129.63 mg, 1.06 mmol) were dissolved in MeCN (35 mL) and di-tert-butyl dicarbonate was added (2.66 g, 12.20 mmol, 2.80 mL). The resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform (75 mL). The resulting solution was washed with NaHSO 4 solution (2*40 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain 4-isobutyl-5-methyl-2-oxypiperidine-1 - tert-butyl formate (2.77 g, 10.28 mmol, 96.91% yield).

LCMS(ESI)：[M-tBu]+ m/z：計算值214.2；實測值214.2；Rt=1.575min。LCMS (ESI): [M-tBu] + m/z: calculated 214.2; found 214.2; Rt=1.575 min.

步驟6：4-異丁基-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 6: Synthesis of 4-isobutyl-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將六甲基二矽氮烷(2.07g，12.85mmol，2.68mL)溶解於THF(30mL)中且在氬氣氣氛下將所得溶液冷卻至-78℃。在-78℃下逐滴添加正丁基鋰(803.64mg，12.55mmol)且將所得混合物攪拌30min。在-78℃下逐滴添加4-異丁基-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2.77g，10.28mmol)於THF(10mL)中之溶液且在添加完成之後，將所得混合物在-78℃下攪拌1.5h。將1,1,1-三氟-N-苯基-N-(三氟甲基磺醯基)甲磺醯胺(3.86g，10.80mmol)一次性添加到將反應混合物且將所得混合物在-78℃下攪拌30min。然後，使反應混合物升溫至室溫且攪拌隔夜。將反應混合物用水(15mL)及MTBE(50mL)稀釋且分離有機層。將水層另外用MTBE(35mL)萃取且將經合併之有機層用10%氫氧化鈉水溶液(3*15mL)洗滌，經碳酸鉀乾燥且在真空中濃縮。將殘餘物用己烷/MTBE混合物稀釋(3：1，40mL，重複5次)且攪拌30min。將所得混濁溶液自油狀殘餘物傾析透過矽膠短墊(20g無水矽膠)過濾且蒸發，以獲得粗品4-異丁基-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.92g，9.76mmol，94.91%產率)，其不經純化即用於進一步的步驟中。Hexamethyldisilazane (2.07 g, 12.85 mmol, 2.68 mL) was dissolved in THF (30 mL) and the resulting solution was cooled to -78 °C under an argon atmosphere. n-Butyllithium (803.64 mg, 12.55 mmol) was added dropwise at -78 °C and the resulting mixture was stirred for 30 min. A solution of tert-butyl 4-isobutyl-5-methyl-2-oxypiperidine-1-carboxylate (2.77 g, 10.28 mmol) in THF (10 mL) was added dropwise at -78 °C and After the addition was complete, the resulting mixture was stirred at -78 °C for 1.5 h. 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (3.86 g, 10.80 mmol) was added to the reaction mixture in one portion and the resulting mixture was placed in- Stir for 30 min at 78°C. Then, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (15 mL) and MTBE (50 mL) and the organic layer was separated. The aqueous layer was additionally extracted with MTBE (35 mL) and the combined organic layers were washed with 10% aqueous sodium hydroxide solution (3*15 mL), dried over potassium carbonate and concentrated in vacuo. The residue was diluted with a hexane/MTBE mixture (3:1, 40 mL, repeated 5 times) and stirred for 30 min. The resulting cloudy solution was decanted from the oily residue, filtered through a short pad of silica gel (20 g anhydrous silica) and evaporated to give crude 4-isobutyl-3-methyl-6-(trifluoromethylsulfonyloxyloxy) )-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.92 g, 9.76 mmol, 94.91% yield), which was used in the further step without purification.

LCMS(ESI)：[M-Tf-tBu]+ m/z：計算值214.2；實測值214.2；Rt=1.291min。LCMS (ESI): [M-Tf-tBu] + m/z: calculated 214.2; found 214.2; Rt=1.291 min.

步驟7：6-(1,3-苯并噻唑-5-基)-4-異丁基-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 7: Synthesis of 6-(1,3-benzothiazol-5-yl)-4-isobutyl-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將4-異丁基-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.2g，2.99mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(936.76mg，3.59mmol)及碳酸鈉(633.66mg，5.98mmol，250.26μL)混合於二噁烷(9mL)及水(3mL)之混合物中。將所得混合物抽真空且用氬氣回填三次，且添加Pd(dppf)Cl2 -CH2 Cl2 (122.06mg，149.46μmol)。將所得混合物抽真空且用氬氣回填，且將所得混合物在90℃下加熱隔夜。將所得混合物冷卻且用水(45mL)稀釋。將所得混合物用EtOAc(2*75mL)萃取且將經合併之有機層 用鹽水(10mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。將殘餘物(1.3g粗產物)與殘餘物(240mg粗產物)合併且藉由管柱層析(梯度，於己烷中之EtOAc，0%至9%)純化，以獲得6-(1,3-苯并噻唑-5-基)-4-異丁基-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.922g，2.39mmol，79.79%產率)。4-Isobutyl-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.2 g, 2.99 mmol ), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazole (936.76 mg, 3.59 mmol ) and sodium carbonate (633.66 mg, 5.98 mmol, 250.26 μL) were mixed in a mixture of dioxane (9 mL) and water (3 mL). The resulting mixture was evacuated and backfilled with argon three times, and Pd(dppf)Cl2- CH2Cl2 ( 122.06 mg , 149.46 μmol) was added. The resulting mixture was evacuated and backfilled with argon, and the resulting mixture was heated at 90°C overnight. The resulting mixture was cooled and diluted with water (45 mL). The resulting mixture was extracted with EtOAc (2*75 mL) and the combined organic layers were washed with brine (10 mL), dried over Na2SO4 , filtered and concentrated in vacuo. The residue (1.3 g crude) was combined with the residue (240 mg crude) and purified by column chromatography (gradient, EtOAc in hexanes, 0% to 9%) to give 6-(1, 3-Benzothiazol-5-yl)-4-isobutyl-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.922 g, 2.39 mmol, 79.79% yield Rate).

LCMS(ESI)：[M+H]+ m/z：計算值387.2；實測值387.5；Rt=1.756min。LCMS (ESI): [M+H] + m/z: calculated 387.2; found 387.5; Rt=1.756 min.

步驟8：5-(4-異丁基-3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑之合成Step 8: Synthesis of 5-(4-isobutyl-3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole

將6-(1,3-苯并噻唑-5-基)-4-異丁基-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.922g，2.39mmol)溶解於DCM(4mL)中且添加TFA(4mL)。攪拌所得混合物1h。將反應混合物倒入到NaHCO3 水溶液(7g於40mL水中)中且將所得混合物用DCM(2*45mL)萃取。將經合併之有機層用水(20mL)洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得5-(4-異丁基-3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(642mg，2.24mmol，93.97%產率)。6-(1,3-Benzothiazol-5-yl)-4-isobutyl-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.922 g, 2.39 mmol) was dissolved in DCM (4 mL) and TFA (4 mL) was added. The resulting mixture was stirred for 1 h. The reaction mixture was poured into aqueous NaHCO 3 (7 g in 40 mL water) and the resulting mixture was extracted with DCM (2*45 mL). The combined organic layers were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 5-(4-isobutyl-3-methyl-2,3,4,5-tetrahydro Pyridin-6-yl)-1,3-benzothiazole (642 mg, 2.24 mmol, 93.97% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.88-1.01(m,9H),1.50-2.01(m,4H),2.25(m,1H),2.48-2.96(m,2H),3.86-4.02(m,2H),7.96(d,1H),8.01(d,1H),8.46(s,1H),9.01(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.88-1.01(m, 9H), 1.50-2.01(m, 4H), 2.25(m, 1H), 2.48-2.96(m, 2H), 3.86 -4.02(m, 2H), 7.96(d, 1H), 8.01(d, 1H), 8.46(s, 1H), 9.01(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值287.2；實測值287.2；Rt=0.904min。LCMS (ESI): [M+H] + m/z: calculated 287.2; found 287.2; Rt=0.904 min.

步驟9：外消旋-5-[(2R,5S)-4-異丁基-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 9: Synthesis of racemic-5-[(2R,5S)-4-isobutyl-5-methyl-2-piperidinyl]-1,3-benzothiazole

溶解5-(4-異丁基-3-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(642mg，2.24mmol)且添加硼氫化鈉(169.59mg，4.48mmol，157.91μL)。將所得混合物攪拌隔夜。將水(10mL)添加到反應混合物中且將所得混合物在真空中濃縮。將殘餘物用水(20mL)稀釋且將所得混合物用DCM(2*45mL)萃取。將經合併之有機層經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得5-[(2R,5S)-4-異丁基-5-甲基-2-哌啶基]-1,3-苯并噻唑(644mg，2.23mmol，99.61%產率)。5-(4-Isobutyl-3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole (642 mg, 2.24 mmol) was dissolved and sodium borohydride was added (169.59 mg, 4.48 mmol, 157.91 μL). The resulting mixture was stirred overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water (20 mL) and the resulting mixture was extracted with DCM (2*45 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 5-[(2R,5S)-4-isobutyl-5-methyl-2-piperidinyl]-1,3 - benzothiazole (644 mg, 2.23 mmol, 99.61% yield).

LCMS(ESI)：[M+H]+ m/z：計算值289.0；實測值289.0；Rt=0.963min。LCMS (ESI): [M+H] + m/z: calculated 289.0; found 289.0; Rt=0.963 min.

步驟10：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成：Step 10: Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl) Synthesis of -4-isobutyl-5-methyl-1-piperidinyl]-2-oxoacetamide:

將5-[(2R,5S)-4-異丁基-5-甲基-2-哌啶基]-1,3-苯并噻唑(235mg，814.70μmol)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(159.01mg，814.70μmol)及三乙胺(412.20mg，4.07mmol，567.76μL)一起混合於DMF(2mL)中且添加HATU(371.73mg，977.64μmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min；55-70%甲醇+NH3 ；流速30mL/min(裝載泵4mL/min甲醇)，管柱Sun Fire C18 100*19mm，5um)，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(158.4mg，340.20μmol，41.76%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(42.6mg，91.49μmol，11.23%產率)。5-[(2R,5S)-4-isobutyl-5-methyl-2-piperidinyl]-1,3-benzothiazole (235 mg, 814.70 μmol), 2-[(6-amino -5-Methyl-3-pyridyl)amino]-2-oxoacetic acid (159.01 mg, 814.70 μmol) and triethylamine (412.20 mg, 4.07 mmol, 567.76 μL) were mixed together in DMF (2 mL) And HATU (371.73 mg, 977.64 μmol) was added. The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min; 55-70% methanol + NH3 ; flow rate 30 mL/min (load pump 4 mL/min methanol), column Sun Fire C18 100*19 mm, 5um) to obtain N -(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-4-isobutyl-5 -Methyl-1-piperidinyl]-2-oxyacetamide (158.4 mg, 340.20 μmol, 41.76% yield) and N-(6-amino-5-methyl-3-pyridyl) -2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]-2-side oxyethyl Amide (42.6 mg, 91.49 μmol, 11.23% yield).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=1.107min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=1.107 min.

步驟11：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4S,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1157)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1284)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1210)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,4R,5R)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(化合物1190)之合成Step 11: rel-N-(6-amino-5-methyl-3-pyridinyl)-2-oxy-2-[rac-(2R,4S,5S)-2-(1, 3-Benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (Compound 1157), rel-N-(6-amino-5-methyl) -3-Pyridinyl)-2-oxo-2-[racemic-(2R,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-isobutyl- 5-Methyl-1-piperidinyl]acetamide (Compound 1284), rel-N-(6-amino-5-methyl-3-pyridyl)-2-oxo-2-[exo Racemic-(2S,4S,5R)-2-(1,3-benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (Compound 1210 ) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[racemic-(2S,4R,5R)-2-(1,3 - Synthesis of benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (compound 1190)

對外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(158.4mg，340.20μmol)進行掌性分離(管柱：Chiralcel OD-H(250 x 20mm，5mkm)；流動 相：己烷-IPA-MeOH，80-10-10；流速：12mL/min；管柱溫度：24℃；波長：205nm、215nm；保留時間(化合物1157)=29,35min；保留時間(化合物1284)=35,45min；保留時間(化合物1210)=41,11min；保留時間(化合物1190)=44,65min)，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4S,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(44.91mg，96.45μmol，28.35%產率)、N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(24.39mg，52.38μmol，15.40%產率)、N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(23.15mg，49.72μmol，14.61%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,4R,5R)-2-(1,3-苯并噻唑-5-基)-4-異丁基-5-甲基-1-哌啶基]乙醯胺(47.5mg，102.02μmol，29.99%產率)。Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-(1,3-benzene Chiral separation of thiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (158.4 mg, 340.20 μmol) (Column: Chiralcel OD-H (250 x 20mm, 5mkm); flow Phase: Hexane-IPA-MeOH, 80-10-10; Flow Rate: 12mL/min; Column Temperature: 24°C; Wavelength: 205nm, 215nm; Retention Time (Compound 1157)=29,35min; Retention Time (Compound 1284 ) = 35, 45 min; retention time (compound 1210) = 41, 11 min; retention time (compound 1190) = 44, 65 min) to obtain N-(6-amino-5-methyl-3-pyridyl)- 2-Pendant oxy-2-[racemic-(2R,4S,5S)-2-(1,3-benzothiazol-5-yl)-4-isobutyl-5-methyl-1- piperidinyl]acetamide (44.91 mg, 96.45 μmol, 28.35% yield), N-(6-amino-5-methyl-3-pyridyl)-2-oxo-2-[elimination Spin-(2R,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (24.39 mg, 52.38 μmol, 15.40% yield), N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[rac-(2S,4S,5R)-2 -(1,3-Benzothiazol-5-yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (23.15 mg, 49.72 μmol, 14.61% yield) and N- (6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[racemic-(2S,4R,5R)-2-(1,3-benzothiazole-5 -yl)-4-isobutyl-5-methyl-1-piperidinyl]acetamide (47.5 mg, 102.02 μmol, 29.99% yield).

化合物1157 ：產率：44.91mg(28.35%) Compound 1157 : Yield: 44.91 mg (28.35%)

RT(Chiralpak OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=26.450min。RT (Chiralpak OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 80-10-10, 0.6 mL/min) = 26.450 min.

1 H NMR(600MHz,dmso)δ 0.80-0.86(m,6H),0.98-1.02(m,3H),1.07-1.20(m,3H),1.48-1.55(m,1H),1.58-1.71(m,2H),1.86-2.04(m,3H),2.11-2.22(m,1H),3.41-3.68(m,1H),3.74-4.12(m,1H),5.14-5.38(m,1H),5.47-5.68(m,2H),7.35-7.63(m,2H),7.89-8.03(m,2H),8.03-8.15(m,1H),9.27-9.40(m,1H),9.85-10.53(m,1H)。 1 H NMR(600MHz,dmso)δ 0.80-0.86(m,6H),0.98-1.02(m,3H),1.07-1.20(m,3H),1.48-1.55(m,1H),1.58-1.71(m ,2H),1.86-2.04(m,3H),2.11-2.22(m,1H),3.41-3.68(m,1H),3.74-4.12(m,1H),5.14-5.38(m,1H),5.47 -5.68(m, 2H), 7.35-7.63(m, 2H), 7.89-8.03(m, 2H), 8.03-8.15(m, 1H), 9.27-9.40(m, 1H), 9.85-10.53(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=1.104min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=1.104 min.

化合物1284： 產率：24.39mg(15.40%) Compound 1284: Yield: 24.39 mg (15.40%)

RT(Chiralpak OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=31.136min。RT (Chiralpak OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 80-10-10, 0.6 mL/min) = 31.136 min.

1 H NMR(600MHz,dmso)δ 0.42-0.64(m,3H),0.71-0.81(m,6H),0.83-0.98(m, 2H),1.42-1.57(m,1H),1.74-1.83(m,1H),1.87-2.10(m,5H),2.12-2.20(m,1H),2.71-3.05(m,1H),3.80-4.34(m,1H),5.23-5.70(m,3H),7.21-7.56(m,2H),7.77-8.07(m,2H),8.07-8.16(m,1H),9.34-9.41(m,1H),10.30-10.59(m,1H)。 1 H NMR(600MHz,dmso)δ 0.42-0.64(m,3H),0.71-0.81(m,6H),0.83-0.98(m,2H),1.42-1.57(m,1H),1.74-1.83(m ,1H),1.87-2.10(m,5H),2.12-2.20(m,1H),2.71-3.05(m,1H),3.80-4.34(m,1H),5.23-5.70(m,3H),7.21 -7.56(m, 2H), 7.77-8.07(m, 2H), 8.07-8.16(m, 1H), 9.34-9.41(m, 1H), 10.30-10.59(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=1.118min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=1.118 min.

化合物1210： 產率：23.15mg(14.61%) Compound 1210: Yield: 23.15 mg (14.61%)

RT(Chiralpak OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=35.461min。RT (Chiralpak OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 80-10-10, 0.6 mL/min) = 35.461 min.

1 H NMR(600MHz,dmso)δ 0.41-0.63(m,3H),0.70-0.81(m,6H),0.82-0.98(m,2H),1.43-1.56(m,1H),1.71-1.84(m,1H),1.91-2.09(m,5H),2.12-2.21(m,1H),2.72-3.06(m,1H),3.78-4.36(m,1H),5.28-5.68(m,3H),7.22-7.56(m,2H),7.75-8.07(m,2H),8.07-8.16(m,1H),9.35-9.40(m,1H),10.27-10.57(m,1H)。 1 H NMR(600MHz,dmso)δ 0.41-0.63(m,3H),0.70-0.81(m,6H),0.82-0.98(m,2H),1.43-1.56(m,1H),1.71-1.84(m ,1H),1.91-2.09(m,5H),2.12-2.21(m,1H),2.72-3.06(m,1H),3.78-4.36(m,1H),5.28-5.68(m,3H),7.22 -7.56(m, 2H), 7.75-8.07(m, 2H), 8.07-8.16(m, 1H), 9.35-9.40(m, 1H), 10.27-10.57(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=1.121min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=1.121 min.

化合物1190： 產率：47.5mg(29.99%) Compound 1190: Yield: 47.5 mg (29.99%)

RT(Chiralpak OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，80-10-10，0.6mL/min)=38.015min。RT (Chiralpak OD-H (250*4.6, 5mkm), Hexane-IPA-MeOH, 80-10-10, 0.6mL/min)=38.015min.

1 H NMR(600MHz,dmso)δ 0.80-0.87(m,6H),0.98-1.02(m,3H),1.08-1.25(m,3H),1.48-1.55(m,1H),1.57-1.69(m,2H),1.87-2.05(m,3H),2.11-2.21(m,1H),3.39-3.67(m,1H),3.75-4.09(m,1H),5.11-5.37(m,1H),5.46-5.67(m,2H),7.31-7.52(m,2H),7.87-8.18(m,3H),9.33-9.41(m,1H),9.93-10.51(m,1H)。 1 H NMR(600MHz,dmso)δ 0.80-0.87(m,6H),0.98-1.02(m,3H),1.08-1.25(m,3H),1.48-1.55(m,1H),1.57-1.69(m ,2H),1.87-2.05(m,3H),2.11-2.21(m,1H),3.39-3.67(m,1H),3.75-4.09(m,1H),5.11-5.37(m,1H),5.46 -5.67(m, 2H), 7.31-7.52(m, 2H), 7.87-8.18(m, 3H), 9.33-9.41(m, 1H), 9.93-10.51(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=1.119min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=1.119 min.

實例263.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-(2-(二甲胺基)乙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1175)之合成Example 263. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-(2-(dimethylamino)ethoxy)benzene yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1175)

Figure 110128222-A0202-12-1386-362
Figure 110128222-A0202-12-1386-362

將N,N -二甲基-2-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]乙胺(293mg，1.12mmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(233.61mg，1.12mmol)及TEA(564.97mg，5.58mmol，778.20μL)一起混合於DMF(3mL)中且向其中添加HATU(509.51mg，1.34mmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 10-50% MeCN+FA，30mL/min(裝載泵4mL MeCN+FA)管柱：SunFire 100*19mm，5微米)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[3-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18.7mg，37.43μmol，3.35%產率，HCOOH)。 N,N -dimethyl-2-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]ethanamine (293 mg, 1.12 mmol), 2-[(6 -Amino-5-ethyl-3-pyridyl)amino]-2-side oxyacetic acid (233.61 mg, 1.12 mmol) and TEA (564.97 mg, 5.58 mmol, 778.20 μL) were mixed together in DMF (3 mL) and to it was added HATU (509.51 mg, 1.34 mmol). The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 10-50% MeCN+FA, 30 mL/min (loading pump 4 mL MeCN+FA) Column: SunFire 100*19 mm, 5 microns) to obtain N- (6- Amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-[3-[2-(dimethylamino)ethoxy]phenyl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide (18.7 mg, 37.43 μmol, 3.35% yield, HCOOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.06(m,3H),1.06-1.17(m,3H),1.27-1.38(m,1H),1.58-1.76(m,1H),1.82-1.92(m,1H),1.97-2.15(m,1H),2.19-2.21(m,6H),2.36-2.43(m,2H),2.59-2.76(m,3H),3.22-3.24(m,1H),3.42-3.48(m,1H),4.01-4.07(m,2H),5.09-5.57(m,1H),5.57-5.66(m,2H),6.77-6.94(m,3H),7.25-7.32(m,1H),7.43-7.52(m,1H),7.97-8.07(m,1H),10.49-10.56(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.06(m,3H), 1.06-1.17(m,3H), 1.27-1.38(m,1H), 1.58-1.76(m,1H) ,1.82-1.92(m,1H),1.97-2.15(m,1H),2.19-2.21(m,6H),2.36-2.43(m,2H),2.59-2.76(m,3H),3.22-3.24( m,1H),3.42-3.48(m,1H),4.01-4.07(m,2H),5.09-5.57(m,1H),5.57-5.66(m,2H),6.77-6.94(m,3H), 7.25-7.32(m,1H), 7.43-7.52(m,1H), 7.97-8.07(m,1H), 10.49-10.56(m,1H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.946min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.946 min.

Figure 110128222-A0202-12-1386-363
Figure 110128222-A0202-12-1386-363

對N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(117.1mg，258.17μmol)進行掌性分離(Chiralpak AD-H-V(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(99.36mg，219.06μmol，84.85%產率)(RT=41.69min)。p- N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2-[3-[2-(dimethylamino)ethyl oxy]phenyl]-5-methyl-1-piperidinyl]acetamide (117.1 mg, 258.17 μmol) for chiral separation (Chiralpak AD-HV (250*20 mm, 5 mkm), hexane-IPA- MeOH, 50-25-25, 12 mL/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2 -[3-[2-(Dimethylamino)ethoxy]phenyl]-5-methyl-1-piperidinyl]acetamide (99.36 mg, 219.06 μmol, 84.85% yield) (RT= 41.69min).

化合物1175於分析條件下(管柱：AD-H，以IPA-MeOH，50-50，0.6mL/min為流動相)之保留時間為35.98minThe retention time of compound 1175 under analytical conditions (column: AD-H, with IPA-MeOH, 50-50, 0.6 mL/min as mobile phase) was 35.98 min

化合物1175 ：保留時間：35.98min Compound 1175 : retention time: 35.98min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.06-1.14(m,3H),1.26-1.39(m,1H),1.60-1.72(m,1H),1.82-1.92(m,1H),1.96-2.13(m,1H),2.13-2.18(m,1H),2.18-2.23(m,6H),2.34-2.41(m,2H),2.58-2.61(m,2H),2.72-3.24(m,1H),3.42-4.00(m,1H),4.00-4.06(m,2H),5.06-5.57(m,1H),5.57-5.66(m,2H),6.77-6.84(m,1H),6.84-6.93(m,2H),7.20-7.34(m,1H),7.41-7.56(m,1H),7.96-8.11(m,1H),10.46-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.03(m,3H), 1.06-1.14(m,3H), 1.26-1.39(m,1H), 1.60-1.72(m,1H) ,1.82-1.92(m,1H),1.96-2.13(m,1H),2.13-2.18(m,1H),2.18-2.23(m,6H),2.34-2.41(m,2H),2.58-2.61( m,2H),2.72-3.24(m,1H),3.42-4.00(m,1H),4.00-4.06(m,2H),5.06-5.57(m,1H),5.57-5.66(m,2H), 6.77-6.84(m, 1H), 6.84-6.93(m, 2H), 7.20-7.34(m, 1H), 7.41-7.56(m, 1H), 7.96-8.11(m, 1H), 10.46-10.57(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=0.895min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=0.895 min.

實例264.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-(1-甲基哌啶-3-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1353、化合物1285及化合物1090)之合成Example 264. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-(1-methylpiperidine-3 Synthesis of -yl)phenyl)piperidin-1-yl)-2-oxoacetamide (Compound 1353, Compound 1285 and Compound 1090)

Figure 110128222-A0202-12-1388-364
Figure 110128222-A0202-12-1388-364

步驟1：(2R,5S)-2-(3-溴苯基)-5-甲基哌啶之合成Step 1: Synthesis of (2R,5S)-2-(3-bromophenyl)-5-methylpiperidine

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸第三丁 酯(4.3g，12.14mmol)溶解於DCM(16mL)中且向其中添加TFA(16mL)。攪拌所得混合物1h。將反應混合物在真空中濃縮且將K2 CO3 水溶液(70mL水中之25g)小心添加到殘餘物中。將所得混合物用DCM(2*40mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-2-(3-溴苯基)-5-甲基哌啶(2.70g，10.60mmol，87.36%產率)。( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (4.3 g, 12.14 mmol) was dissolved in DCM (16 mL) and TFA was added to it (16 mL). The resulting mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and aqueous K2CO3 ( 25 g in 70 mL water) was carefully added to the residue. The resulting mixture was extracted with DCM (2*40 mL) and the combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo to obtain ( 2R,5S )-2-(3-bromophenyl)- 5-Methylpiperidine (2.70 g, 10.60 mmol, 87.36% yield).

LCMS(ESI)：[M]+ m/z：計算值254.2；實測值255.2；Rt=0.619min。LCMS (ESI): [M] + m/z: calculated 254.2; found 255.2; Rt=0.619 min.

步驟2：(2R,5S)-2-(3-溴苯基)-5-甲基哌啶-1-甲酸苯甲酯之合成Step 2: Synthesis of (2R,5S)-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylic acid benzyl ester

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶(2.7g，10.62mmol)溶解於THF(25mL)中且向其中添加碳酸鈉(2.25g，21.25mmol，889.35μL)，隨後添加水(30mL)。將所得混合物在冰浴中冷卻至0℃且在0℃下逐滴添加氯甲酸苯甲酯(1.90g，11.15mmol，1.59mL)於THF(5mL)中之溶液。在添加完成之後，使反應混合物升溫至室溫且攪拌隔夜。將反應混合物在真空中濃縮且將殘餘物用水(50mL)稀釋。將所得混合物用MTBE(2*50mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸苯甲酯(4.27g，粗品)。( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine (2.7 g, 10.62 mmol) was dissolved in THF (25 mL) and to it was added sodium carbonate (2.25 g, 21.25 mmol, 889.35 μL), followed by the addition of water (30 mL). The resulting mixture was cooled to 0 °C in an ice bath and a solution of benzyl chloroformate (1.90 g, 11.15 mmol, 1.59 mL) in THF (5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with water (50 mL). The resulting mixture was extracted with MTBE (2*50 mL) and the combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo to obtain ( 2R,5S )-2-(3-bromophenyl)- Benzyl 5-methylpiperidine-1-carboxylate (4.27 g, crude).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=1.636min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=1.636 min.

步驟3：3-(3-((2R,5S)-1-((苯甲基氧基)羰基)-5-甲基哌啶-2-基)苯基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: 3-(3-((2R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-2-yl)phenyl)-5,6-dihydropyridine -1(2H)-Synthesis of tert-butyl formate

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸苯甲酯(1g，2.58mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H -吡啶-1-甲酸第三丁 酯(915.76mg，2.96mmol)及碳酸鈉(545.92mg，5.15mmol，215.61μL)溶解於二噁烷(7.5mL)及水(2.5mL)之混合物中。將所得混合物抽真空且用氬氣回填三次，且向其中添加Pd(dppf)Cl2 *DCM(105.16mg，128.77μmol)。將所得混合物在90℃下加熱隔夜。將反應混合物在真空中濃縮且將殘餘物用水(20mL)稀釋。將所得混合物用EtOAc(2*30mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由管柱層析純化殘餘物，以獲得5-[3-[(2R,5S )-1-苯甲基氧基羰基-5-甲基-2-哌啶基]苯基]-3,6-二氫-2H -吡啶-1-甲酸第三丁 酯(800mg，1.63mmol，63.31%產率)。( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylic acid benzyl ester (1 g, 2.58 mmol), 5-(4,4,5,5-tetramethyl) tert-butyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro- 2H -pyridine-1- carboxylate (915.76 mg, 2.96 mmol) and carbonic acid Sodium (545.92 mg, 5.15 mmol, 215.61 μL) was dissolved in a mixture of dioxane (7.5 mL) and water (2.5 mL). The resulting mixture was evacuated and backfilled with argon three times, and to it was added Pd(dppf)Cl 2 *DCM (105.16 mg, 128.77 μmol). The resulting mixture was heated at 90°C overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2*30 mL) and the combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain 5-[3-[( 2R,5S )-1-benzyloxycarbonyl-5-methyl-2-piperidinyl]phenyl]-3, 6-Dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (800 mg, 1.63 mmol, 63.31% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值390.2；實測值391.2；Rt=1.885min。LCMS (ESI): [M-Boc] + m/z: calculated 390.2; found 391.2; Rt=1.885 min.

步驟4：3-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of 3-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

將5-[3-[(2R,5S )-1-苯甲基氧基羰基-5-甲基-2-哌啶基]苯基]-3,6-二氫-2H -吡啶-1-甲酸第三丁 酯(800.00mg，1.63mmol)溶解於MeOH(30mL)中且向其中添加鈀(10%於碳上)(433.81mg，407.64μmol，10%純度)。將所得混合物在50atm下氫化隔夜。過濾出催化劑且將濾液在真空中濃縮，以獲得3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]哌啶-1-甲酸第三丁 酯(661mg，粗品)。5-[3-[( 2R,5S )-1-benzyloxycarbonyl-5-methyl-2-piperidinyl]phenyl]-3,6-dihydro- 2H -pyridine-1- 3 -Butyl formate (800.00 mg, 1.63 mmol) was dissolved in MeOH (30 mL) and to this was added palladium (10% on carbon) (433.81 mg, 407.64 μmol, 10% pure). The resulting mixture was hydrogenated at 50 atm overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give tert- butyl 3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]piperidine-1-carboxylate ( 661 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=1.201min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=1.201 min.

步驟5：1-甲基-3-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)哌啶之合成Step 5: Synthesis of 1-methyl-3-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)piperidine

將LAH(349.88mg，9.22mmol)溶解於THF(8mL)中且將3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]哌啶-1-甲酸第三丁 酯(661.00mg，1.84mmol)於THF(2mL)中之溶液逐滴添加到前一混合物中。將所得混合物加熱至回流且 回流3h。使反應混合物冷卻至室溫且攪拌隔夜。將水(350mkl)添加到反應混合物中，隨後添加KOH水溶液(350mkl)及水(700mkl)。將反應混合物攪拌30min且過濾。將濾餅用THF(15mL)洗滌且將濾液濃縮，以獲得1-甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]哌啶(450mg，1.65mmol，89.59%產率)。LAH (349.88 mg, 9.22 mmol) was dissolved in THF (8 mL) and 3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]piperidine-1-carboxylic acid A solution of tertiary butyl ester (661.00 mg, 1.84 mmol) in THF (2 mL) was added dropwise to the previous mixture. The resulting mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and stirred overnight. Water (350mkl) was added to the reaction mixture followed by aqueous KOH (350mkl) and water (700mkl). The reaction mixture was stirred for 30 min and filtered. The filter cake was washed with THF (15 mL) and the filtrate was concentrated to obtain 1-methyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]piperidine ( 450 mg, 1.65 mmol, 89.59% yield).

LCMS(ESI)：[M]+ m/z：計算值272.2；實測值273.2；Rt=0.684min。LCMS (ESI): [M] + m/z: calculated 272.2; found 273.2; Rt=0.684 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-(1-甲基哌啶-3-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1353)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(1-methylpiperidine-3 Synthesis of -yl)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1353)

將1-甲基-3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]哌啶(250mg，917.68μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(191.98mg，917.68μmol)及TEA(464.30mg，4.59mmol，639.53μL)混合於DMF(2.5mL)中且向其中添加HATU(418.71mg，1.10mmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 60-80% MeOH+NH3 30min(裝載泵4mL MeOH)，管柱：SunFire 100*19mm，5微米)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(1-甲基-3-哌啶基)苯基]-1-哌啶基]-2-側氧基乙醯胺(165.3mg，356.55μmol，38.85%產率)。1-Methyl-3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]piperidine (250 mg, 917.68 μmol), 2-[(6-amino- 5-Ethyl-3-pyridyl)amino]-2-oxoacetic acid (191.98 mg, 917.68 μmol) and TEA (464.30 mg, 4.59 mmol, 639.53 μL) were mixed in DMF (2.5 mL) and added thereto HATU (418.71 mg, 1.10 mmol) was added. The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 60-80% MeOH+ NH3 30 min (load pump 4 mL MeOH), column: SunFire 100*19 mm, 5 microns) to obtain N- (6-amino- 5-Ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[3-(1-methyl-3-piperidinyl)phenyl]-1-piperidine yl]-2-oxoacetamide (165.3 mg, 356.55 μmol, 38.85% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.06-1.13(m,3H),1.29-1.41(m,2H),1.55-1.69(m,3H),1.72-1.79(m,1H),1.82-1.90(m,3H),1.95-2.11(m,1H),2.14-2.16(m,3H),2.18-2.28(m,1H),2.39-2.42(m,1H),2.69-3.24(m,5H),3.42-4.04(m,1H),5.10-5.58(m,1H),5.58-5.68(m,2H),7.11-7.19(m,3H),7.24-7.33(m,1H),7.42-7.53(m,1H),7.98-8.07(m,1H),10.49-10.56(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.03(m,3H), 1.06-1.13(m,3H), 1.29-1.41(m,2H), 1.55-1.69(m,3H) ,1.72-1.79(m,1H),1.82-1.90(m,3H),1.95-2.11(m,1H),2.14-2.16(m,3H),2.18-2.28(m,1H),2.39-2.42( m,1H),2.69-3.24(m,5H),3.42-4.04(m,1H),5.10-5.58(m,1H),5.58-5.68(m,2H),7.11-7.19(m,3H), 7.24-7.33(m,1H), 7.42-7.53(m,1H), 7.98-8.07(m,1H), 10.49-10.56(m,1H).

LCMS(ESI)：[M]+ m/z：計算值463.2；實測值464.2；Rt=2.113min。LCMS (ESI): [M] + m/z: calculated 463.2; found 464.2; Rt=2.113 min.

步驟7：掌性分離(化合物1396及化合物1090)Step 7: Chiral separation (compound 1396 and compound 1090)

對外消旋N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(1-甲基-3-哌啶基)苯基]-1-哌啶基]乙醯胺(50.7mg，109.36μmol)進行掌性分 離(管柱：Chiralpak IA(250，20mm，5mkm)；流動相：IPA-MeOH，50-50；流速：10mL/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-[(3S )-1-甲基-3-哌啶基]苯基]-1-哌啶基]乙醯胺(19.97mg，43.07μmol，39.39%產率)(RT=15.04min)及N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-[(3R )-1-甲基-3-哌啶基]苯基]-1-哌啶基]乙醯胺(25.54mg，55.09μmol，50.37%產率)(RT=23.16min)。Racemic N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3-(1- Methyl-3-piperidinyl)phenyl]-1-piperidinyl]acetamide (50.7 mg, 109.36 μmol) for chiral separation (column: Chiralpak IA (250, 20 mm, 5 mkm); mobile phase: IPA-MeOH, 50-50; flow rate: 10 mL/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S ) -5-Methyl-2-[3-[( 3S )-1-methyl-3-piperidinyl]phenyl]-1-piperidinyl]acetamide (19.97 mg, 43.07 μmol, 39.39% yield rate) (RT=15.04min) and N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2- [3-[( 3R )-1-methyl-3-piperidinyl]phenyl]-1-piperidinyl]acetamide (25.54 mg, 55.09 μmol, 50.37% yield) (RT=23.16 min) .

化合物1396於分析條件下(管柱：IA，以MeOH，50-50，0.6mL/min為流動相)之保留時間為21.21min且化合物1090之保留時間為12.00min。The retention time of compound 1396 under analytical conditions (column: IA, with MeOH, 50-50, 0.6 mL/min as mobile phase) was 21.21 min and the retention time of compound 1090 was 12.00 min.

化合物1396 ：保留時間：21.21min Compound 1396 : retention time: 21.21min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.06-1.15(m,3H),1.28-1.41(m,2H),1.51-1.70(m,3H),1.72-1.79(m,1H),1.80-1.92(m,3H),1.96-2.36(m,6H),2.38-2.42(m,1H),2.72-3.22(m,4H),3.41-4.04(m,1H),5.11-5.57(m,1H),5.58-5.67(m,2H),7.11-7.20(m,3H),7.27-7.32(m,1H),7.41-7.53(m,1H),7.98-8.09(m,1H),10.49-10.55(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.04(m,3H), 1.06-1.15(m,3H), 1.28-1.41(m,2H), 1.51-1.70(m,3H) ,1.72-1.79(m,1H),1.80-1.92(m,3H),1.96-2.36(m,6H),2.38-2.42(m,1H),2.72-3.22(m,4H),3.41-4.04( m,1H),5.11-5.57(m,1H),5.58-5.67(m,2H),7.11-7.20(m,3H),7.27-7.32(m,1H),7.41-7.53(m,1H), 7.98-8.09 (m, 1H), 10.49-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值463.2；實測值464.2；Rt=2.107min。LCMS (ESI): [M] + m/z: calculated 463.2; found 464.2; Rt=2.107 min.

化合物1090：保留時間：12.00minCompound 1090: retention time: 12.00min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.06-1.13(m,3H),1.28-1.41(m,2H),1.54-1.70(m,3H),1.72-1.80(m,1H),1.81-1.90(m,3H),1.97-2.12(m,1H),2.13-2.16(m,3H),2.18-2.27(m,1H),2.32-2.36(m,1H),2.38-2.42(m,1H),2.72-3.22(m,4H),3.42-4.06(m,1H),5.11-5.58(m,1H),5.59-5.67(m,2H),7.09-7.21(m,3H),7.26-7.32(m,1H),7.43-7.52(m,1H),7.99-8.08(m,1H),10.48-10.55(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.03(m,3H), 1.06-1.13(m,3H), 1.28-1.41(m,2H), 1.54-1.70(m,3H) ,1.72-1.80(m,1H),1.81-1.90(m,3H),1.97-2.12(m,1H),2.13-2.16(m,3H),2.18-2.27(m,1H),2.32-2.36( m,1H),2.38-2.42(m,1H),2.72-3.22(m,4H),3.42-4.06(m,1H),5.11-5.58(m,1H),5.59-5.67(m,2H), 7.09-7.21(m,3H), 7.26-7.32(m,1H), 7.43-7.52(m,1H), 7.99-8.08(m,1H), 10.48-10.55(m,1H).

LCMS(ESI)：[M]+ m/z：計算值463.2；實測值464.2；Rt=2.104min。LCMS (ESI): [M] + m/z: calculated 463.2; found 464.2; Rt=2.104 min.

實例265. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[3-氯Example 265. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[3-chloro -4-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(化合物1305)之合成- Synthesis of 4-[2-(dimethylamino)ethoxy]phenyl]-5-methyl-1-piperidinyl]acetamide (compound 1305)

Figure 110128222-A0202-12-1392-365
Figure 110128222-A0202-12-1392-365

步驟1：4-溴-3-氯苯甲醯氯之合成Step 1: Synthesis of 4-bromo-3-chlorobenzyl chloride

將4-溴-3-氯苯甲酸(22g，93.43mmol)懸浮於DCM(250mL)中。添加二甲基甲醯胺(204.88mg，2.80mmol，217.04uL)。將所得混合物在25℃下攪拌15h。當氣體逸出停止時，在減壓下濃縮所得澄清溶液。將殘餘物再溶解於己烷(30mL)中，過濾且在真空中蒸發，得到4-溴-3-氯苯甲醯氯(21.8g，85.86mmol，91.89%產率)。4-Bromo-3-chlorobenzoic acid (22 g, 93.43 mmol) was suspended in DCM (250 mL). Dimethylformamide (204.88 mg, 2.80 mmol, 217.04 uL) was added. The resulting mixture was stirred at 25 °C for 15 h. When gas evolution ceased, the resulting clear solution was concentrated under reduced pressure. The residue was redissolved in hexanes (30 mL), filtered and evaporated in vacuo to give 4-bromo-3-chlorobenzyl chloride (21.8 g, 85.86 mmol, 91.89% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)7.71(d,1H),7.81(d,1H),7.98(s,1H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 7.71 (d, 1H), 7.81 (d, 1H), 7.98 (s, 1H).

步驟2：3-(4-溴-3-氯苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-(4-bromo-3-chlorobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

在-78℃下，將雙(三甲基矽基)醯胺化鈉(15.17g，82.71mmol)逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁基酯(8.40g，39.38mmol)於THF(50mL)中之經預冷卻之溶液中。添加完成之後，將其在同一溫度下攪拌1h。此後，逐 滴添加4-溴-3-氯苯甲醯氯(10g，39.38mmol)於THF中之溶液。添加完成之後，移除冷卻浴。將所得混合物緩慢升高至20℃且在此溫度下攪拌1h。然後，將其用15%NH4 Cl(150mL)淬滅且用乙酸乙酯(2*200mL)萃取。將有機層用20%NaCl(2x100mL)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，得到3-(4-溴-3-氯苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(16g，37.15mmol，94.32%產率)。Sodium bis(trimethylsilyl)amide (15.17 g, 82.71 mmol) was added dropwise to tert-butyl 5-methyl-2-oxypiperidine-1-carboxylic acid at -78°C A precooled solution of the ester (8.40 g, 39.38 mmol) in THF (50 mL). After the addition was complete, it was stirred at the same temperature for 1 h. After this time, a solution of 4-bromo-3-chlorobenzyl chloride (10 g, 39.38 mmol) in THF was added dropwise. After the addition was complete, the cooling bath was removed. The resulting mixture was slowly raised to 20 °C and stirred at this temperature for 1 h. It was then quenched with 15% NH4Cl (150 mL) and extracted with ethyl acetate (2*200 mL). The organic layer was washed with 20% NaCl (2×100 mL), dried over Na 2 SO 4 and evaporated under reduced pressure to give 3-(4-bromo-3-chlorobenzyl)-5-methyl-2-side Tert-butyl oxypiperidine-1-carboxylate (16 g, 37.15 mmol, 94.32% yield).

LCMS(ESI)：[M+H]+ m/z：計算值430.2；實測值430.0；Rt=1.598min。LCMS (ESI): [M+H] + m/z: calculated 430.2; found 430.0; Rt=1.598 min.

步驟3：6-(4-溴-3-氯苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-(4-bromo-3-chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將3-(4-溴-3-氯苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(16g，37.15mmol)溶解於AcOH(100mL)中且分批添加36% w/w鹽酸水溶液(19.23g，527.49mmol，24.04mL)。添加完成之後，將所得混合物在100℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(100mL)與DCM(200mL)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至pH

Figure 110128222-A0202-12-1393-431
10且用DCM(2x200mL)萃取。將DCM層合併，經Na2 SO4 乾燥且在減壓下蒸發，得到6-(4-溴-3-氯苯基)-3-甲基-2,3,4,5-四氫吡啶(1.6g，5.58mmol，15.03%產率)。3-(4-Bromo-3-chlorobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (16 g, 37.15 mmol) was dissolved in AcOH (100 mL) And 36% w/w aqueous hydrochloric acid (19.23 g, 527.49 mmol, 24.04 mL) was added portionwise. After the addition was complete, the resulting mixture was stirred at 100 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (100 mL) and DCM (200 mL). The organic layer was separated and discarded. The aqueous layer was basified to pH with 10% NaOH
Figure 110128222-A0202-12-1393-431
10 and extracted with DCM (2x200 mL). The DCM layers were combined, dried over Na 2 SO 4 and evaporated under reduced pressure to give 6-(4-bromo-3-chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine ( 1.6 g, 5.58 mmol, 15.03% yield).

LCMS(ESI)：[M+H]+ m/z：計算值286.0；實測值286.0；Rt=0.775min。LCMS (ESI): [M+H] + m/z: calculated 286.0; found 286.0; Rt=0.775 min.

步驟4：(5S)-2-(4-溴-3-氯苯基)-5-甲基哌啶之合成Step 4: Synthesis of (5S)-2-(4-bromo-3-chlorophenyl)-5-methylpiperidine

在0℃下，向(3S)-6-(4-溴-3-氯苯基)-3-甲基-2,3,4,5-四氫吡啶(3.3g，11.51mmol)於MeOH(34.19mL)中之經攪拌之溶液中添加硼氫化鈉(871.25mg，23.03mmol，811.22μL)。將所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物在減壓下濃縮，然後用水20mL及50mL EtOAc淬滅。將經合併之有機相用鹽水20mL洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得(5S)-2-(4-溴-3-氯苯基)-5-甲基哌啶(3.2g，11.09mmol，96.29%產率)。To (3S)-6-(4-bromo-3-chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (3.3 g, 11.51 mmol) in MeOH ( To the stirred solution in 34.19 mL) was added sodium borohydride (871.25 mg, 23.03 mmol, 811.22 μL). The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure, then quenched with 20 mL of water and 50 mL of EtOAc. The combined organic phases were washed with brine 20 mL, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain (5S)-2-(4-bromo-3-chlorophenyl)-5-methylpiperidine (3.2 g, 11.09 mmol, 96.29% yield).

LCMS(ESI)：[M+H]+ m/z：計算值288.0；實測值288.0；Rt=0.851min。LCMS (ESI): [M+H] + m/z: calculated 288.0; found 288.0; Rt=0.851 min.

步驟5：(5S)-2-(4-溴-3-氯苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of (5S)-2-(4-bromo-3-chlorophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在25℃下，向(5S)-2-(4-溴-3-氯苯基)-5-甲基哌啶(3.2g，11.09mmol)於DCM(47.46mL)中之經攪拌之溶液中添加2.0M於THF中之二碳酸二-第三丁酯(2.42g，11.09mmol，2.54mL)。將所得反應混合物在25℃下攪拌15h。完成之後，將反應混合物在減壓下濃縮，以獲得(5S)-2-(4-溴-3-氯苯基)-5-甲基哌啶-1-甲酸第三丁酯(4g，10.29mmol，92.81%產率)。To a stirred solution of (5S)-2-(4-bromo-3-chlorophenyl)-5-methylpiperidine (3.2 g, 11.09 mmol) in DCM (47.46 mL) at 25 °C 2.0M di-tert-butyl dicarbonate in THF (2.42 g, 11.09 mmol, 2.54 mL) was added. The resulting reaction mixture was stirred at 25 °C for 15 h. After completion, the reaction mixture was concentrated under reduced pressure to obtain tert-butyl (5S)-2-(4-bromo-3-chlorophenyl)-5-methylpiperidine-1-carboxylate (4 g, 10.29 g mmol, 92.81% yield).

LCMS(ESI)：[M-tBu]+ m/z：計算值332.0；實測值332.0；Rt=1.793min。LCMS (ESI): [M-tBu] + m/z: calculated 332.0; found 332.0; Rt=1.793 min.

步驟6：(5S)-2-[3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 6: (5S)-2-[3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl Synthesis of 3-butyl ]-5-methylpiperidine-1-carboxylate

向(5S)-2-(4-溴-3-氯苯基)-5-甲基哌啶-1-甲酸第三丁酯(4g，10.29mmol)之溶液中添加乙酸鉀(2.02g，20.58mmol，1.29mL)及雙(頻哪醇)二硼(2.61g，10.29mmol)。將反應混合物除氣且一次性添加Pd(dppf)Cl2 *DCM(420.16mg，514.50μmol)。將混合物用Ar進一步除氣且在90℃下加熱16h。在此時間之後，使反應混合物冷卻至室溫，過濾且在真空中移除溶劑，以獲得(5S)-2-[3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-5-甲基哌啶-1-甲酸第三丁酯(4g，9.18mmol，89.20%產率)。To a solution of tert-butyl (5S)-2-(4-bromo-3-chlorophenyl)-5-methylpiperidine-1-carboxylate (4 g, 10.29 mmol) was added potassium acetate (2.02 g, 20.58 g mmol, 1.29 mL) and bis(pinacol)diboron (2.61 g, 10.29 mmol). The reaction mixture was degassed and Pd(dppf)Cl2*DCM ( 420.16 mg, 514.50 μmol) was added in one portion. The mixture was further degassed with Ar and heated at 90 °C for 16 h. After this time, the reaction mixture was cooled to room temperature, filtered and the solvent was removed in vacuo to give (5S)-2-[3-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (4 g, 9.18 mmol, 89.20% yield).

LCMS(ESI)：[M-tBu]+ m/z：計算值380.2；實測值380.2；Rt=1.886min。LCMS (ESI): [M-tBu] + m/z: calculated 380.2; found 380.2; Rt=1.886 min.

步驟7：(5S)-2-(3-氯-4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 7: Synthesis of (5S)-2-(3-chloro-4-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(5S)-2-[3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-5-甲基哌啶-1-甲酸第三丁酯(4g，9.18mmol)於水(18.94mL)及THF(18.94mL)之混合物中之溶液中添加35%過氧化氫(2.34g，68.84mmol，2.13mL)且攪拌隔夜。將反應混合物用水(40mL)及MTBE(40mL)稀釋，且用硫代硫酸鈉處理，然後將有機相用水洗滌，經Na2 SO4 乾燥且在真空中濃縮。使粗品經歷CC(將CHCl3 /MTBE用作溶析液混合物)，以得到(5S)-2-(3-氯-4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯(2g，6.14mmol，66.87%產率)。To (5S)-2-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]- To a solution of tert-butyl 5-methylpiperidine-1-carboxylate (4 g, 9.18 mmol) in a mixture of water (18.94 mL) and THF (18.94 mL) was added 35% hydrogen peroxide (2.34 g, 68.84 mmol) , 2.13 mL) and stirred overnight. The reaction mixture was diluted with water (40 mL) and MTBE (40 mL) and treated with sodium thiosulfate, then the organic phase was washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was subjected to CC ( CHCl3 /MTBE was used as eluent mixture) to give (5S)-2-(3-chloro-4-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid third Butyl ester (2 g, 6.14 mmol, 66.87% yield).

LCMS(ESI)：[M-tBu]+ m/z：計算值270.0；實測值270.0；Rt=1.461min。LCMS (ESI): [M-tBu] + m/z: calculated 270.0; found 270.0; Rt=1.461 min.

步驟8：(5S)-2-[3-氯-4-[2-(二甲胺基)乙氧基]苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 8: Synthesis of (5S)-2-[3-chloro-4-[2-(dimethylamino)ethoxy]phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(5S)-2-(3-氯-4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯(2g，6.14mmol)溶解於DMF(50mL)中且添加碳酸銫(18.00g，55.24mmol)。然後，添加2-溴-N,N-二甲基乙胺(6.43g，27.62mmol，HBr)。將反應混合物在65℃下攪拌隔夜。此後，將其蒸發且在水與EtOAc之間萃取，然後將其用鹽水洗滌且經Na2 SO4 乾燥。將其蒸發，以得到(5S)-2-[3-氯-4-[2-(二甲胺基)乙氧基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(1.3g，3.27mmol，53.35%產率)。(5S)- tert-butyl 2-(3-chloro-4-hydroxyphenyl)-5-methylpiperidine-1-carboxylate (2 g, 6.14 mmol) was dissolved in DMF (50 mL) and cesium carbonate was added (18.00 g, 55.24 mmol). Then, 2-bromo-N,N-dimethylethylamine (6.43 g, 27.62 mmol, HBr) was added. The reaction mixture was stirred at 65°C overnight. After this time, it was evaporated and extracted between water and EtOAc, then it was washed with brine and dried over Na2SO4 . It was evaporated to give (5S)-2-[3-chloro-4-[2-(dimethylamino)ethoxy]phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.3 g, 3.27 mmol, 53.35% yield).

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值397.2；Rt=0.998min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 397.2; Rt=0.998 min.

步驟9：2-[2-氯-4-[(5S)-5-甲基-2-哌啶基]苯氧基]-N,N-二甲基乙胺之合成Step 9: Synthesis of 2-[2-Chloro-4-[(5S)-5-methyl-2-piperidinyl]phenoxy]-N,N-dimethylethylamine

將(5S)-2-[3-氯-4-[2-(二甲胺基)乙氧基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(0.65g，1.64mmol)溶解於DCM(5.74mL)中且添加TFA(1.87g，16.37mmol，1.26mL)。然後，將反應物在室溫下攪拌1h。將其蒸發，以得到2-[2-氯-4-[(5S)-5-甲基-2-哌啶基]苯氧基]-N,N-二甲基乙胺(0.7g，1.34mmol，81.76%產率，2TFA)。(5S)-2-[3-Chloro-4-[2-(dimethylamino)ethoxy]phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.64 g mmol) was dissolved in DCM (5.74 mL) and TFA (1.87 g, 16.37 mmol, 1.26 mL) was added. Then, the reaction was stirred at room temperature for 1 h. It was evaporated to give 2-[2-chloro-4-[(5S)-5-methyl-2-piperidinyl]phenoxy]-N,N-dimethylethylamine (0.7 g, 1.34 g mmol, 81.76% yield, 2TFA).

LCMS(ESI)：[M+H]+ m/z：計算值297.2；實測值297.2；Rt=0.354min。LCMS (ESI): [M+H] + m/z: calculated 297.2; found 297.2; Rt=0.354 min.

步驟10：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[3-氯-4-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(化合物1305)之合成Step 10: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[3-chloro-4- Synthesis of [2-(dimethylamino)ethoxy]phenyl]-5-methyl-1-piperidinyl]acetamide (compound 1305)

將DIPEA(1.73g，13.39mmol，2.33mL)添加到相應2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(280.07mg，1.34mmol)及2-[2-氯-4-[(5S)-5-甲基-2-哌啶基]苯氧基]-N,N-二甲基乙胺(0.7g，1.34mmol，2TFA)於DMF(7.67mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(559.95mg，1.47mmol)。然後，將反應混合物在室溫下攪拌隔夜。反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液，將其溶解於EtOAc中且用水及鹽水洗滌，經Na2 SO4 乾燥。 使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN+FA為溶析液混合物)，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[3-氯-4-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(51.8mg，97.00μmol，7.25%產率，HCOOH)。DIPEA (1.73 g, 13.39 mmol, 2.33 mL) was added to the corresponding 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (280.07 mg, 1.34 mmol) ) and 2-[2-chloro-4-[(5S)-5-methyl-2-piperidinyl]phenoxy]-N,N-dimethylethylamine (0.7g, 1.34mmol, 2TFA) in DMF (7.67 mL). The resulting mixture was stirred for 5 min before HATU (559.95 mg, 1.47 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure, dissolved in EtOAc and washed with water and brine, dried over Na2SO4 . The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN+FA as eluent mixture) to give N-(6-amino-5-ethyl-3-pyridyl)- 2-Pendant oxy-2-[rac-(2R,5S)-2-[3-chloro-4-[2-(dimethylamino)ethoxy]phenyl]-5-methyl- 1-Piperidinyl]acetamide (51.8 mg, 97.00 μmol, 7.25% yield, HCOOH).

1 H NMR(600MHz,dmso)δ 0.96-1.06(m,3H),1.05-1.14(m,3H),1.26-1.37(m,1H),1.62-1.70(m,1H),1.80-1.91(m,1H),1.96-2.10(m,1H),2.11-2.20(m,1H),2.23(s,6H),2.37-2.42(m,2H),2.64-2.68(m,2H),2.69-3.23(m,1H),3.43-4.02(m,1H),4.09-4.16(m,2H),5.05-5.55(m,1H),5.57-5.70(m,2H),7.09-7.26(m,2H),7.28-7.39(m,1H),7.43-7.53(m,1H),7.97-8.08(m,1H),10.30-10.68(m,1H)。 1 H NMR(600MHz,dmso)δ 0.96-1.06(m,3H),1.05-1.14(m,3H),1.26-1.37(m,1H),1.62-1.70(m,1H),1.80-1.91(m ,1H),1.96-2.10(m,1H),2.11-2.20(m,1H),2.23(s,6H),2.37-2.42(m,2H),2.64-2.68(m,2H),2.69-3.23 (m,1H),3.43-4.02(m,1H),4.09-4.16(m,2H),5.05-5.55(m,1H),5.57-5.70(m,2H),7.09-7.26(m,2H) , 7.28-7.39(m, 1H), 7.43-7.53(m, 1H), 7.97-8.08(m, 1H), 10.30-10.68(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值488.2；實測值488.2；Rt=2.126min。LCMS (ESI): [M+H] + m/z: calculated 488.2; found 488.2; Rt=2.126 min.

實例266. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[3-氯-4-(4-甲基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]乙醯胺(化合物1265)之合成Example 266. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[3-chloro-4- Synthesis of (4-methylpiperazin-1-yl)phenyl]-5-methyl-1-piperidinyl]acetamide (compound 1265)

Figure 110128222-A0202-12-1396-366
Figure 110128222-A0202-12-1396-366

步驟4：1-[2-氯-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]-4-甲基哌嗪之合成Step 4: Synthesis of 1-[2-Chloro-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenyl]-4-methylpiperazine

在Ar氣氛下，向1-甲基哌嗪(524.23mg，5.23mmol，580.55uL)、6-(4-溴-3-氯苯基)-3-甲基-2,3,4,5-四氫吡啶(1.5g，5.23mmol)及[1,1'-聯苯基]-2-基二環己基膦(366.87mg，1.05mmol)於甲苯(10mL)中之懸浮液中添加第三丁醇鈉(754.49mg，7.85mmol)及參(二苯亞甲基丙酮)二鈀(0)(143.78mg，157.02umol)。將所得混合物在80℃下攪拌16h。將反應混合物冷卻，將沉澱過濾，將溶劑蒸發，以獲得1-[2-氯-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]-4-甲基哌嗪(1g，3.27mmol，62.47%產率)。Under Ar atmosphere, 1-methylpiperazine (524.23 mg, 5.23 mmol, 580.55 uL), 6-(4-bromo-3-chlorophenyl)-3-methyl-2,3,4,5- To a suspension of tetrahydropyridine (1.5 g, 5.23 mmol) and [1,1'-biphenyl]-2-yldicyclohexylphosphine (366.87 mg, 1.05 mmol) in toluene (10 mL) was added tert-butyl Sodium alkoxide (754.49 mg, 7.85 mmol) and gins(dibenzylideneacetone)dipalladium(0) (143.78 mg, 157.02 umol). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled, the precipitate was filtered, and the solvent was evaporated to obtain 1-[2-chloro-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenyl]- 4-Methylpiperazine (1 g, 3.27 mmol, 62.47% yield).

LCMS(ESI)：[M+H]+ m/z：計算值306.2；實測值306.2；Rt=0.650min。LCMS (ESI): [M+H] + m/z: calculated 306.2; found 306.2; Rt=0.650 min.

步驟5：1-[2-氯-4-(5-甲基-2-哌啶基)苯基]-4-甲基哌嗪之合成Step 5: Synthesis of 1-[2-Chloro-4-(5-methyl-2-piperidinyl)phenyl]-4-methylpiperazine

在0℃下，將硼氫化鈉(247.40mg，6.54mmol，230.35μL)一次性添加到1-[2-氯-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]-4-甲基哌嗪(1g，3.27mmol)於MeOH(49.77mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌15h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用EtOAc(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以MeCN+NH3 為溶析液混合物)，以得到1-[2-氯-4-(5-甲基-2-哌啶基)苯基]-4-甲基哌嗪(0.13g，422.27μmol，12.91%產率)。Sodium borohydride (247.40 mg, 6.54 mmol, 230.35 μL) was added in one portion to 1-[2-chloro-4-(3-methyl-2,3,4,5-tetrahydropyridine- 6-yl)phenyl]-4-methylpiperazine (1 g, 3.27 mmol) in a stirred solution of MeOH (49.77 mL). The resulting mixture was stirred at 25 °C for 15 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The oil obtained was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with MeCN+ NH3 as eluent mixture) to give 1-[2-chloro-4-(5-methyl-2 -Piperidinyl)phenyl]-4-methylpiperazine (0.13 g, 422.27 μmol, 12.91% yield).

LCMS(ESI)：[M+H]+ m/z：計算值308.2；實測值308.2；Rt=1.500min。LCMS (ESI): [M+H] + m/z: calculated 308.2; found 308.2; Rt=1.500 min.

步驟6：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[3-氯-4-(4-甲基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]乙醯胺(化合物1265)之合成Step 6: N-(6-Amino-5-ethyl-3-pyridinyl)-2-oxy-2-[rac-(2R,5S)-2-[3-chloro-4- Synthesis of (4-methylpiperazin-1-yl)phenyl]-5-methyl-1-piperidinyl]acetamide (compound 1265)

將DIPEA(136.44mg，1.06mmol，183.88μL)添加到相應2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(88.34mg，422.27μmol)及1-[2-氯-4-(5-甲基-2-哌啶基)苯基]-4-甲基哌嗪(0.13g，422.27μmol)於DMF(4.82mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(176.62mg，464.50μmol)。然後，將反應混合物在室溫下攪拌隔夜。反應完成(藉由LCMS監測)之後，在減壓下濃縮 所得懸浮液，將其溶解於EtOAc中且用水及鹽水洗滌，經Na2 SO4 乾燥。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以水-MeCN+FA為溶析液混合物)，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[3-氯-4-(4-甲基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]乙醯胺(17mg，28.76μmol，6.81%產率，2HCOOH)。DIPEA (136.44 mg, 1.06 mmol, 183.88 μL) was added to the corresponding 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (88.34 mg, 422.27 μmol ) and 1-[2-chloro-4-(5-methyl-2-piperidinyl)phenyl]-4-methylpiperazine (0.13 g, 422.27 μmol) in DMF (4.82 mL) . The resulting mixture was stirred for 5 min before HATU (176.62 mg, 464.50 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure, dissolved in EtOAc and washed with water and brine, dried over Na2SO4 . The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with water-MeCN+FA as eluent mixture) to give N-(6-amino-5-ethyl-3-pyridyl )-2-oxy-2-[rac-(2R,5S)-2-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-5-methyl -1-Piperidinyl]acetamide (17 mg, 28.76 μmol, 6.81% yield, 2HCOOH).

1 H NMR(600MHz,dmso)δ 0.97-1.05(m,3H),1.12-1.18(m,3H),1.26-1.38(m,1H),1.60-1.70(m,1H),1.82-1.93(m,1H),1.99-2.09(m,1H),2.14-2.25(m,1H),2.62-2.85(m,1H),2.88(s,3H),2.96-3.02(m,2H),3.17-3.26(m,4H),3.50-3.55(m,4H),3.70-4.05(m,1H),5.09-5.58(m,1H),7.22-7.30(m,2H),7.31-7.40(m,1H),7.42-7.80(m,2H),7.80-7.87(m,1H),8.24-8.35(m,1H),9.68-9.84(m,1H),11.01-11.16(m,1H)。 1 H NMR(600MHz,dmso)δ 0.97-1.05(m,3H),1.12-1.18(m,3H),1.26-1.38(m,1H),1.60-1.70(m,1H),1.82-1.93(m ,1H),1.99-2.09(m,1H),2.14-2.25(m,1H),2.62-2.85(m,1H),2.88(s,3H),2.96-3.02(m,2H),3.17-3.26 (m,4H),3.50-3.55(m,4H),3.70-4.05(m,1H),5.09-5.58(m,1H),7.22-7.30(m,2H),7.31-7.40(m,1H) , 7.42-7.80(m, 2H), 7.80-7.87(m, 1H), 8.24-8.35(m, 1H), 9.68-9.84(m, 1H), 11.01-11.16(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值500.2；實測值500.2；Rt=1.580min。LCMS (ESI): [M+H] + m/z: calculated 500.2; found 500.2; Rt=1.580 min.

實例267. rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,4S,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶-1-基)-2-側氧基乙醯胺(化合物1323)及rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,4S,SR)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶-1-基)-2-側氧基乙醯胺(化合物1213)之合成Example 267. rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,4S,5R)-2-(4-fluorophenyl)-5-methyl- 4-(Trifluoromethoxy)piperidin-1-yl)-2-oxyacetamide (Compound 1323) and rel-N-(6-amino-5-methylpyridin-3-yl) -2-((2R,4S,SR)-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidin-1-yl)-2-side oxyethyl Synthesis of amide (compound 1213)

Figure 110128222-A0202-12-1399-367
Figure 110128222-A0202-12-1399-367

步驟3：[(2R,5R)-2-(4-氟苯基)-4-羥基-5-甲基-1-哌啶基]-苯基甲酮之合成Step 3: Synthesis of [(2R,5R)-2-(4-fluorophenyl)-4-hydroxy-5-methyl-1-piperidinyl]-phenylmethanone

將(2R,5R)-2-(4-氟苯基)-5-甲基哌啶-4-醇(1.7g，6.92mmol，HCl)及TEA(3.50g，34.59mmol，4.82mL)一起混合於DCM(20mL)中且在冰/甲醇浴中將所得溶液冷卻至0℃。將苯甲醯氯(1.07g，7.61mmol)逐滴添加到前一溶液中且使所得混合物升溫至室溫且攪拌隔夜。將反應混合物用DCM稀釋且將所得溶液用水洗滌，經Na2 SO4 乾燥，過濾且蒸發，以獲得[(2R,5R)-2-(4-氟苯基)-4-羥基-5-甲基-1-哌啶基]-苯基甲酮(2.15g，6.86mmol，99.17%產率)，其不經進一步純化即用於下一步驟中。Combine (2R,5R)-2-(4-fluorophenyl)-5-methylpiperidin-4-ol (1.7 g, 6.92 mmol, HCl) and TEA (3.50 g, 34.59 mmol, 4.82 mL) together The resulting solution was cooled to 0 °C in DCM (20 mL) in an ice/methanol bath. Benzyl chloride (1.07 g, 7.61 mmol) was added dropwise to the previous solution and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with DCM and the resulting solution was washed with water, dried over Na 2 SO 4 , filtered and evaporated to give [(2R,5R)-2-(4-fluorophenyl)-4-hydroxy-5-methane yl-1-piperidinyl]-phenylmethanone (2.15 g, 6.86 mmol, 99.17% yield), which was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值314.2；實測值314.2；Rt=1.276min。LCMS (ESI): [M+H] + m/z: calculated 314.2; found 314.2; Rt=1.276 min.

步驟4：O-[(2R,5R)-1-苯甲醯基-2-(4-氟苯基)-5-甲基-4-哌啶基]甲基氫硫基甲硫酸Step 4: O-[(2R,5R)-1-benzyl-2-(4-fluorophenyl)-5-methyl-4-piperidinyl]methylhydrogenthiomethanesulfuric acid 酯之合成Synthesis of Esters

將(2R,5R)-2-(4-氟苯基)-4-羥基-5-甲基-1-哌啶基]-苯基甲酮(2.15g，6.86mmol)溶解於THF(20mL)中且在用冰/水之冷卻下向所得混合物中添加於礦物油中之氫化鈉(油分散物)60%分散物(473.20mg，20.58mmol)，使反應混合物攪拌1h，然後在用冰/水之冷卻下添加二硫化碳(1.57g，20.58mmol)，將反應混合物加熱至室溫且攪拌30min，然後將反應混合物再次用冰/水冷卻且添加碘甲烷(2.92g，20.58mmol，1.28mL)，將所得混合物加熱至室溫且攪拌隔夜。將反應混合物用EA稀釋且用鹽水洗滌兩次。獲得呈棕色膠狀物之O-[(2R,5R)-1-苯甲醯基-2-(4-氟苯基)-5-甲基-4-哌啶基]甲基氫硫基甲硫酸酯(2.5g，6.20mmol，90.30%產率)。所獲得之產物不經進一步純化即用於下一步驟中(2R,5R)-2-(4-Fluorophenyl)-4-hydroxy-5-methyl-1-piperidinyl]-phenylmethanone (2.15 g, 6.86 mmol) was dissolved in THF (20 mL) To the resulting mixture was added sodium hydride (oil dispersion) 60% dispersion in mineral oil (473.20 mg, 20.58 mmol) under cooling with ice/water, and the reaction mixture was stirred for 1 h, then cooled with ice/water. Carbon disulfide (1.57 g, 20.58 mmol) was added under cooling with water, the reaction mixture was warmed to room temperature and stirred for 30 min, then the reaction mixture was cooled again with ice/water and iodomethane (2.92 g, 20.58 mmol, 1.28 mL) was added, The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with EA and washed twice with brine. O-[(2R,5R)-1-benzyl-2-(4-fluorophenyl)-5-methyl-4-piperidinyl]methylsulfanylmethyl was obtained as a brown gum Sulfate (2.5 g, 6.20 mmol, 90.30% yield). The product obtained was used in the next step without further purification

LCMS(ESI)：[M+H]+ m/z：計算值404.2；實測值404.2；Rt=1.483min。LCMS (ESI): [M+H] + m/z: calculated 404.2; found 404.2; Rt=1.483 min.

步驟5：[(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)-1-哌啶基]-苯基甲酮之合成Step 5: Synthesis of [(2R,5R)-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)-1-piperidinyl]-phenylmethanone

將1,3-二溴-5,5-二甲基乙內醯脲(7.09g，24.78mmol)溶解於DCM(60mL)中且將所獲得之溶液冷卻至-70℃，且在此溫度下，添加氟化氫-吡啶(70% HF)(8.60g，86.73mmol，7.54mL)，使反應混合物在-70℃下攪拌30min。然後，在-70℃下添加O-[(2R,5R)-1-苯甲醯基-2-(4-氟苯基)-5-甲基-4-哌啶基]甲基氫硫基甲硫酸酯(2.5g，6.20mmol)於DCM(5mL)中之溶液且將所獲得之混合物攪拌1h，然後加熱至室溫，攪拌隔夜。將反應混合物倒入到Na2 CO3 之飽和水溶液中，將DCM層分離且將水層用額外DCM萃取，將經合併之有機相經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由FCC(於己烷中之EtOAc，0%至100%)純化所獲得之粗產物。獲得呈黃色膠狀物之[(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)-1-哌啶基]-苯基甲酮(0.3g，786.65μmol，12.70%產率)。1,3-Dibromo-5,5-dimethylhydantoin (7.09 g, 24.78 mmol) was dissolved in DCM (60 mL) and the resulting solution was cooled to -70 °C and at this temperature , hydrogen fluoride-pyridine (70% HF) (8.60 g, 86.73 mmol, 7.54 mL) was added and the reaction mixture was stirred at -70 °C for 30 min. Then, O-[(2R,5R)-1-benzyl-2-(4-fluorophenyl)-5-methyl-4-piperidinyl]methylsulfanyl was added at -70°C A solution of methosulfate (2.5 g, 6.20 mmol) in DCM (5 mL) and the resulting mixture was stirred for 1 h, then warmed to room temperature and stirred overnight. The reaction mixture was poured into saturated aqueous Na2CO3 , the DCM layer was separated and the aqueous layer was extracted with additional DCM, the combined organic phases were dried over Na2SO4 , filtered and concentrated in vacuo. The crude product obtained was purified by FCC (EtOAc in hexanes, 0% to 100%). [(2R,5R)-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)-1-piperidinyl]-phenylmethanone was obtained as a yellow gum (0.3 g, 786.65 μmol, 12.70% yield).

LCMS(ESI)：[M+H]+ m/z：計算值382.0；實測值382.0；Rt=1.538min。LCMS (ESI): [M+H] + m/z: calculated 382.0; found 382.0; Rt=1.538 min.

步驟6：(2R,5R)-1-苯甲基-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶之合成Step 6: Synthesis of (2R,5R)-1-benzyl-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidine

將氫化鋰鋁(40.91mg，1.21mmol)懸浮於THF(10mL)中且在回流下加熱，然後逐滴添加[(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)-1-哌啶基]-苯基甲酮(0.115g，301.55μmol)於THF(2mL)中之溶液且將反應混合物在66℃下攪拌12h。將反應混合物用冰/甲醇冷卻且逐滴添加水(1mL/g LiAlH4 )，然後逐滴添加40% KOH水溶液(1mL/g LiAlH4 )，然後逐滴添加水(2mL/g LiAlH4 )。過濾出所形成之固體且將其用EA洗滌三次，將濾液在真空中濃縮。獲得呈黃色膠狀物之(2R,5R)-1-苯甲基-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶(0.1g，272.20μmol，90.27%產率)。Lithium aluminum hydride (40.91 mg, 1.21 mmol) was suspended in THF (10 mL) and heated at reflux, then [(2R,5R)-2-(4-fluorophenyl)-5-methyl- A solution of 4-(trifluoromethoxy)-1-piperidinyl]-phenylmethanone (0.115 g, 301.55 μmol) in THF (2 mL) and the reaction mixture was stirred at 66 °C for 12 h. The reaction mixture was cooled with ice/methanol and water (1 mL/g LiAlH 4 ) was added dropwise, followed by 40% aqueous KOH (1 mL/g LiAlH 4 ), then water (2 mL/g LiAlH 4 ) dropwise. The solid formed was filtered off and washed three times with EA, and the filtrate was concentrated in vacuo. (2R,5R)-1-benzyl-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidine (0.1 g, 272.20 g) was obtained as a yellow gum μmol, 90.27% yield).

LCMS(ESI)：[M+H]+ m/z：計算值368.2；實測值368.2；Rt=1.196min。LCMS (ESI): [M+H] + m/z: calculated 368.2; found 368.2; Rt=1.196 min.

步驟7：(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶之合成Step 7: Synthesis of (2R,5R)-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidine

將(2R,5R)-1-苯甲基-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶(0.1g，272.20μmol)溶解於MeOH中且向其中添加Pd/C(10%)(0.01g，272.20μmol)。將所得反應混合物除氣且用氫氣填充且在20℃下攪拌60h。將反應混合物過濾，將濾餅用額外MeOH洗滌且將濾液在真空中濃縮。獲得呈黃色膠狀物之(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶(0.07g，252.47μmol，92.75%產率)。(2R,5R)-1-benzyl-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidine (0.1 g, 272.20 μmol) was dissolved in MeOH And Pd/C (10%) (0.01 g, 272.20 μmol) was added thereto. The resulting reaction mixture was degassed and filled with hydrogen and stirred at 20 °C for 60 h. The reaction mixture was filtered, the filter cake was washed with additional MeOH and the filtrate was concentrated in vacuo. (2R,5R)-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidine (0.07 g, 252.47 μmol, 92.75% yield) was obtained as a yellow gum ).

LCMS(ESI)：[M+H]+ m/z：計算值278.0；實測值278.0；Rt=0.967min。LCMS (ESI): [M+H] + m/z: calculated 278.0; found 278.0; Rt=0.967 min.

步驟8：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 8: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5R)-2-(4-fluorophenyl)-5-methyl-4-(tris Synthesis of Fluoromethoxy)-1-piperidinyl]-2-oxoacetamide

將(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶(0.07g，252.47μmol)、TEA(76.64mg，757.42μmol，105.57μL)及2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(49.28mg，252.47μmol)溶解於DMF(4mL)中且一次性添加HATU(105.60mg，277.72μmol)，將所得混合物在20℃下攪拌3h。藉由反相HPLC(2-10min；65-75% MeCN流速30mL/min(裝載泵4mL MeCN)管柱：SunFire 100*19mm，5微米)純化粗產物。分離呈淡黃色固體之所要產物N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)-1-哌啶基]-2-側氧基乙醯胺(0.028g，61.62μmol，24.41%產率)。(2R,5R)-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidine (0.07 g, 252.47 μmol), TEA (76.64 mg, 757.42 μmol, 105.57 μL) and 2-[(6-amino-5-methyl-3-pyridinyl)amino]-2-oxoacetic acid (49.28 mg, 252.47 μmol) were dissolved in DMF (4 mL) and added in one portion HATU (105.60 mg, 277.72 μmol), the resulting mixture was stirred at 20 °C for 3 h. By reverse phase HPLC (2-10 min; 65-75% MeCN flow rate 30 mL/min (loading pump 4 mL MeCN) Column: SunFire 100*19 mm, 5 microns) to purify the crude product. The desired product N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-(4-fluorophenyl)-5-methyl was isolated as a pale yellow solid -4-(Trifluoromethoxy)-1-piperidinyl]-2-oxoacetamide (0.028 g, 61.62 μmol, 24.41% yield).

LCMS(ESI)：[M+H]+ m/z：計算值455.2；實測值455.2；Rt=1.225min。LCMS (ESI): [M+H] + m/z: calculated 455.2; found 455.2; Rt=1.225 min.

步驟9：實例1. rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,4S,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶-1-基)-2-側氧基乙醯胺(化合物1323)及rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,4S,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶-1-基)-2-側氧基乙醯胺(化合物1213)之合成Step 9: Example 1. rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,4S,5R)-2-(4-fluorophenyl)-5- Methyl-4-(trifluoromethoxy)piperidin-1-yl)-2-oxyacetamide (Compound 1323) and rel-N-(6-amino-5-methylpyridine-3) -yl)-2-((2R,4S,5R)-2-(4-fluorophenyl)-5-methyl-4-(trifluoromethoxy)piperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 1213)

使用以下進行掌性拆分：Use the following for palm splitting:

管柱：ChiralART YMC(250*20mm，5mkm)，己烷-IPA-MeOH，90-5-5，流速12mL/min；管柱溫度：24℃；波長：205nm、215nm，以得到：化合物1323 rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,4S,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶-1-基)-2-側氧基乙醯胺(0.008g，17.60μmol，28.57%產率)(其中保留時間=12.706min(分析型)、43.854min(製備型))及化合物1213 rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,4S,5R)-2-(4-氟苯基)-5-甲基-4-(三氟甲氧基)哌啶-1-基)-2-側氧基乙醯胺(0.009g，19.81μmol，32.14%產率)(其中保留時間=17.66min(分析型)、66.502min(製備型))。Column: ChiralART YMC (250*20mm, 5mkm), hexane-IPA-MeOH, 90-5-5, flow rate 12mL/min; column temperature: 24°C; wavelength: 205nm, 215nm to give: compound 1323 rel -N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,4S,5R)-2-(4-fluorophenyl)-5-methyl-4-(tri Fluoromethoxy)piperidin-1-yl)-2-oxyacetamide (0.008g, 17.60μmol, 28.57% yield) (wherein retention time=12.706min (analytical), 43.854min (preparative) )) and compound 1213 rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,4S,5R)-2-(4-fluorophenyl)-5-methyl yl-4-(trifluoromethoxy)piperidin-1-yl)-2-oxyacetamide (0.009 g, 19.81 μmol, 32.14% yield) (wherein retention time = 17.66 min (analytical) , 66.502min (preparative type)).

化合物1323： RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，70-15-15，0.6mL/min)=12.607min。 Compound 1323: RT (Chiralpak IC (250*4.6, 5 mkm), Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 12.607 min.

1 H NMR(600MHz,dmso)δ 0.98-1.03(m,3H),2.00-2.07(m,3H),2.14-2.30(m,2H),2.60-2.66(m,1H),2.80-3.26(m,1H),3.63-4.27(m,1H),4.43-4.57(m,1H),5.34-6.14(m,3H),7.23-7.30(m,2H),7.31-7.41(m,2H),7.48-7.57(m,1H),8.00-8.09(m,1H),10.59-10.69(m,1H)。 1 H NMR(600MHz,dmso)δ 0.98-1.03(m,3H),2.00-2.07(m,3H),2.14-2.30(m,2H),2.60-2.66(m,1H),2.80-3.26(m ,1H),3.63-4.27(m,1H),4.43-4.57(m,1H),5.34-6.14(m,3H),7.23-7.30(m,2H),7.31-7.41(m,2H),7.48 -7.57(m, 1H), 8.00-8.09(m, 1H), 10.59-10.69(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值455.2；實測值455.2；Rt=2.941min。LCMS (ESI): [M+H] + m/z: calculated 455.2; found 455.2; Rt=2.941 min.

化合物1213： RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，70-15-15，0.6mL/min)=17.532min。 Compound 1213: RT (Chiralpak IC (250*4.6, 5 mkm), Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 17.532 min.

1 H NMR(600MHz,dmso)δ 0.99-1.04(m,3H),1.99-2.07(m,3H),2.13-2.30(m,2H),2.60-2.65(m,1H),2.78-3.25(m,1H),3.61-4.30(m,1H),4.47-4.54(m,1H),5.34-6.00(m,3H),7.24-7.30(m,2H),7.31-7.42(m,2H),7.49-7.56(m,1H),7.98-8.10(m,1H),10.58-10.67(m,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.04(m,3H),1.99-2.07(m,3H),2.13-2.30(m,2H),2.60-2.65(m,1H),2.78-3.25(m ,1H),3.61-4.30(m,1H),4.47-4.54(m,1H),5.34-6.00(m,3H),7.24-7.30(m,2H),7.31-7.42(m,2H),7.49 -7.56(m, 1H), 7.98-8.10(m, 1H), 10.58-10.67(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值455.2；實測值455.2；Rt=2.938min。LCMS (ESI): [M+H] + m/z: calculated 455.2; found 455.2; Rt=2.938 min.

實例268.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-(2-(二甲胺基)乙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1226)之合成Example 268. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-(2-(dimethylamino)ethyl)phenyl )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1226) Synthesis

Figure 110128222-A0202-12-1403-368
Figure 110128222-A0202-12-1403-368

步驟1：2-(3-溴苯基)-N,N-二甲基乙胺之合成Step 1: Synthesis of 2-(3-bromophenyl)-N,N-dimethylethylamine

將甲酸(6.61g，143.50mmol，5.41mL)小心添加到2-(3-溴苯基)乙胺(9.57g，47.83mmol)中。此後，添加用7-8% MeOH穩定之37% w/w甲醛水溶液(4.31g，143.50mmol，3.98mL)(小心：有氣體逸出！)且將反應混合物在80℃下攪拌16h。將混合物冷卻且添加20mL 6N HCl。將其用30mL MTBE洗滌。然後，將水層用K2 CO3 鹼化且用DCM(3x15mL)萃取。將DCM層合併，經Na2 SO4 乾燥且在減壓下蒸發。藉由管柱層析純化粗產物，以得到2-(3-溴苯基)-N,N -二甲基乙胺(2g，8.77mmol，18.33%產率)。Formic acid (6.61 g, 143.50 mmol, 5.41 mL) was carefully added to 2-(3-bromophenyl)ethanamine (9.57 g, 47.83 mmol). After this time, 37% w/w aqueous formaldehyde stabilized with 7-8% MeOH (4.31 g, 143.50 mmol, 3.98 mL) was added (caution: gas evolution!) and the reaction mixture was stirred at 80 °C for 16 h. The mixture was cooled and 20 mL of 6N HCl was added. It was washed with 30 mL of MTBE. The aqueous layer was then basified with K 2 CO 3 and extracted with DCM (3×15 mL). The DCM layers were combined, dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography to give 2-(3-bromophenyl) -N,N -dimethylethylamine (2 g, 8.77 mmol, 18.33% yield).

LCMS(ESI)：[M]+ m/z：計算值228.2；實測值229.2；Rt=0.840min。LCMS (ESI): [M] + m/z: calculated 228.2; found 229.2; Rt=0.840 min.

步驟2：N,N-二甲基-2-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)乙胺之合成Step 2: N,N-Dimethyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl ) Synthesis of ethylamine

將2-(3-溴苯基)-N,N -二甲基乙胺(1g，4.38mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.11g，4.38mmol)及乙酸鉀(860.39mg，8.77mmol，548.02μL)於二噁烷(24.45mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後添加Pd(dppf)Cl2 *DCM(178.99mg，219.17μmol)且將反應混合物在氬氣、100℃下攪拌15h。完成之後，在減壓下蒸發混合物；藉由穿過SiO2 (以MeOH為溶析液)來純化粗產物。將經合併之層在真空中濃縮，添加30mL CHCl3 ，將混合物攪拌30min且過濾出沉澱。在減壓下蒸發母液，以得到N,N -二甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]乙胺(1.2g，4.36mmol，99.48%產率)。2-(3-Bromophenyl) -N,N -dimethylethylamine (1 g, 4.38 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (1.11 g, 4.38 mmol) and potassium acetate (860.39 mg, 8.77 mmol, 548.02 μL) in dioxane (24.45 mL) was evacuated and backfilled with argon. This operation was repeated twice, then Pd(dppf)Cl2*DCM (178.99 mg , 219.17 μmol) was added and the reaction mixture was stirred under argon at 100 °C for 15 h. After completion, the mixture was evaporated under reduced pressure; the crude product was purified by passing through SiO2 with MeOH as eluent. The combined layers were concentrated in vacuo, 30 mL of CHCl3 was added, the mixture was stirred for 30 min and the precipitate was filtered off. The mother liquor was evaporated under reduced pressure to give N,N -dimethyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl]ethanamine (1.2 g, 4.36 mmol, 99.48% yield).

LCMS(ESI)：[M]+ m/z：計算值275.2；實測值276.2；Rt=0.870min。LCMS (ESI): [M] + m/z: calculated 275.2; found 276.2; Rt=0.870 min.

步驟3：(S)-6-(3-(2-(二甲胺基)乙基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(3-(2-(dimethylamino)ethyl)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl Synthesis of Esters

將碳酸鈉(924.35mg，8.72mmol，365.07μL)添加到N,N -二甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]乙胺(1.2g，4.36mmol)及(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.81g，5.23mmol)於水(7.95mL)及二噁烷(23.86mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2 *DCM(178.05mg，218.03μmol)。在90℃、惰性氣氛下將所得混合物攪拌15h。完成之後，蒸發溶劑，將40mL CHCl3 添加到殘餘物中，過濾出沉澱。將母液濃縮至乾，以得到(3S )-6-[3-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(2g，粗品)。Sodium carbonate (924.35 mg, 8.72 mmol, 365.07 μL) was added to N,N -dimethyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxa Borol-2-yl)phenyl]ethanamine (1.2 g, 4.36 mmol) and ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4- A solution of tert -butyl dihydro- 2H -pyridine-1-carboxylate (1.81 g, 5.23 mmol) in water (7.95 mL) and dioxane (23.86 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, Pd(dppf)Cl 2 *DCM (178.05 mg, 218.03 μmol) was added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 15 h. After completion, the solvent was evaporated, 40 mL of CHCl3 was added to the residue, and the precipitate was filtered off. The mother liquor was concentrated to dryness to give ( 3S )-6-[3-[2-(dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1 - tert -butyl formate (2 g, crude).

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=1.214min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=1.214 min.

步驟4：(S)-N,N-二甲基-2-(3-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)乙胺之合成Step 4: Synthesis of (S)-N,N-dimethyl-2-(3-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)ethanamine

向(3S )-6-[3-[2-(二甲胺基)乙基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(2g，5.81mmol)於DCM(40mL)中之混合物中一次性添加TFA(9.93g，87.09mmol，6.71mL)且使所得混合物在25℃下攪拌48h。反應完成之後，將溶劑濃縮，將40mL水添加到殘餘物中。將所得混合物用K2 CO3 鹼化至鹼性pH，用DCM(3*20mL)萃取，將經合併之有機層經Na2 SO4 乾燥，過濾且濃縮，以獲得N,N -二甲基-2-[3-[(3S )-3-甲基-1,2,3,4-四氫吡啶-6-基]苯基]乙胺(0.7g，粗品)。To ( 3S )-6-[3-[2-(dimethylamino)ethyl]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester ( To a mixture of 2 g, 5.81 mmol) in DCM (40 mL) was added TFA (9.93 g, 87.09 mmol, 6.71 mL) in one portion and the resulting mixture was stirred at 25 °C for 48 h. After the reaction was completed, the solvent was concentrated, and 40 mL of water was added to the residue. The resulting mixture was basified with K2CO3 to basic pH, extracted with DCM ( 3 *20 mL), the combined organic layers were dried over Na2SO4 , filtered and concentrated to obtain N,N -dimethyl -2-[3-[( 3S )-3-methyl-1,2,3,4-tetrahydropyridin-6-yl]phenyl]ethanamine (0.7 g, crude).

LCMS(ESI)：[M]+ m/z：計算值244.2；實測值245.2；Rt=0.224min。LCMS (ESI): [M] + m/z: calculated 244.2; found 245.2; Rt=0.224 min.

步驟5：N,N-二甲基-2-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)乙胺之合成Step 5: Synthesis of N,N-dimethyl-2-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)ethanamine

向N,N -二甲基-2-[3-[(3S )-3-甲基-1,2,3,4-四氫吡啶-6-基]苯基]乙胺(0.7g，2.86mmol)於MeOH(30mL)中之混合物中一次性添加硼氫化鈉(130.04mg，3.44mmol，121.08μL)。使所得混合物在25℃下攪拌隔夜。完成之後，將溶劑蒸發至乾。使殘餘物經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：50-50-75% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeOH))，以得到N,N -二甲基-2-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]乙胺(0.0587g，238.24μmol，8.32%產率)。To N,N -dimethyl-2-[3-[( 3S )-3-methyl-1,2,3,4-tetrahydropyridin-6-yl]phenyl]ethanamine (0.7 g, 2.86 g mmol) in MeOH (30 mL) was added sodium borohydride (130.04 mg, 3.44 mmol, 121.08 μL) in one portion. The resulting mixture was stirred at 25°C overnight. After completion, the solvent was evaporated to dryness. The residue was subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 50-50-75% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min (loading pump 4 mL/min MeOH)) to give N,N -dimethyl-2-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]ethanamine (0.0587 g, 238.24 g μmol, 8.32% yield).

LCMS(ESI)：[M]+ m/z：計算值246.2；實測值247.2；Rt=0.603min。LCMS (ESI): [M] + m/z: calculated 246.2; found 247.2; Rt=0.603 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-(2-(二甲胺基)乙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1226)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-(2-(dimethylamino)ethyl)phenyl )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1226) Synthesis

向N,N -二甲基-2-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]乙胺(0.0587g，238.24μmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(49.84mg，238.24μmol)及TEA(120.54mg，1.19mmol，166.03μL)於DMF(3mL)中之混合物中一次性添加HATU(108.70mg，285.89μmol)。使所得混合物在25℃下攪拌15h。完成之後，將DMF蒸發，使殘餘物經歷HPLC(管柱：XBridge BEH C18 5um 130A； 流動相：30-80% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeOH))，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[2-(二甲胺基)乙基]苯基]-5-甲基-1-哌啶基]乙醯胺(67.2mg，153.57μmol，64.46%產率)。To N,N -dimethyl-2-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]ethanamine (0.0587 g, 238.24 μmol), 2-[(6 -Amino-5-ethyl-3-pyridinyl)amino]-2-side oxyacetic acid (49.84 mg, 238.24 μmol) and TEA (120.54 mg, 1.19 mmol, 166.03 μL) in DMF (3 mL) HATU (108.70 mg, 285.89 μmol) was added to the mixture in one portion. The resulting mixture was stirred at 25 °C for 15 h. After completion, DMF was evaporated and the residue was subjected to HPLC (column: XBridge BEH C18 5um 130A; mobile phase: 30-80% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min ( Load pump 4 mL/min MeOH)) to give N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2-[3- [2-(Dimethylamino)ethyl]phenyl]-5-methyl-1-piperidinyl]acetamide (67.2 mg, 153.57 μmol, 64.46% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.75-1.03(m,3H),1.06-1.15(m,3H),1.22-1.41(m,1H),1.59-1.71(m,1H),1.79-1.92(m,1H),1.97-2.10(m,1H),2.12-2.16(m,6H),2.18-2.29(m,1H),2.37-2.44(m,4H),2.68-2.73(m,2H),3.18-3.26(m,1H),3.48-4.04(m,1H),5.13-5.59(m,1H),5.59-5.72(m,2H),7.07-7.19(m,3H),7.24-7.32(m,1H),7.41-7.53(m,1H),7.97-8.11(m,1H),10.45-10.62(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.75-1.03(m,3H), 1.06-1.15(m,3H), 1.22-1.41(m,1H), 1.59-1.71(m,1H) ,1.79-1.92(m,1H),1.97-2.10(m,1H),2.12-2.16(m,6H),2.18-2.29(m,1H),2.37-2.44(m,4H),2.68-2.73( m, 2H), 3.18-3.26(m, 1H), 3.48-4.04(m, 1H), 5.13-5.59(m, 1H), 5.59-5.72(m, 2H), 7.07-7.19(m, 3H), 7.24-7.32 (m, 1H), 7.41-7.53 (m, 1H), 7.97-8.11 (m, 1H), 10.45-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=1.759min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=1.759 min.

實例269. 2-[(2R,5S)-2-[4-[(3aR,7aS)-2-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-5-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1349)之合成Example 269. 2-[(2R,5S)-2-[4-[(3aR,7aS)-2-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3 ,4-c]pyridin-5-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxygen Synthesis of Ethylacetamide (Compound 1349)

Figure 110128222-A0202-12-1406-369
Figure 110128222-A0202-12-1406-369

步驟1：(3aS,7aR)-2-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-5-甲酸第三丁Step 1: (3aS,7aR)-2-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl 酯之合成Synthesis of Esters

向(3aS,7aR)-1,2,3,3a,4,6,7,7a-八氫吡咯并[3,4-c]吡啶-5-甲酸第三丁酯(2g，8.84mmol)及用10-15%甲醇穩定之37%甲醛水溶液(ACS 36.5-38.0%)(610.38mg，20.33mmol，563.60μL)於EtOH(30mL)中之溶液中添加乾燥的487型鈀(10%於碳上)(188.09mg，1.77mmol)。在氫氣氛、30℃下攪拌所得混合物12h。過濾出催化劑且在真空中移除溶劑，以得到(3aS,7aR)-2-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-5-甲酸第三丁酯(1.9g，7.91mmol，89.46%產率)。產率：1.9g(89.46%)To (3aS,7aR)-1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (2 g, 8.84 mmol) and To a solution of 37% aqueous formaldehyde (ACS 36.5-38.0%) (610.38 mg, 20.33 mmol, 563.60 μL) in EtOH (30 mL) stabilized with 10-15% methanol was added dry palladium type 487 (10% on carbon) ) (188.09 mg, 1.77 mmol). The resulting mixture was stirred under a hydrogen atmosphere at 30 °C for 12 h. The catalyst was filtered off and the solvent was removed in vacuo to give (3aS,7aR)-2-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c] 3-butyl pyridine-5-carboxylate (1.9 g, 7.91 mmol, 89.46% yield). Yield: 1.9g (89.46%)

1 H NMR(500MHz,CDCl3 )δ(ppm)1.20(m,2H),1.45(s,9H),1.62(m,2H),2.18-2.30(m,5H),2.72-2.78(m,2H),3.15-3.16(m,2H),3.64-3.68(m,3H),4.78-4.91(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.20(m, 2H), 1.45(s, 9H), 1.62(m, 2H), 2.18-2.30(m, 5H), 2.72-2.78(m, 2H) ), 3.15-3.16 (m, 2H), 3.64-3.68 (m, 3H), 4.78-4.91 (m, 1H).

步驟2：(3aR,7aR)-2-甲基-1,3,3a,4,5,6,7,7a-八氫吡咯并[3,4-c]吡啶之合成Step 2: Synthesis of (3aR,7aR)-2-methyl-1,3,3a,4,5,6,7,7a-octahydropyrrolo[3,4-c]pyridine

將(3aS,7aR)-2-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-5-甲酸第三丁酯(1,9g，7.91mmol)及4M於99% 1,4-二噁烷中之氯化氫(4.00g，109.71mmol，5mL)於MeOH(30mL)中之溶液在20℃下攪拌8h。將所得混合物在真空中蒸發且將殘餘物用MTBE研磨，過濾且乾燥，以得到(3aR,7aR)-2-甲基-1,3,3a,4,5,6,7,7a-八氫吡咯并[3,4-c]吡啶(1.5g，7.04mmol，89.02%產率，2HCl)。(3aS,7aR)-2-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (1, 9 g, 7.91 mmol) and a solution of 4M hydrogen chloride in 99% 1,4-dioxane (4.00 g, 109.71 mmol, 5 mL) in MeOH (30 mL) was stirred at 20 °C for 8 h. The resulting mixture was evaporated in vacuo and the residue was triturated with MTBE, filtered and dried to give (3aR,7aR)-2-methyl-1,3,3a,4,5,6,7,7a-octahydro Pyrrolo[3,4-c]pyridine (1.5 g, 7.04 mmol, 89.02% yield, 2HCl).

產率：1.5g(89.02%)Yield: 1.5g (89.02%)

LCMS(ESI)：[M-Boc]+ m/z：計算值141.2；實測值141.2；Rt=0.133min。LCMS (ESI): [M-Boc] + m/z: calculated 141.2; found 141.2; Rt=0.133 min.

步驟3：(5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl (5S)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylate

藉由一般程序2製備。Prepared by General Procedure 2.

產率：14g(87.34%)Yield: 14g (87.34%)

LCMS(ESI)：[M-Boc]+ m/z：計算值254.0；實測值254.0；Rt=1.539min。LCMS (ESI): [M-Boc] + m/z: calculated 254.0; found 254.0; Rt=1.539 min.

步驟4：(2R,5S)-2-[4-[(3aS,7aR)-2-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶Step 4: (2R,5S)-2-[4-[(3aS,7aR)-2-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridine -5-基]苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Synthesis of -5-yl]phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

藉由一般程序2(方法B)製備。產率：0.7g(粗品)。Prepared by General Procedure 2 (Method B). Yield: 0.7 g (crude).

LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值414.4；Rt=2.565min。LCMS (ESI): [M+H] + m/z: calculated 414.2; found 414.4; Rt=2.565 min.

步驟5：(3aS,7aR)-2-甲基-5-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶之合成Step 5: (3aS,7aR)-2-Methyl-5-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]-3,3a,4,6,7 Synthesis of ,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine

藉由一般程序2(方法A)製備。產率：0.55g(76.85%，3HCl)。Prepared by General Procedure 2 (Method A). Yield: 0.55 g (76.85%, 3HCl).

LCMS(ESI)：[M+2H]+ m/z：計算值315.2；實測值315.2；Rt=0.542min。LCMS (ESI): [M+2H] + m/z: calculated 315.2; found 315.2; Rt=0.542 min.

步驟6：2-[(2R,5S)-2-[4-[(3aR,7aS)-2-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-5-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1349)之合成Step 6: 2-[(2R,5S)-2-[4-[(3aR,7aS)-2-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3 ,4-c]pyridin-5-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxygen Synthesis of Ethylacetamide (Compound 1349)

藉由一般程序2製備。產率：82.30mg(20.45%)。Prepared by General Procedure 2. Yield: 82.30 mg (20.45%).

HPLC條件： 管柱：SunFire 100*19mm，5微米；2-10min 50-50-80% MeOH+NH3 30mL/min(裝載泵4mL MeOH)。 HPLC conditions: Column: SunFire 100*19mm, 5 microns; 2-10 min 50-50-80% MeOH+ NH3 30 mL/min (loading pump 4 mL MeOH).

1 H NMR(500MHz,dmso)δ 0.70-1.01(m,3H),1.06-1.14(m,3H),1.23-1.40(m,1H),1.62-1.73(m,2H),1.79-1.90(m,2H),1.92-2.07(m,1H),2.09-2.17(m,1H),2.21(s,3H),2.24-2.30(m,2H),2.36-2.44(m,4H),2.59-2.71(m,2H),3.05-3.12(m,2H),3.16-3.26(m,2H),3.38-4.00(m,2H),4.96-5.55(m,1H),5.58-5.68(m,2H),6.63-6.75(m,2H),7.03-7.15(m,2H),7.42-7.55(m,1H),7.93-8.12(m,1H),10.42-10.54(m,1H)。 1 H NMR (500MHz, dmso) δ 0.70-1.01 (m, 3H), 1.06-1.14 (m, 3H), 1.23-1.40 (m, 1H), 1.62-1.73 (m, 2H), 1.79-1.90 (m ,2H),1.92-2.07(m,1H),2.09-2.17(m,1H),2.21(s,3H),2.24-2.30(m,2H),2.36-2.44(m,4H),2.59-2.71 (m,2H),3.05-3.12(m,2H),3.16-3.26(m,2H),3.38-4.00(m,2H),4.96-5.55(m,1H),5.58-5.68(m,2H) , 6.63-6.75(m, 2H), 7.03-7.15(m, 2H), 7.42-7.55(m, 1H), 7.93-8.12(m, 1H), 10.42-10.54(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值506.2；Rt=1.916min。LCMS (ESI): [M] + m/z: calculated 506.2; found 506.2; Rt=1.916 min.

實例270.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(4-((1-甲基哌啶-4-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1216)之合成Example 270. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(4-((1-methylpiperidine- Synthesis of 4-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1216)

Figure 110128222-A0202-12-1409-370
Figure 110128222-A0202-12-1409-370

步驟1：(2R,5S)-5-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)哌啶-1-甲酸第三丁酯之合成Step 1: (2R,5S)-5-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) ) Synthesis of 3-butyl phenyl)piperidine-1-carboxylate

在氬氣下，向(2R,5S )-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁 酯(1g，2.82mmol)、乙酸鉀(637.13mg，6.49mmol，405.81μL)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(788.45mg，3.10mmol)於二噁烷(15mL)中之溶液中添加Pd(dppf)Cl2 *DCM(138.30mg，169.36μmol)。將反應混合物在90℃下攪拌14h。然後，將反應混合物濃縮，溶解於10mL乙酸乙酯中且用水洗滌。將有機層用硫酸鈉乾燥且在減壓下蒸發。藉由FCC純化殘餘物，以得到(2R,5S )-5-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁 酯(0.6g，1.49mmol，52.96%產率)。To ( 2R,5S )-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (1 g, 2.82 mmol), potassium acetate (637.13 mg, 6.49 mmol) under argon mmol, 405.81 μL) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-1,3,2-dioxaborolane (788.45 mg, 3.10 mmol) in dioxane (15 mL) was added Pd(dppf)Cl2*DCM ( 138.30 mg, 169.36 μmol ). The reaction mixture was stirred at 90 °C for 14 h. Then, the reaction mixture was concentrated, dissolved in 10 mL of ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by FCC to give ( 2R,5S )-5-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborocycle Pentan-2-yl)phenyl]piperidine-1-carboxylic acid tert -butyl ester (0.6 g, 1.49 mmol, 52.96% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值301.2；實測值302.2；Rt=1.769min。LCMS (ESI): [M-Boc] + m/z: calculated 301.2; found 302.2; Rt=1.769 min.

步驟2：(2R,5S)-2-(4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-2-(4-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(2R,5S )-5-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁 酯(700mg，1.57mmol)於H2 O(6mL)及THF(6mL)之混合物中之溶液中添加35%過氧化氫(400mg，11.76mmol，363.64μL)且攪拌隔夜。 將反應混合物用水(40mL)及MTBE(40mL)稀釋，且用硫代硫酸鈉處理，然後將有機相用水洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到(2R,5S )-2-(4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁 酯(0.5g，粗品)。To ( 2R,5S )-5-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzene To a solution of tert- butyl ]piperidine-1-carboxylate (700 mg, 1.57 mmol) in a mixture of H2O (6 mL) and THF (6 mL) was added 35% hydrogen peroxide (400 mg, 11.76 mmol, 363.64 μL ) and stirred overnight. The reaction mixture was diluted with water (40 mL) and MTBE (40 mL) and treated with sodium thiosulfate, then the organic phase was washed with water, dried over Na 2 SO 4 and concentrated in vacuo to give ( 2R,5S )-2 -(4-Hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (0.5 g, crude).

LCMS(ESI)：[M-Boc]+ m/z：計算值191.2；實測值192.2；Rt=1.456min。LCMS (ESI): [M-Boc] + m/z: calculated 191.2; found 192.2; Rt=1.456 min.

步驟3：(2R,5S)-5-甲基-2-(4-((1-甲基哌啶-4-基)甲氧基)苯基)哌啶-1-甲酸第三丁酯之合成Step 3: (2R,5S)-5-methyl-2-(4-((1-methylpiperidin-4-yl)methoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester synthesis

將(2R,5S )-2-(4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁 酯(250mg，857.97μmol)、4-(溴甲基)-1-甲基哌啶(257.66mg，943.77μmol，HBr)及碳酸銫(838.63mg，2.57mmol)混合於DMFA(5mL)中且在攪拌之情況下在90℃下加熱24h。將反應混合物用水稀釋且用30mL EtOAc萃取，經Na2 SO4 乾燥且在真空中濃縮。使DMSO溶液經歷HPLC(2-10min 30-45%水/MeOH+NH3 ；30mL/min；裝載泵MeOH；4mL/min；管柱SunFire 19*100mm)。獲得(2R,5S )-5-甲基-2-[4-[(1-甲基-4-哌啶基)甲氧基]苯基]哌啶-1-甲酸第三丁 酯(72.2mg，179.35μmol，20.90%產率)。( 2R,5S )-2-(4-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (250 mg, 857.97 μmol), 4-(bromomethyl)-1-methyl Piperidine (257.66 mg, 943.77 μmol, HBr) and cesium carbonate (838.63 mg, 2.57 mmol) were mixed in DMFA (5 mL) and heated at 90 °C with stirring for 24 h. The reaction mixture was diluted with water and extracted with 30 mL of EtOAc, dried over Na2SO4 and concentrated in vacuo. The DMSO solution was subjected to HPLC (2-10 min 30-45% water/MeOH+ NH3 ; 30 mL/min; loading pump MeOH; 4 mL/min; column SunFire 19*100 mm). ( 2R,5S )-5-methyl-2-[4-[(1-methyl-4-piperidinyl)methoxy]phenyl]piperidine-1-carboxylic acid tert- butyl ester (72.2 mg) was obtained , 179.35 μmol, 20.90% yield).

LCMS(ESI)：[M]+ m/z：計算值402.2；實測值403.2；Rt=3.477min。LCMS (ESI): [M] + m/z: calculated 402.2; found 403.2; Rt=3.477 min.

步驟4：1-甲基-4-((4-((2R,5S)-5-甲基哌啶-2-基)苯氧基)甲基)哌啶之合成Step 4: Synthesis of 1-methyl-4-((4-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)methyl)piperidine

將(2R,5S )-5-甲基-2-[4-[(1-甲基-4-哌啶基)甲氧基]苯基]哌啶-1-甲酸第三丁 酯(72.2mg，179.35μmol)溶解於5mL HCl/二噁烷(10%)(6.54mg，179.35μmol)中，然後添加1mL MeOH以便使產物更好溶解。在攪拌1h之後，將RM在真空中濃縮。獲得1-甲基-4-[[4-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]甲基]哌啶(80mg，粗品，2HCl)。( 2R,5S )-5-methyl-2-[4-[(1-methyl-4-piperidinyl)methoxy]phenyl]piperidine-1-carboxylic acid tert- butyl ester (72.2 mg , 179.35 μmol) was dissolved in 5 mL of HCl/dioxane (10%) (6.54 mg, 179.35 μmol), then 1 mL of MeOH was added for better solubilization of the product. After stirring for 1 h, the RM was concentrated in vacuo. 1-Methyl-4-[[4-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]methyl]piperidine (80 mg, crude, 2HCl) was obtained.

LCMS(ESI)：[M]+ m/z：計算值302.2；實測值303.2；Rt=0.602min。LCMS (ESI): [M] + m/z: calculated 302.2; found 303.2; Rt=0.602 min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(4-((1-甲基哌啶-4-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1250)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(4-((1-methylpiperidine- Synthesis of 4-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1250)

將1-甲基-4-[[4-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]甲基]哌啶(80mg，213.12μmol，2HCl)及TEA(107.83mg，1.07mmol，148.52μL)混合於DMSO(2mL)中且攪拌5min。然後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(44.59mg，213.12μmol)且再攪拌10min。最後添加HATU(105.35mg，277.06μmol)且攪拌2h。使反應混合物經歷HPLC。第一裝載HPLC資料：裝置(流動相，管柱)：SYSTEM 2-10min 10-50% MeOH+FA 30mL/min(裝載泵4mL MeOH)管柱：SunFire 100*19mm，5微米。第二裝載HPLC資料：裝置(流動相，管柱)：SYSTEM 2-10min 10-50% MeOH+NH3 ,30mL/min(裝載泵4mL MeOH)管柱：SunFire 100*19mm，5微米。獲得呈異構物之混合物之N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[4-[(1-甲基-4-哌啶基)甲氧基]苯基]-1-哌啶基]-2-側氧基乙醯胺(36.2mg，73.33μmol，34.41%產率)。1-Methyl-4-[[4-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]methyl]piperidine (80 mg, 213.12 μmol, 2HCl) and TEA ( 107.83 mg, 1.07 mmol, 148.52 μL) were mixed in DMSO (2 mL) and stirred for 5 min. Then 2-[(6-amino-5-ethyl-3-pyridinyl)amino]-2-pendoxoacetic acid (44.59 mg, 213.12 μmol) was added and stirred for an additional 10 min. Finally HATU (105.35 mg, 277.06 μmol) was added and stirred for 2 h. The reaction mixture was subjected to HPLC. 1st load HPLC data: Apparatus (mobile phase, column): SYSTEM 2-10min 10-50% MeOH+FA 30mL/min (load pump 4mL MeOH) Column: SunFire 100*19mm, 5 microns. 2nd load HPLC data: Apparatus (mobile phase, column): SYSTEM 2-10min 10-50% MeOH+ NH3 , 30mL/min (load pump 4mL MeOH) Column: SunFire 100*19mm, 5 microns. N- (6-amino-5-ethyl-3-pyridinyl)-2-[( 2R,5S )-5-methyl-2-[4-[(1- Methyl-4-piperidinyl)methoxy]phenyl]-1-piperidinyl]-2-oxoacetamide (36.2 mg, 73.33 μmol, 34.41% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.76-1.02(m,3H),1.06-1.14(m,3H),1.17-1.43(m,3H),1.64-1.76(m,3H),1.81-1.85(m,1H),1.86-2.04(m,2H),2.05-2.10(m,1H),2.13-2.20(m,3H),2.20-2.28(m,1H),2.32-2.41(m,3H),2.60-2.65(m,1H),2.68-2.78(m,1H),3.13-3.28(m,1H),3.38-3.45(m,1H),3.77-3.95(m,2H),4.93-5.58(m,1H),5.58-5.74(m,2H),6.85-7.01(m,2H),7.16-7.31(m,2H),7.38-7.57(m,1H),7.96-8.16(m,1H),10.42(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.76-1.02(m,3H), 1.06-1.14(m,3H), 1.17-1.43(m,3H), 1.64-1.76(m,3H) ,1.81-1.85(m,1H),1.86-2.04(m,2H),2.05-2.10(m,1H),2.13-2.20(m,3H),2.20-2.28(m,1H),2.32-2.41( m,3H),2.60-2.65(m,1H),2.68-2.78(m,1H),3.13-3.28(m,1H),3.38-3.45(m,1H),3.77-3.95(m,2H), 4.93-5.58(m, 1H), 5.58-5.74(m, 2H), 6.85-7.01(m, 2H), 7.16-7.31(m, 2H), 7.38-7.57(m, 1H), 7.96-8.16(m , 1H), 10.42(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值493.2；實測值494.2；Rt=1.753min。LCMS (ESI): [M] + m/z: calculated 493.2; found 494.2; Rt=1.753 min.

實例271.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-((1-甲基哌啶-2-基)甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1273)之合成Example 271. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-((1-methylpiperidine- Synthesis of 2-yl)methyl)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1273)

Figure 110128222-A0202-12-1412-371
Figure 110128222-A0202-12-1412-371

步驟1：2-(3-溴苯甲基)-1-甲基哌啶之合成Step 1: Synthesis of 2-(3-Bromobenzyl)-1-methylpiperidine

在25℃下，向2-[(3-溴苯基)甲基]哌啶(1g，3.93mmol)於DCM中之經攪拌之溶液中分別添加37% w/w甲醛水溶液(7.87mmol)及乙酸(708.79mg，11.80mmol，675.68μL)。將所得反應混合物在25℃下攪拌1h。然後添加氰基硼氫化鈉(494.48mg，7.87mmol)。將混合物繼續攪拌12h。完成之後，將反應混合物用20mL NaHCO3 溶液淬滅。然後將有機相用水20mL洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈黃色狀態之粗產物。藉由反相HPLC(裝置(流動相，管柱)：SYSTEM 20-20-65% 0-1-5min H2 O/MeOH/0.01% HCl，流速：30mL/min(裝載泵4mL/min MeOH)；管柱：Chromatorex 18 SMB100-5T 100x19mm 5um)純化所獲得之粗產物，以得到呈黃色狀態之產物之鹽酸鹽。及另一個裝置((流動相，管柱)：SYSTEM 40-40-90% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeOH)，以獲得呈鹼之產物。分離呈白色狀態之所要產物2-[(3-溴苯基)甲基]-1-甲基哌啶(0.25g，932.17μmol，23.69%產率)。To a stirred solution of 2-[(3-bromophenyl)methyl]piperidine (1 g, 3.93 mmol) in DCM at 25°C was added 37% w/w aqueous formaldehyde (7.87 mmol) and Acetic acid (708.79 mg, 11.80 mmol, 675.68 [mu]L). The resulting reaction mixture was stirred at 25 °C for 1 h. Then sodium cyanoborohydride (494.48 mg, 7.87 mmol) was added. The mixture was continued to stir for 12 h. After completion, the reaction mixture was quenched with 20 mL of NaHCO3 solution. The organic phase was then washed with water 20 mL, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product in yellow state. By reverse phase HPLC (device (mobile phase, column): SYSTEM 20-20-65% 0-1-5 min H2O /MeOH/0.01% HCl, flow rate: 30 mL/min (loading pump 4 mL/min MeOH) ; Column: Chromatorex 18 SMB100-5T 100x19mm 5um) The crude product obtained was purified to obtain the hydrochloride salt of the product in a yellow state. and another device ((mobile phase, column): SYSTEM 40-40-90% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min (load pump 4 mL/min MeOH) to obtain the product as a base. The desired product 2-[(3-bromophenyl)methyl]-1-methylpiperidine (0.25 g, 932.17 μmol, 23.69% yield) was isolated as a white state.

LCMS(ESI)：[M]+ m/z：計算值268.2；實測值269.2；Rt=2.094min。LCMS (ESI): [M] + m/z: calculated 268.2; found 269.2; Rt=2.094 min.

步驟2：1-甲基-2-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯甲基)哌啶之合成Step 2: 1-Methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzyl)piperidine Synthesis of pyridine

向2-[(3-溴苯基)甲基]-1-甲基哌啶(1.2g，4.47mmol)於二噁烷(6.45mL)中之經攪拌之溶液中添加4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧雜硼雜環戊烷 -2-基)-1,3,2-二氧雜硼雜環戊烷(1.25g，4.92mmol)及乙酸鉀(1.10g，11.19mmol，699.23μL)。將所得懸浮液用氬氣除氣。添加Pd(dppf)Cl2 *DCM(327.08mg，447.44μmol)。將反應混合物在90℃下攪拌16h。完成之後，過濾反應混合物且在真空中蒸發濾液，以得到油狀殘餘物。然後將產物用MTBE/水(50mL/50mL)萃取。將有機層經Na2 SO4 乾燥且蒸發。然後添加二噁烷/HCl(15mL)且再次蒸發。然後將化合物用MTBE(20mL)洗滌且過濾。在減壓下乾燥沉澱。分離所要產物1-甲基-2-[[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]甲基]哌啶(0.9g，2.56mmol，57.19%產率，HCl)。To a stirred solution of 2-[(3-bromophenyl)methyl]-1-methylpiperidine (1.2 g, 4.47 mmol) in dioxane (6.45 mL) was added 4,4,5, 5-Tetramethyl-2-(tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.25g , 4.92 mmol) and potassium acetate (1.10 g, 11.19 mmol, 699.23 μL). The resulting suspension was degassed with argon. Pd(dppf)Cl2*DCM ( 327.08 mg, 447.44 μmol) was added. The reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was filtered and the filtrate was evaporated in vacuo to give an oily residue. The product was then extracted with MTBE/water (50 mL/50 mL). The organic layer was dried over Na2SO4 and evaporated. Dioxane/HCl (15 mL) was then added and evaporated again. The compound was then washed with MTBE (20 mL) and filtered. The precipitate was dried under reduced pressure. Isolation of the desired product 1-methyl-2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]methane yl]piperidine (0.9 g, 2.56 mmol, 57.19% yield, HCl).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=2.758min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=2.758 min.

步驟3：(3S)-3-甲基-6-(3-((1-甲基哌啶-2-基)甲基)苯基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (3S)-3-Methyl-6-(3-((1-methylpiperidin-2-yl)methyl)phenyl)-3,4-dihydropyridine-1(2H)- Synthesis of tert-butyl formate

向1-甲基-2-[[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]甲基]哌啶(0.7g，1.99mmol，HCl)及(3R )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(687.30mg，1.99mmol)於二噁烷(5mL)中之經攪拌之溶液中添加碳酸鈉(210.94mg，1.99mmol，83.31μL)。將所得懸浮液用氬氣除氣。添加Pd(dppf)Cl2 *DCM(1.63g，1.99mmol)。將反應混合物在90℃下攪拌16h。完成之後，過濾反應混合物且在真空中蒸發濾液，以得到油狀殘餘物。分離所要產物(3S )-3-甲基-6-[3-[(1-甲基-2-哌啶基)甲基]苯基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(0.9g，2.34mmol，117.59%產率)。to 1-methyl-2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]methyl] Piperidine (0.7 g, 1.99 mmol, HCl) and ( 3R )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid To a stirred solution of tributyl ester ( 687.30 mg, 1.99 mmol) in dioxane (5 mL) was added sodium carbonate (210.94 mg, 1.99 mmol, 83.31 [mu]L). The resulting suspension was degassed with argon. Pd(dppf)Cl2*DCM (1.63 g , 1.99 mmol) was added. The reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was filtered and the filtrate was evaporated in vacuo to give an oily residue. Isolation of the desired product ( 3S )-3-methyl-6-[3-[(1-methyl-2-piperidinyl)methyl]phenyl]-3,4-dihydro- 2H -pyridine-1- 3 -Butyl formate (0.9 g, 2.34 mmol, 117.59% yield).

LCMS(ESI)：[M]+ m/z：計算值384.2；實測值385.2；Rt=3.113min。LCMS (ESI): [M] + m/z: calculated 384.2; found 385.2; Rt=3.113 min.

步驟4：(3S)-3-甲基-6-(3-((1-甲基哌啶-2-基)甲基)苯基)-2,3,4,5-四氫吡啶之合成Step 4: Synthesis of (3S)-3-methyl-6-(3-((1-methylpiperidin-2-yl)methyl)phenyl)-2,3,4,5-tetrahydropyridine

在25℃下，向(3S )-3-甲基-6-[3-[(1-甲基-2-哌啶基)甲基]苯基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(0.9g，2.34mmol)於DCM中之經攪拌之溶液中分別添加TFA(13.34g，117.02mmol，9.02mL)。將所得反應混合物在25℃下攪拌12h。 完成之後，將反應混合物在減壓下濃縮。然後將粗產物三氟乙酸鹽溶解於100mL水中，將水用MTBE(30mL)洗滌。然後將水層用Na2 CO3 鹼化且用DCM萃取兩次(100mL)。將有機層用水(50mL)洗滌，經Na2 SO4 乾燥且蒸發。分離呈棕色狀態之所要產物(3S )-3-甲基-6-[3-[(1-甲基-2-哌啶基)甲基]苯基]-2,3,4,5-四氫吡啶(0.5g，粗品)。To ( 3S )-3-methyl-6-[3-[(1-methyl-2-piperidinyl)methyl]phenyl]-3,4-dihydro- 2H -pyridine at 25°C To a stirred solution of tert -butyl 1-carboxylate (0.9 g, 2.34 mmol) in DCM was added TFA (13.34 g, 117.02 mmol, 9.02 mL) separately. The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude product trifluoroacetate was then dissolved in 100 mL of water, which was washed with MTBE (30 mL). The aqueous layer was then basified with Na2CO3 and extracted twice with DCM (100 mL). The organic layer was washed with water (50 mL), dried over Na2SO4 and evaporated. The desired product ( 3S )-3-methyl-6-[3-[(1-methyl-2-piperidinyl)methyl]phenyl]-2,3,4,5-tetrakis was isolated as a brown state Hydropyridine (0.5 g, crude).

LCMS(ESI)：[M]+ m/z：計算值284.2；實測值285.2；Rt=0.650min。LCMS (ESI): [M] + m/z: calculated 284.2; found 285.2; Rt=0.650 min.

步驟5：1-甲基-2-(3-((2R,5S)-5-甲基哌啶-2-基)苯甲基)哌啶之合成Step 5: Synthesis of 1-methyl-2-(3-((2R,5S)-5-methylpiperidin-2-yl)benzyl)piperidine

在25℃下，向(3S )-3-甲基-6-[3-[(1-甲基-2-哌啶基)甲基]苯基]-2,3,4,5-四氫吡啶(0.5g，1.76mmol)於MeOH(9.94mL)中之經攪拌之溶液中分別添加硼氫化鈉(66.50mg，1.76mmol，61.92μL)。將所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物在減壓下濃縮。然後將化合物用DCM/H2 O(100mL/20mL)萃取。將有機層用水洗滌，經Na2 SO4 乾燥且蒸發。藉由反相HPLC(裝置(流動相，管柱)：SYSTEM 40-80% 0-6min H2 O/MeCN/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeOH)；管柱：XBridge BEH C18 5um)純化所獲得之粗產物，以得到呈棕色狀態之產物1-甲基-2-[[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]甲基]哌啶(37mg，129.17μmol，7.35%產率)。To ( 3S )-3-methyl-6-[3-[(1-methyl-2-piperidinyl)methyl]phenyl]-2,3,4,5-tetrahydro at 25°C To a stirred solution of pyridine (0.5 g, 1.76 mmol) in MeOH (9.94 mL) was added sodium borohydride (66.50 mg, 1.76 mmol, 61.92 μL), respectively. The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The compound was then extracted with DCM/ H2O (100 mL/20 mL). The organic layer was washed with water, dried over Na2SO4 and evaporated. By reverse phase HPLC (device (mobile phase, column): SYSTEM 40-80% 0-6 min H2O /MeCN/0.1% NH4OH , flow rate: 30 mL/min (loading pump 4 mL/min MeOH); tube Column: XBridge BEH C18 5um) to purify the crude product obtained to give the product 1-methyl-2-[[3-[( 2R,5S )-5-methyl-2-piperidinyl] in brown state Phenyl]methyl]piperidine (37 mg, 129.17 μmol, 7.35% yield).

LCMS(ESI)：[M]+ m/z：計算值286.2；實測值287.2；Rt=1.011min。LCMS (ESI): [M] + m/z: calculated 286.2; found 287.2; Rt=1.011 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-((1-甲基哌啶-2-基)甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1273)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-((1-methylpiperidine- Synthesis of 2-yl)methyl)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1273)

在25℃下，向1-甲基-2-[[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]甲基]哌啶(37mg，129.17μmol)於DMF(1.98mL)中之經攪拌之溶液中分別添加DIPEA(33.39mg，258.33μmol，45.00μL)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(27.02mg，129.17μmol)及HATU(49.11mg，129.17μmol)。使所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物在減壓下濃縮，以獲得呈棕色 狀態之粗產物。藉由反相HPLC(裝置(流動相，管柱)：SYSTEM 40-40-70% 0-1-6min H2 O/MeCN/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeOH)；管柱：YMC Triart C18 100x20mm，5um)純化所獲得之粗產物，以得到呈棕色狀態之產物N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-[(1-甲基-2-哌啶基)甲基]苯基]-1-哌啶基]-2-側氧基乙醯胺(23mg，48.15μmol，37.28%產率)。To 1-methyl-2-[[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]methyl]piperidine (37 mg, 129.17 μmol) at 25 °C To the stirred solution in DMF (1.98 mL) were added DIPEA (33.39 mg, 258.33 μmol, 45.00 μL), 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2, respectively - Pendant oxyacetic acid (27.02 mg, 129.17 μmol) and HATU (49.11 mg, 129.17 μmol). The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product in brown state. by reverse phase HPLC (device (mobile phase, column): SYSTEM 40-40-70% 0-1-6 min H2O /MeCN/0.1% NH4OH , flow rate: 30 mL/min (load pump 4 mL/min) MeOH); Column: YMC Triart C18 100x20mm, 5um) The crude product obtained was purified to give the product N- (6-amino-5-ethyl-3-pyridinyl)-2-[( 2R,5S )-5-methyl-2-[3-[(1-methyl-2-piperidinyl)methyl]phenyl]-1-piperidinyl]-2-oxoacetamide (23 mg, 48.15 μmol, 37.28% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.14(m,8H),1.19-1.37(m,2H),1.37-1.47(m,2H),1.49-1.58(m,1H),1.59-1.73(m,1H),1.79-1.94(m,1H),1.95-2.07(m,2H),2.09-2.21(m,1H),2.24-2.29(m,3H),2.33-2.43(m,3H),2.60-2.76(m,2H),2.93-3.23(m,2H),3.45-4.04(m,1H),5.12-5.59(m,1H),5.58-5.68(m,2H),7.03-7.17(m,3H),7.24-7.32(m,1H),7.42-7.54(m,1H),7.97-8.10(m,1H),10.52(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.14(m, 8H), 1.19-1.37(m, 2H), 1.37-1.47(m, 2H), 1.49-1.58(m, 1H) ,1.59-1.73(m,1H),1.79-1.94(m,1H),1.95-2.07(m,2H),2.09-2.21(m,1H),2.24-2.29(m,3H),2.33-2.43( m,3H), 2.60-2.76(m,2H), 2.93-3.23(m,2H), 3.45-4.04(m,1H), 5.12-5.59(m,1H), 5.58-5.68(m,2H), 7.03-7.17(m,3H), 7.24-7.32(m,1H), 7.42-7.54(m,1H), 7.97-8.10(m,1H), 10.52(s,1H).

LCMS(ESI)：[M]+ m/z：計算值477.2；實測值478.2；Rt=1.698min。LCMS (ESI): [M] + m/z: calculated 477.2; found 478.2; Rt=1.698 min.

實例272.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(4-(2-(二甲胺基)乙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1292)之合成Example 272. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(4-(2-(dimethylamino)ethoxy)benzene yl)-5-methylpiperidin-1-yl)-2-oxyacetamide (compound 1292)

Figure 110128222-A0202-12-1415-372
Figure 110128222-A0202-12-1415-372

步驟1：(2R,5S)-2-(4-(2-(二甲胺基)乙氧基)苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,5S)-2-(4-(2-(dimethylamino)ethoxy)phenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5S )-2-(4-羥基苯基)-5-甲基哌啶-1-甲酸第三丁 酯(50mg，171.59μmol)、2-溴-N,N -二甲基乙胺(43.97mg，188.75μmol，HBr)及第三丁醇鉀(48.14mg，428.99μmol)混合於DMF(5mL)中且在攪拌之情況下在90℃下加熱12h。12h之後之轉化率-55%。另外添加20mg2-溴-N,N -二甲基乙胺及25mg第三丁醇鉀。+24h之後之轉化率-71%。另外添加20mg 2-溴-N,N -二甲基乙胺及25mg第 三丁醇鉀。+24h之後之轉化率-100%。將反應混合物用水稀釋且用30mL EtOAc萃取，經Na2 SO4 乾燥且在真空中濃縮，以得到(2R,5S )-2-[4-[2-(二甲胺基)乙氧基]苯基]-5-甲基哌啶-1-甲酸第三丁 酯(120mg，粗品)。( 2R,5S )-2-(4-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (50 mg, 171.59 μmol), 2-bromo- N,N -dimethylethyl The amine (43.97 mg, 188.75 μmol, HBr) and potassium tert-butoxide (48.14 mg, 428.99 μmol) were mixed in DMF (5 mL) and heated at 90° C. with stirring for 12 h. Conversion after 12h -55%. Additional 20 mg of 2-bromo- N,N -dimethylethylamine and 25 mg of potassium tert-butoxide were added. Conversion after +24h -71%. Additional 20 mg of 2-bromo- N,N -dimethylethylamine and 25 mg of potassium tert-butoxide were added. Conversion rate after +24h -100%. The reaction mixture was diluted with water and extracted with 30 mL of EtOAc, dried over Na 2 SO 4 and concentrated in vacuo to give ( 2R,5S )-2-[4-[2-(dimethylamino)ethoxy]benzene [methyl]-5-methylpiperidine-1-carboxylic acid tert- butyl ester (120 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值362.2；實測值363.2；Rt=1.169min。LCMS (ESI): [M] + m/z: calculated 362.2; found 363.2; Rt=1.169 min.

步驟2：N,N-二甲基-2-(4-((2R,5S)-5-甲基哌啶-2-基)苯氧基)乙胺之合成Step 2: Synthesis of N,N-dimethyl-2-(4-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)ethanamine

將(2R,5S )-2-[4-[2-(二甲胺基)乙氧基]苯基]-5-甲基哌啶-1-甲酸第三丁 酯(120mg，182.07μmol)溶解於5mL HCl/二噁烷(10%)(6.64mg，182.07μmol)中，然後添加1mL MeOH以使產物更好溶解。在攪拌2h之後，將RM在真空中濃縮。獲得N,N -二甲基-2-[4-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]乙胺(70mg，粗品，2HCl)。( 2R,5S )-2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-methylpiperidine-1-carboxylic acid tert- butyl ester (120 mg, 182.07 μmol) was dissolved In 5 mL HCl/dioxane (10%) (6.64 mg, 182.07 μmol), then 1 mL MeOH was added to dissolve the product better. After stirring for 2 h, the RM was concentrated in vacuo. Obtained N,N -dimethyl-2-[4-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]ethanamine (70 mg, crude, 2HCl).

LCMS(ESI)：[M]+ m/z：計算值262.2；實測值263.2；Rt=0.243min。LCMS (ESI): [M] + m/z: calculated 262.2; found 263.2; Rt=0.243 min.

步驟3：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(4-(2-(二甲胺基)乙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1292)之合成Step 3: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(4-(2-(dimethylamino)ethoxy)benzene Synthesis of )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1292)

將N,N -二甲基-2-[4-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]乙胺(70mg，177.45μmol，2HCl)及HATU(87.71mg，230.68μmol)混合於DMSO(1.91mL)中且攪拌5min。然後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(44.55mg，212.94μmol)且再攪拌10min。最後添加TEA(89.78mg，887.24μmol，123.66μL)且攪拌2h。使反應混合物經歷HPLC。第一裝載HPLC資料：裝置(流動相，管柱)：SYSTEM 2-10min 10-50% MeOH+FA 30mL/min(裝載泵4mL MeOH)管柱：SunFire 100*19mm，5微米。第二裝載HPLC資料：2-10min 10-50%水/MeOH+NH3 30mL/min；裝載泵4mL/min MeOH+NH3 ；管柱SunFire 19*100mm。獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[4-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(19.3mg，42.55μmol，23.98%產率)。 N,N -dimethyl-2-[4-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]ethanamine (70 mg, 177.45 μmol, 2HCl) and HATU (87.71 mg, 230.68 μmol) in DMSO (1.91 mL) and stirred for 5 min. 2-[(6-Amino-5-ethyl-3-pyridinyl)amino]-2-pendoxoacetic acid (44.55 mg, 212.94 μmol) was then added and stirred for an additional 10 min. Finally TEA (89.78 mg, 887.24 μmol, 123.66 μL) was added and stirred for 2 h. The reaction mixture was subjected to HPLC. 1st load HPLC data: Apparatus (mobile phase, column): SYSTEM 2-10min 10-50% MeOH+FA 30mL/min (load pump 4mL MeOH) Column: SunFire 100*19mm, 5 microns. 2nd load HPLC profile: 2-10min 10-50% water/MeOH+ NH3 30mL/min; load pump 4mL/min MeOH+ NH3 ; column SunFire 19*100mm. Obtained N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-[4-[2-(dimethylamino)ethoxy]phenyl] -5-Methyl-1-piperidinyl]-2-oxoacetamide (19.3 mg, 42.55 μmol, 23.98% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.71-1.02(m,3H),1.07-1.15(m,3H),1.26 -1.39(m,1H),1.59-1.73(m,1H),1.79-1.92(m,1H),1.96-2.12(m,1H),2.12-2.18(m,1H),2.19(s,6H),2.35-2.41(m,2H),2.58-2.61(m,2H),2.67-3.21(m,1H),3.37-3.99(m,1H),3.99-4.06(m,2H),5.02-5.58(m,1H),5.58-5.69(m,2H),6.90-6.98(m,2H),7.15-7.28(m,2H),7.43-7.54(m,1H),7.98-8.11(m,1H),10.52(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.71-1.02(m,3H), 1.07-1.15(m,3H), 1.26-1.39(m,1H), 1.59-1.73(m,1H) ,1.79-1.92(m,1H),1.96-2.12(m,1H),2.12-2.18(m,1H),2.19(s,6H),2.35-2.41(m,2H),2.58-2.61(m, 2H), 2.67-3.21(m, 1H), 3.37-3.99(m, 1H), 3.99-4.06(m, 2H), 5.02-5.58(m, 1H), 5.58-5.69(m, 2H), 6.90- 6.98 (m, 2H), 7.15-7.28 (m, 2H), 7.43-7.54 (m, 1H), 7.98-8.11 (m, 1H), 10.52 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.532min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.532 min.

實例273. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4S,5S)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1159)、外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,4S,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1349)、rel-N-(6-胺基-5-乙基吡啶-3-基)-2-((2S,4R,5S)-4-甲氧基-5-甲基-2-(4-(4-甲基哌嗪-1-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1089)之合成Example 273. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,4S,5S)-4-methoxy-5-methyl-2-[4 -(4-Methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1159), rac-N-(6-amino-5 -Ethyl-3-pyridyl)-2-[(2R,4S,5R)-4-methoxy-5-methyl-2-[4-(4-methylpiperazin-1-yl)benzene yl]-1-piperidinyl]-2-oxoacetamide (Compound 1349), rel-N-(6-amino-5-ethylpyridin-3-yl)-2-((2S, 4R,5S)-4-methoxy-5-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)piperidin-1-yl)-2-side oxyethyl Synthesis of amide (compound 1089)

Figure 110128222-A0202-12-1418-373
Figure 110128222-A0202-12-1418-373

步驟1：外消旋-(6R,9R)-9-(4-溴苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷之合成Step 1: Synthesis of racemic-(6R,9R)-9-(4-bromophenyl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane

向其中添加2-(2-甲基-1,3-二氧環戊烷-2-基)丙-1-胺(6.9g，47.52mmol)溶解於甲苯(150mL)及4-溴苯甲醛(8.79g，47.52mmol)，隨後添加p-TSA(24.55g，142.56mmol)。將所得混合物加熱至回流且以迪安-斯塔克分離器回流隔夜。To this was added 2-(2-methyl-1,3-dioxolan-2-yl)propan-1-amine (6.9 g, 47.52 mmol) dissolved in toluene (150 mL) and 4-bromobenzaldehyde ( 8.79 g, 47.52 mmol) followed by p-TSA (24.55 g, 142.56 mmol). The resulting mixture was heated to reflux and refluxed with a Dean-Stark separator overnight.

冷卻反應混合物且添加K2 CO3 水溶液(50mL)。將所得混合物轉移至分離漏斗且分離有機層。用EtOAc(50mL)萃取水層，且將經合併之有機層經Na2 SO4 乾燥，過濾且濃縮。將殘餘物溶解於CHCl3 (100mL)中且將所得混合物用NaHSO4 水溶液(於50mL水中之5g，2*50mL)萃取。將經合併之水層用CHCl3 (2*50mL)洗滌，然後用K2 CO3 (10g)鹼化。將所得混合物用CHCl3 (2*50mL)萃 取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得(6R,9R)-9-(4-溴苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(2.7g，8.65mmol，18.20%產率)。 The reaction mixture was cooled and aqueous K2CO3 ( 50 mL) was added. The resulting mixture was transferred to a separation funnel and the organic layer was separated. The aqueous layer was extracted with EtOAc (50 mL), and the combined organic layers were dried over Na2SO4 , filtered and concentrated. The residue was dissolved in CHCl3 (100 mL) and the resulting mixture was extracted with aqueous NaHSO4 ( 5 g in 50 mL water, 2*50 mL). The combined aqueous layers were washed with CHCl3 ( 2 *50 mL), then basified with K2CO3 ( 10 g). The resulting mixture was extracted with CHCl3 (2*50 mL) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to give (6R,9R)-9-(4-bromophenyl)-6- Methyl-1,4-dioxa-8-azaspiro[4.5]decane (2.7 g, 8.65 mmol, 18.20% yield).

LCMS(ESI)：[M+H]+ m/z：計算值312.0；實測值312.0；Rt=0.712min。LCMS (ESI): [M+H] + m/z: calculated 312.0; found 312.0; Rt=0.712 min.

步驟2：(2R,5R)-2-(4-溴苯基)-5-甲基哌啶-4-酮之合成Step 2: Synthesis of (2R,5R)-2-(4-bromophenyl)-5-methylpiperidin-4-one

將(6R,9R)-9-(4-溴苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(2.7g，8.65mmol)溶解於6N HCl(80mL)中且將所得混合物在80℃下(在油浴中)加熱隔夜。將反應混合物冷卻，用MTBE萃取(兩次)，然後將水層用K2 CO3 鹼化。將所得混合物用CHCl3 萃取(兩次)且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得(2R,5R)-2-(4-溴苯基)-5-甲基哌啶-4-酮(1g，3.73mmol，43.12%產率)。(6R,9R)-9-(4-Bromophenyl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane (2.7 g, 8.65 mmol) was dissolved in 6N HCl (80 mL) and the resulting mixture was heated at 80 °C (in an oil bath) overnight. The reaction mixture was cooled, extracted with MTBE (twice), and the aqueous layer was basified with K2CO3. The resulting mixture was extracted with CHCl 3 (twice) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to obtain (2R,5R)-2-(4-bromophenyl)-5-methane ylpiperidin-4-one (1 g, 3.73 mmol, 43.12% yield).

LCMS(ESI)：[M+H]+ m/z：計算值270.2；實測值270.2；Rt=0.812min。LCMS (ESI): [M+H] + m/z: calculated 270.2; found 270.2; Rt=0.812 min.

步驟3：(2R,5R)-2-(4-溴苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of (2R,5R)-2-(4-bromophenyl)-5-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester

將(2R,5R)-2-(4-溴苯基)-5-甲基哌啶-4-酮(2.1g，7.83mmol)及三乙胺(1.19g，11.75mmol，1.64mL)溶解於DCM(20mL)中，然後在冰/水冷卻下逐滴添加二碳酸二-第三丁酯(1.97g，9.01mmol，2.07mL)，此後將反應混合物在20℃下攪拌12h。在將反應混合物用NaHSO4 (水溶液)洗滌三次，將DCM層經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由FCC純化粗產物，以獲得(2R,5R)-2-(4-溴苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯(3g，粗品)。(2R,5R)-2-(4-bromophenyl)-5-methylpiperidin-4-one (2.1 g, 7.83 mmol) and triethylamine (1.19 g, 11.75 mmol, 1.64 mL) were dissolved in DCM (20 mL), then di-tert-butyl dicarbonate (1.97 g, 9.01 mmol, 2.07 mL) was added dropwise under ice/water cooling, after which the reaction mixture was stirred at 20 °C for 12 h. After the reaction mixture was washed three times with NaHSO4 (aq), the DCM layer was dried over Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by FCC to obtain (2R,5R)-2-(4-bromophenyl)-5-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester (3 g, crude) .

LCMS(ESI)：[M+H]+ m/z：計算值368.2；實測值368.2；Rt=1.545min。LCMS (ESI): [M+H] + m/z: calculated 368.2; found 368.2; Rt=1.545 min.

步驟4：(2R,5R)-2-(4-溴苯基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of (2R,5R)-2-(4-bromophenyl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將硼氫化鈉(148.95mg，3.94mmol，138.69μL)分批添加到於無水甲醇(30mL)中之(2R,5R)-2-(4-溴苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯(2.9g，7.87mmol)中，然後攪拌隔夜。藉由添加飽和氯化銨水溶液來淬滅反應物。用乙酸乙酯(15mL x 3)萃取且將經合併之有機層用飽和鹽水洗滌且經無水硫酸鈉乾燥。過濾且在減壓下濃縮濾液，得到(2R,5R)-2-(4-溴苯基)-4-羥基-5-甲基哌 啶-1-甲酸第三丁酯(2.5g，6.75mmol，85.74%產率)Sodium borohydride (148.95 mg, 3.94 mmol, 138.69 μL) was added portionwise to (2R,5R)-2-(4-bromophenyl)-5-methyl-4-side in dry methanol (30 mL) oxypiperidine-1-carboxylate (2.9 g, 7.87 mmol), then stirred overnight. The reaction was quenched by addition of saturated aqueous ammonium chloride. Extracted with ethyl acetate (15 mL x 3) and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure to give (2R,5R)-2-(4-bromophenyl)-4-hydroxy-5-methylpiperidine 3-butyl pyridine-1-carboxylate (2.5 g, 6.75 mmol, 85.74% yield)

LCMS(ESI)：[M-Boc]+ m/z：計算值272.2；實測值272.2；Rt=1.300min。LCMS (ESI): [M-Boc] + m/z: calculated 272.2; found 272.2; Rt=1.300 min.

步驟5：(2R,5R)-2-(4-溴苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of (2R,5R)-2-(4-bromophenyl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將(2R,5R)-2-(4-溴苯基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯(1g，2.70mmol)溶解於DMF(10.00mL)中且向其中添加於礦物油中之氫化鈉(油分散物)60%分散物(186.26mg，8.10mmol，310.44μL)。將所得混合物攪拌1h且將碘甲烷(1.15g，8.10mmol，504.38μL)添加到前一混合物中且將所得混合物攪拌隔夜。將反應混合物倒入到水(30mL)中且將所得混合物用MTBE(3*20mL)萃取。將經合併之有機層用水(3*20mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。由於轉化率較差，用殘餘物重複該程序，以獲得(2R,5R)-2-(4-溴苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(1.0g，粗品)(2R,5R)-2-(4-bromophenyl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1 g, 2.70 mmol) was dissolved in DMF (10.00 mL) and To this was added sodium hydride (oil dispersion) 60% dispersion in mineral oil (186.26 mg, 8.10 mmol, 310.44 μL). The resulting mixture was stirred for 1 h and iodomethane (1.15 g, 8.10 mmol, 504.38 μL) was added to the previous mixture and the resulting mixture was stirred overnight. The reaction mixture was poured into water (30 mL) and the resulting mixture was extracted with MTBE (3*20 mL). The combined organic layers were washed with water (3*20 mL), dried over Na2SO4 , filtered and concentrated in vacuo. Due to poor conversion, the procedure was repeated with the residue to obtain (2R,5R)-2-(4-bromophenyl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.0g, crude)

步驟6：(2R,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酸第三丁酯之合成Step 6: (2R,5R)-4-Methoxy-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester synthesis

將(2R,5R)-2-(4-溴苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(700.00mg，1.82mmol)、1-甲基哌嗪(182.44mg，1.82mmol，202.04μL)、4,5-雙(二苯基膦基)-9,9-二甲基氧雜蒽(105.39mg，182.15μmol)及第三丁醇鈉(262.56mg，2.73mmol)一起混合於二噁烷(15mL)中且將所得混合物抽真空且用氬氣回填三次。將參(二苯亞甲基丙酮)二鈀(0)氯仿加合物(94.27mg，91.07μmol)添加到前一混合物中且將所得混合物在100℃下(油浴)加熱隔夜。將反應混合物冷卻且用水(5mL)稀釋。將所得混合物用EtOAc(2*5mL)萃取。將經合併之有機層用鹽水(2mL)洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由管柱層析純化殘餘物，以獲得(2R,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酸第三丁酯(0.6g，粗品)。(2R,5R)-2-(4-Bromophenyl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (700.00 mg, 1.82 mmol), 1-methylpiperidine oxazine (182.44 mg, 1.82 mmol, 202.04 μL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (105.39 mg, 182.15 μmol) and sodium tert-butoxide (262.56 mg, 2.73 mmol) were mixed together in dioxane (15 mL) and the resulting mixture was evacuated and backfilled with argon three times. Ps(dibenzylideneacetone)dipalladium(0) chloroform adduct (94.27 mg, 91.07 μmol) was added to the previous mixture and the resulting mixture was heated at 100° C. (oil bath) overnight. The reaction mixture was cooled and diluted with water (5 mL). The resulting mixture was extracted with EtOAc (2*5 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography to obtain (2R,5R)-4-methoxy-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]piperidine 3-butyl pyridine-1-carboxylate (0.6 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值402.2；Rt=1.082min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 402.2; Rt=1.082 min.

步驟7：1-[4-[(2R,5R)-4-甲氧基-5-甲基-2-哌啶基]苯基]-4-甲基哌嗪之合成Step 7: Synthesis of 1-[4-[(2R,5R)-4-methoxy-5-methyl-2-piperidinyl]phenyl]-4-methylpiperazine

將(2R,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酸第三丁酯(400.00mg，991.19μmol)溶解於DCM(1.5mL)中且添加TFA(1.5mL)。攪拌所得混合物1h。將反應混合物倒入到K2 CO3 水溶液中且將所得混合物用DCM萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得1-[4-[(2R,5R)-4-甲氧基-5-甲基-2-哌啶基]苯基]-4-甲基哌嗪，其不經進一步純化即用於下一步驟中。(2R,5R)-4-methoxy-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (400.00 mg, 991.19 μmol) was dissolved in DCM (1.5 mL) and TFA (1.5 mL) was added. The resulting mixture was stirred for 1 h. The reaction mixture was poured into aqueous K2CO3 and the resulting mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to give 1-[4-[(2R,5R)-4-methoxy-5-methyl-2-piperidinyl]phenyl ]-4-methylpiperazine, which was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值304.2；實測值304.2；Rt=0.227min。LCMS (ESI): [M+H] + m/z: calculated 304.2; found 304.2; Rt=0.227 min.

步驟8：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 8: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5R)-4-methoxy-5-methyl-2-[4-(4- Synthesis of Methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide

將1-[4-[(2R,5R)-4-甲氧基-5-甲基-2-哌啶基]苯基]-4-甲基哌嗪(300.00mg，988.66μmol)溶解於DMF(5mL)中且添加三乙胺(1.00g，9.89mmol，1.38mL)，隨後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(206.83mg，988.66μmol)。然後逐滴添加HATU(563.88mg，1.48mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC(1.2-10min 40-60%甲醇+nh3 30min(裝載泵4mL甲醇)，管柱：SunFire 100*19mm，5微米；2.2-10min 0-25%乙腈+fa 30min(裝載泵4mL乙腈)，管柱：SunFire 100*19mm，微米)純化，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(400.0mg，粗品)。1-[4-[(2R,5R)-4-methoxy-5-methyl-2-piperidinyl]phenyl]-4-methylpiperazine (300.00 mg, 988.66 μmol) was dissolved in DMF (5 mL) and triethylamine (1.00 g, 9.89 mmol, 1.38 mL) was added, followed by 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pentoxy Acetic acid (206.83 mg, 988.66 μmol). HATU (563.88 mg, 1.48 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and analyzed by HPLC (1.2-10 min 40-60% methanol + nh3 30 min (load pump 4 mL methanol), column: SunFire 100*19 mm, 5 microns; 2.2-10 min 0-25% Acetonitrile+fa 30min (load pump 4mL acetonitrile), column: SunFire 100*19mm, micron) purification to obtain N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R, 5R)-4-Methoxy-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (400.0 mg, crude).

LCMS(ESI)：[M+2H]+ m/z：計算值496.2；實測值496.2；Rt=0.802min。LCMS (ESI): [M+2H] + m/z: calculated 496.2; found 496.2; Rt=0.802 min.

步驟9：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4S,5S)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1159)、外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,4S,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1349)、rel-N-(6-胺基-5-乙基吡啶-3-Step 9: rel-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,4S,5S)-4-methoxy-5-methyl-2-[4 -(4-Methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1159), rac-N-(6-amino-5 -Ethyl-3-pyridyl)-2-[(2R,4S,5R)-4-methoxy-5-methyl-2-[4-(4-methylpiperazin-1-yl)benzene yl]-1-piperidinyl]-2-oxoacetamide (compound 1349), rel-N-(6-amino-5-ethylpyridine-3- 基)-2-((2S,4R,5S)-4-甲氧基-5-甲基-2-(4-(4-甲基哌嗪-1-基)苯基)哌啶-1-基)-2-側氧基乙醯胺之合成yl)-2-((2S,4R,5S)-4-methoxy-5-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)piperidine-1- Synthesis of )-2-side oxyacetamide

對N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5R)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(17.60mg，35.58μmol)進行掌性分離(管柱：Chiralpak IB(250，20mm，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：10mL/min；管柱溫度：24℃；波長：205nm。保留時間(異構物A)=22,31min；保留時間(異構物B)=25,87minp-N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5R)-4-methoxy-5-methyl-2-[4-(4-methyl Piperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (17.60 mg, 35.58 μmol) for chiral separation (column: Chiralpak IB (250, 20 mm, 5 mkm) ; Mobile phase: Hexane-IPA-MeOH, 60-20-20; Flow rate: 10 mL/min; Column temperature: 24°C; Wavelength: 205 nm. Retention time (isomer A)=22,31 min; Isomer B)=25,87min

管柱：Chiralcel OD-H(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，80-10-10；流速：12mL/min；管柱溫度：24℃；波長：205nm。保留時間(異構物A)=74,42min；保留時間(異構物B)=90,87min)，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4S,5S)-4-甲氧基-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(6.17mg，12.47μmol，35.06%產率)及Column: Chiralcel OD-H (250*20mm, 5mkm); Mobile Phase: Hexane-IPA-MeOH, 80-10-10; Flow Rate: 12mL/min; Column Temperature: 24°C; Wavelength: 205nm. Retention time (Isomer A) = 74, 42 min; Retention time (Isomer B) = 90, 87 min) to obtain N-(6-amino-5-ethyl-3-pyridinyl)-2- [(2S,4S,5S)-4-methoxy-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2- Pendant oxyacetamide (6.17 mg, 12.47 μmol, 35.06% yield) and

化合物1159： LCMS(ESI)：[M+H]+ m/z：計算值495.2；實測值495.2；Rt=1.419min。 Compound 1159: LCMS (ESI): [M+H] + m/z: calcd 495.2; found 495.2; Rt=1.419 min.

化合物1349： LCMS(ESI)：[M+H]+ m/z：計算值495.2；實測值495.2；Rt=1.440min。 Compound 1349: LCMS (ESI): [M+H] + m/z: calcd 495.2; found 495.2; Rt=1.440 min.

實例274.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-(1-甲基吡咯啶-3-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1342)之合成Example 274. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-(1-methylpyrrolidine-3 Synthesis of -yl)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1342)

Figure 110128222-A0202-12-1423-374
Figure 110128222-A0202-12-1423-374

步驟1：(2R,5S)-2-(3-溴苯基)-5-甲基哌啶-1-甲酸苯甲酯之合成Step 1: Synthesis of benzyl (2R,5S)-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylate

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶(2.7g，10.62mmol)溶解於THF(25mL)中且向其中添加碳酸鈉(2.25g，21.25mmol，889.35μL)，隨後添加水(30mL)。將所得混合物在冰浴中冷卻至0℃且在0℃下逐滴添加CbzCl(1.90g，11.15mmol，1.59mL)於THF(5mL)中之溶液。在添加完成之後，使反應混合物升溫至室溫且攪拌隔夜。將反應混合物在真空中濃縮且將殘餘物用水(50ml)稀釋。將所得混合物用MTBE(2*50ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸苯甲酯(4.27g，粗品)。( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine (2.7 g, 10.62 mmol) was dissolved in THF (25 mL) and to it was added sodium carbonate (2.25 g, 21.25 mmol, 889.35 μL), followed by the addition of water (30 mL). The resulting mixture was cooled to 0 °C in an ice bath and a solution of CbzCl (1.90 g, 11.15 mmol, 1.59 mL) in THF (5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with water (50 ml). The resulting mixture was extracted with MTBE (2*50ml) and the combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo to obtain ( 2R,5S )-2-(3-bromophenyl)- Benzyl 5-methylpiperidine-1-carboxylate (4.27 g, crude).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=1.636min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=1.636 min.

步驟2：(2R,5S)-2-(3-(1-(第三丁氧基羰基)-2,5-二氫-1H-吡咯-3-基)苯基)-5-甲基哌啶.1-甲酸苯甲酯之合成Step 2: (2R,5S)-2-(3-(1-(Third-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)phenyl)-5-methylpiperidine Synthesis of benzyl pyridine.1-carboxylate

將(2R,5S )-2-(3-溴苯基)-5-甲基哌啶-1-甲酸苯甲酯(1g，2.58mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2,5-二氫吡咯-1-甲酸第三丁 酯(874.22mg，2.96mmol)及碳酸鈉(545.92mg，5.15mmol，215.61μL)一起混合於二噁烷(7.5mL)及水(2.5mL)之混合物中。將含有前一混合物之燒瓶抽真空且用氬氣回填三次。將Pd(dppf)Cl2 *DCM(105.16mg，128.77μmol)添加到先前混合物 中且將所得混合物在90℃下加熱隔夜。將反應混合物在真空中濃縮且將殘餘物用水(20ml)稀釋。將所得混合物用EtOAc(2*30ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由管柱層析純化殘餘物，以獲得(2R,5S )-2-[3-(1-第三丁氧基 羰基-2,5-二氫吡咯-3-基)苯基]-5-甲基哌啶-1-甲酸苯甲酯(750mg，1.57mmol，61.10%產率)。( 2R,5S )-2-(3-bromophenyl)-5-methylpiperidine-1-carboxylic acid benzyl ester (1 g, 2.58 mmol), 3-(4,4,5,5-tetramethyl) 3-butyl-1,3,2-dioxaborol-2-yl)-2,5-dihydropyrrole-1- carboxylate (874.22 mg, 2.96 mmol) and sodium carbonate (545.92 mg) , 5.15 mmol, 215.61 μL) were mixed together in a mixture of dioxane (7.5 mL) and water (2.5 mL). The flask containing the previous mixture was evacuated and backfilled three times with argon. Pd(dppf)Cl2*DCM (105.16 mg , 128.77 μmol) was added to the previous mixture and the resulting mixture was heated at 90°C overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with water (20 ml). The resulting mixture was extracted with EtOAc (2*30 ml) and the combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain ( 2R,5S )-2-[3-(1 -tert- butoxycarbonyl-2,5-dihydropyrrol-3-yl)phenyl]-5 - Benzyl methylpiperidine-1-carboxylate (750 mg, 1.57 mmol, 61.10% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值376.2；實測值377.2；Rt=1.594min。LCMS (ESI): [M-Boc] + m/z: calculated 376.2; found 377.2; Rt=1.594 min.

步驟3：3-(3-((2R,5S)-5-甲基哌啶-2-基)苯基)吡咯啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 3-(3-((2R,5S)-5-methylpiperidin-2-yl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

將(2R,5S )-2-[3-(1-第三丁氧基 羰基-2,5-二氫吡咯-3-基)苯基]-5-甲基哌啶-1-甲酸苯甲酯(750mg，1.57mmol)溶解於MeOH(10mL)中且向其中添加乾燥的487型鈀(10%於碳上)(251.20mg，2.36mmol)。在週末內將所得混合物在50atm下氫化。過濾出催化劑，且在真空中濃縮濾液。將殘餘物再溶解於MeOH(10mL)中且向其中添加乾燥的487型鈀(10%於碳上)(251.20mg，2.36mmol)。將所得混合物在50atm下氫化隔夜。過濾出催化劑且將濾液在真空中濃縮，以獲得3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]吡咯啶-1-甲酸第三丁 酯(416mg，1.21mmol，76.74%產率)。( 2R,5S )-2-[3-(1 -tert- butoxycarbonyl-2,5-dihydropyrrol-3-yl)phenyl]-5-methylpiperidine-1-carboxylic acid benzyl The ester (750 mg, 1.57 mmol) was dissolved in MeOH (10 mL) and to it was added dry palladium type 487 (10% on carbon) (251.20 mg, 2.36 mmol). The resulting mixture was hydrogenated at 50 atm over the weekend. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was redissolved in MeOH (10 mL) and to it was added dry palladium type 487 (10% on carbon) (251.20 mg, 2.36 mmol). The resulting mixture was hydrogenated at 50 atm overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to obtain 3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]pyrrolidine-1-carboxylic acid tert- butyl ester ( 416 mg, 1.21 mmol, 76.74% yield).

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=1.160min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=1.160 min.

步驟4：(2R,5S)-5-甲基-2-(3-(1-甲基吡咯啶-3-基)苯基)哌啶之合成Step 4: Synthesis of (2R,5S)-5-methyl-2-(3-(1-methylpyrrolidin-3-yl)phenyl)piperidine

將LAH(152.04mg，4.01mmol)溶解於THF(5mL)中且逐滴添加3-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]吡咯啶-1-甲酸第三丁 酯(276mg，801.19μmol)於THF(2mL)中之溶液。將所得混合物加熱至回流且回流3h。使反應混合物冷卻至室溫且攪拌隔夜。將水(150mkl)添加到反應混合物中，隨後添加KOH水溶液(150mkl)及水(300mkl)。將反應混合物攪拌30min且過濾。將濾餅用THF(10ml)洗滌且將濾液在真空中濃縮，以獲得(2R,5S )-5-甲基-2-[3-(1-甲基吡咯啶-3-基)苯基]哌啶(227mg，粗品)。LAH (152.04 mg, 4.01 mmol) was dissolved in THF (5 mL) and 3-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]pyrrolidine-1 was added dropwise - A solution of tert -butyl formate (276 mg, 801.19 [mu]mol) in THF (2 mL). The resulting mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and stirred overnight. Water (150mkl) was added to the reaction mixture followed by aqueous KOH (150mkl) and water (300mkl). The reaction mixture was stirred for 30 min and filtered. The filter cake was washed with THF (10 ml) and the filtrate was concentrated in vacuo to obtain ( 2R,5S )-5-methyl-2-[3-(1-methylpyrrolidin-3-yl)phenyl] Piperidine (227 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值258.2；實測值259.2；Rt=0.644min。LCMS (ESI): [M] + m/z: calculated 258.2; found 259.2; Rt=0.644 min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-(1-甲基吡咯啶-3-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1342)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(1-methylpyrrolidine-3 Synthesis of -yl)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1342)

將(2R,5S )-5-甲基-2-[3-(1-甲基吡咯啶-3-基)苯基]哌啶(292mg，1.13mmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(236.40mg，1.13mmol)及TEA(571.74mg，5.65mmol，787.52μL)一起混合於DMF(3mL)中且向其中添加HATU(515.60mg，1.36mmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 60-80% MeOH+NH3 30min(裝載泵4ml MeOH)，管柱：SunFire 100*19mm，5微米)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(1-甲基吡咯啶-3-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(87.9mg，195.51μmol，17.30%產率)及N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(1-甲基吡咯啶-3-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(54.3mg，120.78μmol，10.69%產率)。( 2R,5S )-5-methyl-2-[3-(1-methylpyrrolidin-3-yl)phenyl]piperidine (292 mg, 1.13 mmol), 2-[(6-amino- 5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid (236.40 mg, 1.13 mmol) and TEA (571.74 mg, 5.65 mmol, 787.52 μL) were mixed together in DMF (3 mL) and added thereto HATU (515.60 mg, 1.36 mmol) was added. The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 60-80% MeOH+ NH3 30 min (load pump 4 ml MeOH), column: SunFire 100*19 mm, 5 microns) to obtain N- (6-amino- 5-Ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[3-(1-methylpyrrolidin-3-yl)phenyl]-1-piperidine N- (6-amino-5-ethyl-3-pyridinyl)-2-[( 2R,5S )-5-methyl-2-[3-(1-methylpyrrolidin-3-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (54.3 mg, 120.78 μmol, 10.69% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.06-1.13(m,3H),1.28-1.38(m,1H),1.62-1.75(m,2H),1.82-1.92(m,1H),1.96-2.25(m,4H),2.25-2.27(m,3H),2.31-2.36(m,1H),2.38-2.43(m,2H),2.51-2.58(m,2H),2.72-3.24(m,2H),3.43-4.03(m,1H),5.12-5.57(m,1H),5.58-5.67(m,2H),7.09-7.20(m,3H),7.26-7.32(m,1H),7.42-7.52(m,1H),7.98-8.07(m,1H),10.45-10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,3H), 1.06-1.13(m,3H), 1.28-1.38(m,1H), 1.62-1.75(m,2H) ,1.82-1.92(m,1H),1.96-2.25(m,4H),2.25-2.27(m,3H),2.31-2.36(m,1H),2.38-2.43(m,2H),2.51-2.58( m, 2H), 2.72-3.24(m, 2H), 3.43-4.03(m, 1H), 5.12-5.57(m, 1H), 5.58-5.67(m, 2H), 7.09-7.20(m, 3H), 7.26-7.32(m,1H), 7.42-7.52(m,1H), 7.98-8.07(m,1H), 10.45-10.54(m,1H).

LCMS(ESI)：[M]+ m/z：計算值449.2；實測值450.2；Rt=2.033min。LCMS (ESI): [M] + m/z: calculated 449.2; found 450.2; Rt=2.033 min.

實例275. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4S,5S)-2-(1,3-苯并噻唑-5-基)-4-異丙氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1343)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丙氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1094)之合成Example 275. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,4S,5S)-2-(1,3-benzothiazol-5-yl)-4 -Isopropoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 1343) and N-(6-amino-5-ethyl-3-pyridyl)- 2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-isopropoxy-5-methyl-1-piperidinyl]-2-oxygen Synthesis of Ethylacetamide (Compound 1094)

Figure 110128222-A0202-12-1426-375
Figure 110128222-A0202-12-1426-375

步驟7：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4S,5S)-2-(1,3-苯并噻唑-5-基)-4-異丙氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1343)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丙氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1094)之合成Step 7: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,4S,5S)-2-(1,3-benzothiazol-5-yl)-4 -Isopropoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 1343) and N-(6-amino-5-ethyl-3-pyridyl)- 2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-isopropoxy-5-methyl-1-piperidinyl]-2-oxygen Synthesis of Ethylacetamide (Compound 1094)

將5-[(2S,5S)-4-異丙氧基-5-甲基-2-哌啶基]-1,3-苯并噻唑(0.085g，292.68μmol)、TEA(88.85mg，878.03μmol，122.38μL)及2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(61.23mg，292.68μmol)溶解於DMF(4mL)中且一次性添加HATU(122.41mg，321.94μmol)。將所得混合物在20℃下攪拌3h。藉由反相HPLC(2-10min 50-65%甲醇+NH3 流速30mL/min(裝載泵4mL甲醇)，管柱：SunFire 100*19mm，5微米)純化粗反應混合物。分離呈淡黃色固體之所要產物N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4S,5S)-2-(1,3-苯并噻唑-5-基)-4-異丙氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(4.10mg，8.51μmol，2.91%產率)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-異丙氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0029g，6.02μmol，2.06%產率)。5-[(2S,5S)-4-isopropoxy-5-methyl-2-piperidinyl]-1,3-benzothiazole (0.085 g, 292.68 μmol), TEA (88.85 mg, 878.03 μmol, 122.38 μL) and 2-[(6-amino-5-ethyl-3-pyridinyl)amino]-2-oxoacetic acid (61.23 mg, 292.68 μmol) were dissolved in DMF (4 mL) and HATU (122.41 mg, 321.94 μmol) was added in one portion. The resulting mixture was stirred at 20 °C for 3 h. The crude reaction mixture was purified by reverse phase HPLC (2-10 min 50-65% methanol + NH3 flow rate 30 mL/min (loading pump 4 mL methanol), column: SunFire 100*19 mm, 5 microns). The desired product N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,4S,5S)-2-(1,3-benzothiazole-5 was isolated as a pale yellow solid -yl)-4-isopropoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (4.10 mg, 8.51 μmol, 2.91% yield) and N-(6-amine yl-5-ethyl-3-pyridyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-isopropoxy-5-methyl yl-1-piperidinyl]-2-oxoacetamide (0.0029 g, 6.02 μmol, 2.06% yield).

化合物1343： 1 H NMR(600MHz,dmso)δ 0.92(d,3H),1.02-1.05(m,6H),1.13(t,3H),1.84-2.01(m,1H),2.03-2.13(m,1H),2.32-2.36(m,1H),2.39-2.43(m,2H),2.77-3.24(m,1H),3.52-4.27(m,3H),5.44-5.63(m,1H),5.64-5.98(m,2H),7.42-7.48(m,1H),7.48-7.56(m,1H),7.96-8.02(m,1H),8.02-8.11(m,1H),8.17-8.25(m,1H),9.34-9.45(m,1H)。 Compound 1343: 1 H NMR (600 MHz, dmso) δ 0.92 (d, 3H), 1.02-1.05 (m, 6H), 1.13 (t, 3H), 1.84-2.01 (m, 1H), 2.03-2.13 (m, 1H), 2.32-2.36(m, 1H), 2.39-2.43(m, 2H), 2.77-3.24(m, 1H), 3.52-4.27(m, 3H), 5.44-5.63(m, 1H), 5.64- 5.98(m,2H),7.42-7.48(m,1H),7.48-7.56(m,1H),7.96-8.02(m,1H),8.02-8.11(m,1H),8.17-8.25(m,1H) ), 9.34-9.45 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值482.2；實測值482.2；Rt=0.934min。LCMS (ESI): [M+H] + m/z: calculated 482.2; found 482.2; Rt=0.934 min.

化合物1094： 1 H NMR(600MHz,dmso)δ 0.59-0.69(m,3H),0.87-0.93(m,3H),1.02-1.14(m,6H),1.74-1.84(m,1H),2.22-2.30(m,2H),2.37-2.43(m,2H),3.39-3.60(m,3H),3.72-4.11(m,1H),5.35-5.53(m,1H),5.55-5.67(m,2H),7.24-7.46(m,1H),7.47-7.71(m,1H),7.84-8.06(m,2H),8.06-8.28(m,1H),9.28-9.39(m,1H),10.35(br s,1H)。 Compound 1094: 1 H NMR (600 MHz, dmso) δ 0.59-0.69 (m, 3H), 0.87-0.93 (m, 3H), 1.02-1.14 (m, 6H), 1.74-1.84 (m, 1H), 2.22- 2.30(m, 2H), 2.37-2.43(m, 2H), 3.39-3.60(m, 3H), 3.72-4.11(m, 1H), 5.35-5.53(m, 1H), 5.55-5.67(m, 2H ),7.24-7.46(m,1H),7.47-7.71(m,1H),7.84-8.06(m,2H),8.06-8.28(m,1H),9.28-9.39(m,1H),10.35(br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值482.2；實測值482.2；Rt=2.647min。LCMS (ESI): [M+H] + m/z: calculated 482.2; found 482.2; Rt=2.647 min.

實例276.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-N-嗎啉基苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1267)之合成Example 276. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-N-morpholinobenzo[ d Synthesis of ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1267)

Figure 110128222-A0202-12-1427-376
Figure 110128222-A0202-12-1427-376

步驟1：(2R,5S)-5-甲基-2-(2-N-嗎啉基苯并[d]噻唑-5-基)哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,5S)-5-methyl-2-(2-N-morpholinobenzo[d]thiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester

在25℃下，將嗎啉(847.15mg，9.72mmol，850.55μL)一次性添加到(2R,5S )-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁 酯(0.8g，1.94mmol)於MeCN(15mL)中之溶液中。將所得混合物在70℃下攪拌12h，然後冷卻且在真空中濃縮。將殘餘物用10%氫氧化鈉水溶液鹼化至pH 11且用DCM(2*25ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈棕色 固體之(2R,5S )-5-甲基-2-(2-N-嗎啉基-1,3-苯并噻唑-5-基)哌啶-1-甲酸第三丁 酯(0.7g，1.68mmol，86.20%產率)，其直接用於下一步驟中。Morpholine (847.15 mg, 9.72 mmol, 850.55 μL) was added in one portion to ( 2R,5S )-2-(2-bromo-1,3-benzothiazol-5-yl)-5- at 25 °C A solution of tert- butyl methylpiperidine-1-carboxylate (0.8 g, 1.94 mmol) in MeCN (15 mL). The resulting mixture was stirred at 70 °C for 12 h, then cooled and concentrated in vacuo. The residue was basified to pH 11 with 10% aqueous sodium hydroxide solution and extracted with DCM (2*25ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give ( 2R,5S )-5-methyl-2-(2-N-morpholinyl-1,3-benzene as a brown solid Thiazol-5-yl)piperidine-1-carboxylic acid tert -butyl ester (0.7 g, 1.68 mmol, 86.20% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值417.2；實測值418.2；Rt=1.593min。LCMS (ESI): [M] + m/z: calculated 417.2; found 418.2; Rt=1.593 min.

步驟2：4-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)嗎啉之合成Step 2: Synthesis of 4-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)morpholine

將4.0M於二噁烷中之氯化氫溶液(21.00g，80.06mmol，20mL，13.9%純度)一次性添加到(2R,5S )-5-甲基-2-(2-N-嗎啉基-1,3-苯并噻唑-5-基)哌啶-1-甲酸第三丁 酯(0.7g，1.68mmol)於MeOH(15mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌12h，然後在真空中蒸發至乾，以得到呈棕色固體之粗品4-[5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]嗎啉(0.65g，1.67mmol，99.33%產率，2HCl)，其直接用於下一步驟中。A 4.0 M solution of hydrogen chloride in dioxane (21.00 g, 80.06 mmol, 20 mL, 13.9% pure) was added in one portion to ( 2R,5S )-5-methyl-2-(2-N-morpholinyl- A stirred solution of 1,3-benzothiazol-5-yl)piperidine-1-carboxylic acid tert -butyl ester (0.7 g, 1.68 mmol) in MeOH (15 mL). The resulting mixture was stirred at 25 °C for 12 h, then evaporated to dryness in vacuo to give crude 4-[5-[( 2R,5S )-5-methyl-2-piperidinyl]-1 as a brown solid , 3-benzothiazol-2-yl]morpholine (0.65 g, 1.67 mmol, 99.33% yield, 2HCl), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.934min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.934 min.

步驟3：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-N-嗎啉基苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1267)之合成Step 3: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-N-morpholinobenzo[d Synthesis of ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1267)

在25℃下，在0.5h時段內，將HATU(219.16mg，576.38μmol)小批量添加到4-[5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]嗎啉(150mg，384.25μmol，2HCl)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(160.77mg，768.50μmol)及三乙胺(466.59mg，4.61mmol，642.68μL)於DMF(3mL)中之經攪拌之混合物中。將所得混合物攪拌在25℃下攪拌12h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：40-40-80% 0-1-6min H2O/MeOH/0.1% NH4OH，流速：30ml/min(裝載泵4ml/min甲醇)，得到化合物1267 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-N-嗎啉基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(62mg，121.90μmol，31.72%產率)。轉移2mg此產物，剩餘量藉由製備型掌性HPLC(管柱：Chiralpak IC-III(250 * 20mm，5mkm)；流動相：IPA-MeOH 50-50；流速：10mL/min)純化，以得到第2批產物化合物1267 N-(6- 胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-(2-N-嗎啉基-1,3-苯并噻唑-5-基)-1-哌啶基]乙醯胺(44.6mg，87.69μmol，22.82%產率)(保留時間=45.951min)。HATU (219.16 mg, 576.38 μmol) was added in small batches to 4-[5-[(2R,5S)-5-methyl-2-piperidinyl]-1 at 25 °C over a period of 0.5 h, 3-Benzothiazol-2-yl]morpholine (150 mg, 384.25 μmol, 2HCl), 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxyacetic acid (160.77 mg, 768.50 μmol) and triethylamine (466.59 mg, 4.61 mmol, 642.68 μL) in a stirred mixture of DMF (3 mL). The resulting mixture was stirred at 25°C for 12h, then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 40-40-80% 0-1-6 min H2O/MeOH/0.1% NH4OH, Flow rate: 30 ml/min (loading pump 4 ml/min methanol) to give compound 1267 N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl- 2-(2-N-Morpholinyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyacetamide (62 mg, 121.90 μmol, 31.72% yield) 2 mg of this product was transferred and the remainder was purified by preparative chiral HPLC (column: Chiralpak IC-III (250*20 mm, 5 mkm); mobile phase: IPA-MeOH 50-50; flow rate: 10 mL/min) to give The second batch of product compound 1267 N-(6- Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-(2-N-morpholinyl-1 ,3-benzothiazol-5-yl)-1-piperidinyl]acetamide (44.6 mg, 87.69 μmol, 22.82% yield) (retention time=45.951 min).

化合物1267： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.05(m,3H),1.06-1.15(m,3H),1.26-1.39(m,1H),1.62-1.76(m,1H),1.79-1.94(m,1H),2.01-2.19(m,1H),2.21-2.32(m,1H),2.33-2.37(m,1H),2.39-2.42(m,1H),2.74-3.25(m,1H),3.41-3.49(m,0.7H),3.51-3.56(m,4H),3.68-3.73(m,4H),3.98-4.06(m,0.3H),5.15-5.67(m,3H),7.02-7.12(m,1H),7.35-7.53(m,2H),7.71-7.82(m,1H),7.98-8.10(m,1H),10.46-10.64(m,1H)。 Compound 1267: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.97-1.05 (m, 3H), 1.06-1.15 (m, 3H), 1.26-1.39 (m, 1H), 1.62-1.76 (m ,1H),1.79-1.94(m,1H),2.01-2.19(m,1H),2.21-2.32(m,1H),2.33-2.37(m,1H),2.39-2.42(m,1H),2.74 -3.25(m, 1H), 3.41-3.49(m, 0.7H), 3.51-3.56(m, 4H), 3.68-3.73(m, 4H), 3.98-4.06(m, 0.3H), 5.15-5.67( m, 3H), 7.02-7.12 (m, 1H), 7.35-7.53 (m, 2H), 7.71-7.82 (m, 1H), 7.98-8.10 (m, 1H), 10.46-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=2.757min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=2.757 min.

實例277. N-[6-胺基-5-[(3S)-四氫呋喃-3-基]-3-吡啶基]-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1154)及N-[6-胺基-5-[(3R)-四氫呋喃-3-基]-3-吡啶基]-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物 1312)之合成 Example 277. N-[6-Amino-5-[(3S)-tetrahydrofuran-3-yl]-3-pyridyl]-2-[(2R,5S)-5-methyl-2-[2- (1-Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1154) and N-[6 -Amino-5-[(3R)-tetrahydrofuran-3-yl]-3-pyridyl]-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4 Synthesis of -piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1312 )

Figure 110128222-A0202-12-1429-377
Figure 110128222-A0202-12-1429-377

步驟1：N-(5-胺基-3-四氫呋喃-3-基-2-吡啶基)-N-第三丁氧基羰基胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-(5-amino-3-tetrahydrofuran-3-yl-2-pyridyl)-N-tert-butoxycarbonylcarbamate

將N-第三丁氧基羰基-N-[3-(3-呋喃基)-5-硝基-2-吡啶基]胺甲酸第三 丁酯(1g，2.47mmol)、MeOH(6mL)、AcOH(5mL，2.47mmol)及Pd/C(400mg，具有50重量%水之10重量% Pd/C)之混合物在50℃下在氫氣下(在氣球中)攪拌12小時。將所得混合物過濾且在減壓下濃縮，以得到呈白色固體之N-(5-胺基-3-四氫呋喃-3-基-2-吡啶基)-N-第三丁氧基羰基胺甲酸第三丁酯(1.2g，粗品，2CH3 COOH)。N-tert-butoxycarbonyl-N-[3-(3-furyl)-5-nitro-2-pyridyl]carbamic acid tert-butyl ester (1 g, 2.47 mmol), MeOH (6 mL), A mixture of AcOH (5 mL, 2.47 mmol) and Pd/C (400 mg, 10 wt % Pd/C with 50 wt % water) was stirred at 50 °C under hydrogen (in a balloon) for 12 h. The resulting mixture was filtered and concentrated under reduced pressure to give N-(5-amino-3-tetrahydrofuran-3-yl-2-pyridyl)-N-tert-butoxycarbonylcarbamate as a white solid. Tributyl ester (1.2 g, crude, 2CH3COOH ).

步驟2：2-[[6-[雙(第三丁氧基羰基)胺基]-5-四氫呋喃-3-基-3-吡啶基]胺基]-2-側氧基乙酸苯甲酯之合成Step 2: 2-[[6-[Bis(tert-butoxycarbonyl)amino]-5-tetrahydrofuran-3-yl-3-pyridyl]amino]-2-oxoacetate benzyl synthesis

將N-(5-胺基-3-四氫呋喃-3-基-2-吡啶基)-N-第三丁氧基羰基胺甲酸第三丁酯(1.2g，2.40mmol，2CH3 COOH)、2-氯-2-側氧基乙酸苯甲酯(1g，5.04mmol)、DIPEA(2mL，11.5mmol)於MeCN(15mL)中之混合物在20℃下攪拌12小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；25g AgelaFlash Silica Flash二氧化矽急驟Silica Flash管柱，石油醚/EtOAc，其中EtOAc為0~50%，流速=30mL/min,254nm)純化殘餘物，以得到呈白色固體之2-[[6-[雙(第三丁氧基羰基)胺基]-5-四氫呋喃-3-基-3-吡啶基]胺基]-2-側氧基乙酸苯甲酯(1.2g，92.2%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.73(d,J =2.3Hz,1H),8.34(d,J =2.3Hz,1H),7.19-7.41(m,5H),4.60(s,2H),4.11-4.15(m,2H),4.03(t,J =7.9Hz,1H),3.73(dd,J =8.5,5.5Hz,1H),3.37-3.50(m,1H),2.33-2.48(m,1H),1.94-2.00(m,1H),1.40(s,18H)；LCMS(ESI)[M+H]+ m/z：計算值542.2，實測值542.3。N-(5-Amino-3-tetrahydrofuran-3-yl-2-pyridinyl)-N-tert-butoxycarbonylcarbamate tert-butyl ester (1.2 g, 2.40 mmol, 2CH 3 COOH), 2 - A mixture of benzyl chloro-2-pendoxoacetate (1 g, 5.04 mmol), DIPEA (2 mL, 11.5 mmol) in MeCN (15 mL) was stirred at 20 °C for 12 h. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 25g AgelaFlash Silica Flash silica flash Silica Flash column, petroleum ether/EtOAc with 0-50% EtOAc, flow rate = 30 mL/min, 254 nm) to give 2-[[6-[Bis(tert-butoxycarbonyl)amino]-5-tetrahydrofuran-3-yl-3-pyridyl]amino]-2-oxoacetate benzyl (white solid) 1.2 g, 92.2% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.73(d, J =2.3Hz,1H),8.34(d, J =2.3Hz,1H),7.19-7.41(m,5H),4.60(s, 2H), 4.11-4.15(m, 2H), 4.03(t, J =7.9Hz, 1H), 3.73(dd, J =8.5, 5.5Hz, 1H), 3.37-3.50(m, 1H), 2.33-2.48 (m, 1H), 1.94-2.00 (m, 1H), 1.40 (s, 18H); LCMS (ESI) [M+H] + m/z: calculated 542.2, found 542.3.

步驟3：2-[[6-[雙(第三丁氧基羰基)胺基]-5-四氫呋喃-3-基-3-吡啶基]胺基]-2-側氧基乙酸之合成Step 3: Synthesis of 2-[[6-[bis(tert-butoxycarbonyl)amino]-5-tetrahydrofuran-3-yl-3-pyridyl]amino]-2-pendoxoacetic acid

向2-[[6-[雙(第三丁氧基羰基)胺基]-5-四氫呋喃-3-基-3-吡啶基]胺基]-2-側氧基乙酸苯甲酯(1.2g，2.22mmol)於EtOAc(15mL)中之混合物中添加 TEA(0.93mL，6.67mmol)及Pd/C(130mg，具有50重量%水之10重量% Pd/C)。將所得混合物在真空下密封且除氣，且用氫氣吹掃三次，然後在20℃下在氫氣(在氣球中)下攪拌12小時。將所得混合物過濾且在減壓下濃縮，以得到呈白色固體之2-[[6-[雙(第三丁氧基羰基)胺基]-5-四氫呋喃-3-基-3-吡啶基]胺基]-2-側氧基乙酸(850mg，粗品，Et3N)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.74(d,J =2.3Hz,1H),8.35(d,J =2.3Hz,1H),4.09-4.17(m,1H),4.04(t,J =8.0Hz,1H),3.90(q,J =7.9Hz,1H),3.72(dd,J =8.4,6.1Hz,1H),3.35-3.48(m,1H),2.32-2.48(m,1H),2.00-2.06(m,1H),1.39(s,18H)。To 2-[[6-[bis(tert-butoxycarbonyl)amino]-5-tetrahydrofuran-3-yl-3-pyridyl]amino]-2-oxoacetate benzyl ester (1.2 g , 2.22 mmol) in EtOAc (15 mL) was added TEA (0.93 mL, 6.67 mmol) and Pd/C (130 mg, 10 wt % Pd/C with 50 wt % water). The resulting mixture was sealed and degassed under vacuum and purged with hydrogen three times, then stirred at 20°C under hydrogen (in a balloon) for 12 hours. The resulting mixture was filtered and concentrated under reduced pressure to give 2-[[6-[bis(tert-butoxycarbonyl)amino]-5-tetrahydrofuran-3-yl-3-pyridyl] as a white solid Amino]-2-oxoacetic acid (850 mg, crude, Et3N). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.74 (d, J =2.3 Hz, 1H), 8.35 (d, J =2.3 Hz, 1H), 4.09-4.17 (m, 1H), 4.04 (t, J =8.0Hz,1H),3.90(q, J =7.9Hz,1H),3.72(dd, J =8.4,6.1Hz,1H),3.35-3.48(m,1H),2.32-2.48(m,1H) ), 2.00-2.06 (m, 1H), 1.39 (s, 18H).

步驟4：N-第三丁氧基羰基-N-[5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-四氫呋喃-3-基-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-tert-butoxycarbonyl-N-[5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1 ,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-3-tetrahydrofuran-3-yl-2-pyridyl]carbamic acid tert-butyl Synthesis of Esters

向2-[[6-[雙(第三丁氧基羰基)胺基]-5-四氫呋喃-3-基-3-吡啶基]胺基]-2-側氧基乙酸(300mg，0.543mmol，Et3N)及2-(1-甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(195mg，0.592mmol)於DMF(6mL)中之混合物中添加HATU(250mg，0.658mmol)及DIPEA(0.3mL，1.72mmol)。將所得混合物在20℃下攪拌2小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，EtOAc/MeOH，其中MeOH為0~20%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色固體之N-第三丁氧基羰基-N-[5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-四氫呋喃-3-基-2-吡啶基]胺甲酸第三丁酯(280mg，67.6%產率)。LCMS(ESI)[M+H]+ m/z：計算值763.4，實測值763.4。To 2-[[6-[bis(tert-butoxycarbonyl)amino]-5-tetrahydrofuran-3-yl-3-pyridinyl]amino]-2-oxoacetic acid (300 mg, 0.543 mmol, Et3N) and 2-(1-methyl-4-piperidinyl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (195 mg, 0.592 mmol) To a mixture in DMF (6 mL) was added HATU (250 mg, 0.658 mmol) and DIPEA (0.3 mL, 1.72 mmol). The resulting mixture was stirred at 20°C for 2 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, EtOAc/MeOH with 0-20% MeOH, flow = 30 mL/min, 254 nm) to give N as a yellow solid -Third-butoxycarbonyl-N-[5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzene Thiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-3-tetrahydrofuran-3-yl-2-pyridyl]carbamic acid tert-butyl ester (280 mg, 67.6% yield). LCMS (ESI) [M+H] + m/z: calcd 763.4, found 763.4.

步驟5：N-(6-胺基-5-四氫呋喃-3-基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶Step 5: N-(6-Amino-5-tetrahydrofuran-3-yl-3-pyridinyl)-2-[(5S)-5-methyl-2-[2-(1-methyl-4- piperidine 基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide

將N-第三丁氧基羰基-N-[5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-四氫呋喃-3-基-2-吡啶基]胺甲酸第三丁酯(280mg，0.367mmol)、DCM(4mL)及TFA(4mL，51.9mmol)中之混合物在20℃下攪拌2小時。在減壓下濃縮混合物。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80 * 40mm * 3μm；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內20%至50% B，保持100% B達1min；流速：25mL/min；管柱溫度：30℃；波長：220nm、254nm)純化殘餘物，以得到呈白色固體之N-(6-胺基-5-四氫呋喃-3-基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(150mg，72.6%產率)。LCMS(ESI)[M+H]+ m/z：計算值563.3，實測值563.3；HPLC：在220nm下為100%，在254nm下為100%。N-tert-butoxycarbonyl-N-[5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3 -Benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-3-tetrahydrofuran-3-yl-2-pyridyl]carbamic acid tert-butyl ester ( A mixture of 280 mg, 0.367 mmol), DCM (4 mL) and TFA (4 mL, 51.9 mmol) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex Gemini-NX 80*40mm* 3 μm; mobile phase A: with 10 mmol of NH4HCO3 H 2 O (v%); mobile phase B: MeCN; gradient: 20% to 50% B in 9.5 min, hold 100% B for 1 min; flow rate: 25 mL/min; column temperature: 30 °C; wavelength: 220 nm , 254 nm), the residue was purified to give N-(6-amino-5-tetrahydrofuran-3-yl-3-pyridinyl)-2-[(5S)-5-methyl-2-[ as a white solid 2-(1-Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (150 mg, 72.6% yield ). LCMS (ESI) [M+H] + m/z: calcd 563.3, found 563.3; HPLC: 100% at 220 nm, 100% at 254 nm.

步驟6：N-(6-胺基-5-四氫呋喃-3-基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-tetrahydrofuran-3-yl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl- Synthesis of 4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide

將N-(6-胺基-5-四氫呋喃-3-基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(150mg，0.267mmol)藉由SFC(儀器：Berger，Multigr AM-II；管柱：Daicel chiralpak IG(250mm * 30mm * 10μm)；流動相：超臨界CO2 /MeOH(0.1% NH3 - H2 O，IPA v%)=60/40；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化。將級分在減壓下濃縮，然後凍乾隔夜，以得到呈白色乾燥粉末之N-(6-胺基-5-四氫呋喃-3-基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(100mg，峰2，保留時間：5.588min)。HPLC：在220nm下為100%， 在254nm下為100%。N-(6-Amino-5-tetrahydrofuran-3-yl-3-pyridinyl)-2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidine yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (150 mg, 0.267 mmol) by SFC (instrument: Berger, Multigr AM-II; Column: Daicel chiralpak IG (250mm*30mm*10μm); mobile phase: supercritical CO2 /MeOH (0.1% NH3 - H2O , IPA v%)=60/40; flow rate: 80mL/min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; conditioner temperature: 25°C; wavelength: 220 nm) purification. The fractions were concentrated under reduced pressure, then lyophilized overnight to give N-(6-amino-5-tetrahydrofuran-3-yl-3-pyridinyl)-2-[(2R,5S as a white dry powder )-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxy Acetamide (100 mg, peak 2, retention time: 5.588 min). HPLC: 100% at 220 nm, 100% at 254 nm.

步驟7：N-[6-胺基-5-[(3S)-四氫呋喃-3-基]-3-吡啶基]-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1154)及N-[6-胺基-5-[(3R)-四氫呋喃-3-基]-3-吡啶基]-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1312)之合成Step 7: N-[6-Amino-5-[(3S)-tetrahydrofuran-3-yl]-3-pyridinyl]-2-[(2R,5S)-5-methyl-2-[2- (1-Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1154) and N-[6 -Amino-5-[(3R)-tetrahydrofuran-3-yl]-3-pyridyl]-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4 Synthesis of -piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1312)

將N-(6-胺基-5-四氫呋喃-3-基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(50mg，0.0889mmol)藉由SFC(儀器：Berger，Multigr AM-II；管柱：Daicel chiralpak IC(250mm * 30mm * 5μm)；流動相：超臨界己烷-IPA(0.1% NH3 ，IPA v%)=60/40；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化。將級分在減壓下濃縮，然後凍乾隔夜，以得到化合物1154及化合物1312 。N-(6-amino-5-tetrahydrofuran-3-yl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4- Piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (50 mg, 0.0889 mmol) by SFC (instrument: Berger, Multigr AM- II; column: Daicel chiralpak IC (250mm*30mm*5μm); mobile phase: supercritical hexane-IPA (0.1% NH3 , IPA v%)=60/40; flow rate: 80 mL/min; column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; conditioner temperature: 25°C; wavelength: 220 nm) purification. The fractions were concentrated under reduced pressure and then lyophilized overnight to give compound 1154 and compound 1312 .

化合物1154： N-[6-胺基-5-[(3S)-四氫呋喃-3-基]-3-吡啶基]-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(20mg，單一未知鏡像異構物，峰1，保留時間：5.181min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.16(br s,1H),7.91-8.03(m,1H),7.91-8.03(m,1H),7.55-7.77(m,1H),7.34-7.49(m,1H),5.48-5.85(m,1H),4.05(br d,J =7.5Hz,2H),3.71-3.92(m,2H),3.43(br d,J =9.8Hz,2H),3.15(br d,J =13.1Hz,1H),3.03(br d,J =11.0Hz,2H),2.16-2.46(m,10H),1.89-2.07(m,5H),1.36-1.53(m,2H),1.14(d,J =7.0Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值563.3，實測值563.3；HPLC：在220nm下為100%，在254nm下為100%；99.9%ee。 Compound 1154: N-[6-Amino-5-[(3S)-tetrahydrofuran-3-yl]-3-pyridinyl]-2-[(2R,5S)-5-methyl-2-[2- (1-Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (20 mg, single unknown enantiomer , peak 1, retention time: 5.181 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.16 (br s, 1H), 7.91-8.03 (m, 1H), 7.91-8.03 (m, 1H), 7.55-7.77 (m, 1H), 7.34- 7.49(m,1H),5.48-5.85(m,1H),4.05(br d, J =7.5Hz,2H),3.71-3.92(m,2H),3.43(br d, J =9.8Hz,2H) ,3.15(br d, J =13.1Hz,1H),3.03(br d, J =11.0Hz,2H),2.16-2.46(m,10H),1.89-2.07(m,5H),1.36-1.53(m , 2H), 1.14 (d, J = 7.0 Hz, 3H); LCMS (ESI) [M+H] + m/z: calcd 563.3, found 563.3; HPLC: 100% at 220 nm, at 254 nm is 100%; 99.9%ee.

化合物1312 ：N-[6-胺基-5-[(3R)-四氫呋喃-3-基]-3-吡啶基]-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(20.1mg，單一未知鏡像異構物，峰2，保留時間：6.562min，白色固體)。1 H NMR(400 MHz，甲醇-d 4 )δ ppm 8.16(br s,1H),7.91-8.04(m,2H),7.54-7.80(m,1H),7.43(br d,J =8.8Hz,1H),5.47-5.88(m,1H),4.05(br d,J =6.9Hz,2H),3.70-3.92(m,2H),3.43(br d,J =9.6Hz,2H),3.17(br s,1H),3.04(br d,J =11.5Hz,2H),2.15-2.44(m,10H),1.89-2.09(m,5H),1.41-1.54(m,2H),1.14(d,J =6.9Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值563.3，實測值563.3；HPLC：在220nm下為100%，在254nm下為100%；99.2%ee。 Compound 1312 : N-[6-amino-5-[(3R)-tetrahydrofuran-3-yl]-3-pyridyl]-2-[(2R,5S)-5-methyl-2-[2- (1-Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (20.1 mg, single unknown enantiomer compound, peak 2, retention time: 6.562 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.16 (br s, 1H), 7.91-8.04 (m, 2H), 7.54-7.80 (m, 1H), 7.43 (br d, J =8.8Hz, 1H), 5.47-5.88(m, 1H), 4.05(br d, J =6.9Hz, 2H), 3.70-3.92(m, 2H), 3.43(br d, J =9.6Hz, 2H), 3.17(br s, 1H), 3.04(br d, J =11.5Hz, 2H), 2.15-2.44(m, 10H), 1.89-2.09(m, 5H), 1.41-1.54(m, 2H), 1.14(d, J = 6.9 Hz, 3H); LCMS (ESI) [M+H] + m/z: calcd 563.3, found 563.3; HPLC: 100% at 220 nm, 100% at 254 nm; 99.2% ee.

實例278. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺(化合物1374)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺(鏡像異構化合物1374)之合成Example 278. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2S,5R)-2-[1-[2-( Dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide (Compound 1374) and N-(6-amino-5-ethyl-3- Pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5- Synthesis of methyl-1-piperidinyl]acetamide (enantiomer 1374)

Figure 110128222-A0202-12-1434-378
Figure 110128222-A0202-12-1434-378

步驟1：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺之合成Step 1: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-2-[1-[2-( Synthesis of dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide

向N,N-二甲基-2-[5-[(2R,5S)-5-甲基-2-哌啶基]吲唑-1-基]乙胺(220mg，556μmol，3鹽酸鹽)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(128mg，611μmol)及三乙胺(337mg，3.34mmol，465μL)於二甲基甲醯胺(4.00mL)中之經攪拌之混合物中添加HATU(243mg，639μmol)。將反應混合物在20℃下攪拌4h。使所獲得之混合物經歷HPLC(0-1-6min 30-30-80%水-甲醇，+0.1體積%25%NH3 水溶液，30mL/min，管柱：XBridge BEH C18，100x20mm，5μm)，以得到呈黃色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺(160mg， 335μmol，60.3%產率)。To N,N-dimethyl-2-[5-[(2R,5S)-5-methyl-2-piperidinyl]indazol-1-yl]ethanamine (220 mg, 556 μmol, 3 hydrochloride ), 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (128 mg, 611 μmol) and triethylamine (337 mg, 3.34 mmol, 465 μL) in two To the stirred mixture in methylformamide (4.00 mL) was added HATU (243 mg, 639 μmol). The reaction mixture was stirred at 20 °C for 4 h. The obtained mixture was subjected to HPLC (0-1-6 min 30-30-80% water-methanol, + 0.1 vol% 25% NH3 in water, 30 mL/min, column: XBridge BEH C18, 100x20 mm, 5 μm) to N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[1-[2 was obtained as a yellow solid -(Dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide (160 mg, 335 μmol, 60.3% yield).

LCMS(ESI)：[M+H]+ m/z：計算值478.33；實測值479.2；Rt=2.044。LCMS (ESI): [M+H] + m/z: calculated 478.33; found 479.2; Rt=2.044.

步驟2：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺之合成Step 2: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2S,5R)-2-[1-[2-( Dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide and N-(6-amino-5-ethyl-3-pyridyl)- 2-Oxy-2-[racemic-(2R,5S)-2[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1- Synthesis of piperidinyl]acetamide

使N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺(160mg，335.μmol)經歷掌性HPLC(管柱：Chiralpak IA-II(250*20mm，5mkm)，流動相：IPA-MeOH，50-50，流速：10mL/min，5次注入，32mg/注入，V=4L)，以得到：呈淡黃色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺(60.0mg，126μmol，75.0%產率)(化合物1374，其中保留時間=11.570min(分析型)，29.630min(製備型))及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺(53.0mg，111μmol，66.3%產率)(鏡像異構化合物1374，其中保留時間=16.312min(分析型)，49.692min(製備型))。make N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-2-[1-[2-(dimethyl Amino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide (160 mg, 335. μmol) was subjected to chiral HPLC (column: Chiralpak IA-II (250* 20mm, 5mkm), mobile phase: IPA-MeOH, 50-50, flow rate: 10mL/min, 5 injections, 32mg/injection, V=4L) to obtain: N-(6-amino) as a pale yellow solid -5-Ethyl-3-pyridyl)-2-oxo-2-[rac-(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazole -5-yl]-5-methyl-1-piperidinyl]acetamide (60.0 mg, 126 μmol, 75.0% yield) (compound 1374, where retention time = 11.570 min (analytical), 29.630 min (preparation) type)) and N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-2-[1-[2- (Dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide (53.0 mg, 111 μmol, 66.3% yield) (enantiomer 1374, wherein Retention time = 16.312 min (analytical), 49.692 min (preparative)).

化合物1374： N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺 Compound 1374: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2S,5R)-2-[1-[2-( Dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide

1H NMR(600MHz,DMSO-d6 )：δ(ppm)1.03(m,3H),1.11(m,3H),1.36(m,1H),1.76(m,1H),1.88(m,1H),2.06(m,1H),2.14(s,6H),2.30(m,4H),2.68(m,2H),2.76(m,1H),3.74(dd,1H),4.46(m,2H),5.63(t,2H),7.34(m,1H),7.48(m,1H),7.67(m,2H),8.03(m,2H),10.52(m,1H)。1H NMR (600MHz, DMSO-d 6 ): δ(ppm) 1.03(m, 3H), 1.11(m, 3H), 1.36(m, 1H), 1.76(m, 1H), 1.88(m, 1H), 2.06(m, 1H), 2.14(s, 6H), 2.30(m, 4H), 2.68(m, 2H), 2.76(m, 1H), 3.74(dd, 1H), 4.46(m, 2H), 5.63 (t, 2H), 7.34 (m, 1H), 7.48 (m, 1H), 7.67 (m, 2H), 8.03 (m, 2H), 10.52 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值478.33；實測值479.4；Rt=1.656。LCMS (ESI): [M+H] + m/z: calculated 478.33; found 479.4; Rt=1.656.

鏡像異構化合物1374 ：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]乙醯胺 Enantiomer 1374 : N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-2-[1-[ 2-(Dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]acetamide

1H NMR(600MHz,DMSO-d6 )：δ(ppm)1.02(m,3H),1.12(m,3H),1.36(m,1H),1.76(m,1H),1.88(m,1H),2.07(m,1H),2.14(s,6H),2.26(m,1H),2.37(m,3H),2.68(m,2H),3.01(m,1H),3.84(m,1H),4.46(m,2H),5.63(m,3H),7.34(dd,1H),7.48(d,1H),7.67(m,2H),8.03(m,2H),10.52(m,1H)。1H NMR (600MHz, DMSO-d 6 ): δ(ppm) 1.02(m,3H), 1.12(m,3H), 1.36(m,1H), 1.76(m,1H), 1.88(m,1H), 2.07(m, 1H), 2.14(s, 6H), 2.26(m, 1H), 2.37(m, 3H), 2.68(m, 2H), 3.01(m, 1H), 3.84(m, 1H), 4.46 (m, 2H), 5.63 (m, 3H), 7.34 (dd, 1H), 7.48 (d, 1H), 7.67 (m, 2H), 8.03 (m, 2H), 10.52 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值478.33；實測值479.4；Rt=1.651。LCMS (ESI): [M+H] + m/z: calculated 478.33; found 479.4; Rt=1.651.

實例279.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-氯-5-(2-(二甲胺基)乙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1247)之合成Example 279. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-chloro-5-(2-(dimethylamino)ethyl) Synthesis of oxy)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1247)

Figure 110128222-A0202-12-1436-379
Figure 110128222-A0202-12-1436-379

步驟1：2-(3-溴-5-氯苯氧基)-N,N-二甲基乙胺之合成Step 1: Synthesis of 2-(3-bromo-5-chlorophenoxy)-N,N-dimethylethylamine

在50℃下，向3-溴-5-氯苯酚(4g，19.28mmol)於DMF(200mL)中之經攪拌之溶液中分別添加(2-溴乙基)二甲胺氫溴酸鹽(5.39g，23.14mmol)及碳酸銫(21.99g，67.49mmol)。在等分試樣之後，未偵測到產物。然後添加(2-溴乙基)二甲胺氫溴酸鹽(5.39g，23.14mmol)及碳酸銫(43.98g，134.97mmol)且將溫度升高至70℃。次日，添加(2-溴乙基)二甲胺氫溴酸鹽(16.17g，69.41mmol)及碳酸銫(21.99g，67.49mmol)且將溫度升高至80℃。將反應混合物冷卻且倒入水(800ml)中且將所得混合物用MTBE(2*100ml)萃取。將經合併之有機層用水(3*100ml)、鹽水(100ml)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。然後，藉由急驟層析純化粗產物。將其用SiO2 墊過濾。在EtOAc/己烷溶析液中僅獲得 s.m.。然後，將SiO2 墊用MeOH及5% Et3 N之混合物(1000ml)洗滌。分離呈黃色狀態之所要產物2-(3-溴-5-氯苯氧基)-N,N -二甲基乙胺(0.5g，1.79mmol，9.31%產率)。To a stirred solution of 3-bromo-5-chlorophenol (4 g, 19.28 mmol) in DMF (200 mL) at 50 °C was added (2-bromoethyl)dimethylamine hydrobromide (5.39 g) separately. g, 23.14 mmol) and cesium carbonate (21.99 g, 67.49 mmol). After aliquoting, no product was detected. Then (2-bromoethyl)dimethylamine hydrobromide (5.39 g, 23.14 mmol) and cesium carbonate (43.98 g, 134.97 mmol) were added and the temperature was raised to 70°C. The next day, (2-bromoethyl)dimethylamine hydrobromide (16.17 g, 69.41 mmol) and cesium carbonate (21.99 g, 67.49 mmol) were added and the temperature was raised to 80°C. The reaction mixture was cooled and poured into water (800ml) and the resulting mixture was extracted with MTBE (2*100ml). The combined organic layers were washed with water (3*100ml), brine (100ml), dried over Na2SO4 , filtered and concentrated in vacuo. Then, the crude product was purified by flash chromatography. It was filtered through a pad of SiO2 . Only sm was obtained in EtOAc/hexane eluent. Then, the SiO2 pad was washed with a mixture of MeOH and 5% Et3N (1000 ml). The desired product 2-(3-bromo-5-chlorophenoxy) -N,N -dimethylethylamine (0.5 g, 1.79 mmol, 9.31% yield) was isolated as a yellow state.

1 H NMR(500MHz,CDCl3 )δ(ppm)2.33(s,6H),2.71(t,2H),4.03(t,2H),6.86(s,1H),6.96(s,1H),7.09(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 2.33(s, 6H), 2.71(t, 2H), 4.03(t, 2H), 6.86(s, 1H), 6.96(s, 1H), 7.09( s, 1H).

步驟2：2-(3-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)-N,N-二甲基乙胺之合成Step 2: 2-(3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy)-N Synthesis of ,N-dimethylethylamine

向2-(3-溴-5-氯苯氧基)-N,N -二甲基乙胺(200mg，717.95μmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(200.54mg，789.74μmol)於二噁烷(20mL)中之經攪拌之溶液中添加乙酸鉀(176.15mg，1.79mmol，112.20μL)。將所得懸浮液用氬氣除氣。添加Pd(dppf)Cl2 *DCM(58.58mg，71.79μmol)。將反應混合物在85℃下攪拌16h。完成之後，過濾反應混合物且在真空中蒸發濾液，以得到油狀殘餘物。然後將化合物用DCM/水(50ml/10ml)萃取，將有機層經Na2 SO4 乾燥且蒸發。然後，添加10ml二噁烷/HCl且再次蒸發。然後，將粗產物用20ml MTBE洗滌且過濾。分離所要產物2-[3-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-N,N -二甲基乙胺(240mg，粗品，HCl)。To 2-(3-bromo-5-chlorophenoxy) -N,N -dimethylethylamine (200 mg, 717.95 μmol) and 4,4,5,5-tetramethyl-2-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (200.54 mg, 789.74 μmol) To a stirred solution in dioxane (20 mL) was added potassium acetate (176.15 mg, 1.79 mmol, 112.20 [mu]L). The resulting suspension was degassed with argon. Pd(dppf)Cl2*DCM (58.58 mg , 71.79 μmol) was added. The reaction mixture was stirred at 85 °C for 16 h. After completion, the reaction mixture was filtered and the filtrate was evaporated in vacuo to give an oily residue. The compound was then extracted with DCM/water (50ml/10ml), the organic layer was dried over Na2SO4 and evaporated. Then, 10 ml of dioxane/HCl were added and evaporated again. The crude product was then washed with 20 ml of MTBE and filtered. Isolation of the desired product 2-[3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy] -N , N -dimethylethylamine (240 mg, crude, HCl).

LCMS(ESI)：[M]+ m/z：計算值325.2；實測值326.2；Rt=1.154min。LCMS (ESI): [M] + m/z: calculated 325.2; found 326.2; Rt=1.154 min.

步驟3：(S)-6-(3-氯-5-(2-(二甲胺基)乙氧基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(3-Chloro-5-(2-(dimethylamino)ethoxy)phenyl)-3-methyl-3,4-dihydropyridine-1(2H) -Synthesis of tert-butyl formate

向2-[3-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-N,N -二甲基乙胺(240mg，662.80μmol，HCl)及(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(251.78mg，729.08μmol)於二噁烷(6mL)中之經攪拌之溶液中添加碳酸銫(431.91mg，1.33mmol)。將所得懸浮液用 氬氣除氣。添加Pd(dppf)Cl2 *DCM(27.04mg，33.14μmol)。將反應混合物在85℃下攪拌16h。完成之後，將反應混合物過濾且將濾液在真空中蒸發，以獲得油狀殘餘物。然後將化合物用DCM/水(30ml/10ml)萃取，將有機層經Na2 SO4 乾燥且蒸發。分離所要產物(3S )-6-[3-氯-5-[2-(二甲胺基)乙氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(240mg，粗品)。To 2-[3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy] -N,N - Dimethylethylamine (240 mg, 662.80 μmol, HCl) and ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1 - To a stirred solution of tert -butyl formate (251.78 mg, 729.08 [mu]mol) in dioxane (6 mL) was added cesium carbonate (431.91 mg, 1.33 mmol). The resulting suspension was degassed with argon. Pd(dppf)Cl2*DCM (27.04 mg , 33.14 μmol) was added. The reaction mixture was stirred at 85 °C for 16 h. After completion, the reaction mixture was filtered and the filtrate was evaporated in vacuo to obtain an oily residue. The compound was then extracted with DCM/water (30ml/10ml), the organic layer was dried over Na2SO4 and evaporated. Isolation of the desired product ( 3S )-6-[3-chloro-5-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1 - tert -butyl formate (240 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值394.2；實測值395.2；Rt=1.232min。LCMS (ESI): [M] + m/z: calculated 394.2; found 395.2; Rt=1.232 min.

步驟4：(S)-2-(3-氯-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯氧基)-N,N-二甲基乙胺之合成Step 4: (S)-2-(3-Chloro-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenoxy)-N,N-dimethyl Synthesis of ethylamine

在25℃下，向(3S )-6-[3-氯-5-[2-(二甲胺基)乙氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(240mg，607.70μmol)於DCM(3mL)中之經攪拌之溶液中分別添加TFA(2.77g，24.31mmol，1.87mL)。將所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物在減壓下濃縮。然後將水層用10% KOH鹼化且用DCM萃取兩次(10ml)。將有機層用水(10ml)洗滌，經Na2 SO4 乾燥且蒸發。分離呈棕色狀態之所要產物2-[3-氯-5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]-N,N -二甲基乙胺(115mg，390.07μmol，64.19%產率)。To ( 3S )-6-[3-chloro-5-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-3,4-dihydro- 2H at 25°C - To a stirred solution of tert -butyl pyridine-1- carboxylate (240 mg, 607.70 [mu]mol) in DCM (3 mL) was added TFA (2.77 g, 24.31 mmol, 1.87 mL), respectively. The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The aqueous layer was then basified with 10% KOH and extracted twice with DCM (10 ml). The organic layer was washed with water (10 ml), dried over Na2SO4 and evaporated. The desired product 2-[3-chloro-5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenoxy] -N,N was isolated as a brown state - Dimethylethylamine (115 mg, 390.07 μmol, 64.19% yield).

LCMS(ESI)：[M]+ m/z：計算值294.2；實測值295.2；Rt=0.639min。LCMS (ESI): [M] + m/z: calculated 294.2; found 295.2; Rt=0.639 min.

步驟5：2-(3-氯-5-((2R,5S)-5-甲基哌啶-2-基)苯氧基)-N,N-二甲基乙胺之合成Step 5: Synthesis of 2-(3-Chloro-5-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)-N,N-dimethylethylamine

在25℃下，向2-[3-氯-5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]-N,N -二甲基乙胺(115mg，390.07μmol)於MeOH(4.97mL)中之經攪拌之溶液中分別添加硼氫化鈉(29.51mg，780.14μmol，27.48μL)。將所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物蒸發。然後將化合物用DCM/水(40ml/10ml)萃取，將有機層經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈棕色狀態之粗產物。分離呈棕色狀態之所要產物2-[3-氯-5-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]-N,N -二甲基乙胺(52mg，175.18μmol，44.91%產率)。2-[3-Chloro-5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenoxy] -N,N- at 25°C To a stirred solution of dimethylethylamine (115 mg, 390.07 μmol) in MeOH (4.97 mL) was added sodium borohydride (29.51 mg, 780.14 μmol, 27.48 μL), respectively. The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was evaporated. The compound was then extracted with DCM/water (40ml/10ml), the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product in brown state. The desired product 2-[3-chloro-5-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy] -N,N -dimethylethylamine (52 mg) was isolated as a brown state , 175.18 μmol, 44.91% yield).

LCMS(ESI)：[M]+ m/z：計算值296.2；實測值297.2；Rt=0.714min。LCMS (ESI): [M] + m/z: calculated 296.2; found 297.2; Rt=0.714 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-氯-5-(2-(二甲胺基)乙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1247)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-chloro-5-(2-(dimethylamino)ethyl) Synthesis of oxy)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1247)

在25℃下，向2-[3-氯-5-[(2R,5S)-5-甲基-2-哌啶基]苯氧基]-N,N -二甲基乙胺(52mg，175.18μmol)於DMF(2mL)中之經攪拌之溶液中分別添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(36.65mg，175.18μmol)、DIPEA(22.64mg，175.18μmol，30.51μL)及HATU(66.61mg，175.18μmol)。使所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物在減壓下濃縮，以獲得呈棕色狀態之粗產物。藉由反相HPLC(裝置(流動相，管柱)：SYSTEM 5-5-45% 0-1-6min H2 O/MeCN/0.1%FA，流速：30ml/min(裝載泵4ml/min MeCN)；管柱：XBridge BEH C18 5um)純化所獲得之粗產物。分離呈棕色狀態之所要產物N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-氯-5-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(14.9mg，30.53μmol，17.43%產率)。To 2-[3-chloro-5-[(2R,5S)-5-methyl-2-piperidinyl]phenoxy] -N,N -dimethylethylamine (52 mg, To a stirred solution of 175.18 μmol) in DMF (2 mL) were added 2-[(6-amino-5-ethyl-3-pyridinyl)amino]-2-oxyacetic acid (36.65 mg, 175.18 μmol), DIPEA (22.64 mg, 175.18 μmol, 30.51 μL) and HATU (66.61 mg, 175.18 μmol). The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product in brown state. By reverse phase HPLC (device (mobile phase, column): SYSTEM 5-5-45% 0-1-6 min H 2 O/MeCN/0.1% FA, flow rate: 30 ml/min (loading pump 4 ml/min MeCN) ; column: XBridge BEH C18 5um) to purify the crude product obtained. The desired product, N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2-[3-chloro-5-, was isolated as a brown state [2-(Dimethylamino)ethoxy]phenyl]-5-methyl-1-piperidinyl]acetamide (14.9 mg, 30.53 μmol, 17.43% yield).

1 H NMR(600MHz,dmso)δ 0.96-1.03(m,3H),1.07-1.14(m,3H),1.24-1.38(m,1H),1.55-1.70(m,1H),1.78-1.94(m,1H),1.94-2.07(m,1H),2.10-2.17(m,1H),2.20(s,6H),2.37-2.42(m,2H),2.71-2.83(m,1H),3.98-4.10(m,3H),5.07-5.53(m,1H),5.57-5.71(m,2H),6.73-6.86(m,1H),6.86-6.97(m,2H),7.41-7.54(m,1H),7.96-8.09(m,1H),8.12-9.05(m,2H),10.47-10.73(m,1H)。LCMS(ESI)：[M]+ m/z：計算值488.2；實測值489.2；Rt=1.959min。 1 H NMR(600MHz,dmso)δ 0.96-1.03(m,3H),1.07-1.14(m,3H),1.24-1.38(m,1H),1.55-1.70(m,1H),1.78-1.94(m ,1H),1.94-2.07(m,1H),2.10-2.17(m,1H),2.20(s,6H),2.37-2.42(m,2H),2.71-2.83(m,1H),3.98-4.10 (m,3H),5.07-5.53(m,1H),5.57-5.71(m,2H),6.73-6.86(m,1H),6.86-6.97(m,2H),7.41-7.54(m,1H) , 7.96-8.09 (m, 1H), 8.12-9.05 (m, 2H), 10.47-10.73 (m, 1H). LCMS (ESI): [M] + m/z: calculated 488.2; found 489.2; Rt=1.959 min.

實例280. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1182)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1182)之合成Example 280. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazole -5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (enantiomer 1182) and N-(6-amino-5-methyl-3-pyridine) yl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2 - Synthesis of Pendant Oxyacetamide (Compound 1182)

Figure 110128222-A0202-12-1440-380
Figure 110128222-A0202-12-1440-380

步驟1：5-溴吲唑-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-butyl 5-bromoindazole-1-carboxylate

在25℃下，向5-溴-1H -吲唑(50.0g，254mmol)於乙腈(500mL)中之正攪拌溶液中添加三乙胺(25.7g，254mmol，35.4mL)、二碳酸二第三丁酯(66.5g，305mmol，69.9mL)及DMAP(3.10g，25.4mmol)。將反應混合物在同一溫度下攪拌3h。將所獲得之混合物在減壓下濃縮。使粗產物(80.0g)經歷管柱層析(SiO2 ；己烷/MTBE梯度(0-100%於己烷中之MTBE))，以得到呈黃色膠狀物之5-溴吲唑-1-甲酸第三丁酯(49.0g，165mmol，64.9%產率)。To a stirring solution of 5-bromo- 1H -indazole (50.0 g, 254 mmol) in acetonitrile (500 mL) at 25 °C was added triethylamine (25.7 g, 254 mmol, 35.4 mL), dicarbonate dicarbonate Tributyl ester (66.5 g, 305 mmol, 69.9 mL) and DMAP (3.10 g, 25.4 mmol). The reaction mixture was stirred at the same temperature for 3 h. The obtained mixture was concentrated under reduced pressure. The crude product (80.0 g) was subjected to column chromatography ( SiO2 ; hexane/MTBE gradient (0-100% MTBE in hexane)) to give 5-bromoindazole-1 as a yellow gum - tert-butyl formate (49.0 g, 165 mmol, 64.9% yield).

1H NMR(500MHz,CDCl3 )δ 1.72(s,9H),7.26-7.28(m,1H),7.62(s,1H),8.10-8.11(m,2H)。1H NMR (500 MHz, CDCl3 ) δ 1.72 (s, 9H), 7.26-7.28 (m, 1H), 7.62 (s, 1H), 8.10-8.11 (m, 2H).

步驟2：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯之合成Step 2: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid tert-butyl ester

在室溫下，向5-溴吲唑-1-甲酸第三丁酯(49.0g，165mmol)於二噁烷(1000mL)中之經攪拌之溶液中添加4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(46.1g，181mmol)、乙酸鉀(32.4g，330mmol，20.6mL)及Pd(dppf)Cl2 ‧CH2 Cl2 (13.5g，16.5mmol)。將反應混合物在90℃、惰性氣氛下攪拌20h。將所獲得之混合物冷卻至室溫且透過二氧化矽墊過濾。將濾餅用乙酸乙酯(200mL)洗滌。在減壓下濃縮濾液。藉由管柱層析(SiO2 ；己烷/乙酸乙酯梯度(0-100%乙酸乙酯))純化粗產物，以得到呈淡黃色固體之5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯(45.0g，131mmol，79.3%產率)。To a stirred solution of tert-butyl 5-bromoindazole-1-carboxylate (49.0 g, 165 mmol) in dioxane (1000 mL) was added 4,4,5,5-tetramethyl at room temperature yl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane Alkane (46.1 g, 181 mmol), potassium acetate (32.4 g, 330 mmol, 20.6 mL) and Pd(dppf)Cl2 - CH2Cl2 ( 13.5 g, 16.5 mmol). The reaction mixture was stirred at 90 °C under an inert atmosphere for 20 h. The resulting mixture was cooled to room temperature and filtered through a pad of silica. The filter cake was washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography ( SiO2 ; hexane/ethyl acetate gradient (0-100% ethyl acetate)) to give 5-(4,4,5,5-tetrakis as a pale yellow solid Methyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid tert-butyl ester (45.0 g, 131 mmol, 79.3% yield).

1H NMR(500MHz,CDCl3 )δ 1.37(s,12H),1.73(s,9H),7.94(m,1H),8.16-8.23(m,3H)。1H NMR (500 MHz, CDCl3 ) δ 1.37 (s, 12H), 1.73 (s, 9H), 7.94 (m, 1H), 8.16-8.23 (m, 3H).

步驟3：5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)吲唑-1-甲酸第三丁酯之合成Step 3: Synthesis of 5-(1-tert-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)indazole-1-carboxylic acid tert-butyl ester

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁酯(15.7g，45.6mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(18.9g，54.7mmol)及碳酸鈉(14.50g，136.8mmol)於二噁烷(200mL)及水(70.0mL)中之懸浮液抽真空，然後用Ar回填。添加[1,1'-雙(聯苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(1.86g，2.28mmol)。將所得混合物在90℃下攪拌24h。將所獲得之混合物冷卻至25℃，過濾且在真空中濃縮。使殘餘物經歷梯度層析(SiO2 ；己烷-EA)，以得到呈淡黃色膠狀物之5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H -吡啶-6-基)吲唑-1-甲酸第三丁酯(7.30g，17.7mmol，38.7%產率)。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid tert-butyl ester (15.7 g, 45.6 g mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (18.9 g, 54.7 mmol) and carbonic acid A suspension of sodium (14.50 g, 136.8 mmol) in dioxane (200 mL) and water (70.0 mL) was evacuated and backfilled with Ar. [1,1'-Bis(biphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.86 g, 2.28 mmol) was added. The resulting mixture was stirred at 90 °C for 24 h. The resulting mixture was cooled to 25°C, filtered and concentrated in vacuo. The residue was subjected to gradient chromatography ( SiO2 ; hexane-EA) to give 5-(1-tert-butoxycarbonyl-3-methyl-3,4-dihydro- as a pale yellow gum 2H -Pyridin-6-yl)indazole-1-carboxylic acid tert-butyl ester (7.30 g, 17.7 mmol, 38.7% yield).

LCMS(ESI)：[M-boc+H]+ m/z：計算值314.27；實測值314.0；Rt=1.445。LCMS (ESI): [M-boc+H] + m/z: calculated 314.27; found 314.0; Rt=1.445.

步驟4：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 4: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

將三氟乙酸(29.6g，260mmol，20.0mL)添加到5-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H -吡啶-6-基)吲唑-1-甲酸第三丁酯(7.30g，17.6mmol)於二氯甲烷(25.0mL)中之溶液中。將所得混合物在25℃下攪拌14h。將所獲得之混合物在減壓下濃縮。將殘餘物溶解於水(60.0mL)中且透過棉花塞過濾。將濾液用固體K2 CO3 鹼化至pH

Figure 110128222-A0202-12-1442-432
10。過濾所形成之白色固體且乾燥，以得到呈白色固體之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -吲唑(3.40g，15.9mmol，90.3%產率)。Trifluoroacetic acid (29.6 g, 260 mmol, 20.0 mL) was added to 5-(1-tert-butoxycarbonyl-3-methyl-3,4-dihydro- 2H -pyridin-6-yl)indazole - A solution of tert-butyl 1-carboxylate (7.30 g, 17.6 mmol) in dichloromethane (25.0 mL). The resulting mixture was stirred at 25 °C for 14 h. The obtained mixture was concentrated under reduced pressure. The residue was dissolved in water (60.0 mL) and filtered through a cotton plug. The filtrate was basified to pH with solid K2CO3
Figure 110128222-A0202-12-1442-432
10. The resulting white solid was filtered and dried to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1 H -indazole (3.40 g, 15.9 g) as a white solid mmol, 90.3% yield).

LCMS(ESI)：[M+H]+ m/z：計算值214.15；實測值214.2；Rt=0.700。LCMS (ESI): [M+H] + m/z: calculated 214.15; found 214.2; Rt=0.700.

步驟5：5-[(2R,5S)-5-甲基-2-哌啶基]-1H-吲唑之合成Step 5: Synthesis of 5-[(2R,5S)-5-methyl-2-piperidinyl]-1H-indazole

向5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -吲唑(3.40g，15.9mmol)於甲醇(60.0mL)中之正攪拌懸浮液中分批添加硼氫化鈉(905mg，23.9mmol，845μL)。將所得混合物在25℃下攪拌2h。將所獲得之混合物在減壓下濃縮。將殘餘物分配於水(50.0mL)與乙酸乙酯(80.0mL)之間。將有機層分離，經Na2 SO4 乾燥且在真空中濃縮，以得到呈灰色固體之5-[(2R,5S)-5-甲基-2-哌啶基]-1H -吲唑(3.50g，粗品)。To a positive stirring suspension of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) -1H -indazole (3.40 g, 15.9 mmol) in methanol (60.0 mL) Sodium borohydride (905 mg, 23.9 mmol, 845 μL) was added portionwise. The resulting mixture was stirred at 25 °C for 2 h. The obtained mixture was concentrated under reduced pressure. The residue was partitioned between water (50.0 mL) and ethyl acetate (80.0 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo to give 5-[(2R,5S)-5-methyl-2-piperidinyl]-1 H -indazole as a grey solid ( 3.50g, crude product).

LCMS(ESI)：[M+H]+ m/z：計算值216.17；實測值216.3；Rt=0.792。LCMS (ESI): [M+H] + m/z: calculated 216.17; found 216.3; Rt=0.792.

步驟6：(2R,5S)-2-(2H-吲唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 6: Synthesis of (2R,5S)-2-(2H-indazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將碳酸第三丁氧基羰基第三丁酯(2.66g，12.2mmol，2.80mL)添加到5-[(2R,5S)-5-甲基-2-哌啶基]-2H -吲唑(2.60g，12.1mmol)於THF(50.0mL)中之溶液中。將所得混合物在25℃下攪拌15h且在減壓下濃縮，以得到呈淡黃色膠狀物之(2R,5S)-2-(2H -吲唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(3.20g，粗品)。3-Butoxycarbonyl 3-butyl carbonate (2.66 g, 12.2 mmol, 2.80 mL) was added to 5-[(2R,5S)-5-methyl-2-piperidinyl] -2H -indazole (2.60 g, 12.1 mmol) in THF (50.0 mL). The resulting mixture was stirred at 25 °C for 15 h and concentrated under reduced pressure to give (2R,5S)-2-( 2H -indazol-5-yl)-5-methylpiperin as a pale yellow gum 3-butyl pyridine-1-carboxylate (3.20 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值316.23；實測值316.0；Rt=1.458。LCMS (ESI): [M+H] + m/z: calculated 316.23; found 316.0; Rt=1.458.

步驟7：(2S,5R)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯Step 7: (2S,5R)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester 及(2S,5R)-2[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯之合成And the synthesis of (2S,5R)-2[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(2S,5R)-2-(1H -吲唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(500mg，1.59mmol)於ACN(50.0mL)中之經攪拌之溶液中添加99%無水碳酸鉀(548mg，3.96mmol)，隨後添加2-氯-N,N-二甲基乙胺(274mg，1.90mmol，205μL，鹽酸鹽)。將所得混合物在70℃下攪拌90h。使反應混合物經歷HPLC(0-5min 55-65%水-甲醇，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：XBridge C18，100x19mm，5μm)，以得到呈無色油狀物之(2S,5R)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(60.0mg，155μmol，19.6%產率)及(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(70.0mg，181μmol，22.8%產率)。To (2S,5R)-2-( 1H -indazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.59 mmol) in ACN (50.0 mL) To the stirred solution was added 99% anhydrous potassium carbonate (548 mg, 3.96 mmol) followed by 2-chloro-N,N-dimethylethylamine (274 mg, 1.90 mmol, 205 μL, hydrochloride). The resulting mixture was stirred at 70 °C for 90 h. The reaction mixture was subjected to HPLC (0-5 min 55-65% water-methanol, + 0.1 vol% 25% NH3 in water, 30 mL/min, column: XBridge C18, 100x19 mm, 5 μm) to give as a colorless oil (2S,5R)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (60.0 mg, 155 μmol , 19.6% yield) and (2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methylpiperidine-1-carboxylic acid third Butyl ester (70.0 mg, 181 μmol, 22.8% yield).

(2S,5R)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(2S,5R)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

LCMS(ESI)：[M+H]+ m/z：計算值387.32；實測值387.4；Rt=2.687。LCMS (ESI): [M+H] + m/z: calculated 387.32; found 387.4; Rt=2.687.

(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

LCMS(ESI)：[M-H]+ m/z：計算值385.32；實測值386.2；Rt=1.431。LCMS (ESI): [MH] + m/z: calculated 385.32; found 386.2; Rt=1.431.

步驟8：N,N-二甲基-2-[5-[(2S,5R)-5-甲基-2-哌啶基]吲唑-1-基]乙胺之合成Step 8: Synthesis of N,N-dimethyl-2-[5-[(2S,5R)-5-methyl-2-piperidinyl]indazol-1-yl]ethanamine

向(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(71.0mg，184μmol)於MeOH(2.00mL)中之溶液中添加4.0M二噁烷中之氯化氫溶液(837mg，1.84mmol，1.05mL，8%純度)。將反應混合物在25℃下攪拌12h且將溶劑在真空中蒸發，以得到呈淡黃色固體之N,N-二甲基-2-[5-[(2S,5R)-5-甲基-2-哌啶基]吲唑-1-基]乙胺(65.0mg，181μmol，98.5%產率，2鹽酸鹽)。To (2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (71.0 mg, 184 μmol) in MeOH (2.00 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (837 mg, 1.84 mmol, 1.05 mL, 8% purity). The reaction mixture was stirred at 25 °C for 12 h and the solvent was evaporated in vacuo to give N,N-dimethyl-2-[5-[(2S,5R)-5-methyl-2 as a pale yellow solid -Piperidinyl]indazol-1-yl]ethanamine (65.0 mg, 181 μmol, 98.5% yield, 2 hydrochloride).

LCMS(ESI)：[M+H]+ m/z：計算值387.26；實測值387.0；Rt=0.442。LCMS (ESI): [M+H] + m/z: calculated 387.26; found 387.0; Rt=0.442.

步驟9：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-Step 9: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazole -5- 基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Synthesis of [methyl]-5-methyl-1-piperidinyl]-2-oxoacetamide

向N,N-二甲基-2-[5-[(2S,5R)-5-甲基-2-哌啶基]吲唑-1-基]乙胺(65.0mg，181μmol，2鹽酸鹽)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(45.9mg，235μmol)及三乙胺(91.5mg，904μmol，126μL)於DMF(3.00mL)中之溶液中添加HATU(82.5mg，217μmol)。將所得混合物在25℃下攪拌2h。使反應混合物經歷HPLC(0-6min 25-50%水-ACN，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：YMC-Actus Triart C18，100x20mm，5μm)，以得到呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(57.0mg，123μmol，67.9%產率)。To N,N-dimethyl-2-[5-[(2S,5R)-5-methyl-2-piperidinyl]indazol-1-yl]ethanamine (65.0 mg, 181 μmol, 2 HCl salt), 2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (45.9 mg, 235 μmol) and triethylamine (91.5 mg, 904 μmol, 126 μL) To a solution in DMF (3.00 mL) was added HATU (82.5 mg, 217 μmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was subjected to HPLC (0-6 min 25-50% water-ACN, +0.1 vol% 25% NH3 in water, 30 mL/min, column: YMC-Actus Triart C18, 100x20 mm, 5 μm) to give a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazole-5 -yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (57.0 mg, 123 μmol, 67.9% yield).

1H NMR(600MHz,DMSO-d6 )δ 0.98-1.07(m,3H),1.30-1.42(m,1H),1.71-1.82(m,1H),1.82-1.92(m,1H),1.97-2.05(m,3H),2.06-2.13(m,1H),2.15(s,6H),2.24-2.36(m,1H),2.65-2.71(m,2H),2.74-3.23(m,1H),3.44-4.04(m,1H),4.42-4.51(m,2H),5.18-5.60(m,1H),5.60-5.74(m,2H),7.27-7.41(m,1H),7.41-7.52(m,1H),7.64-7.71(m,2H),7.94-8.07(m,2H),10.47-10.56(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 0.98-1.07(m,3H), 1.30-1.42(m,1H), 1.71-1.82(m,1H), 1.82-1.92(m,1H), 1.97-2.05 (m,3H),2.06-2.13(m,1H),2.15(s,6H),2.24-2.36(m,1H),2.65-2.71(m,2H),2.74-3.23(m,1H),3.44 -4.04(m, 1H), 4.42-4.51(m, 2H), 5.18-5.60(m, 1H), 5.60-5.74(m, 2H), 7.27-7.41(m, 1H), 7.41-7.52(m, 1H), 7.64-7.71 (m, 2H), 7.94-8.07 (m, 2H), 10.47-10.56 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值464.31；實測值464.4；Rt=1.507。LCMS (ESI): [M+H] + m/z: calculated 464.31; found 464.4; Rt=1.507.

步驟10：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 (鏡像異構化合物1182)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1182) 之合成 Step 10: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazole -5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (enantiomer 1182) and N- (6-amino-5-methyl-3-pyridine ) yl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2 - Synthesis of Pendant Oxyacetamide (Compound 1182)

使N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(50.0mg，108μmol)經歷掌性分離(管柱：Chiralcel OJ-H(250/20mm/5m)；流動相：己烷-IPA-MeOH，50-25-25，流速：12mL/min；管柱溫度：24℃；波長：205nm，220nm，265nm，298nm)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5- 基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(19.0mg，40.9μmol，76.0%產率)(保留時間(鏡像異構化合物1182)=23.94min)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18.0mg，38.8μmol，72.0%產率)(保留時間(化合物1182) =17.00min)。make N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazole-5 -yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (50.0 mg, 108 μmol) was subjected to chiral separation (column: Chiralcel OJ-H (250/20 mm/5 m); Mobile phase: Hexane-IPA-MeOH, 50-25-25, flow rate: 12 mL/min; column temperature: 24 °C; wavelength: 205 nm, 220 nm, 265 nm, 298 nm) to obtain N-(6-amino- 5-Methyl-3-pyridyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl- 1-Piperidinyl]-2-Oxyacetamide (19.0 mg, 40.9 μmol, 76.0% yield) (retention time (Santiomer 1182) = 23.94 min) and N-(6-amino- 5-Methyl-3-pyridyl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl- 1-Piperidinyl]-2-oxoacetamide (18.0 mg, 38.8 μmol, 72.0% yield) (retention time ( compound 1182) = 17.00 min).

(鏡像異構化合物1182)： N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 (Enantiomer 1182): N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino) Ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

1H NMR(600MHz,DMSO-d6 )δ 1.01-1.04(m,3H),1.32-1.40(m,2H),1.72-1.88(m,2H),1.97-2.16(m,9H),2.25-2.37(m,1H),2.64-2.77(m,2H),3.46(d,1H),4.01(d,1H),4.45-4.47(m,2H),5.57-5.67(m,3H),7.29-7.50(m,2H),7.66-7.75(m,2H),7.96-8.04(m,2H),10.52(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 1.01-1.04 (m, 3H), 1.32-1.40 (m, 2H), 1.72-1.88 (m, 2H), 1.97-2.16 (m, 9H), 2.25-2.37 (m,1H), 2.64-2.77(m,2H), 3.46(d,1H), 4.01(d,1H), 4.45-4.47(m,2H), 5.57-5.67(m,3H), 7.29-7.50 (m, 2H), 7.66-7.75 (m, 2H), 7.96-8.04 (m, 2H), 10.52 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值464.31；實測值464.4；Rt=1.640。LCMS (ESI): [M+H] + m/z: calculated 464.31; found 464.4; Rt=1.640.

(化合物1182)： N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 (Compound 1182): N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl] Indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

1H NMR(600MHz,DMSO-d6 )δ 1.01-1.04(m,3H),1.32-1.39(m,2H),1.68-1.89(m,3H),1.97-2.37(m,8H),2.67-2.98(m,4H),3.45(m,1H),4.01(m,1H),4.46(m,2H),5.57-5.67(m,2H),7.29-7.50(m,2H),7.66-7.73(m,2H),7.96-8.04(m,2H),10.53(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 1.01-1.04(m,3H), 1.32-1.39(m,2H), 1.68-1.89(m,3H), 1.97-2.37(m,8H), 2.67-2.98 (m, 4H), 3.45 (m, 1H), 4.01 (m, 1H), 4.46 (m, 2H), 5.57-5.67 (m, 2H), 7.29-7.50 (m, 2H), 7.66-7.73 (m , 2H), 7.96-8.04 (m, 2H), 10.53 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值464.31；實測值464.4；Rt=1.910。LCMS (ESI): [M+H] + m/z: calculated 464.31; found 464.4; Rt=1.910.

實例281. N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1199)之合成Example 281. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-(2-methylindazol-6-yl)-1 Synthesis of -piperidinyl]-2-oxoacetamide (compound 1199)

Figure 110128222-A0202-12-1446-381
Figure 110128222-A0202-12-1446-381

步驟1：(3S)-3-甲基-6-(2-甲基吲唑-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (3S)-3-methyl-6-(2-methylindazol-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑(1.00g，3.87mmol)、(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.47g，4.26mmol)、碳酸鈉(1.23g，11.6mmol，487μL)及Pd(dppf)Cl2 *DCM(158mg，194μmol)添加到水(5.00mL)及1,4-二噁烷(15.0mL)之混合物中。將反應混合物在惰性氣氛、80℃下攪拌16h。將所得混合物冷卻，用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。將殘餘物懸浮於MTBE中，攪拌2h且過濾。在減壓下濃縮濾液，以得到(3S)-3-甲基-6-(2-甲基吲唑-6-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.00g，粗品)。2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole (1.00 g, 3.87 mmol), (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.47 g, 4.26 mmol), Sodium carbonate (1.23 g, 11.6 mmol, 487 μL) and Pd(dppf)Cl2*DCM (158 mg , 194 μmol) were added to a mixture of water (5.00 mL) and 1,4-dioxane (15.0 mL). The reaction mixture was stirred at 80 °C for 16 h under an inert atmosphere. The resulting mixture was cooled, diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was suspended in MTBE, stirred for 2 h and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-methyl-6-(2-methylindazol-6-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid third Butyl ester (1.00 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值328.23；實測值328.2；Rt=1.367。LCMS (ESI): [M+H] + m/z: calculated 328.23; found 328.2; Rt=1.367.

步驟2：2-甲基-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 2: Synthesis of 2-methyl-6-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]indazole

將(3S)-3-甲基-6-(2-甲基吲唑-6-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.00g，3.05mmol)溶解於TFA(4.00mL)及DCM(6.00mL)之混合物中。將反應混合物在25℃下攪拌0.5h。將所獲得之混合物在減壓下濃縮，以得到2-甲基-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑(0.76g，粗品)。(3S)-3-methyl-6-(2-methylindazol-6-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.00 g, 3.05 mmol ) was dissolved in a mixture of TFA (4.00 mL) and DCM (6.00 mL). The reaction mixture was stirred at 25 °C for 0.5 h. The obtained mixture was concentrated under reduced pressure to give 2-methyl-6-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]indazole (0.76 g, crude product).

LCMS(ESI)：[M+H]+ m/z：計算值228.17；實測值228.2；Rt=0.781。LCMS (ESI): [M+H] + m/z: calculated 228.17; found 228.2; Rt=0.781.

步驟3：2-甲基-6-[(5S)-5-甲基-2-哌啶基]吲唑之合成Step 3: Synthesis of 2-methyl-6-[(5S)-5-methyl-2-piperidinyl]indazole

向2-甲基-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑(0.76g，3.34mmol)於甲醇(8.00mL)中之溶液中分批添加硼氫化鈉(164mg，4.35mmol，154μL)。將反應混合物攪拌隔夜。添加HCl-甲醇之混合物。將所獲得之混合物在減壓下濃縮，以得到2-甲基-6-[(5S)-5-甲基-2-哌啶基]吲唑(1.00g，粗品，鹽酸鹽)。To 2-methyl-6-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]indazole (0.76 g, 3.34 mmol) in methanol (8.00 mL) To this solution was added sodium borohydride (164 mg, 4.35 mmol, 154 μL) in portions. The reaction mixture was stirred overnight. A mixture of HCl-methanol was added. The obtained mixture was concentrated under reduced pressure to give 2-methyl-6-[(5S)-5-methyl-2-piperidinyl]indazole (1.00 g, crude, hydrochloride).

LCMS(ESI)：[M+H]+ m/z：計算值230.19；實測值230.2；Rt=0.821。LCMS (ESI): [M+H] + m/z: calculated 230.19; found 230.2; Rt=0.821.

步驟4：N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1199)之合成Step 4: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-(2-methylindazol-6-yl)-1 Synthesis of -piperidinyl]-2-oxoacetamide (compound 1199)

向2-甲基-6-[(5S)-5-甲基-2-哌啶基]吲唑(0.14g，527μmol，鹽酸鹽)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(121mg，579μmol)及DIPEA(306mg，2.37mmol，413μL)於DMSO(2.00mL)中之經攪拌之溶液中添加HATU(240mg，632μmol)。將反應混合物在25℃下攪拌16h。將所得混合物提交至反相HPLC(第1次運行：2-10min 10-35%水+FA(0.1體積%)-MeOH+FA(0.1體積%)；流速：30mL/min，管柱：Waters SunFire C18，100x19mm，5μm；第2次運行：2-10min 10-35%水-甲醇，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：Waters SunFire C18，100x19mm，5μm)，以得到呈米色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.02g，40.4μmol，7.67%產率)。To 2-methyl-6-[(5S)-5-methyl-2-piperidinyl]indazole (0.14 g, 527 μmol, hydrochloride), 2-[(6-amino-5-ethyl -3-Pyridinyl)amino]-2-pendoxoacetic acid (121 mg, 579 μmol) and DIPEA (306 mg, 2.37 mmol, 413 μL) in DMSO (2.00 mL) was added HATU (240 mg, 632 μmol) to a stirred solution ). The reaction mixture was stirred at 25 °C for 16 h. The resulting mixture was submitted to reverse phase HPLC (run 1: 2-10 min 10-35% water+FA (0.1 vol%)-MeOH+FA (0.1 vol%); flow rate: 30 mL/min, column: Waters SunFire C18, 100x19mm, 5μm; run 2: 2-10min 10-35% water-methanol, + 0.1 vol% 25 % NH in water, 30mL/min, column: Waters SunFire C18, 100x19mm, 5μm), to give N-(6-Amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-(2-methylindazol-6-yl)- 1-Piperidinyl]-2-oxoacetamide (0.02 g, 40.4 μmol, 7.67% yield).

1H NMR(600MHz,DMSO-d6 )：δ(ppm)0.98-1.05(m,3H),1.05-1.16(m,3H),1.30-1.45(m,1H),1.68-1.81(m,1H),1.82-1.92(m,1H),2.04-2.20(m,1H),2.23-2.32(m,1H),2.37-2.44(m,2H),2.74-3.24(m,1H),3.42-4.06(m,1H),4.14(s,3H),5.18-5.61(m,1H),5.61-5.69(m,2H),6.89-7.08(m,1H),7.40-7.53(m,2H),7.62-7.71(m,1H),7.97-8.09(m,1H),8.11-8.36(m,1H),10.45-10.60(m,1H)1H NMR (600MHz, DMSO-d 6 ): δ (ppm) 0.98-1.05 (m, 3H), 1.05-1.16 (m, 3H), 1.30-1.45 (m, 1H), 1.68-1.81 (m, 1H) ,1.82-1.92(m,1H),2.04-2.20(m,1H),2.23-2.32(m,1H),2.37-2.44(m,2H),2.74-3.24(m,1H),3.42-4.06( m, 1H), 4.14(s, 3H), 5.18-5.61(m, 1H), 5.61-5.69(m, 2H), 6.89-7.08(m, 1H), 7.40-7.53(m, 2H), 7.62- 7.71(m,1H),7.97-8.09(m,1H),8.11-8.36(m,1H),10.45-10.60(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值421.26；實測值421.2；Rt=2.443。LCMS (ESI): [M+H] + m/z: calculated 421.26; found 421.2; Rt=2.443.

實例282. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1220)之合成Example 282. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Synthesis of pyridyl)benzothiophen-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1220)

Figure 110128222-A0202-12-1448-382
Figure 110128222-A0202-12-1448-382

步驟1：(3S)-6-(苯并噻吩-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (3S)-6-(benzothiophen-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鈉(4.24g，39.9mmol，1.67mL)添加到(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(8.28g，23.9mmol)及2-(苯并噻吩-5-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(5.20g，19.9mmol)於二噁烷(15.0mL)及水(55.0mL)中之溶液中。將反應混合物抽真空，然後用Ar回填。添加Pd(dppf)Cl2 *DCM(1.63g，2.00mmol)。將所得混合物在90℃下攪拌14h。將所獲得之混合物在減壓下濃縮。使殘餘物經歷梯度管柱層析(SiO2 ；己烷-MTBE)，以得到呈棕色固體之(3S)-6-(苯并噻吩-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.00g，9.11mmol，45.6%產率)。Sodium carbonate (4.24 g, 39.9 mmol, 1.67 mL) was added to (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine- 3-Butyl 1-carboxylate (8.28 g, 23.9 mmol) and 2-(benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of cyclopentane (5.20 g, 19.9 mmol) in dioxane (15.0 mL) and water (55.0 mL). The reaction mixture was evacuated and backfilled with Ar. Pd(dppf)Cl2*DCM (1.63 g, 2.00 mmol) was added. The resulting mixture was stirred at 90 °C for 14 h. The obtained mixture was concentrated under reduced pressure. The residue was subjected to gradient column chromatography ( SiO2 ; hexane-MTBE) to give (3S)-6-(benzothiophen-5-yl)-3-methyl-3,4- as a brown solid Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.00 g, 9.11 mmol, 45.6% yield).

1H NMR(500MHz,CDCl3 )δ 1.01(m,12H),1.84-1.90(m,1H),1.91-1.98(m,1H),2.39-2.45(m,1H),3.01-3.05(m,1H),4.09-4.13(m,1H),5.35-5.37(m,1H),7.25-7.31(m,2H),7.40-7.42(d,1H),7.72(s,1H),7.80-7.82(d,1H)。1H NMR (500MHz, CDCl 3 ) δ 1.01 (m, 12H), 1.84-1.90 (m, 1H), 1.91-1.98 (m, 1H), 2.39-2.45 (m, 1H), 3.01-3.05 (m, 1H) ), 4.09-4.13(m, 1H), 5.35-5.37(m, 1H), 7.25-7.31(m, 2H), 7.40-7.42(d, 1H), 7.72(s, 1H), 7.80-7.82(d , 1H).

步驟2：(3S)-6-(苯并噻吩-5-基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of (3S)-6-(benzothiophen-5-yl)-3-methyl-2,3,4,5-tetrahydropyridine

將(3S)-6-(苯并噻吩-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯 (3.00g，9.11mmol)混合於三氟乙酸(10.4g，91.1mmol，7.02mL)中。將所得混合物在25℃下攪拌1h。將所獲得之混合物在真空中濃縮。將殘餘物用DCM(25.0mL)稀釋且用NaHCO3 溶液(3*15.0mL)洗滌。將有機相經Na2 SO4 乾燥且在真空中濃縮，以得到呈黃色固體之(3S)-6-(苯并噻吩-5-基)-3-甲基-2,3,4,5-四氫吡啶(2.00g，8.72mmol，95.8%產率)。(3S)-6-(benzothiophen-5-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.00 g, 9.11 mmol) was mixed with in trifluoroacetic acid (10.4 g, 91.1 mmol, 7.02 mL). The resulting mixture was stirred at 25°C for 1 h. The obtained mixture was concentrated in vacuo. The residue was diluted with DCM (25.0 mL) and washed with NaHCO3 solution (3*15.0 mL). The organic phase was dried over Na 2 SO 4 and concentrated in vacuo to give (3S)-6-(benzothiophen-5-yl)-3-methyl-2,3,4,5- as a yellow solid Tetrahydropyridine (2.00 g, 8.72 mmol, 95.8% yield).

LCMS(ESI)：[M+H]+ m/z：計算值230.12；實測值230.0；Rt=0.765。LCMS (ESI): [M+H] + m/z: calculated 230.12; found 230.0; Rt=0.765.

步驟3：(2R,5S)-2-(苯并噻吩-5-基)-5-甲基哌啶之合成Step 3: Synthesis of (2R,5S)-2-(benzothiophen-5-yl)-5-methylpiperidine

向(3S)-6-(苯并噻吩-5-基)-3-甲基-2,3,4,5-四氫吡啶(2.00g，8.72mmol)於甲醇(20.0mL)中之經攪拌之溶液中分批添加硼氫化鈉(330mg，8.72mmol，308μL)。將反應混合物在25℃下攪拌1.5h。將所獲得之混合物在真空中濃縮。將殘餘物用水(50.0mL)稀釋且用DCM(2*25.0mL)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到呈棕色固體之(2R,5S)-2-(苯并噻吩-5-基)-5-甲基哌啶(2.00g，8.64mmol，99.1%產率)。To a stirred solution of (3S)-6-(benzothiophen-5-yl)-3-methyl-2,3,4,5-tetrahydropyridine (2.00 g, 8.72 mmol) in methanol (20.0 mL) To this solution was added sodium borohydride (330 mg, 8.72 mmol, 308 μL) portionwise. The reaction mixture was stirred at 25 °C for 1.5 h. The obtained mixture was concentrated in vacuo. The residue was diluted with water (50.0 mL) and extracted with DCM (2*25.0 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give (2R,5S)-2-(benzothiophen-5-yl)-5-methyl as a brown solid Piperidine (2.00 g, 8.64 mmol, 99.1% yield).

LCMS(ESI)：[M+H]+ m/z：計算值232.14；實測值232.2；Rt=0.784。LCMS (ESI): [M+H] + m/z: calculated 232.14; found 232.2; Rt=0.784.

步驟4：(2R,5S)-2-(苯并噻吩-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of (2R,5S)-2-(benzothiophen-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(2R,5S)-2-(苯并噻吩-5-基)-5-甲基哌啶(2.00g，8.64mmol)於DCM(50.0mL)中之經攪拌之溶液中逐滴添加二碳酸二第三丁酯(1.98g，9.08mmol，2.08mL)。將反應混合物在25℃下攪拌14h。將所獲得之混合物用水(3*25.0mL)洗滌。將有機層經Na2 SO4 乾燥且在真空中濃縮，以得到呈淡黃色固體之(2R,5S)-2-(苯并噻吩-5-基)-5-甲基哌啶-1-甲酸第三丁酯(2.50g，7.54mmol，87.3%產率)。To a stirred solution of (2R,5S)-2-(benzothiophen-5-yl)-5-methylpiperidine (2.00 g, 8.64 mmol) in DCM (50.0 mL) was added dicarbonic acid dropwise Di-tert-butyl ester (1.98 g, 9.08 mmol, 2.08 mL). The reaction mixture was stirred at 25 °C for 14 h. The obtained mixture was washed with water (3*25.0 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give (2R,5S)-2-(benzothiophen-5-yl)-5-methylpiperidine-1-carboxylic acid as a pale yellow solid Tertiary butyl ester (2.50 g, 7.54 mmol, 87.3% yield).

LCMS(ESI)：[M-boc]+ m/z：計算值230.2；實測值232.0；Rt=1.603。LCMS (ESI): [M-boc] + m/z: calculated 230.2; found 232.0; Rt=1.603.

步驟5：(2R,5S)-2-(2-溴苯并噻吩-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of (2R,5S)-2-(2-bromobenzothiophen-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(2R,5S)-2-(苯并噻吩-5-基)-5-甲基哌啶-1-甲酸第三丁酯(2.94g， 7.54mmol)於ACN(29.8mL)中之經攪拌之溶液中分批添加N-溴琥珀醯亞胺(1.34g，7.54mmol，640μL)。將反應混合物在25℃下攪拌14h。將所獲得之混合物在真空中濃縮。將殘餘物用DCM(40.0mL)稀釋，用水及NaHSO4 溶液洗滌。將有機層經Na2 SO4 乾燥且在真空中濃縮，以得到呈紅色固體之(2R,5S)-2-(2-溴苯并噻吩-5-基)-5-甲基哌啶-1-甲酸第三丁酯(2.80g，6.82mmol，90.5%產率)。To a stirred solution of tert-butyl (2R,5S)-2-(benzothiophen-5-yl)-5-methylpiperidine-1-carboxylate (2.94 g, 7.54 mmol) in ACN (29.8 mL) To this solution was added N-bromosuccinimide (1.34 g, 7.54 mmol, 640 μL) in portions. The reaction mixture was stirred at 25 °C for 14 h. The obtained mixture was concentrated in vacuo. The residue was diluted with DCM (40.0 mL), washed with water and NaHSO4 solution. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give (2R,5S)-2-(2-bromobenzothiophen-5-yl)-5-methylpiperidine-1 as a red solid - tert-butyl formate (2.80 g, 6.82 mmol, 90.5% yield).

LCMS(ESI)：[M-boc]+ m/z：計算值310.01；實測值310.2；Rt=1.831。LCMS (ESI): [M-boc] + m/z: calculated 310.01; found 310.2; Rt=1.831.

步驟6：(2R,5S)-5-甲基-2-[2-(1-甲基-3,6-二氫-2H-吡啶-4-基)苯并噻吩-5-基]哌啶-1-甲酸第三丁酯之合成Step 6: (2R,5S)-5-Methyl-2-[2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzothiophen-5-yl]piperidine -Synthesis of tert-butyl 1-carboxylate

將碳酸鈉(1.45g，13.7mmol)添加到(2R,5S)-2-(2-溴苯并噻吩-5-基)-5-甲基哌啶-1-甲酸第三丁酯(2.80g，6.82mmol)及1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H -吡啶(1.52g，6.82mmol)於二噁烷(20.0mL)及水(5.00mL)中之溶液中。將反應混合物抽真空，然後用Ar回填。添加Pd(dppf)Cl2 *DCM(279mg，341μmol)。將所得混合物在90℃下攪拌14h。在減壓下濃縮反應混合物。使殘餘物經歷梯度管柱層析(SiO2 ；MTBE-MeOH)，以得到呈棕色固體之(2R,5S)-5-甲基-2-[2-(1-甲基-3,6-二氫-2H -吡啶-4-基)苯并噻吩-5-基]哌啶-1-甲酸第三丁酯(2.90g，6.80mmol，99.6%產率)。Sodium carbonate (1.45 g, 13.7 mmol) was added to tert-butyl (2R,5S)-2-(2-bromobenzothiophen-5-yl)-5-methylpiperidine-1-carboxylate (2.80 g , 6.82 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-di A solution of hydrogen- 2H -pyridine (1.52 g, 6.82 mmol) in dioxane (20.0 mL) and water (5.00 mL). The reaction mixture was evacuated and backfilled with Ar. Pd(dppf)Cl2*DCM (279 mg , 341 μmol) was added. The resulting mixture was stirred at 90 °C for 14 h. The reaction mixture was concentrated under reduced pressure. The residue was subjected to gradient column chromatography ( SiO2 ; MTBE-MeOH) to give (2R,5S)-5-methyl-2-[2-(1-methyl-3,6- as a brown solid Dihydro- 2H -pyridin-4-yl)benzothiophen-5-yl]piperidine-1-carboxylic acid tert-butyl ester (2.90 g, 6.80 mmol, 99.6% yield).

LCMS(ESI)：[M+H]+ m/z：計算值427.29；實測值427.2；Rt=1.315。LCMS (ESI): [M+H] + m/z: calculated 427.29; found 427.2; Rt=1.315.

步驟7：(2R,5S)-5-甲基-2[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]哌啶-1-甲酸第三丁酯之合成Step 7: Synthesis of (2R,5S)-5-methyl-2[2-(1-methyl-4-piperidinyl)benzothiophen-5-yl]piperidine-1-carboxylic acid tert-butyl ester

將鈀(5%於碳上)5R452(0.50g，4.70mmol)添加到(2R,5S)-5-甲基-2-[2-(1-甲基-3,6-二氫-2H -吡啶-4-基)苯并噻吩-5-基]哌啶-1-甲酸第三丁酯(2.30g，5.39mmol)於甲醇(30.0mL)中之溶液中。將反應混合物抽真空，然後用氫氣回填。將所得混合物在50℃下攪拌6天。將反應混合物過濾且在真空中濃縮，以得到呈黃色油狀物之(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]哌啶 -1-甲酸第三丁酯(1.80g，4.20mmol，77.9%產率)。Palladium (5% on carbon) 5R452 (0.50 g, 4.70 mmol) was added to (2R,5S)-5-methyl-2-[2-(1-methyl-3,6-dihydro- 2H) - Pyridin-4-yl)benzothiophen-5-yl]piperidine-1-carboxylic acid tert-butyl ester (2.30 g, 5.39 mmol) in methanol (30.0 mL). The reaction mixture was evacuated and backfilled with hydrogen. The resulting mixture was stirred at 50°C for 6 days. The reaction mixture was filtered and concentrated in vacuo to give (2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)benzothiophene- as a yellow oil 5-yl]piperidine-1-carboxylic acid tert-butyl ester (1.80 g, 4.20 mmol, 77.9% yield).

LCMS(ESI)：[M+H]+ m/z：計算值429.31；實測值429.2；Rt=3.591。LCMS (ESI): [M+H] + m/z: calculated 429.31; found 429.2; Rt=3.591.

步驟8：1-甲基-4-[5-[(2R,5S)-5-甲基-2-哌啶基]苯并噻吩-2-基]哌啶之合成Step 8: Synthesis of 1-methyl-4-[5-[(2R,5S)-5-methyl-2-piperidinyl]benzothiophen-2-yl]piperidine

將(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]哌啶-1-甲酸第三丁酯(1.80g，4.20mmol)混合於4.0M於二噁烷中之氯化氫溶液(40.0g，1.10mol，50.0mL)中。將所得混合物在25℃下攪拌14h。將所獲得之混合物用MTBE(15.0mL)稀釋且過濾。將濾餅用MTBE洗滌且在真空中乾燥，以得到呈棕色固體之1-甲基-4-[5-[(2R,5S)-5-甲基-2-哌啶基]苯并噻吩-2-基]哌啶(1.50g，3.74mmol，88.9%產率，2鹽酸鹽)。(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)benzothiophen-5-yl]piperidine-1-carboxylic acid tert-butyl ester (1.80 g , 4.20 mmol) in a 4.0 M solution of hydrogen chloride in dioxane (40.0 g, 1.10 mol, 50.0 mL). The resulting mixture was stirred at 25 °C for 14 h. The obtained mixture was diluted with MTBE (15.0 mL) and filtered. The filter cake was washed with MTBE and dried in vacuo to give 1-methyl-4-[5-[(2R,5S)-5-methyl-2-piperidinyl]benzothiophene as a brown solid- 2-yl]piperidine (1.50 g, 3.74 mmol, 88.9% yield, 2 hydrochloride).

LCMS(ESI)：[M+H]+ m/z：計算值329.25；實測值329.2；Rt=0.502。LCMS (ESI): [M+H] + m/z: calculated 329.25; found 329.2; Rt=0.502.

步驟9：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1220)之合成Step 9: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Synthesis of pyridyl)benzothiophen-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1220)

向1-甲基-4-[5-[(2R,5S)-5-甲基-2-哌啶基]苯并噻吩-2-基]哌啶(0.50g，1.37mmol，鹽酸鹽)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(267mg，1.37mmol)及三乙胺(693mg，6.85mmol，955μL)於DMF(4.00mL)中之溶液中分批添加HATU(573mg，1.51mmol)。將反應混合物在25℃下攪拌1.5h。使所獲得之混合物經歷反相HPLC(0-1-5min 30-30-60%水-ACN，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：YMC-Actus Triart C18，100x20mm，5μm)，以得到呈黃色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]-1-哌啶基]-2-側氧基乙醯胺(23.0mg，45.5μmol，3.32%產率)。To 1-methyl-4-[5-[(2R,5S)-5-methyl-2-piperidinyl]benzothiophen-2-yl]piperidine (0.50 g, 1.37 mmol, hydrochloride) , 2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (267 mg, 1.37 mmol) and triethylamine (693 mg, 6.85 mmol, 955 μL) in DMF (4.00 mL) was added HATU (573 mg, 1.51 mmol) in portions. The reaction mixture was stirred at 25 °C for 1.5 h. The obtained mixture was subjected to reverse phase HPLC (0-1-5 min 30-30-60% water-ACN, +0.1 vol% 25% NH3 in water, 30 mL/min, column: YMC-Actus Triart C18, 100x20 mm, 5 μm) to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1- Methyl-4-piperidinyl)benzothiophen-5-yl]-1-piperidinyl]-2-oxyacetamide (23.0 mg, 45.5 μmol, 3.32% yield).

1H NMR(600MHz,DMSO-d6 )δ 1.00-1.06(m,3H),1.30-1.40(m,1H),1.59-1.95(m,7H),1.95-2.05(m,4H),2.06-2.12(m,2H),2.19(s,3H),2.30(d,1H),2.82-2.87(m,2H),2.89-3.29(m,1H),3.46-4.06(m,1H),5.23-5.73(m,3H),7.30-7.39(m, 1H),7.40-7.52(m,2H),7.67-7.71(m,1H),7.93-8.09(m,2H),10.46-10.60(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 1.00-1.06(m,3H), 1.30-1.40(m,1H), 1.59-1.95(m,7H), 1.95-2.05(m,4H), 2.06-2.12 (m, 2H), 2.19(s, 3H), 2.30(d, 1H), 2.82-2.87(m, 2H), 2.89-3.29(m, 1H), 3.46-4.06(m, 1H), 5.23-5.73 (m,3H),7.30-7.39(m,1H),7.40-7.52(m,2H),7.67-7.71(m,1H),7.93-8.09(m,2H),10.46-10.60(m,1H) .

LCMS(ESI)：[M+H]+ m/z：計算值506.3；實測值506.2；Rt=1.794。LCMS (ESI): [M+H] + m/z: calculated 506.3; found 506.2; Rt=1.794.

實例283. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1168)之合成Example 283. 2-Methoxy-5-[[2-Pendox-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R, 4S)-1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxylate Synthesis of Amine (Compound 1168)

Figure 110128222-A0202-12-1452-383
Figure 110128222-A0202-12-1452-383

向2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(80mg，0.211mmol，HCl)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(76mg，0.318mmol)及HATU(136mg，0.358mmol)於DMF(2mL)中之混合物中添加DIPEA(0.18mL，1.03mmol)。將混合物在20℃下攪拌2小時。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex C18 80×40mm×3μm；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內36%至66% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化混合物，以得到呈白色無水粉末之2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(48mg，40.4%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.35-8.76(m,2H),7.89-8.03(m,2H),7.37-7.56(m,To 2-[rac-(3R,4S)-1,3-dimethyl-4-piperidinyl]-5-[rac-(2R,5S)-5-methyl-2-piperidine Peridyl]-1,3-benzothiazole (80 mg, 0.211 mmol, HCl), 2-[(5-aminocarbamoyl-6-methoxy-3-pyridyl)amino]-2-oxygen To a mixture of acetic acid (76 mg, 0.318 mmol) and HATU (136 mg, 0.358 mmol) in DMF (2 mL) was added DIPEA (0.18 mL, 1.03 mmol). The mixture was stirred at 20°C for 2 hours. by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex C18 80 x 40 mm x 3 μm; mobile phase A: H2 with 10 mmol NH4HCO3 O(v%); Mobile Phase B: MeCN; Gradient: 36% to 66% B in 9.5min, hold 100% B for 2min; Flow Rate: 25mL/min; Column Temperature: 30°C; Wavelength: 220nm, 254nm ) purify the mixture to give 2-methoxy-5-[[2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[2- as a white anhydrous powder [racemic-(3R,4S)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amine yl]pyridine-3-carboxamide (48 mg, 40.4% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.35-8.76 (m, 2H), 7.89-8.03 (m, 2H), 7.37-7.56 (m,

1H),5.39-5.93(m,1H),4.01-4.16(m,3H),3.76(d,J =13.9Hz,1H),3.44(d,J =12.1Hz,1H),2.99-3.22(m,2H),2.71-2.88(m,1H),1.84-2.50(m,12H),1.47(d,J =11.1Hz,1H),1.14(d,J =6.9Hz,3H),0.86(d,J =6.3Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值565.3；實測值565.2；HPLC：在220nm下為99.71%，在254nm下為99.69%；98.1% ee。1H), 5.39-5.93(m, 1H), 4.01-4.16(m, 3H), 3.76(d, J =13.9Hz, 1H), 3.44(d, J =12.1Hz, 1H), 2.99-3.22(m ,2H),2.71-2.88(m,1H),1.84-2.50(m,12H),1.47(d, J =11.1Hz,1H),1.14(d, J =6.9Hz,3H),0.86(d, J = 6.3 Hz, 3H); LCMS (ESI) [M+H] + m/z: calcd 565.3; found 565.2; HPLC: 99.71% at 220 nm, 99.69% at 254 nm; 98.1% ee.

實例284. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(WX-TGX-1498A_002)及2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(WX-TGX-1498B_001)之合成Example 284. 2-Methoxy-5-[[2-Pendox-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R, 4S)-1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxylate Amine (WX-TGX-1498A_002) and 2-methoxy-5-[[2-sideoxy-2-[rac-(2R,5S)-5-methyl-2-[2-[exo Racemic-(3R,4R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino] Synthesis of pyridine-3-formamide (WX-TGX-1498B_001)

Figure 110128222-A0202-12-1453-384
Figure 110128222-A0202-12-1453-384

步驟1：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1,3-二甲基-4-哌啶基]-1，3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-Pendoxyloxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R) -1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide synthesis

Figure 110128222-A0202-12-1453-385
Figure 110128222-A0202-12-1453-385

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(85mg，355.37μmol)、2-[外消旋-(3R)-1,3-二甲基-4-哌啶基]-5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-1,3-苯 并噻唑(80mg，0.233mmol)、HATU(130mg，0.342mmol)、DIPEA(130μL，0.746mmol)於DMF(4mL)中之混合物在20℃下攪拌2小時。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex C18 80×40mm×3μm；流動相A：具有0.05% NH3 -H2 O(v%)之H2 O；流動相B：MeCN；梯度：在9.5min內40%至70% B，保持100% B達0min；流速：30mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈白色固體之2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(50mg，37.4%產率)。LCMS(ESI)[M+H]+ m/z：計算值565.3，實測值565.32-[(5-Aminocarbamoyl-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (85 mg, 355.37 μmol), 2-[racemic-(3R) -1,3-Dimethyl-4-piperidinyl]-5-[rac-(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (80 mg , 0.233 mmol), HATU (130 mg, 0.342 mmol), DIPEA (130 μL, 0.746 mmol) in DMF (4 mL) was stirred at 20 °C for 2 h. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex C18 80 x 40 mm x 3 μm; mobile phase A: with 0.05% NH3 - H2O (v%) of H 2 O; Mobile phase B: MeCN; Gradient: 40% to 70% B in 9.5 min, hold 100% B for 0 min; Flow rate: 30 mL/min; Column temperature: 30°C; Wavelength: 220nm, 254nm), the residue was purified to give 2-methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2- as a white solid [2-[Rac-(3R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl] Amino]pyridine-3-carboxamide (50 mg, 37.4% yield). LCMS(ESI)[M+H] + m/z: calculated 565.3, found 565.3

步驟2：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(WX-7GX-1498A_002)及2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(WX-TGX-1498B_001)之合成Step 2: 2-Methoxy-5-[[2-Pendoxyloxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R, 4S)-1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxylate Amine (WX-7GX-1498A_002) and 2-methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[exo Racemic-(3R,4R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino] Synthesis of pyridine-3-formamide (WX-TGX-1498B_001)

Figure 110128222-A0202-12-1454-386
Figure 110128222-A0202-12-1454-386

將2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(50mg，0.089mmol)藉由掌性SFC(儀器：Berger，MULTIGR AM-II；管柱：Chiralpak OD 250×30mm I.D.10μm；流動相：超臨界CO2 /EtOH(0.1% NH3 ．H2 O，v%)=40/40； 流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化，以得到WX-TGX-1498A_002 及TGX-1498B_001。 Convert 2-methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R)-1 ,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (50mg, 0.089 mmol) by chiral SFC (instrument: Berger, MULTIGR AM-II; column: Chiralpak OD 250×30 mm ID 10 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 .H 2 O, v%) =40/40; flow rate: 80mL/min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220nm) purification, to obtain WX-TGX-1498A_002 and TGX-1498B_001.

WX-TGX-1498A_002WX-TGX-1498A_002

2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(40mg，峰1，保留時間=3.651min，具有反式相對化學之單一未知鏡像異構物，白色固體)。2-methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R,4S)- 1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (40mg , Peak 1, RT=3.651 min, single unknown enantiomer with trans relative chemistry, white solid).

1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.38-8.90(m,2 H),7.84-8.11(m,2 H),7.46(br d,J =8.5Hz,1 H),5.43-5.96(m,1 H),4.02-4.22(m,3 H),3.40-3.86(m,1 H),3.13(br t,J =13.3Hz,2 H),2.85(br d,J =9.3Hz,1 H),2.47(s,3 H),1.78-2.42(m,9 H),1.48(br d,J =13.1Hz,1H),1.15(d,J =6.8Hz,3 H),0.88(br d,J =5.5Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值565.3，實測值565.3；HPLC：在254nm下為99.9%；98.86%ee。 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.38-8.90 (m, 2 H), 7.84-8.11 (m, 2 H), 7.46 (br d, J =8.5 Hz, 1 H), 5.43-5.96 (m, 1 H), 4.02-4.22 (m, 3 H), 3.40-3.86 (m, 1 H), 3.13 (br t, J =13.3Hz, 2 H), 2.85 (br d, J =9.3Hz ,1H),2.47(s,3H),1.78-2.42(m,9H),1.48(br d, J =13.1Hz,1H),1.15(d, J =6.8Hz,3H),0.88 (br d, J = 5.5 Hz, 3 H); LCMS (ESI) [M+H] + m/z: calcd 565.3, found 565.3; HPLC: 99.9% at 254 nm; 98.86% ee.

WX-TGX-1498B_001WX-TGX-1498B_001

2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(11mg，峰2，保留時間=4.177min，具有反式相對化學之單一未知鏡像異構物，白色固體)。2-Methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R,4R)- 1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (11mg , peak 2, retention time = 4.177 min, single unknown enantiomer with trans relative chemistry, white solid).

1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.38-8.72(m,1 H),7.84-8.06(m,2 H),7.26-7.71(m,2 H),5.36-6.04(m,1 H),3.98-4.27(m,3 H),3.35-3.88(m,2 H),2.77-3.27(m,2 H),1.81-2.58(m,9 H),1.48(br d,J =12.8Hz,1 H),1.28(s,1 H),1.15(d,J =7.0Hz,3 H),0.93(br d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值565.3，實測值565.4；HPLC：在254nm下為100.0%；99.4%ee。 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.38-8.72 (m, 1 H), 7.84-8.06 (m, 2 H), 7.26-7.71 (m, 2 H), 5.36-6.04 (m, 1 H), 3.98-4.27(m, 3 H), 3.35-3.88(m, 2 H), 2.77-3.27(m, 2 H), 1.81-2.58(m, 9 H), 1.48(br d, J = 12.8Hz, 1 H), 1.28(s, 1 H), 1.15(d, J =7.0Hz, 3 H), 0.93(br d, J =7.0Hz, 3 H); LCMS(ESI)[M+H ] + m/z: calcd 565.3, found 565.4; HPLC: 100.0% at 254 nm; 99.4% ee.

實例285. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1127)之合成Example 285. 2-Methoxy-5-[[2-Pendoxyloxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S, 4R)-1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxylate Synthesis of Amine (Compound 1127)

Figure 110128222-A0202-12-1456-387
Figure 110128222-A0202-12-1456-387

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(85mg，0.355mmol)、2-[外消旋-(3S,4R)-1,3-二甲基-4-哌啶基]-5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(80mg，0.233mmol)、HATU(135mg，0.355mmol)、DIPEA(0.13mL，0.746mmol)於DMF(4mL)中之混合物在20℃下攪拌2小時。在減壓下濃縮混合物。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex C18 80 * 40mm * 3μm；流動相A：具有NH4 HCO3 (v%)之H2 O；流動相B：MeCN；梯度：在9.5min內43%至73% B，保持100% B達1min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈白色固體之2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(27mg，20.2%產率，單一未知鏡像異構物)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.59-8.74(m,1H),8.36-8.56(m,1H),7.91-8.04(m,2H),7.45(br s,1H),5.84(br s,1H),4.05-4.13(m,3H),3.76(br d,J =14.0Hz,2H),2.86(br s,2H),2.02-2.45(m,13H),1.49(br s,1H),1.15(br s,3H),0.86(br d,J =6.0Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值565.3，實測值565.3；HPLC：在254nm下為98.22%，在254nm下為99.12%；100% ee。2-[(5-Aminocarbamoyl-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (85 mg, 0.355 mmol), 2-[rac-(3S, 4R)-1,3-Dimethyl-4-piperidinyl]-5-[racemic-(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole A mixture of (80 mg, 0.233 mmol), HATU (135 mg, 0.355 mmol), DIPEA (0.13 mL, 0.746 mmol) in DMF (4 mL) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex C18 80*40mm* 3 μm; mobile phase A: with NH4HCO3 (v%) of H 2 O; mobile phase B: MeCN; gradient: 43% to 73% B in 9.5 min, hold 100% B for 1 min; flow rate: 25 mL/min; column temperature: 30 °C; wavelength: 220 nm, 254 nm) The residue was purified to give 2-methoxy-5-[[2-pendoxyloxy-2-[rac-(2R,5S)-5-methyl-2-[2-[ as a white solid Racemic-(3S,4R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino ]pyridine-3-carboxamide (27 mg, 20.2% yield, single unknown enantiomer). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.59-8.74 (m, 1H), 8.36-8.56 (m, 1H), 7.91-8.04 (m, 2H), 7.45 (br s, 1H), 5.84 ( br s,1H),4.05-4.13(m,3H),3.76(br d, J =14.0Hz,2H),2.86(br s,2H),2.02-2.45(m,13H),1.49(br s, 1H), 1.15 (br s, 3H), 0.86 (br d, J =6.0Hz, 3H); LCMS (ESI) [M+H] + m/z: calcd 565.3, found 565.3; HPLC: at 254 nm 98.22% at 254nm, 99.12% at 254nm; 100% ee.

實例286. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1185)之合成Example 286. 2-Methoxy-5-[[2-Pendox-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S, 4S)-1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxylate Synthesis of Amine (Compound 1185)

Figure 110128222-A0202-12-1457-388
Figure 110128222-A0202-12-1457-388

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(85mg，0.355mmol)、2-[外消旋-(3S,4S)-1,3-二甲基-4-哌啶基]-5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(80mg，0.233mmol)、HATU(130mg，0.342mmol)、DIPEA(130μL，0.746mmol)於DMF(4mL)中之混合物在20℃下攪拌2小時。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex C18 80×40mm×3μm；流動相A：具有0.05% NH3 -H2 O(v%)之H2 O；流動相B：MeCN；梯度：在7.8min內42%至72% B，保持100% B達1min；流速：30mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈白色固體之2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(45mg，33.6%產率)。2-[(5-Aminocarbamoyl-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (85 mg, 0.355 mmol), 2-[rac-(3S, 4S)-1,3-Dimethyl-4-piperidinyl]-5-[racemic-(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole A mixture of (80 mg, 0.233 mmol), HATU (130 mg, 0.342 mmol), DIPEA (130 μL, 0.746 mmol) in DMF (4 mL) was stirred at 20 °C for 2 h. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex C18 80 x 40 mm x 3 μm; mobile phase A: with 0.05% NH3 - H2O (v%) of H 2 O; mobile phase B: MeCN; gradient: 42% to 72% B in 7.8 min, hold 100% B for 1 min; flow rate: 30 mL/min; column temperature: 30°C; wavelength: 220nm, 254nm), the residue was purified to give 2-methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2- as a white solid [2-[Rac-(3S,4S)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetone yl]amino]pyridine-3-carboxamide (45 mg, 33.6% yield).

1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.36-8.75(m,2 H),7.91-8.02(m,2 H),7.37-7.48(m,1 H),5.41-5.93(m,1 H),4.02-4.12(m,3 H),3.35-3.86(m,2 H),3.03-3.26(m,1 H),2.88(br s,1 H),2.14-2.62(m,10 H),1.85-2.13(m,3 H),1.47(br d,J =11.8Hz,1 H),1.14(d,J =7.0Hz,3 H),0.93(br d,J =6.5Hz,3 H)；LCMS(ESI) [M+H]+ m/z：計算值565.3，實測值565.1；HPLC：在254nm下為98.46%；99.7%ee。 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.36-8.75 (m, 2 H), 7.91-8.02 (m, 2 H), 7.37-7.48 (m, 1 H), 5.41-5.93 (m, 1 H), 4.02-4.12 (m, 3 H), 3.35-3.86 (m, 2 H), 3.03-3.26 (m, 1 H), 2.88 (br s, 1 H), 2.14-2.62 (m, 10 H) ), 1.85-2.13(m, 3 H), 1.47(br d, J =11.8Hz, 1 H), 1.14(d, J =7.0Hz, 3 H), 0.93(br d, J =6.5Hz, 3 H); LCMS (ESI) [M+H] + m/z: calcd 565.3, found 565.1; HPLC: 98.46% at 254 nm; 99.7% ee.

實例287. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-7-喹啉基]-1-哌啶基]乙醯胺(化合物1365)之合成Example 287. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[(2R,5S)-5-methyl-2-[2-(1- Synthesis of methyl-4-piperidinyl)-7-quinolinyl]-1-piperidinyl]acetamide (compound 1365)

Figure 110128222-A0202-12-1458-389
Figure 110128222-A0202-12-1458-389

步驟1：7-溴-2-(1-甲基-4-哌啶基)喹啉Step 1: 7-Bromo-2-(1-methyl-4-piperidinyl)quinoline

將2-胺基-4-溴苯甲醛(1.3g，6.50mmol)、1-(1-甲基-4-哌啶基)乙酮(917.72mg，6.50mmol)及第三丁醇鈉(1.25g，13.00mmol)混合於乙醇(20mL)中且在80℃下攪拌12h。將RM在真空中濃縮，然後用DCM處理，用水洗滌。將有機相經Na2SO4乾燥且蒸發，以得到7-溴-2-(1-甲基-4-哌啶基)喹啉(1.65g，粗品)LCMS(ESI)：[M+1 ]+ m/z：計算值304.1；實測值305；Rt=0.934min。2-Amino-4-bromobenzaldehyde (1.3 g, 6.50 mmol), 1-(1-methyl-4-piperidinyl)ethanone (917.72 mg, 6.50 mmol) and sodium tert-butoxide (1.25 g, 13.00 mmol) in ethanol (20 mL) and stirred at 80 °C for 12 h. The RM was concentrated in vacuo, then treated with DCM and washed with water. The organic phase was dried over Na2SO4 and evaporated to give 7-bromo-2-(1-methyl-4-piperidinyl)quinoline (1.65 g, crude) LCMS (ESI): [M+ 1 ] + m/z : Calculated value 304.1; Measured value 305; Rt=0.934min.

步驟2：2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)喹啉Step 2: 2-(1-Methyl-4-piperidinyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base) quinoline

將7-溴-2-(1-甲基-4-哌啶基)喹啉(1.95g，6.39mmol)(300mg)、雙(頻哪醇)二硼(2.11g，8.31mmol)及乙酸鉀(1.88g，19.17mmol，1.20mL)於二噁烷(30.03mL)中之混合物用氬氣除氣10min。接著添加Pd(dppf)Cl2*DCM(521.75mg，638.90μmol)且將反應混合物在80℃下加熱12h。將反應混合物過濾，然後在真空中濃縮。將殘餘物用MTBE-己烷(1：1)之混合物處理，過濾，然後在減壓下濃縮，以得到2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)喹啉(3g，粗品)。7-Bromo-2-(1-methyl-4-piperidinyl)quinoline (1.95 g, 6.39 mmol) (300 mg), bis(pinacol)diboron (2.11 g, 8.31 mmol) and potassium acetate (1.88 g, 19.17 mmol, 1.20 mL) in dioxane (30.03 mL) was degassed with argon for 10 min. Then Pd(dppf)Cl2*DCM (521.75 mg, 638.90 μmol) was added and the reaction mixture was heated at 80 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was treated with a mixture of MTBE-hexanes (1:1), filtered, and concentrated under reduced pressure to give 2-(1-methyl-4-piperidinyl)-7-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)quinoline (3 g, crude).

LCMS(ESI)：[M+1]+ m/z：計算值352.3；實測值353.2；Rt=1.119min。LCMS (ESI): [M+1] + m/z: calculated 352.3; found 353.2; Rt=1.119 min.

步驟3：(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)-7-喹啉基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯Step 3: (3S)-3-Methyl-6-[2-(1-methyl-4-piperidinyl)-7-quinolinyl]-3,4-dihydro-2H-pyridine-1- tert-butyl formate

在氬氣下，將2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)喹啉(2.8g，7.95mmol)、碳酸鈉(2.53g，23.84mmol，998.15μL)、(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.74g，7.95mmol)及Pd(dppf)Cl2*DCM(0.5g，612.75μmol)混合於H2O(15mL)及二噁烷(50mL)中且在75℃下攪拌12h。將反應混合物用水稀釋且將所要產物用DCM萃取，經Na2SO4乾燥且在真空中濃縮。獲得(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)-7-喹啉基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，粗品)。Under argon, 2-(1-methyl-4-piperidinyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)quinoline (2.8 g, 7.95 mmol), sodium carbonate (2.53 g, 23.84 mmol, 998.15 μL), (3S)-3-methyl-6-(trifluoromethylsulfonyloxy) -3,4-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.74 g, 7.95 mmol) and Pd(dppf)Cl2*DCM (0.5 g, 612.75 μmol) were mixed in H2O (15 mL) and dioxane alkane (50 mL) and stirred at 75 °C for 12 h. The reaction mixture was diluted with water and the desired product was extracted with DCM, dried over Na2SO4 and concentrated in vacuo. (3S)-3-methyl-6-[2-(1-methyl-4-piperidinyl)-7-quinolinyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid was obtained Tributyl ester (4 g, crude).

LCMS(ESI)：[M+1]+ m/z：計算值421.3；實測值422.2；Rt=1.174min。LCMS (ESI): [M+1] + m/z: calculated 421.3; found 422.2; Rt=1.174 min.

步驟4：2-(1-甲基-4-哌啶基)-7-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]喹啉Step 4: 2-(1-Methyl-4-piperidinyl)-7-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]quinoline

將(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)-7-喹啉基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，9.49mmol)溶解於DCM(40mL)中且添加CF3COOH(15g，9.49mmol)。將RM攪拌2h，然後濃縮。將殘餘物用MTBE處理兩次。將黑色膠狀物用NaHCO3 水溶液處理，然後用DCM萃取。將有機相經Na2 SO4 乾燥，然後在真空中濃縮，以得到2-(1-甲基-4-哌啶基)-7-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]喹啉(1g，粗品)(3S)-3-methyl-6-[2-(1-methyl-4-piperidinyl)-7-quinolinyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid Tributyl ester (4 g, 9.49 mmol) was dissolved in DCM (40 mL) and CF3COOH (15 g, 9.49 mmol) was added. The RM was stirred for 2 h, then concentrated. The residue was treated with MTBE twice. The black gum was treated with aqueous NaHCO3 , then extracted with DCM. The organic phase was dried over Na 2 SO 4 and concentrated in vacuo to give 2-(1-methyl-4-piperidinyl)-7-[(3S)-3-methyl-2,3,4 ,5-Tetrahydropyridin-6-yl]quinoline (1 g, crude)

LCMS(ESI)：[M+1]+ m/z：計算值321.2；實測值322.2；Rt=0.682min。LCMS (ESI): [M+1] + m/z: calculated 321.2; found 322.2; Rt=0.682 min.

步驟5：2-(1-甲基-4-哌啶基)-7-[(2R,5S)-5-甲基-2-哌啶基]喹啉Step 5: 2-(1-Methyl-4-piperidinyl)-7-[(2R,5S)-5-methyl-2-piperidinyl]quinoline

向2-(1-甲基-4-哌啶基)-7-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]喹啉(1g，2.49mmol)於甲醇(30mL)中之溶液中添加硼氫化鈉(188.30mg，4.98mmol，175.33μL)，然後攪拌隔夜。將RM在真空中濃縮，然後用DCM處理，過濾且蒸發，以得到2-(1-甲基-4-哌啶基)-7-[(2R,5S)-5-甲基-2-哌啶基]喹啉(0.75g，粗品) LCMS(ESI)：[M+1]+ m/z：計算值323.2；實測值324.2；Rt=0.705min。To 2-(1-methyl-4-piperidinyl)-7-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]quinoline (1 g, 2.49 mmol) in methanol (30 mL) was added sodium borohydride (188.30 mg, 4.98 mmol, 175.33 μL), followed by stirring overnight. The RM was concentrated in vacuo, then treated with DCM, filtered and evaporated to give 2-(1-methyl-4-piperidinyl)-7-[(2R,5S)-5-methyl-2-piperidine Peridyl]quinoline (0.75 g, crude) LCMS (ESI): [M+1] + m/z: calcd. 323.2; found 324.2; Rt=0.705 min.

步驟6：N-(6-胺基-5-乙基-3-吡啶基]-2-側氧基-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-7-喹啉基]-1-哌啶基]乙醯胺(化合物1365)之合成Step 6: N-(6-Amino-5-ethyl-3-pyridinyl]-2-oxy-2-[(2R,5S)-5-methyl-2-[2-(1- Synthesis of methyl-4-piperidinyl)-7-quinolinyl]-1-piperidinyl]acetamide (compound 1365)

將來自前一階段之粗產物2-(1-甲基-4-哌啶基)-7-[(2R,5S)-5-甲基-2-哌啶基]喹啉(100.00mg，216.40μmol)與TEA(109.49mg，1.08mmol，150.81μL)混合於DMSO(2mL)中，接著添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(54.33mg，259.68μmol)及HATU(98.74mg，259.68μmol)且攪拌隔夜。將RM用水處理且將所要產物過濾，用水洗滌且溶解於DMSO中，然後經歷HPLC。The crude product from the previous stage, 2-(1-methyl-4-piperidinyl)-7-[(2R,5S)-5-methyl-2-piperidinyl]quinoline (100.00 mg, 216.40 μmol ) was mixed with TEA (109.49 mg, 1.08 mmol, 150.81 μL) in DMSO (2 mL), followed by the addition of 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxygen acetic acid (54.33 mg, 259.68 μmol) and HATU (98.74 mg, 259.68 μmol) and stirred overnight. The RM was treated with water and the desired product was filtered, washed with water and dissolved in DMSO, then subjected to HPLC.

HPLC資料：SYSTEM 2-10min 30-60% ACN+FA 30ml/min(裝載泵4ml ACN)管柱：SunFire 100*19mm，5微米。獲得N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-7-喹啉基]-1-哌啶基]乙醯胺(42.3mg，82.19μmol，37.98%產率)。HPLC data: SYSTEM 2-10min 30-60% ACN+FA 30ml/min (loading pump 4ml ACN) Column: SunFire 100*19mm, 5 microns. Obtained N-(6-amino-5-ethyl-3-pyridyl)-2-oxo-2-[(2R,5S)-5-methyl-2-[2-(1-methyl) -4-Piperidinyl)-7-quinolinyl]-1-piperidinyl]acetamide (42.3 mg, 82.19 μmol, 37.98% yield).

1 H NMR(600MHz,dmso)δ 1.03-1.15(m,6H),1.33-1.44(m,1H),1.70-1.76(m,1H),1.86-1.94(m,5H),2.10-2.20(m,3H),2.27-2.31(m,3H),2.32-2.35(m,1H),2.37-2.43(m,2H),2.80-2.88(m,2H),2.97-3.00(m,2H),4.08-4.24(m,1H),5.35-5.78(m,3H),7.42-7.49(m,2H),7.51-7.57(m,1H),7.80-7.86(m,1H),7.92-7.98(m,1H),7.99-8.10(m,1H),8.23-8.31(m,1H),10.54-10.66(m,1H)。 1 H NMR(600MHz, dmso)δ 1.03-1.15(m, 6H), 1.33-1.44(m, 1H), 1.70-1.76(m, 1H), 1.86-1.94(m, 5H), 2.10-2.20(m ,3H),2.27-2.31(m,3H),2.32-2.35(m,1H),2.37-2.43(m,2H),2.80-2.88(m,2H),2.97-3.00(m,2H),4.08 -4.24(m, 1H), 5.35-5.78(m, 3H), 7.42-7.49(m, 2H), 7.51-7.57(m, 1H), 7.80-7.86(m, 1H), 7.92-7.98(m, 1H), 7.99-8.10 (m, 1H), 8.23-8.31 (m, 1H), 10.54-10.66 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值514.3；實測值515.2；Rt=2.125min。LCMS (ESI): [M+1] + m/z: calculated 514.3; found 515.2; Rt=2.125 min.

實例288. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2-氘-1,3-苯并噻唑-5-yl)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(WX-TANT_17)之合成Example 288. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(2-deutero-1,3-benzothiazole-5-yl) Synthesis of -5-methyl-1-piperidinyl]-2-oxoacetamide (WX-TANT_17)

Figure 110128222-A0202-12-1460-390
Figure 110128222-A0202-12-1460-390

步驟1：(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(ES18795-7)之合成Step 1: Synthesis of (2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (ES18795-7)

Figure 110128222-A0202-12-1461-391
Figure 110128222-A0202-12-1461-391

將5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(2g，8.61mmol，1當量)、TEA(1.74g，17.22mmol，2.40mL，2當量)、Boc2O(2.82g，12.91mmol，2.97mL，1.5當量)於DCM(10mL)中之混合物除氣且用N2吹掃3次，然後在N2氣氛下將混合物在25℃下攪拌16h。LC-MS顯示反應物1完全消耗，DCM經蒸發。藉由管柱層析(SiO2，石油醚/乙酸乙酯=0/1至3/1)純化殘餘物，獲得呈白色固體之化合物(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(2.4g，7.22mmol，83.86%產率)。1H NMR(400MHz,DMSO-d6)δ ppm 9.19-9.52(m,1 H)8.15(d,J=8.38Hz,1 H)7.82-7.94(m,1 H)7.36(dd,J=8.50,1.25Hz,1 H)5.33(t,J=4.57Hz,1 H)3.67(br d,J=13.38Hz,1 H)3.00(dd,J=13.45,3.81Hz,1 H)2.01-2.22(m,2 H)1.82(br s,1 H)1.56-1.72(m,1 H)1.18-1.33(m,1 H)0.99(d,J=6.88Hz,3 H)。LCMS(ESI)[M+H]+ m/z計算值333.1，實測值333.2。5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (2 g, 8.61 mmol, 1 equiv), TEA (1.74 g, 17.22 mmol, 2.40 mL, 2 equiv), Boc2O (2.82 g, 12.91 mmol, 2.97 mL, 1.5 equiv) in DCM (10 mL) was degassed and purged with N2 3 times, then the mixture was stirred at 25 °C for 16 h under N2 atmosphere. LC-MS showed complete consumption of reaction 1 and DCM was evaporated. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=0/1 to 3/1) to obtain compound (2R,5S)-2-(1,3-benzothiazole) as a white solid -5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2.4 g, 7.22 mmol, 83.86% yield). 1H NMR (400MHz, DMSO-d6)δ ppm 9.19-9.52(m,1H)8.15(d,J=8.38Hz,1H)7.82-7.94(m,1H)7.36(dd,J=8.50,1.25 Hz,1H)5.33(t,J=4.57Hz,1H)3.67(br d,J=13.38Hz,1H)3.00(dd,J=13.45,3.81Hz,1H)2.01-2.22(m, 2H)1.82(br s,1H)1.56-1.72(m,1H)1.18-1.33(m,1H)0.99(d,J=6.88Hz,3H). LCMS(ESI) [M+H]+ m/z calculated 333.1, found 333.2.

步驟2：(2R,5S)-2-(2-氘-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(ES18795-8)之合成Step 2: Synthesis of (2R,5S)-2-(2-deutero-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (ES18795-8)

Figure 110128222-A0202-12-1461-392
Figure 110128222-A0202-12-1461-392

在-60℃下，向(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(500mg，1.50mmol，1當量)於THF(8mL)中之溶液中逐滴添加n-BuLi(2.5M，902.37uL，1.5當量)。然後在0℃下添加D2O(602.4mg，30.1mmol，20當量)。將所得混合物在0℃下攪拌30min。LCMS顯示反應完成。將反應混合物濃縮，以得到殘餘物。藉由製備型HPLC(鹼性條件)純化殘餘物。獲得呈白色固體之化合物(2R,5S)-2-(2-氘-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(250mg，749.70umol，49.85%產率)。1H NMR(400MHz,DMSO-d6)δ ppm 9.40(s,1 H)8.15(d,J=8.38Hz,1 H)7.84-7.94(m,1 H)7.36(dd,J=8.38,1.25Hz,1 H)5.33(t,J=4.57Hz,1 H)3.67(br d,J=13.51Hz,1 H)3.01(dd,J=13.51,3.75Hz,1 H)2.04-2.22(m,2 H)1.82(br s,1 H)1.53-1.71(m,1 H)1.22-1.33(m,1 H)1.00(d,J=7.00Hz,3 H)。LCMS(ESI)[M+H]+ m/z計算值334.1，實測值334.1。To (2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.50 mmol, 1 equiv) in THF (8 mL) was added dropwise n-BuLi (2.5 M, 902.37 uL, 1.5 equiv). D2O (602.4 mg, 30.1 mmol, 20 equiv) was then added at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. LCMS showed the reaction was complete. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (basic conditions). Compound (2R,5S)-2-(2-deutero-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (250 mg, 749.70 m) was obtained as a white solid umol, 49.85% yield). 1H NMR(400MHz,DMSO-d6)δppm 9.40(s,1H)8.15(d,J=8.38Hz,1H)7.84-7.94(m,1H)7.36(dd,J=8.38,1.25Hz, 1H)5.33(t,J=4.57Hz,1H)3.67(br d,J=13.51Hz,1H)3.01(dd,J=13.51,3.75Hz,1H)2.04-2.22(m,2H) )1.82(br s,1H)1.53-1.71(m,1H)1.22-1.33(m,1H)1.00(d,J=7.00Hz,3H). LCMS (ESI) [M+H]+ m/z calculated 334.1, found 334.1.

步驟3：2-氘-5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(ES18795-之合成Step 3: Synthesis of 2-deutero-5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (ES18795-

Figure 110128222-A0202-12-1462-393
Figure 110128222-A0202-12-1462-393

將(2R,5S)-2-(2-氘-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(250mg，749.70umol，1當量)於TFA/DCM(5mL)中之混合物除氣且用N2吹掃3次，然後將混合物在N2氣氛、25℃下攪拌2h。LCMS顯示反應完成。蒸發TFA/DCM。呈白色固體之粗產物2-氘-5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(175mg，粗品)不經進一步純化即用於下一步驟中。LCMS(ESI)[M+H]+ m/z計算值234.1，實測值234.1。(2R,5S)-2-(2-deutero-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (250 mg, 749.70 umol, 1 equiv) The mixture in TFA/DCM (5 mL) was degassed and purged 3 times with N2, then the mixture was stirred at 25 °C for 2 h under a N2 atmosphere. LCMS showed the reaction was complete. Evaporate TFA/DCM. Crude 2-deutero-5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (175 mg, crude) as a white solid was used without further purification in the next step. LCMS(ESI) [M+H]+ m/z calculated 234.1, found 234.1.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2-氘-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(ES18795-12)之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(2-deutero-1,3-benzothiazol-5-yl) Synthesis of -5-methyl-1-piperidinyl]-2-oxoacetamide (ES18795-12)

Figure 110128222-A0202-12-1463-394
Figure 110128222-A0202-12-1463-394

將2-氘-5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(175mg，749.95umol，1當量)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(220mg，1.13mmol，1.50當量)、HATU(570.30mg，1.50mmol，2當量)、DIEA(484.63mg，3.75mmol，653.14uL，5當量)於DMF(10mL)中之混合物除氣且用N2吹掃3次，然後將混合物在N2氣氛、25℃下攪拌16h。LC-MS顯示偵測到約80%所要化合物。將反應混合物用30mL EtOAc(10mL * 3)萃取。將經合併之有機層用飽和NaCl水溶液(20mL)洗滌，經Na2SO4乾燥，過濾且在減壓下濃縮，以得到殘餘物。藉由製備型HPLC(鹼性條件)純化殘餘物。獲得呈白色固體之化合物N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2-氘-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(52mg，126.67umol，16.89%產率)。1H NMR(400MHz,DMSO-d6)δ ppm 10.33(br s,1 H)8.15(d,J=8.44Hz,1 H)8.05(s,2 H)7.49(br d,J=8.56Hz,2 H)5.17-5.88(m,3 H)2.12-2.38(m,2 H)2.00-2.11(m,3 H)1.93(br s,1 H)1.72-1.85(m,1 H)1.38(br d,J=9.90Hz,1 H)1.07(d,J=6.97Hz,3 H)。LCMS(ESI)[M+H]+ m/z計算值411.1，實測值411.1。2-Deutero-5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (175 mg, 749.95 umol, 1 equiv.), 2-[(6-amine yl-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (220 mg, 1.13 mmol, 1.50 equiv), HATU (570.30 mg, 1.50 mmol, 2 equiv), DIEA (484.63 mg, 3.75 mmol, 653.14 uL, 5 equiv) in DMF (10 mL) was degassed and purged with N2 3 times, then the mixture was stirred under N2 atmosphere at 25 °C for 16 h. LC-MS showed that about 80% of the desired compound was detected. The reaction mixture was extracted with 30 mL EtOAc (10 mL*3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (basic conditions). Compound N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(2-deutero-1,3-benzothiazole-5 was obtained as a white solid -yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (52 mg, 126.67 umol, 16.89% yield). 1H NMR(400MHz,DMSO-d6)δppm 10.33(br s,1H)8.15(d,J=8.44Hz,1H)8.05(s,2H)7.49(br d,J=8.56Hz,2H )5.17-5.88(m,3H)2.12-2.38(m,2H)2.00-2.11(m,3H)1.93(br s,1H)1.72-1.85(m,1H)1.38(br d, J=9.90Hz,1H)1.07(d,J=6.97Hz,3H). LCMS (ESI) [M+H]+ m/z calculated 411.1, found 411.1.

實例289. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S)-5-甲基-2-[3-甲基-2-(1-甲基-4-哌啶基)-7-喹啉基]-1-哌啶基]乙醯胺(化合物1368)之合成Example 289. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[(2R,5S)-5-methyl-2-[3-methyl- Synthesis of 2-(1-Methyl-4-piperidinyl)-7-quinolinyl]-1-piperidinyl]acetamide (Compound 1368)

Figure 110128222-A0202-12-1464-395
Figure 110128222-A0202-12-1464-395

步驟1：4-(7-溴-3-甲基-2-喹啉基)哌啶-1-甲酸第三丁酯Step 1: 3-Butyl 4-(7-Bromo-3-methyl-2-quinolinyl)piperidine-1-carboxylate

將2-胺基-4-溴苯甲醛(1.5g，7.50mmol)、4-丙醯基哌啶-1-甲酸第三丁酯(1.81g，7.50mmol)及第三丁醇鈉(1.44g，15.00mmol)混合於乙醇(20mL)中且在80℃下攪拌12h。將RM在真空中濃縮，然後用DCM處理，用水洗滌。將有機相經Na2SO4乾燥且蒸發，以得到4-(7-溴-3-甲基-2-喹啉基)哌啶-1-甲酸第三丁酯(2.2g，粗品)2-Amino-4-bromobenzaldehyde (1.5 g, 7.50 mmol), 3-butyl 4-propionylpiperidine-1-carboxylate (1.81 g, 7.50 mmol) and sodium tert-butoxide (1.44 g) , 15.00 mmol) in ethanol (20 mL) and stirred at 80 °C for 12 h. The RM was concentrated in vacuo, then treated with DCM and washed with water. The organic phase was dried over Na2SO4 and evaporated to give tert-butyl 4-(7-bromo-3-methyl-2-quinolinyl)piperidine-1-carboxylate (2.2 g, crude)

LCMS(ESI)：[M+1 ]+ m/z：計算值405.3；實測值406.0；Rt=1.771min。LCMS (ESI): [M+ 1 ] + m/z: calculated 405.3; found 406.0; Rt=1.771 min.

步驟2：7-溴-3-甲基-2-(4-哌啶基)喹啉Step 2: 7-Bromo-3-methyl-2-(4-piperidinyl)quinoline

將4-(7-溴-3-甲基-2-喹啉基)哌啶-1-甲酸第三丁酯(2.5g，6.17mmol)溶解於DCM(19.87mL)中且逐滴添加三氟乙酸(15g，131.55mmol，10.14mL)，然後攪拌0.5h。將RM濃縮，用NaHCO3 水溶液處理且將所要產物用DCM萃取。將有機相經Na2 SO4 乾燥，然後蒸發，以得到7-溴-3-甲基-2-(4-哌啶基)喹啉(1.6g，粗品)4-(7-Bromo-3-methyl-2-quinolinyl)piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 6.17 mmol) was dissolved in DCM (19.87 mL) and trifluoro was added dropwise Acetic acid (15 g, 131.55 mmol, 10.14 mL), then stirred for 0.5 h. The RM was concentrated, treated with aqueous NaHCO3 and the desired product was extracted with DCM. The organic phase was dried over Na2SO4 , then evaporated to give 7-bromo-3-methyl-2-(4-piperidinyl)quinoline (1.6 g, crude)

LCMS(ESI)：[M+1]+ m/z：計算值305.2；實測值306.2；Rt=0.781min。LCMS (ESI): [M+1] + m/z: calculated 305.2; found 306.2; Rt=0.781 min.

步驟3：7-溴-3-甲基-2-(1-甲基-4-哌啶基)喹啉Step 3: 7-Bromo-3-methyl-2-(1-methyl-4-piperidinyl)quinoline

將氰基硼氫化鈉(1.77g，28.10mmol)分4批次添加到7-溴-3-甲基-2-(4-哌啶基)喹啉(1.6g，4.68mmol，HCl)及福馬林(1.90g，23.41mmol，1.75mL，37%純度)於甲醇(20.08mL)中之混合物中且攪拌隔夜。將反應混合物用NaHCO3 水溶液處理且將所要產物用100ml DCM萃取，經Na2SO4乾燥且在真空中濃縮，以得到7-溴-3-甲基-2-(1-甲基-4-哌啶基)喹啉(1.1g，粗品)Sodium cyanoborohydride (1.77 g, 28.10 mmol) was added in 4 batches to 7-bromo-3-methyl-2-(4-piperidinyl)quinoline (1.6 g, 4.68 mmol, HCl) and forma Lin (1.90 g, 23.41 mmol, 1.75 mL, 37% pure) in a mixture of methanol (20.08 mL) and stirred overnight. The reaction mixture was washed with NaHCO3 Aqueous workup and the desired product was extracted with 100 ml DCM, dried over Na2SO4 and concentrated in vacuo to give 7-bromo-3-methyl-2-(1-methyl-4-piperidinyl)quinoline (1.1 g ,Crude)

LCMS(ESI)：[M+1]+ m/z：計算值318.1；實測值321.2；Rt=0.958min。LCMS (ESI): [M+1] + m/z: calculated 318.1; found 321.2; Rt=0.958 min.

步驟4：3-甲基-2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)喹啉Step 4: 3-Methyl-2-(1-methyl-4-piperidinyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborocycle Pentan-2-yl)quinoline

將7-溴-3-甲基-2-(1-甲基-4-哌啶基)喹啉(1.1g，3.45mmol)、雙(頻哪醇)二硼(1.14g，4.48mmol)及乙酸鉀(1.01g，10.34mmol，646.17μL)於二噁烷(20mL)中之混合物用氬氣除氣10min。接著添加Pd(dppf)Cl2*DCM(281.39mg，344.57μmol)且將反應混合物在80℃下加熱12h。將反應混合物過濾，然後在真空中濃縮。將殘餘物用MTBE-己烷之混合物(1：1)處理，過濾，然後在減壓下濃縮，以得到3-甲基-2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)喹啉(2.2g，粗品)。7-Bromo-3-methyl-2-(1-methyl-4-piperidinyl)quinoline (1.1 g, 3.45 mmol), bis(pinacol)diboron (1.14 g, 4.48 mmol) and A mixture of potassium acetate (1.01 g, 10.34 mmol, 646.17 μL) in dioxane (20 mL) was degassed with argon for 10 min. Then Pd(dppf)Cl2*DCM (281.39 mg, 344.57 μmol) was added and the reaction mixture was heated at 80 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was treated with a mixture of MTBE-hexanes (1:1), filtered, and concentrated under reduced pressure to give 3-methyl-2-(1-methyl-4-piperidinyl)-7- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)quinoline (2.2 g, crude).

LCMS(ESI)：[M+1]+ m/z：計算值366.2；實測值367.2；Rt=1.193min。LCMS (ESI): [M+1] + m/z: calculated 366.2; found 367.2; Rt=1.193 min.

步驟5：(3S)-3-甲基-6-[3-甲基-2-(1-甲基-4-哌啶基)-7-喹啉基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯Step 5: (3S)-3-Methyl-6-[3-methyl-2-(1-methyl-4-piperidinyl)-7-quinolinyl]-3,4-dihydro-2H - tert-butyl pyridine-1-carboxylate

在氬氣下，將3-甲基-2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)喹啉(2g，5.46mmol)、碳酸鈉(1.74g，16.38mmol，685.66μL)、(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.89g，5.46mmol)及Pd(dppf)Cl2*DCM(343.47mg，420.92μmol)混合於H2O(15mL)及二噁烷(50mL)中且在75℃下攪拌12h。將反應混合物用水稀釋且將所要產物用DCM萃取，經Na2SO4乾燥且在真空中濃縮。獲得外消旋-(3S)-3-甲基-6-[3-甲基-2-(1-甲基-4-哌啶基)-7-喹啉基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.8g，粗品)。Under argon, 3-methyl-2-(1-methyl-4-piperidinyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxa Boron-2-yl)quinoline (2 g, 5.46 mmol), sodium carbonate (1.74 g, 16.38 mmol, 685.66 μL), (3S)-3-methyl-6-(trifluoromethylsulfonyl) oxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.89 g, 5.46 mmol) and Pd(dppf)Cl2*DCM (343.47 mg, 420.92 μmol) were mixed in H2O (15 mL) ) and dioxane (50 mL) and stirred at 75 °C for 12 h. The reaction mixture was diluted with water and the desired product was extracted with DCM, dried over Na2SO4 and concentrated in vacuo. to obtain racemic-(3S)-3-methyl-6-[3-methyl-2-(1-methyl-4-piperidinyl)-7-quinolinyl]-3,4-dihydro -2H-pyridine-1-carboxylic acid tert-butyl ester (2.8 g, crude).

LCMS(ESI)：[M+1]+ m/z：計算值435.3；實測值436.3；Rt=1.161min。LCMS (ESI): [M+1] + m/z: calculated 435.3; found 436.3; Rt=1.161 min.

步驟6：3-甲基-2-(1-甲基-4-哌啶基)-7-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]喹啉之合成Step 6: 3-Methyl-2-(1-methyl-4-piperidinyl)-7-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl ] The synthesis of quinoline

將外消旋-(3S)-3-甲基-6-[3-甲基-2-(1-甲基-4-哌啶基)-7-喹啉基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.8g，2.89mmol)溶解於DCM(40mL)中且添加CF3COOH(15g，2.89mmol)。將RM攪拌3h，然後濃縮。將殘餘物用MTBE處理兩次。將黑色膠狀物用NaHCO3水溶液處理，然後用DCM萃取。將有機相經Na2SO4乾燥，然後在真空中濃縮，以得到3-甲基-2-(1-甲基-4-哌啶基)-7-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]喹啉(600mg，粗品)rac-(3S)-3-methyl-6-[3-methyl-2-(1-methyl-4-piperidinyl)-7-quinolinyl]-3,4-dihydro -2H-pyridine-1-carboxylic acid tert-butyl ester (2.8 g, 2.89 mmol) was dissolved in DCM (40 mL) and CF3COOH (15 g, 2.89 mmol) was added. The RM was stirred for 3 h, then concentrated. The residue was treated with MTBE twice. The black gum was treated with aqueous NaHCO3, then extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo to give 3-methyl-2-(1-methyl-4-piperidinyl)-7-[rac-(3S)-3-methyl -2,3,4,5-Tetrahydropyridin-6-yl]quinoline (600 mg, crude)

LCMS(ESI)：[M+1]+ m/z：計算值335.2；實測值336.2；Rt=0.737min。LCMS (ESI): [M+1] + m/z: calculated 335.2; found 336.2; Rt=0.737 min.

步驟7：3-甲基-2-(1-甲基-4-哌啶基)-7-[(2R,5S)-5-甲基-2-哌啶基]喹啉之合成Step 7: Synthesis of 3-methyl-2-(1-methyl-4-piperidinyl)-7-[(2R,5S)-5-methyl-2-piperidinyl]quinoline

向3-甲基-2-(1-甲基-4-哌啶基)-7-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]喹啉(600mg，1.25mmol)於甲醇(15mL)中之溶液中添加硼氫化鈉(94.73mg，2.50mmol，88.20μL)，然後攪拌隔夜。將RM在真空中濃縮，然後用DCM及水處理，將有機相用水洗滌，經Na2SO4乾燥且蒸發，以得到3-甲基-2-(1-甲基-4-哌啶基)-7-[外消旋-(2R,5S)-5-甲基-2-哌啶基]喹啉(0.5g，粗品)。To 3-methyl-2-(1-methyl-4-piperidinyl)-7-[racemic-(3S)-3-methyl-2,3,4,5-tetrahydropyridine-6 -yl]quinoline (600 mg, 1.25 mmol) in methanol (15 mL) was added sodium borohydride (94.73 mg, 2.50 mmol, 88.20 μL) and stirred overnight. The RM was concentrated in vacuo, then treated with DCM and water, the organic phase was washed with water, dried over Na2SO4 and evaporated to give 3-methyl-2-(1-methyl-4-piperidinyl)-7- [Rac-(2R,5S)-5-methyl-2-piperidinyl]quinoline (0.5 g, crude).

LCMS(ESI)：[M+1]+ m/z：計算值337.2；實測值338.2；Rt=0.765min。LCMS (ESI): [M+1] + m/z: calculated 337.2; found 338.2; Rt=0.765 min.

步驟8：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S)-5-甲基-2-[3-甲基-2-(1-甲基-4-哌啶基)-7-喹啉基]-1-哌啶基]乙醯胺(化合物1868)之合成Step 8: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[(2R,5S)-5-methyl-2-[3-methyl- Synthesis of 2-(1-Methyl-4-piperidinyl)-7-quinolinyl]-1-piperidinyl]acetamide (Compound 1868)

將來自前一階段之粗產物3-甲基-2-(1-甲基-4-哌啶基)-7-[外消旋-(2R,5S)-5-甲基-2-哌啶基]喹啉(100.00mg，192.59μmol)與TEA(97.44mg，962.96μmol，134.22μL)混合於DMSO(1.95mL)中，接著添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(48.35mg，231.11μmol)及HATU(87.88mg，231.11μmol)且攪拌隔夜。將RM用水處理且將所要產物過濾，用水洗滌且溶解於DMSO中，然後經歷HPLC。HPLC資料：SYSTEM 2-10min 30-60% ACN+FA 30ml/min(裝 載泵4ml ACN)管柱：SunFire 100*19mm，5微米。獲得N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[3-甲基-2-(1-甲基-4-哌啶基)-7-喹啉基]-1-哌啶基]乙醯胺(14.2mg，26.86μmol，13.95%產率)。The crude product from the previous stage, 3-methyl-2-(1-methyl-4-piperidinyl)-7-[rac-(2R,5S)-5-methyl-2-piperidinyl ]quinoline (100.00 mg, 192.59 μmol) and TEA (97.44 mg, 962.96 μmol, 134.22 μL) were mixed in DMSO (1.95 mL) followed by the addition of 2-[(6-amino-5-ethyl-3-pyridine) (48.35 mg, 231.11 μmol) and HATU (87.88 mg, 231.11 μmol) and stirred overnight. The RM was treated with water and the desired product was filtered, washed with water and dissolved in DMSO, then subjected to HPLC. HPLC data: SYSTEM 2-10min 30-60% ACN+FA 30ml/min (packed Carrier pump 4ml ACN) column: SunFire 100*19mm, 5 microns. Obtained N-(6-amino-5-ethyl-3-pyridyl)-2-oxo-2-[rac-(2R,5S)-5-methyl-2-[3-methyl] yl-2-(1-methyl-4-piperidinyl)-7-quinolinyl]-1-piperidinyl]acetamide (14.2 mg, 26.86 μmol, 13.95% yield).

1 H NMR(600MHz,dmso)δ 1.02-1.14(m,6H),1.33-1.42(m,1H),1.69-2.02(m,7H),2.09-2.35(m,9H),2.40-2.43(m,2H),2.94-3.02(m,4H),3.50-4.09(m,1H),5.29-5.77(m,3H),7.41-7.54(m,2H),7.76-7.87(m,2H),7.99-8.09(m,2H),10.53-10.61(m,1H)。 1 H NMR (600MHz, dmso)δ 1.02-1.14(m, 6H), 1.33-1.42(m, 1H), 1.69-2.02(m, 7H), 2.09-2.35(m, 9H), 2.40-2.43(m ,2H),2.94-3.02(m,4H),3.50-4.09(m,1H),5.29-5.77(m,3H),7.41-7.54(m,2H),7.76-7.87(m,2H),7.99 -8.09(m, 2H), 10.53-10.61(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值530.2；實測值528.4；Rt=2.396min。LCMS (ESI): [M+1] + m/z: calculated 530.2; found 528.4; Rt=2.396 min.

實例290. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[4-(4-異丙基哌嗪-1-基)-3-甲基苯基]-5-甲基-1-哌啶基]乙醯胺(化合物1163)之合成Example 290. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[4-(4-iso Synthesis of propylpiperazin-1-yl)-3-methylphenyl]-5-methyl-1-piperidinyl]acetamide (compound 1163)

Figure 110128222-A0202-12-1467-396
Figure 110128222-A0202-12-1467-396

步驟1：1-異丙基-4-(2-甲基-4-硝基苯基)哌嗪之合成Step 1: Synthesis of 1-isopropyl-4-(2-methyl-4-nitrophenyl)piperazine

在Ar下，將1-異丙基哌嗪(2.5g，19.50mmol，2.79mL)、1-氟-2-甲基-4-硝基苯(4.23g，27.30mmol)、碳酸鉀(6.74g，48.75mmol，2.94mL)混合於DMF (20mL)中。將反應混合物在130℃下攪拌隔夜。在冷卻至室溫之後，將反應混合物用水稀釋，用EtOAc萃取。將有機相在真空中蒸發，得到1-異丙基-4-(2-甲基-4-硝基苯基)哌嗪(4.8g，粗品)Under Ar, 1-isopropylpiperazine (2.5 g, 19.50 mmol, 2.79 mL), 1-fluoro-2-methyl-4-nitrobenzene (4.23 g, 27.30 mmol), potassium carbonate (6.74 g) were combined , 48.75mmol, 2.94mL) mixed with DMF (20mL). The reaction mixture was stirred at 130°C overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic phase was evaporated in vacuo to give 1-isopropyl-4-(2-methyl-4-nitrophenyl)piperazine (4.8 g, crude)

LCMS(ESI)：[M+H]+ m/z：計算值264.2；實測值264.2；Rt=0.880min。LCMS (ESI): [M+H] + m/z: calculated 264.2; found 264.2; Rt=0.880 min.

步驟2：4-(4-異丙基哌嗪-1-基)-3-甲基苯胺之合成Step 2: Synthesis of 4-(4-isopropylpiperazin-1-yl)-3-methylaniline

在H2 氣氛下，將1-異丙基-4-(2-甲基-4-硝基苯基)哌嗪(4.8g，18.23mmol)及Pd/C(1.94g，18.23mmol)於甲醇中之混合物在25℃下攪拌16h。過濾混合物且蒸發濾液。使殘餘物在己烷中結晶，以得到4-(4-異丙基哌嗪-1-基)-3-甲基苯胺(2.7g，11.57mmol，63.48%產率)。Under H2 atmosphere, 1-isopropyl-4-(2-methyl-4-nitrophenyl)piperazine (4.8 g, 18.23 mmol) and Pd/C (1.94 g, 18.23 mmol) were dissolved in methanol The mixture was stirred at 25°C for 16h. The mixture was filtered and the filtrate was evaporated. The residue was crystallized from hexanes to give 4-(4-isopropylpiperazin-1-yl)-3-methylaniline (2.7 g, 11.57 mmol, 63.48% yield).

LCMS(ESI)：[M+H]+ m/z：計算值234.2；實測值234.4；Rt=0.539min。LCMS (ESI): [M+H] + m/z: calculated 234.2; found 234.4; Rt=0.539 min.

步驟3：1-異丙基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪之合成Step 3: 1-Isopropyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl )Phenyl]piperazine synthesis

在圓底燒瓶中稱量4-(4-異丙基哌嗪-1-基)-3-甲基苯胺(2.65g，11.36mmol)及雙(頻哪醇)二硼(3.46g，13.63mmol)。然後連續添加MeCN(25mL)及亞硝酸第三丁酯(1.76g，17.03mmol，2.03mL)。將所得反應溶液在80℃下攪拌12h(N2 逸出在5至15min內完成)。然後將溶液在減壓下濃縮，且藉由急驟層析純化粗殘餘物，以獲得1-異丙基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪(6g，粗品)。4-(4-Isopropylpiperazin-1-yl)-3-methylaniline (2.65 g, 11.36 mmol) and bis(pinacol)diboron (3.46 g, 13.63 mmol) were weighed in a round bottom flask ). MeCN (25 mL) and tert-butyl nitrite (1.76 g, 17.03 mmol, 2.03 mL) were then added successively. The resulting reaction solution was stirred at 80 °C for 12 h (N 2 evolution was completed within 5 to 15 min). The solution was then concentrated under reduced pressure, and the crude residue was purified by flash chromatography to obtain 1-isopropyl-4-[2-methyl-4-(4,4,5,5-tetramethyl] -1,3,2-Dioxaborol-2-yl)phenyl]piperazine (6 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值345.2；實測值345.2；Rt=1.027min。LCMS (ESI): [M+H] + m/z: calculated 345.2; found 345.2; Rt=1.027 min.

步驟4：外消旋-(3S)-6-[4-(4-異丙基哌嗪-1-基)-3-甲基苯基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 4: Racemic-(3S)-6-[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]-3-methyl-3,4-dihydro- Synthesis of 2H-pyridine-1-carboxylic acid tert-butyl ester

將1-異丙基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪(5.8g，16.85mmol)、外消旋-(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.82g，16.85mmol)及碳酸鈉(3.57g，33.69 mmol，1.41mL)一起混合於二噁烷(60mL)及水(20mL)之混合物中。將所得混合物用氬氣吹掃10min且添加Pd(dppf)Cl2 DCM(687.85mg，842.29μmol)。將所得混合物在90℃下加熱隔夜。將所得混合物冷卻且用水(5mL)稀釋。將所得混合物用EtOAc(2*15mL)萃取且將經合併之有機層用鹽水(10mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。1-Isopropyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene yl]piperazine (5.8 g, 16.85 mmol), rac-(3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine- 3-Butyl 1-carboxylate (5.82 g, 16.85 mmol) and sodium carbonate (3.57 g, 33.69 mmol, 1.41 mL) were mixed together in a mixture of dioxane (60 mL) and water (20 mL). The resulting mixture was purged with argon for 10 min and Pd(dppf)Cl 2 DCM (687.85 mg, 842.29 μmol) was added. The resulting mixture was heated at 90°C overnight. The resulting mixture was cooled and diluted with water (5 mL). The resulting mixture was extracted with EtOAc (2*15 mL) and the combined organic layers were washed with brine (10 mL), dried over Na2SO4 , filtered and concentrated in vacuo.

LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值414.2；Rt=1.287min。LCMS (ESI): [M+H] + m/z: calculated 414.2; found 414.2; Rt=1.287 min.

步驟5：1-異丙基-4-[2-甲基-4-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪之合成Step 5: 1-Isopropyl-4-[2-methyl-4-[rac-(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]benzene Synthesis of yl]piperazine

將三氟乙酸(23.16g，203.10mmol，15.65mL)一次性添加到外消旋-(3S)-6-[4-(4-異丙基哌嗪-1-基)-3-甲基苯基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7g，16.92mmol)於DCM(20mL)中之經攪拌之溶液中。將所得溶液在25℃下攪拌1h，然後在真空中濃縮。用水(100mL)稀釋殘餘物。將產物之TFA鹽之所得溶液自深棕色油狀殘餘物傾析，將其另外用水(2*25mL)沖洗。透過棉花墊過濾經合併之水溶液，以移除痕量油狀雜質，然後用10%氫氧化鈉水溶液鹼化至pH 11-12且用二氯甲烷(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色膠狀物之1-異丙基-4-[2-甲基-4-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪(1.5g，4.79mmol，28.27%產率)，其直接用於下一步驟中。Trifluoroacetic acid (23.16 g, 203.10 mmol, 15.65 mL) was added in one portion to rac-(3S)-6-[4-(4-isopropylpiperazin-1-yl)-3-methylbenzene [00110] [00110] 3-butyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7 g, 16.92 mmol) in a stirred solution of DCM (20 mL). The resulting solution was stirred at 25 °C for 1 h, then concentrated in vacuo. The residue was diluted with water (100 mL). The resulting solution of the TFA salt of the product was decanted from the dark brown oily residue, which was rinsed with additional water (2*25 mL). The combined aqueous solutions were filtered through a cotton pad to remove traces of oily impurities, then basified to pH 11-12 with 10% aqueous sodium hydroxide and extracted with dichloromethane (2*50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 1-isopropyl-4-[2-methyl-4-[rac-(3S) as a pale yellow gum -3-Methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl]piperazine (1.5 g, 4.79 mmol, 28.27% yield), which was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值314.2；實測值314.2；Rt=0.643min。LCMS (ESI): [M+H] + m/z: calculated 314.2; found 314.2; Rt=0.643 min.

步驟6：1-異丙基-4-[2-甲基-4-[外消旋-(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪之合成Step 6: Synthesis of 1-isopropyl-4-[2-methyl-4-[rac-(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine

將1-異丙基-4-[2-甲基-4-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪(1.5g，4.79mmol)溶解於甲醇(15mL)中且分批添加硼氫化鈉(362.06mg，9.57mmol，337.11μL)。將所得混合物攪拌隔夜。將水(20mL)添加到反應 混合物中且將所得混合物在真空中濃縮。將殘餘物用水(30mL)稀釋且將所得混合物用DCM(2*50mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得1-異丙基-4-[2-甲基-4-[外消旋-(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪(0.5g，1.58mmol，33.12%產率)1-Isopropyl-4-[2-methyl-4-[rac-(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl] Piperazine (1.5 g, 4.79 mmol) was dissolved in methanol (15 mL) and sodium borohydride (362.06 mg, 9.57 mmol, 337.11 μL) was added portionwise. The resulting mixture was stirred overnight. Water (20 mL) was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water (30 mL) and the resulting mixture was extracted with DCM (2*50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 1-isopropyl-4-[2-methyl-4-[rac-(2R,5S)-5 -Methyl-2-piperidinyl]phenyl]piperazine (0.5 g, 1.58 mmol, 33.12% yield)

LCMS(ESI)：[M+H]+ m/z：計算值316.2；實測值316.2；Rt=0.670min。LCMS (ESI): [M+H] + m/z: calculated 316.2; found 316.2; Rt=0.670 min.

步驟7：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[4-(4-異丙基哌嗪-1-基)-3-甲基苯基]-5-甲基-1-哌啶基]乙醯胺(化合物7234)之合成Step 7: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[4-(4-iso Synthesis of propylpiperazin-1-yl)-3-methylphenyl]-5-methyl-1-piperidinyl]acetamide (compound 7234)

將1-異丙基-4-[2-甲基-4-[外消旋-(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪(150mg，475.44μmol)溶解於DMF(2mL)中且添加三乙胺(481.10mg，4.75mmol，662.67μL)，隨後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(99.46mg，475.44μmol)。然後，逐滴添加HATU(271.17mg，713.17μmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC(2-10min 0-65%水/MeOH+NH3 30mL/min；裝載泵4mL/min MeOH；管柱SunFire 19*100mm)純化，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[4-(4-異丙基哌嗪-1-基)-3-甲基苯基]-5-甲基-1-哌啶基]乙醯胺(22.3mg，44.01μmol，9.26%產率)。1-Isopropyl-4-[2-methyl-4-[rac-(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine (150 mg, 475.44 μmol) Dissolve in DMF (2 mL) and add triethylamine (481.10 mg, 4.75 mmol, 662.67 μL) followed by 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2- Pendant oxyacetic acid (99.46 mg, 475.44 μmol). Then, HATU (271.17 mg, 713.17 μmol) was added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC (2-10 min 0-65% water/MeOH+NH3 30 mL/min; loading pump 4 mL/min MeOH; column SunFire 19*100 mm) to obtain N- (6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[4-(4-isopropylpiperazine- 1-yl)-3-methylphenyl]-5-methyl-1-piperidinyl]acetamide (22.3 mg, 44.01 μmol, 9.26% yield).

1 H NMR(600MHz,dmso)δ 0.98-1.01(m,9H),1.07-1.14(m,3H),1.26-1.37(m,1H),1.62-1.73(m,1H),1.80-1.93(m,1H),1.96-2.11(m,1H),2.12-2.20(m,1H),2.21-2.25(m,3H),2.37-2.43(m,2H),2.53-2.58(m,4H),2.65-2.70(m,1H),2.72-2.77(m,0.3H),2.78-2.85(m,4H),3.18-3.23(m,0.7H),3.43-4.01(m,1H),5.03-5.54(m,1H),5.55-5.67(m,2H),6.95-7.02(m,1H),7.05-7.16(m,2H),7.44-7.53(m,1H),7.98-8.10(m,1H),10.39-10.64(m,1H)。 1 H NMR(600MHz, dmso)δ 0.98-1.01(m, 9H), 1.07-1.14(m, 3H), 1.26-1.37(m, 1H), 1.62-1.73(m, 1H), 1.80-1.93(m ,1H),1.96-2.11(m,1H),2.12-2.20(m,1H),2.21-2.25(m,3H),2.37-2.43(m,2H),2.53-2.58(m,4H),2.65 -2.70(m, 1H), 2.72-2.77(m, 0.3H), 2.78-2.85(m, 4H), 3.18-3.23(m, 0.7H), 3.43-4.01(m, 1H), 5.03-5.54( m,1H),5.55-5.67(m,2H),6.95-7.02(m,1H),7.05-7.16(m,2H),7.44-7.53(m,1H),7.98-8.10(m,1H), 10.39-10.64 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值507.2；實測值507.4；Rt=0.838min。LCMS (ESI): [M+H] + m/z: calculated 507.2; found 507.4; Rt=0.838 min.

實例291. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[4-(4-乙Example 291. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-2-[4-(4-ethyl) 基哌嗪-1-基)-3-甲基苯基]-5-甲基-1-哌啶基]乙醯胺(化合物1376)之合成Synthesis of ylpiperazin-1-yl)-3-methylphenyl]-5-methyl-1-piperidinyl]acetamide (compound 1376)

Figure 110128222-A0202-12-1471-398
Figure 110128222-A0202-12-1471-398

步驟1：1-乙基-4-(2-甲基-4-硝基苯基)哌嗪之合成Step 1: Synthesis of 1-ethyl-4-(2-methyl-4-nitrophenyl)piperazine

在Ar下，將1-乙基哌嗪(2.5g，21.89mmol，2.78mL)、1-氟-2-甲基-4-硝基苯(4.75g，30.65mmol)、碳酸鉀(9.08g，65.68mmol，3.96mL)混合於DMF(25mL)中。將反應混合物在130℃下攪拌隔夜。在冷卻至室溫之後，將反應混合物用水稀釋，用EA萃取。將有機相在真空中蒸發，得到1-乙基-4-(2-甲基-4-硝基苯基)哌嗪(5g，粗品)。Under Ar, 1-ethylpiperazine (2.5 g, 21.89 mmol, 2.78 mL), 1-fluoro-2-methyl-4-nitrobenzene (4.75 g, 30.65 mmol), potassium carbonate (9.08 g, 65.68 mmol, 3.96 mL) in DMF (25 mL). The reaction mixture was stirred at 130°C overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EA. The organic phase was evaporated in vacuo to give 1-ethyl-4-(2-methyl-4-nitrophenyl)piperazine (5 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值250.2；實測值250.2；Rt=0.761min。LCMS (ESI): [M+H] + m/z: calculated 250.2; found 250.2; Rt=0.761 min.

步驟2：4-(4-乙基哌嗪-1-基)-3-甲基苯胺之合成Step 2: Synthesis of 4-(4-ethylpiperazin-1-yl)-3-methylaniline

在H2 氣氛下，將1-乙基-4-(2-甲基-4-硝基苯基)哌嗪(5g，20.06mmol)及Pd/C(2.13g，20.06mmol)於甲醇中之混合物在25℃下攪拌16h。過濾混合物且蒸發濾液。將殘餘物在己烷中結晶，以得到4-(4-乙基哌嗪-1-基)-3-甲基苯胺(2.9g，13.22mmol，65.93%產率)。1-Ethyl-4-(2-methyl-4-nitrophenyl)piperazine (5 g, 20.06 mmol) and Pd/C (2.13 g, 20.06 mmol) in methanol under H2 atmosphere The mixture was stirred at 25 °C for 16 h. The mixture was filtered and the filtrate was evaporated. The residue was crystallized in hexanes to give 4-(4-ethylpiperazin-1-yl)-3-methylaniline (2.9 g, 13.22 mmol, 65.93% yield).

LCMS(ESI)：[M+H]+ m/z：計算值220.2；實測值220.4；Rt=0.511min。LCMS (ESI): [M+H] + m/z: calculated 220.2; found 220.4; Rt=0.511 min.

步驟3：1-乙基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪之合成Step 3: 1-Ethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) Synthesis of Phenyl]piperazine

在圓底燒瓶中稱量4-(4-乙基哌嗪-1-基)-3-甲基苯胺(2.8g，12.77mmol)及雙(頻哪醇)二硼(3.89g，15.32mmol)。然後連續添加MeCN(28mL)及亞硝酸第三丁酯(1.97g，19.15mmol，2.28mL)。將所得反應溶液在80℃下攪拌12h(N2逸出在5至15min內完成)。然後將溶液在減壓下濃縮，且藉由急驟層析純化粗殘餘物，以獲得1-乙基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪(7g，粗品)。4-(4-Ethylpiperazin-1-yl)-3-methylaniline (2.8 g, 12.77 mmol) and bis(pinacol)diboron (3.89 g, 15.32 mmol) were weighed in a round bottom flask . MeCN (28 mL) and tert-butyl nitrite (1.97 g, 19.15 mmol, 2.28 mL) were then added successively. The resulting reaction solution was stirred at 80° C. for 12 h (N2 evolution was completed within 5 to 15 min). The solution was then concentrated under reduced pressure, and the crude residue was purified by flash chromatography to obtain 1-ethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)phenyl]piperazine (7 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值331.2；實測值331.2；Rt=1.005min。LCMS (ESI): [M+H] + m/z: calculated 331.2; found 331.2; Rt=1.005 min.

步驟4：外消旋-(3S)-6-[4-(4-乙基哌嗪-1-基)-3-甲基苯基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 4: Racemic-(3S)-6-[4-(4-Ethylpiperazin-1-yl)-3-methylphenyl]-3-methyl-3,4-dihydro-2H -Synthesis of tert-butyl pyridine-1-carboxylate

將1-乙基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪(6.8g，20.59mmol)、外消旋-(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.11g，20.59mmol)及碳酸鈉(4.36g，41.18mmol，1.72mL)一起混合於二噁烷(60mL)及水(20mL)之混合物中。將所得混合物用氬氣吹掃10min且向其中添加Pd(dppf)Cl2 DCM(840.69mg，1.03mmol)。將所得混合物在90℃下加熱隔夜。將所得混合物冷卻且用水(5mL)稀釋。將所得混合物用EtOAc(2*15mL)萃取且將經合併之有機層用鹽水(10mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。1-ethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl ] piperazine (6.8 g, 20.59 mmol), rac-(3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1 - tert-butyl formate (7.11 g, 20.59 mmol) and sodium carbonate (4.36 g, 41.18 mmol, 1.72 mL) were mixed together in a mixture of dioxane (60 mL) and water (20 mL). The resulting mixture was purged with argon for 10 min and to it was added Pd(dppf) Cl2DCM (840.69 mg, 1.03 mmol). The resulting mixture was heated at 90°C overnight. The resulting mixture was cooled and diluted with water (5 mL). The resulting mixture was extracted with EtOAc (2*15 mL) and the combined organic layers were washed with brine (10 mL), dried over Na2SO4 , filtered and concentrated in vacuo.

LCMS(ESI)：[M+H]+ m/z：計算值400.2；實測值400.2；Rt=1.270min。LCMS (ESI): [M+H] + m/z: calculated 400.2; found 400.2; Rt=1.270 min.

步驟5：1-乙基-4-[2-甲基-4-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪之合成Step 5: 1-Ethyl-4-[2-methyl-4-[rac-(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl ] Synthesis of piperazine

將三氟乙酸(23.97g，210.23mmol，16.20mL)一次性添加到外消旋-(3S)-6-[4-(4-乙基哌嗪-1-基)-3-甲基苯基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三 丁酯(7g，17.52mmol)於DCM(20mL)中之經攪拌之溶液中。將所得溶液在25℃下攪拌1h，然後在真空中濃縮。用水(100mL)稀釋殘餘物。將產物之TFA鹽之所得溶液自深棕色油狀殘餘物傾析，將其另外用水(2*25mL)沖洗。透過棉花墊過濾經合併之水溶液，以移除痕量油狀雜質，然後用10%氫氧化鈉水溶液鹼化至pH 11-12且用二氯甲烷(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色膠狀物之1-乙基-4-[2-甲基-4-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪(1.2g，4.01mmol，22.87%產率)，其直接用於下一步驟中。Trifluoroacetic acid (23.97 g, 210.23 mmol, 16.20 mL) was added in one portion to rac-(3S)-6-[4-(4-ethylpiperazin-1-yl)-3-methylphenyl ]-3-Methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid 3rd In a stirred solution of butyl ester (7 g, 17.52 mmol) in DCM (20 mL). The resulting solution was stirred at 25 °C for 1 h, then concentrated in vacuo. The residue was diluted with water (100 mL). The resulting solution of the TFA salt of the product was decanted from the dark brown oily residue, which was rinsed with additional water (2*25 mL). The combined aqueous solutions were filtered through a cotton pad to remove traces of oily impurities, then basified to pH 11-12 with 10% aqueous sodium hydroxide and extracted with dichloromethane (2*50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 1-ethyl-4-[2-methyl-4-[rac-(3S)- as a pale yellow gum 3-Methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl]piperazine (1.2 g, 4.01 mmol, 22.87% yield) was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值300.2；實測值300.4；Rt=0.682min。LCMS (ESI): [M+H] + m/z: calculated 300.2; found 300.4; Rt=0.682 min.

步驟6：1-乙基-4-[2-甲基-4-[外消旋-(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪之合成Step 6: Synthesis of 1-ethyl-4-[2-methyl-4-[rac-(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine

將1-乙基-4-[2-甲基-4-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪(1.2g，4.01mmol)溶解於甲醇(12mL)中且分批添加硼氫化鈉(303.19mg，8.01mmol，282.30μL)。將所得混合物攪拌隔夜。將水(20mL)添加到反應混合物中且將所得混合物在真空中濃縮。將殘餘物用水(30mL)稀釋且將所得混合物用DCM(2*50mL)萃取。將經合併之有機層經Na2SO4乾燥，過濾且在真空中濃縮，以獲得1-乙基-4-[2-甲基-4-[外消旋-(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪(0.5g，1.66mmol，41.39%產率)。1-ethyl-4-[2-methyl-4-[rac-(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl]piperidine The oxazine (1.2 g, 4.01 mmol) was dissolved in methanol (12 mL) and sodium borohydride (303.19 mg, 8.01 mmol, 282.30 μL) was added portionwise. The resulting mixture was stirred overnight. Water (20 mL) was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water (30 mL) and the resulting mixture was extracted with DCM (2*50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 1-ethyl-4-[2-methyl-4-[rac-(2R,5S)-5-methyl- 2-Piperidinyl]phenyl]piperazine (0.5 g, 1.66 mmol, 41.39% yield).

LCMS(ESI)：[M+H]+ m/z：計算值302.2；實測值302.2；Rt=0.643min。LCMS (ESI): [M+H] + m/z: calculated 302.2; found 302.2; Rt=0.643 min.

步驟7：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[4-(4-乙基哌嗪-1-基)-3-甲基苯基]-5-甲基-1-哌啶基]乙醯胺(化合物1376)之合成Step 7: N-(6-Amino-5-ethyl-3-pyridinyl)-2-oxy-2-[rac-(2R,5S)-2-[4-(4-ethyl) Synthesis of ylpiperazin-1-yl)-3-methylphenyl]-5-methyl-1-piperidinyl]acetamide (compound 1376)

將1-乙基-4-[2-甲基-4-[外消旋-(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪(150mg，497.56μmol)溶解於DMF(1.38mL)中且添加三乙胺(503.49mg，4.98mmol，693.51μL)，隨後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(104.09mg，497.56μmol)。然後，逐滴添加HATU(283.78mg，746.35μmol)且 將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC(2-10min 0-55%水/ACN+fa 30ml/min；裝載泵4ml/min ACN；管柱SunFire 19*100mm)純化，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-2-[4-(4-乙基哌嗪-1-基)-3-甲基苯基]-5-甲基-1-哌啶基]乙醯胺(7.9mg，16.04μmol，3.22%產率)。Dissolve 1-ethyl-4-[2-methyl-4-[rac-(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine (150 mg, 497.56 μmol) In DMF (1.38 mL) and triethylamine (503.49 mg, 4.98 mmol, 693.51 μL) was added followed by 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2- Pendant oxyacetic acid (104.09 mg, 497.56 μmol). Then, HATU (283.78 mg, 746.35 μmol) was added dropwise and The reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC (2-10min 0-55% water/ACN+fa 30ml/min; loading pump 4ml/min ACN; column SunFire 19*100mm) to obtain N- (6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-2-[4-(4-ethylpiperazine-1 -yl)-3-methylphenyl]-5-methyl-1-piperidinyl]acetamide (7.9 mg, 16.04 μmol, 3.22% yield).

1 H NMR(600MHz,dmso)δ 0.97-1.04(m,6H),1.07-1.14(m,3H),1.25-1.36(m,1H),1.63-1.75(m,1H),1.79-1.91(m,1H),1.93-2.07(m,1H),2.12-2.18(m,1H),2.21-2.27(m,3H),2.35-2.41(m,5H),2.73-3.06(m,8H),3.95-4.21(m,1H),5.01-5.55(m,1H),5.55-5.68(m,2H),6.95-7.16(m,3H),7.43-7.57(m,1H),7.98-8.09(m,1H),10.43-10.55(m,1H)。 1 H NMR(600MHz,dmso)δ 0.97-1.04(m,6H),1.07-1.14(m,3H),1.25-1.36(m,1H),1.63-1.75(m,1H),1.79-1.91(m ,1H),1.93-2.07(m,1H),2.12-2.18(m,1H),2.21-2.27(m,3H),2.35-2.41(m,5H),2.73-3.06(m,8H),3.95 -4.21(m, 1H), 5.01-5.55(m, 1H), 5.55-5.68(m, 2H), 6.95-7.16(m, 3H), 7.43-7.57(m, 1H), 7.98-8.09(m, 1H), 10.43-10.55 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值494.2；實測值494.4；Rt=0.881min。LCMS (ESI): [M+2H] + m/z: calculated 494.2; found 494.4; Rt=0.881 min.

實例292. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1390)之合成Example 292. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[3-methyl-4-(4-methyl) Synthesis of ylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1390)

Figure 110128222-A0202-12-1474-399
Figure 110128222-A0202-12-1474-399

步驟1：1-甲基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪之合成Step 1: 1-Methyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) Synthesis of Phenyl]piperazine

在圓底燒瓶中稱量3-甲基-4-(4-甲基哌嗪-1-基)苯胺(4.5g，21.92mmol)及雙(頻哪醇)二硼(6.12g，24.11mmol)。然後連續添加MeCN(120mL)及亞硝酸第三丁酯(3.39g，32.88mmol，3.91mL)。將所得反應溶液在80℃下攪拌 12h(N2逸出在5至15min內完成)。然後將溶液在減壓下濃縮，且藉由急驟層析純化粗殘餘物，以獲得1-甲基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪(1.5g，4.74mmol，21.64%產率)3-Methyl-4-(4-methylpiperazin-1-yl)aniline (4.5 g, 21.92 mmol) and bis(pinacol)diboron (6.12 g, 24.11 mmol) were weighed in a round bottom flask . MeCN (120 mL) and tert-butyl nitrite (3.39 g, 32.88 mmol, 3.91 mL) were then added successively. The resulting reaction solution was stirred at 80°C 12h (N2 escape completed within 5 to 15min). The solution was then concentrated under reduced pressure, and the crude residue was purified by flash chromatography to obtain 1-methyl-4-[2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)phenyl]piperazine (1.5 g, 4.74 mmol, 21.64% yield)

LCMS(ESI)：[M+H]+ m/z：計算值317.2；實測值317.2；Rt=0.893min。LCMS (ESI): [M+H] + m/z: calculated 317.2; found 317.2; Rt=0.893 min.

步驟2：(3S)-3-甲基-6-[3-甲基-4-(4-甲基哌嗪-1-基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: (3S)-3-Methyl-6-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-3,4-dihydro-2H-pyridine-1 -Synthesis of tert-butyl formate

將1-甲基-4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌嗪(1.35g，4.27mmol)、(3S)-3-甲基-6-(三氟甲基磺醯基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.41g，4.27mmol)及碳酸鈉(678.68mg，6.40mmol，268.04μL)一起混合於二噁烷(15mL)中且添加H2O(5mL)。將所得混合物抽真空且用氬氣回填三次。將Pd(dppf)Cl2 DCM(174.30mg，213.44μmol)添加到前一混合物中且將所得混合物在90℃下加熱12h。將反應混合物冷卻且用水(15mL)稀釋。將所得混合物過濾且用水(10mL)及EtOAc(20mL)沖洗。將濾液轉移至分液漏斗且分離有機層。將水層用EtOAc(2*20mL)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗品(3S)-3-甲基-6-[3-甲基-4-(4-甲基哌嗪-1-基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.75g，粗品)。1-methyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl ] Piperazine (1.35 g, 4.27 mmol), (3S)-3-methyl-6-(trifluoromethylsulfonyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.41 g, 4.27 mmol) and sodium carbonate (678.68 mg, 6.40 mmol, 268.04 μL) were mixed together in dioxane (15 mL) and H2O (5 mL) was added. The resulting mixture was evacuated and backfilled with argon three times. Pd(dppf)Cl2 DCM (174.30 mg, 213.44 μmol) was added to the previous mixture and the resulting mixture was heated at 90 °C for 12 h. The reaction mixture was cooled and diluted with water (15 mL). The resulting mixture was filtered and rinsed with water (10 mL) and EtOAc (20 mL). The filtrate was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with EtOAc (2*20 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated to give crude (3S)-3-methyl-6-[3-methyl-4-(4-methylpiperazine-1 -yl)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.75 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值386.2；實測值386.2；Rt=1.055min。LCMS (ESI): [M+H] + m/z: calculated 386.2; found 386.2; Rt=1.055 min.

步驟3：1-甲基-4-[2-甲基-4-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪之合成Step 3: 1-Methyl-4-[2-methyl-4-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl]piperazine synthesis

將(3S)-3-甲基-6-[3-甲基-4-(4-甲基哌嗪-1-基)苯基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.75g，1.95mmol)溶解於DCM(3mL)中且向其中添加TFA(3mL)。攪拌所得混合物1h。將反應混合物倒入到K2 CO3 水溶液中且將所得混合物用DCM萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得1-甲基-4-[2-甲基-4-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪(0.6g，粗品)，其不經進一步純化即用於下一步驟中。LCMS(ESI)：[M+H]+ m/z：計算值286.2；實測值286.2； Rt=0.787min。(3S)-3-methyl-6-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid The tertiary butyl ester (0.75 g, 1.95 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) was added to it. The resulting mixture was stirred for 1 h. The reaction mixture was poured into aqueous K2CO3 and the resulting mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to obtain 1-methyl-4-[2-methyl-4-[(3S)-3-methyl-2,3,4, 5-Tetrahydropyridin-6-yl]phenyl]piperazine (0.6 g, crude) was used in the next step without further purification. LCMS (ESI): [M+H] + m/z: calculated 286.2; found 286.2; Rt=0.787 min.

步驟4：1-甲基-4-[2-甲基-4-[(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪之合成Step 4: Synthesis of 1-methyl-4-[2-methyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine

將1-甲基-4-[2-甲基-4-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]苯基]哌嗪(0.6g，2.10mmol)溶解於甲醇(10mL)中且逐滴添加硼氫化鈉(159.05mg，4.20mmol，148.09μL)。將反應混合物在室溫下攪拌隔夜。將反應混合物蒸發至乾。將殘餘物溶解於DCM(10mL)中且將所得混合物用檸檬酸溶液(2*10mL)萃取。將經合併之水層用DCM(3*10mL)洗滌，然後用K2 CO3 鹼化。將所得混合物用DCM(2*15mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得1-甲基-4-[2-甲基-4-[(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪(0.2g，695.79μmol，33.10%產率)。1-Methyl-4-[2-methyl-4-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenyl]piperazine (0.6 g , 2.10 mmol) was dissolved in methanol (10 mL) and sodium borohydride (159.05 mg, 4.20 mmol, 148.09 μL) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (10 mL) and the resulting mixture was extracted with citric acid solution (2*10 mL). The combined aqueous layers were washed with DCM ( 3 * 10 mL), then basified with K2CO3. The resulting mixture was extracted with DCM (2*15 mL) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to obtain 1-methyl-4-[2-methyl-4-[(2R, 5S)-5-Methyl-2-piperidinyl]phenyl]piperazine (0.2 g, 695.79 μmol, 33.10% yield).

LCMS(ESI)：[M+H]+ m/z：計算值288.2；實測值288.2；Rt=0.713min。LCMS (ESI): [M+H] + m/z: calculated 288.2; found 288.2; Rt=0.713 min.

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1390)之合成Step 5: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[3-methyl-4-(4-methyl) Synthesis of ylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1390)

將1-甲基-4-[2-甲基-4-[(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪(270mg，939.32μmol)溶解於DMF(5mL)中且添加三乙胺(950.50mg，9.39mmol，1.31mL)，隨後添加2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(196.51mg，939.32μmol)。然後逐滴添加HATU(535.74mg，1.41mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC(2-10min0-30%乙腈+fa 30min(裝載泵4mL/min乙腈)，管柱：SunFire 100*19mm，5微米)純化，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(12.6mg，26.33μmol，2.80%產率)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(10mg，20.89μmol，2.22%產率)1-Methyl-4-[2-methyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine (270 mg, 939.32 μmol) was dissolved in DMF (5 mL) ) and triethylamine (950.50 mg, 9.39 mmol, 1.31 mL) was added, followed by 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid ( 196.51 mg, 939.32 μmol). HATU (535.74 mg, 1.41 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC (2-10 min 0-30% acetonitrile + fa 30 min (load pump 4 mL/min acetonitrile), column: SunFire 100*19 mm, 5 microns) to obtain N- (6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[3-methyl-4-(4-methylpiperazine-1 -yl)phenyl]-1-piperidinyl]-2-oxoacetamide (12.6 mg, 26.33 μmol, 2.80% yield) and N-(6-amino-5-ethyl-3- Pyridyl)-2-[(2R,5S)-5-methyl-2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl] -2-Oxyacetamide (10 mg, 20.89 μmol, 2.22% yield)

1 H NMR(600MHz,dmso)δ 1.00(t,3H),1.06-1.13(m,3H),1.26-1.36(m,1H),1.63 -1.73(m,1H),1.79-1.92(m,1H),1.93-2.09(m,1H),2.11-2.19(m,1H),2.20-2.25(m,7H),2.31-2.36(m,1H),2.38-2.42(m,2H),2.72-3.22(m,7H),3.40-4.00(m,1H),5.03-5.53(m,1H),5.58-5.68(m,2H),6.97-7.02(m,1H),7.03-7.07(m,1H),7.08-7.14(m,1H),7.42-7.53(m,1H),7.96-8.09(m,1H),10.41-10.55(m,1H)。 1 H NMR(600MHz,dmso)δ 1.00(t,3H),1.06-1.13(m,3H),1.26-1.36(m,1H),1.63-1.73(m,1H),1.79-1.92(m,1H) ),1.93-2.09(m,1H),2.11-2.19(m,1H),2.20-2.25(m,7H),2.31-2.36(m,1H),2.38-2.42(m,2H),2.72-3.22 (m,7H),3.40-4.00(m,1H),5.03-5.53(m,1H),5.58-5.68(m,2H),6.97-7.02(m,1H),7.03-7.07(m,1H) , 7.08-7.14 (m, 1H), 7.42-7.53 (m, 1H), 7.96-8.09 (m, 1H), 10.41-10.55 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值480.2；實測值480.2；Rt=0.741min。LCMS (ESI): [M+2H] + m/z: calculated 480.2; found 480.2; Rt=0.741 min.

方案C. 式3化合物之合成Scheme C. Synthesis of compounds of formula 3

式3、3a、3b、3c及3d化合物為式(I)、(Ia)、(Ib)、(Ic)及(Id)化合物，其中R1 為NH2 且R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 3, 3a, 3b, 3c and 3d are compounds of formula (I), (Ia), (Ib), (Ic) and (Id) wherein R 1 is NH 2 and R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as described herein.

一般程序3General Procedure 3

Figure 110128222-A0202-12-1477-400
Figure 110128222-A0202-12-1477-400

注意，分離步驟為視情況任選的，且在某些情況下用於分離順式/反式非鏡像異構物，且在某些情況下分離不同的鏡像異構物，如詳細程序中所述。在某些情況下，起始哌啶呈限定順式或反式組態，在彼等情況下，掌性分離步驟僅得到所描繪之四種鏡像異構物中之兩者。Note that the separation step is optional, and in some cases is used to separate cis/trans non-enantiomers, and in some cases different enantiomers, as described in the detailed procedure described. In some cases, the starting piperidine is in a defined cis or trans configuration, in which case the chiral separation step yields only two of the four enantiomers depicted.

如方案C中所示，式(3a)、(3b)、(3c)及(3d)化合物可自式(3-1)化合物之混合物分離，其中R1 、R2 、R3 、R4 、R6 、R7、 R8 及n如本文所述。掌性分離方法為熟習此項技術者已知的。例如，在一些實施例中，可透過使用掌性HPLC純化 (管柱：AD-H III(250*20mm，5μm)完成掌性分離。示範性溶析液包括但不限於己烷、IPA、MeOH、MeCN及H2 O及其混合物。As shown in Scheme C, compounds of formula (3a), (3b), (3c) and (3d) can be isolated from a mixture of compounds of formula ( 3-1 ), wherein R1, R2, R3 , R4 , R 6 , R 7 , R 8 and n are as described herein. Methods of chiral separation are known to those skilled in the art. For example, in some embodiments, chiral separation can be accomplished by using chiral HPLC purification (column: AD-H III (250*20 mm, 5 μm). Exemplary eluents include, but are not limited to, hexane, IPA, MeOH , MeCN and H 2 O and mixtures thereof.

替代地，式(3a)、(3b)、(3c)及(3d)可由中間物(3a-1)、(3b-1)、(3c-1)及(3d-1)製備。在一些實施例中，可在掌性分離之前或之後進行去保護。用於移除保護基-PG(例如， -Boc)之條件可採用例如酸性條件(例如， 水/二噁烷、於質子性溶劑(例如，甲醇 )中之鹽酸、於非質子性溶劑(例如， 二噁烷)中之鹽酸、於非質子性溶劑(例如，二氯甲烷 、氯仿等)中之TFA)。在一些實施例中，去保護步驟採用於二噁烷中之HCl(4.0M)。在一些實施例中，去保護步驟採用於DCM中之HCl(4.0M)。Alternatively, formulae (3a), (3b), (3c) and (3d) can be prepared from intermediates (3a-1), (3b-1), (3c-1) and (3d-1). In some embodiments, deprotection can be performed before or after chiral separation. Conditions for removing the protecting group -PG ( eg, -Boc) can employ, for example, acidic conditions ( eg, water/dioxane, hydrochloric acid in a protic solvent ( eg, methanol ), in an aprotic solvent ( eg , , hydrochloric acid in dioxane), TFA) in an aprotic solvent ( eg, dichloromethane , chloroform, etc.). In some embodiments, the deprotection step employs HCl (4.0 M) in dioxane. In some embodiments, the deprotection step employs HCl (4.0 M) in DCM.

在一些實施例中，本揭露之化合物可透過包含醯胺鍵偶合之方法來製備。在一些實施例中，醯胺鍵偶合採用哌啶及羧酸。已知促進醯胺鍵偶合之條件之實例包括但不限於：添加偶合劑(諸如CDI、HATU、HOBT、HBTU或PyBOP)、鹼(諸如氫化物鹼(例如 NaH或KH)、胺鹼(諸如DBU、NEt3 及NEt( i Pr)2 )或碳酸鹽鹼(例如， Na2 CO3 、K2 CO3 或Cs2 CO3 ))；以及在一個實施例中在0℃至室溫下或在另一個實施例中在70℃或更高溫度下(例如在70℃至110℃範圍內或在70℃至80℃範圍內的溫度下、或在80℃下)攪拌反應物。可在諸如但不限於DMF及MTBE之溶劑中進行反應。在一些實施例中，反應包含HATU、Et3 N及DMF。在一些實施例中，反應包含採用HATU、Et3 N及MeCN。在一些實施例中，反應包含TATU、Et3 N及DMF。在一些實施例中，反應包含HATU、DIPEA及DMSO。在一些實施例中，反應包含HATU、DIPEA及DMF。在一些實施例中，反應包含HATU、TEA及DMSO。In some embodiments, the compounds of the present disclosure can be prepared by methods involving coupling of amide linkages. In some embodiments, the amide linkage coupling employs a piperidine and a carboxylic acid. Examples of conditions known to promote the coupling of amide linkages include, but are not limited to, the addition of a coupling agent such as CDI, HATU, HOBT, HBTU or PyBOP, a base such as a hydride base such as NaH or KH, an amine base such as DBU , NEt 3 and NEt( iPr ) 2 ) or a carbonate base ( eg, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 )); and in one embodiment at 0°C to room temperature or at In another embodiment the reactants are stirred at a temperature of 70°C or higher (eg, at a temperature in the range of 70°C to 110°C or at a temperature in the range of 70°C to 80°C, or at 80°C). The reaction can be carried out in solvents such as, but not limited to, DMF and MTBE. In some embodiments, the reaction comprises HATU, Et3N , and DMF. In some embodiments, the reaction comprises employing HATU, Et3N , and MeCN. In some embodiments, the reaction comprises TATU, Et3N , and DMF. In some embodiments, the reaction comprises HATU, DIPEA, and DMSO. In some embodiments, the reaction comprises HATU, DIPEA, and DMF. In some embodiments, the reaction comprises HATU, TEA and DMSO.

實例293.外消旋 -N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(1-甲基-1H -吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物235)之合成Example 293. Racemic - N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(1-methyl- 1H- Synthesis of Pyrazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 235)

Figure 110128222-A0202-12-1479-401
Figure 110128222-A0202-12-1479-401

將三乙胺(1.41g，13.95mmol，1.94mL)添加到來自中間物合成2A之5-甲基-2-(2-甲基吡唑-3-基)哌啶(250mg，1.39mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(411.82mg，1.39mmol)及HATU(583.30mg，1.53mmol)於DMF(5mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌2h，然後在真空中蒸發。將殘餘物溶解於DCM(4mL)中且添加於二噁烷中之4.0M氯化氫溶液(4.20g，16.01mmol，5.25mL，13.9%純度)。將所得懸浮液在25℃下攪拌18h，然後在真空中蒸發且藉由反相HPLC(管柱：XBridge C18 100x20mm，5um)使用20-40% 0-5min 0.1% NH3 -甲醇純化殘餘物，以得到呈白色固體之化合物235 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯胺(201mg，563.94μmol，40.44%產率)。Triethylamine (1.41 g, 13.95 mmol, 1.94 mL) was added to 5-methyl-2-(2-methylpyrazol-3-yl)piperidine (250 mg, 1.39 mmol) from Intermediate Synthesis 2A, 2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (411.82 mg, 1.39 mmol) and HATU (583.30 mg, 1.53 mmol) in a stirred mixture of DMF (5 mL). The resulting mixture was stirred at 25 °C for 2 h, then evaporated in vacuo. The residue was dissolved in DCM (4 mL) and a 4.0 M solution of hydrogen chloride in dioxane (4.20 g, 16.01 mmol, 5.25 mL, 13.9% pure) was added. The resulting suspension was stirred at 25°C for 18h, then evaporated in vacuo and the residue purified by reverse phase HPLC (column: XBridge C18 100x20mm, 5um) using 20-40% 0-5min 0.1% NH3 -methanol, to give compound 235 as a white solid N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(2-methylpyrazole -3-yl)-1-piperidinyl]-2-oxoacetamide (201 mg, 563.94 μmol, 40.44% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.96-1.05(m,3H),1.35-1.46(m,1H),1.82-1.91(m,1H),1.93-2.00(m,1H),2.01-2.14(m,5H),3.16-3.29(m,1H),3.43-3.54(m,1H),3.70-3.80(m,3H),5.40-5.66(m,2H),5.66-5.79(m,1H),6.38-6.54(m,1H),7.30-7.40(m,1H),7.47(s,1H),7.91-8.23(m,1H),10.34-10.54(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.96-1.05(m,3H), 1.35-1.46(m,1H), 1.82-1.91(m,1H), 1.93-2.00(m,1H) ,2.01-2.14(m,5H),3.16-3.29(m,1H),3.43-3.54(m,1H),3.70-3.80(m,3H),5.40-5.66(m,2H),5.66-5.79( m, 1H), 6.38-6.54 (m, 1H), 7.30-7.40 (m, 1H), 7.47 (s, 1H), 7.91-8.23 (m, 1H), 10.34-10.54 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值356.4；實測值357.2；Rt=1.889min。LCMS (ESI): [M+1] m/z: calculated 356.4; found 357.2; Rt=1.889 min.

實例294.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺(化合物122、化合物115)之合成Example 294. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 122, Compound 115)

Figure 110128222-A0202-12-1480-402
Figure 110128222-A0202-12-1480-402

步驟1：(3-甲基-5-(2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-(5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)pyridine-2 -Synthesis of tertiary butyl carbamate

將DIPEA(461.13mg，3.57mmol，621.47μL)添加到2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(421.43mg，1.43mmol)及5-甲基-2-(2-噻吩基)哌啶(258.74mg，1.43mmol)於DMF(10mL)中之溶液。將所得混合物攪拌5min，隨後添加HATU(569.78mg，1.50mmol)於DMF中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在減壓下濃縮所得懸浮液且使其經歷HPLC(管柱SunFire 100*20mm 5um，以MeCN+NH3 為溶析液混合物)，以得到純的N -[3-甲基-5-[[2-[5-甲基-2-(2-噻吩基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.27g，588.78μmol，41.26%產率)。DIPEA (461.13 mg, 3.57 mmol, 621.47 μL) was added to 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxyl A solution of acetic acid (421.43 mg, 1.43 mmol) and 5-methyl-2-(2-thienyl)piperidine (258.74 mg, 1.43 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (569.78 mg, 1.50 mmol) in DMF was added. Then, the reaction mixture was stirred at room temperature overnight. The resulting suspension was concentrated under reduced pressure and subjected to HPLC (column SunFire 100*20mm 5um with MeCN+ NH3 as eluent mixture) to give pure N- [3-methyl-5-[[ 2-[5-Methyl-2-(2-thienyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.27 g, 588.78 μmol, 41.26% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.08(d,3H),1.48(s,9H),2.04(m,3H),2.28(s,3H),2.62(m,1H),3.48(m,2H),4.72(m,2H),6.65(m,1H),6.96(m,2H),7.22(m,1H),8.02(m,1H),8.32(m,1H),9.31(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.08(d, 3H), 1.48(s, 9H), 2.04(m, 3H), 2.28(s, 3H), 2.62(m, 1H), 3.48( m, 2H), 4.72(m, 2H), 6.65(m, 1H), 6.96(m, 2H), 7.22(m, 1H), 8.02(m, 1H), 8.32(m, 1H), 9.31(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值458.4；實測值459.2；Rt=3.715min。LCMS (ESI): [M] + m/z: calculated 458.4; found 459.2; Rt=3.715 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(thiophen-2-yl)piperidin-1-yl)-2-side Synthesis of Oxyacetamide

將N -[3-甲基-5-[[2-[5-甲基-2-(2-噻吩基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(279.14mg，608.71μmol)溶解於二噁烷(2mL)及水(5mL)中。然後，將所得混合物在100℃下攪拌隔夜。此後，將溶液在真空 中蒸發，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-噻吩基)-1-哌啶基]-2-側氧基乙醯胺(87mg，242.71μmol，39.87%產率)。 N- [3-methyl-5-[[2-[5-methyl-2-(2-thienyl)-1-piperidinyl]-2-oxyacetoxy]amino]- 3- Butyl 2-pyridyl]carbamate (279.14 mg, 608.71 [mu]mol) was dissolved in dioxane (2 mL) and water (5 mL). Then, the resulting mixture was stirred at 100°C overnight. After this time, the solution was evaporated in vacuo to give N- (6-amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-(2-thienyl)-1-piperidine Peridyl]-2-Pendant oxyacetamide (87 mg, 242.71 μmol, 39.87% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.11(d,3H),1.46(m,1H),2.18(m,3H),2.32(m,2H),3.48(s,3H),3.88(m,1H),4.51(m,2H),5.55(m,1H),6.99(m,2H),7.22(m,1H),7.72(m,1H),8.09(m,1H),9.07(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.11(d,3H), 1.46(m,1H), 2.18(m,3H), 2.32(m,2H), 3.48(s,3H), 3.88( m, 1H), 4.51(m, 2H), 5.55(m, 1H), 6.99(m, 2H), 7.22(m, 1H), 7.72(m, 1H), 8.09(m, 1H), 9.07(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值358.4；實測值359.2；Rt=2.688min。LCMS (ESI): [M] + m/z: calculated 358.4; found 359.2; Rt=2.688 min.

步驟3：掌性分離(化合物122 及化合物115 )Step 3: Chiral separation ( Compound 122 and Compound 115 )

在體系Hex-IPA-MeOH，75-15-15，12mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：900mkl。自87mg外消旋物獲得17.8mg及22.7mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 75-15-15, 12 mL/min. Injection times: 1, injection volume: 900mkl. From 87 mg of racemate, 17.8 mg and 22.7 mg of individual enantiomers were obtained.

rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2S,5R)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺化合物122：rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2S,5R)-5-methyl-2-(thiophen-2-yl)piperidin-1-yl )-2-oxyacetamide compound 122:

保留時間：23.37minRetention time: 23.37min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(m,3H),1.40(m,1H),1.83(m,2H),1.95(m,1H),2.01(m,3H),2.09(m,1H),2.86(m,1H),3.82(m,1H),5.67(m,3H),7.01(m,2H),7.48(m,2H),8.00(s,1H),10.48(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98(m, 3H), 1.40(m, 1H), 1.83(m, 2H), 1.95(m, 1H), 2.01(m, 3H), 2.09(m, 1H), 2.86(m, 1H), 3.82(m, 1H), 5.67(m, 3H), 7.01(m, 2H), 7.48(m, 2H), 8.00(s, 1H), 10.48 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值358.4；實測值359.2；Rt=2.275min。LCMS (ESI): [M] + m/z: calculated 358.4; found 359.2; Rt=2.275 min.

rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺化合物115：rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(thiophen-2-yl)piperidin-1-yl )-2-oxyacetamide compound 115:

保留時間：18.58minRetention time: 18.58min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(m,3H),1.40(t,1H),1.91(m,3H),2.01(m,3H),2.11(m,1H),2.85(m,1H),3.72(m,1H),5.51(m,1H),5.71(m,2H),7.01(m,2H),7.48(m,2H),8.00(m,1H),10.48(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98(m, 3H), 1.40(t, 1H), 1.91(m, 3H), 2.01(m, 3H), 2.11(m, 1H), 2.85(m, 1H), 3.72(m, 1H), 5.51(m, 1H), 5.71(m, 2H), 7.01(m, 2H), 7.48(m, 2H), 8.00(m, 1H), 10.48 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值358.4；實測值359.2；Rt=2.278min。LCMS (ESI): [M] + m/z: calculated 358.4; found 359.2; Rt=2.278 min.

實例295. 2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物95、化合物94、化合物96)之合成Example 295. 2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1 - yl)-N-(6-amino-5-methylpyridine-3 Synthesis of -yl)-2-oxoacetamide (Compound 95, Compound 94, Compound 96)

Figure 110128222-A0202-12-1482-403
Figure 110128222-A0202-12-1482-403

步驟1：(5-(2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1-yl)-2-oxyacetamido)- Synthesis of 3-methylpyridin-2-yl)carbamic acid tert-butyl ester

向1-[4-[3-(2-哌啶基)苯基]-1-哌啶基]乙酮(161.65mg，564.42μmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.2g，677.30μmol)及HATU(257.53mg，677.30μmol)於DMF(3mL)中之懸浮液中添加三乙胺(171.34mg，1.69mmol，236.01μL)。將所得混合物在25℃下攪拌3h。將所得混合物蒸發至乾，以獲得N -[5-[[2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.7g，粗品)。其不經純化即用於下一步驟中。To 1-[4-[3-(2-piperidinyl)phenyl]-1-piperidinyl]ethanone (161.65 mg, 564.42 μmol), 2-[[6-( tertiary butoxycarbonylamine (0.2 g, 677.30 μmol) and HATU (257.53 mg, 677.30 μmol) in DMF (3 mL) were added Triethylamine (171.34 mg, 1.69 mmol, 236.01 μL). The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was evaporated to dryness to obtain N- [5-[[2-[2-[3-(1-acetyl-4-piperidinyl)phenyl]-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.7 g, crude). It was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值563.6；實測值564.2；Rt=1.371min。LCMS (ESI): [M] + m/z: calculated 563.6; found 564.2; Rt=1.371 min.

步驟2：2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物95 )之合成Step 2: 2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1-yl)-N-(6-amino-5-methylpyridine-3 Synthesis of -yl)-2-side oxyacetamide ( compound 95 )

將N -[5-[[2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.3g，532.21μmol)溶解於於二噁烷中之4.0M氯化氫溶液(3.20g，87.77mmol，4mL)中且在25℃下攪拌12h。將溶 劑蒸發且在真空中乾燥殘餘物，以獲得粗產物(0.7g)。此化合物藉由HPLC(LC 09 40-40-60% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量463，管柱：YMC Triart C18 100x20mm，5um)、第二HPLC(LC 11 50-50-60% 0-1-5min水-乙腈，流速：30ml/min(裝載泵4ml/min乙腈)，目標質量463管柱：SunFire C18 100x19mm，5um)純化，以獲得2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(61mg，131.59μmol，24.72%產率)。 N- [5-[[2-[2-[3-(1-Acetyl-4-piperidinyl)phenyl]-1-piperidinyl]-2-oxyacetyl]amine tert-butyl]-3-methyl-2-pyridyl] carbamate (0.3 g, 532.21 μmol) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (3.20 g, 87.77 mmol, 4 mL) and in Stir at 25°C for 12h. The solvent was evaporated and the residue was dried in vacuo to obtain crude product (0.7 g). This compound was analyzed by HPLC (LC 09 40-40-60% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 463, column: YMC Triart C18 100x20mm, 5um), second HPLC (LC 11 50-50-60% 0-1-5min water-acetonitrile, flow rate: 30ml/min (loading pump 4ml/min acetonitrile), target mass 463 column: SunFire C18 100x19mm, 5um) to obtain 2-[2-[3-(1-acetyl-4-piperidinyl)phenyl]-1 - piperidinyl]-N-(6-amino-5-methyl) -3-Pyridinyl)-2-oxoacetamide (61 mg, 131.59 μmol, 24.72% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.67(m,6H),1.84(m,2H),1.97(m,1H),2.11(m,6H),2.52(m,2H),2.93(m,3H),4.14(m,3H),4.84(m,2H),6.15(m,1H),7.08(m,3H),7.31(m,1H),7.74(m,1H),8.06(m,1H),9.08(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.67(m, 6H), 1.84(m, 2H), 1.97(m, 1H), 2.11(m, 6H), 2.52(m, 2H), 2.93( m, 3H), 4.14(m, 3H), 4.84(m, 2H), 6.15(m, 1H), 7.08(m, 3H), 7.31(m, 1H), 7.74(m, 1H), 8.06(m , 1H), 9.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值463.6；實測值464.2；Rt=2.592min。LCMS (ESI): [M] + m/z: calculated 463.6; found 464.2; Rt=2.592 min.

步驟3：掌性分離(化合物94 及化合物96 )Step 3: Chiral separation ( compound 94 and compound 96 )

在體系Hex-IPA-MeOH，60-20-20，0.6mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：1mkl。自53mg外消旋物獲得16mg及18mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 60-20-20, 0.6 mL/min. Injection times: 1, injection volume: 1mkl. 16 mg and 18 mg of individual enantiomers were obtained from 53 mg of racemate.

rel-(R)-2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺峰1(化合物94)：rel-(R)-2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1-yl)-N-(6-amino-5-methyl) Pyridin-3-yl)-2-oxyacetamide Peak 1 (Compound 94):

保留時間：18.09minRetention time: 18.09min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.42(m,2H),1.59(m,4H),1.79(m,3H),2.01(m,6H),2.62(m,2H),3.03(m,2H),3.65(m,2H),4.30(m,2H),5.61(m,3H),7.16(m,3H),7.31(m,1H),7.48(m,1H),8.00(m,1H),10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.42(m, 2H), 1.59(m, 4H), 1.79(m, 3H), 2.01(m, 6H), 2.62(m, 2H), 3.03(m, 2H), 3.65(m, 2H), 4.30(m, 2H), 5.61(m, 3H), 7.16(m, 3H), 7.31(m, 1H), 7.48(m, 1H), 8.00 (m, 1H), 10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值463.6；實測值464.2；Rt=3.543min。LCMS (ESI): [M] + m/z: calculated 463.6; found 464.2; Rt=3.543 min.

rel-(R)-2-(2-(3-(1-乙醯基哌啶-4-基)苯基)哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺峰2(化合物96)：rel-(R)-2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)piperidin-1-yl)-N-(6-amino-5-methyl) Pyridin-3-yl)-2-oxyacetamide Peak 2 (Compound 96):

保留時間：23.84minRetention time: 23.84min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.42(m,2H),1.59(m,4H),1.79(m,3H),2.01(m,6H),2.66(m,2H),3.03(m,2H),3.73(m,2H),4.31(m,2H),5.60(m,3H),7.13(m,2H),7.17(m,1H),7.31(m,1H),7.52(m,1H),8.04(m,1H),10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.42(m, 2H), 1.59(m, 4H), 1.79(m, 3H), 2.01(m, 6H), 2.66(m, 2H), 3.03(m, 2H), 3.73(m, 2H), 4.31(m, 2H), 5.60(m, 3H), 7.13(m, 2H), 7.17(m, 1H), 7.31(m, 1H), 7.52 (m, 1H), 8.04 (m, 1H), 10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值463.6；實測值464.2；Rt=3.544min。LCMS (ESI): [M] + m/z: calculated 463.6; found 464.2; Rt=3.544 min.

實例296. 2-(2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物324、化合物331)之合成Example 296. 2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)-5-methylpiperidin - 1-yl)-N-(6-amino-5- Synthesis of methylpyridin-3-yl)-2-oxoacetamide (compound 324, compound 331)

Figure 110128222-A0202-12-1484-404
Figure 110128222-A0202-12-1484-404

步驟1：(5-(2-(2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-2-pendoxoethyl Synthesis of Amino)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

向1-[4-[3-(5-甲基-2-哌啶基)苯基]-1-哌啶基]乙酮(0.4g，1.33mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(393.15mg，1.33mmol)及HATU(556.86mg，1.46mmol)於DMF(5mL)中之懸浮液中添加三乙胺(673.62mg，6.66mmol，927.85μL)。將所得混合物在25℃下攪拌24h，溶解於水(50ml)中且用EtOAc(3*20ml)萃取。將經合併之有機層用鹽水(3*20ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得N -[5-[[2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.7g，粗品)。此化合物不經純化即用於下一步驟。To 1-[4-[3-(5-methyl-2-piperidinyl)phenyl]-1-piperidinyl]ethanone (0.4 g, 1.33 mmol), 2-[[6-( 3rd Butoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (393.15 mg, 1.33 mmol) and HATU (556.86 mg, 1.46 mmol) in DMF (5 mL) To this suspension was added triethylamine (673.62 mg, 6.66 mmol, 927.85 μL). The resulting mixture was stirred at 25°C for 24h, dissolved in water (50ml) and extracted with EtOAc (3*20ml). The combined organic layers were washed with brine (3*20ml), dried over Na2SO4 and evaporated to obtain N- [5-[[2-[2-[3-(1-acetyl-4- Piperidinyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester ( 0.7g, crude). This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.40(s,9H),1.73(m,3H),1.98 (m,5H),2.16(m,3H),2.65(m,5H),3.07(m,1H),3.86(m,1H),4.50(m,1H),5.35(m,1H),7.14(m,3H),7.23(m,2H),7.91(m,3H),8.39(m,1H),9.04(m,1H),11.03(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.99(m,3H), 1.40(s,9H), 1.73(m,3H), 1.98(m,5H), 2.16(m,3H), 2.65(m, 5H), 3.07(m, 1H), 3.86(m, 1H), 4.50(m, 1H), 5.35(m, 1H), 7.14(m, 3H), 7.23(m, 2H), 7.91 (m, 3H), 8.39 (m, 1H), 9.04 (m, 1H), 11.03 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值577.6；實測值578.2；Rt=1.396min。LCMS (ESI): [M] + m/z: calculated 577.6; found 578.2; Rt=1.396 min.

步驟2：2-(2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺之合成Step 2: 2-(2-(3-(1-Acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6-amino-5- Synthesis of methylpyridin-3-yl)-2-oxoacetamide

向N -[5-[[2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.7g，1.21mmol)於DCM(10mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌12h且在真空中蒸發且使其經歷HPLC：50-55% 0-5min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量478，管柱：YMC Triart C18 100x20mm,5um)，以得到2-[2-[3-(1-乙醯基-4-哌啶基)苯基]-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(200mg，418.76μmol，34.56%產率)。To N- [5-[[2-[2-[3-(1-acetoxy-4-piperidinyl)phenyl]-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.7 g, 1.21 mmol) in DCM (10 mL) was added 4.0 M hydrogen chloride in dioxane solution (8.00 g, 219.41 mmol, 10 mL). The resulting mixture was stirred at 25°C for 12 h and evaporated in vacuo and subjected to HPLC: 50-55% 0-5 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 478, column: YMC Triart C18 100x20mm, 5um) to give 2-[2-[3-(1-acetyl-4-piperidinyl)phenyl]-5-methyl-1-piperidinyl ]-N-(6-amino - 5-methyl-3-pyridyl)-2-oxyacetamide (200 mg, 418.76 μmol, 34.56% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.32(m,3H),1.78(m,7H),2.02(m,4H),2.12(m,1H),2.55(m,1H),2.74(m,1H),3.16(m,2H),3.43(m,1H),3.89(m,1H),4.51(m,1H),5.63(m,3H),7.16(m,3H),7.32(m,1H),7.51(m,1H),8.02(m,1H),10.54(m,1H)。 1 H NMR (500MHz, DMSO- d 6 ) δ(ppm) 1.02(m, 3H), 1.32(m, 3H), 1.78(m, 7H), 2.02(m, 4H), 2.12(m, 1H), 2.55(m, 1H), 2.74(m, 1H), 3.16(m, 2H), 3.43(m, 1H), 3.89(m, 1H), 4.51(m, 1H), 5.63(m, 3H), 7.16 (m, 3H), 7.32 (m, 1H), 7.51 (m, 1H), 8.02 (m, 1H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值477.6；實測值478.2；Rt=2.475min。LCMS (ESI): [M] + m/z: calculated 477.6; found 478.2; Rt=2.475 min.

步驟3：掌性分離(化合物324 及化合物331 )Step 3: Chiral separation ( compound 324 and compound 331 )

在體系Hex-IPA-MeOH，50-25-25，10mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：500mkl。自200mg外消旋物獲得63mg及60mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 50-25-25, 10 mL/min. Injection times: 1, injection volume: 500mkl. 63 mg and 60 mg of individual enantiomers were obtained from 200 mg of racemate.

rel-2-((2R,5S)-2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲rel-2-((2R,5S)-2-(3-(1-acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6- Amino-5-methyl 基吡啶-3-基)-2-側氧基乙醯胺峰2(化合物324)：pyridin-3-yl)-2-oxyacetamide peak 2 (compound 324):

保留時間：36.18minRetention time: 36.18min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00(m,3H),1.31(m,1H),1.42(m,1H),1.58(m,2H),1.74(m,2H),1.86(m,1H),2.00(m,6H),2.05(m,1H),2.19(m,1H),2.54(m,1H),2.81(m,2H),3.17(m,1H),3.83(m,2H),4.50(m,1H),5.33(m,1H),5.60(m,2H),7.13(m,3H),7.30(m,1H),7.46(m,1H),7.98(m,1H),10.50(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00(m, 3H), 1.31(m, 1H), 1.42(m, 1H), 1.58(m, 2H), 1.74(m, 2H), 1.86(m,1H),2.00(m,6H),2.05(m,1H),2.19(m,1H),2.54(m,1H),2.81(m,2H),3.17(m,1H),3.83 (m,2H),4.50(m,1H),5.33(m,1H),5.60(m,2H),7.13(m,3H),7.30(m,1H),7.46(m,1H),7.98( m, 1H), 10.50 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值477.6；實測值478.2；Rt=2.441min。LCMS (ESI): [M] + m/z: calculated 477.6; found 478.2; Rt=2.441 min.

rel-2-((2R,5S)-2-(3-(1-乙醯基哌啶-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺峰1(化合物331)：rel-2-((2R,5S)-2-(3-(1-acetylpiperidin-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6- Amino-5-methylpyridin-3-yl)-2-oxyacetamide Peak 1 (Compound 331):

保留時間：22.94minRetention time: 22.94min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00(m,3H),1.31(m,1H),1.42(m,1H),1.58(m,2H),1.75(m,2H),1.85(m,1H),2.00(m,6H),2.07(m,1H),2.20(m,1H),2.54(m,1H),2.85(m,2H),3.17(m,1H),3.83(m,2H),4.50(m,1H),5.33(m,1H),5.60(m,2H),7.12(m,2H),7.17(m,1H),7.30(m,1H),7.46(m,1H),7.98(m,1H),10.50(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00(m, 3H), 1.31(m, 1H), 1.42(m, 1H), 1.58(m, 2H), 1.75(m, 2H), 1.85(m, 1H), 2.00(m, 6H), 2.07(m, 1H), 2.20(m, 1H), 2.54(m, 1H), 2.85(m, 2H), 3.17(m, 1H), 3.83 (m,2H),4.50(m,1H),5.33(m,1H),5.60(m,2H),7.12(m,2H),7.17(m,1H),7.30(m,1H),7.46( m, 1H), 7.98 (m, 1H), 10.50 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值477.6；實測值478.2；Rt=2.445min。LCMS (ESI): [M] + m/z: calculated 477.6; found 478.2; Rt=2.445 min.

實例297. N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(化合物53)、N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-苯基-1-哌啶基]乙醯胺(化合物55)及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-苯基-1-哌啶基]乙醯胺(化合物51)之合成Example 297. N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-(2-phenyl-1-piperidinyl)acetamide (Compound 53), N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-phenyl-1-piperidinyl]acetamide (Compound 55) and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2S)-2-phenyl-1-piperidinyl]acetamide (Compound 51 ) synthesis

Figure 110128222-A0202-12-1487-405
Figure 110128222-A0202-12-1487-405

步驟1：N-[3-甲基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]-2-吡啶基]胺甲酸酯之合成Step 1: N-[3-Methyl-5-[[2-Oxy-2-(2-phenyl-1-piperidinyl)acetoxy]amino]-2-pyridyl]aminomethane Synthesis of acid esters

在-78℃、Ar下，向2-苯基哌啶(345.82mg，1.75mmol，HCl)於THF(15mL)中之溶液中逐滴添加丁基鋰(481.83mg，7.52mmol，3mL)。將反應混合物在-78℃下攪拌20min，然後分批添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.66g，1.75mmol)。將所得溶液在-78℃下攪拌30min且在室溫下攪拌1h。將所得溶液冷卻至-50℃且用飽和NH4 Cl(水溶液)(40ml)淬滅。分離有機層且將水層用EtOAc(20mL×2)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且濃縮至乾，以得到N-[3-甲基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.67g，粗品)。To a solution of 2-phenylpiperidine (345.82 mg, 1.75 mmol, HCl) in THF (15 mL) at -78 °C under Ar was added butyllithium (481.83 mg, 7.52 mmol, 3 mL) dropwise. The reaction mixture was stirred at -78 °C for 20 min, then 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen was added portionwise 2,2,2-trifluoroethyl acetate (0.66 g, 1.75 mmol). The resulting solution was stirred at -78 °C for 30 min and at room temperature for 1 h. The resulting solution was cooled to -50°C and quenched with saturated NH4Cl (aq) (40ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to give N-[3-methyl-5-[[2-oxy-2-(2-phenyl-1 -Piperidinyl)acetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.67 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值438.2；實測值439.2；Rt=1.352min。LCMS (ESI): [M+H] + m/z: calculated 438.2; found 439.2; Rt=1.352 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(化合物53 )之合成Step 2: N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-(2-phenyl-1-piperidinyl)acetamide ( compound 53 ) synthesis

將於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)添加到N-[3-甲基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.67g，1.53mmol)於DCM(10mL)中之溶液中。將反應混合物在25℃下攪拌8h，然後在真空中蒸發且藉由製備型(45-70% 0-9.5min水-甲醇，流速30ml/min)純化0.5g所獲得之粗產物，以得到產物N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(16.30mg，43.48μmol，2.85%產率，HCl)。1 H NMR(400MHz,CDCl3 )δ 1.58(m,3H),1.99(m,3H),2.11(m,3H),2.47(m,1H),2.98(m,1H),4.64(m,3H),6.19(m,1H),7.26(m,3H),7.35(m,2H),7.74(m,1H),8.05(m,1H),9.12(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值338.2；實測值339.2；Rt=0.922min。A 4.0M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL) was added to N-[3-methyl-5-[[2-oxy-2-(2-phenyl-1- A solution of tert-butyl piperidinyl)acetoxy]amino]-2-pyridyl]carbamate (0.67 g, 1.53 mmol) in DCM (10 mL). The reaction mixture was stirred at 25°C for 8 h, then evaporated in vacuo and 0.5 g of the obtained crude product was purified by preparative (45-70% 0-9.5 min water-methanol, flow rate 30 ml/min) to give the product N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-(2-phenyl-1-piperidinyl)acetamide (16.30 mg, 43.48 μmol, 2.85 % yield, HCl). 1 H NMR (400 MHz, CDCl 3 ) δ 1.58 (m, 3H), 1.99 (m, 3H), 2.11 (m, 3H), 2.47 (m, 1H), 2.98 (m, 1H), 4.64 (m, 3H) ), 6.19 (m, 1H), 7.26 (m, 3H), 7.35 (m, 2H), 7.74 (m, 1H), 8.05 (m, 1H), 9.12 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 338.2; found 339.2; Rt=0.922 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-苯基-1-哌啶基]乙醯胺(化合物55 )及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-苯基-1-哌啶基]乙醯胺(化合物51 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-oxo-2-[(2R)-2-phenyl-1-piperidinyl]acetamide ( Compound 55 ) and N-(6-amino-5-methyl-3-pyridyl)-2-oxygen-2-[(2S)-2-phenyl-1-piperidinyl]acetamide Synthesis of ( Compound 51 )

藉由掌性HPLC(管柱：OJ-H(250* 20，5mkm)，以己烷-IPA-MeOH，50-25-25%，15ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物55 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-苯基-1-哌啶基]乙醯胺(0.0027g，7.20μmol，16.56%產率，HCl；RT=34.348min)及化合物51 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-苯基-1-哌啶基]乙醯胺(0.0026g，6.94μmol，15.95%產率，HCl；RT=15.833min)。The enantiomers were separated by chiral HPLC (column: OJ-H (250 * 20, 5mkm) with hexane-IPA-MeOH, 50-25-25%, 15ml/min as mobile phase) to give Two separate enantiomers compound 55 N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-phenyl-1-piperidine Peridyl]acetamide (0.0027 g, 7.20 μmol, 16.56% yield, HCl; RT=34.348 min) and compound 51 N-(6-amino-5-methyl-3-pyridyl)-2-side Oxy-2-[(2S)-2-phenyl-1-piperidinyl]acetamide (0.0026 g, 6.94 μmol, 15.95% yield, HCl; RT=15.833 min).

化合物51： RT(OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=15.411min。 Compound 51: RT (OJ-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 15.411 min.

LCMS(ESI)：[M+H]+ m/z：計算值338.2；實測值339.2；Rt=1.048min。LCMS (ESI): [M+H] + m/z: calculated 338.2; found 339.2; Rt=1.048 min.

化合物55： RT(OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=41.216min。 Compound 55: RT (OJ-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 41.216 min.

LCMS(ESI)：[M+H]+ m/z：計算值338.2；實測值339.2；Rt=1.043min。LCMS (ESI): [M+H] + m/z: calculated 338.2; found 339.2; Rt=1.043 min.

實例298. N-(6-胺基-5-甲基-3-吡啶基)-2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(化合物27)、N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(化合物33)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物37)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物43)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物40)之合成Example 298. N-(6-Amino-5-methyl-3-pyridyl)-2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetamide (Compound 27), N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-phenylpiperidin-1-yl)- 2-Oxyacetamide (compound 33), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-5-methyl-2-phenyl -1-Piperidinyl]-2-oxyacetamide (compound 37), N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-5 -Methyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (compound 43) and N-(6-amino-5-methyl-3-pyridyl)-2- Synthesis of [(2R,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-oxoacetamide (Compound 40)

Figure 110128222-A0202-12-1489-406
Figure 110128222-A0202-12-1489-406

步驟1：N-[3-甲基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]-2- Synthesis of tert-butyl pyridyl]carbamate

在-78℃、Ar下，向5-甲基-2-苯基哌啶(222.97mg，1.27mmol)於THF(15mL)中之溶液中逐滴添加丁基鋰(268.91mg，4.20mmol，2.4mL)。將反應混合物在-78℃下攪拌20min，然後分批添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.48g，1.27mmol)。將所得溶液在-78℃下攪拌30min且在室溫下攪拌1h。將所得溶液冷卻至-50℃且用飽和NH4 Cl(水溶液)(30ml)淬滅。分離有機層且將水層用EtOAc(20mL×2)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且濃縮至乾，以得到N-[3-甲基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.54g，粗品)。1 H NMR(400MHz,CDCl3 )δ 0.87(d,3H),1.16(m,4H),1.48(s,9H),1.62(m,2H),1.82(m,2H),2.27(m,2H),3.72(m,2H),6.68(m,1H),7.19(m,5H),8.04(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值452.2；實測值453.2；Rt=1.419min。To a solution of 5-methyl-2-phenylpiperidine (222.97 mg, 1.27 mmol) in THF (15 mL) at -78°C under Ar was added butyllithium (268.91 mg, 4.20 mmol, 2.4 mmol) dropwise mL). The reaction mixture was stirred at -78 °C for 20 min, then 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen was added portionwise 2,2,2-trifluoroethyl acetate (0.48 g, 1.27 mmol). The resulting solution was stirred at -78 °C for 30 min and at room temperature for 1 h. The resulting solution was cooled to -50°C and quenched with saturated NH4Cl (aq) (30ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to give N-[3-methyl-5-[[2-(5-methyl-2-phenyl-1- piperidinyl)-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.54 g, crude). 1 H NMR (400MHz, CDCl 3 )δ 0.87(d,3H), 1.16(m,4H), 1.48(s,9H), 1.62(m,2H), 1.82(m,2H), 2.27(m,2H) ), 3.72 (m, 2H), 6.68 (m, 1H), 7.19 (m, 5H), 8.04 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 452.2; found 453.2; Rt=1.419 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(化合物27 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetamide Synthesis of ( Compound 27 )

將於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)添 加到N-[3-甲基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.54g，1.19mmol)於DCM(10mL)中之溶液中。將反應混合物在25℃下攪拌6h，然後在真空中蒸發且藉由製備型(50-75% 0-10.5min水-甲醇，流速30ml/min)純化0.4g所獲得之粗產物，以得到產物N-(6-胺基-5-甲基-3-吡啶基)-2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(0.0167g，42.94μmol，3.60%產率，HCl)1 H NMR(400MHz,CD3 OD)δ 0.85(m,2H),1.13(m,3H),1.35(m,1H),1.64(m,1H),1.87(m,2H),2.13(m,3H),2.26(m,1H),3.60(m,1H),5.62(m,1H),7.26(m,1H),7.37(m,4H),7.57(m,1H),8.02(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.4；Rt=2.499min。A 4.0M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL) was added to N-[3-methyl-5-[[[2-(5-methyl-2-phenyl-1-piperidine A solution of tert-butyl pyridinyl)-2-pendoxetyl]amino]-2-pyridyl]carbamate (0.54 g, 1.19 mmol) in DCM (10 mL). The reaction mixture was stirred at 25°C for 6 h, then evaporated in vacuo and 0.4 g of the obtained crude product was purified by preparative (50-75% 0-10.5 min water-methanol, flow rate 30 ml/min) to give the product N-(6-Amino-5-methyl-3-pyridyl)-2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetamide (0.0167g , 42.94 μmol, 3.60% yield, HCl) 1 H NMR (400 MHz, CD 3 OD) δ 0.85 (m, 2H), 1.13 (m, 3H), 1.35 (m, 1H), 1.64 (m, 1H), 1.87(m, 2H), 2.13(m, 3H), 2.26(m, 1H), 3.60(m, 1H), 5.62(m, 1H), 7.26(m, 1H), 7.37(m, 4H), 7.57 (m, 1H), 8.02 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.4; Rt=2.499 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(化合物33 )、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物37 )、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物43 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物40 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-phenylpiperidin-1-yl)-2- Pendant oxyacetamide ( compound 33 ), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-5-methyl-2-phenyl-1 -Piperidinyl]-2-oxyacetamide ( compound 37 ), N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-5-methyl yl-2-phenyl-1-piperidinyl]-2-oxyacetamide ( compound 43 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[( Synthesis of 2R,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-oxoacetamide ( Compound 40 )

使用(OJ-H Chiralpak管柱，己烷-IPA-MeOH為溶劑混合物，70-15-15，流速15ml/min)進行N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(22.0mg，62.42μmol)之掌性分離，得到呈黃色固體之化合物33 N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(7.8mg，22.13μmol，35.45%產率；RT=22.466min)、化合物37 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(3.4mg，9.65μmol，15.45%產率；RT=17.308min)、化合物43 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(2.7mg，7.66μmol，12.27%產率；RT=42.900min)及化合物40 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(7.8mg，22.13μmol， 35.45%產率；RT=49.446min)。N-(6-amino-5-methylpyridin-3-yl)- Chiral isolation of 2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxoacetamide (22.0 mg, 62.42 μmol) afforded compound 33 N-( 6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamide (7.8 mg, 22.13 μmol, 35.45% yield; RT=22.466 min), Compound 37 N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-5- Methyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (3.4 mg, 9.65 μmol, 15.45% yield; RT=17.308 min), compound 43 N-(6-amino) -5-Methyl-3-pyridyl)-2-[(2R,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxoacetamide (2.7 mg, 7.66 μmol, 12.27% yield; RT=42.900 min) and compound 40 N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2 - Phenyl-1-piperidinyl]-2-oxoacetamide (7.8 mg, 22.13 μmol, 35.45% yield; RT=49.446 min).

化合物33： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6ml/min)=23.187min。 Compound 33: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 23.187 min.

1 H NMR(500MHz,CDCl3 )δ 1.11(d,3H),1.41(m,1H),1.90(m,2H),2.15(m,3H),2.23(m,2H),3.26(m,1H),4.62(m,3H),5.82(m,1H),7.30(m,3H),7.38(m,2H),7.76(s,1H),8.04(m,1H),9.08(s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.0；Rt=3.821min。 1 H NMR (500MHz, CDCl 3 )δ 1.11(d,3H), 1.41(m,1H), 1.90(m,2H), 2.15(m,3H), 2.23(m,2H), 3.26(m,1H) ),4.62(m,3H),5.82(m,1H),7.30(m,3H),7.38(m,2H),7.76(s,1H),8.04(m,1H),9.08(s,1H) . LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.0; Rt=3.821 min.

化合物37： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6ml/min)=16.722min。 Compound 37: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 16.722 min.

1 H NMR(500MHz,CDCl3 )δ 0.86(m,3H),1.32(m,1H),1.44(m,1H),1.72(m,2H),1.86(m,1H),2.03(m,1H),2.15(m,3H),2.56(m,2H),4.65(m,2H),6.25(m,1H),7.30(m,2H),7.39(m,2H),7.78(m,1H),8.07(m,1H),9.03(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.0；Rt=3.789min。 1 H NMR (500MHz, CDCl 3 )δ 0.86(m,3H), 1.32(m,1H), 1.44(m,1H), 1.72(m,2H), 1.86(m,1H), 2.03(m,1H) ), 2.15(m, 3H), 2.56(m, 2H), 4.65(m, 2H), 6.25(m, 1H), 7.30(m, 2H), 7.39(m, 2H), 7.78(m, 1H) , 8.07 (m, 1H), 9.03 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.0; Rt=3.789 min.

化合物43： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6ml/min)=47.178min。1 H NMR(500MHz,CDCl3 )δ 0.86(m,3H),1.31(m,1H),1.46(m,1H),1.73(m,2H),1.87(m,1H),2.03(m,1H),2.15(m,3H),2.53(m,2H),4.66(m,2H),6.24(m,1H),7.30(m,2H),7.39(m,2H),7.78(m,1H),8.07(m,1H),9.04(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.0；Rt=3.792min。 Compound 43: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 47.178 min. 1 H NMR (500MHz, CDCl 3 )δ 0.86(m,3H), 1.31(m,1H), 1.46(m,1H), 1.73(m,2H), 1.87(m,1H), 2.03(m,1H) ), 2.15(m, 3H), 2.53(m, 2H), 4.66(m, 2H), 6.24(m, 1H), 7.30(m, 2H), 7.39(m, 2H), 7.78(m, 1H) , 8.07 (m, 1H), 9.04 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.0; Rt=3.792 min.

化合物40： RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6ml/min)=57.061min。 Compound 40: RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 57.061 min.

1 H NMR(500MHz,CDCl3 ))δ 1.11(d,3H),1.41(m,1H),1.92(m,2H),2.15(m,3H),2.26(m,2H),3.32(m,1H),4.73(m,3H),6.17(m,1H),7.30(m,3H),7.38(m,2H),7.76(s,1H),8.07(m,1H),9.08(s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.0；Rt=3.710min。 1 H NMR (500MHz, CDCl 3 ))δ 1.11(d,3H), 1.41(m,1H), 1.92(m,2H), 2.15(m,3H), 2.26(m,2H), 3.32(m, 1H), 4.73(m, 3H), 6.17(m, 1H), 7.30(m, 3H), 7.38(m, 2H), 7.76(s, 1H), 8.07(m, 1H), 9.08(s, 1H ). LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.0; Rt=3.710 min.

實例299. N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(4-吡啶基)-1-哌啶基]乙醯胺(化合物36)、N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(4-吡啶基)-1-哌啶基]乙醯胺(化合物50)及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(4-Example 299. N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[2-(4-pyridyl)-1-piperidinyl]acetamide ( Compound 36), N-(6-amino-5-methyl-3-pyridyl)-2-oxygen-2-[(2R)-2-(4-pyridyl)-1-piperidinyl ] Acetamide (Compound 50) and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2S)-2-(4- 吡啶基)-1-哌啶基]乙醯胺(化合物47)之合成Synthesis of pyridyl)-1-piperidinyl]acetamide (compound 47)

Figure 110128222-A0202-12-1492-407
Figure 110128222-A0202-12-1492-407

步驟1：N-[3-甲基-5-[[2-側氧基-2-[2-(4-吡啶基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-oxy-2-[2-(4-pyridyl)-1-piperidinyl]acetyl]amino]-2-pyridine Synthesis of tert-butyl]carbamate

在-78℃、Ar下，向4-(2-哌啶基)吡啶(300.97mg，1.86mmol)於THF(19mL)中之溶液中逐滴添加丁基鋰(392.19mg，6.12mmol，2.45mL)。將反應混合物在-78℃下攪拌20min，然後分批添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.7g，1.86mmol)。將所得溶液在-78℃下攪拌30min且在室溫下攪拌1h。將所得溶液冷卻至-50℃且用飽和NH4 Cl(水溶液)(30ml)淬滅。分離有機層且將水層用EtOAc(20mL×2)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且濃縮至乾燥，以得到N-[3-甲基-5-[[2-側氧基-2-[2-(4-吡啶基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.48g，1.09mmol，58.87%產率)。1 H NMR(500MHz,DCMSO-d6 )δ 0.87(m,3H),1.44(s,9H),2.08(m,2H),2.31(m,4H),2.60(m,2H),3.71(m,2H),6.75(d,1H),7.22(d,1H),7.99(d,1H),8.05(s,1H),8.33(d,1H),8.62(s,1H),9.45(m,1H)。LCMS(ESI)：[M-Boc]+ m/z：計算值339.2；實測值340.2；Rt=1.033min。To a solution of 4-(2-piperidinyl)pyridine (300.97 mg, 1.86 mmol) in THF (19 mL) at -78°C under Ar was added butyllithium (392.19 mg, 6.12 mmol, 2.45 mL) dropwise ). The reaction mixture was stirred at -78 °C for 20 min, then 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen was added portionwise 2,2,2-trifluoroethyl acetate (0.7 g, 1.86 mmol). The resulting solution was stirred at -78 °C for 30 min and at room temperature for 1 h. The resulting solution was cooled to -50°C and quenched with saturated NH4Cl (aq) (30ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to give N-[3-methyl-5-[[2-oxy-2-[2-(4-pyridine (0.48 g, 1.09 mmol, 58.87% yield). 1 H NMR (500MHz, DCMSO-d 6 )δ 0.87 (m, 3H), 1.44 (s, 9H), 2.08 (m, 2H), 2.31 (m, 4H), 2.60 (m, 2H), 3.71 (m ,2H),6.75(d,1H),7.22(d,1H),7.99(d,1H),8.05(s,1H),8.33(d,1H),8.62(s,1H),9.45(m, 1H). LCMS (ESI): [M-Boc] + m/z: calculated 339.2; found 340.2; Rt=1.033 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(4-吡啶基)-1-哌啶基]乙醯胺(化合物36 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[2-(4-pyridyl)-1-piperidinyl]acetamide ( Synthesis of compound 36 )

將於二噁烷中之4.0M氯化氫溶液(640.00mg，17.55mmol，0.8mL)添加到N-[3-甲基-5-[[2-側氧基-2-[2-(4-吡啶基)-1-哌啶基]乙醯基]胺基]-2-吡啶基] 胺甲酸第三丁酯(0.48g，1.09mmol)於DCM(5mL)中之溶液中。將反應混合物在25℃下攪拌1h，然後在真空中蒸發且藉由製備型(20-70%甲醇-NH3 ，流速30ml/min)純化0.32g所獲得之粗產物，以得到產物N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(4-吡啶基)-1-哌啶基]乙醯胺(0.037g，109.02μmol，9.98%產率)。1 H NMR(500MHz,DMSO-d6 )δ 1.45(m,2H),1.65(m,2H),1.73(m,1H),1.96(m,1H),2.07(m,3H),2.45(m,1H),4.12(m,1H),5.24(m,2H),5.55(m,1H),7.30(m,2H),7.55(m,1H),8.03(m,1H),8.53(m,2H),10.41(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值339.2；實測值340.2；Rt=0.522min。A 4.0M solution of hydrogen chloride in dioxane (640.00 mg, 17.55 mmol, 0.8 mL) was added to N-[3-methyl-5-[[2-oxy-2-[2-(4-pyridine (0.48 g, 1.09 mmol) in DCM (5 mL). The reaction mixture was stirred at 25°C for 1 h, then evaporated in vacuo and 0.32 g of the obtained crude product was purified by preparative (20-70% methanol- NH3 , flow rate 30 ml/min) to give the product N-( 6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[2-(4-pyridyl)-1-piperidinyl]acetamide (0.037 g, 109.02 μmol, 9.98% yield). 1 H NMR (500MHz, DMSO-d 6 )δ 1.45(m, 2H), 1.65(m, 2H), 1.73(m, 1H), 1.96(m, 1H), 2.07(m, 3H), 2.45(m ,1H),4.12(m,1H),5.24(m,2H),5.55(m,1H),7.30(m,2H),7.55(m,1H),8.03(m,1H),8.53(m, 2H), 10.41 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 339.2; found 340.2; Rt=0.522 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(4-吡啶基)-1-哌啶基]乙醯胺(化合物50 )及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(4-吡啶基)-1-哌啶基]乙醯胺(化合物47 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-(4-pyridyl)-1-piperidinyl] Acetamide ( Compound 50 ) and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2S)-2-(4-pyridyl)-1 Synthesis of -Piperidinyl]acetamide ( Compound 47 )

藉由掌性HPLC(管柱：OJ-H(250* 20，5mkm)，以己烷-IPA-MeOH，50-25-25%，15ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物50 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(4-吡啶基)-1-哌啶基]乙醯胺(0.0125g，36.83μmol，31.25%產率；RT=27.483min)及化合物47 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(4-吡啶基)-1-哌啶基]乙醯胺(0.0108g，31.82μmol，27.00%產率；RT=14.224min)。The enantiomers were separated by chiral HPLC (column: OJ-H (250 * 20, 5mkm) with hexane-IPA-MeOH, 50-25-25%, 15ml/min as mobile phase) to give Two separate enantiomers compound 50 N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-(4-pyridyl) -1-Piperidinyl]acetamide (0.0125 g, 36.83 μmol, 31.25% yield; RT=27.483 min) and compound 47 N-(6-amino-5-methyl-3-pyridyl)-2 - Pendant oxy-2-[(2S)-2-(4-pyridyl)-1-piperidinyl]acetamide (0.0108 g, 31.82 μmol, 27.00% yield; RT=14.224 min).

化合物47： RT(OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=15.367min。 Compound 47: RT (OJ-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 15.367 min.

1 H NMR(500MHz,CDCl3 )δ 1.53(m,1H),1.86(m,1H),2.04(m,2H),2.17(m,3H),2.46(m,1H),2.71(m,1H),3.05(m,1H),4.79(m,3H),6.26(m,1H),7.22(m,2H),7.77(m,1H),8.14(m,1H),8.62(m,2H),9.14(m,1H)。LCMS(ESI)：[M+2H]+ m/z：計算值339.2；實測值341.2；Rt=2.309min。 1 H NMR (500MHz, CDCl 3 )δ 1.53(m,1H), 1.86(m,1H), 2.04(m,2H), 2.17(m,3H), 2.46(m,1H), 2.71(m,1H) ), 3.05(m, 1H), 4.79(m, 3H), 6.26(m, 1H), 7.22(m, 2H), 7.77(m, 1H), 8.14(m, 1H), 8.62(m, 2H) , 9.14 (m, 1H). LCMS (ESI): [M+2H] + m/z: calculated 339.2; found 341.2; Rt=2.309 min.

化合物50： RT(OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=39.557min。 Compound 50: RT (OJ-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 39.557 min.

1 H NMR(500MHz,CDCl3 )δ 1.54(m,2H),2.04(m,2H),2.20(m,3H),2.48(m,1H), 2.71(m,1H),3.05(m,1H),4.81(m,3H),6.26(m,1H),7.22(m,2H),7.76(m,1H),8.13(m,1H),8.62(m,2H),9.13(m,1H)。LCMS(ESI)：[M+2H]+ m/z：計算值339.2；實測值341.2；Rt=2.352min。 1 H NMR (500 MHz, CDCl 3 ) δ 1.54 (m, 2H), 2.04 (m, 2H), 2.20 (m, 3H), 2.48 (m, 1H), 2.71 (m, 1H), 3.05 (m, 1H) ), 4.81(m, 3H), 6.26(m, 1H), 7.22(m, 2H), 7.76(m, 1H), 8.13(m, 1H), 8.62(m, 2H), 9.13(m, 1H) . LCMS (ESI): [M+2H] + m/z: calculated 339.2; found 341.2; Rt=2.352 min.

實例300. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物31)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物57)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物54)之合成Example 300. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(m-tolyl)-1-piperidinyl]-2-oxoacetamide (compound 31), N-(6-amino-5-methyl-3-pyridyl)-2-[(2R)-2-(m-tolyl)-1-piperidinyl]-2-side oxyethyl Amide (compound 57) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S)-2-(m-tolyl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 54)

Figure 110128222-A0202-12-1494-408
Figure 110128222-A0202-12-1494-408

步驟1：N-[3-甲基-5-[[2-[2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[2-(m-tolyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl ] Synthesis of tertiary butyl carbamate

在-78℃、Ar下，向2-(間甲苯基)哌啶(315.87mg，1.80mmol)於THF(15mL)中之溶液中逐滴添加丁基鋰(380.98mg，5.95mmol，2.4mL)。將反應混合物在-78℃下攪拌20min，然後分批添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(0.68g，1.80mmol)。將所得溶液在-78℃下攪拌30min且在室溫下攪拌1h。將所得溶液冷卻至-50℃且用飽和NH4 Cl(水溶液)(30ml)淬滅。分離有機層且將水層用EtOAc(20mL×2)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且濃縮至乾，以得到N-[3-甲基-5-[[2-[2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.64g，1.41mmol，78.47%產率)。LCMS(ESI)：[M+H]+ m/z：計算值452.2；實測值453.2；Rt=1.449min。To a solution of 2-(m-tolyl)piperidine (315.87 mg, 1.80 mmol) in THF (15 mL) at -78°C under Ar was added butyllithium (380.98 mg, 5.95 mmol, 2.4 mL) dropwise . The reaction mixture was stirred at -78 °C for 20 min, then 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen was added portionwise 2,2,2-trifluoroethyl acetate (0.68 g, 1.80 mmol). The resulting solution was stirred at -78 °C for 30 min and at room temperature for 1 h. The resulting solution was cooled to -50°C and quenched with saturated NH4Cl (aq) (30ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to give N-[3-methyl-5-[[2-[2-(m-tolyl)-1-piperidine [00111] tert-butyl]-2-pendant oxyacetoxy]amino]-2-pyridyl]carbamate (0.64 g, 1.41 mmol, 78.47% yield). LCMS (ESI): [M+H] + m/z: calculated 452.2; found 453.2; Rt=1.449 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物31 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(m-tolyl)-1-piperidinyl]-2-oxoacetamide ( compound 31 ) synthesis

將於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)添加到N-[3-甲基-5-[[2-[2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.64g，1.41mmol)於DCM(5mL)中之溶液中。將反應混合物在25℃下攪拌1h，然後在真空中蒸發且藉由製備型(50-100% 0-9.5min水-甲醇，流速30ml/min)純化0.51g所獲得之粗產物，以得到產物N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(54.70mg，140.66μmol，9.95%產率，HCl)。1 H NMR(400MHz,CDCl3 )δ 1.59(m,3H),1.95(m,2H),2.10(m,3H),2.33(s,3H),2.45(m,1H),3.00(m,1H),4.73(m,3H),6.13(m,1H),7.05(m,3H),7.23(m,1H),7.73(m,1H),8.04(m,1H),9.18(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.2；Rt=1.013min。A 4.0M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL) was added to N-[3-methyl-5-[[2-[2-(m-tolyl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.64 g, 1.41 mmol) in DCM (5 mL). The reaction mixture was stirred at 25°C for 1 h, then evaporated in vacuo and 0.51 g of the obtained crude product was purified by preparative (50-100% 0-9.5 min water-methanol, flow rate 30 ml/min) to give the product N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(m-tolyl)-1-piperidinyl]-2-oxyacetamide (54.70 mg, 140.66 g μmol, 9.95% yield, HCl). 1 H NMR (400MHz, CDCl 3 )δ 1.59(m,3H), 1.95(m,2H), 2.10(m,3H), 2.33(s,3H), 2.45(m,1H), 3.00(m,1H) ), 4.73(m, 3H), 6.13(m, 1H), 7.05(m, 3H), 7.23(m, 1H), 7.73(m, 1H), 8.04(m, 1H), 9.18(m, 1H) . LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.2; Rt=1.013 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物57 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物54 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R)-2-(m-tolyl)-1-piperidinyl]-2-pendoxoethyl Amide ( compound 57 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S)-2-(m-tolyl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 54 )

藉由掌性HPLC(管柱：OJ-H(250* 20，5mkm)，以己烷-IPA-MeOH，50-25-25，5ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物57 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(0.0145g，41.14μmol，94.62%產率；RT=24.885min)及化合物54 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯胺(13.70mg，38.87μmol，89.40%產率；RT=11.660min)。The enantiomers were separated by chiral HPLC (column: OJ-H (250 * 20, 5mkm) with hexane-IPA-MeOH, 50-25-25, 5ml/min as mobile phase) to give two An individual enantiomer compound 57 N-(6-amino-5-methyl-3-pyridyl)-2-[(2R)-2-(m-tolyl)-1-piperidinyl]- 2-Oxyacetamide (0.0145 g, 41.14 μmol, 94.62% yield; RT=24.885 min) and compound 54 N-(6-amino-5-methyl-3-pyridyl)-2-[ (2S)-2-(m-Tolyl)-1-piperidinyl]-2-oxyacetamide (13.70 mg, 38.87 μmol, 89.40% yield; RT=11.660 min).

化合物54： RT(OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=11.352min。 Compound 54: RT (OJ-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 11.352 min.

1 H NMR(氯仿-d,400MHz)：δ(ppm)1.62(m,4H),1.96(m,1H),2.11(m,3H),2.34(s,3H),2.45(m,1H),2.94(m,1H),4.60(m,3H),6.17(m,1H),7.05(m,4H),7.75(m, 1H),8.05(m,1H),9.08(s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.0；Rt=3.847min。 1 H NMR (chloroform-d, 400MHz): δ(ppm) 1.62(m, 4H), 1.96(m, 1H), 2.11(m, 3H), 2.34(s, 3H), 2.45(m, 1H), 2.94(m, 1H), 4.60(m, 3H), 6.17(m, 1H), 7.05(m, 4H), 7.75(m, 1H), 8.05(m, 1H), 9.08(s, 1H). LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.0; Rt=3.847 min.

化合物57： RT(OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min)=31.245min。 Compound 57: RT (OJ-H, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 31.245 min.

1 H NMR(氯仿-d,400MHz)：δ(ppm)1.19(d,3H),1.60(m,2H),1.96(m,1H),2.13(m,1H),2.33(s,3H),2.45(m,1H),2.94(m,1H),4.15(m,3H),4.69(m,1H),6.16(m,1H),7.05(m,4H),7.74(m,1H),8.04(m,1H),9.08(s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.0；Rt=3.854min。 1 H NMR (chloroform-d, 400MHz): δ(ppm) 1.19(d,3H), 1.60(m,2H), 1.96(m,1H), 2.13(m,1H), 2.33(s,3H), 2.45(m, 1H), 2.94(m, 1H), 4.15(m, 3H), 4.69(m, 1H), 6.16(m, 1H), 7.05(m, 4H), 7.74(m, 1H), 8.04 (m, 1H), 9.08 (s, 1H). LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.0; Rt=3.854 min.

實例301. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(4-甲基噻唑-2-基)-1-哌啶基]-2-側氧基乙醯胺(化合物49)之合成Example 301. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(4-methylthiazol-2-yl)-1-piperidinyl]-2-oxygen Synthesis of Ethylacetamide (Compound 49)

Figure 110128222-A0202-12-1496-409
Figure 110128222-A0202-12-1496-409

步驟1：N-[3-甲基-5-[[2-[2-(4-甲基噻唑-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[2-(4-Methylthiazol-2-yl)-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of 3-butyl ]-2-pyridyl]carbamate

在-70℃、Ar下，向4-甲基-2-(2-哌啶基)噻唑(217.40mg，1.19mmol)及2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸2,2,2-三氟乙酯(600.00mg，1.19mmol)於THF(15mL)中之溶液中逐滴添加於己烷中之2.5M正丁基鋰溶液(252.12mg，3.94mmol，1.6mL)。將反應混合物在-70℃下攪拌30min且在室溫下攪拌1h。將所得溶液冷卻至-50℃且用飽和NH4 Cl(水溶液)(40ml)淬滅。分離有機層且將水層用EtOAc(20mL×2)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且濃縮至乾，以得到N-[3-甲基-5-[[2-[2-(4-甲基噻唑-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.5g，粗品)。To 4-methyl-2-(2-piperidinyl)thiazole (217.40 mg, 1.19 mmol) and 2-[[6-(tertiary butoxycarbonylamino)-5 at -70°C under Ar -Methyl-3-pyridyl]amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (600.00 mg, 1.19 mmol) in THF (15 mL) was added dropwise to hexane A 2.5M solution of n-butyllithium in alkane (252.12 mg, 3.94 mmol, 1.6 mL). The reaction mixture was stirred at -70 °C for 30 min and at room temperature for 1 h. The resulting solution was cooled to -50°C and quenched with saturated NH4Cl (aq) (40ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to dryness to give N-[3-methyl-5-[[2-[2-(4-methylthiazol-2-yl )-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.5 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值459.2；實測值460.2；Rt=1.318min。LCMS (ESI): [M+H] + m/z: calculated 459.2; found 460.2; Rt=1.318 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2[2-(4-甲基噻唑-2-基)-1-哌啶基]-2-側氧基乙醯胺(化合物49 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2[2-(4-methylthiazol-2-yl)-1-piperidinyl]-2-pendoxyl Synthesis of Acetamide ( Compound 49 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(141.67mg，544.00μmol，177.09μL，14%純度)小心添加到N-[3-甲基-5-[[2-[2-(4-甲基噻唑-2-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.5g，54.40μmol)於DCM(20mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑，以得到0.5g粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；以40-40-65%，0-1-6min 0.1% NH3 -甲醇為流動相)，以得到化合物49 N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(4-甲基噻唑-2-基)-1-哌啶基]-2-側氧基乙醯胺(8mg，22.26μmol，40.91%產率)。1 H NMR(400MHz,CDCl3 )δ 1.74(m,2H),1.96(m,3H),2.11(m,3H),2.41(m,3H),2.53(m,1H),3.02(m,1H),4.41(m,2H),4.63(m,1H),6.25(m,1H),6.83(m,1H),7.73(m,1H),8.01(m,1H),9.19(m,1H)。A 4.0 M solution of hydrogen chloride in dioxane (141.67 mg, 544.00 μmol, 177.09 μL, 14% pure) was carefully added to N-[3-methyl-5-[[2-[2-( 4-Methylthiazol-2-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.5 g, 54.40 μmol) in solution in DCM (20 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo to give 0.5 g of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; 40-40-65%, 0-1-6 min 0.1% NH3 -methanol as mobile phase) to give compound 49 N-( 6-Amino-5-methyl-3-pyridyl)-2-[2-(4-methylthiazol-2-yl)-1-piperidinyl]-2-oxoacetamide (8mg , 22.26 μmol, 40.91% yield). 1 H NMR (400MHz, CDCl 3 ) δ 1.74 (m, 2H), 1.96 (m, 3H), 2.11 (m, 3H), 2.41 (m, 3H), 2.53 (m, 1H), 3.02 (m, 1H) ), 4.41(m, 2H), 4.63(m, 1H), 6.25(m, 1H), 6.83(m, 1H), 7.73(m, 1H), 8.01(m, 1H), 9.19(m, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值359.2；實測值360.2；Rt=2.128min。LCMS (ESI): [M+H] + m/z: calculated 359.2; found 360.2; Rt=2.128 min.

實例302.N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(化合物134及化合物137)之合成Example 302. N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[( 1S , 4S , 5R )-4-(2-thienyl) - Synthesis of 3-azabicyclo[3.2.1]oct-3-yl]acetamide (Compound 134 and Compound 137)

Figure 110128222-A0202-12-1497-410
Figure 110128222-A0202-12-1497-410

步驟1：N-[3-甲基-5-[[2-側氧基-2-[(1S,4S,5R)-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-oxy-2-[(1S,4S,5R)-4-(2-thienyl)-3-azabicyclo[3.2.1 Synthesis of 3-butyl ]oct-3-yl]acetyl]amino]-2-pyridyl]carbamate

將(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛烷(400.00mg，2.07mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(611.03mg，2.07mmol)、HATU(826.13mg，2.17mmol)及三乙胺(1.05g，10.35mmol，1.44mL)於DMF(3mL)中之懸浮液在30℃下攪拌3小時。3小時之後，在真空中濃縮反應混合物且使粗產物經歷反相HPLC純化(溶析液：1-6min，45%水-乙腈；流速：30mL/min；裝載泵：4mL/min，乙腈)，以獲得呈白色固體之產物N -[3-甲基-5-[[2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(170mg，361.25μmol，17.46%產率)。(1 S ,4 S ,5 R )-4-(2-thienyl)-3-azabicyclo[3.2.1]octane (400.00 mg, 2.07 mmol), 2-[[6-(the third Butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (611.03 mg, 2.07 mmol), HATU (826.13 mg, 2.17 mmol) and triethylamine (1.05 g, 10.35 mmol, 1.44 mL) in DMF (3 mL) was stirred at 30 °C for 3 h. After 3 hours, the reaction mixture was concentrated in vacuo and the crude product was subjected to reverse phase HPLC purification (eluent: 1-6 min, 45% water-acetonitrile; flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile), to obtain the product N- [3-methyl-5-[[2-oxy-2-[( 1S , 4S , 5R )-4-(2-thienyl)-3- as a white solid Azabicyclo[3.2.1]oct-3-yl]acetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (170 mg, 361.25 μmol, 17.46% yield).

LCMS(ESI)：[M+H]+ m/z：計算值470.2；實測值471.2；Rt=3.682min。LCMS (ESI): [M+H] + m/z: calculated 470.2; found 471.2; Rt=3.682 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S,4S,5R)-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(1S,4S,5R)-4-(2-thienyl)-3- Synthesis of Azabicyclo[3.2.1]oct-3-yl]acetamide

將N -[3-甲基-5-[[2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(170.00mg，361.25μmol)於水(3mL)及二噁烷(1mL)中之懸浮液在100℃下加熱24小時。使粗反應混合物經歷反相HPLC純化(溶析液：40-40-90%，0-1-5min 0.1% NH3 -甲醇，流速：30mL/min；裝載泵：4mL/min，甲醇；管柱：YMC Triart C18 100 x 20mm，5um)，以獲得呈白色固體之產物N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(78mg，210.54μmol，58.28%產率)。 N- [3-methyl-5-[[2-oxy-2-[(1 S ,4 S ,5 R )-4-(2-thienyl)-3-azabicyclo[3.2. 1] A suspension of tert-butyl oct-3-yl]acetyl]amino]-2-pyridyl] carbamate (170.00 mg, 361.25 μmol) in water (3 mL) and dioxane (1 mL) Heated at 100°C for 24 hours. The crude reaction mixture was subjected to reverse phase HPLC purification (eluent: 40-40-90%, 0-1-5 min 0.1% NH3 -methanol, flow rate: 30 mL/min; loading pump: 4 mL/min, methanol; column : YMC Triart C18 100 x 20mm, 5um) to obtain the product N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[( 1S , 4S , 5R )-4-(2-thienyl)-3-azabicyclo[3.2.1]oct-3-yl]acetamide (78 mg, 210.54 μmol, 58.28% yield).

LCMS(ESI)：[M+H]+ m/z：計算值370.2；實測值371.2；Rt=2.184min。LCMS (ESI): [M+H] + m/z: calculated 370.2; found 371.2; Rt=2.184 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S,4S,5R)-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1R,4R,5S)-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基)乙醯胺(化合物134 及化合物137 )之掌性分離Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(1S,4S,5R)-4-(2-thienyl)-3- Azabicyclo[3.2.1]oct-3-yl]acetamide and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(1R,4R ,5S)-4-(2-thienyl)-3-azabicyclo[3.2.1]oct-3-yl)acetamide ( Compound 134 and Compound 137 ) Chiral Separation

使N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(40.00mg，107.97μmol)經歷掌性HPLC純化(管柱：Chiralpak OJ(250 x 30mm，20um；流動相：己烷-IPA-MeOH，50-25-25；流速：28mL/min；管柱溫度：24℃；波長：205nm)，以獲得呈白色固體之產物N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1S ,4S ,5R )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(化合物134 ，17mg，45.89μmol)及N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(1R ,4R ,5S )-4-(2-噻吩基)-3-氮雜雙環[3.2.1]辛-3-基]乙醯胺(化合物137 ，16mg，43.19μmol)。make N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[( 1S , 4S , 5R )-4-(2-thienyl)-3 - Azabicyclo[3.2.1]oct-3-yl]acetamide (40.00 mg, 107.97 μmol) was purified by chiral HPLC (column: Chiralpak OJ (250 x 30 mm, 20 um; mobile phase: hexane-IPA) -MeOH, 50-25-25; flow rate: 28 mL/min; column temperature: 24°C; wavelength: 205 nm) to obtain the product N- (6-amino-5-methyl-3-pyridine as a white solid) base)-2-oxy-2-[(1 S ,4 S ,5 R )-4-(2-thienyl)-3-azabicyclo[3.2.1]oct-3-yl]acetone Amine ( compound 134 , 17 mg, 45.89 μmol) and N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(1 R ,4 R ,5 S )- 4-(2-Thienyl)-3-azabicyclo[3.2.1]oct-3-yl]acetamide ( Compound 137 , 16 mg, 43.19 μmol).

化合物134 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)1.41(m,5H),1.63(m,2H),2.00(m,4H),3.92(m,1H),5.56(m,3H),6.88(m,3H),7.42(m,2H),8.03(m,1H),10.34(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值370.2；實測值371.0；Rt=3.685min掌性HPLC：Rt=14.19min(OJ-H，流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。 Compound 134 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 1.41 (m, 5H), 1.63 (m, 2H), 2.00 (m, 4H), 3.92 (m, 1H), 5.56 (m, 3H), 6.88 (m, 3H), 7.42 (m, 2H), 8.03 (m, 1H), 10.34 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 370.2; found 371.0; Rt=3.685min chiral HPLC: Rt=14.19min (OJ-H, mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

化合物137 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)1.41(m,5H),1.63(m,2H),2.01(m,4H),3.92(m,1H),5.56(m,3H),6.88(m,3H),7.42(m,2H),8.02(m,1H),10.34(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值370.2；實測值371.0；Rt=3.689min掌性HPLC：Rt=28.84min(OJ-H，流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。 Compound 137 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 1.41 (m, 5H), 1.63 (m, 2H), 2.01 (m, 4H), 3.92 (m, 1H), 5.56 (m, 3H), 6.88 (m, 3H), 7.42 (m, 2H), 8.02 (m, 1H), 10.34 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 370.2; found 371.0; Rt=3.689 min Chiral HPLC: Rt=28.84 min (OJ-H, mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

實例303. N-(6-胺基-5-甲基吡啶-3-基)-2-(5,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(化合物56、化合物52及化合物58)之合成Example 303. N-(6-Amino-5-methylpyridin-3-yl)-2-(5,5-dimethyl-2-phenylpiperidin-1-yl)-2-oxygen Synthesis of Acetamide (Compound 56, Compound 52 and Compound 58)

Figure 110128222-A0202-12-1500-411
Figure 110128222-A0202-12-1500-411

步驟1：(5-(2-(5,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(5,5-Dimethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridin-2-yl ) Synthesis of tertiary butyl carbamate

向5,5-二甲基-2-苯基哌啶(0.3g，1.58mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(561.58mg，1.90mmol)及HATU(723.12mg，1.90mmol)於DMF(3mL)中之懸浮液中添加三乙胺(481.10mg，4.75mmol，662.68μL)。將所得混合物在25℃下攪拌3h且使其經歷HPLC(管柱：SunFireC18 100*19 5um且以水-MeCN為流動相)，以獲得N -[5-[[2-(5,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.3g，642.99μmol，40.57%產率)。To 5,5-dimethyl-2-phenylpiperidine (0.3 g, 1.58 mmol), 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl] Amino]-2-oxoacetic acid (561.58 mg, 1.90 mmol) and HATU (723.12 mg, 1.90 mmol) in DMF (3 mL) was added triethylamine (481.10 mg, 4.75 mmol, 662.68 μL) . The resulting mixture was stirred at 25°C for 3 h and subjected to HPLC (column: SunFireC18 100*19 5um with water-MeCN as mobile phase) to obtain N- [5-[[2-(5,5-di Methyl-2-phenyl-1-piperidinyl)-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.3 g, 642.99 μmol , 40.57% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.87(m,3H),1.05(m,3H),1.36(m,2H),1.51(s,9H),1.59(m,2H),2.45(s,3H),2.75(m,1H),4.55(m,1H),5.89(m,1H),6.51(d,1H),7.26(m,3H),7.38(m,2H),8.06(s,1H),8.38(d,1H),9.33(s,1H)。LCMS(ESI)：[M]+ m/z：計算值466.6；實測值467.2；Rt=4.129min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.87(m, 3H), 1.05(m, 3H), 1.36(m, 2H), 1.51(s, 9H), 1.59(m, 2H), 2.45( s, 3H), 2.75(m, 1H), 4.55(m, 1H), 5.89(m, 1H), 6.51(d, 1H), 7.26(m, 3H), 7.38(m, 2H), 8.06(s , 1H), 8.38 (d, 1H), 9.33 (s, 1H). LCMS (ESI): [M] + m/z: calculated 466.6; found 467.2; Rt=4.129 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(化合物56 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5,5-dimethyl-2-phenylpiperidin-1-yl)-2-oxygen Synthesis of Acetamide ( Compound 56 )

將N -[5-[[2-(5,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.3g，642.99μmol)溶解於於二噁烷中之4.0M氯化氫溶液(2.00g，54.85mmol，2.5mL)中且在25℃下攪拌3h。將溶劑蒸發且將殘餘物在真空中乾燥且經歷HPLC(管柱：YMC Actus Triart C18 100x20mm，5um 且以MeOH為流動相)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-(5,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(0.220g，546.02μmol，84.92%產率，HCl)。 N- [5-[[2-(5,5-Dimethyl-2-phenyl-1-piperidinyl)-2-oxyacetyl]amino]-3-methyl-2 - tert -butyl pyridyl]carbamate (0.3 g, 642.99 μmol) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (2.00 g, 54.85 mmol, 2.5 mL) and stirred at 25 °C for 3 h. The solvent was evaporated and the residue was dried in vacuo and subjected to HPLC (column: YMC Actus Triart C18 100x20mm, 5um with MeOH as mobile phase) to obtain N- (6-amino-5-methyl-3- Pyridyl)-2-(5,5-dimethyl-2-phenyl-1-piperidinyl)-2-oxyacetamide (0.220 g, 546.02 μmol, 84.92% yield, HCl).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.78(m,3H),0.97(m,3H),1.33(m,2H),2.03(m,1H),2.18(m,3H),2.30(m,2H),2.77(m,0,5H),3.93(m,0,5H),5.42(m,1H),7.29(m,2H),7.38(m,3H),7.90(m,3H),8.29(m,1H),11.20(m,1H),13.94(m,1H)。LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=2.915min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.78(m, 3H), 0.97(m, 3H), 1.33(m, 2H), 2.03(m, 1H), 2.18(m, 3H), 2.30(m, 2H), 2.77(m, 0, 5H), 3.93(m, 0, 5H), 5.42(m, 1H), 7.29(m, 2H), 7.38(m, 3H), 7.90(m, 3H), 8.29 (m, 1H), 11.20 (m, 1H), 13.94 (m, 1H). LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=2.915min.

步驟3：掌性分離(化合物52 及化合物58 )Step 3: Chiral separation ( Compound 52 and Compound 58 )

在體系Hex-IPA-MeOH，50-25-25，0.15mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：1mkl。自50mg外消旋物獲得18mg及15mg個別鏡像異構物。Purification was performed on a chiral column in the system Hex-IPA-MeOH, 50-25-25, 0.15 mL/min. Injection times: 1, injection volume: 1mkl. From 50 mg of racemate, 18 mg and 15 mg of individual enantiomers were obtained.

化合物52 ：保留時間：5.22min。1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.84(m,3H),1.02(m,3H),1.40(m,2H),2.08(m,1H),2.22(m,3H),2.33(m,1H),2.79(m,1H),3.75(m,1H),5.53(m,1H),7.26(m,2H),7.34(m,3H),7.75(m,2H),7.92(m,1H),8.32(m,1H),11.04(m,1H)。LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=4.009min。 Compound 52 : Retention time: 5.22 min. 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.84(m,3H), 1.02(m,3H), 1.40(m,2H), 2.08(m,1H), 2.22(m,3H), 2.33(m, 1H), 2.79(m, 1H), 3.75(m, 1H), 5.53(m, 1H), 7.26(m, 2H), 7.34(m, 3H), 7.75(m, 2H), 7.92 (m, 1H), 8.32 (m, 1H), 11.04 (m, 1H). LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=4.009 min.

化合物58：保留時間：8.92min 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.83(m,3H),1.03(m,3H),1.40(m,2H),2.08(m,3H),2.28(m,2H),2.78(m,1H),3.81(m,1H),5.30(m,2H),5.72(m,1H),7.26(m,2H),7.35(m,3H),7.55(m,1H),8.09(m,1H),10.40(m,1H)。LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=4.033min。 Compound 58: Retention time: 8.92 min 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.83 (m, 3H), 1.03 (m, 3H), 1.40 (m, 2H), 2.08 (m, 3H) ,2.28(m,2H),2.78(m,1H),3.81(m,1H),5.30(m,2H),5.72(m,1H),7.26(m,2H),7.35(m,3H), 7.55 (m, 1H), 8.09 (m, 1H), 10.40 (m, 1H). LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=4.033 min.

實例304.N -(6-胺基-5-甲基-3-吡啶基)-2-(3,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(化合物314、化合物339、化合物343)之合成Example 304. N- (6-amino-5-methyl-3-pyridyl)-2-(3,5-dimethyl-2-phenyl-1-piperidinyl)-2-pendoxyl Synthesis of Acetamide (Compound 314, Compound 339, Compound 343)

Figure 110128222-A0202-12-1502-412
Figure 110128222-A0202-12-1502-412

步驟1：(5-(2-(3,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(3,5-Dimethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridin-2-yl ) Synthesis of tertiary butyl carbamate

將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(779.97mg，2.64mmol)、HATU(1.10g，2.91mmol)及TEA(534.56mg，5.28mmol，736.31μL)一起混合於DMF(8mL)中且向其中添加3,5-二甲基-2-苯基哌啶(500mg，2.64mmol)。將所得混合物在25℃下攪拌4h。然後，將其用水(30ml)稀釋且用乙酸乙酯(2x30ml)萃取。將有機層用水(3x20ml)及鹽水(30ml)連續洗滌，經Na2 SO4 乾燥且在真空中濃縮，得到N -[5-[[2-(3,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(930mg，1.99mmol，75.46%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (779.97 mg, 2.64 mmol), HATU (1.10 g , 2.91 mmol) and TEA (534.56 mg, 5.28 mmol, 736.31 μL) were mixed together in DMF (8 mL) and to this was added 3,5-dimethyl-2-phenylpiperidine (500 mg, 2.64 mmol). The resulting mixture was stirred at 25 °C for 4 h. It was then diluted with water (30ml) and extracted with ethyl acetate (2x30ml). The organic layer was washed successively with water (3x20ml) and brine (30ml), dried over Na2SO4 and concentrated in vacuo to give N- [5-[[2-(3,5-dimethyl-2-phenyl -1-Piperidinyl)-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (930 mg, 1.99 mmol, 75.46% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.95(d,3H),1.04(d,3H),1.17(m,1H),1.43(s,9H),1.98(m,1H),2.16(s,3H),2.91(m,2H),3.83(m,1H),4.03(m,1H),4.46(m,1H),7.88(m,7H),8.39(m,1H),9.04(m,1H)。LCMS(ESI)：[M]+ m/z：計算值466.5；實測值467.2；Rt=1.490min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.95(d,3H), 1.04(d,3H), 1.17(m,1H), 1.43(s,9H), 1.98(m,1H), 2.16(s, 3H), 2.91(m, 2H), 3.83(m, 1H), 4.03(m, 1H), 4.46(m, 1H), 7.88(m, 7H), 8.39(m, 1H), 9.04 (m, 1H). LCMS (ESI): [M] + m/z: calculated 466.5; found 467.2; Rt=1.490 min.

步驟2：掌性分離(化合物314、化合物339 及化合物343 )Step 2: Chiral separation ( Compound 314, Compound 339 and Compound 343 )

將於二噁烷中之4.0M氯化氫溶液(6.25g，17.15mmol，7.82mL，10%純度)添加到N -[5-[[2-(3,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(800.07mg，1.71mmol)於DCM(5mL)中之溶液中。將所得混合物在25℃下攪拌15h。然後，將其在減壓下濃縮且使殘餘物經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；40-40-90% 0-1-6min 0.1% NH3 -甲醇， 流速：30ml/min)，得到167mg異構物混合物。使所獲得之外消旋物經歷掌性HPLC(管柱：OD-H(250*30，5mkm)，己烷-IPA-MeOH，90-5-5，30ml/min)，得到：N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,3S,5R )-3,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(20mg，54.58μmol，3.18%產率)、N -(6-胺基-5-甲基-3-吡啶基)-2-(3,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(59mg，161.00μmol，9.39%產率)、N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,3R,5R )-3,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(29mg，79.14μmol，4.61%產率)。A 4.0 M solution of hydrogen chloride in dioxane (6.25 g, 17.15 mmol, 7.82 mL, 10% purity) was added to N- [5-[[2-(3,5-dimethyl-2-phenyl- 1-Piperidinyl)-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (800.07 mg, 1.71 mmol) in DCM (5 mL) in solution. The resulting mixture was stirred at 25 °C for 15 h. It was then concentrated under reduced pressure and the residue was subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; 40-40-90% 0-1-6min 0.1% NH3 -methanol, flow rate: 30ml/min) , yielding 167 mg of a mixture of isomers. The obtained racemate was subjected to chiral HPLC (column: OD-H (250*30, 5mkm), hexane-IPA-MeOH, 90-5-5, 30ml/min) to give: N- ( 6-Amino-5-methyl-3-pyridyl)-2-[( 2S,3S,5R )-3,5-dimethyl-2-phenyl-1-piperidinyl]-2-side Oxyacetamide (20 mg, 54.58 μmol, 3.18% yield), N- (6-amino-5-methyl-3-pyridyl)-2-(3,5-dimethyl-2-benzene yl-1-piperidinyl)-2-oxyacetamide (59 mg, 161.00 μmol, 9.39% yield), N- (6-amino-5-methyl-3-pyridyl)-2- [( 2S,3R,5R )-3,5-Dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (29 mg, 79.14 μmol, 4.61% yield).

化合物314：保留時間：34.68+37.54min LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=2.434min。化合物339：保留時間：41.95min 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.78(m,1H),0.84(m,3H),0.94(m,3H),1.85(m,1H),1.99(m,4H),2.12(m,1H),3.53(m,1H),3.77(m,1H),4.48(m,1H),5.59(m,2H),7.33(m,6H),7.94(m,1H),10.37(m,1H)。LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=4.059min。 Compound 314: Retention time: 34.68+37.54 min LCMS (ESI): [M] + m/z: calcd. 366.2; found 367.2; Rt=2.434 min. Compound 339: Retention time: 41.95 min 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.78 (m, 1H), 0.84 (m, 3H), 0.94 (m, 3H), 1.85 (m, 1H) ,1.99(m,4H),2.12(m,1H),3.53(m,1H),3.77(m,1H),4.48(m,1H),5.59(m,2H),7.33(m,6H), 7.94 (m, 1H), 10.37 (m, 1H). LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=4.059 min.

化合物343：保留時間：31.46min 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.70(m,3H),1.02(m,3H),1.38(m,1H),1.90(td,1H),1.99(m,3H),2.15(m,1H),2.26(m,1H),3.40(m,1H),3.69(m,1H),5.18(m,1H),5.61(m,2H),7.31(m,4H),7.44(m,2H),7.95(m,1H),10.29(m,1H)。LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=4.101min。 Compound 343: Retention time: 31.46 min 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.70 (m, 3H), 1.02 (m, 3H), 1.38 (m, 1H), 1.90 (td, 1H) ,1.99(m,3H),2.15(m,1H),2.26(m,1H),3.40(m,1H),3.69(m,1H),5.18(m,1H),5.61(m,2H), 7.31 (m, 4H), 7.44 (m, 2H), 7.95 (m, 1H), 10.29 (m, 1H). LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=4.101 min.

實例305. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(苯并噻吩-3-基)-1-哌啶基]-2-側氧基乙醯胺(化合物123)之合成Example 305. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(benzothiophen-3-yl)-1-piperidinyl]-2-side oxyethyl Synthesis of amide (compound 123)

Figure 110128222-A0202-12-1503-413
Figure 110128222-A0202-12-1503-413

步驟1：N-[5-[[2-[2-(苯并噻吩-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-Step 1: N-[5-[[2-[2-(benzothiophen-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl- 2- 吡啶基]胺甲酸第三丁酯之合成Synthesis of tert-butyl pyridyl]carbamate

向2-(苯并噻吩-3-基)哌啶(0.4g，1.84mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(543.49mg，1.84mmol)及HATU(699.82mg，1.84mmol)於DMF(3mL)中之懸浮液中添加三乙胺(931.21mg，9.20mmol，1.28mL)。將所得混合物在環境溫度下攪拌12h。然後，將混合物溶解於水(40ml)中且用EtOAc(3* 20ml)萃取。將經合併之有機層用鹽水洗滌(3* 20ml)，經Na2 SO4 乾燥且蒸發，以獲得N-[5-[[2-[2-(苯并噻吩-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.9g，粗品)。此化合物不經純化即用於下一步驟。To 2-(benzothiophen-3-yl)piperidine (0.4 g, 1.84 mmol), 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amine [00100] Triethylamine (931.21 mg, 9.20 mmol, 1.28 mL) was added to a suspension of [00124]-2-pendoxoacetic acid (543.49 mg, 1.84 mmol) and HATU (699.82 mg, 1.84 mmol) in DMF (3 mL). The resulting mixture was stirred at ambient temperature for 12 h. Then, the mixture was dissolved in water (40ml) and extracted with EtOAc (3 * 20ml). The combined organic layers were washed with brine (3 * 20ml), dried over Na2SO4 and evaporated to obtain N-[5-[[2-[2-(benzothiophen-3-yl)-1- Piperidinyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.9 g, crude). This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.43(s,9H),1.69(m,2H),1.98(m,2H),2.18(s,3H),2.32(m,2H),3.09(m,2H),3.67(m,1H),5.99(m,1H),7.39(m,2H),7.93(m,3H),8.45(s,1H),9.06(s,1H),11.02(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.43(s, 9H), 1.69(m, 2H), 1.98(m, 2H), 2.18(s, 3H), 2.32(m, 2H), 3.09(m ,2H),3.67(m,1H),5.99(m,1H),7.39(m,2H),7.93(m,3H),8.45(s,1H),9.06(s,1H),11.02(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值494.2；實測值495.2；Rt=1.417min。LCMS (ESI): [M+H] + m/z: calculated 494.2; found 495.2; Rt=1.417 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(苯并噻吩-3-基)-1-哌啶基]-2-側氧基乙醯胺(化合物123 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(benzothiophen-3-yl)-1-piperidinyl]-2-pendoxoethyl Synthesis of amide ( compound 123 )

向N-[5-[[2-[2-(苯并噻吩-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.9g，1.82mmol)於DCM(20mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌12h且在真空中蒸發，以獲得粗產物(0.g)。藉由HPLC(40/60% 0-5min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量394，管柱：YMC Triart C18 100* 20mm，5um)純化粗產物，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(苯并噻吩-3-基)-1-哌啶基]-2-側氧基乙醯胺(57mg，144.49μmol，7.94%產率)。To N-[5-[[2-[2-(benzothiophen-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2- To a solution of tert-butyl pyridyl]carbamate (0.9 g, 1.82 mmol) in DCM (20 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (8.00 g, 219.41 mmol, 10 mL). The resulting mixture was stirred at 25°C for 12h and evaporated in vacuo to obtain crude product (0.g). The crude was purified by HPLC (40/60% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 394, column: YMC Triart C18 100 * 20mm, 5um) product to give N-(6-amino-5-methyl-3-pyridinyl)-2-[2-(benzothiophen-3-yl)-1-piperidinyl]-2-side oxy Acetamide (57 mg, 144.49 μmol, 7.94% yield).

1 H NMR(500MHz,DMSO+CCL4)δ 1.72(m,3H),1.89(m,1H),2.01(m,4H),2.32 (m,1H),3.08(m,1H),3.68(m,1H),5.87(m,3H),7.41(m,3H),7.82(m,1H),7.90(m,1H),8.02(m,2H),10.50(m,1H)。 1 H NMR (500MHz, DMSO+CCL4)δ 1.72(m,3H), 1.89(m,1H), 2.01(m,4H), 2.32(m,1H), 3.08(m,1H), 3.68(m, 1H), 5.87 (m, 3H), 7.41 (m, 3H), 7.82 (m, 1H), 7.90 (m, 1H), 8.02 (m, 2H), 10.50 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.2；Rt=2.609min。LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.2; Rt=2.609 min.

實例306.外消旋 -N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物187)之合成Example 306. Racemic - N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine Synthesis of pyridin-1-yl)-2-oxoacetamide (compound 187)

Figure 110128222-A0202-12-1505-414
Figure 110128222-A0202-12-1505-414

步驟1：(5-(2-(2-(3-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(3-Hydroxyphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridine-2 -Synthesis of tertiary butyl carbamate

將TEA(2.49g，24.57mmol，3.42mL)添加到3-(5-甲基-2-哌啶基)苯酚(0.47g，2.46mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(725.61mg，2.46mmol)及HATU(1.03g，2.70mmol)於DMF(5mL)中之混合物中。將反應混合物在25℃下攪拌1h，然後提交至反相HPLC(管柱：SunFireC18 100x19mm 5um，流動相35-40% 0-5min水-MeCN)，以得到呈白色固體之N -[5-[[2-[2-(3-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(130mg，277.46μmol，11.29%產率)。TEA (2.49 g, 24.57 mmol, 3.42 mL) was added to 3-(5-methyl-2-piperidinyl)phenol (0.47 g, 2.46 mmol), 2-[[6-( tert- butoxycarbonyl) amino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (725.61 mg, 2.46 mmol) and HATU (1.03 g, 2.70 mmol) in DMF (5 mL). The reaction mixture was stirred at 25°C for 1 h, then submitted to reverse phase HPLC (column: SunFire C18 100x19mm 5um, mobile phase 35-40% 0-5min water-MeCN) to give N- [5-[ as a white solid [2-[2-(3-Hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]amine tert -butyl formate (130 mg, 277.46 [mu]mol, 11.29% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.11(d,3H),1.32(m,1H),1.48(s,9H),1.99(m,2H),2.12(m,2H),2.28(s,3H),2.98(m,1H),3.42(d,1H),4.38(m,1H),5.98(m,1H),6.76(m,4H),7.18(m,1H),7.97(m,1H),8.34(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.11(d, 3H), 1.32(m, 1H), 1.48(s, 9H), 1.99(m, 2H), 2.12(m, 2H), 2.28( s, 3H), 2.98(m, 1H), 3.42(d, 1H), 4.38(m, 1H), 5.98(m, 1H), 6.76(m, 4H), 7.18(m, 1H), 7.97(m , 1H), 8.34 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值468.5；實測值469.2；Rt=3.448min。LCMS (ESI): [M] + m/z: calculated 468.5; found 469.2; Rt=3.448 min.

步驟2：外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-2-(3-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物187 )之合成Step 2: Racemic-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(3-hydroxyphenyl)-5-methylpiperidine Synthesis of pyridin-1-yl)-2-oxoacetamide ( compound 187 )

將N -[5-[[2-[2-(3-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺 基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(130mg，277.46μmol)溶解於1,4-二噁烷(1.5mL)及水(2.5mL)之混合物中。將所得混合物在90℃下攪拌48h，然後冷卻且提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um，流動相：40-60% 0-5min 0.1% NH3 -MeOH)，以得到51mg粗產物，其使用反相HPLC(管柱：YMC Triart C18 100x20mm，5um，流動相：15-40% 0-5min 0.1% NH3 -MeOH)再次再純化，以得到呈白色固體之兩種級分之化合物187 ：11mg(第1級分)及20mg(第2級分)N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31mg，84.14μmol，30.33%產率)。 N- [5-[[2-[2-(3-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl 3 -Butyl-2-pyridyl]carbamate (130 mg, 277.46 [mu]mol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (2.5 mL). The resulting mixture was stirred at 90°C for 48h, then cooled and submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um, mobile phase: 40-60% 0-5min 0.1% NH3 -MeOH) to give 51 mg The crude product was repurified again using reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um, mobile phase: 15-40% 0-5 min 0.1% NH3 -MeOH) to give two fractions as white solids Compound 187 : 11 mg (fraction 1) and 20 mg (fraction 2) N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-( 3-Hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (31 mg, 84.14 μmol, 30.33% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.32(m,1H),1.69(m,1H),1.88(m,1H),2.02(m,4H),2.12(m,1H),3.08(m,1H),3.74(m,1H),5.62(m,3H),6.71(m,3H),7.17(m,1H),7.48(m,1H),8.01(m,1H),9.40(m,1H),10.48(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.32(m, 1H), 1.69(m, 1H), 1.88(m, 1H), 2.02(m, 4H), 2.12(m, 1H), 3.08(m, 1H), 3.74(m, 1H), 5.62(m, 3H), 6.71(m, 3H), 7.17(m, 1H), 7.48(m, 1H), 8.01 (m, 1H), 9.40 (m, 1H), 10.48 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值368.4；實測值369.2；Rt=2.020min。LCMS (ESI): [M] + m/z: calculated 368.4; found 369.2; Rt=2.020 min.

實例307.外消旋 -N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S )-2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物164)之合成Example 307. Racemic - N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5S )-2-(4-hydroxyphenyl)-5-methylpiperidine Synthesis of pyridin-1-yl)-2-oxoacetamide (compound 164)

Figure 110128222-A0202-12-1506-415
Figure 110128222-A0202-12-1506-415

將TEA(1.75g，17.25mmol，2.40mL)添加到4-(5-甲基-2-哌啶基)苯酚(2.2g，1.73mmol)(來自前一步驟之粗品)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(509.47mg，1.73mmol)及HATU(1.31g，3.45mmol)於DMF(15mL)之混合物中。將反應混合物在25℃下攪拌12h，然後在真空中蒸發。將殘餘物用水(30ml)稀釋且用乙酸乙酯(2*20ml)萃取。將經合併之 有機萃取物用鹽水(10ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，留下800mg殘餘物，其藉由反相HPLC(管柱：SunFire C18 100x18mm 5um)使用25-50% 0-5min水-MeCN作為流動相進行純化，以得到兩種級分之羥boc 保護之醯胺：20mg(藉由LCMS測得40%，第1級分)及40mg(藉由LCMS測得73%，第2級分)。將兩種級分合併，溶解於1,4-二噁烷(1.5mL)及水(2mL)之混合物中，且在95℃下攪拌48h。等分試樣之LCMS顯示完全boc -去保護，將反應混合物冷卻且提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um)使用35-60% 0-5min 0.1% NH3 -MeOH作為流動相，以得到呈白色固體之化合物164 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(16mg，43.43μmol，2.52%產率)。TEA (1.75 g, 17.25 mmol, 2.40 mL) was added to 4-(5-methyl-2-piperidinyl)phenol (2.2 g, 1.73 mmol) (crude from previous step), 2-[[6 -( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (509.47 mg, 1.73 mmol) and HATU (1.31 g, 3.45 mmol) in DMF (15 mL) of the mixture. The reaction mixture was stirred at 25 °C for 12 h, then evaporated in vacuo. The residue was diluted with water (30ml) and extracted with ethyl acetate (2*20ml). The combined organic extracts were washed with brine (10 ml), dried over sodium sulfate and evaporated in vacuo to leave a residue of 800 mg which was 25-50% by reverse phase HPLC (column: SunFire C18 100x18mm 5um) Purification with water-MeCN as mobile phase for 0-5 min gave two fractions of the hydroxyboc protected amide: 20 mg (40% by LCMS, fraction 1) and 40 mg (73 by LCMS) %, grade 2). The two fractions were combined, dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (2 mL) and stirred at 95 °C for 48 h. LCMS of an aliquot showed complete boc -deprotection, the reaction mixture was cooled and submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um) using 35-60% 0-5min 0.1% NH3 -MeOH as flow phase to give compound 164 as a white solid N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(4-hydroxyphenyl)-5- Methyl-1-piperidinyl]-2-oxyacetamide (16 mg, 43.43 μmol, 2.52% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.00(m,3H),1.30(m,1H),1.68(m,1H),1.86(m,1H),2.02(m,4H),2.14(m,1H),2.96(m,2H),3.97(m,1H),5.58(m,3H),6.76(m,2H),7.12(m,2H),7.48(m,1H),8.00(m,1H),10.46(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.00(m, 3H), 1.30(m, 1H), 1.68(m, 1H), 1.86(m, 1H), 2.02(m, 4H), 2.14(m, 1H), 2.96(m, 2H), 3.97(m, 1H), 5.58(m, 3H), 6.76(m, 2H), 7.12(m, 2H), 7.48(m, 1H), 8.00 (m, 1H), 10.46 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值368.4；實測值369.2；Rt=2.266min。LCMS (ESI): [M] + m/z: calculated 368.4; found 369.2; Rt=2.266 min.

實例308.外消旋 -N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5R )-5-甲基-2-(1-甲基-1H -吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物66)之合成Example 308. Racemic - N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5R )-5-methyl-2-(1-methyl- 1H- Synthesis of Pyrazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 66)

Figure 110128222-A0202-12-1507-416
Figure 110128222-A0202-12-1507-416

將TEA(1.20g，11.90mmol，1.66mL)添加到5-甲基-2-(2-甲基吡唑-3-基)哌啶(300mg，1.19mmol，2HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(351.28mg，1.19mmol)及HATU(497.56mg，1.31mmol)於DMF(15mL)中之混合物中。將反應混合物在25℃下攪拌1h，然後在真空中蒸發。將殘餘物溶解於二氯甲烷(10mL)中且添加於二噁烷中之4.0M氯化氫溶液 (21.00g，80.06mmol，26.25mL，13.9%純度)。將所得混合物在25℃下攪拌2h，然後在真空中蒸發且藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um)使用30-50%，50-60% 0-5min 0.1% NH3 -甲醇作為流動相純化殘餘物，以得到化合物66 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S )-5-甲基-2-(2-甲基吡唑-3-基)-1-哌啶基]-2-側氧基乙醯胺(98mg，274.96μmol，23.11%產率)。TEA (1.20 g, 11.90 mmol, 1.66 mL) was added to 5-methyl-2-(2-methylpyrazol-3-yl)piperidine (300 mg, 1.19 mmol, 2HCl), 2-[[6- ( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-side oxyacetic acid (351.28 mg, 1.19 mmol) and HATU (497.56 mg, 1.31 mmol) in DMF ( 15mL) in the mixture. The reaction mixture was stirred at 25°C for 1 h, then evaporated in vacuo. The residue was dissolved in dichloromethane (10 mL) and a 4.0 M solution of hydrogen chloride in dioxane (21.00 g, 80.06 mmol, 26.25 mL, 13.9% pure) was added. The resulting mixture was stirred at 25°C for 2h, then evaporated in vacuo and purified by reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um) using 30-50%, 50-60% 0-5 min 0.1% NH3- The residue was purified with methanol as mobile phase to give compound 66 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5S )-5-methyl-2-(2- Methylpyrazol-3-yl)-1-piperidinyl]-2-oxoacetamide (98 mg, 274.96 μmol, 23.11% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.82(m,3H),1.56(m,2H),1.74(m,2H),1.92(m,1H),2.03(m,5H),2.62(m,1H),3.54(m,1H),5.71(m,4H),6.44(m,1H),7.37(m,1H),7.50(m,1H),8.02(m,1H),10.47(m,1H)。LCMS(ESI)：[M+1]m/z：計算值356.4；實測值357.2；Rt=2.214min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.82(m, 3H), 1.56(m, 2H), 1.74(m, 2H), 1.92(m, 1H), 2.03(m, 5H), 2.62(m, 1H), 3.54(m, 1H), 5.71(m, 4H), 6.44(m, 1H), 7.37(m, 1H), 7.50(m, 1H), 8.02(m, 1H), 10.47 (m, 1H). LCMS (ESI): [M+1] m/z: calculated 356.4; found 357.2; Rt=2.214 min.

實例309. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物498)之合成Example 309. N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]- Synthesis of 1-Piperidinyl]-2-Oxyacetamide (Compound 498)

Figure 110128222-A0202-12-1508-417
Figure 110128222-A0202-12-1508-417

步驟1：(3-甲基-5-(2-((2S,5R)-5-甲基-2-(4-(甲胺基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-((2S,5R)-5-methyl-2-(4-(methylamino)phenyl)piperidin-1-yl)-2-side Synthesis of tert-butyl oxyacetamido)pyridin-2-yl)carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(213.03mg，721.42μmol)、N-甲基-4-[(2S,5R)-5-甲基-2-哌啶基]苯胺(0.2g，721.42μmol，2HCl)、HATU(301.73mg，793.56μmol)及DIPEA(279.71mg，2.16mmol，376.96μL)一起混合於DMSO(4mL)中且攪拌4h。使所獲得之於DMSO中之溶液經歷HPLC(依次重複兩次純化，以獲得95+%純度之產物：第1次裝載：2-10min以35-100% MeOH/H2 O為流動相；流速30mL/min；裝載泵4ml MeOH；SunFire 100* 19mm，5微米管柱；第2次裝載：2-10min以40-60%水/MeCN+NH3 為流動 相；裝載泵4mL MeCN+NH3 ；TRIART 100* 20 5微米管柱)，以獲得N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(16mg，33.22μmol，4.61%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (213.03 mg, 721.42 μmol), N-methyl -4-[(2S,5R)-5-methyl-2-piperidinyl]aniline (0.2 g, 721.42 μmol, 2HCl), HATU (301.73 mg, 793.56 μmol) and DIPEA (279.71 mg, 2.16 mmol, 376.96 μL) were mixed together in DMSO (4 mL) and stirred for 4 h. The obtained solution in DMSO was subjected to HPLC (purification was repeated twice in sequence to obtain 95+% pure product: 1st load: 2-10 min with 35-100% MeOH/ H2O as mobile phase; flow rate 30mL/min; loading pump 4ml MeOH; SunFire 100 * 19mm, 5 micron column; 2nd loading: 2-10min with 40-60% water/MeCN+ NH3 as mobile phase; loading pump 4mL MeCN+ NH3 ; TRIART 100 * 20 5 micron column) to obtain N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl ]-1-Piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (16 mg, 33.22 μmol, 4.61% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值481.2；實測值483.2；Rt=1.074min。LCMS (ESI): [M+2H] + m/z: calculated 481.2; found 483.2; Rt=1.074 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物498 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 498 )

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(16mg，33.22μmol)溶解於水(0.5mL)及二噁烷(0.5mL)之混合物中。將反應混合物在100℃下攪拌16h。然後，使當前溶液中之粗產物經歷HPLC(2-10min以40-60%水/MeCN+NH3 為流動相；裝載泵4mL MeCN+NH3 ；TRIART 100* 20 5微米管柱)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(8.7mg，22.81μmol，68.65%產率)。N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (16 mg, 33.22 μmol) was dissolved in a mixture of water (0.5 mL) and dioxane (0.5 mL). The reaction mixture was stirred at 100 °C for 16 h. The crude product in the current solution was then subjected to HPLC (2-10 min with 40-60% water/MeCN+ NH3 as mobile phase; loading pump 4 mL MeCN+ NH3 ; TRIART 100 * 20 5 micron column) to obtain N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(methylamino)phenyl]-1-piperidine Peridyl]-2-Pendant oxyacetamide (8.7 mg, 22.81 μmol, 68.65% yield).

1 H NMR(600MHz,DMSO-d6 )δ 1.04-1.22(m,3H),1.27-1.41(m,1H),1.63-1.94(m,2H),1.95-2.11(m,4H),2.10-2.18(m,1H),2.69(s,3H),2.74-2.79(m,0.4H),3.19-3.26(m,0.6H),3.50-4.04(m,1H),5.06-5.13(m,0.4H),5.16-5.35(m,3H),5.53-5.62(m,0.6H),6.44-6.53(m,2H),6.92-6.98(m,1H),6.99-7.08(m,1H),7.48-7.59(m,1H),7.97-8.05(m,1H),10.24-10.35(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.04-1.22(m,3H), 1.27-1.41(m,1H), 1.63-1.94(m,2H), 1.95-2.11(m,4H), 2.10- 2.18(m, 1H), 2.69(s, 3H), 2.74-2.79(m, 0.4H), 3.19-3.26(m, 0.6H), 3.50-4.04(m, 1H), 5.06-5.13(m, 0.4 H), 5.16-5.35(m, 3H), 5.53-5.62(m, 0.6H), 6.44-6.53(m, 2H), 6.92-6.98(m, 1H), 6.99-7.08(m, 1H), 7.48 -7.59(m, 1H), 7.97-8.05(m, 1H), 10.24-10.35(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=2.042min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=2.042 min.

實例310. 2-(2-(1H -吲哚-5-基)-5-甲基哌啶-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物385、化合物388)之合成Example 310. 2-(2-( 1H -Indol-5-yl)-5-methylpiperidin - 1-yl)-N-(6-amino-5-methylpyridin-3-yl)- Synthesis of 2-Pendant Oxyacetamide (Compound 385, Compound 388)

Figure 110128222-A0202-12-1510-418
Figure 110128222-A0202-12-1510-418

步驟1：(5-(2-(2-(1H-吲哚-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(1H-Indol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methyl Synthesis of tert-butyl pyridin-2-yl)carbamate

在室溫下將HATU(603.24mg，1.59mmol)分批添加到2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(468.48mg，1.59mmol)、5-(5-甲基-2-哌啶基)-1H -吲哚(400mg，1.59mmol)及TEA(963.24mg，9.52mmol，1.33mL)於DMF(9mL)中之懸浮液中。將澄清溶液在30℃下攪拌32h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：SunFireC18 100x19mm 5um；以65-56-90% 0-1-5min水-MeOH為流動相)，以得到N -[5-[[2-[2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(192.8mg，392.20μmol，24.72%產率)。HATU (603.24 mg, 1.59 mmol) was added portionwise to 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2- at room temperature Pendant oxyacetic acid (468.48 mg, 1.59 mmol), 5-(5-methyl-2-piperidinyl)-1H-indole (400 mg, 1.59 mmol) and TEA ( 963.24 mg, 9.52 mmol, 1.33 mL) were added to suspension in DMF (9 mL). The clear solution was stirred at 30 °C for 32 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: SunFire C18 100x19mm 5um; 65-56-90% 0-1-5 min water-MeOH as mobile phase) to give N- [5-[[2-[2-( 1H -Indol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (192.8 mg, 392.20 μmol, 24.72% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值491.2；實測值492.2；Rt=3.712min。LCMS (ESI): [M] + m/z: calculated 491.2; found 492.2; Rt=3.712 min.

步驟2：2-(2-(1H-吲哚-5-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺之合成Step 2: 2-(2-(1H-Indol-5-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridin-3-yl)- Synthesis of 2-Pendant Oxyacetamide

將N -[5-[[2-[2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(170mg，345.82μmol)於二噁烷(2mL)及水(1mL)中之溶液在95℃下攪拌12h且在真空中蒸發溶劑，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(120mg，306.54μmol，88.64%產率)。 N- [5-[[2-[2-( 1H -indol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3 A solution of -methyl-2-pyridyl]carbamic acid tert- butyl ester (170 mg, 345.82 μmol) in dioxane (2 mL) and water (1 mL) was stirred at 95 °C for 12 h and the solvent was evaporated in vacuo to give to give N- (6-amino-5-methyl-3-pyridinyl)-2-[2-( 1H -indol-5-yl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetamide (120 mg, 306.54 μmol, 88.64% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值391.2；實測值392.2；Rt=1.051min。LCMS (ESI): [M] + m/z: calculated 391.2; found 392.2; Rt=1.051 min.

步驟3：掌性分離(化合物385 及化合物388 )Step 3: Chiral separation ( compound 385 and compound 388 )

藉由掌性HPLC分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物385 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(50mg，127.73μmol，83.33%產率)(保留時間=56.6min)及化合物388 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(1H -吲哚-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(50mg，127.73μmol，83.33%產率)(保留時間=68.8min)。體系1.管柱：Chiralpak IA(250*20，5mkm)；流動相：己烷-IPA-MeOH，70-15-15；Separation of the enantiomers by chiral HPLC to give two separate enantiomers Compound 385 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R ) -2-( 1H -indol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (50 mg, 127.73 μmol, 83.33% yield) (retention time=56.6 min) and compound 388 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-( 1H -indol-5-yl)-5-methyl -1-Piperidinyl]-2-oxoacetamide (50 mg, 127.73 μmol, 83.33% yield) (retention time = 68.8 min). System 1. Column: Chiralpak IA (250*20, 5mkm); Mobile phase: Hexane-IPA-MeOH, 70-15-15;

流速：12mL/min；管柱溫度：24℃；波長：205nm，225nm，372nm)；Flow rate: 12mL/min; column temperature: 24°C; wavelength: 205nm, 225nm, 372nm);

體系2.管柱：Chiralpak IC(250*20，5mkm)；流動相：己烷-IPA-MeOH，80-10-10System 2. Column: Chiralpak IC (250*20, 5mkm); Mobile phase: Hexane-IPA-MeOH, 80-10-10

流速：12mL/min；管柱溫度：24℃；波長：205nm，225nm，372nm)。Flow rate: 12 mL/min; column temperature: 24°C; wavelength: 205 nm, 225 nm, 372 nm).

化合物385 於分析條件下(管柱：IC，己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為19.53min且化合物388 之保留時間為27.05min。The retention time of compound 385 under analytical conditions (column: IC, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 19.53 min and the retention time of compound 388 was 27.05 min.

化合物385：保留時間：19.53minCompound 385: retention time: 19.53min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.03(m,3H),1.26-1.39(m,1H),1.74-1.90(m,2H),1.96-2.03(m,3H),2.04-2.21(m,1H),2.23-2.32(m,1H),2.75-3.24(m,1H),3.37-4.01(m,1H),5.14-5.58(m,1H),5.58-5.72(m,2H),6.34-6.42(m,1H),6.96-7.12(m,1H),7.29-7.32(m,1H),7.33-7.39(m,1H),7.41-7.47(m,1H),7.48-7.52(m,1H),7.91-8.09(m,1H),10.41-10.58(m,1H),11.03(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.03(m,3H), 1.26-1.39(m,1H), 1.74-1.90(m,2H), 1.96-2.03(m,3H) ,2.04-2.21(m,1H),2.23-2.32(m,1H),2.75-3.24(m,1H),3.37-4.01(m,1H),5.14-5.58(m,1H),5.58-5.72( m,2H),6.34-6.42(m,1H),6.96-7.12(m,1H),7.29-7.32(m,1H),7.33-7.39(m,1H),7.41-7.47(m,1H), 7.48-7.52(m,1H), 7.91-8.09(m,1H), 10.41-10.58(m,1H), 11.03(s,1H).

LCMS(ESI)：[M]+ m/z：計算值391.2；實測值392.2；Rt=2.214min。LCMS (ESI): [M] + m/z: calculated 391.2; found 392.2; Rt=2.214 min.

化合物388：保留時間：27.05minCompound 388: retention time: 27.05min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.28-1.39(m,1H),1.72-1.91(m,2H),1.95-2.03(m,3H),2.04-2.21(m,1H),2.22-2.33(m,1H),2.77-3.24 (m,1H),3.39-4.03(m,1H),5.19-5.57(m,1H),5.57-5.74(m,2H),6.38(s,1H),6.96-7.12(m,1H),7.27-7.33(m,1H),7.33-7.40(m,1H),7.40-7.48(m,1H),7.48-7.54(m,1H),7.92-8.09(m,1H),10.38-10.62(m,1H),11.03(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.05(m,3H), 1.28-1.39(m,1H), 1.72-1.91(m,2H), 1.95-2.03(m,3H) ,2.04-2.21(m,1H),2.22-2.33(m,1H),2.77-3.24(m,1H),3.39-4.03(m,1H),5.19-5.57(m,1H),5.57-5.74( m,2H),6.38(s,1H),6.96-7.12(m,1H),7.27-7.33(m,1H),7.33-7.40(m,1H),7.40-7.48(m,1H),7.48- 7.54 (m, 1H), 7.92-8.09 (m, 1H), 10.38-10.62 (m, 1H), 11.03 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值391.2；實測值392.2；Rt=2.228min。LCMS (ESI): [M] + m/z: calculated 391.2; found 392.2; Rt=2.228 min.

實例311. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物518)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物535)之合成Example 311. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S)-2-(1H-indazol-5-yl)-1-piperidinyl]-2 - Pendant oxyacetamide (compound 518) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R)-2-(1H-indazol-5-yl) Synthesis of -1-piperidinyl]-2-oxoacetamide (Compound 535)

Figure 110128222-A0202-12-1512-420
Figure 110128222-A0202-12-1512-420

步驟1：N-[5-[[2-[2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(1H-Indazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl Synthesis of -2-pyridyl]carbamic acid tert-butyl ester

在25℃下，向5-(2-哌啶基)-1H-吲唑(200mg，993.70μmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(293.43mg，993.70μmol)及DIPEA(642.15mg，4.97mmol，865.43μL)於DMF(5mL)中之正攪拌溶 液中添加HATU(566.75mg，1.49mmol)。將所得反應混合物在25℃下攪拌16h。將反應混合物樣品提交用於LCMS分析。LCMS指示在RT=1.169min處34.89%所要產物質量曲線下面積。藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um，流動相：40-40-80% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min，裝載泵4ml/min甲醇)純化粗反應混合物，以得到呈淡黃色固體之N-[5-[[2-[2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(267mg，557.94μmol，56.15%產率)。To 5-(2-piperidinyl)-1H-indazole (200 mg, 993.70 μmol), 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3 at 25°C -Pyridinyl]amino]-2-oxoacetic acid (293.43 mg, 993.70 μmol) and DIPEA (642.15 mg, 4.97 mmol, 865.43 μL) in DMF (5 mL) was added HATU (566.75 mg, 1.49 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. A sample of the reaction mixture was submitted for LCMS analysis. LCMS indicated the area under the curve of 34.89% desired product mass at RT=1.169 min. By reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um, mobile phase: 40-40-80% 0-1-6min 0.1% NH3 -methanol, flow rate: 30ml/min, loading pump 4ml/min methanol) The crude reaction mixture was purified to give N-[5-[[2-[2-(1H-indazol-5-yl)-1-piperidinyl]-2-pendoxetylacetone as a pale yellow solid ]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (267 mg, 557.94 μmol, 56.15% yield).

1 H NMR(500MHz,DMSO)δ 1.20-1.30(m,9H),1.45-1.70(m,4H),1.95(m,1H),2.13(m,3H),2.59及3.02(m，兩種旋轉異構體之2H),3.70及4.29(d，兩種旋轉異構體之1H),5.25及5.78(s，兩種旋轉異構體之1H),7.29及7.37(d，兩種旋轉異構體之1H),7.55(m,1H),7.73(d,1H),7.88及7.97(s，兩種旋轉異構體之1H),8.07(s,1H),8.37及8.48(s，兩種旋轉異構體之1H),9.02及9.07(s，兩種旋轉異構體之1H),11.07(s,1H),13.05(s,1H)。 1 H NMR (500MHz, DMSO) δ 1.20-1.30 (m, 9H), 1.45-1.70 (m, 4H), 1.95 (m, 1H), 2.13 (m, 3H), 2.59 and 3.02 (m, two rotations 2H of both rotamers), 3.70 and 4.29 (d, 1H of both rotamers), 5.25 and 5.78 (s, 1H of both rotamers), 7.29 and 7.37 (d, of both rotamers 1H), 7.55(m, 1H), 7.73(d, 1H), 7.88 and 7.97(s, 1H of two rotamers), 8.07(s, 1H), 8.37 and 8.48(s, two 1H of rotamer), 9.02 and 9.07 (s, 1H of both rotamers), 11.07 (s, 1H), 13.05 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值478.3；實測值479.2；Rt=2.787min。LCMS (ESI): [M+H] + m/z: calculated 478.3; found 479.2; Rt=2.787 min.

步驟2：N-[5-[[2-[(2S)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P1)及N-[5-[[2-[(2R)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P2)之合成Step 2: N-[5-[[2-[(2S)-2-(1H-indazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]- 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (P1) and N-[5-[[2-[(2R)-2-(1H-indazol-5-yl)-1-piperidine Synthesis of pyridyl]-2-side oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P2)

將外消旋N-[5-[[2-[2--(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(267mg，557.94μmol)提交至製備型掌性HPLC(管柱：Chiralpak IA-II(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 60-20-20；流速：12mL/min)，以得到呈淡黃色固體之N-[5-[[2-[(2S)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P1)(88mg，183.89μmol，32.96%產率)(R.T.=23.157min)及N-[5-[[2-[(2R)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P2) (83mg，173.44μmol，31.09%產率)(R.T.=32.819)。The racemic N-[5-[[2-[2--(1H-indazol-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]-3- 3-butyl methyl-2-pyridyl]carbamate (267 mg, 557.94 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IA-II (250*20 mm, 5 mkm); mobile phase: Hexane-IPA -MeOH 60-20-20; flow rate: 12 mL/min) to give N-[5-[[2-[(2S)-2-(1H-indazol-5-yl)-1 as a pale yellow solid -Piperidinyl]-2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P1) (88 mg, 183.89 μmol, 32.96% yield) ( R.T.=23.157min) and N-[5-[[2-[(2R)-2-(1H-indazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amine tert-butyl]-3-methyl-2-pyridyl]carbamate (P2) (83 mg, 173.44 μmol, 31.09% yield) (R.T.=32.819).

P1： 1 H NMR(500MHz,DMSO)δ 1.20-1.30(m,9H),1.45-1.70(m,4H),1.95(m,1H),2.13(m,3H),2.59及3.02(m，兩種旋轉異構體之2H),3.70及4.29(d，兩種旋轉異構體之1H),5.25及5.78(s，兩種旋轉異構體之1H),7.29及7.37(d，兩種旋轉異構體之1H),7.55(m,1H),7.73(d,1H),7.88及7.97(s，兩種旋轉異構體之1H),8.07(s,1H),8.37及8.48(s，兩種旋轉異構體之1H),9.02及9.07(s，兩種旋轉異構體之1H),11.07(s,1H),13.05(s,1H)。 P1: 1 H NMR (500 MHz, DMSO) δ 1.20-1.30 (m, 9H), 1.45-1.70 (m, 4H), 1.95 (m, 1H), 2.13 (m, 3H), 2.59 and 3.02 (m, two 2H of two rotamers), 3.70 and 4.29 (d, 1H of both rotamers), 5.25 and 5.78 (s, 1H of both rotamers), 7.29 and 7.37 (d, of both rotamers 1H), 7.55(m, 1H), 7.73(d, 1H), 7.88 and 7.97(s, 1H of the two rotamers), 8.07(s, 1H), 8.37 and 8.48(s, 1H of the two rotamers), 9.02 and 9.07 (s, of the two rotamers 1H), 11.07 (s, 1H), 13.05 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值478.3；實測值479.2；Rt=3.158min。LCMS (ESI): [M+H] + m/z: calculated 478.3; found 479.2; Rt=3.158 min.

RT(IA-3，己烷-IPA-MeOH，60-20-20，12ml/min)=24.48minRT(IA-3, Hexane-IPA-MeOH, 60-20-20, 12ml/min)=24.48min

P2： 1 H NMR(500MHz,DMSO)δ 1.20-1.30(m,9H),1.45-1.70(m,4H),1.95(m,1H),2.13(m,3H),2.59及3.02(m，兩種旋轉異構體之2H),3.70及4.29(d，兩種旋轉異構體之1H),5.25及5.78(s，兩種旋轉異構體之1H),7.29及7.37(d，兩種旋轉異構體之1H),7.55(m,1H),7.73(d,1H),7.88及7.97(s，兩種旋轉異構體之1H),8.07(s,1H),8.37及8.48(s，兩種旋轉異構體之1H),9.02及9.07(s，兩種旋轉異構體之1H),11.07(s,1H),13.05(s,1H)。 P2: 1 H NMR (500 MHz, DMSO) δ 1.20-1.30 (m, 9H), 1.45-1.70 (m, 4H), 1.95 (m, 1H), 2.13 (m, 3H), 2.59 and 3.02 (m, two 2H of two rotamers), 3.70 and 4.29 (d, 1H of both rotamers), 5.25 and 5.78 (s, 1H of both rotamers), 7.29 and 7.37 (d, of both rotamers 1H), 7.55(m, 1H), 7.73(d, 1H), 7.88 and 7.97(s, 1H of the two rotamers), 8.07(s, 1H), 8.37 and 8.48(s, 1H of the two rotamers), 9.02 and 9.07 (s, of the two rotamers 1H), 11.07 (s, 1H), 13.05 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值478.3；實測值479.2；Rt=3.159min。LCMS (ESI): [M+H] + m/z: calculated 478.3; found 479.2; Rt=3.159 min.

RT(IA-3，己烷-IPA-MeOH，60-20-20，12ml/min)=34.42minRT(IA-3, Hexane-IPA-MeOH, 60-20-20, 12ml/min)=34.42min

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物518 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S)-2-(1H-indazol-5-yl)-1-piperidinyl]-2 - Synthesis of Pendant Oxyacetamide ( Compound 518 )

將N-[5-[[2-[(2S)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P1)(88mg，183.89μmol)於水(2mL)及1.4-二噁烷(2mL)之混合物中之溶液在95℃下攪拌24h，然後冷卻且提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相30-30-80% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min)，以得到呈白色固體之化合物518 N-(6-胺基-5-甲基 -3-吡啶基)-2-[(2S)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(48.4mg，127.90μmol，69.55%產率)。N-[5-[[2-[(2S)-2-(1H-indazol-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]-3- A solution of tert-butyl methyl-2-pyridyl]carbamate (P1) (88 mg, 183.89 μmol) in a mixture of water (2 mL) and 1.4-dioxane (2 mL) was stirred at 95 °C for 24 h, then Cool and submit to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase 30-30-80% 0-1-5min 0.1% NH3 -methanol, flow rate: 30ml/min) to give a white solid Compound 518 N-(6-amino-5-methyl-3-pyridyl)-2-[(2S)-2-(1H-indazol-5-yl)-1-piperidinyl]-2 - Pendant oxyacetamide (48.4 mg, 127.90 μmol, 69.55% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.43-1.61(m,3H),1.61-1.70(m,1H),1.77-1.96(m,1H),1.96-2.07(m,3H),2.51-2.57(m,2H),2.93-3.27(m,1H),3.61-4.29(m,1H),5.17-5.57(m,1H),5.57-5.79(m,2H),7.24-7.38(m,1H),7.41-7.58(m,2H),7.65-7.73(m,1H),7.93-8.06(m,2H),10.45-13.05(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.43-1.61(m,3H), 1.61-1.70(m,1H), 1.77-1.96(m,1H), 1.96-2.07(m,3H), 2.51- 2.57(m, 2H), 2.93-3.27(m, 1H), 3.61-4.29(m, 1H), 5.17-5.57(m, 1H), 5.57-5.79(m, 2H), 7.24-7.38(m, 1H ), 7.41-7.58(m, 2H), 7.65-7.73(m, 1H), 7.93-8.06(m, 2H), 10.45-13.05(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值378.2；實測值379.2；Rt=1.420min。LCMS (ESI): [M+H]+ m/z: calculated 378.2; found 379.2; Rt=1.420 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物535 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R)-2-(1H-indazol-5-yl)-1-piperidinyl]-2 - Synthesis of Pendant Oxyacetamide ( Compound 535 )

將N-[5-[[2-[(2R)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P2)(83mg，173.44μmol)於水(2mL)及1.4-二噁烷(2mL)之混合物中之溶液在95℃下攪拌24h，然後冷卻且提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相30-30-80% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min)，以得到呈白色固體之化合物535 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-(1H-吲唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(49.2mg，130.01μmol，74.96%產率)。N-[5-[[2-[(2R)-2-(1H-indazol-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]-3- A solution of tert-butyl methyl-2-pyridyl]carbamate (P2) (83 mg, 173.44 μmol) in a mixture of water (2 mL) and 1.4-dioxane (2 mL) was stirred at 95 °C for 24 h, then Cool and submit to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase 30-30-80% 0-1-5min 0.1% NH3 -methanol, flow rate: 30ml/min) to give a white solid Compound 535 N-(6-amino-5-methyl-3-pyridyl)-2-[(2R)-2-(1H-indazol-5-yl)-1-piperidinyl]-2 - Pendant oxyacetamide (49.2 mg, 130.01 μmol, 74.96% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.42-1.61(m,3H),1.62-1.68(m,1H),1.81-1.95(m,1H),1.95-2.06(m,3H),2.50-2.56(m,2H),2.94-3.27(m,1H),3.59-4.32(m,1H),5.20-5.59(m,1H),5.59-6.00(m,2H),7.24-7.39(m,1H),7.40-7.59(m,2H),7.65-7.73(m,1H),7.92-8.07(m,2H),10.30-13.30(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.42-1.61(m,3H), 1.62-1.68(m,1H), 1.81-1.95(m,1H), 1.95-2.06(m,3H), 2.50- 2.56(m, 2H), 2.94-3.27(m, 1H), 3.59-4.32(m, 1H), 5.20-5.59(m, 1H), 5.59-6.00(m, 2H), 7.24-7.39(m, 1H) ), 7.40-7.59(m, 2H), 7.65-7.73(m, 1H), 7.92-8.07(m, 2H), 10.30-13.30(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值378.2；實測值379.2；Rt=1.413min。LCMS (ESI): [M+H]+ m/z: calculated 378.2; found 379.2; Rt=1.413 min.

實例312. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物364)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,SR)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物Example 312. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1 -Piperidinyl]-2-oxoacetamide (Compound 364), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,SR)-2-( 1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 363)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1083)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物392)之合成363), N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-(1H-indazol-5-yl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide (Compound 1083) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-2-( Synthesis of 1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 392)

Figure 110128222-A0202-12-1516-421
Figure 110128222-A0202-12-1516-421

步驟1：N-[5-[[2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Synthesis of -3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向5-(5-甲基-2-哌啶基)-1H-吲唑(0.23g，1.07mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(315.46mg，1.07mmol)及HATU(446.82mg，1.18mmol)於DMF(6mL)中之懸浮液中添加三乙胺(540.51mg，5.34mmol，744.51μL)。將所得混合物在30℃下攪拌12h，用水(50ml)淬滅且用EtOAc(3* 30ml)萃取。將經合併之有機層用鹽水(3* 20ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得N-[5-[[2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.6g，粗品)。To 5-(5-methyl-2-piperidinyl)-1H-indazole (0.23 g, 1.07 mmol), 2-[[6-(tertiary butoxycarbonylamino)-5-methyl- To a suspension of 3-pyridyl]amino]-2-side oxyacetic acid (315.46 mg, 1.07 mmol) and HATU (446.82 mg, 1.18 mmol) in DMF (6 mL) was added triethylamine (540.51 mg, 5.34 mg) mmol, 744.51 μL). The resulting mixture was stirred at 30°C for 12h, quenched with water (50ml) and extracted with EtOAc (3 * 30ml). The combined organic layers were washed with brine (3 * 20ml), dried over Na2SO4 and evaporated to give N-[5-[[2-[2-(1H-indazol-5-yl)-5 -Methyl-1-piperidinyl]-2-oxoacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.6 g, crude).

此化合物不經純化即用於下一步驟。This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.00(d,3H),1.40(s,9H),1.74(m,4H),2.16(s,3H),3.98(m,2H),5.21(m,2H),5.67(m,2H),7.27(d,1H),7.49(d,1H),7.67(s,1H),8.02(s,1H),8.44(s,1H),9.04(s,1H),11.03(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.00(d, 3H), 1.40(s, 9H), 1.74(m, 4H), 2.16(s, 3H), 3.98(m, 2H), 5.21(m ,2H),5.67(m,2H),7.27(d,1H),7.49(d,1H),7.67(s,1H),8.02(s,1H),8.44(s,1H),9.04(s, 1H), 11.03 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值492.2；實測值493.2；Rt=1.158min。LCMS (ESI): [M+H] + m/z: calculated 492.2; found 493.2; Rt=1.158 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide

向N-[5-[[2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.6g，1.22mmol)於DCM(10mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌18h，在真空中蒸發且使其經歷HPLC(40-40-80% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量392，管柱：YMC Triart C18 100x20mm，5um)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(152mg，387.31μmol，31.80%產率)。To N-[5-[[2-[2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]-3 - tert-butyl methyl-2-pyridyl]carbamate (0.6 g, 1.22 mmol) in DCM (10 mL) was added to a solution of 4.0 M hydrogen chloride in dioxane (8.00 g, 219.41 mmol, 10 mL) ). The resulting mixture was stirred at 25°C for 18 h, evaporated in vacuo and subjected to HPLC (40-40-80% 0-1-5 min 0.1% NH3 -methanol, flow rate: 30 ml/min (load pump 4 ml/min methanol) ), target mass 392, column: YMC Triart C18 100x20mm, 5um) to obtain N-(6-amino-5-methyl-3-pyridyl)-2-[2-(1H-indazole-5 -yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (152 mg, 387.31 μmol, 31.80% yield).

未獲得此化合物之NMR譜且將其直接用於掌性拆分。An NMR spectrum for this compound was not obtained and was used directly for chiral resolution.

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=2.085min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=2.085 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物364 )、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物363 )、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1083 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物392 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide ( compound 364 ), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-( 1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide ( compound 363 ), N-(6-amino-5-methyl-3- Pyridyl)-2-[(2R,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 1083 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidine Synthesis of pyridyl]-2-side oxyacetamide ( compound 392 )

使N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(152.0mg)經歷HPLC(IA_II管柱，以己烷-IPA-MeOH，50-25-25為流動相；流速10ml/min)，以得到化合物364 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(43.0mg，62.87%產率；RT=41.665min)、化合物363 N-(6-胺基-5-甲基-3-吡啶 基)-2-[(2S,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(42.0mg，61.4%產率；RT=26.796min)、化合物1083 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(2.0mg，26.32%產率；RT=36.456min)及化合物392 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(4.0mg，52.63%產率；RT=23.296min)。make N-(6-amino-5-methyl-3-pyridyl)-2-[2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetamide (152.0 mg) was subjected to HPLC (IA_II column with hexane-IPA-MeOH, 50-25-25 as mobile phase; flow rate 10 ml/min) to give compound 364 N-(6-amine) yl-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetamide (43.0 mg, 62.87% yield; RT=41.665 min), compound 363 N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)- 2-(1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (42.0 mg, 61.4% yield; RT=26.796 min), compound 1083 N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-(1H-indazol-5-yl)-5-methyl-1-piperidine N-(6- amino -5-methyl-3-pyridyl)-2-[ (2S,5S)-2-(1H-Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (4.0 mg, 52.63% yield; RT= 23.296min).

化合物364： RT(IA-3，己烷-IPA-MeOH，60-20-20，0.15ml/min)=28.600min。 Compound 364: RT (IA-3, Hexane-IPA-MeOH, 60-20-20, 0.15 ml/min) = 28.600 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.04(m,3H),1.29-1.40(m,1H),1.71-1.80(m,1H),1.81-1.91(m,1H),1.95-2.03(m,3H),2.05-2.20(m,1H),2.25-2.34(m,1H),2.75-3.23(m,1H),3.35-4.05(m,1H),5.19-5.57(m,1H),5.57-5.70(m,2H),7.31(dd,1H),7.40-7.55(m,2H),7.66-7.72(m,1H),7.93-8.07(m,2H),10.40-10.56(m,1H),12.96-13.07(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.00-1.04(m,3H), 1.29-1.40(m,1H), 1.71-1.80(m,1H), 1.81-1.91(m,1H), 1.95- 2.03(m, 3H), 2.05-2.20(m, 1H), 2.25-2.34(m, 1H), 2.75-3.23(m, 1H), 3.35-4.05(m, 1H), 5.19-5.57(m, 1H) ), 5.57-5.70(m, 2H), 7.31(dd, 1H), 7.40-7.55(m, 2H), 7.66-7.72(m, 1H), 7.93-8.07(m, 2H), 10.40-10.56(m , 1H), 12.96-13.07 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=3.563min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=3.563 min.

化合物363： RT(IA-3，己烷-IPA-MeOH，60-20-20，0.15ml/min)=16.782min。 Compound 363: RT (IA-3, Hexane-IPA-MeOH, 60-20-20, 0.15 ml/min) = 16.782 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.03(m,3H),1.29-1.40(m,1H),1.71-1.79(m,1H),1.82-1.94(m,1H),1.96-2.04(m,3H),2.05-2.20(m,1H),2.22-2.30(m,1H),2.74-3.23(m,1H),3.41-4.03(m,1H),5.20-5.58(m,1H),5.59-5.70(m,2H),7.24-7.38(m,1H),7.40-7.57(m,2H),7.67-7.73(m,1H),7.93-8.07(m,2H),10.43-10.55(m,1H),12.94-13.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.03(m,3H), 1.29-1.40(m,1H), 1.71-1.79(m,1H), 1.82-1.94(m,1H), 1.96- 2.04(m, 3H), 2.05-2.20(m, 1H), 2.22-2.30(m, 1H), 2.74-3.23(m, 1H), 3.41-4.03(m, 1H), 5.20-5.58(m, 1H) ), 5.59-5.70(m, 2H), 7.24-7.38(m, 1H), 7.40-7.57(m, 2H), 7.67-7.73(m, 1H), 7.93-8.07(m, 2H), 10.43-10.55 (m, 1H), 12.94-13.08 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=3.551min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=3.551 min.

化合物1083： RT(IA-3，己烷-IPA-MeOH，60-20-20，0.15ml/min)=24.432min。 Compound 1083: RT (IA-3, Hexane-IPA-MeOH, 60-20-20, 0.15 ml/min) = 24.432 min.

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=3.599min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=3.599 min.

化合物392： RT(IA-3，己烷-IPA-MeOH，60-20-20，0.15ml/min)=15.413min。 Compound 392: RT (IA-3, Hexane-IPA-MeOH, 60-20-20, 0.15 ml/min) = 15.413 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.68-0.79(m,3H),1.10-1.21(m,1H),1.57-1.78 (m,2H),1.81-1.96(m,1H),1.96-2.07(m,3H),2.54-2.57(m,1H),3.52-3.60(m,1.7H),4.16-4.22(m,0.3H),5.17-6.02(m,3H),7.24-7.39(m,1H),7.41-7.52(m,1H),7.52-7.56(m,1H),7.64-7.75(m,1H),7.92-8.03(m,1H),8.04-8.20(m,1H),10.49-10.61(m,1H),13.02(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.68-0.79(m,3H), 1.10-1.21(m,1H), 1.57-1.78(m,2H), 1.81-1.96(m,1H), 1.96- 2.07(m, 3H), 2.54-2.57(m, 1H), 3.52-3.60(m, 1.7H), 4.16-4.22(m, 0.3H), 5.17-6.02(m, 3H), 7.24-7.39(m ,1H),7.41-7.52(m,1H),7.52-7.56(m,1H),7.64-7.75(m,1H),7.92-8.03(m,1H),8.04-8.20(m,1H),10.49 -10.61 (m, 1H), 13.02 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=3.600min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=3.600 min.

實例313.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物551及化合物572)之合成Example 313. N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R , 5S )-2-(4-hydroxy-3-methylphenyl)-5- Methyl-1-piperidinyl]-2-oxyacetamide and N- (6-amino-5-methyl-3-pyridyl)-2-[(2 S ,5 R )-2 Synthesis of -(4-Hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 551 and Compound 572)

Figure 110128222-A0202-12-1519-422
Figure 110128222-A0202-12-1519-422

步驟1：N-[5-[[2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(4-Hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amine Synthesis of tert-butyl]-3-methyl-2-pyridyl]carbamate

向2-甲基-4-(5-甲基-2-哌啶基)苯酚(250mg，1.22mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(359.59mg，1.22mmol)及HATU(509.33mg，1.34mmol)於DMSO(4mL)中之經攪拌之溶液中添加Et3 N(246.45mg，2.44mmol，339.46μL)。將反應混合物在20℃下攪拌16小時。16小 時之後，LCMS指示起始材料未完全消耗。將HATU(120mg)進一步添加到反應混合物中且將反應混合物攪拌40小時。40小時之後，藉由反相HPLC(溶析液：2-10min，40-60%，H2 O-MeOH；流速：30mL/min；裝載泵：4mL，MeOH；管柱：TRIART 100 x 20mm，5μM)純化反應混合物，以獲得呈棕色固體之N -[5-[[2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.12g，248.67μmol，20.42%產率)。To 2-methyl-4-(5-methyl-2-piperidinyl)phenol (250 mg, 1.22 mmol), 2-[[6-( tert- butoxycarbonylamino)-5-methyl- To a stirred solution of 3-pyridyl]amino]-2-pendoxoacetic acid (359.59 mg, 1.22 mmol) and HATU (509.33 mg, 1.34 mmol) in DMSO (4 mL) was added Et3N (246.45 mg) , 2.44 mmol, 339.46 μL). The reaction mixture was stirred at 20°C for 16 hours. After 16 hours, LCMS indicated incomplete consumption of starting material. HATU (120 mg) was further added to the reaction mixture and the reaction mixture was stirred for 40 hours. After 40 hours, by reverse phase HPLC (eluent: 2-10 min, 40-60%, H2O -MeOH; flow rate: 30 mL/min; loading pump: 4 mL, MeOH; column: TRIART 100 x 20 mm, 5 μM), the reaction mixture was purified to obtain N- [5-[[2-[2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2 as a brown solid - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.12 g, 248.67 [mu]mol, 20.42% yield).

LCMS(ESI)：[M+H]+ m/z：計算值482.3；實測值483.2；Rt=3.257min。LCMS (ESI): [M+H] + m/z: calculated 482.3; found 483.2; Rt=3.257 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl Synthesis of ]-2-oxyacetamide

將N -[5-[[2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.12g，248.67μmol)溶解於1,4-二噁烷(1mL)及水(1mL)中。將所得反應混合物在100℃下攪拌隔夜。然後藉由反相HPLC(溶析液：2-10min，40-60%，水+NH3 /MeOH+NH3 ；裝載泵：4mL，MeOH+NH3 ；管柱：TRIART 100 x 20mm，5μM)純化反應混合物，以獲得呈淡棕色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(69mg，180.41μmol，72.55%產率)。 N- [5-[[2-[2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] 3-Methyl-2-pyridyl]carbamic acid tert- butyl ester (0.12 g, 248.67 [mu]mol) was dissolved in 1,4-dioxane (1 mL) and water (1 mL). The resulting reaction mixture was stirred at 100°C overnight. Then by reverse phase HPLC (eluent: 2-10 min, 40-60%, water+ NH3 /MeOH+ NH3 ; loading pump: 4 mL, MeOH+ NH3 ; column: TRIART 100 x 20 mm, 5 μM) The reaction mixture was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[2-(4-hydroxy-3-methylphenyl)-5- as a light brown solid Methyl-1-piperidinyl]-2-oxoacetamide (69 mg, 180.41 μmol, 72.55% yield).

LCMS(ESI)：[M+H]+ m/z：計算值382.3；實測值383.4；Rt=1.960min。LCMS (ESI): [M+H] + m/z: calculated 382.3; found 383.4; Rt=1.960 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物551 及化合物572 )之掌性分離Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(4-hydroxy-3-methylphenyl)-5-methyl -1-Piperidinyl]-2-oxyacetamide and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4- Chiral isolation of hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 551 and Compound 572 )

使N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(69mg，180.41μmol)經歷掌性HPLC純化(管柱：OJ-H-I(250 x 20mm，5um)，溶析液：己烷-MeOH-IPA，60-20-20，流速：12mL/min)， 以獲得呈淡黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物551 ，24.61mg)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-(4-羥基-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物572 ，24.03mg)。Make N- (6-amino-5-methyl-3-pyridyl)-2-[2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]- 2-Pendoxacetamide (69 mg, 180.41 μmol) was purified by chiral HPLC (column: OJ-HI (250 x 20 mm, 5 um), eluent: Hexane-MeOH-IPA, 60-20-20 , flow rate: 12 mL/min) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[(2 R ,5 S )-2-(4- Hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide ( Compound 551 , 24.61 mg) and N-(6-amino-5-methyl) -3-Pyridinyl)-2-[( 2S , 5R )-2-(4-hydroxy-3-methylphenyl)-5-methyl-1-piperidinyl]-2-side oxy Acetamide ( compound 572 , 24.03 mg).

化合物551：Compound 551:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.94-1.03(m,3H),1.23-1.35(m,1H),1.63-1.76(m,1H),1.77-1.88(m,1H),1.90-1.97(m,1H),1.96-2.02(m,3H),2.07-2.16(m,4H),2.68-3.23(m,1H),3.37-3.99(m,1H),4.94-5.52(m,1H),5.52-5.63(m,2H),6.70-6.77(m,1H),6.84-6.94(m,1H),6.95-7.04(m,1H),7.39-7.51(m,1H),7.91-8.05(m,1H),9.20(s,1H),10.34-10.53(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.94-1.03 (m, 3H), 1.23-1.35 (m, 1H), 1.63-1.76 (m, 1H), 1.77-1.88 (m, 1H) ),1.90-1.97(m,1H),1.96-2.02(m,3H),2.07-2.16(m,4H),2.68-3.23(m,1H),3.37-3.99(m,1H),4.94-5.52 (m,1H),5.52-5.63(m,2H),6.70-6.77(m,1H),6.84-6.94(m,1H),6.95-7.04(m,1H),7.39-7.51(m,1H) , 7.91-8.05 (m, 1H), 9.20 (s, 1H), 10.34-10.53 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值382.3；實測值383.2；Rt=1.265min。LCMS (ESI): [M+H] + m/z: calculated 382.3; found 383.2; Rt=1.265 min.

掌性HPLC：Rt=21.77min(管柱：AD-H；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=21.77 min (column: AD-H; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

化合物572：Compound 572:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.95-1.01(m,3H),1.24-1.33(m,1H),1.63-1.75(m,1H),1.78-1.89(m,1H),1.90-1.97(m,1H),1.98-2.03(m,3H),2.08-2.17(m,4H),2.68-3.21(m,1H),3.37-3.97(m,1H),4.95-5.53(m,1H),5.55-5.63(m,2H),6.69-6.80(m,1H),6.86-6.95(m,1H),6.95-7.03(m,1H),7.39-7.55(m,1H),7.93-8.09(m,1H),9.03-9.43(m,1H),10.32-10.60(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.95-1.01 (m, 3H), 1.24-1.33 (m, 1H), 1.63-1.75 (m, 1H), 1.78-1.89 (m, 1H) ),1.90-1.97(m,1H),1.98-2.03(m,3H),2.08-2.17(m,4H),2.68-3.21(m,1H),3.37-3.97(m,1H),4.95-5.53 (m,1H),5.55-5.63(m,2H),6.69-6.80(m,1H),6.86-6.95(m,1H),6.95-7.03(m,1H),7.39-7.55(m,1H) , 7.93-8.09 (m, 1H), 9.03-9.43 (m, 1H), 10.32-10.60 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值382.3；實測值383.2；Rt=1.265min。LCMS (ESI): [M+H] + m/z: calculated 382.3; found 383.2; Rt=1.265 min.

掌性HPLC：Rt=19.12min(管柱：AD-H；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=19.12 min (column: AD-H; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

實例314.N -(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物373)之合成Example 314. N- (6-Amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(2-oxyindolin-5-yl)-1-piperidine Synthesis of pyridyl]-2-oxoacetamide (compound 373)

Figure 110128222-A0202-12-1522-423
Figure 110128222-A0202-12-1522-423

步驟1：N-[3-甲基-5-[[2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[5-methyl-2-(2-oxoindolin-5-yl)-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-2-pyridyl]carbamate

在室溫下，向5-(5-甲基-2-哌啶基)吲哚啉-2-酮(0.4g，1.74mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(512.87mg，1.74mmol)及三乙胺(1.76g，17.37mmol，2.42mL)於DMF(5mL)中之經攪拌之溶液中添加HATU(990.59mg，2.61mmol)。將所得反應混合物在同一溫度下攪拌18小時。18小時之後，在減壓下濃縮反應混合物。藉由HPLC(溶析液：2-10min，60-85%，MeOH/H2 O；流速：30mL/min；裝載泵：4mL，MeOH；管柱：SunFire 100 x19mm，5μM)純化所獲得之殘餘物，以獲得呈紅色固體之N -[3-甲基-5-[[2--[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.1017g，200.36μmol，11.54%產率)。To 5-(5-methyl-2-piperidinyl)indolin-2-one (0.4 g, 1.74 mmol), 2-[[6-( tert- butoxycarbonylamino) at room temperature )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (512.87 mg, 1.74 mmol) and triethylamine (1.76 g, 17.37 mmol, 2.42 mL) in DMF (5 mL) To the stirred solution was added HATU (990.59 mg, 2.61 mmol). The resulting reaction mixture was stirred at the same temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by HPLC (eluent: 2-10 min, 60-85%, MeOH/ H2O ; flow rate: 30 mL/min; loading pump: 4 mL, MeOH; column: SunFire 100 x 19 mm, 5 μM) to obtain N- [3-methyl-5-[[2--[5-methyl-2-(2-oxyindolin-5-yl)-1-piperidine as a red solid tert-butyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamate ( 0.1017 g, 200.36 [mu]mol, 11.54% yield).

LCMS(ESI)：[M+H]+ m/z：計算值507.3；實測值508.2；Rt=1.298min。LCMS (ESI): [M+H] + m/z: calculated 507.3; found 508.2; Rt=1.298 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物373 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(2-oxyindolin-5-yl)-1-piperidine Synthesis of pyridyl]-2-oxoacetamide ( compound 373 )

將N -[3-甲基-5-[[2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.1017g，200.36μmol)溶解於二噁烷(2mL)及水(2mL)中。將所得反應混合物在100℃下加熱18小時。完成之後，將反應混合物蒸發至乾，以獲得呈紅色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物373 ，0.056g，137.44μmol，68.59%產率)。 N- [3-methyl-5-[[2-[5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxygen Acetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (0.1017 g, 200.36 [mu]mol) was dissolved in dioxane (2 mL) and water (2 mL). The resulting reaction mixture was heated at 100°C for 18 hours. After completion, the reaction mixture was evaporated to dryness to obtain N- (6-amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-(2-oxoside as a red solid indolin-5-yl)-1-piperidinyl]-2-oxoacetamide ( compound 373 , 0.056 g, 137.44 μmol, 68.59% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.99-1.03(m,3H),1.22-1.37(m,1H),1.67-1.77(m,1H),1.82-1.93(m,1H),2.00-2.07(m,3H),2.09-2.24(m,1H),2.72-2.81(m,0.3H),3.21-3.25(m,0.7H),3.40-3.53(m,3H),3.64-4.02(m,1H),5.03-5.58(m,1H),5.58-5.70(m,2H),6.78-6.89(m,1H),7.07-7.27(m,2H),7.40-7.54(m,1H),7.93-8.08(m,1H),10.36(s,1H),10.43-10.57(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.99-1.03 (m, 3H), 1.22-1.37 (m, 1H), 1.67-1.77 (m, 1H), 1.82-1.93 (m, 1H) ), 2.00-2.07(m, 3H), 2.09-2.24(m, 1H), 2.72-2.81(m, 0.3H), 3.21-3.25(m, 0.7H), 3.40-3.53(m, 3H), 3.64 -4.02(m, 1H), 5.03-5.58(m, 1H), 5.58-5.70(m, 2H), 6.78-6.89(m, 1H), 7.07-7.27(m, 2H), 7.40-7.54(m, 1H), 7.93-8.08 (m, 1H), 10.36 (s, 1H), 10.43-10.57 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.2；Rt=0.856min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.2; Rt=0.856 min.

實例315. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5R)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物304)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物299)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物313)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5R)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物305)之合成Example 315. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,4R,5R)-4,5-dimethyl-2-phenyl-1-piperidine yl]-2-oxyacetamide (compound 304), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4S,5S)-4,5- Dimethyl-2-phenyl-1-piperidinyl]-2-oxoacetamide (Compound 299), N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,4R,5S)-4,5-dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (compound 313) and N-(6-amino- 5-Methyl-3-pyridyl)-2-[(2S,4S,5R)-4,5-dimethyl-2-phenyl-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 305)

Figure 110128222-A0202-12-1523-424
Figure 110128222-A0202-12-1523-424

步驟1：N-[5-[[2-(4,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-(4,5-Dimethyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]-3-methyl Synthesis of -2-pyridyl]carbamic acid tert-butyl ester

將4,5-二甲基-2-苯基哌啶(0.076g，401.49μmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(118.56mg，401.49μmol)、TEA(406.27mg，4.01mmol，559.59μL)及HATU(228.99mg，602.23μmol)溶解於DMF(2mL)中。將反應混合物在20℃下攪拌3h。將所得混合物用水稀釋且用EtOAc 萃取三次。然後將EtOAc用鹽水萃取三次。將有機相經Na2 SO4 乾燥，過濾出且在40℃下蒸發，以得到N-[5-[[2-(4,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.164g，351.50μmol，87.55%產率)，其不經進一步純化即用於下一步驟中。4,5-Dimethyl-2-phenylpiperidine (0.076 g, 401.49 μmol), 2-[[6-(3-butoxycarbonylamino)-5-methyl-3-pyridyl] Amino]-2-oxoacetic acid (118.56 mg, 401.49 μmol), TEA (406.27 mg, 4.01 mmol, 559.59 μL) and HATU (228.99 mg, 602.23 μmol) were dissolved in DMF (2 mL). The reaction mixture was stirred at 20 °C for 3 h. The resulting mixture was diluted with water and extracted three times with EtOAc. The EtOAc was then extracted three times with brine. The organic phase was dried over Na2SO4 , filtered off and evaporated at 40°C to give N-[5-[[2-(4,5-dimethyl-2-phenyl-1-piperidinyl) -2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.164 g, 351.50 μmol, 87.55% yield), which was used without further purification in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值467.2；Rt=3.991min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 467.2; Rt=3.991 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-(4,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-(4,5-dimethyl-2-phenyl-1-piperidinyl)-2-pendoxyl Synthesis of Acetamide

將N-[5-[[2-(4,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.164g，351.50μmol)溶解於二噁烷(2mL)及水(2mL)之混合物中。然後，在100℃下攪拌12h。在真空、55℃下濃縮反應混合物，以得到粗產物，其藉由HPLC(35-60%水-甲醇+NH3 ，2-10min，流速30ml/min(裝載泵4ml/min甲醇+NH3 )，管柱：SUNFIRE C18 100* 20mm)進行純化，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-(4,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(0.047g，128.26μmol，36.49%產率)。N-[5-[[2-(4,5-Dimethyl-2-phenyl-1-piperidinyl)-2-oxyacetyl]amino]-3-methyl-2 - tert-butyl pyridyl]carbamate (0.164 g, 351.50 μmol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL). Then, it was stirred at 100 °C for 12 h. The reaction mixture was concentrated under vacuum at 55°C to give the crude product, which was purified by HPLC (35-60% water-methanol+ NH3 , 2-10 min, flow rate 30 ml/min (loading pump 4 ml/min methanol+ NH3 ) , column: SUNFIRE C18 100 * 20mm) for purification to give N-(6-amino-5-methyl-3-pyridyl)-2-(4,5-dimethyl-2-phenyl- 1-Piperidinyl)-2-oxyacetamide (0.047 g, 128.26 μmol, 36.49% yield).

1 H NMR(400MHz,DMSO-d6 )δ 0.72(m,2H),0.93(m,3H),1.45(m,1H),2.03(m,3H),3.66(m,1H),5.64(m,2H),7.31(m,4H),7.48(m,1H),8.02(d,1H),10.46(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.72(m, 2H), 0.93(m, 3H), 1.45(m, 1H), 2.03(m, 3H), 3.66(m, 1H), 5.64(m , 2H), 7.31 (m, 4H), 7.48 (m, 1H), 8.02 (d, 1H), 10.46 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=1.110min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=1.110 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5R)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物304 )、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物299 )、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物313 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5R)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物305 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,4R,5R)-4,5-dimethyl-2-phenyl-1-piperidine base]-2-oxyacetamide ( compound 304 ), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4S,5S)-4,5- Dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetamide ( compound 299 ), N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,4R,5S)-4,5-dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetamide ( compound 313 ) and N-(6-amino- 5-Methyl-3-pyridyl)-2-[(2S,4S,5R)-4,5-dimethyl-2-phenyl-1-piperidinyl]-2-oxoacetamide Synthesis of ( Compound 305 )

將N-(6-胺基-5-甲基-3-吡啶基)-2-(4,5-二甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(0.047g，128.26μmol)使用管柱：Chiralpak IB(250* 20mm，5mkm)；流動相：己烷-IPA-MeOH，80-10-10流速：12mL/min；管柱溫度：24℃；波長：205nm，266nm，308nm)進行掌性分離，得到化合物304 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5R)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(6.5mg，17.74μmol，13.83%產率；RT=20.645min)、化合物299 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(6.90mg，18.83μmol，14.68%產率；RT=28.632min)、化合物313 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4R,5S)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(14.8mg，40.39μmol，31.49%產率；RT=22.209min)及化合物305 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S,5R)-4,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(14.1mg，38.48μmol，30.0%產率；RT=25.742min)。N-(6-Amino-5-methyl-3-pyridyl)-2-(4,5-dimethyl-2-phenyl-1-piperidinyl)-2-oxoacetyl Amine (0.047g, 128.26μmol) using column: Chiralpak IB (250 * 20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 80-10-10 flow rate: 12mL/min; column temperature: 24°C; Wavelength: 205nm, 266nm, 308nm) for chiral separation to obtain compound 304 N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4R,5R)-4,5- Dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (6.5 mg, 17.74 μmol, 13.83% yield; RT=20.645 min), compound 299 N-(6-amine) yl-5-methyl-3-pyridyl)-2-[(2S,4S,5S)-4,5-dimethyl-2-phenyl-1-piperidinyl]-2-side oxyethyl Amide (6.90 mg, 18.83 μmol, 14.68% yield; RT=28.632 min), compound 313 N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4R,5S )-4,5-dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (14.8 mg, 40.39 μmol, 31.49% yield; RT=22.209 min) and compound 305 N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,4S,5R)-4,5-dimethyl-2-phenyl-1-piperidinyl]- 2-Pendant oxyacetamide (14.1 mg, 38.48 μmol, 30.0% yield; RT=25.742 min).

化合物304： RT(IB，己烷-IPA-MeOH，80-10-10，0.6ml/min)=20.891min。 Compound 304: RT (IB, Hexane-IPA-MeOH, 80-10-10, 0.6 ml/min) = 20.891 min.

1 H NMR(500MHz,DMSO-d 6 )δ 0.44-0.63(m,3H),0.70-0.83(m,3H),1.87-1.92(m,1H),1.94-2.15(m,6H),2.91-3.01(m,1H),3.43-4.27(m,1H),5.12-5.47(m,1H),5.91(br s,2H),7.18-7.29(m,2H),7.29-7.39(m,3H),7.40-7.63(m,1H),7.87-8.14(m,1H),10.39-10.67(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.44-0.63(m,3H), 0.70-0.83(m,3H), 1.87-1.92(m,1H), 1.94-2.15(m,6H), 2.91- 3.01(m,1H),3.43-4.27(m,1H),5.12-5.47(m,1H),5.91(br s,2H),7.18-7.29(m,2H),7.29-7.39(m,3H) , 7.40-7.63 (m, 1H), 7.87-8.14 (m, 1H), 10.39-10.67 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.101min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.101 min.

化合物299： RT(IB，己烷-IPA-MeOH，80-10-10，0.6ml/min)=28.641min。 Compound 299: RT (IB, Hexane-IPA-MeOH, 80-10-10, 0.6 ml/min) = 28.641 min.

1 H NMR(500MHz,DMSO-d 6 )δ 0.45-0.60(m,3H),0.70-0.80(m,3H),1.89-1.94(m,1H),1.97-2.09(m,5H),2.09-2.18(m,1H),2.84-3.09(m,1H),3.40-4.35(m,1H),5.13-5.45(m,1H),5.56-5.97(m,2H),7.21-7.36(m,5H),7.38-7.58(m,1H),7.68-8.14(m,1H),9.82-10.60(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.45-0.60(m,3H), 0.70-0.80(m,3H), 1.89-1.94(m,1H), 1.97-2.09(m,5H), 2.09- 2.18(m,1H), 2.84-3.09(m,1H), 3.40-4.35(m,1H), 5.13-5.45(m,1H), 5.56-5.97(m,2H), 7.21-7.36(m,5H) ), 7.38-7.58(m, 1H), 7.68-8.14(m, 1H), 9.82-10.60(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.069min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.069 min.

化合物313： RT(IB，己烷-IPA-MeOH，80-10-10，0.6ml/min)=22.277min。 Compound 313: RT (IB, Hexane-IPA-MeOH, 80-10-10, 0.6 ml/min) = 22.277 min.

1 H NMR(500MHz,DMSO-d 6 )δ 0.91-1.04(m,6H),1.14-1.27(m,1H),1.45-1.55(m,1H),1.55-1.68(m,1H),1.96-2.10(m,4H),3.42-4.03(m,2H),5.03-5.26(m,1H),5.51-5.71(m,2H),7.19-7.35(m,5H),7.36-7.54(m,1H),7.70-8.08(m,1H),9.98-10.53(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.91-1.04(m,6H), 1.14-1.27(m,1H), 1.45-1.55(m,1H), 1.55-1.68(m,1H), 1.96- 2.10(m, 4H), 3.42-4.03(m, 2H), 5.03-5.26(m, 1H), 5.51-5.71(m, 2H), 7.19-7.35(m, 5H), 7.36-7.54(m, 1H ), 7.70-8.08 (m, 1H), 9.98-10.53 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.036min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.036 min.

化合物305： RT(IB，己烷-IPA-MeOH，80-10-10，0.6ml/min)=25.609min。 Compound 305: RT (IB, Hexane-IPA-MeOH, 80-10-10, 0.6 ml/min) = 25.609 min.

1 H NMR(500MHz,DMSO-d 6 )δ 0.89-1.00(m,6H),1.15-1.25(m,1H),1.44-1.53(m,1H),1.55-1.68(m,1H),1.97-2.10(m,4H),3.55-4.02(m,2H),5.03-5.27(m,1H),5.53-5.67(m,2H),7.18-7.34(m,5H),7.36-7.54(m,1H),7.68-8.10(m,1H),9.98-10.51(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.89-1.00(m,6H), 1.15-1.25(m,1H), 1.44-1.53(m,1H), 1.55-1.68(m,1H), 1.97- 2.10(m, 4H), 3.55-4.02(m, 2H), 5.03-5.27(m, 1H), 5.53-5.67(m, 2H), 7.18-7.34(m, 5H), 7.36-7.54(m, 1H ), 7.68-8.10 (m, 1H), 9.98-10.51 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值366.2；實測值367.2；Rt=4.009min。LCMS (ESI): [M+H] + m/z: calculated 366.2; found 367.2; Rt=4.009 min.

實例316. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物522)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物528)之合成Example 316. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(2,2,2-trifluoro Ethylamino)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 522) and N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 528)

Figure 110128222-A0202-12-1526-425
Figure 110128222-A0202-12-1526-425

步驟1：N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶Step 1: N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl ]-1-piperidine 基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Synthesis of tert-butyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamate

將4-[(2R,5S)-5-甲基-2-哌啶基]-N-(2,2,2-三氟乙基)苯胺(300mg，1.10mmol，2HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(325.32mg，1.10mmol，HCl)及三乙胺(557.40mg，5.51mmol，767.77μL)一起混合於二甲基甲醯胺(5mL)中。將所獲得之混合物簡單加熱至60-70℃，直到形成澄清溶液。冷卻至5-10℃之後，在5min期間分批添加HATU(460.78mg，1.21mmol)。將所得溶液在25℃下攪拌15h。然後使其經歷HPLC(管柱：SunFireC18 100* 19mm，5um；60-60-90% 0-1-6min水-甲醇，流速：30ml/min)，得到N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(99mg，180.14μmol，16.35%產率)。4-[(2R,5S)-5-methyl-2-piperidinyl]-N-(2,2,2-trifluoroethyl)aniline (300 mg, 1.10 mmol, 2HCl), 2-[[ 6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (325.32 mg, 1.10 mmol, HCl) and triethylamine (557.40 mg, 5.51 mmol, 767.77 μL) were mixed together in dimethylformamide (5 mL). The obtained mixture was heated briefly to 60-70°C until a clear solution formed. After cooling to 5-10 °C, HATU (460.78 mg, 1.21 mmol) was added portionwise over 5 min. The resulting solution was stirred at 25 °C for 15 h. It was then subjected to HPLC (column: SunFire C18 100 * 19mm, 5um; 60-60-90% 0-1-6min water-methanol, flow rate: 30ml/min) to give N-[3-methyl-5-[ [2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-side oxy Acetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (99 mg, 180.14 μmol, 16.35% yield).

1 H NMR(500MHz,DMSO-d6 )δ 0.73(m,2H),1.01(m,2H),1.43(m,9H),1.64(m,2H),2.19(d,3H),3.54(m,2H),3.90(m,2H),4.15(m,2H),5.00(m,1H),5.57(m,1H),6.22(s,1H),6.76(m,2H),7.06(m,2H),7.96(m,1H),8.45(m,1H),9.05(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.73(m, 2H), 1.01(m, 2H), 1.43(m, 9H), 1.64(m, 2H), 2.19(d, 3H), 3.54(m ,2H),3.90(m,2H),4.15(m,2H),5.00(m,1H),5.57(m,1H),6.22(s,1H),6.76(m,2H),7.06(m, 2H), 7.96 (m, 1H), 8.45 (m, 1H), 9.05 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值549.2；實測值550.2；Rt=3.496min。LCMS (ESI): [M+H] + m/z: calculated 549.2; found 550.2; Rt=3.496 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoro Synthesis of ethylamino)phenyl]-1-piperidinyl]-2-oxoacetamide

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(99mg，180.14μmol)溶解於二噁烷(1mL)及水(0.5mL)中。將所得溶液在100℃下攪拌15h。然後，使其經歷HPLC(管柱：YMC Triart C18 100* 20mm，5um；50-90% 0-5min 0.1% NH3 -甲醇，流速：30ml/min)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(55mg，122.37μmol，67.93%產率)。N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]- 1-Piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (99 mg, 180.14 μmol) was dissolved in dioxane (1 mL) and water (0.5 mL) )middle. The resulting solution was stirred at 100 °C for 15 h. Then, it was subjected to HPLC (column: YMC Triart C18 100 * 20mm, 5um; 50-90% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min) to give N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidine Peridyl]-2-oxoacetamide (55 mg, 122.37 μmol, 67.93% yield).

LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.2；Rt=2.468min。LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.2; Rt=2.468 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物522 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物528 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(2,2,2-trifluoro Ethylamino)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 522 ) and N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-oxoacetamide Synthesis of ( Compound 528 )

藉由掌性HPLC(管柱：Chiralpak IB(250* 20mm，5mkm；流動相：己烷-IPA-MeOH，60-20-20；流速：12mL/min；溫度=24℃)將N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(55mg，122.37μmol)分成鏡像異構物，得到：化合物522 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(19mg，42.27μmol，69.09%產率)(其中保留時間=16.417min)(化合物522 )及化合物528 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2,2,2-三氟乙基胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(33.9mg，粗品)(其中保留時間=36.985-38.961min)(化合物528 )N-(6) was purified by chiral HPLC (column: Chiralpak IB (250 * 20mm, 5mkm; mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12 mL/min; temperature=24°C) -Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl ]-1-Piperidinyl]-2-oxoacetamide (55 mg, 122.37 μmol) was split into enantiomers to give: compound 522 N-(6-amino-5-methyl-3-pyridyl) )-2-[(2S,5R)-5-methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-oxygen Ethylacetamide (19 mg, 42.27 μmol, 69.09% yield) (wherein retention time=16.417 min) ( compound 522 ) and compound 528 N-(6-amino-5-methyl-3-pyridyl)-2 -[(2R,5S)-5-Methyl-2-[4-(2,2,2-trifluoroethylamino)phenyl]-1-piperidinyl]-2-pendant oxyacetyl Amine (33.9 mg, crude) (wherein retention time=36.985-38.961 min) ( compound 528 )

化合物522： RT(IB，己烷-IPA-MeOH，60-20-20，0.15mL/min)=7.556min。 Compound 522: RT (IB, Hexane-IPA-MeOH, 60-20-20, 0.15 mL/min) = 7.556 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.70-0.78(m,3H),1.08-1.15(m,1H),1.56-1.65(m,2H),1.72-1.86(m,1H),1.86-2.18(m,5H),3.46-3.54(m,0.5H),3.85-3.89(m,2H),4.09-4.17(m,0.5H),4.94-5.53(m,1H),5.57-5.63(m,2H),6.18-6.21(m,1H),6.70-6.73(m,2H),7.01-7.08(m,2H),7.43-7.52(m,1H),7.95-8.05(m,1H),10.46-10.51(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.70-0.78(m,3H), 1.08-1.15(m,1H), 1.56-1.65(m,2H), 1.72-1.86(m,1H), 1.86- 2.18(m, 5H), 3.46-3.54(m, 0.5H), 3.85-3.89(m, 2H), 4.09-4.17(m, 0.5H), 4.94-5.53(m, 1H), 5.57-5.63(m ,2H),6.18-6.21(m,1H),6.70-6.73(m,2H),7.01-7.08(m,2H),7.43-7.52(m,1H),7.95-8.05(m,1H),10.46 -10.51(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.2；Rt=2.543min。LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.2; Rt=2.543 min.

化合物528： RT(IB，己烷-IPA-MeOH，60-20-20，0.15mL/min)=4.220min。 Compound 528: RT (IB, Hexane-IPA-MeOH, 60-20-20, 0.15 mL/min) = 4.220 min.

1 H NMR(600MHz,DMSO-d6 )δ 0.69-0.99(m,3H),1.03-1.18(m,1H),1.45-1.72(m,2H),1.74-1.90(m,1H),1.97-2.03(m,3H),2.04-2.20(m,1H),2.65-3.28(m, 1H),3.36-3.54(m,0.7H),3.84-3.92(m,2H),4.10-4.16(m,0.3H),4.92-5.55(m,1H),5.54-5.66(m,2H),6.14-6.25(m,1H),6.65-6.78(m,2H),7.00-7.12(m,2H),7.39-7.55(m,1H),7.89-8.07(m,1H),10.38-10.58(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.69-0.99(m,3H), 1.03-1.18(m,1H), 1.45-1.72(m,2H), 1.74-1.90(m,1H), 1.97- 2.03(m, 3H), 2.04-2.20(m, 1H), 2.65-3.28(m, 1H), 3.36-3.54(m, 0.7H), 3.84-3.92(m, 2H), 4.10-4.16(m, 0.3H),4.92-5.55(m,1H),5.54-5.66(m,2H),6.14-6.25(m,1H),6.65-6.78(m,2H),7.00-7.12(m,2H),7.39 -7.55(m, 1H), 7.89-8.07(m, 1H), 10.38-10.58(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.2；Rt=19.009min。LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.2; Rt=19.009 min.

實例317. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物720)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物729)之合成Example 317. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-di Hydrogen-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 720) and N-(6-amino-5-ethyl-3-pyridyl) -2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 729)

Figure 110128222-A0202-12-1529-426
Figure 110128222-A0202-12-1529-426

步驟1：N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethyl-3-pyridyl)-2-[5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline Synthesis of -6-yl)-1-piperidinyl]-2-oxoacetamide

將HATU(176.04mg，462.98μmol)在室溫下分批添加到2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(96.86mg，462.98μmol)、6-(5-甲基-2-哌啶基)-3,4-二氫-1H-喹啉-2-酮(130mg，462.98μmol，HCl)及TEA(281.09mg，2.78mmol，387.18μL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；以1-6min 45-55%水-甲醇(NH3 0.1%)，流速：30ml/min為流動相)，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(2-側氧基 -3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(75mg，172.21μmol，37.20%產率)。HATU (176.04 mg, 462.98 μmol) was added portionwise at room temperature to 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (96.86 mg, 462.98 μmol), 6-(5-methyl-2-piperidinyl)-3,4-dihydro-1H-quinolin-2-one (130 mg, 462.98 μmol, HCl) and TEA (281.09 mg, 2.78 mmol) , 387.18 μL) in DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 1-6min 45-55% water-methanol ( NH3 0.1%), flow rate: 30ml/min as mobile phase) , to give N-(6-amino-5-ethyl-3-pyridyl)-2-[5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline -6-yl)-1-piperidinyl]-2-oxoacetamide (75 mg, 172.21 μmol, 37.20% yield).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=2.017min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=2.017 min.

步驟2：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物720 )及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物729 )之合成Step 2: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(2-oxo-3,4-di Hydrogen-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide ( Compound 720 ) and N-(6-amino-5-ethyl-3-pyridyl) -2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 729 )

藉由掌性HPLC(管柱：IA(250* 20，5mkm)，以己烷-IPA-MeOH，60-20-20，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物720 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(28.7mg，65.90μmol，76.53%產率)(保留時間=59.6min)及化合物729 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(28.6mg，65.67μmol，76.27%產率)(保留時間=79.4min)。The enantiomers were separated by chiral HPLC (column: IA (250 * 20, 5mkm) with hexane-IPA-MeOH, 60-20-20, 12ml/min as mobile phase) to give two separate The enantiomer of compound 720 N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(2-sideoxy-3 ,4-Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (28.7 mg, 65.90 μmol, 76.53% yield) (retention time=59.6 min) and compound 729 N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxo-3,4-di Hydrogen-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (28.6 mg, 65.67 μmol, 76.27% yield) (retention time=79.4 min).

化合物720： RT(IA，己烷-IPA-MeOH，60-20-20，0.6mL/min)=43.376min。 Compound 720: RT (IA, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 43.376 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.06(m,6H),1.29(m,1H),1.69(m,1H),1.92(m,2H),2.11(m,2H),2.42(m,2H),2.99(m,4H),3.79(m,1H),5.57(m,3H),6.84(m,1H),7.08(m,2H),7.46(m,1H),8.03(m,1H),10.02(m,1H),10.45(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.06 (m, 6H), 1.29 (m, 1H), 1.69 (m, 1H), 1.92 (m, 2H), 2.11 (m, 2H) ,2.42(m,2H),2.99(m,4H),3.79(m,1H),5.57(m,3H),6.84(m,1H),7.08(m,2H),7.46(m,1H), 8.03 (m, 1H), 10.02 (m, 1H), 10.45 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.4；Rt=1.014min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.4; Rt=1.014 min.

化合物729： RT(IA，己烷-IPA-MeOH，60-20-20，0.6mL/min)=60.621min。 Compound 729: RT (IA, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 60.621 min.

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.03(m,6H),1.33(m,1H),1.67(m,1H),1.85(m,1H),1.97(m,1H),2.14(m,1H),2.39(m,2H),2.86(m,4H),3.45(m,1H),4.09(m,1H),5.57(m,3H),6.84(m,1H),7.08(m,2H),7.46(m,1H),8.03(m,1H),10.02(m,1H),10.45(m,1H)。 1 H NMR (DMSO-d 6 , 600MHz): δ(ppm) 1.03(m, 6H), 1.33(m, 1H), 1.67(m, 1H), 1.85(m, 1H), 1.97(m, 1H) ,2.14(m,1H),2.39(m,2H),2.86(m,4H),3.45(m,1H),4.09(m,1H),5.57(m,3H),6.84(m,1H), 7.08 (m, 2H), 7.46 (m, 1H), 8.03 (m, 1H), 10.02 (m, 1H), 10.45 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=0.778min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=0.778 min.

實例318. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物860)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物848)之合成Example 318. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl yl-1-piperidinyl]-2-oxoacetamide (Compound 860) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R )-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 848)

Figure 110128222-A0202-12-1531-427
Figure 110128222-A0202-12-1531-427

步驟1：N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxyl Synthesis of Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

將5-(5-甲基-2-哌啶基)吡啶-2-胺(300mg，1.57mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(463.15mg，1.57mmol)、三乙胺(793.56mg，7.84mmol，1.09mL)混合於DMF(5mL)中，然後添加HATU(894.56mg，2.35mmol)。將所得混合物在25℃下攪拌12h。將溶劑蒸發且將所得混合物與於甲醇(10mL)中之SiliaMetS® DMT(50mg)一起攪拌。將混合物過濾出且在減壓下蒸發。藉由HPLC(2-10min 50-75%甲醇/H2 O，30mL/min)純化所獲得之粗材料，以獲得N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(48.5mg，103.51 μmol，6.60%產率)。5-(5-Methyl-2-piperidinyl)pyridin-2-amine (300 mg, 1.57 mmol), 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3 -Pyridinyl]amino]-2-oxoacetic acid (463.15 mg, 1.57 mmol), triethylamine (793.56 mg, 7.84 mmol, 1.09 mL) were mixed in DMF (5 mL), then HATU (894.56 mg, 1.09 mL) was added. 2.35 mmol). The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the resulting mixture was stirred with SiliaMetS® DMT (50 mg) in methanol (10 mL). The mixture was filtered off and evaporated under reduced pressure. The obtained crude material was purified by HPLC (2-10 min 50-75% methanol/ H2O , 30 mL/min) to obtain N-[5-[[2-[(2R,5S)-2-(6 -Amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (48.5 mg, 103.51 μmol, 6.60% yield).

LCMS(ESI)：[M+H]+ m/z：計算值468.2；實測值469.2；Rt=0.943min。LCMS (ESI): [M+H] + m/z: calculated 468.2; found 469.2; Rt=0.943 min.

步驟2：rel-N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及rel-N-[5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: rel-N-[5-[[2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and rel-N-[5-[[2-[(2S,5R)-2-(6- Amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester synthesis

藉由掌性層析(IA-II(250* 20mm，5mkm)，IPA-MeOH，50-50，12mL/min)分離非鏡像異構物之混合物，以獲得N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(14.71mg，31.39μmol，30.33%產率；P1)及N-[5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(11.26mg，24.03μmol，23.22%產率；P2)。The mixture of diastereomers was separated by chiral chromatography (IA-II (250 * 20mm, 5mkm), IPA-MeOH, 50-50, 12mL/min) to obtain N-[5-[[[2- [(2R,5S)-2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl - 3-Butyl 2-pyridyl]carbamate (14.71 mg, 31.39 μmol, 30.33% yield; P1) and N-[5-[[2-[(2S,5R)-2-(6-amino) -3-Pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (11.26 mg, 24.03 μmol, 23.22% yield; P2).

製備型：P2之RT(IC-II(250* 20，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)=35.062min。Preparative: RT for P2 (IC-II (250 * 20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 12mL/min)=35.062min.

分析型：P2之RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=29.410min。Analytical: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) for P2 = 29.410 min.

LCMS(ESI)：[M+2H]+ m/z：計算值468.2；實測值470.2；Rt=2.001min。LCMS (ESI): [M+2H] + m/z: calculated 468.2; found 470.2; Rt=2.001 min.

製備型：P1之RT(IC-II(250* 20，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)=76.389min。Preparative: RT of P1 (IC-II (250 * 20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 12mL/min)=76.389min.

分析型：P1之RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=64.482min。Analytical: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) for P1 = 64.482 min.

LCMS(ESI)：[M+H]+ m/z：計算值468.2；實測值469.2；Rt=2.005min。LCMS (ESI): [M+H] + m/z: calculated 468.2; found 469.2; Rt=2.005 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物860 )之合成Step 3: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 860 )

將N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(14.71mg，31.39μmol)於二噁烷 (1mL)及水(1mL)中之溶液在100℃下加熱13h。蒸發溶劑且藉由HPLC(2-10min 20-65%甲醇/H2 O+NH3 30mL/min(裝載泵4mL甲醇+NH3 ))純化所得沉澱，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(6.9mg，18.73μmol，59.65%產率)。N-[5-[[2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone A solution of tert-butyl]amino]-3-methyl-2-pyridyl]carbamate (14.71 mg, 31.39 μmol) in dioxane (1 mL) and water (1 mL) was heated at 100 °C for 13 h . The solvent was evaporated and the resulting precipitate was purified by HPLC (2-10 min 20-65% methanol/ H2O + NH3 30 mL/min (loading pump 4 mL methanol+ NH3 )) to give N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetamide (6.9 mg, 18.73 μmol, 59.65% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.94-1.01(m,3H),1.26-1.36(m,1H),1.66-1.73(m,1H),1.75-1.88(m,1H),1.88-1.96(m,1H),1.98-2.02(m,3H),2.04-2.12(m,1H),2.67-3.19(m,1H),3.34-3.96(m,1H),4.93-5.49(m,1H),5.56-5.63(m,2H),5.84(s,2H),6.40-6.45(m,1H),7.23-7.38(m,1H),7.43-7.49(m,1H),7.82-7.88(m,1H),7.94-8.02(m,1H),10.26-10.48(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.94-1.01 (m, 3H), 1.26-1.36 (m, 1H), 1.66-1.73 (m, 1H), 1.75-1.88 (m, 1H) ,1.88-1.96(m,1H),1.98-2.02(m,3H),2.04-2.12(m,1H),2.67-3.19(m,1H),3.34-3.96(m,1H),4.93-5.49( m,1H),5.56-5.63(m,2H),5.84(s,2H),6.40-6.45(m,1H),7.23-7.38(m,1H),7.43-7.49(m,1H),7.82- 7.88 (m, 1H), 7.94-8.02 (m, 1H), 10.26-10.48 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值368.2；實測值370.2；Rt=0.514min。LCMS (ESI): [M+2H] + m/z: calculated 368.2; found 370.2; Rt=0.514 min.

步驟4：reL-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物848 )之合成Step 4: reL-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxoacetamide ( compound 848 )

將N-[5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(11.26mg，24.03μmol)於二噁烷(1mL)及水(1mL)中之溶液在100℃下加熱12h。蒸發溶劑且藉由HPLC(2-10min 20-65%甲醇/H2 O+NH3 30mL/min(裝載泵4mL甲醇+NH3 ))純化所得沉澱，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(5.2mg，14.11μmol，58.73%產率)。N-[5-[[2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone A solution of tert-butyl]amino]-3-methyl-2-pyridyl]carbamate (11.26 mg, 24.03 μmol) in dioxane (1 mL) and water (1 mL) was heated at 100 °C for 12 h . The solvent was evaporated and the resulting precipitate was purified by HPLC (2-10 min 20-65% methanol/ H2O + NH3 30 mL/min (loading pump 4 mL methanol+ NH3 )) to give N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetamide (5.2 mg, 14.11 μmol, 58.73% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.94-1.01(m,3H),1.26-1.36(m,1H),1.66-1.73(m,1H),1.75-1.88(m,1H),1.88-1.96(m,1H),1.98-2.02(m,3H),2.04-2.12(m,1H),2.67-3.19(m,1H),3.34-3.96(m,1H),4.93-5.49(m,1H),5.56-5.63(m,2H),5.84(s,2H),6.40-6.45(m,1H),7.23-7.38(m,1H),7.43-7.49(m,1H),7.82-7.88(m,1H),7.94-8.02(m,1H),10.26-10.48(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.94-1.01 (m, 3H), 1.26-1.36 (m, 1H), 1.66-1.73 (m, 1H), 1.75-1.88 (m, 1H) ,1.88-1.96(m,1H),1.98-2.02(m,3H),2.04-2.12(m,1H),2.67-3.19(m,1H),3.34-3.96(m,1H),4.93-5.49( m,1H),5.56-5.63(m,2H),5.84(s,2H),6.40-6.45(m,1H),7.23-7.38(m,1H),7.43-7.49(m,1H),7.82- 7.88 (m, 1H), 7.94-8.02 (m, 1H), 10.26-10.48 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值368.2；實測值370.2；Rt=0.516min。LCMS (ESI): [M+H] + m/z: calculated 368.2; found 370.2; Rt=0.516 min.

實例319. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物980)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物998)之合成Example 319. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl ]-5-Methyl-1-piperidinyl]-2-oxoacetamide (Compound 980) and rel-N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,5S)-2-[6-(Methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 998) synthesis

Figure 110128222-A0202-12-1534-428
Figure 110128222-A0202-12-1534-428

步驟1：N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of tert-butyl ]-3-methyl-2-pyridyl]carbamate

在室溫下，將HATU(496.98mg，1.31mmol)分批添加到2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(424.55mg，1.44mmol)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2 at room temperature - Pendant oxyacetic acid (424.55 mg, 1.44 mmol), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) Suspension in DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give N-[5-[[2-[2-(6-amino-3-pyridyl)-5-methyl-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值468.2；實測值469.2；Rt=0.974min。LCMS (ESI): [M+H] + m/z: calculated 468.2; found 469.2; Rt=0.974 min.

步驟2：N-[5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[2-[6-(Methylsulfonamido)-3-pyridyl]-5-methyl 1-piperidinyl]-2-pendoxetylacetone Synthesis of tert-butyl]amino]-3-methyl-2-pyridyl]carbamate

在室溫下將甲磺醯氯(165.07mg，1.44mmol，111.53μL)逐滴添加到N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(1.33g，1.31mmol)、TEA(795.35mg，7.86mmol，1.10mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；以30-75% 0-1-6min H2 O/MeOH，流速：30mL/min為流動相)純化殘餘物，以得到N-[5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(165mg，301.85μmol，23.04%產率)。Methanesulfonyl chloride (165.07 mg, 1.44 mmol, 111.53 μL) was added dropwise to N-[5-[[[2-[2-(6-amino-3-pyridyl)-5-methane at room temperature tert-butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate (1.33 g, 1.31 mmol), TEA (795.35 mg) , 7.86 mmol, 1.10 mL) in DMF (10 mL). The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; with 30-75% 0-1-6 min H2O /MeOH, flow rate: 30 mL/min as mobile phase) to give N -[5-[[2-[2-[6-(Methylsulfonamido)-3-pyridinyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine tert-butyl]-3-methyl-2-pyridyl]carbamate (165 mg, 301.85 μmol, 23.04% yield).

LCMS(ESI)：[M+H]+ m/z：計算值546.2；實測值547.2；Rt=1.876min。LCMS (ESI): [M+H] + m/z: calculated 546.2; found 547.2; Rt=1.876 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1 -Piperidinyl]-2-Side Oxyacetamide Synthesis

將N-[5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(165mg，301.85μmol)於二噁烷(2mL)及水(1mL)中之溶液在90℃下攪拌18h且在真空中蒸發溶劑，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(130mg，291.14μmol，96.45%產率)。N-[5-[[2-[2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-pendoxetyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (165 mg, 301.85 μmol) in dioxane (2 mL) and water (1 mL) was stirred at 90° C. for 18 h and added to The solvent was evaporated in vacuo to give N-(6-amino-5-methyl-3-pyridinyl)-2-[2-[6-(methylsulfonamido)-3-pyridinyl]-5- Methyl-1-piperidinyl]-2-oxoacetamide (130 mg, 291.14 μmol, 96.45% yield).

LCMS(ESI)：[M+H]+ m/z：計算值446.2；實測值447.0；Rt=0.827min。LCMS (ESI): [M+H] + m/z: calculated 446.2; found 447.0; Rt=0.827 min.

步驟4：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物980 )及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物998 )之合成Step 4: rel-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl ]-5-methyl-1-piperidinyl]-2-oxyacetamide ( compound 980 ) and rel-N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,5S)-2-[6-(Methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide ( Compound 998 ) synthesis

藉由掌性HPLC(管柱：Chiralpak IA-I(250* 20mm，5mkm)，以 IPA-MeOH，50-50，12mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物980 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31.2mg，69.87μmol，48.00%產率)(保留時間=31.1min)及化合物998 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31.4mg，70.32μmol，48.31%產率)(保留時間=45.6min)。The enantiomers were separated by chiral HPLC (column: Chiralpak IA-I (250 * 20mm, 5mkm) with IPA-MeOH, 50-50, 12mL/min as mobile phase) to give two separate mirror images Isomer compound 980 rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[6-(methylsulfonamido)-3- Pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (31.2 mg, 69.87 μmol, 48.00% yield) (retention time=31.1 min) and compound 998 rel-N- (6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide (31.4 mg, 70.32 μmol, 48.31% yield) (retention time=45.6 min).

化合物980： RT(IA(250*4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=30.873min。 Compound 980: RT (IA (250*4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=30.873min.

LCMS(ESI)：[M+H]+ m/z：計算值446.2；實測值447.2；Rt=1.493min。LCMS (ESI): [M+H] + m/z: calculated 446.2; found 447.2; Rt=1.493 min.

化合物998： RT(IA(250*4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=48.374min。 Compound 998: RT (IA (250*4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=48.374min.

LCMS(ESI)：[M+H]+ m/z：計算值446.2；實測值447.2；Rt=1.495min。LCMS (ESI): [M+H] + m/z: calculated 446.2; found 447.2; Rt=1.495 min.

實例320. rel-2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物927)及rel-2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物915)之合成Example 320. rel-2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-N-(6-amino- 5-Methyl-3-pyridyl)-2-oxoacetamide (Compound 927) and rel-2-[(2R,5S)-2-(6-acetamido-3-pyridyl) Synthesis of -5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxyacetamide (compound 915)

Figure 110128222-A0202-12-1537-429
Figure 110128222-A0202-12-1537-429

步驟1：N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of tert-butyl ]-3-methyl-2-pyridyl]carbamate

在室溫下，將HATU(496.98mg，1.31mmol)分批添加到2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(424.55mg，1.44mmol)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2 at room temperature - Pendant oxyacetic acid (424.55 mg, 1.44 mmol), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) Suspension in DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give N-[5-[[2-[2-(6-amino-3-pyridyl)-5-methyl-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值468.2；實測值469.2；Rt=0.901min。LCMS (ESI): [M+H] + m/z: calculated 468.2; found 469.2; Rt=0.901 min.

步驟2：N-[5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[2-(6-Acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxoacetyl] Synthesis of tert-butyl amino]-3-methyl-2-pyridyl]carbamate

在室溫下將乙醯氯(113.11mg，1.44mmol，87.69μL)逐滴添加到N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(1.33g，1.31mmol)、TEA(795.35mg，7.86mmol，1.10 mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：Chromatorex 18 SMB100-5T 100* 19mm 5um；以0-1-6min 30-40%水-MeCN，流速30mL/min為流動相)純化殘餘物，以得到N-[5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(209mg，409.34μmol，31.25%產率)。Acetyl chloride (113.11 mg, 1.44 mmol, 87.69 μL) was added dropwise to N-[5-[[2-[2-(6-amino-3-pyridyl)-5-methyl at room temperature -1-Piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (1.33 g, 1.31 mmol), TEA (795.35 mg, 7.86 mmol, 1.10 mL) in DMF (10 mL). The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: Chromatorex 18 SMB100-5T 100 * 19mm 5um; 0-1-6min 30-40% water-MeCN, flow rate 30mL/min as mobile phase) to obtain N-[ 5-[[2-[2-(6-Acetylamino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3- 3-butyl methyl-2-pyridyl]carbamate (209 mg, 409.34 μmol, 31.25% yield).

LCMS(ESI)：[M+H]+ m/z：計算值510.2；實測值511.2；Rt=2.557min。LCMS (ESI): [M+H] + m/z: calculated 510.2; found 511.2; Rt=2.557 min.

步驟3：2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺之合成Step 3: 2-[2-(6-Acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridine Synthesis of )-2-side oxyacetamide

將N-[5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(203.41mg，398.39μmol)於二噁烷(2mL)及水(1mL)中之溶液在85℃下攪拌24h且在真空中蒸發溶劑，以得到2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(160mg，389.80μmol，97.84%產率)。N-[5-[[2-[2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amino A solution of tert-butyl ]-3-methyl-2-pyridyl]carbamate (203.41 mg, 398.39 μmol) in dioxane (2 mL) and water (1 mL) was stirred at 85 °C for 24 h and in vacuo The solvent was evaporated to give 2-[2-(6-acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3 -Pyridinyl)-2-pendant oxyacetamide (160 mg, 389.80 μmol, 97.84% yield).

LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值411.2；Rt=0.725min。LCMS (ESI): [M+H] + m/z: calculated 410.2; found 411.2; Rt=0.725 min.

步驟4：rel-2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物927 )及rel-2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物915 )之合成Step 4: rel-2-[(2S,5R)-2-(6-acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-N-(6-amino- 5-Methyl-3-pyridyl)-2-oxyacetamide ( compound 927 ) and rel-2-[(2R,5S)-2-(6-acetamido-3-pyridyl) Synthesis of -5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxoacetamide ( compound 915 )

藉由掌性HPLC(管柱：IB(250* 30，5mkm)，以CO2 -MeOH，60-40，80mL/min補充流速-30mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物927 rel-2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(31.2mg，76.01μmol，39.00%產率)(保留時間=5.99min)及化合物915 rel-2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(31.8mg， 77.47μmol，39.75%產率)(保留時間=6.76min)。Separation of mirror isomers by chiral HPLC (column: IB (250 * 30, 5mkm) with CO2 -MeOH, 60-40, 80mL/min supplemental flow - 30mL/min as mobile phase) to give two An individual enantiomer compound 927 rel-2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-N- (6-amino-5-methyl-3-pyridyl)-2-oxyacetamide (31.2 mg, 76.01 μmol, 39.00% yield) (retention time=5.99 min) and compound 915 rel-2 -[(2R,5S)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3 -Pyridinyl)-2-oxoacetamide (31.8 mg, 77.47 μmol, 39.75% yield) (retention time = 6.76 min).

化合物927： RT(OJ-H(250* 4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=15.921min。 Compound 927: RT (OJ-H (250 * 4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=15.921min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.99(m,3H),1.32(m,1H),1.66(m,1H),1.84(m,1H),2.03(m,7H),2.18(m,1H),2.89(m,1H),3.71(dd,1H),5.58(m,3H),7.45(m,1H),7.69(m,1H),8.00(m,2H),8.22(m,1H),10.48(s,2H)LCMS(ESI)：[M+2H]+ m/z：計算值410.2；實測值412.2；Rt=0.894min。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.99 (m, 3H), 1.32 (m, 1H), 1.66 (m, 1H), 1.84 (m, 1H), 2.03 (m, 7H), 2.18(m, 1H), 2.89(m, 1H), 3.71(dd, 1H), 5.58(m, 3H), 7.45(m, 1H), 7.69(m, 1H), 8.00(m, 2H), 8.22 (m, 1H), 10.48 (s, 2H) LCMS (ESI): [M+2H] + m/z: calculated 410.2; found 412.2; Rt=0.894 min.

化合物915： RT(OJ-H(250* 4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=24.255min。 Compound 915: RT (OJ-H (250 * 4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=24.255min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.66(m,1H),1.86(m,1H),2.02(m,7H),2.19(m,1H),2.97(dd,1H),3.71(dd,1H),5.58(m,3H),7.45(m,1H),7.70(m,1H),8.00(m,2H),8.22(m,1H),10.48(s,2H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.32(m, 1H), 1.66(m, 1H), 1.86(m, 1H), 2.02(m, 7H), 2.19(m, 1H), 2.97(dd, 1H), 3.71(dd, 1H), 5.58(m, 3H), 7.45(m, 1H), 7.70(m, 1H), 8.00(m, 2H), 8.22 (m,1H),10.48(s,2H)

LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值412.2；Rt=0.894min。LCMS (ESI): [M+H] + m/z: calculated 410.2; found 412.2; Rt=0.894 min.

實例321. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物856)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物851)之合成Example 321. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl yl-1-piperidinyl]-2-oxoacetamide (Compound 856) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S )-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 851) synthesis

Figure 110128222-A0202-12-1540-430
Figure 110128222-A0202-12-1540-430

步驟1：N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxyl Synthesis of Acetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester

將5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)、2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(404.29mg，1.31mmol)、三乙胺(661.30mg，6.54mmol，910.88μL)混合於DMF(5mL)中，然後添加HATU(745.46mg，1.96mmol)。將所得混合物在25℃下攪拌12h。將溶劑蒸發且將所得混合物與於甲醇(10mL)中之SiliaMetS® DMT(50mg)一起攪拌。將混合物過濾出且在減壓下蒸發。藉由HPLC(2-10min 50-65%甲醇/H2 O，30mL/min)純化所獲得之粗材料，以獲得N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(61.6mg，127.65μmol，9.77%產率)。5-(5-Methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol), 2-[[6-(tert-butoxycarbonylamino)-5-ethyl-3 -Pyridinyl]amino]-2-oxoacetic acid (404.29 mg, 1.31 mmol), triethylamine (661.30 mg, 6.54 mmol, 910.88 μL) were mixed in DMF (5 mL), followed by the addition of HATU (745.46 mg, 1.96 mmol). The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the resulting mixture was stirred with SiliaMetS® DMT (50 mg) in methanol (10 mL). The mixture was filtered off and evaporated under reduced pressure. The obtained crude material was purified by HPLC (2-10 min 50-65% methanol/ H2O , 30 mL/min) to obtain N-[5-[[2-[(2R,5S)-2-(6 -Amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl Ester (61.6 mg, 127.65 μmol, 9.77% yield).

LCMS(ESI)：[M+H]+ m/z：計算值482.2；實測值483.2；Rt=0.984min。步驟2：rel-N-[5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯及rel-N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶 基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯之合成 LCMS (ESI): [M+H] + m/z: calculated 482.2; found 483.2; Rt=0.984 min. Step 2: rel-N-[5-[[2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester and rel-N-[5-[[2-[(2R,5S)-2-(6- Amino-3-pyridyl )-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester synthesis

藉由掌性層析(IA-II(250* 20，5mkm)，IPA-MeOH，50-50，12mL/min)分離非鏡像異構物之混合物，以獲得N-[5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(21.02mg，43.56μmol，34.12%產率；P1)及N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(22.05mg，45.69μmol，35.80%產率；P2)。The mixture of diastereomers was separated by chiral chromatography (IA-II (250 * 20, 5mkm), IPA-MeOH, 50-50, 12mL/min) to obtain N-[5-[[2- [(2S,5R)-2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-ethyl - 3-Butyl 2-pyridyl]carbamate (21.02 mg, 43.56 μmol, 34.12% yield; P1) and N-[5-[[2-[(2R,5S)-2-(6-amino) -3-Pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester (22.05 mg, 45.69 μmol, 35.80% yield; P2).

製備型：P1之RT(IA(250* 30，5mkm)，IPA-MeOH，50-50，20mL/min)=19.231min。分析型：P1之RT(IA，IPA-MeOH，50-50，0.6mL/min)=16.786min。Preparative: RT of P1 (IA(250 * 30, 5mkm), IPA-MeOH, 50-50, 20mL/min)=19.231min. Analytical type: RT (IA, IPA-MeOH, 50-50, 0.6 mL/min) of P1 = 16.786 min.

LCMS(ESI)：[M+2H]+ m/z：計算值482.2；實測值484.2；Rt=2.159min。LCMS (ESI): [M+2H] + m/z: calculated 482.2; found 484.2; Rt=2.159 min.

製備型：P2之RT(IA(250* 30，5mkm)，IPA-MeOH，50-50，20mL/min)=42.391min。分析型：P2之RT(IA，IPA-MeOH，50-50，0.6mL/min)=38.638min。Preparative: RT of P2 (IA(250 * 30, 5mkm), IPA-MeOH, 50-50, 20mL/min)=42.391min. Analytical type: RT (IA, IPA-MeOH, 50-50, 0.6 mL/min) of P2 = 38.638 min.

LCMS(ESI)：[M+2H]+ m/z：計算值482.2；實測值484.2；Rt=2.174min。LCMS (ESI): [M+2H] + m/z: calculated 482.2; found 484.2; Rt=2.174 min.

步驟3：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物856 )之合成Step 3: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 856 )

將N-[5-[[2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(21.02mg，43.56μmol)於二噁烷(1mL)及水(1mL)中之溶液在100℃下加熱12h。蒸發溶劑且藉由HPLC(2-10min 20-65%甲醇/H2 O+NH3 30mL/min(裝載泵4mL甲醇+NH3 ))純化所得沉澱，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(10.8mg，28.24μmol，64.83%產率)。N-[5-[[2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone A solution of tert-butyl]amino]-3-ethyl-2-pyridyl]carbamate (21.02 mg, 43.56 μmol) in dioxane (1 mL) and water (1 mL) was heated at 100 °C for 12 h . The solvent was evaporated and the resulting precipitate was purified by HPLC (2-10 min 20-65% methanol/ H2O + NH3 30 mL/min (loading pump 4 mL methanol+ NH3 )) to give N-(6-amino-5 -Ethyl-3-pyridyl)-2-[(2S,5R)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetamide (10.8 mg, 28.24 μmol, 64.83% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.95-1.02(m,3H),1.06-1.14(m,3H),1.23-1.37(m,1H),1.64-1.75(m,1H),1.80-2.06(m,2H),2.06-2.15(m,1H),2.36-2.41 (m,2H),2.65-3.20(m,1H),3.35-3.99(m,1H),4.95-5.50(m,1H),5.58-5.65(m,2H),5.84(s,2H),6.39-6.47(m,1H),7.19-7.35(m,1H),7.43-7.52(m,1H),7.78-7.88(m,1H),7.98-8.06(m,1H),10.36-10.54(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.95-1.02 (m, 3H), 1.06-1.14 (m, 3H), 1.23-1.37 (m, 1H), 1.64-1.75 (m, 1H) ,1.80-2.06(m,2H),2.06-2.15(m,1H),2.36-2.41(m,2H),2.65-3.20(m,1H),3.35-3.99(m,1H),4.95-5.50( m,1H),5.58-5.65(m,2H),5.84(s,2H),6.39-6.47(m,1H),7.19-7.35(m,1H),7.43-7.52(m,1H),7.78- 7.88 (m, 1H), 7.98-8.06 (m, 1H), 10.36-10.54 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值382.4；實測值383.4；Rt=0.557min。LCMS (ESI): [M+H] + m/z: calculated 382.4; found 383.4; Rt=0.557 min.

步驟4：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物851 )之合成Step 4: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 851 )

將N-[5-[[2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(22.05mg，45.69μmol)於二噁烷(1mL)及水(1mL)中之溶液在100℃下加熱12h。蒸發溶劑且藉由HPLC(2-10min 20-65%甲醇/H2 O+NH3 30mL/min(裝載泵4mL甲醇+NH3 ))純化所得沉澱，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(8.2mg，21.44μmol，46.92%產率)。N-[5-[[2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone A solution of tert-butyl]amino]-3-ethyl-2-pyridyl]carbamate (22.05 mg, 45.69 μmol) in dioxane (1 mL) and water (1 mL) was heated at 100 °C for 12 h . The solvent was evaporated and the resulting precipitate was purified by HPLC (2-10 min 20-65% methanol/ H2O + NH3 30 mL/min (loading pump 4 mL methanol+ NH3 )) to give N-(6-amino-5 -Ethyl-3-pyridyl)-2-[(2R,5S)-2-(6-amino-3-pyridyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetamide (8.2 mg, 21.44 μmol, 46.92% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.97-1.02(m,3H),1.07-1.11(m,3H),1.26-1.34(m,1H),1.61-1.77(m,1H),1.78-1.90(m,1H),1.90-2.05(m,1H),2.06-2.17(m,1H),2.36-2.41(m,2H),2.64-3.21(m,1H),3.35-3.98(m,1H),4.93-5.49(m,1H),5.59-5.65(m,2H),5.85(s,2H),6.40-6.48(m,1H),7.25-7.36(m,1H),7.43-7.51(m,1H),7.81-7.87(m,1H),7.94-8.05(m,1H),10.43-10.51(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.97-1.02 (m, 3H), 1.07-1.11 (m, 3H), 1.26-1.34 (m, 1H), 1.61-1.77 (m, 1H) ,1.78-1.90(m,1H),1.90-2.05(m,1H),2.06-2.17(m,1H),2.36-2.41(m,2H),2.64-3.21(m,1H),3.35-3.98( m,1H),4.93-5.49(m,1H),5.59-5.65(m,2H),5.85(s,2H),6.40-6.48(m,1H),7.25-7.36(m,1H),7.43- 7.51 (m, 1H), 7.81-7.87 (m, 1H), 7.94-8.05 (m, 1H), 10.43-10.51 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值382.4；實測值383.4；Rt=0.554min。LCMS (ESI): [M+H] + m/z: calculated 382.4; found 383.4; Rt=0.554 min.

實例322. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物995)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物983)之合成Example 322. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl ]-5-Methyl-1-piperidinyl]-2-oxoacetamide (Compound 995) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2- [(2R,5S)-2-[6-(Methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 983) synthesis

Figure 110128222-A0202-12-1543-431
Figure 110128222-A0202-12-1543-431

步驟1：5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺之合成Step 1: 5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2 -Synthesis of -methoxypyridine-3-carboxamide

在室溫下將HATU(496.98mg，1.31mmol)分批添加到2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(359.52mg，1.50mmol)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[(5-aminocarboxy-6-methoxy-3-pyridyl)amino]-2-pendoxoacetic acid ( 359.52 mg, 1.50 mmol), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) in DMF (10 mL) in the suspension. The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 5-[[2-[2-(6-amino-3-pyridinyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值482.2；實測值483.4；Rt=1.021min。LCMS (ESI): [M+H] + m/z: calculated 482.2; found 483.4; Rt=1.021 min.

步驟2：N-[3-乙基-5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[3-Ethyl-5-[[2-[2-[6-(methylsulfonamido)-3-pyridinyl]-5-methyl-1-piperidinyl]-2 -Synthesis of tert-butyl oxyacetyl]amino]-2-pyridyl]carbamate

在室溫下將甲磺醯氯(165.07mg，1.44mmol，111.53μL)逐滴添加到N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2- 吡啶基]胺甲酸第三丁酯(1.92g，1.31mmol)、TEA(795.35mg，7.86mmol，1.10mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；以40-70% 0-1-6min H2 O/MeOH，流速：30mL/min為流動相)純化殘餘物，以得到N-[3-乙基-5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(135mg，240.79μmol，18.38%產率)。Methanesulfonyl chloride (165.07 mg, 1.44 mmol, 111.53 μL) was added dropwise to N-[5-[[[2-[2-(6-amino-3-pyridyl)-5-methane at room temperature tert-butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamate (1.92 g, 1.31 mmol), TEA (795.35 mg) , 7.86 mmol, 1.10 mL) in DMF (10 mL). The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; 40-70% 0-1-6 min H2O /MeOH, flow rate: 30 mL/min as mobile phase) to give N -[3-Ethyl-5-[[2-[2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (135 mg, 240.79 μmol, 18.38% yield).

LCMS(ESI)：[M+H]+ m/z：計算值560.2；實測值561.2；Rt=2.029min。LCMS (ESI): [M+H] + m/z: calculated 560.2; found 561.2; Rt=2.029 min.

步驟3：N-(6-胺基-5-乙基-3-吡啶基)-2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 3: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[2-[6-(methylsulfonamido)-3-pyridinyl]-5-methyl-1 -Piperidinyl]-2-Side Oxyacetamide Synthesis

將N-[3-乙基-5-[[2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(135mg，240.79μmol)於二噁烷(2mL)及水(1mL)中之溶液在90℃下攪拌18h且在真空中蒸發溶劑，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(110mg，238.85μmol，99.19%產率)。N-[3-ethyl-5-[[2-[2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-side A solution of tert-butyl oxyacetoxy]amino]-2-pyridyl]carbamate (135 mg, 240.79 μmol) in dioxane (2 mL) and water (1 mL) was stirred at 90 °C for 18 h and was The solvent was evaporated in vacuo to give N-(6-amino-5-ethyl-3-pyridinyl)-2-[2-[6-(methylsulfonamido)-3-pyridinyl]-5- Methyl-1-piperidinyl]-2-oxoacetamide (110 mg, 238.85 μmol, 99.19% yield).

LCMS(ESI)：[M+H]+ m/z：計算值460.2；實測值461.2；Rt=0.854min。LCMS (ESI): [M+H] + m/z: calculated 460.2; found 461.2; Rt=0.854 min.

步驟4：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物995 )及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物983 )之合成Step 4: rel-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-2-[6-(methylsulfonamido)-3-pyridyl ]-5-methyl-1-piperidinyl]-2-oxyacetamide ( compound 995 ) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2- [(2R,5S)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide ( Compound 983 ) synthesis

藉由掌性HPLC(管柱：Chiralpak IA-I(250* 20，5mkm)，以IPA-MeOH，50-50，12mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物995 rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(29.3mg，63.62μmol，53.27%產率)(保留時間=23.87min)及化合物983 rel-N-(6-胺基-5-乙基-3-吡啶 基)-2-[(2R,5S)-2-[6-(甲磺醯胺基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(33.8mg，73.39μmol，61.45%產率)(保留時間=41.22min)。Separation of enantiomers by chiral HPLC (column: Chiralpak IA-I (250 * 20, 5mkm) with IPA-MeOH, 50-50, 12mL/min as mobile phase) to give two separate mirror images Isomer compound 995 rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-[6-(methylsulfonamido)-3- Pyridyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (29.3 mg, 63.62 μmol, 53.27% yield) (retention time=23.87 min) and compound 983 rel-N- (6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[6-(methylsulfonamido)-3-pyridyl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide (33.8 mg, 73.39 μmol, 61.45% yield) (retention time = 41.22 min).

化合物995： RT(IA(250* 4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=23.505min。 Compound 995: RT (IA(250 * 4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=23.505min.

LCMS(ESI)：[M+H]+ m/z：計算值460.2；實測值461.2；Rt=1.647min。LCMS (ESI): [M+H] + m/z: calculated 460.2; found 461.2; Rt=1.647 min.

化合物983： RT(IA(250* 4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=41.482min。 Compound 983: RT (IA(250 * 4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=41.482min.

LCMS(ESI)：[M+H]+ m/z：計算值460.2；實測值461.2；Rt=1.640min。LCMS (ESI): [M+H] + m/z: calculated 460.2; found 461.2; Rt=1.640 min.

實例323. rel-2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物921)及rel-2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物925)之合成Example 323. rel-2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-N-(6-amino- 5-Ethyl-3-pyridyl)-2-oxoacetamide (Compound 921) and rel-2-[(2R,5S)-2-(6-acetamido-3-pyridyl) Synthesis of -5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxyacetamide (compound 925)

Figure 110128222-A0202-12-1545-432
Figure 110128222-A0202-12-1545-432

步驟1：N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(6-Amino-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of 3-butyl ]-3-ethyl-2-pyridyl]carbamate

在室溫下，將HATU(496.98mg，1.31mmol)分批添加到2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(444.72mg，1.44mmol)、5-(5-甲基-2-哌啶基)吡啶-2-胺(250mg，1.31mmol)及TEA(793.56mg，7.84mmol，1.09mL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(1g，粗品)。HATU (496.98 mg, 1.31 mmol) was added portionwise to 2-[[6-(tert-butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2 at room temperature - Pendant oxyacetic acid (444.72 mg, 1.44 mmol), 5-(5-methyl-2-piperidinyl)pyridin-2-amine (250 mg, 1.31 mmol) and TEA (793.56 mg, 7.84 mmol, 1.09 mL) Suspension in DMF (10 mL). The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give N-[5-[[2-[2-(6-amino-3-pyridyl)-5-methyl-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester (1 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值482.2；實測值483.2；Rt=0.944min。LCMS (ESI): [M+H] + m/z: calculated 482.2; found 483.2; Rt=0.944 min.

步驟2：N-[5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[2-(6-Acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxoacetyl] Synthesis of tert-butyl amino]-3-ethyl-2-pyridyl]carbamate

在室溫下將乙醯氯(113.11mg，1.44mmol，87.69μL)逐滴添加到N-[5-[[2-[2-(6-胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(632.17mg，1.31mmol)、TEA(795.35mg，7.86mmol，1.10mL)於DMF(10mL)中之懸浮液中。將溶液在25℃下攪拌18h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：YMC Triart C18 100* 20mml.D.S-5um；以0-5min 48-65%水-甲醇(NH3 0.1%)，流速30mL/min為流動相)純化殘餘物，以得到N-[5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(169mg，322.14μmol，24.59%產率)。Acetyl chloride (113.11 mg, 1.44 mmol, 87.69 μL) was added dropwise to N-[5-[[2-[2-(6-amino-3-pyridyl)-5-methyl at room temperature -1-Piperidinyl]-2-oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester (632.17 mg, 1.31 mmol), TEA (795.35 mg, 7.86 mmol, 1.10 mL) in DMF (10 mL). The solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: YMC Triart C18 100 * 20mml.DS-5um; 0-5min 48-65% water-methanol ( NH3 0.1%), flow rate 30mL/min as mobile phase), to give N-[5-[[2-[2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amine tert-butyl]-3-ethyl-2-pyridyl]carbamate (169 mg, 322.14 μmol, 24.59% yield).

LCMS(ESI)：[M+H]+ m/z：計算值524.2；實測值525.2；Rt=2.093min。LCMS (ESI): [M+H] + m/z: calculated 524.2; found 525.2; Rt=2.093 min.

步驟3：2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺之合成Step 3: 2-[2-(6-Acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridine Synthesis of )-2-side oxyacetamide

在室溫下將於二噁烷中之4.0M氯化氫溶液(838.98mg，3.22mmol，791.49μL，14%純度)小心添加到N-[5-[[2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(169mg，322.14μmol)於DCM(2mL)中之溶液中。然後將反應混合物在室溫下攪拌18h且在真空 中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；以35-60% 0-5min以H2 O/MeOH/0.1% NH4 OH，流速：30mL/min為流動相)，以得到2-[2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(70.6mg，166.32μmol，51.63%產率)。A 4.0 M solution of hydrogen chloride in dioxane (838.98 mg, 3.22 mmol, 791.49 μL, 14% purity) was carefully added to N-[5-[[2-[2-(6-acetamide at room temperature ( 169 mg, 322.14 μmol) in DCM (2 mL). The reaction mixture was then stirred at room temperature for 18 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; 35-60% 0-5 min in H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min as mobile phase) , to give 2-[2-(6-acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridine (70.6 mg, 166.32 μmol, 51.63% yield).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.4；Rt=1.712min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.4; Rt=1.712 min.

步驟4：rel-2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(EN-TG1-4950)及rel-2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物925 )之合成Step 4: rel-2-[(2S,5R)-2-(6-acetamido-3-pyridinyl)-5-methyl-1-piperidinyl]-N-(6-amino- 5-Ethyl-3-pyridyl)-2-oxyacetamido (EN-TG1-4950) and rel-2-[(2R,5S)-2-(6-acetamido-3- Synthesis of Pyridyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxoacetamide ( Compound 925 )

藉由掌性HPLC(管柱：Chiralcel OJ-H(250* 20mm，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：12mL/min；然後用於化合物921 之另外條件：管柱OJ-H(250* 20，5mkm)，以己烷-IPA-MeOH，70-15-15，14mL/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物921 rel-2-[(2S,5R)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(24.2mg，57.01μmol，29.25%產率)(保留時間=13.8min)及化合物925 rel-2-[(2R,5S)-2-(6-乙醯胺基-3-吡啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(28.5mg，67.14μmol，34.45%產率)(保留時間=22.7min)。by chiral HPLC (column: Chiralcel OJ-H (250 * 20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 60-20-20 ; flow rate: 12mL/min; Conditions: column OJ-H (250 * 20, 5mkm) with hexane-IPA-MeOH, 70-15-15, 14mL/min as mobile phase) to separate enantiomers to give two separate enantiomers Construct Compound 921 rel-2-[(2S,5R)-2-(6-acetamido-3-pyridyl)-5-methyl-1-piperidinyl]-N-(6-amino -5-ethyl-3-pyridyl)-2-oxoacetamide (24.2 mg, 57.01 μmol, 29.25% yield) (retention time = 13.8 min) and compound 925 rel-2-[(2R, 5S)-2-(6-Acetylamino-3-pyridyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)- 2-Pendant oxyacetamide (28.5 mg, 67.14 μmol, 34.45% yield) (retention time = 22.7 min).

化合物921： RT(OJ-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=13.066min。 Compound 921: RT (OJ-H (250*4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=13.066min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.04(m,6H),1.34(m,1H),1.68(m,1H),1.88(m,1H),2.06(m,4H),2.19(m,1H),2.39(m,2H),3.05(m,1H),3.62(m,1H),5.60(m,3H),7.45(m,1H),7.69(dd,1H),8.01(m,2H),8.22(m,1H),10.49(m,2H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.04(m, 6H), 1.34(m, 1H), 1.68(m, 1H), 1.88(m, 1H), 2.06(m, 4H), 2.19(m, 1H), 2.39(m, 2H), 3.05(m, 1H), 3.62(m, 1H), 5.60(m, 3H), 7.45(m, 1H), 7.69(dd, 1H), 8.01 (m, 2H), 8.22 (m, 1H), 10.49 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=0.909min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=0.909 min.

化合物925： RT(OJ-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min) =19.819min。 Compound 925: RT (OJ-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 19.819 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.08(m,3H),1.32(m,1H),1.66(m,1H),1.87(m,1H),2.06(m,4H),2.18(m,1H),2.38(m,2H),2.88(m,1H),3.81(m,1H),5.60(m,3H),7.48(m,1H),7.70(m,1H),8.01(m,2H),8.22(m,1H),10.49(m,2H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.08(m, 3H), 1.32(m, 1H), 1.66(m, 1H), 1.87(m, 1H), 2.06(m, 4H), 2.18(m, 1H), 2.38(m, 2H), 2.88(m, 1H), 3.81(m, 1H), 5.60(m, 3H), 7.48(m, 1H), 7.70 (m, 1H), 8.01 (m, 2H), 8.22 (m, 1H), 10.49 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=0.906min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=0.906 min.

實例324. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物617)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物634)之合成Example 324. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1- Piperidinyl]-2-oxyacetamide (Compound 617) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(benzene Synthesis of thiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 634)

Figure 110128222-A0202-12-1548-433
Figure 110128222-A0202-12-1548-433

步驟1：N-[5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone Synthesis of tert-butyl]amino]-3-methyl-2-pyridyl]carbamate

向(2S,5R)-2-(苯并噻吩-5-基)-5-甲基哌啶(0.3g，1.30mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(382.91mg，1.30mmol)及三乙胺(656.07mg，6.48mmol，903.67μL)之溶液中分批添加HATU(542.35mg，1.43mmol)。將所得混合物在25℃下攪拌3h，溶解於水(50ml)中且用EtOAc(3*20ml)萃取。將經合併之有機層用鹽水洗滌(2*15ml)，經Na2 SO4 乾燥且移除溶劑，以得到N-[5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.6g，1.18mmol，90.97%產率)。To (2S,5R)-2-(benzothiophen-5-yl)-5-methylpiperidine (0.3 g, 1.30 mmol), 2-[[6-(tert-butoxycarbonylamino)- To a solution of 5-methyl-3-pyridyl]amino]-2-oxoacetic acid (382.91 mg, 1.30 mmol) and triethylamine (656.07 mg, 6.48 mmol, 903.67 μL) was added HATU (542.35 μL) in portions mg, 1.43 mmol). The resulting mixture was stirred at 25°C for 3h, dissolved in water (50ml) and extracted with EtOAc (3*20ml). The combined organic layers were washed with brine (2*15ml), dried over Na2SO4 and solvent removed to give N-[5-[[2-[(2S,5R)-2-(benzothiophene -5-yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.6 g , 1.18 mmol, 90.97% yield).

此化合物不經進一步純化即用於下一步驟。This compound was used in the next step without further purification.

LCMS(ESI)：[M+1]+ m/z：計算值508.2；實測值509.2；Rt=1.306min。LCMS (ESI): [M+1] + m/z: calculated 508.2; found 509.2; Rt=1.306 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1- Synthesis of Piperidinyl]-2-Pendant Oxyacetamide

將N-[5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.6g，1.18mmol)於DCM(20mL)以及於二噁烷中之4.0M氯化氫溶液(4.00g，109.71mmol，5mL)中之溶液在25℃下攪拌12h。移除溶劑且藉由HPLC(60-65% 0-5min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量409，管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(190mg，465.10μmol，39.43%產率)。N-[5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.6 g, 1.18 mmol) in DCM (20 mL) and a 4.0 M solution of hydrogen chloride in dioxane (4.00 g, 109.71 mmol, The solution in 5 mL) was stirred at 25 °C for 12 h. The solvent was removed and analyzed by HPLC (60-65% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 409, column: YMC Triart C18 100x20mm, 5um) The residue was purified to obtain N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl -1-Piperidinyl]-2-oxoacetamide (190 mg, 465.10 μmol, 39.43% yield).

LCMS(ESI)：[M+1]+ m/z：計算值408.2；實測值409.2；Rt=2.556min。LCMS (ESI): [M+1] + m/z: calculated 408.2; found 409.2; Rt=2.556 min.

步驟3 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 3 N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidine Synthesis of Peridyl]-2-Pendant Oxyacetamide

將N-[5-[[2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.6g，1.18mmol)於DCM(20mL)以及於二噁烷中之4.0M氯化氫溶液(4.00g，109.71mmol，5mL)中之溶液在25℃下攪拌12h。移除溶劑且藉由HPLC(60-65% 0-5min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量409，管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(190mg，465.10μmol，39.43%產率)。N-[5-[[2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.6 g, 1.18 mmol) in DCM (20 mL) and a 4.0 M solution of hydrogen chloride in dioxane (4.00 g, 109.71 mmol, The solution in 5 mL) was stirred at 25 °C for 12 h. The solvent was removed and analyzed by HPLC (60-65% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 409, column: YMC Triart C18 100x20mm, 5um) The residue was purified to obtain N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl -1-Piperidinyl]-2-oxoacetamide (190 mg, 465.10 μmol, 39.43% yield).

LCMS(ESI)：[M+1]+ m/z：計算值408.2；實測值409.2；Rt=2.556min。LCMS (ESI): [M+1] + m/z: calculated 408.2; found 409.2; Rt=2.556 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物617 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物634 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1- Piperidinyl]-2-oxyacetamide ( Compound 617 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(benzene Synthesis of thiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 634 )

對N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(190mg，465.10μmol)進行掌性分離(注入體積：100mkl；樣品資訊：IB(250*20，5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min)，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(56mg，137.08μmol，58.95%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(苯并噻吩-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(55mg，134.63μmol，57.89%產率)。保留時間(化合物617 )=20.82min；保留時間(化合物634 )=22.48min，其中順式雜質少於5%p-N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5-methyl-1-piperidine chiral separation (injection volume: 100mkl; sample information: IB (250*20, 5mkm), Hexane-IPA-MeOH, 70-15- 15, 12 ml/min) to obtain N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(benzothiophen-5-yl)-5 -Methyl-1-piperidinyl]-2-oxyacetamide (56 mg, 137.08 μmol, 58.95% yield) and N-(6-amino-5-methyl-3-pyridyl)- 2-[(2R,5S)-2-(benzothiophen-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (55 mg, 134.63 μmol, 57.89% yield Rate). Retention time ( Compound 617 )=20.82min; Retention time ( Compound 634 )=22.48min, wherein the cis impurity is less than 5%

化合物617： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.04(m,3H),1.30-1.40(m,1H),1.69-1.77(m,1H),1.81-1.92(m,1H),1.93-2.03(m,3H),2.04-2.22(m,1H),2.24-2.35(m,1H),2.76-3.27(m,1H),3.37-4.08(m,1H),5.22-5.73(m,3H),7.26-7.38(m,1H),7.39-7.51(m,2H),7.72-7.77(m,1H),7.79-7.87(m,1H),7.92-7.99(m,1H),7.99-8.05(m,1H),10.46-10.56(m,1H)。 Compound 617: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.04 (m, 3H), 1.30-1.40 (m, 1H), 1.69-1.77 (m, 1H), 1.81-1.92 (m, 1H) ,1.93-2.03(m,3H),2.04-2.22(m,1H),2.24-2.35(m,1H),2.76-3.27(m,1H),3.37-4.08(m,1H),5.22-5.73( m,3H),7.26-7.38(m,1H),7.39-7.51(m,2H),7.72-7.77(m,1H),7.79-7.87(m,1H),7.92-7.99(m,1H), 7.99-8.05 (m, 1H), 10.46-10.56 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值408.2；實測值409.2；Rt=2.677min。LCMS (ESI): [M+1] + m/z: calculated 408.2; found 409.2; Rt=2.677 min.

RT(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)=33.903minRT(IA, Hexane-IPA-MeOH, 50-25-25, 0.6ml/min)=33.903min

化合物634： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.03(m,3H),1.28-1.41(m,1H),1.66-1.78(m,1H),1.80-1.93(m,1H),1.94-2.04(m,3H),2.05-2.22(m,1H),2.24-2.36(m,1H),2.77-3.28(m,1H),3.31-4.11(m,1H),5.21-5.57(m,1H),5.65(d,2H),7.27-7.38(m,1H),7.39-7.52(m,2H),7.72-7.77(m,1H),7.80-7.88(m,1H),7.93-8.06(m,2H),10.40-10.61(m,1H)。 Compound 634: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.03 (m, 3H), 1.28-1.41 (m, 1H), 1.66-1.78 (m, 1H), 1.80-1.93 (m, 1H) ,1.94-2.04(m,3H),2.05-2.22(m,1H),2.24-2.36(m,1H),2.77-3.28(m,1H),3.31-4.11(m,1H),5.21-5.57( m,1H),5.65(d,2H),7.27-7.38(m,1H),7.39-7.52(m,2H),7.72-7.77(m,1H),7.80-7.88(m,1H),7.93- 8.06 (m, 2H), 10.40-10.61 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值408.2；實測值409.2；Rt=2.676min。LCMS (ESI): [M+1] + m/z: calculated 408.2; found 409.2; Rt=2.676 min.

RT(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)=45.004minRT(IA, Hexane-IPA-MeOH, 50-25-25, 0.6ml/min)=45.004min

實例325. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物694)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物701)之合成Example 325. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methan yl-1-piperidinyl]-2-oxyacetamide (compound 694) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)- Synthesis of 2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 701)

Figure 110128222-A0202-12-1551-434
Figure 110128222-A0202-12-1551-434

步驟1.N-(6-胺基-5-乙基-3-吡啶基)-2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物495 )之合成Step 1. N-(6-Amino-5-ethyl-3-pyridyl)-2-[2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidine [Synthesis of]-2-oxyacetamide ( Compound 495 )

在室溫下將HATU(392.76mg，1.03mmol)分批添加到2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(216.10mg，1.03mmol)、5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(240mg，1.03mmol)及TEA(627.15mg，6.20mmol，863.84μL)於DMF(10mL)中之懸浮液中。將澄清溶液在20℃下攪拌18h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；以1-6min 55-60%水-甲醇(NH3 0.1%)，流速：30ml/min為流動相)，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(265mg，625.69μmol，60.57%產率)。HATU (392.76 mg, 1.03 mmol) was added portionwise at room temperature to 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-pendoxoacetic acid (216.10 mg, 1.03 mmol), 5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (240 mg, 1.03 mmol) and TEA (627.15 mg, 6.20 mmol, 863.84 μL) in DMF (10 mL) in the suspension. The clear solution was stirred at 20 °C for 18 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um; 1-6min 55-60% water-methanol ( NH3 0.1%), flow rate: 30ml/min as mobile phase) , to give N-(6-amino-5-ethyl-3-pyridinyl)-2-[2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidine yl]-2-oxoacetamide (265 mg, 625.69 μmol, 60.57% yield).

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值424.2；Rt=2.048min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 424.2; Rt=2.048 min.

步驟2.N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物694 )及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物 Step 2. N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl yl-1-piperidinyl]-2-oxyacetamide ( compound 694 ) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)- 2-(1,3-Benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( compound 701701 )之合成) synthesis

藉由掌性HPLC(管柱：OJ-H(250*.0，5mkm)，以己烷-IPA-MeOH，80-10-10，14ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物701 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(49mg，115.69μmol，52.45%產率)(保留時間=39.0min)及化合物694 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(40.9mg，96.57μmol，43.78%產率)(保留時間=46.3min)。The enantiomers were separated by chiral HPLC (column: OJ-H (250*.0, 5mkm) with hexane-IPA-MeOH, 80-10-10, 14ml/min as mobile phase) to give Two separate enantiomers Compound 701 N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazole-5 -yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (49 mg, 115.69 μmol, 52.45% yield) (retention time = 39.0 min) and compound 694 N-(6- Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl] -2-Oxyacetamide (40.9 mg, 96.57 μmol, 43.78% yield) (retention time = 46.3 min).

化合物694Compound 694

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.09(m,6H),1.36(m,2H),1.70(m,1H),1.87(m,1H),2.14(m,1H),2.34(m,2H),2.39(m,1H),2.78(m,1H),3.77(m,1H),5.65(m,3H),7.42(s,1H),7.50(m,1H),7.99(m,1H),8.05(m,1H),8.17(m,1H),9.39(s,1H),10.55(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.09(m, 6H), 1.36(m, 2H), 1.70(m, 1H), 1.87(m, 1H), 2.14(m, 1H), 2.34(m, 2H), 2.39(m, 1H), 2.78(m, 1H), 3.77(m, 1H), 5.65(m, 3H), 7.42(s, 1H), 7.50(m, 1H), 7.99 (m,1H),8.05(m,1H),8.17(m,1H),9.39(s,1H),10.55(m,1H)

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值424.2；Rt=2.048min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 424.2; Rt=2.048 min.

化合物701Compound 701

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.09(m,6H),1.36(m,2H),1.70(m,1H),1.87(m,1H),2.14(m,1H),2.34(m,2H),2.39(m,1H),2.78(m,1H),3.77(m,1H),5.65(m,3H),7.42(s,1H),7.50(m,1H),7.99(m,1H),8.05(m,1H),8.17(m,1H),9.39(s,1H),10.55(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.09(m, 6H), 1.36(m, 2H), 1.70(m, 1H), 1.87(m, 1H), 2.14(m, 1H), 2.34(m, 2H), 2.39(m, 1H), 2.78(m, 1H), 3.77(m, 1H), 5.65(m, 3H), 7.42(s, 1H), 7.50(m, 1H), 7.99 (m,1H),8.05(m,1H),8.17(m,1H),9.39(s,1H),10.55(m,1H)

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值424.2；Rt=2.048min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 424.2; Rt=2.048 min.

實例326.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(2-甲基苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物730及化合物719)之合成Example 326. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(2-methylbenzo[ d ]thiazol-5-yl)piperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 730 and Compound 719)

Figure 110128222-A0202-12-1553-435
Figure 110128222-A0202-12-1553-435

步驟1：(3-甲基-5-(2-(5-甲基-2-(2-甲基苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-(5-methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxygen Synthesis of tert-butyl acetamido)pyridin-2-yl)carbamate

在室溫下將HATU(463.00mg，1.22mmol)分批添加到2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(359.57mg，1.22mmol)、2-甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(300mg，1.22mmol)及TEA(739.30mg，7.31mmol，1.02mL)於DMF(10mL)中之懸浮液中。將澄清溶液在25℃下攪拌18h且在真空中蒸發溶劑。將殘餘物溶解於EtOAc(50mL)中，用水(3x10mL)洗滌且在真空中蒸發，以得到N -[3-甲基-5-[[2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(700mg，粗品)。HATU (463.00 mg, 1.22 mmol) was added portionwise to 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2- at room temperature Pendant oxyacetic acid (359.57 mg, 1.22 mmol), 2-methyl-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (300 mg, 1.22 mmol) and TEA (739.30 mg) , 7.31 mmol, 1.02 mL) in DMF (10 mL). The clear solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with water (3 x 10 mL) and evaporated in vacuo to give N- [3-methyl-5-[[2-[5-methyl-2-(2-methyl 3-butyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (700 mg, crude ).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.96(m,1H),1.09(d,3H),1.22(m,1H),1.48(s,9H),2.02(m,2H),2.27(m,4H),2.78(s,3H),2.84(m,1H),3.86(m,1H),4.12(m,1H),6.25(m,1H),7.80(m,4H),8.09(m,1H),9.61(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.96(m, 1H), 1.09(d, 3H), 1.22(m, 1H), 1.48(s, 9H), 2.02(m, 2H), 2.27( m, 4H), 2.78(s, 3H), 2.84(m, 1H), 3.86(m, 1H), 4.12(m, 1H), 6.25(m, 1H), 7.80(m, 4H), 8.09(m , 1H), 9.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值523.2；實測值524.2；Rt=1.396min。LCMS (ESI): [M] + m/z: calculated 523.2; found 524.2; Rt=1.396 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(2-甲基苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidine Synthesis of -1-yl)-2-oxyacetamide

在室溫下將於二噁烷中之4.0M氯化氫溶液(3.48g，13.37mmol，3.32mL，14%純度)小心添加到N -[3-甲基-5-[[2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(700mg，1.34 mmol)於DCM(10mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以50-50-80% 0-1-6min 0.1%水-MeOH-0.1% NH3 為流動相)，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(178mg，420.28μmol，31.44%產率)。A 4.0 M solution of hydrogen chloride in dioxane (3.48 g, 13.37 mmol, 3.32 mL, 14% purity) was carefully added to N- [3-methyl-5-[[[2-[5-methyl at room temperature yl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid A solution of tertiary butyl ester (700 mg, 1.34 mmol) in DCM (10 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; 50-50-80% 0-1-6 min 0.1% water-MeOH-0.1% NH3 as mobile phase) to give N- ( 6-Amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(2-methyl-1,3-benzothiazol-5-yl)-1-piperidinyl ]-2-Pendant oxyacetamide (178 mg, 420.28 μmol, 31.44% yield).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=2.323min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=2.323 min.

步驟3：掌性分離(化合物730 及化合物719 )Step 3: Chiral separation ( compound 730 and compound 719 )

藉由掌性HPLC(管柱：IC-II(250*20，5mkm)，以己烷-MeOH-IPA，50-25-25，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物730 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(42.5mg，100.35μmol，47.75%產率)(保留時間=32.9min)及化合物719 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(2-甲基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(43.3mg，102.24μmol，48.65%產率)(保留時間=51.1min)。The enantiomers were separated by chiral HPLC (column: IC-II (250*20, 5mkm) with hexane-MeOH-IPA, 50-25-25, 12ml/min as mobile phase) to give two An individual enantiomer compound 730 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-(2-methyl- 1,3-Benzothiazol-5-yl)-1-piperidinyl]-2-oxyacetamide (42.5 mg, 100.35 μmol, 47.75% yield) (retention time=32.9 min) and compound 719 N-(6-Amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(2-methyl-1,3-benzothiazole-5 -yl)-1-piperidinyl]-2-oxoacetamide (43.3 mg, 102.24 μmol, 48.65% yield) (retention time = 51.1 min).

化合物719 於分析條件下(管柱：IC，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為22.22min且化合物730 之保留時間為15.44min。The retention time of compound 719 under analytical conditions (column: IC, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 22.22 min and the retention time of compound 730 was 15.44 min.

化合物719：保留時間：22.22minCompound 719: retention time: 22.22min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.34(m,1H),1.69(m,1H),1.86(m,1H),1.99(m,3H),2.19(m,1H),2.29(m,1H),2.77(m,3H),3.25(m,1H),3.65(m,1H),5.62(m,3H),7.35(m,1H),7.45(m,1H),7.84(m,1H),7.99(m,2H),10.52(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.69(m, 1H), 1.86(m, 1H), 1.99(m, 3H), 2.19(m, 1H), 2.29(m, 1H), 2.77(m, 3H), 3.25(m, 1H), 3.65(m, 1H), 5.62(m, 3H), 7.35(m, 1H), 7.45 (m, 1H), 7.84 (m, 1H), 7.99 (m, 2H), 10.52 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=2.399min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=2.399 min.

化合物730：保留時間：15.44minCompound 730: retention time: 15.44min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(d,3H),1.35(m,1H),1.69(m,1H),1.86 (m,1H),1.99(m,3H),2.12(m,1H),2.28(m,1H),2.77(s,3H),3.25(m,1H),3.74(m,1H),5.62(m,3H),7.32(m,1H),7.49(m,1H),7.84(m,1H),7.99(m,2H),10.52(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(d,3H), 1.35(m,1H), 1.69(m,1H), 1.86(m,1H), 1.99(m,3H), 2.12(m, 1H), 2.28(m, 1H), 2.77(s, 3H), 3.25(m, 1H), 3.74(m, 1H), 5.62(m, 3H), 7.32(m, 1H), 7.49 (m, 1H), 7.84 (m, 1H), 7.99 (m, 2H), 10.52 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=2.422min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=2.422 min.

實例327. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物549)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物573)之合成Example 327. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[3,4-b ]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide (Compound 549) and N-(6-amino-5-methyl-3-pyridyl)-2-[ (2R,5S)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide (compound 573) synthesis

Figure 110128222-A0202-12-1555-436
Figure 110128222-A0202-12-1555-436

步驟1：N-[3-甲基-5-[[2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl Synthesis of tert-butyl ]-2-oxyacetyl]amino]-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(1.10g，2.77mmol，C6H15N)及5-(5-甲基-2-哌啶基)-1H-吡唑并[3,4-b]吡啶(0.6g，2.77mmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(1.05g，2.77mmol)，隨後添加TEA(842.15mg，8.32mmol，1.16mL)，且在環境溫度下攪拌15h。將反應混合物在真空中蒸發且倒入水(150ml)中且用EtOAc(2x50ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中 蒸發，以得到產物N-[3-甲基-5-[[2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.8g，1.62mmol，58.43%產率)2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (1.10 g, 2.77 mmol, C6H15N) and 5- (5-Methyl-2-piperidinyl)-1H-pyrazolo[3,4-b]pyridine (0.6 g, 2.77 mmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0 °C and HATU (1.05 g, 2.77 mmol) was added followed by TEA (842.15 mg, 8.32 mmol, 1.16 mL) and stirred at ambient temperature for 15 h. The reaction mixture was evaporated in vacuo and poured into water (150ml) and extracted with EtOAc (2x50ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and in vacuo Evaporation to give the product N-[3-methyl-5-[[2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.8 g, 1.62 mmol, 58.43% yield)

LCMS(ESI)：[M+H]+ m/z：計算值493.6；實測值494.2；Rt=1.194min。LCMS (ESI): [M+H] + m/z: calculated 493.6; found 494.2; Rt=1.194 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl )-1-piperidinyl]-2-side oxyacetamide synthesis

在室溫下將水(20mL)一次性添加到N-[3-甲基-5-[[2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.8g，1.62mmol)於二噁烷(10mL)中之經攪拌之溶液中。將所得混合物在90℃下攪拌48h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用二氯甲烷(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發且藉由製備型HPLC(10-30% 2-7min水-乙腈+nh3；流速：30ml/min)純化0.5g所獲得之粗產物，以得到產物N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.106g，269.42μmol，16.62%產率)Water (20 mL) was added in one portion to N-[3-methyl-5-[[2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine- 5-yl)-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.8 g, 1.62 mmol) in dioxane (10 mL) in the stirred solution. The resulting mixture was stirred at 90 °C for 48 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo and 0.5 g of the crude product obtained was purified by preparative HPLC (10-30% 2-7 min water-acetonitrile+nh3; flow rate: 30 ml/min) , to give the product N-(6-amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-5- (0.106 g, 269.42 μmol, 16.62% yield)

1 H NMR(600MHz,DMSO-d6)0.98-1.06(m,3H),1.30-1.41(m,1H),1.65-1.79(m,1H),1.79-1.93(m,1H),1.95-2.06(m,3H),2.07-2.21(m,1H),2.22-2.34(m,1H),2.79-3.16(m,1H),3.43-4.04(m,1H),5.25-5.77(m,3H),7.38-7.52(m,1H),7.90-8.03(m,1H),8.08-8.20(m,2H),8.44-8.55(m,1H),10.48-10.60(m,1H),13.54-13.68(m,1H)。 1 H NMR (600MHz, DMSO-d6) 0.98-1.06 (m, 3H), 1.30-1.41 (m, 1H), 1.65-1.79 (m, 1H), 1.79-1.93 (m, 1H), 1.95-2.06 ( m,3H), 2.07-2.21(m,1H), 2.22-2.34(m,1H), 2.79-3.16(m,1H), 3.43-4.04(m,1H), 5.25-5.77(m,3H), 7.38-7.52(m, 1H), 7.90-8.03(m, 1H), 8.08-8.20(m, 2H), 8.44-8.55(m, 1H), 10.48-10.60(m, 1H), 13.54-13.68(m , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值393.2；實測值394.2；Rt=1.715min。LCMS (ESI): [M+H] + m/z: calculated 393.2; found 394.2; Rt=1.715 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物549 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物573 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[3,4-b ]pyridin-5-yl)-1-piperidinyl]-2-oxyacetamide ( compound 549 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[ (2R,5S)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide ( compound 573 ) synthesis

藉由掌性HPLC(OD-H(250*30，5mkm)，以己烷-IPA-MeOH，50-25-2，25ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物549 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(33.96mg，86.32μmol，32.04%產率)及化合物573 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑并[3,4-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.03314g，84.23μmol，31.26%產率)The enantiomers were separated by chiral HPLC (OD-H (250*30, 5mkm) with hexane-IPA-MeOH, 50-25-2, 25ml/min as mobile phase) to give two separate Enantiomer compound 549 N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1H-pyrazolo[3, 4-b]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide (33.96 mg, 86.32 μmol, 32.04% yield) and compound 573 N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-piperidine [0.03314 g, 84.23 μmol, 31.26% yield]

化合物549：Compound 549:

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.06(m,3H),1.30-1.41(m,1H),1.65-1.79(m,1H),1.79-1.93(m,1H),1.95-2.06(m,3H),2.07-2.21(m,1H),2.22-2.34(m,1H),2.79-3.16(m,1H),3.43-4.04(m,1H),5.25-5.77(m,3H),7.38-7.52(m,1H),7.90-8.03(m,1H),8.08-8.20(m,2H),8.44-8.55(m,1H),10.48-10.60(m,1H),13.54-13.68(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.06(m,3H), 1.30-1.41(m,1H), 1.65-1.79(m,1H), 1.79-1.93(m,1H), 1.95- 2.06(m,3H), 2.07-2.21(m,1H), 2.22-2.34(m,1H), 2.79-3.16(m,1H), 3.43-4.04(m,1H), 5.25-5.77(m,3H) ),7.38-7.52(m,1H),7.90-8.03(m,1H),8.08-8.20(m,2H),8.44-8.55(m,1H),10.48-10.60(m,1H),13.54-13.68 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值393.4；實測值416.0；Rt=3.349min。LCMS (ESI): [M+H] + m/z: calculated 393.4; found 416.0; Rt=3.349 min.

RT(己烷-IPA-MeOH，50-25-25，25ml/min)=30.1052min。RT (Hexane-IPA-MeOH, 50-25-25, 25 ml/min) = 30.1052 min.

化合物573：Compound 573:

1H NMR(600MHz,DMSO-d 6 )δ 0.99-1.05(m,3H),1.29-1.42(m,1H),1.71-1.79(m,1H),1.85-1.93(m,1H),1.96-2.06(m,3H),2.08-2.20(m,1H),2.23-2.34(m,1H),2.75-3.27(m,1H),3.44-4.05(m,1H),5.19-5.74(m,3H),7.36-7.53(m,1H),7.89-8.05(m,1H),8.07-8.21(m,2H),8.42-8.55(m,1H),10.47-10.57(m,1H),13.42-13.68(m,1H)。1H NMR (600MHz, DMSO- d 6 )δ 0.99-1.05(m,3H), 1.29-1.42(m,1H), 1.71-1.79(m,1H), 1.85-1.93(m,1H), 1.96-2.06 (m,3H), 2.08-2.20(m,1H), 2.23-2.34(m,1H), 2.75-3.27(m,1H), 3.44-4.05(m,1H), 5.19-5.74(m,3H) ,7.36-7.53(m,1H),7.89-8.05(m,1H),8.07-8.21(m,2H),8.42-8.55(m,1H),10.47-10.57(m,1H),13.42-13.68( m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值393.4；實測值394.0；Rt=3.330min。LCMS (ESI): [M+H] + m/z: calculated 393.4; found 394.0; Rt=3.330 min.

RT(己烷-IPA-MeOH，50-25-25，25ml/min)=13.1472min。RT (Hexane-IPA-MeOH, 50-25-25, 25 ml/min) = 13.1472 min.

實例328. 外消旋N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物526)、N-(6-胺基-5-甲基-3-吡啶Example 328. Racemic N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazole- 5-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 526), N-(6-amino-5-methyl-3-pyridine 基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物675)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物676)之合成yl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidinyl]-2-side oxyacetyl Amine (Compound 675) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(1H-pyrazole- Synthesis of 5-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 676)

Figure 110128222-A0202-12-1558-437
Figure 110128222-A0202-12-1558-437

步驟1：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1- Synthesis of tertiary butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate

向(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]哌啶(125mg，397.77μmol，2HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(117.46mg，397.77μmol)及三乙胺(241.50mg，2.39mmol，332.65μL)之溶液中分批添加HATU(166.37mg，437.55μmol)。將所得混合物在25℃下攪拌3h，用水(30ml)淬滅且用EtOAc(3*20ml)萃取。將經合併之有機層用鹽水(2*20ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，385.65μmol，96.95%產率)。To (2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]piperidine (125 mg, 397.77 μmol, 2HCl), 2-[[6-(3rd Butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (117.46 mg, 397.77 μmol) and triethylamine (241.50 mg, 2.39 mmol, 332.65 μL) To the solution was added HATU (166.37 mg, 437.55 μmol) in portions. The resulting mixture was stirred at 25°C for 3h, quenched with water (30ml) and extracted with EtOAc (3*20ml). The combined organic layers were washed with brine (2*20ml), dried over Na2SO4 and evaporated in vacuo to give N-[3-methyl-5-[[2-[(2S,5R)- 5-Methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]amine tert-butyl formate (0.2 g, 385.65 μmol, 96.95% yield).

此化合物不經純化即用於下一步驟。This compound was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值518.3；實測值519.2；Rt=1.190min。LCMS (ESI): [M+H] + m/z: calculated 518.3; found 519.2; Rt=1.190 min.

步驟2：外消旋N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物526 )之合成Step 2: Racemic N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazole- Synthesis of 5-yl)phenyl]-1-piperidinyl]-2-oxoacetamide ( Compound 526 )

向N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，385.65μmol)於DCM(5mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(4.00g，109.71mmol，5mL)。將所得混合物在25℃下攪拌12h，移除溶劑且藉由HPLC(40-60% 0-5min 0.1%NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量419，管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(40mg，95.58μmol，24.78%產率)。to N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidine (0.2 g, 385.65 μmol) in DCM (5 mL) added in dioxane 4.0M hydrogen chloride solution (4.00 g, 109.71 mmol, 5 mL). The resulting mixture was stirred at 25 °C for 12 h, the solvent was removed and analyzed by HPLC (40-60% 0-5 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 419, Column: YMC Triart C18 100x20mm, 5um) The residue was purified to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2 -[4-(1H-Pyrazol-5-yl)phenyl]-1-piperidinyl]-2-oxyacetamide (40 mg, 95.58 μmol, 24.78% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.08(m,3H),1.29-1.39(m,1H),1.63-1.74(m,1H),1.80-1.92(m,1H),1.95-2.04(m,4H),2.12-2.29(m,1H),2.72-3.24(m,1H),3.35-4.06(m,1H),5.14-5.58(m,1H),5.58-5.65(m,2H),6.68(s,1H),7.30-7.39(m,2H),7.42-7.51(m,1H),7.66-7.74(m,1H),7.74-7.81(m,2H),7.95-8.05(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.08(m,3H), 1.29-1.39(m,1H), 1.63-1.74(m,1H), 1.80-1.92(m,1H), 1.95- 2.04(m, 4H), 2.12-2.29(m, 1H), 2.72-3.24(m, 1H), 3.35-4.06(m, 1H), 5.14-5.58(m, 1H), 5.58-5.65(m, 2H ),6.68(s,1H),7.30-7.39(m,2H),7.42-7.51(m,1H),7.66-7.74(m,1H),7.74-7.81(m,2H),7.95-8.05(m , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.805min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.805 min.

步驟3：N-(6-胺基-5-甲基3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物675 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl) Phenyl]-1-piperidinyl]-2-oxoacetamide ( Compound 675 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S )-5-methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (化合物676)之合成Synthesis of (Compound 676)

對N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(200mg，477.91μmol)進行掌性分離(樣品資訊：IC-II(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶 基]-2-側氧基乙醯胺(88mg，210.28μmol，88.00%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(1H-吡唑-5-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(91mg，217.45μmol，91.00%產率)。p-N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-5-yl)benzene chiral separation (sample information: IC-II (250*20, 5mkm), hexane-IPA-MeOH, 60-20-20, 12 ml/min) to obtain N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4 -(1H-pyrazol-5-yl)phenyl]-1-piperidine yl]-2-oxyacetamide (88 mg, 210.28 μmol, 88.00% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S) -5-Methyl-2-[4-(1H-pyrazol-5-yl)phenyl]-1-piperidinyl]-2-oxyacetamide (91 mg, 217.45 μmol, 91.00% yield ).

化合物675：Compound 675:

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.35(m,1H),1.69(m,1H),1.88(m,1H),1.99(m,4H),2.21(m,1H),2.98(m,1H),3.75(m,1H),5.59(m,3H),6.68(m,1H),7.43(m,3H),7.78(m,3H),7.99(m,1H),10.50(m,1H),12.84(m,1H)LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.016min。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.02(m, 3H), 1.35(m, 1H), 1.69(m, 1H), 1.88(m, 1H), 1.99(m, 4H), 2.21(m, 1H), 2.98(m, 1H), 3.75(m, 1H), 5.59(m, 3H), 6.68(m, 1H), 7.43(m, 3H), 7.78(m, 3H), 7.99 (m, 1H), 10.50 (m, 1H), 12.84 (m, 1H) LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.016min.

RT(己烷-IPA-MeOH，60-20-20，12ml/min)=41.6162min。RT (Hexane-IPA-MeOH, 60-20-20, 12 ml/min) = 41.6162 min.

化合物676：Compound 676:

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.34(m,1H),1.68(m,1H),1.86(m,1H),1.99(m,4H),2.18(m,2H),3.23(m,1H),3.59(m,1H),5.59(m,3H),6.68(s,1H),7.35(m,2H),7.49(m,1H),7.77(m,3H),7.99(m,1H),10.49(m,1H)LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.011min。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.34(m, 1H), 1.68(m, 1H), 1.86(m, 1H), 1.99(m, 4H), 2.18(m, 2H), 3.23(m, 1H), 3.59(m, 1H), 5.59(m, 3H), 6.68(s, 1H), 7.35(m, 2H), 7.49(m, 1H), 7.77 (m, 3H), 7.99 (m, 1H), 10.49 (m, 1H) LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.011 min.

RT(己烷-IPA-MeOH，60-20-20，12ml/min)=59.3602min。RT (Hexane-IPA-MeOH, 60-20-20, 12 ml/min) = 59.3602 min.

實例329. 外消旋N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物525)、rel-2-((2R,5S)-2-(4-(1H-吡唑-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物628)及rel-2-((2R,5S)-2-(4-(1H-吡唑-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物629)之合成Example 329. Racemic N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazole- 4-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 525), rel-2-((2R,5S)-2-(4-(1H-pyrazole- 4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridin-3-yl)-2-oxoacetamide (Compound 628 ) and rel-2-((2R,5S)-2-(4-(1H-pyrazol-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6-amine Synthesis of yl-5-methylpyridin-3-yl)-2-oxoacetamide (Compound 629)

Figure 110128222-A0202-12-1561-438
Figure 110128222-A0202-12-1561-438

步驟1：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]-1- Synthesis of tertiary butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate

將(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]哌啶(250mg，795.54μmol，2HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(234.92mg，795.54μmol)及三乙胺(402.50mg，3.98mmol，554.41μL)一起混合於二甲基甲醯胺(3mL)中。將所獲得之混合物簡單加熱至60-70℃，直到形成澄清溶液。冷卻至5-10℃之後，在5min期間分批添加HATU(332.74mg，875.09μmol)。將所得溶液在20℃下攪拌4h。然後，將其用水(15ml)稀釋且用乙酸乙酯(30ml)萃取。將有機層用水(2x15ml)及鹽水(15ml)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，得到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(330mg，636.32μmol，79.99%產率)。(2S,5R)-5-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]piperidine (250 mg, 795.54 μmol, 2HCl), 2-[[6-(3rd Butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (234.92 mg, 795.54 μmol) and triethylamine (402.50 mg, 3.98 mmol, 554.41 μL) together Mix in dimethylformamide (3 mL). The obtained mixture was heated briefly to 60-70°C until a clear solution formed. After cooling to 5-10°C, HATU (332.74 mg, 875.09 μmol) was added portionwise during 5 min. The resulting solution was stirred at 20 °C for 4 h. It was then diluted with water (15ml) and extracted with ethyl acetate (30ml). The organic layer was washed with water (2x15ml) and brine (15ml), dried over Na2SO4 and evaporated under reduced pressure to give N-[3-methyl-5-[[2-[(2S,5R)-5 -Methyl-2-[4-(1H-pyrazol-4-yl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Tertiary butyl ester (330 mg, 636.32 μmol, 79.99% yield).

1 H NMR(DMSO-d6,600MHz)δ 0.83(m,3H),1.13(m,1H),1.41(s,9H),1.67(m,1H),1.94(m,1H),2.00(d,4H),2.16(m,1H),2.28(m,1H),3.00(m,1H),5.10-5.57(m,2H),7.22-7.33(m,2H),7.26(m,1H),7.48(m,2H),7.60-7.85(m,3H),11.03(s,1H)。 1 H NMR(DMSO-d6,600MHz)δ 0.83(m,3H),1.13(m,1H),1.41(s,9H),1.67(m,1H),1.94(m,1H),2.00(d, 4H), 2.16(m, 1H), 2.28(m, 1H), 3.00(m, 1H), 5.10-5.57(m, 2H), 7.22-7.33(m, 2H), 7.26(m, 1H), 7.48 (m, 2H), 7.60-7.85 (m, 3H), 11.03 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值518.3；實測值519.4；Rt=1.171min。LCMS (ESI): [M+H] + m/z: calculated 518.3; found 519.4; Rt=1.171 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物525 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-4-yl ) phenyl]-1-piperidinyl]-2-side oxyacetamide ( compound 525 ) synthesis

將於99% 1,4-二噁烷中之4.0M氯化氫(2.32g，6.36mmol，2.30mL，10%純度)添加到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(330mg，636.32μmol)於二氯甲烷(10mL)中之溶液中。將所得混合物在20℃下攪拌18h。然後，將其在減壓下濃縮且使殘餘物經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；40-40-80% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(1H-吡唑-4-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(100mg，238.95μmol，37.55%產率)。4.0 M hydrogen chloride in 99% 1,4-dioxane (2.32 g, 6.36 mmol, 2.30 mL, 10% purity) was added to N-[3-methyl-5-[[2-[(2S, 5R)-5-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridine tert-butyl]carbamate (330 mg, 636.32 μmol) in dichloromethane (10 mL). The resulting mixture was stirred at 20 °C for 18 h. It was then concentrated under reduced pressure and the residue was subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; 40-40-80% 0-1-5min 0.1% NH3 -methanol, flow rate: 30ml/min) , to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(1H-pyrazol-4-yl) Phenyl]-1-piperidinyl]-2-oxoacetamide (100 mg, 238.95 μmol, 37.55% yield).

1 H NMR(600MHz,DMSO-d6)δ 0.93-1.05(m,3H),1.27-1.39(m,1H),1.61-1.74(m,1H),1.80-1.93(m,1H),2.00(d,4H),2.11-2.28(m,1H),2.71-3.22(m,1H),3.41-4.04(m,1H),5.05-5.73(m,3H),7.22-7.33(m,2H),7.41-7.54(m,1H),7.54-7.61(m,2H),7.87-8.17(m,3H),10.42-10.64(m,1H),12.89(s,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.93-1.05(m,3H), 1.27-1.39(m,1H), 1.61-1.74(m,1H), 1.80-1.93(m,1H), 2.00(d ,4H),2.11-2.28(m,1H),2.71-3.22(m,1H),3.41-4.04(m,1H),5.05-5.73(m,3H),7.22-7.33(m,2H),7.41 -7.54(m, 1H), 7.54-7.61(m, 2H), 7.87-8.17(m, 3H), 10.42-10.64(m, 1H), 12.89(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.761min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.761 min.

步驟3：rel-2-((2R,5S)-2-(4-(1H-吡唑-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物628 )及rel-2-((2R,5S)-2-(4-(1H-吡唑-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物629 )之合成Step 3: rel-2-((2R,5S)-2-(4-(1H-pyrazol-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6- Amino-5-methylpyridin-3-yl)-2-oxyacetamide ( Compound 628 ) and rel-2-((2R,5S)-2-(4-(1H-pyrazole-4) -yl)phenyl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridin-3-yl)-2-oxoacetamide ( Compound 629 ) synthesis

化合物525 外消旋-2-((2R,5S)-2-(4-(1H-吡唑-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(103mg，246.12μmol)之掌性分離使用(Chiralpak IA-II(250 * 20mm，5mkm)管柱；以IPA-MeOH，50-50為流動相；流速：10mL/min；管柱溫度：22℃；波長：254nm)進行，得到化合物628 rel-2-((2R,5S)-2-(4-(1H-吡唑-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶 -3-基)-2-側氧基乙醯胺(41.65mg，99.52μmol，40.44%產率)(保留時間(鏡像異構物A)=22.41min)及化合物629 rel-2-((2R,5S)-2-(4-(1H-吡唑-4-基)苯基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(38.47mg，91.93μmol，37.35%產率)(保留時間(鏡像異構物B)=35.83min)。 Compound 525 Racemic-2-((2R,5S)-2-(4-(1H-pyrazol-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6 - Chiral separation of amino-5-methylpyridin-3-yl)-2-oxoacetamide (103 mg, 246.12 μmol) using (Chiralpak IA-II (250*20 mm, 5 mkm) column; with IPA-MeOH, 50-50 as mobile phase; flow rate: 10 mL/min; column temperature: 22 °C; wavelength: 254 nm) to obtain compound 628 rel-2-((2R,5S)-2-(4-( 1H-Pyrazol-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridin-3-yl)-2-side oxyethyl Amide (41.65 mg, 99.52 μmol, 40.44% yield) (retention time (enantiomer A)=22.41 min) and compound 629 rel-2-((2R,5S)-2-(4-(1H- Pyrazol-4-yl)phenyl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridin-3-yl)-2-oxoacetamide (38.47 mg, 91.93 μmol, 37.35% yield) (retention time (enantiomer B) = 35.83 min).

化合物628： 1H NMR(600MHz,DMSO-d 6 )δ 0.96-1.03(m,3H),1.28-1.37(m,1H),1.63-1.73(m,1H),1.80-1.92(m,1H),1.97-2.03(m,3H),2.03-2.16(m,1H),2.18-2.28(m,1H),2.70-3.22(m,1H),3.40-4.04(m,1H),5.09-5.66(m,3H),7.22-7.33(m,2H),7.42-7.51(m,1H),7.56-7.63(m,2H),7.86-7.94(m,1H),7.95-8.20(m,2H),10.40-10.61(m,1H),12.90(s,1H)。 Compound 628: 1H NMR (600 MHz, DMSO- d 6 ) δ 0.96-1.03 (m, 3H), 1.28-1.37 (m, 1H), 1.63-1.73 (m, 1H), 1.80-1.92 (m, 1H), 1.97-2.03(m, 3H), 2.03-2.16(m, 1H), 2.18-2.28(m, 1H), 2.70-3.22(m, 1H), 3.40-4.04(m, 1H), 5.09-5.66(m ,3H),7.22-7.33(m,2H),7.42-7.51(m,1H),7.56-7.63(m,2H),7.86-7.94(m,1H),7.95-8.20(m,2H),10.40 -10.61(m, 1H), 12.90(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.998min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.998 min.

RT(IPA-MeOH，50-50，10ml/min)=21.379minRT(IPA-MeOH, 50-50, 10ml/min)=21.379min

化合物629： 1H NMR(600MHz,DMSO-d 6 )δ 0.98-1.03(m,3H),1.28-1.40(m,1H),1.62-1.74(m,1H),1.80-1.91(m,1H),1.97-2.03(m,3H),2.02-2.16(m,1H),2.17-2.28(m,1H),2.73-3.21(m,1H),3.40-4.04(m,1H),5.08-5.66(m,3H),7.23-7.33(m,2H),7.42-7.50(m,1H),7.56-7.65(m,2H),7.82-7.97(m,1H),7.97-8.05(m,1H),8.05-8.22(m,1H),10.45-10.61(m,1H),12.90(s,1H)。 Compound 629: 1H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.03 (m, 3H), 1.28-1.40 (m, 1H), 1.62-1.74 (m, 1H), 1.80-1.91 (m, 1H), 1.97-2.03(m, 3H), 2.02-2.16(m, 1H), 2.17-2.28(m, 1H), 2.73-3.21(m, 1H), 3.40-4.04(m, 1H), 5.08-5.66(m ,3H),7.23-7.33(m,2H),7.42-7.50(m,1H),7.56-7.65(m,2H),7.82-7.97(m,1H),7.97-8.05(m,1H),8.05 -8.22(m, 1H), 10.45-10.61(m, 1H), 12.90(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.990min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.990 min.

RT(IPA-MeOH，50-50，10ml/min)=33.245min。RT (IPA-MeOH, 50-50, 10 ml/min) = 33.245 min.

實例330.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-羥基-4-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物580)之合成Example 330. N- (6-amino-5-methylpyridin-3-yl)-2-(2-(3-hydroxy-4-methylphenyl)-5-methylpiperidin-1-yl )-2-side oxyacetamide (compound 580) synthesis

Figure 110128222-A0202-12-1563-439
Figure 110128222-A0202-12-1563-439

步驟1：外消旋-(5-(2-((2R,5S)-2-(3-羥基-4-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基Step 1: Racemic-(5-(2-((2R,5S)-2-(3-hydroxy-4-methylphenyl)-5-methylpiperidin-1-yl)-2-side Oxygen 乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Synthesis of acetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

向2-甲基-5-[(2S,5R )-5-甲基-2-哌啶基]苯酚(0.25g，1.03mmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(241.67mg，818.42μmol)及TEA(732.48mg，7.24mmol，1.01mL)於DMF(5mL)中之溶液中分批添加HATU(432.52mg，1.14mmol)。將混合物在25℃下攪拌2h。將反應混合物提交用於HPLC(0-1-6min 45-45-90%水-MeOH(NH3 0.1%)，流速30ml/min；管柱：YMC-Actus Triart C18 100*20mml)，以得到N -[5-[[2-[(2S,5R )-2-(3-羥基-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(69mg，142.98μmol，13.83%產率)。To 2-methyl-5-[( 2S,5R )-5-methyl-2-piperidinyl]phenol (0.25 g, 1.03 mmol, HCl), 2-[[6-( tert- butoxycarbonyl amino)-5-methyl-3-pyridinyl]amino]-2-oxoacetic acid (241.67 mg, 818.42 μmol) and TEA (732.48 mg, 7.24 mmol, 1.01 mL) in DMF (5 mL) To the solution was added HATU (432.52 mg, 1.14 mmol) in portions. The mixture was stirred at 25 °C for 2 h. The reaction mixture was submitted for HPLC (0-1-6 min 45-45-90% water-MeOH ( NH3 0.1%), flow rate 30 ml/min; column: YMC-Actus Triart C18 100*20 mml) to give N -[5-[[2-[( 2S,5R )-2-(3-Hydroxy-4-methylphenyl)-5-methyl-1-piperidinyl]-2-side oxyacetyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (69 mg, 142.98 [mu]mol, 13.83% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(d,3H),1.40(m,1H),1.42(s,9H),1.92(m,3H),2.08(m,4H),2.17(s,3H),5.25(m,1H),6.62(m,1H),6.67(m,1H),7.05(m,1H),7.91(m,1H),8.44(m,1H),9.05(m,1H),9.27(m,1H),11.01(m,1H)。 1 H NMR (500MHz, DMSO- d 6 ) δ(ppm) 1.03(d, 3H), 1.40(m, 1H), 1.42(s, 9H), 1.92(m, 3H), 2.08(m, 4H), 2.17(s,3H),5.25(m,1H),6.62(m,1H),6.67(m,1H),7.05(m,1H),7.91(m,1H),8.44(m,1H),9.05 (m, 1H), 9.27 (m, 1H), 11.01 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值482.4；實測值483.2；Rt=3.265min。LCMS (ESI): [M] + m/z: calculated 482.4; found 483.2; Rt=3.265 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-羥基-4-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物580 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3-hydroxy-4-methylphenyl)-5-methylpiperidin-1-yl )-2-side oxyacetamide ( compound 580 ) synthesis

將N -[5-[[2-[(2S,5R )-2-(3-羥基-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(69mg，142.98μmol)溶解於二噁烷(1mL)及水(1.5mL)中且在95℃下攪拌14h。蒸發溶劑。藉由反相HPLC(40-90% 0-9.5min水-MeOH(NH3 0.1%))純化殘餘物，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3-羥基-4-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(29mg，75.83μmol，53.03%產率)。產物含有6%順式異構物。 N- [5-[[2-[( 2S,5R )-2-(3-hydroxy-4-methylphenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (69 mg, 142.98 μmol) was dissolved in dioxane (1 mL) and water (1.5 mL) and stirred at 95 °C 14h. Evaporate the solvent. The residue was purified by reverse phase HPLC (40-90% 0-9.5 min water-MeOH ( NH3 0.1%)) to give N- (6-amino-5-methyl-3-pyridinyl)-2 -[( 2S,5R )-2-(3-hydroxy-4-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (29 mg, 75.83 μmol, 53.03 %Yield). The product contained 6% cis isomer.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.02(m,3H),1.25-1.35(m,1H),1.64-1.73(m,1H),1.79-1.88(m,1H),1.97-2.02(m,3H),2.03-2.10(m,5H),2.74-3.22(m,1H),3.39-4.02(m,1H),5.00-5.53(m,1H),5.55-5.62(m,2H),6.59-6.67(m, 1H),6.69-6.77(m,1H),7.00-7.05(m,1H),7.41-7.49(m,1H),7.95-8.02(m,1H),9.21(br.s,1H),10.44(br.s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.02(m,3H), 1.25-1.35(m,1H), 1.64-1.73(m,1H), 1.79-1.88(m,1H) ,1.97-2.02(m,3H),2.03-2.10(m,5H),2.74-3.22(m,1H),3.39-4.02(m,1H),5.00-5.53(m,1H),5.55-5.62( m,2H),6.59-6.67(m,1H),6.69-6.77(m,1H),7.00-7.05(m,1H),7.41-7.49(m,1H),7.95-8.02(m,1H), 9.21 (br.s, 1H), 10.44 (br.s, 1H).

LCMS(ESI)：[M]+ m/z：計算值382.4；實測值383.2；Rt=2.173min。LCMS (ESI): [M] + m/z: calculated 382.4; found 383.2; Rt=2.173 min.

實例331. 外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物690)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(2H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物785)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物790)之合成Example 331. Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5- Methyl-1-piperidinyl]-2-oxyacetamide (Compound 690), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R) -2-(2H-Indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 785) and N-(6-amino-5-methyl) yl-3-pyridyl)-2-[(2R,5S)-2-(2H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 790)

Figure 110128222-A0202-12-1565-440
Figure 110128222-A0202-12-1565-440

步驟1：N-[5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-pendoxoethyl Synthesis of Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向4-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(360mg，1.43mmol，HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(422.25mg，1.43mmol)及三乙胺(1.01g，10.01mmol，1.40mL)於DMF(3mL)中之溶液中分批添加HATU(598.09mg，1.57mmol)。將混合物在25℃下攪拌2h。將反應混合物用水(50ml)稀釋且將產物用EtOAc(3*25ml)萃取。將經合併之有機層用水、鹽水洗滌且經Na2 SO4 乾燥。將溶劑蒸發，以得到N-[5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯 (320mg，649.66μmol，45.43%產率)。To 4-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (360 mg, 1.43 mmol, HCl), 2-[[6-(tert-butoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (422.25 mg, 1.43 mmol) and triethylamine (1.01 g, 10.01 mmol, 1.40 mL) in DMF (3 mL) To the solution was added HATU (598.09 mg, 1.57 mmol) in portions. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50ml) and the product was extracted with EtOAc (3*25ml). The combined organic layers were washed with water, brine and dried over Na2SO4 . The solvent was evaporated to give N-[5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (320 mg, 649.66 μmol, 45.43% yield).

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.11(m,3H),1.40(s,9H),1.95(m,4H),2.16(s,3H),2.21(m,2H),2.65(m,2H),2.85(m,2H),7.05(m,1H),7.44(d,2H),7.91(s,1H),8.12(s,1H),8.43(s,1H),11.07(m,1H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 1.11 (m, 3H), 1.40 (s, 9H), 1.95 (m, 4H), 2.16 (s, 3H), 2.21 (m, 2H) ,2.65(m,2H),2.85(m,2H),7.05(m,1H),7.44(d,2H),7.91(s,1H),8.12(s,1H),8.43(s,1H), 11.07 (m, 1H).

LCMS(ESI)：[M-Boc+H]+ m/z：計算值492.3；實測值392.2；Rt=1.278min。LCMS (ESI): [M-Boc+H] + m/z: calculated 492.3; found 392.2; Rt=1.278 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物690 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1 Synthesis of -Piperidinyl]-2-oxyacetamide ( Compound 690 )

向N-[5-[[2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(320mg，649.66μmol)於DCM(10mL)中之經攪拌之溶液中添加於99% 1,4-二噁烷中之4M氯化氫(236.87mg，6.50mmol，296.09μL)。將反應混合物在25℃下攪拌2h。在真空中蒸發溶劑，以得到粗產物(220mg)，其藉由反相HPLC(0-5min 20-70%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，目標質量392.46管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)進行純化，以得到呈2種級分之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(42mg，107.02μmol，16.47%產率)：To N-[5-[[2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoacetyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (320 mg, 649.66 μmol) in DCM (10 mL) was added to a stirred solution of 99% 1,4-dioxane 4M hydrogen chloride (236.87 mg, 6.50 mmol, 296.09 μL). The reaction mixture was stirred at 25 °C for 2 h. The solvent was evaporated in vacuo to give the crude product (220 mg), which was purified by reverse phase HPLC (0-5 min 20-70% water-methanol (NH 3 0.1%), flow rate 30 ml/min (load pump 4 ml/min methanol ( NH3 0.1%)), target mass 392.46 column: YMC-Actus Triart C18 100*20mml.DS-5um) was purified to obtain N-(6-amino-5-methyl- 3-Pyridinyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (42 mg , 107.02 μmol, 16.47% yield):

第1級分：42mg(100% LCMS)Fraction 1: 42mg (100% LCMS)

第2級分：78mg(89%反式異構物；9.5%順式異構物)Fraction 2: 78 mg (89% trans isomer; 9.5% cis isomer)

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.32(m,1H),1.90(m,3H),2.02(s,3H),2.21(m,2H),3.54(m,1H),5.74(m,3H),7.05(m,1H),7.31(t,1H),7.44(d,1H),7.49(s,1H),8.03(s,1H),8.13(s,1H),10.45(m,1H),13.10(s,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.32(m, 1H), 1.90(m, 3H), 2.02(s, 3H), 2.21(m, 2H), 3.54(m, 1H), 5.74(m, 3H), 7.05(m, 1H), 7.31(t, 1H), 7.44(d, 1H), 7.49(s, 1H), 8.03(s, 1H), 8.13 (s,1H),10.45(m,1H),13.10(s,1H)

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=1.626min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=1.626 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(2H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物785 )及N-(6-胺基-5-甲基-3-吡啶Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-(2H-indazol-4-yl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide ( compound 785 ) and N-(6-amino-5-methyl-3-pyridine 基)-2-[(2R,5S)-2-(2H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物790 )之合base)-2-[(2R,5S)-2-(2H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 790 ) combine

使用(IA-II(250*20，5mkm)管柱，以己烷-IPA-MeOH，40-30-30為流動相；流速12ml/min；24℃，波長：205nm，210nm)對N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(2H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(82.0mg，208.94μmol)進行掌性分離，得到呈黃色固體之化合物785 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(2H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(49.32mg，125.67μmol，60.15%產率)(RT=65.675min)及呈黃色固體之化合物790 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31.2mg，79.50μmol，38.05%產率)(RT=46.697min)。Use (IA-II (250*20, 5mkm) column, with hexane-IPA-MeOH, 40-30-30 as mobile phase; flow rate 12ml/min; 24℃, wavelength: 205nm, 210nm) to N-( 6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(2H-indazol-4-yl)-5-methyl-1-piperidinyl]- Chiral separation of 2-oxoacetamide (82.0 mg, 208.94 μmol) afforded compound 785 N-(6-amino-5-methyl-3-pyridyl)-2-[( as a yellow solid 2S,5R)-2-(2H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (49.32 mg, 125.67 μmol, 60.15% yield) (RT=65.675 min) and compound 790 as a yellow solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(2H-indazole-4 -yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (31.2 mg, 79.50 μmol, 38.05% yield) (RT=46.697 min).

化合物785： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.03(m,3H),1.28-1.34(m,1H),1.74-1.86(m,1H),1.86-1.92(m,1H),1.93-2.04(m,3H),2.13-2.33(m,2H),3.31-3.37(m,1H),3.54-4.09(m,1H),5.54-5.93(m,3H),7.00-7.08(m,1H),7.29-7.33(m,1H),7.39-7.45(m,1H),7.50(s,1H),7.82-8.03(m,1H),8.03-8.17(m,1H),10.33-10.58(m,1H),13.11(s,1H)。 Compound 785: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.03 (m, 3H), 1.28-1.34 (m, 1H), 1.74-1.86 (m, 1H), 1.86-1.92 (m, 1H) ,1.93-2.04(m,3H),2.13-2.33(m,2H),3.31-3.37(m,1H),3.54-4.09(m,1H),5.54-5.93(m,3H),7.00-7.08( m,1H),7.29-7.33(m,1H),7.39-7.45(m,1H),7.50(s,1H),7.82-8.03(m,1H),8.03-8.17(m,1H),10.33- 10.58 (m, 1H), 13.11 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=1.777min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=1.777 min.

RT(己烷-IPA-MeOH，40-30-30，12ml/min)=34.8612min。RT (Hexane-IPA-MeOH, 40-30-30, 12 ml/min) = 34.8612 min.

化合物790： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.03(m,3H),1.27-1.37(m,1H),1.73-1.86(m,1H),1.86-1.92(m,1H),1.93-2.05(m,3H),2.12-2.32(m,2H),2.94-3.01(m,0.2H),3.32-3.36(m,0.8H),3.51-4.12(m,1H),5.53-5.91(m,3H),6.98-7.08(m,1H),7.26-7.32(m,1H),7.32-7.44(m,1H),7.44-7.52(m,1H),7.84-8.03(m,1H),8.03-8.15(m,1H),10.36-10.59(m,1H),13.10(s,1H)。 Compound 790: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.03 (m, 3H), 1.27-1.37 (m, 1H), 1.73-1.86 (m, 1H), 1.86-1.92 (m, 1H) ,1.93-2.05(m,3H),2.12-2.32(m,2H),2.94-3.01(m,0.2H),3.32-3.36(m,0.8H),3.51-4.12(m,1H),5.53- 5.91(m,3H),6.98-7.08(m,1H),7.26-7.32(m,1H),7.32-7.44(m,1H),7.44-7.52(m,1H),7.84-8.03(m,1H) ), 8.03-8.15(m, 1H), 10.36-10.59(m, 1H), 13.10(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值392.3；實測值393.2；Rt=1.771min。LCMS (ESI): [M+H] + m/z: calculated 392.3; found 393.2; Rt=1.771 min.

RT(己烷-IPA-MeOH，40-30-30，12ml/min)=25.8692min。RT (Hexane-IPA-MeOH, 40-30-30, 12 ml/min) = 25.8692 min.

實例332. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物911)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物928)之合成Example 332. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide (Compound 911) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-( Synthesis of 1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 928)

Figure 110128222-A0202-12-1568-441
Figure 110128222-A0202-12-1568-441

步驟1：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1 -Piperidinyl]-2-Side Oxyacetamide Synthesis

向4-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(475mg，1.32mmol，2HCl)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(275.82mg，1.32mmol)及三乙胺(667.07mg，6.59mmol，918.83μL)於二甲基甲醯胺(4mL)中之經攪拌之混合物中添加HATU(551.45mg，1.45mmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(30-30-55% 0-1-6min H2 O/ACN/0.1% NH4OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(88mg，216.49μmol，16.42%產率)。To 4-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (475 mg, 1.32 mmol, 2HCl), 2-[(6-amino-5-ethyl-3 -Pyridinyl)amino]-2-oxoacetic acid (275.82 mg, 1.32 mmol) and triethylamine (667.07 mg, 6.59 mmol, 918.83 μL) in dimethylformamide (4 mL) under stirring To the mixture was added HATU (551.45 mg, 1.45 mmol). The resulting reaction mixture was stirred at 20 °C for 4 h. It was then subjected to HPLC (30-30-55% 0-1-6 min H2O /ACN/0.1% NH4OH, flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give N-(6 -Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2 - Pendant oxyacetamide (88 mg, 216.49 μmol, 16.42% yield).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=2.041min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=2.041 min.

步驟2：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物911 )及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物928 )之合成Step 2: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide ( Compound 911 ) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-( Synthesis of 1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( compound 928 )

藉由掌性HPLC(管柱：Chiralpak IA-I(250*20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：12mL/min；5次注入，17mg/注入，V=6L， 時間=9,3h.)將N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(88mg，216.49μmol)分成鏡像異構物，得到：化合物911 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31.7mg，77.99μmol，72.05%產率)(其中保留時間=62.752min)及化合物928 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1H-吲唑-4-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(27.9mg，68.64μmol，63.41%產率)(其中保留時間=75.464min)。By chiral HPLC (column: Chiralpak IA-I (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH 50-25-25; flow rate: 12mL/min; 5 injections, 17mg/injection, V=6L, time=9,3h.) N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazole-4- yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (88 mg, 216.49 μmol) was separated into the enantiomers to give: compound 911 N-(6-amino-5-ethyl) yl-3-pyridyl)-2-[(2S,5R)-2-(1H-indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (31.7 mg, 77.99 μmol, 72.05% yield) (wherein retention time = 62.752 min) and compound 928 N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S) -2-(1H-Indazol-4-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (27.9 mg, 68.64 μmol, 63.41% yield) (wherein retention time =75.464min).

化合物911：Compound 911:

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.06(m,6H),1.32(m,1H),1.85(m,2H),2.19(m,2H),2.29(m,1H),2.39(m,1H),2.97(m,1H),3.54(m,1H),5.76(m,3H),7.06(d,1H),7.31(t,1H),7.44(d,1H),7.51(s,1H),8.07(m,2H),10.46(m,1H),13.11(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.06(m, 6H), 1.32(m, 1H), 1.85(m, 2H), 2.19(m, 2H), 2.29(m, 1H), 2.39(m, 1H), 2.97(m, 1H), 3.54(m, 1H), 5.76(m, 3H), 7.06(d, 1H), 7.31(t, 1H), 7.44(d, 1H), 7.51 (s, 1H), 8.07 (m, 2H), 10.46 (m, 1H), 13.11 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.4；Rt=2.015min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.4; Rt=2.015 min.

RT(己烷-IPA-MeOH，50-25-25，12ml/min)=55.1092min。RT (Hexane-IPA-MeOH, 50-25-25, 12 ml/min) = 55.1092 min.

化合物928：Compound 928:

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.05(m,6H),1.32(m,1H),1.85(m,2H),2.18(m,2H),2.30(m,1H),2.39(m,2H),3.72(m,1H),5.76(m,3H),7.06(d,1H),7.31(t,1H),7.44(d,1H),7.51(s,1H),8.09(m,2H),10.47(m,1H),13.11(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.05(m, 6H), 1.32(m, 1H), 1.85(m, 2H), 2.18(m, 2H), 2.30(m, 1H), 2.39(m, 2H), 3.72(m, 1H), 5.76(m, 3H), 7.06(d, 1H), 7.31(t, 1H), 7.44(d, 1H), 7.51(s, 1H), 8.09 (m, 2H), 10.47 (m, 1H), 13.11 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.4；Rt=2.008min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.4; Rt=2.008 min.

RT(己烷-IPA-MeOH，50-25-25，12ml/min)=72.1832min。RT (Hexane-IPA-MeOH, 50-25-25, 12 ml/min) = 72.1832 min.

實例333.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物582、化合物657及化合物656)之合成Example 333. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-oxyisoindolin-5-yl)piperidine- Synthesis of 1-yl)-2-oxoacetamide (Compound 582, Compound 657 and Compound 656)

Figure 110128222-A0202-12-1570-442
Figure 110128222-A0202-12-1570-442

步驟1：(3-甲基-5-(2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-(5-methyl-2-(3-oxyisoindolin-5-yl)piperidin-1-yl)-2-oxygenyl Synthesis of acetamido)pyridin-2-yl)carbamic acid tert-butyl ester

將DIPEA(322.68mg，2.50mmol，434.88μL)添加到相應2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(294.90mg，998.68μmol)及6-(5-甲基-2-哌啶基)異吲哚啉-1-酮(0.23g，998.68μmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(417.70mg，1.10mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到純的N -[3-甲基-5-[[2-[5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(291.6mg，574.49μmol，57.53%產率)。DIPEA (322.68 mg, 2.50 mmol, 434.88 μL) was added to the corresponding 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (294.90 mg, 998.68 μmol) and 6-(5-methyl-2-piperidinyl)isoindolin-1-one (0.23 g, 998.68 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (417.70 mg, 1.10 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure N- [3-methyl-5-[[2-[5-methyl-2-(3-oxyisoindolin-5-yl)- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (291.6 mg, 574.49 [mu]mol, 57.53% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(d,3H),1.48(s,9H),1.68(m,1H),1.92(m,1H),2.18(m,3H),2.22(s,3H),2.78(m,1H),3.86(m,1H),4.36(s,2H),5.55(m,1H),7.68(m,3H),7.96(m,1H),8.49(m,2H),8.98(m,1H),11.08(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03(d,3H), 1.48(s,9H), 1.68(m,1H), 1.92(m,1H), 2.18(m,3H), 2.22(s, 3H), 2.78(m, 1H), 3.86(m, 1H), 4.36(s, 2H), 5.55(m, 1H), 7.68(m, 3H), 7.96(m, 1H), 8.49 (m, 2H), 8.98 (m, 1H), 11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值507.2；實測值508.2；Rt=2.791min。LCMS (ESI): [M] + m/z: calculated 507.2; found 508.2; Rt=2.791 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-oxyisoindolin-5-yl)piperidine- Synthesis of 1-yl)-2-oxyacetamide

將N -[3-甲基-5-[[2-[5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.29g，571.34μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌14h。在反 應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC，以得到純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(112.2mg，275.36μmol，48.20%產率)。樣品含有95%反式異構物及5%順式異構物。 N- [3-methyl-5-[[2-[5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxygen 3-butylacetylacetoxy]amino]-2-pyridyl]carbamate (0.29 g, 571.34 [mu]mol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 14 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(3- Pendant oxyisoindolin-5-yl)-1-piperidinyl]-2-pendant oxyacetamide (112.2 mg, 275.36 μmol, 48.20% yield). The sample contained 95% trans isomer and 5% cis isomer.

化合物582： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.01(d,3H),1.33(m,1H),1.66(m,1H),1.84(m,1H),1.97(s,3H),2.02(m,1H),2.28(m,1H),3.02(m,1H),3.78(m,1H),4.34(s,2H),5.57(m,3H),7.48(m,2H),7.59(m,2H),8.02(m,1H),8.55(s,1H),10.54(m,1H)。 Compound 582: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.01 (d, 3H), 1.33 (m, 1H), 1.66 (m, 1H), 1.84 (m, 1H), 1.97 (s, 3H), 2.02(m, 1H), 2.28(m, 1H), 3.02(m, 1H), 3.78(m, 1H), 4.34(s, 2H), 5.57(m, 3H), 7.48(m, 2H) ), 7.59(m, 2H), 8.02(m, 1H), 8.55(s, 1H), 10.54(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值407.2；實測值408.2；Rt=1.300min。LCMS (ESI): [M] + m/z: calculated 407.2; found 408.2; Rt=1.300 min.

步驟3：掌性分離(化合物657 及化合物656 )Step 3: Chiral separation ( Compound 657 and Compound 656 )

使用(Chiralpak AS(250 * 20mm，10mkm)管柱；以己烷-IPA-MeOH 60-20-20為流動相；流速：12mL/min；4pin)進行N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(60mg，147.25μmol)之掌性分離，得到呈米色固體之化合物656 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(27.22mg，66.80μmol，45.37%產率)(RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=40.546min)及呈米色固體之化合物657 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(26.87mg，65.94μmol，44.78%產率)(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=50.183min)。 N- (6-amino-5-methyl) was performed using (Chiralpak AS (250*20mm, 10mkm) column; hexane-IPA-MeOH 60-20-20 as mobile phase; flow rate: 12mL/min; 4pin) yl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-side Chiral isolation of oxyacetamide (60 mg, 147.25 μmol) afforded compound 656 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R ) as a beige solid -5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyacetamide (27.22 mg, 66.80 μmol, 45.37% yield ) (RT(IC, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)=40.546 min) and compound 657 N- (6-amino-5-methyl-3- Pyridinyl)-2-[( 2R,5S )-5-methyl-2-(3-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyacetylacetone Amine (26.87 mg, 65.94 μmol, 44.78% yield) (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 50.183 min).

化合物656：保留時間：40.54minCompound 656: retention time: 40.54min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.34(m,1H),1.65(m,1H),1.85(m,1H),1.99(m,3H),2.14(m,1H),2.26(m,1H),3.21(m,1H),3.76(m,1H),4.33(m,2H),5.61(m,3H),7.47(m,2H),7.58(m,2H),7.98(m,1H),8.54(s,1H), 10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.65(m, 1H), 1.85(m, 1H), 1.99(m, 3H), 2.14(m, 1H), 2.26(m, 1H), 3.21(m, 1H), 3.76(m, 1H), 4.33(m, 2H), 5.61(m, 3H), 7.47(m, 2H), 7.58 (m, 2H), 7.98 (m, 1H), 8.54 (s, 1H), 10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值407.2；實測值408.2；Rt=1.687min。LCMS (ESI): [M] + m/z: calculated 407.2; found 408.2; Rt=1.687 min.

化合物657：保留時間：50.18minCompound 657: retention time: 50.18min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.34(m,1H),1.66(m,1H),1.84(m,1H),1.99(m,3H),2.14(m,1H),2.24(m,1H),3.05(m,1H),3.66(m,1H),4.33(m,2H),5.61(m,3H),7.55(m,4H),7.98(m,1H),8.54(m,1H),10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.66(m, 1H), 1.84(m, 1H), 1.99(m, 3H), 2.14(m, 1H), 2.24(m, 1H), 3.05(m, 1H), 3.66(m, 1H), 4.33(m, 2H), 5.61(m, 3H), 7.55(m, 4H), 7.98 (m, 1H), 8.54 (m, 1H), 10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值407.2；實測值408.2；Rt=1.696min。LCMS (ESI): [M] + m/z: calculated 407.2; found 408.2; Rt=1.696 min.

實例334.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯-4,5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物857及化合物847)之合成Example 334. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chloro-4,5-difluorophenyl)-5-methylpiperidine-1 Synthesis of -yl)-2-oxoacetamide (Compound 857 and Compound 847)

Figure 110128222-A0202-12-1572-443
Figure 110128222-A0202-12-1572-443

步驟1：外消旋-(5-(2-((2R,5S)-2-(3-氯-4,5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-2-(3-chloro-4,5-difluorophenyl)-5-methylpiperidin-1-yl)-2 -Synthesis of tert-butyl oxyacetamido)-3-methylpyridin-2-yl)carbamate

向(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基哌啶(200mg，814.02μmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(240.37mg，814.02μmol)及TEA(164.74mg，1.63mmol，226.92μL)於DCM(3mL)中之經攪拌之混合物中添加HATU(340.46mg，895.42μmol)。將所得反應混合物在20℃下攪拌5h。然後，使其經歷HPLC(55-90% 0-5min H2 O/MeOH/0.1% NH4 OH，流 速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到N -[5-[[2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(220mg，420.67μmol，51.68%產率)。To ( 2R,5S )-2-(3-chloro-4,5-difluorophenyl)-5-methylpiperidine (200 mg, 814.02 μmol), 2-[[6-( tert- butoxycarbonyl Amino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (240.37 mg, 814.02 μmol) and TEA (164.74 mg, 1.63 mmol, 226.92 μL) in DCM (3 mL) To the stirred mixture was added HATU (340.46 mg, 895.42 μmol). The resulting reaction mixture was stirred at 20 °C for 5 h. It was then subjected to HPLC (55-90% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give N- [5-[ [2-[( 2R,5S )-2-(3-Chloro-4,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (220 mg, 420.67 [mu]mol, 51.68% yield).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=3.873min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=3.873 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯-4,5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chloro-4,5-difluorophenyl)-5-methylpiperidine-1 -Base)-2-Side Oxyacetamide Synthesis

將水(1.00g，55.51mmol，1mL)添加到N -[5-[[2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(220mg，420.67μmol)於二噁烷(2mL)中之溶液中。將所得混合物在100℃下攪拌15h。然後，使其經歷HPLC(60-60-90% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(145mg，342.91μmol，81.51%產率)。Water (1.00 g, 55.51 mmol, 1 mL) was added to N- [5-[[2-[( 2R,5S )-2-(3-chloro-4,5-difluorophenyl)-5-methyl -1-Piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (220 mg, 420.67 μmol) in dioxane (2 mL) in the solution. The resulting mixture was stirred at 100 °C for 15 h. It was then subjected to HPLC (60-60-90% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give N- (6-Amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(3-chloro-4,5-difluorophenyl)-5-methyl-1- Piperidinyl]-2-oxoacetamide (145 mg, 342.91 μmol, 81.51% yield).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=2.565min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=2.565 min.

步驟3：掌性分離(化合物847 及化合物857 )Step 3: Chiral separation ( compound 847 and compound 857 )

藉由掌性HPLC(Chiralpak AD-H(250 * 20mm，5mkm)；己烷-IPA-MeOH，50-25-25，10mL/min；管柱溫度：20℃)將N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(145mg，342.91μmol)分成鏡像異構物，得到：N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(59mg，139.53μmol，81.38%產率)(其中保留時間=18.50min)(化合物847 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(3-氯-4,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(62mg，146.62μmol，85.52%產率)(其中保留時間=25.84min)(化合物857 )。 N- (6-Amino) was determined by chiral HPLC (Chiralpak AD-H (250*20mm, 5mkm); Hexane-IPA-MeOH, 50-25-25, 10 mL/min; column temperature: 20°C). -5-Methyl-3-pyridyl)-2-[( 2R,5S )-2-(3-chloro-4,5-difluorophenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetamide (145 mg, 342.91 μmol) split into enantiomers to give: N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S,5R )- 2-(3-Chloro-4,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (59 mg, 139.53 μmol, 81.38% yield) (wherein Retention time=18.50min) ( compound 847 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(3-chloro-4,5- Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (62 mg, 146.62 μmol, 85.52% yield) (wherein retention time = 25.84 min) ( compound 857 ).

化合物847 於分析條件下(管柱：AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min 為流動相)之保留時間為18.96min且化合物857 之保留時間為32.05min。The retention time of compound 847 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 18.96 min and the retention time of compound 857 was 32.05 min .

化合物847：保留時間：18.96minCompound 847: retention time: 18.96min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.00(m,3H),1.21-1.36(m,1H),1.58-1.68(m,1H),1.80-1.91(m,1H),1.96-2.04(m,4H),2.12-2.24(m,1H),2.71-3.25(m,1H),3.41-4.05(m,1H),5.04-5.50(m,1H),5.56-5.69(m,2H),7.28-7.42(m,2H),7.42-7.50(m,1H),7.91-8.05(m,1H),10.34-10.64(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.00(m,3H), 1.21-1.36(m,1H), 1.58-1.68(m,1H), 1.80-1.91(m,1H) ,1.96-2.04(m,4H),2.12-2.24(m,1H),2.71-3.25(m,1H),3.41-4.05(m,1H),5.04-5.50(m,1H),5.56-5.69( m, 2H), 7.28-7.42 (m, 2H), 7.42-7.50 (m, 1H), 7.91-8.05 (m, 1H), 10.34-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=2.680min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=2.680 min.

化合物857：保留時間：32.05minCompound 857: retention time: 32.05min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.01(m,3H),1.23-1.35(m,1H),1.57-1.66(m,1H),1.82-1.91(m,1H),1.95-2.04(m,4H),2.12-2.25(m,1H),2.71-3.24(m,1H),3.42-4.05(m,1H),5.02-5.50(m,1H),5.56-5.68(m,2H),7.28-7.42(m,2H),7.42-7.51(m,1H),7.85-8.05(m,1H),10.38-10.71(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.01(m,3H), 1.23-1.35(m,1H), 1.57-1.66(m,1H), 1.82-1.91(m,1H) ,1.95-2.04(m,4H),2.12-2.25(m,1H),2.71-3.24(m,1H),3.42-4.05(m,1H),5.02-5.50(m,1H),5.56-5.68( m, 2H), 7.28-7.42 (m, 2H), 7.42-7.51 (m, 1H), 7.85-8.05 (m, 1H), 10.38-10.71 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=2.684min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=2.684 min.

實例335.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯-5-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物665及化合物679)之合成Example 335. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpiperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 665 and Compound 679)

Figure 110128222-A0202-12-1574-444
Figure 110128222-A0202-12-1574-444

步驟1：外消旋-(5-(2-((2R,5S)-2-(3-氯-5-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-2-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpiperidin-1-yl) Synthesis of -2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(265.82mg，900.21μmol)、(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基哌啶(250 mg，900.21μmol)、HATU(342.29mg，900.21μmol)及TEA(91.09mg，900.21μmol，125.47μL)混合於DMSO(2mL)中且在20℃下攪拌3h。使反應混合物經歷HPLC，2-10min 45-60%水/ACN(裝載泵4ml ACN)管柱：TRIART 100*20 5微米。獲得N -[5-[[2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(306mg，551.36μmol，61.25%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (265.82 mg, 900.21 μmol), ( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methylpiperidine (250 mg, 900.21 μmol), HATU (342.29 mg, 900.21 μmol) and TEA (91.09 mg, 900.21 μmol) μmol, 125.47 μL) were mixed in DMSO (2 mL) and stirred at 20° C. for 3 h. The reaction mixture was subjected to HPLC, 2-10 min 45-60% water/ACN (loading pump 4 ml ACN) Column: TRIART 100*20 5 microns. Obtained N- [5-[[2-[( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (306 mg, 551.36 [mu]mol, 61.25% yield).

LCMS(ESI)：[M]+ m/z：計算值554.2；實測值555.2；Rt=4.179min。LCMS (ESI): [M] + m/z: calculated 554.2; found 555.2; Rt=4.179 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯-5-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpiperidine Synthesis of -1-yl)-2-oxyacetamide

將N -[5-[[2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(306mg，551.36μmol)溶解於用HCl飽和之二噁烷(4mL)中。劇烈攪拌1h之後，在真空中濃縮反應混合物。獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(270mg，粗品)。使粗產物經歷掌性分離。 N- [5-[[2-[( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (306 mg, 551.36 [mu]mol) was dissolved in dioxane (4 mL) saturated with HCl. After vigorous stirring for 1 h, the reaction mixture was concentrated in vacuo. Obtained N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5- Methyl-1-piperidinyl]-2-oxyacetamide (270 mg, crude). The crude product was subjected to chiral separation.

LCMS(ESI)：[M]+ m/z：計算值454.2；實測值455.2；Rt=1.223min。LCMS (ESI): [M] + m/z: calculated 454.2; found 455.2; Rt=1.223 min.

步驟3：掌性分離(化合物665 及化合物679 )Step 3: Chiral separation ( Compound 665 and Compound 679 )

使用(Chiralpak AD-H-III 250*20，5mkm管柱；以己烷-IPA-MeOH，60-20-20為流動相；流速12mL/min；注入體積：900mkl)分離外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(150mg，329.76μmol)，得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(20mg，43.97μmol，26.67%產率)及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[3-氯-5-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(53mg，116.52μmol，70.67%產率)。化合物665 於分析條件下(管柱：AD-H，己烷-IPA-MeOH，60-20-20，0.6ml/min為流 動相)之保留時間為31.13min且化合物679 之保留時間為13.31min。The racemic N- ( 6-Amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-1 -Piperidinyl]-2-oxoacetamide (150 mg, 329.76 μmol) to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )- 2-[3-Chloro-5-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (20 mg, 43.97 μmol, 26.67% yield) and N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[3-chloro-5-(trifluoromethyl)phenyl]-5- Methyl-1-piperidinyl]-2-oxoacetamide (53 mg, 116.52 μmol, 70.67% yield). The retention time of compound 665 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 31.13 min and the retention time of compound 679 was 13.31 min .

化合物665：保留時間：31.13minCompound 665: retention time: 31.13min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.61(m,1H),1.88(m,1H),2.01(m,4H),2.26(m,3H),3.76(m,1H),5.37(m,1H),5.76(s,2H),7.48(m,1H),7.57(m,1H),7.66(m,1H),7.77(m,1H),7.99(m,1H),10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99(m, 3H), 1.61(m, 1H), 1.88(m, 1H), 2.01(m, 4H), 2.26(m, 3H), 3.76(m,1H),5.37(m,1H),5.76(s,2H),7.48(m,1H),7.57(m,1H),7.66(m,1H),7.77(m,1H),7.99 (m, 1H), 10.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值454.2；實測值455.2；Rt=2.869min。LCMS (ESI): [M] + m/z: calculated 454.2; found 455.2; Rt=2.869 min.

化合物679：保留時間：13.31minCompound 679: retention time: 13.31min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(m,3H),1.30(m,1H),1.58(m,1H),1.86(m,1H),2.02(m,4H),2.20(m,2H),3.82(m,1H),5.37(m,1H),5.61(m,2H),7.45(m,1H),7.57(m,1H),7.66(m,1H),7.77(m,1H),7.96(m,1H),10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98(m, 3H), 1.30(m, 1H), 1.58(m, 1H), 1.86(m, 1H), 2.02(m, 4H), 2.20(m, 2H), 3.82(m, 1H), 5.37(m, 1H), 5.61(m, 2H), 7.45(m, 1H), 7.57(m, 1H), 7.66(m, 1H), 7.77 (m, 1H), 7.96 (m, 1H), 10.57 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值454.2；實測值455.2；Rt=2.874min。LCMS (ESI): [M] + m/z: calculated 454.2; found 455.2; Rt=2.874 min.

實例336.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物684及化合物705)之合成Example 336. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidine Synthesis of pyridin-1-yl)-2-oxoacetamide (Compound 684 and Compound 705)

Figure 110128222-A0202-12-1576-445
Figure 110128222-A0202-12-1576-445

步驟1：外消旋-(5-(2-((2R,5R)-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5R)-2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidin-1-yl )-2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

向(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶(0.3g，1.21mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(358.32mg，1.21mmol)及TEA(613.94mg，6.07mmol，845.65μL)中之溶液中分批添加HATU (507.52mg，1.33mmol)。將所得混合物在25℃下攪拌3h，溶解於水(50ml)中且用EtOAc(3*20ml)萃取。將經合併之有機層用鹽水(2*25ml)洗滌，經Na2 SO4 乾燥且移除溶劑，以得到N -[5-[[2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.6g，1.14mmol，94.27%產率)。此化合物不經進一步純化即用於下一步驟。To ( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidine (0.3 g, 1.21 mmol), 2-[[6-( 3rd A solution of butoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (358.32 mg, 1.21 mmol) and TEA (613.94 mg, 6.07 mmol, 845.65 μL) HATU (507.52 mg, 1.33 mmol) was added in portions. The resulting mixture was stirred at 25°C for 3h, dissolved in water (50ml) and extracted with EtOAc (3*20ml). The combined organic layers were washed with brine (2*25ml), dried over Na2SO4 and solvent removed to give N- [5-[[2-[( 2S,5S )-2-(3,4 -Difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]amine 3-Butyl formate (0.6 g, 1.14 mmol, 94.27% yield). This compound was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.07(d,3H),1.42(s,9H),2.18(s,3H),2.87(m,1H),2.97(m,1H),3.73(m,1H),4.02(m,1H),5.75(m,1H),7.23(m,1H),7.43(m,3H),7.95(m,1H),8.46(m,1H),9.08(m,1H),11.15(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.07(d,3H), 1.42(s,9H), 2.18(s,3H), 2.87(m,1H), 2.97(m,1H), 3.73(m, 1H), 4.02(m, 1H), 5.75(m, 1H), 7.23(m, 1H), 7.43(m, 3H), 7.95(m, 1H), 8.46(m, 1H), 9.08 (m, 1H), 11.15 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值524.2；實測值525.2；Rt=1.475min。LCMS (ESI): [M] + m/z: calculated 524.2; found 525.2; Rt=1.475 min.

步驟2：外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5R)-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: Racemic-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5R)-2-(3,4-difluorophenyl)-4, Synthesis of 4-difluoro-5-methylpiperidin-1-yl)-2-oxoacetamide

將N -[5-[[2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.6g，1.14mmol)於DCM(20mL)以及於二噁烷中之4.0M氯化氫溶液(5g，137.13mmol，6.25mL)中之溶液在25℃下攪拌12h。移除溶劑且藉由HPLC(50-65% 0-5min水/MeOH/0.1% NH3 ，流速：30ml/min(裝載泵4ml/min MeOH)目標質量425管柱：YMC Triart C18 100x20mm，5um)純化殘餘物(0.5g)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(127mg，299.25μmol，26.16%產率)。此化合物不經H-NMR即用於掌性拆分。 N- [5-[[2-[( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.6 g, 1.14 mmol) in DCM (20 mL) and 4.0 M hydrogen chloride in dioxane The solution in solution (5 g, 137.13 mmol, 6.25 mL) was stirred at 25 °C for 12 h. The solvent was removed and analyzed by HPLC (50-65% 0-5 min water/MeOH/0.1% NH3 , flow rate: 30ml/min (load pump 4ml/min MeOH) target mass 425 column: YMC Triart C18 100x20mm, 5um) The residue (0.5 g) was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5S )-2-(3,4-difluorophenyl) -4,4-Difluoro-5-methyl-1-piperidinyl]-2-oxoacetamide (127 mg, 299.25 μmol, 26.16% yield). This compound was used for chiral resolution without H-NMR.

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=2.412min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=2.412 min.

步驟3：掌性分離(化合物684 及化合物705 )Step 3: Chiral separation ( compound 684 and compound 705 )

對N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(127mg，299.25μmol)進行掌性分離(樣品資訊：OJ-H-I(250*.0,5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(49mg，115.46μmol，77.17%產率)及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S )-2-(3,4-二氟苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(49mg，115.46μmol，77.17%產率)。p- N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5 -Methyl-1-piperidinyl]-2-oxyacetamide (127 mg, 299.25 μmol) for chiral separation (sample information: OJ-HI (250*.0,5mkm), hexane-IPA- MeOH, 60-20-20, 12 ml/min) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5R )-2-(3,4- Difluorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyacetamide (49 mg, 115.46 μmol, 77.17% yield) and N- (6- Amino-5-methyl-3-pyridyl)-2-[( 2S,5S )-2-(3,4-difluorophenyl)-4,4-difluoro-5-methyl-1- Piperidinyl]-2-oxoacetamide (49 mg, 115.46 μmol, 77.17% yield).

化合物684 於分析條件下(管柱：AD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為38.68min且化合物705 之保留時間為27.92min。The retention time of compound 684 under analytical conditions (column: AD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 38.68 min and the retention time of compound 705 was 27.92 min .

化合物684：保留時間：38.68minCompound 684: retention time: 38.68min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.05(m,3H),2.00(m,3H),2.19(m,2H),2.86(m,1H),3.41(m,1H),4.03(m,1H),5.56(m,1H),5.71(m,2H),7.14(m,1H),7.44(m,3H),7.99(m,1H),10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.05(m,3H), 2.00(m,3H), 2.19(m,2H), 2.86(m,1H), 3.41(m,1H), 4.03 (m, 1H), 5.56 (m, 1H), 5.71 (m, 2H), 7.14 (m, 1H), 7.44 (m, 3H), 7.99 (m, 1H), 10.57 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=2.424min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=2.424 min.

化合物705：保留時間：27.92minCompound 705: retention time: 27.92min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.05(m,3H),2.00(m,3H),2.19(m,2H),2.86(m,1H),3.41(m,1H),3.95(m,1H),5.68(m,3H),7.44(m,4H),7.99(m,1H),10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.05(m,3H), 2.00(m,3H), 2.19(m,2H), 2.86(m,1H), 3.41(m,1H), 3.95 (m, 1H), 5.68 (m, 3H), 7.44 (m, 4H), 7.99 (m, 1H), 10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=2.426min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=2.426 min.

實例337.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-胺磺醯基苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物688)之合成Example 337. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-aminosulfonylphenyl)piperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide (Compound 688)

Figure 110128222-A0202-12-1578-446
Figure 110128222-A0202-12-1578-446

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(3-胺磺醯基苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(3-aminosulfonylphenyl)piperidin-1-yl)- Synthesis of 2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester

向3-[(2S,5R )-5-甲基-2-哌啶基]苯磺醯胺(490mg，1.93mmol)、 2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(568.88mg，1.93mmol)及TEA(584.83mg，5.78mmol，805.55μL)於DMF(4mL)中之經攪拌之混合物中添加HATU(805.76mg，2.12mmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；40-90% 1-6min水-MeOH(NH3 0.1%)，流速30ml/min)，得到N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(3-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(200mg，376.21μmol，19.53%產率)。To 3-[( 2S,5R )-5-methyl-2-piperidinyl]benzenesulfonamide (490 mg, 1.93 mmol), 2-[[6-( tertiary butoxycarbonylamino)-5 -Methyl-3-pyridyl]amino]-2-oxoacetic acid (568.88 mg, 1.93 mmol) and TEA (584.83 mg, 5.78 mmol, 805.55 μL) in a stirred mixture of DMF (4 mL) HATU (805.76 mg, 2.12 mmol) was added. The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 40-90% 1-6min water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N- [3- Methyl-5-[[2-[( 2S,5R )-5-methyl-2-(3-aminosulfonylphenyl)-1-piperidinyl]-2-oxyethanoyl] Amino]-2-pyridyl]carbamic acid tert -butyl ester (200 mg, 376.21 [mu]mol, 19.53% yield).

LCMS(ESI)：[M]+ m/z：計算值531.4；實測值532.2；Rt=2.752min。LCMS (ESI): [M] + m/z: calculated 531.4; found 532.2; Rt=2.752 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-胺磺醯基苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物688 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-sulfamonophenyl)piperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 688 )

將N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(3-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(200mg，376.21μmol)溶解於水(1.00g，55.49mmol，1mL)及二噁烷(2mL)之混合物中。將所得溶液在100℃下攪拌18h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；0-5min 20-70水-MeOH(NH3 0.1%))，得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(3-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(45mg，104.29μmol，27.72%產率)。 N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-(3-aminosulfonylphenyl)-1-piperidinyl]-2-side Oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (200 mg, 376.21 [mu]mol) was dissolved in a mixture of water (1.00 g, 55.49 mmol, 1 mL) and dioxane (2 mL). The resulting solution was stirred at 100 °C for 18 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 0-5min 20-70 water-MeOH ( NH3 0.1%)) to give N- (6-amino-5-methyl) yl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-(3-sulfamoylphenyl)-1-piperidinyl]-2-oxoacetamide (45 mg, 104.29 μmol, 27.72% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.35(m,1H),1.64(m,1H),1.87(m,1H),1.99(m,5H),2.18(m,2H),2.96(m,1H),3.79(m,1H),5.60(m,3H),7.46(m,2H),7.58(m,2H),7.72(d,1H),7.77(d,1H),8.00(m,1H)。LCMS(ESI)：[M]+ m/z：計算值431.4；實測值432.2；Rt=1.582min。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.35(m, 1H), 1.64(m, 1H), 1.87(m, 1H), 1.99(m, 5H), 2.18(m, 2H), 2.96(m, 1H), 3.79(m, 1H), 5.60(m, 3H), 7.46(m, 2H), 7.58(m, 2H), 7.72(d, 1H), 7.77 (d, 1H), 8.00 (m, 1H). LCMS (ESI): [M] + m/z: calculated 431.4; found 432.2; Rt=1.582 min.

實例338.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(甲基磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物667、化合物901、化合物895)之合成Example 338. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(methylsulfonyl)phenyl)piperidine-1- Synthesis of yl)-2-oxoacetamide (Compound 667, Compound 901, Compound 895)

Figure 110128222-A0202-12-1580-447
Figure 110128222-A0202-12-1580-447

步驟1：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(甲基磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(methylsulfonyl)phenyl)piperidine-1- Synthesis of )-2-side oxyacetamide

在25℃下，在0.5h內，向(2R,5S )-5-甲基-2-(3-甲基磺醯基苯基)哌啶(250.00mg，986.74μmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(291.37mg，986.74μmol)及TEA(998.48mg，9.87mmol，1.38mL)於DMF(5mL)中之正攪拌溶液中小批量添加HATU(412.71mg，1.09mmol)。將所得反應混合物在25℃下攪拌18h。在真空中濃縮反應混合物，將殘餘物溶解於二氯甲烷(10mL)中，且一次性添加於二噁烷中之4.0M氯化氫溶液(15.75g，60.04mmol，15.00mL，13.9%純度)。將所得混合物在25℃下攪拌3h，然後在真空中濃縮。藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：35-45% 0-5min水/MeOH/0.1% NH3 ，流速：30ml/min(裝載泵4ml/min MeOH))純化殘餘物，以得到呈白色固體之化合物667 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(111mg，257.83μmol，26.13%產率)。To ( 2R,5S )-5-methyl-2-(3-methylsulfonylphenyl)piperidine (250.00 mg, 986.74 μmol), 2-[[6 -( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (291.37 mg, 986.74 μmol) and TEA (998.48 mg, 9.87 mmol, 1.38 mL) ) to a stirring solution in DMF (5 mL) was added HATU (412.71 mg, 1.09 mmol) in small portions. The resulting reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in dichloromethane (10 mL), and a 4.0 M solution of hydrogen chloride in dioxane (15.75 g, 60.04 mmol, 15.00 mL, 13.9% purity) was added in one portion. The resulting mixture was stirred at 25 °C for 3 h, then concentrated in vacuo. Purification by reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 35-45% 0-5min water/MeOH/0.1% NH3 , flow rate: 30ml/min (load pump 4ml/min MeOH)) residue to give compound 667 as a white solid N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(3-methyl) Sulfonylphenyl)-1-piperidinyl]-2-oxoacetamide (111 mg, 257.83 μmol, 26.13% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.35(m,1H),1.62(m,1H),1.87(m,1H),1.99(m,3H),2.19(m,2H),3.21(m,4H),3.77(m,1H),5.41(m,1H),5.62(m,2H),7.45(m,1H),7.65(m,2H),7.83(m,2H),7.97(m,1H),10.54(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.35(m, 1H), 1.62(m, 1H), 1.87(m, 1H), 1.99(m, 3H), 2.19(m, 2H), 3.21(m, 4H), 3.77(m, 1H), 5.41(m, 1H), 5.62(m, 2H), 7.45(m, 1H), 7.65(m, 2H), 7.83 (m, 2H), 7.97 (m, 1H), 10.54 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值430.2；實測值431.2；Rt=1.744min。LCMS (ESI): [M] + m/z: calculated 430.2; found 431.2; Rt=1.744 min.

步驟2：掌性分離(化合物901 及化合物895 )Step 2: Chiral separation ( compound 901 and compound 895 )

管柱：Chiralpak IA-II(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 40-30-30；流速：12mL/min；m=0.09Γ ，2次注入，45mL/注入，V=2L，2.5h， RT(化合物895 )=20.805min，RT(化合物901 )=37.044min。在以下條件下另外純化鏡像異構物：化合物895 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(3-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(30.78mg，71.50μmol，32.68%產率)。管柱：Chiralcel OJ-H-I(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：12mL/min；m=0,04Γ ，2次注入，20mL/注入，V=2L，2小時(RT=28.825min)。化合物901 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(30.81mg，71.56μmol，32.71%產率)。管柱：Chiralpak IC-II(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：12mL/min；m=0,04Γ ，2次注入，20mL/注入，V=1.5L，2.5小時(RT=31.957min)。化合物901 於分析條件下(管柱：OJ-H，己烷-IPA-MeOH 50-25-25，0.6ml/min為流動相)之保留時間為31.97min且化合物895 之保留時間為28.82min。Column: Chiralpak IA-II (250*20mm, 5mkm); Mobile phase: Hexane-IPA-MeOH 40-30-30 ; Flow rate: 12mL/min; m=0.09°, 2 injections, 45mL/injection, V =2L, 2.5h, RT(Compound 895 )=20.805min, RT(Compound 901 )=37.044min. The enantiomer was additionally purified under the following conditions: Compound 895 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-(3 -Methylsulfonylphenyl)-1-piperidinyl]-2-oxoacetamide (30.78 mg, 71.50 μmol, 32.68% yield). Column: Chiralcel OJ-HI (250*20mm, 5mkm); Mobile phase: Hexane-IPA-MeOH 50-25-25 ; Flow rate: 12mL/min; m=0,04°, 2 injections, 20mL/injection , V=2L, 2 hours (RT=28.825min). Compound 901 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(3-methylsulfonylphenyl)-1 -Piperidinyl]-2-oxoacetamide (30.81 mg, 71.56 μmol, 32.71% yield). Column: Chiralpak IC-II (250*20mm, 5mkm); Mobile phase: Hexane-IPA-MeOH 50-25-25 ; Flow rate: 12mL/min; m=0,04°, 2 injections, 20mL/injection , V=1.5L, 2.5 hours (RT=31.957min). The retention time of compound 901 under analytical conditions (column: OJ-H, hexane-IPA-MeOH 50-25-25, 0.6 ml/min as mobile phase) was 31.97 min and the retention time of compound 895 was 28.82 min.

化合物901：保留時間：31.97minCompound 901: retention time: 31.97min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.04(m,3H),1.32(m,1H),1.64(m,1H),1.88(m,1H),2.00(m,3H),2.21(m,1H),3.22(m,3H),3.42(m,2H),3.78(m,1H),5.61(m,3H),7.46(d,1H),7.67(m,2H),7.83(m,2H),7.98(d,1H),10.55(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.04(m,3H), 1.32(m,1H), 1.64(m,1H), 1.88(m,1H), 2.00(m,3H), 2.21(m, 1H), 3.22(m, 3H), 3.42(m, 2H), 3.78(m, 1H), 5.61(m, 3H), 7.46(d, 1H), 7.67(m, 2H), 7.83 (m, 2H), 7.98 (d, 1H), 10.55 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值430.2；實測值431.2；Rt=1.703min。LCMS (ESI): [M] + m/z: calculated 430.2; found 431.2; Rt=1.703 min.

化合物895：保留時間：28.82minCompound 895: retention time: 28.82min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.34(m,1H),1.61(m,1H),1.89(m,1H),2.00(m,3H),2.18(m,2H),3.22(m,4H),3.78(dd,1H),5.61(m,3H),7.46(d,1H),7.66(m,2H),7.84(m,2H),7.98(d,1H),10.55(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.02(m, 3H), 1.34(m, 1H), 1.61(m, 1H), 1.89(m, 1H), 2.00(m, 3H), 2.18(m, 2H), 3.22(m, 4H), 3.78(dd, 1H), 5.61(m, 3H), 7.46(d, 1H), 7.66(m, 2H), 7.84(m, 2H), 7.98 (d, 1H), 10.55 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值430.2；實測值431.2；Rt=1.768min。LCMS (ESI): [M] + m/z: calculated 430.2; found 431.2; Rt=1.768 min.

實例339.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(N -甲基胺磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物691)之合成Example 339. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-( N -methylaminosulfonyl)phenyl)piperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 691)

Figure 110128222-A0202-12-1582-448
Figure 110128222-A0202-12-1582-448

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(3-(N-甲基胺磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(3-(N-methylaminosulfonyl)phenyl)piperidine Synthesis of -1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester

向N -甲基-3-[(2S,5R )-5-甲基-2-哌啶基]苯磺醯胺(535mg，1.99mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(588.66mg，1.99mmol)及TEA(605.16mg，5.98mmol，833.56μL)於DMF(4mL)中之經攪拌之混合物中添加HATU(833.78mg，2.19mmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；40-90% 1-6min水-MeOH(NH3 0.1%)，流速30ml/min)，得到N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[3-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(242mg，443.51μmol，22.25%產率)。To N -methyl-3-[( 2S,5R )-5-methyl-2-piperidinyl]benzenesulfonamide (535 mg, 1.99 mmol), 2-[[6-( tert- butoxycarbonyl amino)-5-methyl-3-pyridinyl]amino]-2-oxoacetic acid (588.66 mg, 1.99 mmol) and TEA (605.16 mg, 5.98 mmol, 833.56 μL) in DMF (4 mL) To the stirred mixture was added HATU (833.78 mg, 2.19 mmol). The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 40-90% 1-6min water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N- [3- Methyl-5-[[2-[( 2S,5R )-5-methyl-2-[3-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2-side oxy Acetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (242 mg, 443.51 [mu]mol, 22.25% yield).

LCMS(ESI)：[M]+ m/z：計算值545.4；實測值546.2；Rt=2.969min。LCMS (ESI): [M] + m/z: calculated 545.4; found 546.2; Rt=2.969 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(N-甲基胺磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物691 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(N-methylaminosulfonyl)phenyl)piperidine Synthesis of -1-yl)-2-oxoacetamide ( Compound 691 )

將N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[3-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(242mg，443.51μmol)溶解於水(1.00g，55.51mmol，1mL)及二噁烷(2mL)之混合物中。將所得溶液在100℃下攪拌18h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；0-5min 30-70%水-MeOH(NH3 0.1%)，流速30ml/min)，得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[3-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯胺(107mg，240.16μmol，54.15%產率)。 N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-[3-(methylaminosulfonyl)phenyl]-1-piperidinyl] 3-butyl-2-oxyacetoxy]amino]-2-pyridyl] carbamate (242 mg, 443.51 μmol) was dissolved in water (1.00 g, 55.51 mmol, 1 mL) and dioxane (2 mL) in the mixture. The resulting solution was stirred at 100 °C for 18 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 0-5min 30-70% water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N- (6- Amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-[3-(methylaminosulfonyl)phenyl]-1-piperidinyl ]-2-Oxyacetamide (107 mg, 240.16 μmol, 54.15% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.34(m,1H),1.62(m,1H), 1.89(m,1H),1.99(m,3H),2.12(m,2H),2.36(m,1H),2.40(m,3H),2.87(m,1H),3.77(m,1H),5.60(m,3H),7.45(m,1H),7.58(m,3H),7.68(m,2H),7.97(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.62(m, 1H), 1.89(m, 1H), 1.99(m, 3H), 2.12(m, 2H), 2.36(m, 1H), 2.40(m, 3H), 2.87(m, 1H), 3.77(m, 1H), 5.60(m, 3H), 7.45(m, 1H), 7.58 (m, 3H), 7.68 (m, 2H), 7.97 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值445.4；實測值446.2；Rt=1.824min。LCMS (ESI): [M] + m/z: calculated 445.4; found 446.2; Rt=1.824 min.

實例340.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(2-(甲胺基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物852及化合物855)之合成Example 340. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(2-(methylamino)benzo[ d ]thiazol-5-yl) ) Piperidin-1-yl)-2-oxoacetamide (Compound 852 and Compound 855) Synthesis

Figure 110128222-A0202-12-1583-449
Figure 110128222-A0202-12-1583-449

步驟1：(3-甲基-5-(2-(5-甲基-2-(2-(甲胺基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-(5-methyl-2-(2-(methylamino)benzo[d]thiazol-5-yl)piperidin-1-yl)-2 -Synthesis of tert-butyl oxyacetamido)pyridin-2-yl)carbamate

將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(338.91mg，1.15mmol)及N -甲基-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑-2-胺(0.3g，1.15mmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(523.68mg，1.38mmol)，隨後添加TEA(348.42mg，3.44mmol，479.91μL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且倒入到水(100ml)中且用EtOAc(2x40ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物N -[3-甲基-5-[[2-[5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.35g，649.76μmol，56.61%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (338.91 mg, 1.15 mmol) and N -methyl -5-(5-Methyl-2-piperidinyl)-1,3-benzothiazol-2-amine (0.3 g, 1.15 mmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (523.68 mg, 1.38 mmol) was added followed by TEA (348.42 mg, 3.44 mmol, 479.91 μL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and poured into water (100ml) and extracted with EtOAc (2x40ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo to give the product N- [3-methyl-5-[[2-[5-methyl-2- [2-(Methylamino)-1,3-benzothiazol- 5 -yl]-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid Tributyl ester (0.35 g, 649.76 [mu]mol, 56.61% yield).

1 H NMR(600MHz,CDCl3 )δ(ppm)1.11(d,3H),1.22(d,3H),1.44(m,1H),1.53(s, 9H),1.98(m,1H),2.24(s,3H),2.30(m,3H),3.11(m,1H),4.56(m,1H),5.48(m,1H),6.68(m,1H),7.02(m,1H),7.55(m,3H),8.04(m,1H),8.35(m,1H),9.40(m,1H)。 1 H NMR (600MHz, CDCl 3 )δ(ppm) 1.11(d,3H), 1.22(d,3H), 1.44(m,1H), 1.53(s, 9H), 1.98(m,1H), 2.24( s, 3H), 2.30(m, 3H), 3.11(m, 1H), 4.56(m, 1H), 5.48(m, 1H), 6.68(m, 1H), 7.02(m, 1H), 7.55(m , 3H), 8.04 (m, 1H), 8.35 (m, 1H), 9.40 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值538.2；實測值539.2；Rt=1.356min。LCMS (ESI): [M] + m/z: calculated 538.2; found 539.2; Rt=1.356 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(2-(甲胺基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(2-(methylamino)benzo[d]thiazol-5-yl) ) Synthesis of piperidin-1-yl)-2-side oxyacetamide

在室溫下將二噁烷(20mL)添加到N -[3-甲基-5-[[2-[5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.35g，649.76μmol)於水(10mL)中之經攪拌之溶液中。將所得混合物在100℃下攪拌12h，然後在真空中蒸發且藉由製備型(55-55-75% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)目標質量)純化0.25g所獲得之粗產物，以得到產物N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.12g，273.63μmol，42.11%產率)。Dioxane (20 mL) was added to N- [3-methyl-5-[[2-[5-methyl-2-[2-(methylamino)-1,3-benzoyl at room temperature Thiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.35 g, 649.76 μmol) in water (10 mL) in the stirred solution. The resulting mixture was stirred at 100 °C for 12 h, then evaporated in vacuo and washed by preparative (55-55-75% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min ( Loading pump 4ml/min MeOH) target mass) 0.25g of the obtained crude product was purified to obtain the product N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )- 5-Methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (0.12 g, 273.63 μmol , 42.11% yield).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=1.828min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=1.828 min.

步驟3：掌性分離(化合物852 及化合物855 )Step 3: Chiral separation ( compound 852 and compound 855 )

使N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(120.00mg，273.63μmol)經歷掌性HPLC純化(管柱：IA-II(250*20,5mkm)，溶析液：己烷-IPA-MeOH，50-25-25，流速：12mL/min)，以得到兩種單獨的鏡像異構物化合物855 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.05076g，115.75μmol，42.30%產率)及化合物852 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[2-(甲胺基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(58.16mg，132.62μmol，48.47%產率)。make N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzene Thiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (120.00 mg, 273.63 μmol) was subjected to chiral HPLC purification (column: IA-II (250*20,5 mkm), Eluent: Hexane-IPA-MeOH, 50-25-25, flow rate: 12 mL/min) to give two separate enantiomer compounds 855 N- (6-amino-5-methyl-3 -pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]- 2-Pendant oxyacetamide (0.05076 g, 115.75 μmol, 42.30% yield) and compound 852 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R ) -5-Methyl-2-[2-(methylamino)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (58.16 mg, 132.62 g μmol, 48.47% yield).

化合物852 於分析條件下(管柱：IC，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為38.91min且化合物855 之保留時間為29.63min。The retention time of compound 852 under analytical conditions (column: IC, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 38.91 min and the retention time of compound 855 was 29.63 min.

化合物852：保留時間：38.91minCompound 852: retention time: 38.91min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.02(m,3H),1.26-1.39(m,1H),1.63-1.74(m,1H),1.77-1.90(m,1H),1.97-2.03(m,3H),2.03-2.17(m,1H),2.19-2.29(m,1H),2.72-2.78(m,0.4H),2.88-2.95(m,3H),3.20-3.26(m,0.6H),3.41-4.04(m,1H),5.11-5.59(m,1H),5.59-5.67(m,2H),6.90-7.02(m,1H),7.28-7.38(m,1H),7.39-7.51(m,1H),7.59-7.66(m,1H),7.88-7.94(m,1H),7.94-8.05(m,1H),10.34-10.77(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.02(m,3H), 1.26-1.39(m,1H), 1.63-1.74(m,1H), 1.77-1.90(m,1H) ,1.97-2.03(m,3H),2.03-2.17(m,1H),2.19-2.29(m,1H),2.72-2.78(m,0.4H),2.88-2.95(m,3H),3.20-3.26 (m,0.6H),3.41-4.04(m,1H),5.11-5.59(m,1H),5.59-5.67(m,2H),6.90-7.02(m,1H),7.28-7.38(m,1H) ), 7.39-7.51(m, 1H), 7.59-7.66(m, 1H), 7.88-7.94(m, 1H), 7.94-8.05(m, 1H), 10.34-10.77(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=0.821min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=0.821 min.

化合物855：保留時間：29.63minCompound 855: retention time: 29.63min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.02(m,3H),1.28-1.37(m,1H),1.63-1.78(m,1H),1.80-1.91(m,1H),1.96-2.02(m,3H),2.03-2.17(m,1H),2.18-2.28(m,1H),2.73-2.78(m,0.4H),2.88-2.93(m,3H),3.21-3.26(m,0.6H),3.41-4.03(m,1H),5.12-5.58(m,1H),5.58-5.64(m,2H),6.93-7.01(m,1H),7.27-7.38(m,1H),7.41-7.50(m,1H),7.60-7.66(m,1H),7.85-7.93(m,1H),7.95-8.05(m,1H),10.44-10.65(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.02(m,3H), 1.28-1.37(m,1H), 1.63-1.78(m,1H), 1.80-1.91(m,1H) ,1.96-2.02(m,3H),2.03-2.17(m,1H),2.18-2.28(m,1H),2.73-2.78(m,0.4H),2.88-2.93(m,3H),3.21-3.26 (m,0.6H),3.41-4.03(m,1H),5.12-5.58(m,1H),5.58-5.64(m,2H),6.93-7.01(m,1H),7.27-7.38(m,1H) ), 7.41-7.50(m, 1H), 7.60-7.66(m, 1H), 7.85-7.93(m, 1H), 7.95-8.05(m, 1H), 10.44-10.65(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值438.2；實測值439.2；Rt=0.821min。LCMS (ESI): [M] + m/z: calculated 438.2; found 439.2; Rt=0.821 min.

實例341. 2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物732)及2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物717)之合成Example 341. 2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-N-(6-amino-5- Methyl-3-pyridyl)-2-oxyacetamide (Compound 732) and 2-[(2R,5S)-2-(5-acetamido-2-thienyl)-5-methyl Synthesis of yl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxoacetamide (compound 717)

Figure 110128222-A0202-12-1586-450
Figure 110128222-A0202-12-1586-450

步驟1：N-[5-[[2-[2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(5-Acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2-pendoxetyl] Synthesis of tert-butyl amino]-3-methyl-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(1.01g，3.41mmol)及N-[5-(5-甲基-2-哌啶基)-2-噻吩基]乙醯胺(1.2g，3.41mmol，CF3 COOH)混合於DMF中。將反應懸浮液冷卻至20℃且添加HATU(1.29g，3.41mmol)，隨後添加TEA(1.38g，13.62mmol，1.90mL)，且在環境溫度下攪拌15h。將反應混合物在真空中蒸發且倒入水(100ml)中且用EtOAc(2* 30ml)萃取。將經合併之有機萃取物用水(2* 30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物N-[5-[[2-[2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.8g，1.55mmol，45.56%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (1.01 g, 3.41 mmol) and N-[5 -(5-Methyl-2-piperidinyl)-2-thienyl]acetamide (1.2 g, 3.41 mmol, CF3COOH ) was mixed in DMF. The reaction suspension was cooled to 20°C and HATU (1.29 g, 3.41 mmol) was added followed by TEA (1.38 g, 13.62 mmol, 1.90 mL) and stirred at ambient temperature for 15 h. The reaction mixture was evaporated in vacuo and poured into water (100ml) and extracted with EtOAc (2 * 30ml). The combined organic extracts were washed with water (2 * 30ml), dried over sodium sulfate and evaporated in vacuo to give the product N-[5-[[2-[2-(5-acetamido-2- Thienyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.8 g, 1.55 g mmol, 45.56% yield).

1 H NMR(400MHz,CDCl3 )δ 0.88(m,3H),1.21(m,1H),1.47(s,9H),2.02(m,3H),2.24(s,3H),2.26(m,4H),4.10(m,2H),6.43(d,1H),6.56(d,1H),6.80(s,1H),8.02(s,1H),8.58(m,1H),9.32(m,1H),9.58(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.88(m,3H), 1.21(m,1H), 1.47(s,9H), 2.02(m,3H), 2.24(s,3H), 2.26(m,4H) ), 4.10(m, 2H), 6.43(d, 1H), 6.56(d, 1H), 6.80(s, 1H), 8.02(s, 1H), 8.58(m, 1H), 9.32(m, 1H) , 9.58(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值515.2；實測值516.4；Rt=1.227min。LCMS (ESI): [M+H] + m/z: calculated 515.2; found 516.4; Rt=1.227 min.

步驟2：2-[2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺之合成Step 2: 2-[2-(5-Acetylamino-2-thienyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridine Synthesis of )-2-side oxyacetamide

在室溫下將水(10mL)添加到N-[5-[[2-[2-(5-乙醯胺基-2-噻吩基)-5-甲 基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.8g，1.55mmol)於二噁烷(20mL)中之經攪拌之溶液中。將所得混合物在95℃下攪拌15h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用EtOAc(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發且藉由製備型(40-55% 1-6min水-甲醇(NH3 0.1%)，流速30ml/min)純化0.55g所獲得之粗產物，以得到產物2-[2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.16g，385.07μmol，24.82%產率)。Water (10 mL) was added to N-[5-[[2-[2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-2 at room temperature - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.8 g, 1.55 mmol) in a stirred solution of dioxane (20 mL). The resulting mixture was stirred at 95 °C for 15 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo and 0.55 g of obtained was purified by preparative (40-55% 1-6 min water-methanol ( NH3 0.1%), flow rate 30 ml/min) crude product to give the product 2-[2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl- 3-Pyridinyl)-2-oxoacetamide (0.16 g, 385.07 μmol, 24.82% yield).

LCMS(ESI)：[M+H]+ m/z：計算值415.2；實測值416.4；Rt=1.777min。LCMS (ESI): [M+H] + m/z: calculated 415.2; found 416.4; Rt=1.777 min.

步驟3：2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物732 )及2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物717 )之合成Step 3: 2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-N-(6-amino-5- Methyl-3-pyridyl)-2-oxyacetamide ( Compound 732 ) and 2-[(2R,5S)-2-(5-acetamido-2-thienyl)-5-methyl Synthesis of yl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxoacetamide ( compound 717 )

藉由掌性HPLC(管柱：OJ-H(250* 20，5mkm))，以己烷-MeOH-IPA，80-10-10，13ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物732 2-[(2S,5R)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.126g，303.24μmol，78.75%產率)及化合物717 2-[(2R,5S)-2-(5-乙醯胺基-2-噻吩基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(0.0426g，102.53μmol，26.63%產率)。The enantiomers were separated by chiral HPLC (column: OJ-H (250 * 20, 5mkm) with hexane-MeOH-IPA, 80-10-10, 13ml/min as mobile phase) to give Two separate enantiomers Compound 732 2-[(2S,5R)-2-(5-acetamido-2-thienyl)-5-methyl-1-piperidinyl]-N-( 6-Amino-5-methyl-3-pyridyl)-2-oxyacetamide (0.126 g, 303.24 μmol, 78.75% yield) and compound 717 2-[(2R,5S)-2- (5-Acetamido-2-thienyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-side oxy Acetamide (0.0426 g, 102.53 μmol, 26.63% yield).

化合物717： RT(OD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=20.402min。 Compound 717: RT (OD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 20.402 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.78(m,3H),1.29(m,1H),1.67(m,2H),1.88(m,1H),2.00(m,6H),2.22(m,1H),2.69(m,1H),3.86(m,1H),5.64(m,3H),6.46(m,1H),6.66(m,1H),7.48(d,1H),8.00(d,1H),10.49(m,1H),11.03(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.78(m, 3H), 1.29(m, 1H), 1.67(m, 2H), 1.88(m, 1H), 2.00(m, 6H), 2.22(m, 1H), 2.69(m, 1H), 3.86(m, 1H), 5.64(m, 3H), 6.46(m, 1H), 6.66(m, 1H), 7.48(d, 1H), 8.00 (d, 1H), 10.49 (m, 1H), 11.03 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值415.2；實測值416.2；Rt=1.837min。LCMS (ESI): [M+H] + m/z: calculated 415.2; found 416.2; Rt=1.837 min.

化合物732： RT(OD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=7.887min。 Compound 732: RT (OD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 7.887 min.

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.79(m,3H),1.29(m,1H),1.67(m,2H), 1.88(m,1H),2.01(d,6H),2.24(m,1H),2.68(m,1H),3.86(m,1H),5.61(m,3H),6.47(m,1H),6.66(m,1H),7.50(d,1H),8.01(d,1H),10.51(m,1H),11.04(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.79(m, 3H), 1.29(m, 1H), 1.67(m, 2H), 1.88(m, 1H), 2.01(d, 6H), 2.24(m, 1H), 2.68(m, 1H), 3.86(m, 1H), 5.61(m, 3H), 6.47(m, 1H), 6.66(m, 1H), 7.50(d, 1H), 8.01 (d, 1H), 10.51 (m, 1H), 11.04 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值415.2；實測值416.2；Rt=1.831min。LCMS (ESI): [M+H] + m/z: calculated 415.2; found 416.2; Rt=1.831 min.

實例342. 5-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)噻吩-2-甲醯胺(化合物644、化合物823、化合物733及化合物733)之合成Example 342. 5-(1-(2-((6-amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-5-methylpiperidine-2 Synthesis of -yl)thiophene-2-carboxamide (Compound 644, Compound 823, Compound 733 and Compound 733)

Figure 110128222-A0202-12-1588-451
Figure 110128222-A0202-12-1588-451

步驟1：外消旋-(5-(2-((2R,5S)-2-(5-胺甲醯基噻吩-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-2-(5-aminocarboxythiophen-2-yl)-5-methylpiperidin-1-yl)-2- Synthesis of tert-butyl oxyacetamido)-3-methylpyridin-2-yl)carbamate

向5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(185mg，824.71μmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(243.53mg，824.71μmol)及TEA(250.36mg，2.47mmol，344.84μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(344.94mg，907.18μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mml，5um；50-75% 1-6min水-MeOH(NH3 0.1%)，流速30ml/min)，得到N -[5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(165mg，328.95μmol，39.89%產率)。To 5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (185 mg, 824.71 μmol), 2-[[6-( tert- butoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (243.53 mg, 824.71 μmol) and TEA (250.36 mg, 2.47 mmol, 344.84 μL) in DMF (3 mL) with stirring To the mixture was added HATU (344.94 mg, 907.18 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mml, 5um; 50-75% 1-6min water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N- [5- [[2-[( 2S,5R )-2-(5-Aminocarbamoyl-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (165 mg, 328.95 [mu]mol, 39.89% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值501.2；實測值502.2；Rt=2.438min。LCMS (ESI): [M] + m/z: calculated 501.2; found 502.2; Rt=2.438 min.

步驟2：5-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)噻吩-2-甲醯胺(化合物644 Step 2: 5-(1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyacetyl)-5-methylpiperidine-2 -yl)thiophene-2-carboxamide ( Compound 644 )之合成) synthesis

將水(1.00g，55.51mmol，1mL)添加到N -[5-[[2-[(2S,5R )-2-(5-胺甲醯基-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(165mg，328.95μmol)於二噁烷(2mL)中之溶液中。將所得溶液在100℃下攪拌16h。然後，使其經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；以10-60% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min)，得到5-[(2S,5R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(130mg，323.80μmol，98.43%產率)。Water (1.00 g, 55.51 mmol, 1 mL) was added to N- [5-[[2-[( 2S,5R )-2-(5-aminocarboxy-2-thienyl)-5-methyl- 1-Piperidinyl]-2-oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (165 mg, 328.95 μmol) in dioxane (2 mL) in the solution. The resulting solution was stirred at 100 °C for 16 h. It was then subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; with 10-60% 0-5min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min) to give 5-[( 2S ,5R )-1-[2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl ]thiophene-2-carboxamide (130 mg, 323.80 μmol, 98.43% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.40(m,1H),1.79(m,1H),1.90(m,1H),2.00(m,4H),2.07(m,1H),2.16(m,1H),3.73(m,1H),5.66(m,3H),6.99(m,1H),7.31(s,1H),7.48(d,1H),7.61(m,1H),7.91(s,1H),8.00(s,1H),10.48(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98(d,3H), 1.40(m,1H), 1.79(m,1H), 1.90(m,1H), 2.00(m,4H), 2.07(m, 1H), 2.16(m, 1H), 3.73(m, 1H), 5.66(m, 3H), 6.99(m, 1H), 7.31(s, 1H), 7.48(d, 1H), 7.61 (m, 1H), 7.91 (s, 1H), 8.00 (s, 1H), 10.48 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值401.2；實測值402.2；Rt=1.607min。LCMS (ESI): [M] + m/z: calculated 401.2; found 402.2; Rt=1.607 min.

步驟3：掌性分離(化合物823、化合物733 及化合物733 )Step 3: Chiral separation ( Compound 823, Compound 733 and Compound 733 )

藉由掌性HPLC將5-[(2S,5R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(130mg，323.80μmol)分成鏡像異構物：體系1：管柱：Chiralcel OJ-H(250 x 20mm，5mkm)；流動相：己烷-IPA-MeOH，70-15-15，流速：12mL/min；管柱溫度：24℃；波長：205nm，272nm)；體系2：體系2.管柱：Chiralpak IC(250 x 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25，流速：12mL/min；管柱溫度：24℃；波長：205nm，272nm)，得到：5-[(2S,5R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(50mg，124.54μmol，76.92%產率)(其中保留時間=34.629min)(化合物823 )及5-[(2R,5S )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺 基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]噻吩-2-甲醯胺(52mg，129.52μmol，80.00%產率)(其中保留時間=50.495min)(化合物733 )。5-[( 2S,5R )-1-[2-[(6-amino-5-methyl-3-pyridinyl)amino]-2-oxyethanoyl] by chiral HPLC -5-Methyl-2-piperidinyl]thiophene-2-carboxamide (130 mg, 323.80 μmol) split into enantiomers: System 1: Column: Chiralcel OJ-H (250 x 20 mm, 5 mkm); flow Phase: Hexane-IPA-MeOH, 70-15-15, Flow Rate: 12 mL/min; Column Temperature: 24°C; Wavelength: 205nm, 272nm); System 2: System 2. Column: Chiralpak IC (250 x 20mm) , 5mkm); mobile phase: hexane-IPA-MeOH, 50-25-25, flow rate: 12mL/min; column temperature: 24°C; wavelength: 205nm, 272nm), yield: 5-[( 2S, 5R ) -1-[2-[(6-Amino-5-methyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl]thiophene- 2-Carboxamide (50 mg, 124.54 μmol, 76.92% yield) (wherein retention time=34.629 min) ( compound 823 ) and 5-[( 2R,5S )-1-[2-[(6-amino- 5-Methyl-3-pyridinyl)amino]-2-oxyacetyl]-5-methyl-2-piperidinyl]thiophene-2-carbamide (52 mg, 129.52 μmol, 80.00% yield) (wherein retention time = 50.495 min) ( compound 733 ).

化合物823 於分析條件下(管柱：IB，以CO2 -MeOH，80-20，3ml/min為流動相)之保留時間為17.78min且化合物733 、化合物733 之保留時間為19.47min。The retention time of compound 823 under analytical conditions (column: IB, with CO 2 -MeOH, 80-20, 3 ml/min as mobile phase) was 17.78 min and the retention time of compound 733 and compound 733 was 19.47 min.

化合物823：保留時間：17.78minCompound 823: retention time: 17.78min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.01(m,3H),1.36-1.44(m,1H),1.74-1.85(m,1H),1.85-1.96(m,1H),1.97-2.04(m,4H),2.04-2.19(m,1H),2.83-3.28(m,1H),3.42-4.05(m,1H),5.37-5.85(m,3H),6.94-7.02(m,1H),7.32(br s,1H),7.45-7.51(m,1H),7.58-7.67(m,1H),7.90(br s,1H),7.98-8.03(m,1H),10.36-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.01(m,3H), 1.36-1.44(m,1H), 1.74-1.85(m,1H), 1.85-1.96(m,1H) ,1.97-2.04(m,4H),2.04-2.19(m,1H),2.83-3.28(m,1H),3.42-4.05(m,1H),5.37-5.85(m,3H),6.94-7.02( m,1H),7.32(br s,1H),7.45-7.51(m,1H),7.58-7.67(m,1H),7.90(br s,1H),7.98-8.03(m,1H),10.36- 10.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值401.2；實測值402.2；Rt=0.915min。LCMS (ESI): [M] + m/z: calculated 401.2; found 402.2; Rt=0.915min.

化合物733：保留時間：19.47minCompound 733: retention time: 19.47min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.01(m,3H),1.36-1.44(m,1H),1.74-1.85(m,1H),1.85-1.96(m,1H),1.97-2.04(m,4H),2.04-2.19(m,1H),2.83-3.28(m,1H),3.42-4.05(m,1H),5.37-5.85(m,3H),6.94-7.02(m,1H),7.32(br s,1H),7.45-7.51(m,1H),7.58-7.67(m,1H),7.90(br s,1H),7.98-8.03(m,1H),10.36-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.01(m,3H), 1.36-1.44(m,1H), 1.74-1.85(m,1H), 1.85-1.96(m,1H) ,1.97-2.04(m,4H),2.04-2.19(m,1H),2.83-3.28(m,1H),3.42-4.05(m,1H),5.37-5.85(m,3H),6.94-7.02( m,1H),7.32(br s,1H),7.45-7.51(m,1H),7.58-7.67(m,1H),7.90(br s,1H),7.98-8.03(m,1H),10.36- 10.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值401.2；實測值402.2；Rt=0.917min。LCMS (ESI): [M] + m/z: calculated 401.2; found 402.2; Rt=0.917 min.

實例343. 5-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)-N -甲基 噻吩-2-甲醯胺(化合物859及化合物849)之合成Example 343. 5-(1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-5-methylpiperidine-2 Synthesis of -yl) -N -methylthiophene -2-carboxamide (Compound 859 and Compound 849)

Figure 110128222-A0202-12-1591-452
Figure 110128222-A0202-12-1591-452

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(5-(甲基胺甲醯基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(5-(methylaminocarboxy)thiophen-2-yl)piperidine) Synthesis of 3-butyl pyridin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamate

向N -甲基-5-[(2S,5R )-5-甲基-2-哌啶基]噻吩-2-甲醯胺(186mg，780.37μmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(230.44mg，780.37μmol)及TEA(157.93mg，1.56mmol，217.54μL)於DMF(3mL)中之經攪拌之混合物中添加HATU(326.39mg，858.41μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(20-50% 0-5min H2 O/ACN，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(167mg，323.88μmol，41.50%產率)。To N -methyl-5-[( 2S,5R )-5-methyl-2-piperidinyl]thiophene-2-carboxamide (186 mg, 780.37 μmol), 2-[[6-( tertiary butyl Oxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (230.44 mg, 780.37 μmol) and TEA (157.93 mg, 1.56 mmol, 217.54 μL) in DMF (3 mL) ) was added to the stirred mixture in HATU (326.39 mg, 858.41 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (20-50% 0-5min H2O /ACN, flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give N- [3-methyl-5-[[ 2-[( 2S,5R )-5-methyl-2-[5-(methylaminocarboxy)-2-thienyl]-1-piperidinyl]-2-oxyethanoyl] Amino]-2-pyridyl]carbamic acid tert -butyl ester (167 mg, 323.88 [mu]mol, 41.50% yield).

LCMS(ESI)：[M]+ m/z：計算值515.2；實測值516.2；Rt=2.621min。LCMS (ESI): [M] + m/z: calculated 515.2; found 516.2; Rt=2.621 min.

步驟2：5-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)-N-甲基噻吩-2-甲醯胺之合成Step 2: 5-(1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyacetyl)-5-methylpiperidine-2 -Synthesis of -N-methylthiophene-2-formamide

將水(5.83mg，323.88μmol，5.83μL)添加到N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[5-(甲基胺甲醯基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(167mg，323.88μmol)於二噁烷(2mL)中之溶液中。將所得混合物在100℃下攪拌15h。然後，使其經歷HPLC(30-30-80% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20 mm，5um)，得到5-[(2S,5R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基-噻吩-2-甲醯胺(89mg，214.20μmol，66.13%產率)。Water (5.83 mg, 323.88 μmol, 5.83 μL) was added to N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-[5-(methylaminomethane Acetyl)-2-thienyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (167 mg, 323.88 μmol) in dioxane alkane (2 mL). The resulting mixture was stirred at 100 °C for 15 h. It was then subjected to HPLC (30-30-80% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min; column: YMC Triart C18 100x20 mm, 5um) to give 5 -[( 2S,5R )-1-[2-[(6-amino-5-methyl-3-pyridinyl)amino]-2-side oxyacetyl]-5-methyl-2 -Piperidinyl] -N -methyl-thiophene-2-carboxamide (89 mg, 214.20 μmol, 66.13% yield).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.708min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.708 min.

步驟3：掌性分離(化合物859 及化合物849 )Step 3: Chiral separation ( compound 859 and compound 849 )

藉由掌性HPLC(Chiralpak IA 250*20mm，5mkm；己烷-IPA-MeOH，50-25-25，12ml/min)將5-[(2S,5R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基-噻吩-2-甲醯胺(89mg，214.20μmol)分成鏡像異構物，得到：5-[(2S,5R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基-噻吩-2-甲醯胺(28.9mg，69.55μmol，64.94%產率)(其中保留時間=24.6min)(化合物849 )及5-[(2R,5S )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基-噻吩-2-甲醯胺(33.3mg，80.14μmol，74.83%產率)(其中保留時間=56.64min)(化合物859 )。5-[( 2S,5R )-1-[2-[(6- Amino-5-methyl-3-pyridyl)amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl] -N -methyl-thiophene-2-carboxylate The amine (89 mg, 214.20 μmol) split into enantiomers to give: 5-[( 2S,5R )-1-[2-[(6-amino-5-methyl-3-pyridinyl)amino]- 2-Oxyacetyl]-5-methyl-2-piperidinyl] -N -methyl-thiophene-2-carboxamide (28.9 mg, 69.55 μmol, 64.94% yield) (wherein retention time =24.6min) ( Compound 849 ) and 5-[( 2R,5S )-1-[2-[(6-amino-5-methyl-3-pyridyl)amino]-2-side oxyethyl Acyl]-5-methyl-2-piperidinyl] -N -methyl-thiophene-2-carboxamide (33.3 mg, 80.14 μmol, 74.83% yield) (wherein retention time = 56.64 min) ( compound 859 ).

化合物859 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為49.85min且化合物849 之保留時間為29.12min。The retention time of compound 859 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 49.85 min and the retention time of compound 849 was 29.12 min.

化合物859：保留時間：49.85minCompound 859: retention time: 49.85min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.01(m,3H),1.34-1.49(m,2H),1.75-1.84(m,1H),1.86-1.96(m,1H),2.03-2.06(m,3H),2.06-2.19(m,1H),2.70-2.74(m,3H),2.84-3.24(m,1H),3.45-4.06(m,1H),5.34-5.85(m,1H),6.21(br s,2H),6.97-7.02(m,1H),7.54-7.62(m,2H),8.08(s,1H),8.33-8.41(m,1H),10.55-10.79(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.01(m,3H), 1.34-1.49(m,2H), 1.75-1.84(m,1H), 1.86-1.96(m,1H) ,2.03-2.06(m,3H),2.06-2.19(m,1H),2.70-2.74(m,3H),2.84-3.24(m,1H),3.45-4.06(m,1H),5.34-5.85( m,1H),6.21(br s,2H),6.97-7.02(m,1H),7.54-7.62(m,2H),8.08(s,1H),8.33-8.41(m,1H),10.55-10.79 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.755min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.755 min.

化合物849：保留時間：29.12minCompound 849: retention time: 29.12min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.00(m,3H),1.37-1.44(m,1H),1.76-1.84(m,1H),1.86-1.96(m,1H),2.00-2.04(m,1H),2.12-2.19(m,3H),2.69-2.74 (m,3H),2.84-3.21(m,1H),3.46-4.09(m,1H),5.38-5.88(m,1H),6.98-7.03(m,1H),7.25(br s,2H),7.53-7.60(m,1H),7.71-7.84(m,1H),8.22(s,1H),8.35-8.41(m,1H),10.95(s,1H),13.14(brs,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.00(m,3H), 1.37-1.44(m,1H), 1.76-1.84(m,1H), 1.86-1.96(m,1H) ,2.00-2.04(m,1H),2.12-2.19(m,3H),2.69-2.74(m,3H),2.84-3.21(m,1H),3.46-4.09(m,1H),5.38-5.88( m,1H),6.98-7.03(m,1H),7.25(br s,2H),7.53-7.60(m,1H),7.71-7.84(m,1H),8.22(s,1H),8.35-8.41 (m, 1H), 10.95 (s, 1H), 13.14 (brs, 1H).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.756min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.756 min.

實例344. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物616)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物635)之合成Example 344. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5 -Methyl-1-piperidinyl]-2-oxoacetamide (Compound 616) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R Synthesis of ,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 635)

Figure 110128222-A0202-12-1593-453
Figure 110128222-A0202-12-1593-453

步驟1：N-[5-[[2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(1,3-Benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Synthesis of tert-butyl amino]-3-methyl-2-pyridyl]carbamate

在室溫下將HATU(490.95mg，1.29mmol)分批添加到2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(381.28mg，1.29mmol)、5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(300mg，1.29mmol)及TEA(783.93mg，7.75mmol，1.08mL)於DMF(10mL)中之懸浮液中。將澄清溶液在25℃下攪拌18h且在真空中蒸發溶劑。將殘餘物溶解於EtOAc(100mL)中，用水(3x50mL)洗滌且在真空中蒸發，以得到N-[5-[[2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(700mg，粗品)。HATU (490.95 mg, 1.29 mmol) was added portionwise to 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2- at room temperature Pendant oxyacetic acid (381.28 mg, 1.29 mmol), 5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (300 mg, 1.29 mmol) and TEA (783.93 mg, 7.75 mmol, 1.08 mL) in DMF (10 mL). The clear solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (3 x 50 mL) and evaporated in vacuo to give N-[5-[[2-[2-(1,3-benzothiazol-5-yl)- 5-Methyl-1-piperidinyl]-2-oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (700 mg, crude).

1 H NMR(DMSO-d6,400MHz)：δ 1.01(d,3H),1.39(m,13H),2.09(m,8H),5.71(m,1H),7.43(m,2H),8.12(m,1H),8.43(s,1H),9.03(s,1H),9.38(m,1H),11.00(s, 1H)。 1 H NMR (DMSO-d6, 400MHz): δ 1.01 (d, 3H), 1.39 (m, 13H), 2.09 (m, 8H), 5.71 (m, 1H), 7.43 (m, 2H), 8.12 (m , 1H), 8.43(s, 1H), 9.03(s, 1H), 9.38(m, 1H), 11.00(s, 1H).

LCMS(ESI)：1H NMR(DMSO d6，400MHz)：δ 1.01(m,2H),1.39(m,3H),2.09(m,1H),5.71(m,3H),7.43(m,1H),8.12(m,2H),8.43(m,1H),9.03(m,1H),9.38(d,1H),11.00(s,1H)。LCMS (ESI): 1H NMR (DMSO d6, 400MHz): δ 1.01 (m, 2H), 1.39 (m, 3H), 2.09 (m, 1H), 5.71 (m, 3H), 7.43 (m, 1H), 8.12 (m, 2H), 8.43 (m, 1H), 9.03 (m, 1H), 9.38 (d, 1H), 11.00 (s, 1H).

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidine Synthesis of Radix]-2-Pendant Oxyacetamide

在室溫下將於二噁烷中之4.0M氯化氫溶液(3.58g，13.74mmol，3.41mL，14%純度)小心添加到N-[5-[[2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(700mg，1.37mmol)於DCM(10mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以40-40-90% 0-1-5min 0.1% NH3 -甲醇為流動相)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(331mg，808.30μmol，58.85%產率)。A 4.0 M solution of hydrogen chloride in dioxane (3.58 g, 13.74 mmol, 3.41 mL, 14% purity) was carefully added to N-[5-[[2-[2-(1,3-benzene at room temperature Thiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester ( 700 mg, 1.37 mmol) in DCM (10 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; 40-40-90% 0-1-5 min 0.1% NH3 -methanol as mobile phase) to give N-(6-amino -5-Methyl-3-pyridyl)-2-[2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetone Amine (331 mg, 808.30 μmol, 58.85% yield).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.2；Rt=2.176min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.2; Rt=2.176 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物616 )及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物635 )之合成Step 3: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5 -Methyl-1-piperidinyl]-2-oxyacetamide ( compound 616 ) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R Synthesis of ,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 635 )

藉由掌性HPLC(管柱：IC II，以己烷-IPA-MeOH，50-25-25，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物化合物635 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(161mg，393.16μmol，97.28%產率)(保留時間=32.4min，[α]21D=-176.7°)(c=0.1g/100mL，EtOH)及化合物616 N-(6-胺基-5-甲基-3-吡啶 基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(160mg，390.72μmol，96.68%產率)(保留時間=45.8min，[α]21D=+191.5°)(c=0.1g/100mL，EtOH)。The enantiomers were separated by chiral HPLC (column: IC II with hexane-IPA-MeOH, 50-25-25, 12 ml/min as mobile phase) to give two separate enantiomer compounds 635 N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazol-5-yl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide (161 mg, 393.16 μmol, 97.28% yield) (retention time=32.4 min, [α]21D=-176.7°) (c=0.1 g/100 mL, EtOH) and compound 616 N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5 -Methyl-1-piperidinyl]-2-oxyacetamide (160 mg, 390.72 μmol, 96.68% yield) (retention time=45.8 min, [α]21D=+191.5°) (c=0.1 g/100 mL, EtOH).

化合物616： RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=47.098min。 Compound 616: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 47.098 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.06(m,3H),1.30-1.42(m,1H),1.66-1.75(m,1H),1.82-1.91(m,1H),1.95-2.04(m,3H),2.06-2.23(m,1H),2.26-2.35(m,1H),2.76-3.27(m,1H),3.38-4.06(m,1H),5.26-5.60(m,1H),5.60-5.76(m,2H),7.39-7.46(m,1H),7.50(s,1H),7.92-8.01(m,1H),8.01-8.06(m,1H),8.13-8.20(m,1H),9.37-9.43(m,1H),10.50-10.70(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.06(m,3H), 1.30-1.42(m,1H), 1.66-1.75(m,1H), 1.82-1.91(m,1H), 1.95- 2.04(m,3H),2.06-2.23(m,1H),2.26-2.35(m,1H),2.76-3.27(m,1H),3.38-4.06(m,1H),5.26-5.60(m,1H) ), 5.60-5.76(m, 2H), 7.39-7.46(m, 1H), 7.50(s, 1H), 7.92-8.01(m, 1H), 8.01-8.06(m, 1H), 8.13-8.20(m , 1H), 9.37-9.43 (m, 1H), 10.50-10.70 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.0；Rt=1.992min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.0; Rt=1.992 min.

化合物635 RT(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)=35.176min。 Compound 635 RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 35.176 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.05(m,3H),1.27-1.40(m,1H),1.64-1.75(m,1H),1.82-1.93(m,1H),1.95-2.04(m,3H),2.07-2.25(m,1H),2.27-2.35(m,1H),2.75-3.27(m,1H),3.42-4.11(m,1H),5.28-5.59(m,1H),5.60-5.74(m,2H),7.40-7.45(m,1H),7.49(s,1H),7.94-8.01(m,1H),8.01-8.06(m,1H),8.13-8.19(m,1H),9.36-9.42(m,1H),10.52-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.00-1.05(m,3H), 1.27-1.40(m,1H), 1.64-1.75(m,1H), 1.82-1.93(m,1H), 1.95- 2.04(m, 3H), 2.07-2.25(m, 1H), 2.27-2.35(m, 1H), 2.75-3.27(m, 1H), 3.42-4.11(m, 1H), 5.28-5.59(m, 1H) ), 5.60-5.74(m, 2H), 7.40-7.45(m, 1H), 7.49(s, 1H), 7.94-8.01(m, 1H), 8.01-8.06(m, 1H), 8.13-8.19(m , 1H), 9.36-9.42 (m, 1H), 10.52-10.58 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.2；Rt=2.001min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.2; Rt=2.001 min.

實例345.N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯胺(化合物186)之合成Example 345. N- (6-Amino-5-methyl-3-pyridyl)-2-[2-(4,4-difluorocyclohexyl)-1-piperidinyl]-2-pendantoxy Synthesis of Acetamide (Compound 186)

Figure 110128222-A0202-12-1595-454
Figure 110128222-A0202-12-1595-454

步驟1：N-[5-[[2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-Step 1: N-[5-[[2-[2-(4,4-Difluorocyclohexyl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl -2- 吡啶基]胺甲酸第三丁酯之合成Synthesis of tert-butyl pyridyl]carbamate

將2-(4,4-二氟環己基)哌啶(0.2g，983.91μmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(330.77mg，1.12mmol)及三乙胺(844.19mg，8.34mmol，1.16mL)於DMF(3mL)中之混合物在25℃下攪拌20分鐘。20分鐘之後，添加HATU(475.82mg，1.25mmol)。將所得反應混合物在25℃下攪拌隔夜。完成之後，將水(20mL)添加到反應混合物中且用乙酸乙酯(2 x 25mL)萃取。將經合併之有機相用水(3 x 25mL)、鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下乾燥。使粗反應混合物經歷反相HPLC純化(溶析液：10-50%，2-10min，甲醇；流速：30mL/min；裝載泵：4mL MeOH；管柱：SunFire 100*19mm，5μM)，以獲得呈淡黃色固體之N -[5-[[2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(81.10mg，168.77μmol，20.23%產率)。2-(4,4-Difluorocyclohexyl)piperidine (0.2 g, 983.91 μmol), 2-[[6-(3-butoxycarbonylamino)-5-methyl-3-pyridyl] A mixture of amino]-2-pendoxoacetic acid (330.77 mg, 1.12 mmol) and triethylamine (844.19 mg, 8.34 mmol, 1.16 mL) in DMF (3 mL) was stirred at 25 °C for 20 min. After 20 minutes, HATU (475.82 mg, 1.25 mmol) was added. The resulting reaction mixture was stirred at 25°C overnight. After completion, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water (3 x 25 mL), brine, dried over Na2SO4 , filtered and dried under reduced pressure. The crude reaction mixture was subjected to reverse phase HPLC purification (eluent: 10-50%, 2-10 min, methanol; flow rate: 30 mL/min; loading pump: 4 mL MeOH; column: SunFire 100*19 mm, 5 μM) to obtain N- [5-[[2-[2-(4,4-difluorocyclohexyl)-1-piperidinyl]-2-side oxyacetyl]amino]-3- as a pale yellow solid 3 -butyl methyl-2-pyridyl]carbamate (81.10 mg, 168.77 [mu]mol, 20.23% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值480.3；實測值481.2；Rt=1.386min。LCMS (ESI): [M+Boc] + m/z: calculated 480.3; found 481.2; Rt=1.386 min.

步驟2：N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯胺(化合物186 )之合成Step 2: N- (6-Amino-5-methyl-3-pyridinyl)-2-[2-(4,4-difluorocyclohexyl)-1-piperidinyl]-2-pendoxyl Synthesis of Acetamide ( Compound 186 )

將N -[5-[[2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(81.10mg，168.77μmol)於二噁烷(2mL)及水(2mL)中之正攪拌溶液在100℃下加熱18小時。然後，將反應混合物蒸發至乾且藉由HPLC(溶析液：2-10min，35-60%，水-MeOH+NH3 ；裝載泵：4mL/min，MeOH+NH3 ；管柱：Sunfire 100 * 20mm，5μM)純化粗產物，以獲得呈淡黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(4,4-二氟環己基)-1-哌啶基]-2-側氧基乙醯胺(化合物186 ,22.60mg，59.41μmol，35.20%產率)。 N- [5-[[2-[2-(4,4-difluorocyclohexyl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2 A positive stirring solution of -pyridyl]carbamic acid tert -butyl ester (81.10 mg, 168.77 [mu]mol) in dioxane (2 mL) and water (2 mL) was heated at 100&lt;0&gt;C for 18 hours. The reaction mixture was then evaporated to dryness and analyzed by HPLC (eluent: 2-10 min, 35-60%, water-MeOH+ NH3 ; loading pump: 4 mL/min, MeOH+ NH3 ; column: Sunfire 100 *20 mm, 5 μM) crude product was purified to obtain N- (6-amino-5-methyl-3-pyridinyl)-2-[2-(4,4-difluorocyclohexyl) as pale yellow solid -1-Piperidinyl]-2-oxyacetamide (Compound 186 , 22.60 mg, 59.41 μmol, 35.20% yield).

化合物186： 1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.18(m,2H),1.44(m,2H),1.63(m,4H),1.81(m,4H),2.01(d,6H),2.91(m,1H),3.53(m,1H),4.21(m,1H),5.63(m, 2H),7.47(m,1H),7.99(m,1H),10.34(m,1H)。 Compound 186: 1 H NMR (DMSO- d 6 , 400 MHz): δ (ppm) 1.18 (m, 2H), 1.44 (m, 2H), 1.63 (m, 4H), 1.81 (m, 4H), 2.01 (d ,6H),2.91(m,1H),3.53(m,1H),4.21(m,1H),5.63(m,2H),7.47(m,1H),7.99(m,1H),10.34(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.1；Rt=1.014min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.1; Rt=1.014 min.

實例346.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-異丙基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物165)之合成Example 346. N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )-2-isopropyl-5-methyl-1-piperidinyl] - Synthesis of 2-oxoacetamide (Compound 165)

Figure 110128222-A0202-12-1597-455
Figure 110128222-A0202-12-1597-455

步驟1：N-[5-[[2-(2-異丙基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-(2-Isopropyl-5-methyl-1-piperidinyl)-2-oxyacetyl]amino]-3-methyl-2 -Synthesis of tert-butyl pyridyl]carbamate

向2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.33g，1.12mmol)及2-異丙基-5-甲基哌啶(198.60mg，1.12mmol，HCl)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(505.52mg，3.91mmol，681.29μL)。將所得混合物攪拌5分鐘。5分鐘之後，添加HATU(446.17mg，1.17mmol)於DMF(2mL)中之溶液。將所得反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液且藉由HPLC純化粗產物，以得到呈淡黃色固體之N -[5-[[2-(2-異丙基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(131.5mg，314.20μmol，28.11%產率)。To 2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (0.33 g, 1.12 mmol) and 2-isopropyl To a stirred solution of yl-5-methylpiperidine (198.60 mg, 1.12 mmol, HCl) in DMF (10 mL) was added DIPEA (505.52 mg, 3.91 mmol, 681.29 μL). The resulting mixture was stirred for 5 minutes. After 5 minutes, a solution of HATU (446.17 mg, 1.17 mmol) in DMF (2 mL) was added. The resulting reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure and the crude product was purified by HPLC to give N- [5-[[2-(2-isopropyl-5-methyl-1-piperidine as a pale yellow solid pyridinyl)-2-pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (131.5 mg, 314.20 [mu]mol, 28.11% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值418.2；實測值419.4；Rt=3.635min。LCMS (ESI): [M+Boc] + m/z: calculated 418.2; found 419.4; Rt=3.635 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-異丙基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物165 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-isopropyl-5-methyl-1-piperidinyl]-2 - Synthesis of Pendant Oxyacetamide ( Compound 165 )

將N -[5-[[2-[(2S ,5R )-2-異丙基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(131.50mg，314.20μmol)於二噁烷(2mL)及水(5mL)中之正攪拌溶液在100℃下加熱17小時。然後，將反應混合物蒸發至 乾且藉由HPLC(溶析液：2-10min，10-50% CH3 CN+NH3 ；流速：30mL/min；裝載泵：4mL/min，CH3 CN；管柱：Triart C18 100*20mm，5um)純化粗產物，以獲得呈淡黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-異丙基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物165 ，50mg，157.03μmol，49.98%產率)。 N- [5-[[2-[( 2S , 5R )-2-isopropyl-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]- A stirring solution of tert- butyl 3-methyl-2-pyridyl]carbamate (131.50 mg, 314.20 [mu]mol) in dioxane (2 mL) and water (5 mL) was heated at 100&lt;0&gt;C for 17 hours. The reaction mixture was then evaporated to dryness and analyzed by HPLC (eluent: 2-10 min, 10-50% CH3CN + NH3 ; flow rate: 30 mL/min; loading pump: 4 mL/min, CH3CN ; tube Column: Triart C18 100*20mm, 5um) The crude product was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S ,5R) as a pale yellow solid -2-Isopropyl-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 165 , 50 mg, 157.03 μmol, 49.98% yield).

化合物165： 1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.94(m,8H),1.29(m,1H),1.82(m,5H),2.11(s,4H),3.11(m,1H),4.21(m,1H),4.43(s,2H),4.65(m,1H),7.70(d,1H),8.02(s,1H),9.14(s,1H)。 Compound 165: 1 H NMR (CDCl 3 , 400 MHz): δ (ppm) 0.94 (m, 8H), 1.29 (m, 1H), 1.82 (m, 5H), 2.11 (s, 4H), 3.11 (m, 1H) ), 4.21(m, 1H), 4.43(s, 2H), 4.65(m, 1H), 7.70(d, 1H), 8.02(s, 1H), 9.14(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值318.2；實測值319.4Rt=2.464min。LCMS (ESI): [M+H] + m/z: calculated 318.2; found 319.4 Rt=2.464 min.

實例347.N -(6-胺基-5-甲基-3-吡啶基)-2-(2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物135)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-異丙基-1-哌啶基)-2-側氧基乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物204及化合物192) 之合成Example 347. N- (6-Amino-5-methyl-3-pyridyl)-2-(2-isopropyl-1-piperidinyl)-2-oxoacetamide (Compound 135) , N- (6-amino-5-methyl-3-pyridyl)-2-[(2R)-2-isopropyl-1-piperidinyl)-2-side oxyacetamide and N -(6-Amino-5-methyl-3-pyridyl)-2-[(2S)-2-isopropyl-1-piperidinyl)-2-oxoacetamide (compound 204 and Synthesis of compound 192)

Figure 110128222-A0202-12-1598-456
Figure 110128222-A0202-12-1598-456

步驟1：N-[5-[[2-(2-異丙基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-(2-Isopropyl-1-piperidinyl)-2-oxyethanoyl]amino]-3-methyl-2-pyridinyl]amine Synthesis of tert-butyl formate

在21℃下，將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)、TATU(392.65mg，1.22mmol)及三乙胺(308.41mg，3.05mmol，424.81μL)一起混合於無水CH3 CN(25mL)中且將所得混合物攪 拌6小時。6小時之後，添加2-異丙基哌啶(182.93mg，1.12mmol，鹽酸鹽)，且將所得混合物在21℃下攪拌隔夜。然後將所得混合物蒸發至乾且使其經歷HPLC純化(溶析液：0.1%甲酸/CH3 CN，5-95% CH3 CN，6min；管柱：Zorbax Eclipse-plus C18，4.6*100mm，3.5um)，以獲得呈白色固體之N -[5-[[2-(2-異丙基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(45.7mg，112.98μmol，11.12%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (0.3 g, 1.02 mmol) at 21 °C , TATU (392.65 mg, 1.22 mmol) and triethylamine (308.41 mg, 3.05 mmol, 424.81 μL) were mixed together in dry CH3CN (25 mL) and the resulting mixture was stirred for 6 h. After 6 hours, 2-isopropylpiperidine (182.93 mg, 1.12 mmol, hydrochloride) was added, and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was then evaporated to dryness and subjected to HPLC purification (eluent: 0.1% formic acid/ CH3CN , 5-95% CH3CN , 6 min; column: Zorbax Eclipse-plus C18, 4.6*100 mm, 3.5 um) to obtain N- [5-[[2-(2-isopropyl-1-piperidinyl)-2-oxyethanoyl]amino]-3-methyl- 3- Butyl 2-pyridyl]carbamate (45.7 mg, 112.98 [mu]mol, 11.12% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值404.3；實測值405.4；Rt=3.291min。LCMS (ESI): [M+Boc] + m/z: calculated 404.3; found 405.4; Rt=3.291 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-(2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物135 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-(2-isopropyl-1-piperidinyl)-2-oxoacetamide ( Compound 135 ) synthesis

在21℃下，向N -[5-[[2-(2-異丙基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(45.7mg，112.98μmol)於二噁烷(5mL)中之經攪拌之溶液中添加於二噁烷中之4.0M HCl(800.00mg，21.94mmol，1mL)。將所得反應混合物攪拌12小時。完成之後，過濾出經沉澱之固體，用MTBE洗滌且在高壓下(0.3毫巴)乾燥。藉由反相HPLC(溶析液：2-7min，15-30% CH3 CN，流速：30mL/min；管柱：SunFire C18 100*19mm，5μM)純化所獲得之粗產物，以得到呈淡黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-(2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物135 ,15.9mg，52.24μmol，46.24%產率)。At 21 °C, to N- [5-[[2-(2-isopropyl-1-piperidinyl)-2-oxyethanoyl]amino]-3-methyl-2-pyridine To a stirred solution of tert -butyl ]carbamate (45.7 mg, 112.98 [mu]mol) in dioxane (5 mL) was added 4.0 M HCl in dioxane (800.00 mg, 21.94 mmol, 1 mL). The resulting reaction mixture was stirred for 12 hours. After completion, the precipitated solid was filtered off, washed with MTBE and dried under high pressure (0.3 mbar). The crude product obtained was purified by reverse phase HPLC (eluent: 2-7 min, 15-30% CH3CN , flow rate: 30 mL/min; column: SunFire C18 100*19 mm, 5 μM) to give a pale Yellow solid N- (6-amino-5-methyl-3-pyridyl)-2-(2-isopropyl-1-piperidinyl)-2-oxoacetamide (compound 135 , 15.9 mg, 52.24 μmol, 46.24% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.85(m,6H),1.33(m,2H),1.59(m,4H),1.82(m,1H),2.16(m,1H),2.97(m,2H),3.47(m,2H),4.13(m,1H),5.60(m,2H),7.48(m,1H),8.00(m,1H),10.32(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.85 (m, 6H), 1.33 (m, 2H), 1.59 (m, 4H), 1.82 (m, 1H), 2.16 (m, 1H) , 2.97(m, 2H), 3.47(m, 2H), 4.13(m, 1H), 5.60(m, 2H), 7.48(m, 1H), 8.00(m, 1H), 10.32(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值304.2；實測值305.2；Rt=0.973min。LCMS (ESI): [M+H] + m/z: calculated 304.2; found 305.2; Rt=0.973 min.

N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-異丙基-1-哌啶基)-2-側氧基乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物204 及化合物192 )之掌性分離N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R)-2-isopropyl-1-piperidinyl)-2-oxoacetamide and N- (6-amino-5-methyl-3-pyridyl)-2-[(2S)-2-isopropyl-1-piperidinyl)-2-oxyacetamide ( compound 204 and compound 192 ) of palmar separation

使外消旋 -N -(6-胺基-5-甲基-3-吡啶基)-2-(2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物135 )經歷掌性層析，以得到呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R )-2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物204 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S )-2-異丙基-1-哌啶基)-2-側氧基乙醯胺(化合物192 )。Make rac - N- (6-amino-5-methyl-3-pyridyl)-2-(2-isopropyl-1-piperidinyl)-2-oxoacetamide ( compound 135 ) was subjected to chiral chromatography to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R )-2-isopropyl-1-piperidine as a white solid pyridyl)-2-oxyacetamide ( compound 204 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S )-2-isopropyl- 1-Piperidinyl)-2-oxoacetamide ( compound 192 ).

化合物204： LCMS(ESI)：[M+H]+ m/z：計算值304.2；實測值305.0；Rt=3.318min。 Compound 204: LCMS (ESI): [M+H] + m/z: calcd 304.2; found 305.0; Rt=3.318 min.

掌性HPLC：Rt=11.54min(管柱：OJ-H；溶析液：己烷-MeOH-IPA，80-10-10；流速：0.6mL/min)。Chiral HPLC: Rt=11.54 min (column: OJ-H; eluent: hexane-MeOH-IPA, 80-10-10; flow rate: 0.6 mL/min).

化合物192： LCMS(ESI)：[M+H]+ m/z：計算值304.2；實測值305.0；Rt=3.363min。 Compound 192: LCMS (ESI): [M+H] + m/z: calcd 304.2; found 305.0; Rt=3.363 min.

掌性HPLC：Rt=13.54min(管柱：OJ-H；溶析液：己烷-MeOH-IPA，80-10-10；流速：0.6Chiral HPLC: Rt=13.54min (column: OJ-H; eluent: hexane-MeOH-IPA, 80-10-10; flow rate: 0.6

實例348. 5-[[2-[(2R ,5S )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物161)之合成Example 348. 5-[[2-[( 2R ,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2- oxyethanoyl ]amino]pyridine- Synthesis of 3-formamide (Compound 161)

Figure 110128222-A0202-12-1600-457
Figure 110128222-A0202-12-1600-457

步驟1：5-[[2-[(2R,5S)-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155 )之合成Step 1: 5-[[2-[(2R,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Synthesis of formamide ( compound 155 )

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.23g，1.10mmol)及2-環丁基-5-甲基哌啶(168.54mg，1.10mmol)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(355.30mg，2.75mmol，478.84μL)。將所得混合物攪拌5分鐘。5分鐘之後，添加HATU(439.02mg，1.15mmol)於DMF(2mL)中之溶液。將所得 反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液且藉由HPLC純化粗產物且冷凍乾燥，以得到呈白色固體之外消旋 -5-[[2-[(2R ,5S )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155 ，20.4mg，59.23μmol，5.39%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.23 g, 1.10 mmol) and 2-cyclobutyl-5-methylpiperidine (168.54 mg , 1.10 mmol) in DMF (10 mL) was added DIPEA (355.30 mg, 2.75 mmol, 478.84 μL) to a stirred solution. The resulting mixture was stirred for 5 minutes. After 5 minutes, a solution of HATU (439.02 mg, 1.15 mmol) in DMF (2 mL) was added. The resulting reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure and the crude product was purified by HPLC and lyophilized to give rac -5-[[2-[( 2R , 5S )-2-ring as a white solid Butyl-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 155 , 20.4 mg, 59.23 μmol, 5.39% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.95(dd,3H),1.32(m,2H),1.80(m,9H),2.93(m,2H),3.81(m,1H),4.24(m,1H),7.62(m,1H),8.18(m,1H),8.50(m,1H),8.78(m,1H),8.90(m,1H),11.09(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.95 (dd, 3H), 1.32 (m, 2H), 1.80 (m, 9H), 2.93 (m, 2H), 3.81 (m, 1H) , 4.24(m, 1H), 7.62(m, 1H), 8.18(m, 1H), 8.50(m, 1H), 8.78(m, 1H), 8.90(m, 1H), 11.09(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.4；Rt=2.876min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.4; Rt=2.876 min.

步驟2：5-[[2-[(2R,5S)-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155 )之合成Step 2: 5-[[2-[(2R,5S)-2-cyclobutyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Synthesis of formamide ( compound 155 )

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.23g，1.10mmol)及2-環丁基-5-甲基哌啶(168.54mg，1.10mmol)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(355.30mg，2.75mmol，478.84μL)。將所得混合物攪拌5分鐘。5分鐘之後，添加HATU(439.02mg，1.15mmol)於DMF(2mL)中之溶液。將所得反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液且藉由HPLC純化粗產物且冷凍乾燥，以得到呈白色固體之外消旋 -5-[[2-[(2R ,5S )-2-環丁基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物155 ，20.4mg，59.23μmol，5.39%產率)。To 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.23 g, 1.10 mmol) and 2-cyclobutyl-5-methylpiperidine (168.54 mg , 1.10 mmol) in DMF (10 mL) was added DIPEA (355.30 mg, 2.75 mmol, 478.84 μL) to a stirred solution. The resulting mixture was stirred for 5 minutes. After 5 minutes, a solution of HATU (439.02 mg, 1.15 mmol) in DMF (2 mL) was added. The resulting reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure and the crude product was purified by HPLC and lyophilized to give rac -5-[[2-[( 2R , 5S )-2-ring as a white solid Butyl-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 155 , 20.4 mg, 59.23 μmol, 5.39% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.95(dd,3H),1.32(m,2H),1.80(m,9H),2.93(m,2H),3.81(m,1H),4.24(m,1H),7.62(m,1H),8.18(m,1H),8.50(m,1H),8.78(m,1H),8.90(m,1H),11.09(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.95 (dd, 3H), 1.32 (m, 2H), 1.80 (m, 9H), 2.93 (m, 2H), 3.81 (m, 1H) , 4.24(m, 1H), 7.62(m, 1H), 8.18(m, 1H), 8.50(m, 1H), 8.78(m, 1H), 8.90(m, 1H), 11.09(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.4；Rt=2.876min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.4; Rt=2.876 min.

實例349.N -(6-胺基-5-甲基-3-吡啶基)-2-(2-環丁基-1-哌啶基)-2-側氧基乙醯胺(化合物182)之合成Example 349. N- (6-Amino-5-methyl-3-pyridyl)-2-(2-cyclobutyl-1-piperidinyl)-2-oxoacetamide (Compound 182) synthesis

Figure 110128222-A0202-12-1602-458
Figure 110128222-A0202-12-1602-458

步驟1：N-[5-[[2-(2-環丁基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-(2-Cyclobutyl-1-piperidinyl)-2-oxyethanoyl]amino]-3-methyl-2-pyridinyl]amine Synthesis of tert-butyl formate

在21℃下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)、TATU(392.65mg，1.22mmol)及三乙胺(205.61mg，2.03mmol，283.21μL)混合於無水CH3 CN(25mL)中且將所得混合物攪拌15分鐘。15分鐘之後，添加2-環丁基哌啶(155.60mg，1.12mmol)，且將所得混合物在21℃下攪拌隔夜。將所得混合物蒸發至乾且使其經歷HPLC(溶析液：50-90%，0-9.5min，H2 O-MeOH(0.1% NH3 )；流速：30mL/min；裝載泵：4mL/min，MeOH(0.1% NH3 )；管柱：YMC-Actus Triart C18 100*20mm，5um)，以獲得呈白色固體之N -[5-[[2-(2-環丁基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(7.3mg，17.53μmol，1.73%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (0.3 g, 1.02 mmol) at 21 °C , TATU (392.65 mg, 1.22 mmol) and triethylamine (205.61 mg, 2.03 mmol, 283.21 μL) were mixed in anhydrous CH3CN (25 mL) and the resulting mixture was stirred for 15 min. After 15 minutes, 2-cyclobutylpiperidine (155.60 mg, 1.12 mmol) was added, and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was evaporated to dryness and subjected to HPLC (eluent: 50-90%, 0-9.5 min, H2O -MeOH (0.1% NH3 ); flow rate: 30 mL/min; loading pump: 4 mL/min , MeOH (0.1% NH3 ); column: YMC-Actus Triart C18 100*20mm, 5um) to obtain N- [5-[[2-(2-cyclobutyl-1-piperidine as a white solid (7.3 mg, 17.53 [mu]mol, 1.73% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值416.3；實測值417.2；Rt=3.640min。LCMS (ESI): [M+Boc] + m/z: calculated 416.3; found 417.2; Rt=3.640 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-(2-環丁基-1-哌啶基)-2-側氧基乙醯胺(化合物182 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-(2-cyclobutyl-1-piperidinyl)-2-oxoacetamide ( Compound 182 ) synthesis

在21℃下，向N -[5-[[2-(2-環丁基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(7.3mg，17.53μmol)於二噁烷(1mL)中之正攪拌溶液中添加於二噁烷中之4.0M氯化氫溶液(3.20mg，87.63μmol，3.99μL)。將所得混合物攪拌2小時。2小時之後，將所得混合物蒸發至乾且藉由HPLC(溶析液：2-7min，15-30% CH3 CN；流速：30mL/min；管柱：SunFire C18 100*19mm，5μM)純化且冷凍乾燥，以獲得呈黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-(2-環丁基-1-哌啶基)-2-側氧基乙醯胺(化合物182 ，3.3mg，10.43μmol， 59.51%產率)。To N- [5-[[2-(2-cyclobutyl-1-piperidinyl)-2-oxyethanoyl]amino]-3-methyl-2-pyridine at 21°C To a stirring solution of tert -butyl ]carbamate (7.3 mg, 17.53 [mu]mol) in dioxane (1 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (3.20 mg, 87.63 [mu]mol, 3.99 [mu]L). The resulting mixture was stirred for 2 hours. After 2 hours, the resulting mixture was evaporated to dryness and purified by HPLC (eluent: 2-7 min, 15-30% CH3CN ; flow rate: 30 mL/min; column: SunFire C18 100*19 mm, 5 μM) and Lyophilized to give N- (6-amino-5-methyl-3-pyridinyl)-2-(2-cyclobutyl-1-piperidinyl)-2-pendoxoethyl as a yellow solid Amide ( compound 182 , 3.3 mg, 10.43 μmol, 59.51% yield).

1H NMR(CDCl3 ,400MHz)：δ(ppm)1.54(m,4H),1.85(m,8H),2.12(m,3H),2.86(m,2H),4.69(m,3H),4.99(m,1H),7.72(d,1H),8.03(s,1H),9.00(s,1H)。1H NMR (CDCl 3 , 400MHz): δ (ppm) 1.54 (m, 4H), 1.85 (m, 8H), 2.12 (m, 3H), 2.86 (m, 2H), 4.69 (m, 3H), 4.99 ( m, 1H), 7.72 (d, 1H), 8.03 (s, 1H), 9.00 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值316.2；實測值317.2；Rt=0.953min。LCMS (ESI): [M+H] + m/z: calculated 316.2; found 317.2; Rt=0.953 min.

實例350.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-環戊基-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物190)之合成Example 350. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-cyclopentyl-5-methylpiperidin-1-yl)-2-oxoacetone Synthesis of Amine (Compound 190)

Figure 110128222-A0202-12-1603-459
Figure 110128222-A0202-12-1603-459

步驟1：(5-(2-(2-環戊基-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-Cyclopentyl-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridin-2-yl)amine Synthesis of tert-butyl formate

將2-環戊基-5-甲基哌啶(200mg，1.20mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(353.03mg，1.20mmol)、TEA(604.88mg，5.98mmol，833.16μL)混合於DMF(5mL)中，然後添加HATU(681.86mg，1.79mmol)。將所得混合物在25℃下攪拌12h。將混合物在減壓下蒸發且藉由HPLC(2-10min 10-50% MeOH，30ml/min)純化，以獲得N -[5-[[2-(2-環戊基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(176.1mg，396.12μmol，33.13%產率)。2-Cyclopentyl-5-methylpiperidine (200 mg, 1.20 mmol), 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino] -2-Pendoxoacetic acid (353.03 mg, 1.20 mmol), TEA (604.88 mg, 5.98 mmol, 833.16 μL) were mixed in DMF (5 mL), then HATU (681.86 mg, 1.79 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The mixture was evaporated under reduced pressure and purified by HPLC (2-10 min 10-50% MeOH, 30 ml/min) to obtain N- [5-[[2-(2-cyclopentyl-5-methyl- 1-Piperidinyl)-2-oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (176.1 mg, 396.12 [mu]mol, 33.13% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.97(d,3H),1.26(m,3H),1.44(s,9H),1.65(m,7H),1.88(m,2H),2.17(s,3H),3.16(m,1H),3.45(m,1H),4.17(m,3H),7.91(d,1H),8.42(s,1H),9.06(s,1H),10.86(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.97(d, 3H), 1.26(m, 3H), 1.44(s, 9H), 1.65(m, 7H), 1.88(m, 2H), 2.17( s, 3H), 3.16(m, 1H), 3.45(m, 1H), 4.17(m, 3H), 7.91(d, 1H), 8.42(s, 1H), 9.06(s, 1H), 10.86(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值113.2；實測值114.2；Rt=1.524min。LCMS (ESI): [M] + m/z: calculated 113.2; found 114.2; Rt=1.524 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-環戊基-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物190 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-cyclopentyl-5-methylpiperidin-1-yl)-2-oxoacetone Synthesis of Amine ( Compound 190 )

將N -[5-[[2-[(2S,5R )-2-環戊基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(171.60mg，385.99μmol)於二噁烷(2mL)及水(2mL)中之溶液在100℃下加熱12h。將混合物在減壓下蒸發且藉由HPLC(2-10min 10-50% MeCN+NH3 )純化，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-環戊基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(16.7mg，48.48μmol，12.56%產率)。 N- [5-[[2-[( 2S,5R )-2-cyclopentyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3- A solution of tert-butyl methyl-2-pyridyl]carbamate ( 171.60 mg, 385.99 [mu]mol) in dioxane (2 mL) and water (2 mL) was heated at 100 &lt;0&gt;C for 12 h. The mixture was evaporated under reduced pressure and purified by HPLC (2-10 min 10-50% MeCN+ NH3 ) to obtain N- (6-amino-5-methyl-3-pyridinyl)-2-[ ( 2S,5R )-2-cyclopentyl-5-methyl-1-piperidinyl]-2-oxyacetamide (16.7 mg, 48.48 μmol, 12.56% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.92(m,3H),1.22(m,3H),1.57(m,8H),1.89(m,2H),2.00(s,3H),3.48(m,3H),4.08(dd,1H),5.59(m,2H),7.44(m,1H),7.98(s,1H),10.28(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.92(m, 3H), 1.22(m, 3H), 1.57(m, 8H), 1.89(m, 2H), 2.00(s, 3H), 3.48(m, 3H), 4.08(dd, 1H), 5.59(m, 2H), 7.44(m, 1H), 7.98(s, 1H), 10.28(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值344.4；實測值345.2；Rt=1.070min。LCMS (ESI): [M] + m/z: calculated 344.4; found 345.2; Rt=1.070 min.

實例351.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-溴苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物600)之合成Example 351. N- (6-amino-5-methylpyridin-3-yl)-2-(2-(3-bromophenyl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 600)

Figure 110128222-A0202-12-1604-460
Figure 110128222-A0202-12-1604-460

步驟1：外消旋-(5-(2-((2R,5S)-2-(3-溴苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-2-(3-bromophenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide Synthesis of tert-butyl)-3-methylpyridin-2-yl)carbamate

向(2S,5R )-2-(3-溴苯基)-5-甲基哌啶(262.83mg，1.03mmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(400mg，1.35mmol)及TEA(1.05g，10.34mmol，1.44mL)於DMF(3mL)中之溶液中分批添加HATU(432.52mg，1.14mmol)。將混合物在25℃下攪拌1.5h。將反應混合物用水(20ml)稀釋且將產物用EtOAc(3*25ml)萃取。將經合併之有機層用水、鹽水洗滌且經Na2 SO4 乾燥。蒸發溶劑，以得到N -[5-[[2-[(2S,5R )-2-(3-溴苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(800mg，粗 品)。粗產物不經進一步純化即用於下一步驟中。To ( 2S,5R )-2-(3-bromophenyl)-5-methylpiperidine (262.83 mg, 1.03 mmol, HCl), 2-[[6-( tertiary butoxycarbonylamino)- 5-Methyl-3-pyridyl]amino]-2-pendoxoacetic acid (400 mg, 1.35 mmol) and TEA (1.05 g, 10.34 mmol, 1.44 mL) in DMF (3 mL) were added portionwise HATU (432.52 mg, 1.14 mmol). The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with water (20ml) and the product was extracted with EtOAc (3*25ml). The combined organic layers were washed with water, brine and dried over Na2SO4 . The solvent was evaporated to give N- [5-[[2-[( 2S,5R )-2-(3-bromophenyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone yl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (800 mg, crude). The crude product was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.05(d,3H),1.23(m,1H),1.48(s,9H),1.98(m,2H),2.21(s,3H),2.28(m,2H),2.93(m,1H),3.35(m,1H),4.08(m,1H),5.72(m,1H),6.71(m,1H),7.24(m,2H),7.37(m,1H),8.01(m,1H),8.35(m,1H),9.39(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.05(d, 3H), 1.23(m, 1H), 1.48(s, 9H), 1.98(m, 2H), 2.21(s, 3H), 2.28( m, 2H), 2.93(m, 1H), 3.35(m, 1H), 4.08(m, 1H), 5.72(m, 1H), 6.71(m, 1H), 7.24(m, 2H), 7.37(m , 1H), 8.01 (m, 1H), 8.35 (m, 1H), 9.39 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值531.4；實測值532.2；Rt=1.527min。LCMS (ESI): [M] + m/z: calculated 531.4; found 532.2; Rt=1.527 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-溴苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物600 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3-bromophenyl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide ( Compound 600 )

向N -[5-[[2-[(2S,5R )-2-(3-溴苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(800mg，1.51mmol)於DCM(15mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(548.86mg，15.05mmol，686.08μL)且在25℃下將反應混合物攪拌2h。蒸發溶劑，以得到粗產物(700mg)，其藉由反相HPLC(60-60-90% 0-1-5min 0.1% NH3 -MeOH，流速：30ml/min(裝載泵4ml/min MeOH)目標質量431管柱：YMC Triart C18 100x20mm，5um)進行純化，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3-溴苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(270mg，625.98μmol，41.58%產率)。to N- [5-[[2-[( 2S,5R )-2-(3-bromophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-Methyl-2-pyridinyl]carbamic acid tert- butyl ester (800 mg, 1.51 mmol) in DCM (15 mL) to a stirred solution of 4.0 M hydrogen chloride in dioxane (548.86 mg) was added , 15.05 mmol, 686.08 μL) and the reaction mixture was stirred at 25 °C for 2 h. The solvent was evaporated to give crude product (700 mg) which was targeted by reverse phase HPLC (60-60-90% 0-1-5 min 0.1% NH3 -MeOH, flow rate: 30 ml/min (loading pump 4 ml/min MeOH) Mass 431 column: YMC Triart C18 100x20mm, 5um) was purified to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(3- bromophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (270 mg, 625.98 μmol, 41.58% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.25-1.37(m,1H),1.58-1.66(m,1H),1.80-1.93(m,1H),1.97-2.07(m,4H),2.13-2.25(m,1H),2.68-3.25(m,1H),3.33-4.07(m,1H),5.12-5.57(m,1H),5.57-5.68(m,2H),7.29-7.38(m,2H),7.42-7.55(m,3H),7.93-8.04(m,1H),10.42-10.64(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.03(m,3H), 1.25-1.37(m,1H), 1.58-1.66(m,1H), 1.80-1.93(m,1H) ,1.97-2.07(m,4H),2.13-2.25(m,1H),2.68-3.25(m,1H),3.33-4.07(m,1H),5.12-5.57(m,1H),5.57-5.68( m, 2H), 7.29-7.38 (m, 2H), 7.42-7.55 (m, 3H), 7.93-8.04 (m, 1H), 10.42-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值431.4；實測值432.2；Rt=2.503min。LCMS (ESI): [M] + m/z: calculated 431.4; found 432.2; Rt=2.503 min.

實例352.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(6-羥基螺[3.3 ]庚-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物711、化合物768、化合物769、化合物766及化合物767)之合成Example 352. N- (6-amino-5-methylpyridin-3-yl)-2-(2-(6-hydroxyspiro[ 3.3 ]hept-2-yl)-5-methylpiperidine-1 Synthesis of -yl)-2-oxoacetamide (Compound 711, Compound 768, Compound 769, Compound 766 and Compound 767)

Figure 110128222-A0202-12-1606-461
Figure 110128222-A0202-12-1606-461

步驟1：外消旋-(5-(2-((2R,5S)-2-(6-羥基螺[3.3]庚-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-2-(6-hydroxyspiro[3.3]hept-2-yl)-5-methylpiperidin-1-yl)-2 -Synthesis of tert-butyl oxyacetamido)-3-methylpyridin-2-yl)carbamate

向6-[(2S,5R )-5-甲基-2-哌啶基]螺[3.3 ]庚-2-醇(250mg，1.19mmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(352.67mg，1.19mmol)及TEA(845.96mg，8.36mmol，1.17mL)於DMF(4mL)中之溶液中分批添加HATU(499.52mg，1.31mmol)。將混合物在25℃下攪拌2h。將反應混合物用水(50ml)稀釋且將產物用EtOAc(3*25ml)萃取。將經合併之有機層用水、鹽水洗滌且經Na2 SO4 乾燥。蒸發溶劑，以得到N -[5-[[2-[(2S,5R )-2-(2-羥基螺[3.3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(500mg，1.03mmol，86.04%產率)。To 6-[( 2S,5R )-5-methyl-2-piperidinyl]spiro[ 3.3 ]hept-2-ol (250 mg, 1.19 mmol, HCl), 2-[[6-( tertiary butoxy ( 352.67 mg, 1.19 mmol) and TEA (845.96 mg, 8.36 mmol, 1.17 mL) in DMF (4 mL) To the solution was added HATU (499.52 mg, 1.31 mmol) in portions. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50ml) and the product was extracted with EtOAc (3*25ml). The combined organic layers were washed with water, brine and dried over Na2SO4 . The solvent was evaporated to give N- [5-[[2-[( 2S,5R )-2-(2-hydroxyspiro[ 3.3 ]hept-6-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (500 mg, 1.03 mmol, 86.04% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.89(d,3H),1.22(m,3H),1.42(s,9H),1.88(m,6H),2.08(m,6H),2.15(m,1H),2.87(s,3H),3.98(m,2H),4.98(m,1H),7.88(m,1H),8.39(m,1H),9.05(s,1H),10.87(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.89(d,3H), 1.22(m,3H), 1.42(s,9H), 1.88(m,6H), 2.08(m,6H), 2.15(m, 1H), 2.87(s, 3H), 3.98(m, 2H), 4.98(m, 1H), 7.88(m, 1H), 8.39(m, 1H), 9.05(s, 1H), 10.87 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值486.2；實測值487.2；Rt=1.252min。LCMS (ESI): [M] + m/z: calculated 486.2; found 487.2; Rt=1.252 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2-羥基螺[3.3]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物711 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(2-hydroxyspiro[3.3]hept-6-yl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide ( compound 711 )

向N -[5-[[2-[(2S,5R )-2-(2-羥基螺[3.3]庚-6-基)-5-甲基-1-哌啶基]-2-側 氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(500mg，1.03mmol)於DCM(15mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(374.64mg，10.28mmol，468.30μL)且在25℃下將反應混合物攪拌2h。蒸發溶劑，以得到粗產物(550mg)，其藉由反相HPLC(30-30-65% 0-1-6min H2 O/MeOH/0.1% NH3 ，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量386，管柱：YMC Triart C18 100x20mm，5um)進行純化，以得到呈單一非鏡像異構物之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(2-羥基螺[3.3]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(25mg，64.69μmol，6.30%產率)及呈非鏡像異構物之混合物之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(2-羥基螺[3.3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(60mg，155.24μmol，15.11%產率)。將所有量之產物(85mg)提交用於掌性拆分。To N- [5-[[2-[( 2S,5R )-2-(2-hydroxyspiro[3.3]hept-6-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (500 mg, 1.03 mmol) in DCM (15 mL) was added to a stirred solution in dioxane 4.0 M hydrogen chloride solution (374.64 mg, 10.28 mmol, 468.30 μL) and the reaction mixture was stirred at 25 °C for 2 h. The solvent was evaporated to give the crude product (550 mg), which was purified by reverse phase HPLC (30-30-65% 0-1-6 min H2O /MeOH/0.1% NH3 , flow rate: 30 ml/min (loading pump 4 ml/min) min methanol), target mass 386, column: YMC Triart C18 100x20mm, 5um) was purified to give N- (6-amino-5-methyl-3-pyridyl)- 2-[( 2R,5S )-2-(2-hydroxyspiro[3.3]hept-6-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (25 mg, 64.69 μmol, 6.30% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(2- Hydroxyspiro[ 3.3 ]hept-6-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (60 mg, 155.24 μmol, 15.11% yield). The entire amount of product (85 mg) was submitted for chiral resolution.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.89(m,3H),1.26(m,2H),1.73(m,7H),1.92(m,3H),2.01(m,3H),2.22(m,1H),2.76(m,2H),3.95(m,3H),4.79(m,1H),5.58(m,2H),7.44(m,1H),7.98(m,1H),10.28(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.89(m, 3H), 1.26(m, 2H), 1.73(m, 7H), 1.92(m, 3H), 2.01(m, 3H), 2.22(m, 1H), 2.76(m, 2H), 3.95(m, 3H), 4.79(m, 1H), 5.58(m, 2H), 7.44(m, 1H), 7.98(m, 1H), 10.28 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.788min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.788 min.

步驟3：掌性分離(化合物768 、化合物769 、化合物766 及化合物767 )Step 3: Chiral separation ( Compound 768 , Compound 769 , Compound 766 and Compound 767 )

將外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(2-羥基螺[3.3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(85mg，219.93μmol)提交用於掌性拆分，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(2-羥基螺[3.3]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(6.4mg，16.56μmol，7.53%產率)(保留時間=47.305min)；N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(2-羥基螺[3.3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(13.6mg，35.19μmol，16.00%產率)(保留時間=21.24)；N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(2-羥基螺[3.3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(4.6mg，11.90μmol，5.41%產率)(保留時間=20.477)；N -(6- 胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(2-羥基螺[3.3]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(15.7mg，40.62μmol，18.47%產率)(保留時間=34.600)。化合物767 於分析條件下(管柱：IC，以己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為47.30min，化合物766 之保留時間為20.48min，化合物769 之保留時間為21.24min且化合物768 之保留時間為34.60min。Racemic N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(2-hydroxyspiro[ 3.3 ]hept-6-yl)-5 -Methyl-1-piperidinyl]-2-oxyacetamide (85 mg, 219.93 μmol) was submitted for chiral resolution to give N- (6-amino-5-methyl-3- Pyridyl)-2-[( 2S,5R )-2-(2-hydroxyspiro[3.3]hept-6-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (6.4 mg, 16.56 μmol, 7.53% yield) (retention time=47.305 min); N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2- (2-Hydroxyspiro[ 3.3 ]hept-6-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (13.6 mg, 35.19 μmol, 16.00% yield) (retention time) =21.24); N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(2-hydroxyspiro[ 3.3 ]hept-6-yl)-5 -Methyl-1-piperidinyl]-2-oxyacetamide (4.6 mg, 11.90 μmol, 5.41% yield) (retention time=20.477); N- (6-amino-5-methyl) -3-Pyridinyl)-2-[( 2R,5S )-2-(2-hydroxyspiro[3.3]hept-6-yl)-5-methyl-1-piperidinyl]-2-side oxy Acetamide (15.7 mg, 40.62 μmol, 18.47% yield) (retention time = 34.600). The retention time of compound 767 under analytical conditions (column: IC, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 47.30 min, and the retention time of compound 766 was 20.48 min, The retention time of compound 769 was 21.24 min and the retention time of compound 768 was 34.60 min.

化合物767：保留時間：47.30minCompound 767: retention time: 47.30min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.84-0.94(m,3H),1.20-1.49(m,3H),1.53-1.64(m,1H),1.65-1.78(m,4H),1.79-1.83(m,1H),1.84-1.93(m,2H),1.93-1.98(m,1.5H),1.99-2.04(m,3H),2.15-2.19(m,0.5H),2.25-2.30(m,1H),2.69-2.76(m,1H),2.79-3.25(m,1H),3.61-3.75(m,0.5H),3.80-3.90(m,1H),4.27-4.42(m,0.5H),4.71-4.85(m,1H),5.50-5.64(m,2H),7.36-7.50(m,1H),7.90-8.05(m,1H),10.18-10.37(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.84-0.94(m,3H), 1.20-1.49(m,3H), 1.53-1.64(m,1H), 1.65-1.78(m,4H) ,1.79-1.83(m,1H),1.84-1.93(m,2H),1.93-1.98(m,1.5H),1.99-2.04(m,3H),2.15-2.19(m,0.5H),2.25- 2.30(m, 1H), 2.69-2.76(m, 1H), 2.79-3.25(m, 1H), 3.61-3.75(m, 0.5H), 3.80-3.90(m, 1H), 4.27-4.42(m, 0.5H), 4.71-4.85(m, 1H), 5.50-5.64(m, 2H), 7.36-7.50(m, 1H), 7.90-8.05(m, 1H), 10.18-10.37(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.835min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.835 min.

化合物766：保留時間：20.48minCompound 766: retention time: 20.48min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.86-0.92(m,3H),1.20-1.30(m,2H),1.45-1.62(m,2H),1.64-1.78(m,4H),1.78-1.92(m,3H),1.93-1.98(m,1.5H),1.99-2.03(m,3H),2.11-2.21(m,0.5H),2.23-2.31(m,1H),2.66-2.79(m,1H),2.79-3.24(m,1H),3.65-3.71(m,0.5H),3.79-3.89(m,1H),4.32-4.38(m,1H),4.75-4.82(m,0.5H),5.53-5.64(m,2H),7.38-7.48(m,1H),7.92-8.01(m,1H),10.19-10.37(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.86-0.92(m,3H), 1.20-1.30(m,2H), 1.45-1.62(m,2H), 1.64-1.78(m,4H) ,1.78-1.92(m,3H),1.93-1.98(m,1.5H),1.99-2.03(m,3H),2.11-2.21(m,0.5H),2.23-2.31(m,1H),2.66- 2.79(m, 1H), 2.79-3.24(m, 1H), 3.65-3.71(m, 0.5H), 3.79-3.89(m, 1H), 4.32-4.38(m, 1H), 4.75-4.82(m, 0.5H), 5.53-5.64 (m, 2H), 7.38-7.48 (m, 1H), 7.92-8.01 (m, 1H), 10.19-10.37 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.837min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.837 min.

化合物769：保留時間：21.24minCompound 769: retention time: 21.24min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.83-0.94(m,3H),1.20-1.30(m,2H),1.44-1.62(m,2H),1.63-1.76(m,4H),1.78-1.93(m,3H),1.93-1.98(m,1H),2.00-2.02 (m,3H),2.02-2.15(m,1H),2.24-2.34(m,1H),2.68-2.76(m,1H),2.77-3.25(m,1H),3.66-3.73(m,0.5H),3.87-3.94(m,1H),4.31-4.38(m,0.5H),4.74-4.83(m,1H),5.50-5.62(m,2H),7.39-7.47(m,1H),7.93-8.02(m,1H),10.20-10.35(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.83-0.94(m,3H), 1.20-1.30(m,2H), 1.44-1.62(m,2H), 1.63-1.76(m,4H) ,1.78-1.93(m,3H),1.93-1.98(m,1H),2.00-2.02(m,3H),2.02-2.15(m,1H),2.24-2.34(m,1H),2.68-2.76( m,1H), 2.77-3.25(m,1H), 3.66-3.73(m,0.5H), 3.87-3.94(m,1H), 4.31-4.38(m,0.5H), 4.74-4.83(m,1H) ), 5.50-5.62(m, 2H), 7.39-7.47(m, 1H), 7.93-8.02(m, 1H), 10.20-10.35(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=2.066min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=2.066 min.

化合物768：保留時間：34.60minCompound 768: retention time: 34.60min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.86-0.93(m,3H),1.19-1.31(m,2H),1.45-1.62(m,2H),1.64-1.76(m,4H),1.78-1.92(m,3H),1.93-1.99(m,1H),2.00-2.02(m,3H),2.03-2.14(m,1H),2.25-2.33(m,1H),2.66-2.77(m,1H),2.77-3.24(m,1H),3.67-3.73(m,0.5H),3.86-3.94(m,1H),4.31-4.42(m,0.5H),4.74-4.84(m,1H),5.52-5.63(m,2H),7.39-7.49(m,1H),7.93-8.03(m,1H),10.19-10.39(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.86-0.93(m,3H), 1.19-1.31(m,2H), 1.45-1.62(m,2H), 1.64-1.76(m,4H) ,1.78-1.92(m,3H),1.93-1.99(m,1H),2.00-2.02(m,3H),2.03-2.14(m,1H),2.25-2.33(m,1H),2.66-2.77( m,1H), 2.77-3.24(m,1H), 3.67-3.73(m,0.5H), 3.86-3.94(m,1H), 4.31-4.42(m,0.5H), 4.74-4.84(m,1H) ), 5.52-5.63(m, 2H), 7.39-7.49(m, 1H), 7.93-8.03(m, 1H), 10.19-10.39(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=2.078min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=2.078 min.

N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(5-氯吡啶-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1025)之合成 N- (6-amino-5-methylpyridin-3-yl)-2-(2-(5-chloropyridin-3-yl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 1025)

Figure 110128222-A0202-12-1609-462
Figure 110128222-A0202-12-1609-462

步驟1：外消旋-(5-(2-((2R,5S)-2-(5-氯吡啶-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-2-(5-chloropyridin-3-yl)-5-methylpiperidin-1-yl)-2-pendoxyl Synthesis of acetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

在輕微加熱下，將3-氯-5-[(2R,5S )-5-甲基-2-哌啶基]吡啶(0.3g，1.42mmol)及2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(358.03mg，1.21mmol，HCl)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(649.65mg，1.71mmol)。反應完成(藉由反應混合物之LCMS 推測)之後，藉由HPLC(42% 0.5-6.5min水-MeCN；流速30ml/min(42% 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min MeCN)；目標質量487；管柱SunFireC18 100x19mm 5um(R))純化混合物，以得到呈純度不同之2種級分之N -[5-[[2-[(2R,5S )-2-(5-氯-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(290mg，594.29μmol，41.74%產率)。3-Chloro-5-[( 2R,5S )-5-methyl-2-piperidinyl]pyridine (0.3 g, 1.42 mmol) and 2-[[6-( tertiary butoxy ( 358.03 mg, 1.21 mmol, HCl) was dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (649.65 mg, 1.71 mmol) was added in small batches. After completion of the reaction (presumed by LCMS of the reaction mixture), flow rate 30 ml/min (42% 0.5-6.5 min water-MeCN) by HPLC (42% 0.5-6.5 min water-MeCN; flow rate 30 ml/min (load pump 4 ml /min MeCN); target mass 487; column SunFire C18 100x19mm 5um (R)) purify the mixture to obtain N- [5-[[2-[( 2R,5S )-2- in 2 fractions of different purity (5-Chloro-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid 3rd Butyl ester (290 mg, 594.29 [mu]mol, 41.74% yield).

LCMS(ESI)：[M]+ m/z：計算值487.2；實測值488.2；Rt=3.236min。LCMS (ESI): [M] + m/z: calculated 487.2; found 488.2; Rt=3.236 min.

步驟2：N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(5-氯吡啶-3-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1025 )之合成Step 2: N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(5-chloropyridin-3-yl)-5-methylpiperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 1025 )

將N -[5-[[2-[(2R,5S )-2-(5-氯-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(99mg，202.88μmol)溶解於二噁烷(4mL)及H2 O(0.5mL)中。將所獲得之溶液在100℃下攪拌48h；反應完成之後，使混合物經歷HPLC(20-30% 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min MeCN)；目標質量387；管柱SunFire 100x19mm 5um(R))，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(5-氯-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(21mg，54.14μmol，26.69%產率)及3%相應順式異構物雜質。 N- [5-[[2-[( 2R,5S )-2-(5-chloro-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (99 mg, 202.88 [mu]mol) was dissolved in dioxane (4 mL) and H2O (0.5 mL). The obtained solution was stirred at 100°C for 48h; after completion of the reaction, the mixture was subjected to HPLC (20-30% 0.5-6.5min water-MeCN; flow rate 30ml/min (loading pump 4ml/min MeCN); target mass 387; Column SunFire 100x19mm 5um(R)) to give N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R,5S )-2-(5-chloro-3-pyridine (21 mg, 54.14 μmol, 26.69% yield) and 3% of the corresponding cis isomer impurity.

化合物1025： LCMS(ESI)：[M]+ m/z：計算值387.2；實測值388.2；Rt=1.898min。 Compound 1025: LCMS (ESI): [M] + m/z: calcd 387.2; found 388.2; Rt=1.898 min.

實例353. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-氟-3-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物555)之合成Example 353. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(4-fluoro-3-hydroxyphenyl)-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetamide (Compound 555)

Figure 110128222-A0202-12-1610-463
Figure 110128222-A0202-12-1610-463

在25℃下，向2-氟-5-[(2R,5S)-5-甲基-2-哌啶基]苯酚(550mg，1.90mmol，HBr)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸 (559.70mg，1.90mmol)及三乙胺(1.92g，18.95mmol，2.64mL)於DMF(20mL)中之經攪拌之溶液中小批量添加HATU(1.44g，3.79mmol)。將所得反應混合物在25℃下攪拌16h，然後在真空中濃縮至大約5ml且提交至反相HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um，流動相：0-5min 25-80%水-甲醇(NH3 0.1%)，流速：30ml/min)，以得到經Boc保護之醯胺之3種級分：75mg，藉由LCMS為91%純度(第1級分)；68mg，藉由LCMS為95.66%純度(第2級分)；及70mg，藉由LCMS為93.86%純度(第3級分)。將經Boc保護之醯胺之第二級分(68mg)溶解於1,4-二噁烷(2mL)及水(2.5mL)之混合物中。將所得混合物在95℃下攪拌12h，然後冷卻且提交至反相HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um，流動相：20-40% 1-6min水-甲醇(NH3 0.1%)，流速：30ml/min)，以得到25mg產物(藉由LCMS為93.69%純度)，其藉由反相HPLC(管柱：SunFireC18 100*19mm 5um，流動相：15-45% 1-6min水-乙腈，流速：30ml/min)進行再次再純化，以得到呈白色固體之化合物555 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-氟-3-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18mg，46.58μmol，2.46%產率)。To 2-fluoro-5-[(2R,5S)-5-methyl-2-piperidinyl]phenol (550 mg, 1.90 mmol, HBr), 2-[[6-(tert-butylene) at 25 °C Oxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (559.70 mg, 1.90 mmol) and triethylamine (1.92 g, 18.95 mmol, 2.64 mL) in DMF To the stirred solution in (20 mL) HATU (1.44 g, 3.79 mmol) was added in small portions. The resulting reaction mixture was stirred at 25°C for 16h, then concentrated in vacuo to approximately 5ml and submitted to reverse phase HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um, mobile phase: 0-5min 25- 80% water-methanol ( NH3 0.1%), flow rate: 30 ml/min) to give 3 fractions of Boc-protected amide: 75 mg, 91% pure by LCMS (fraction 1); 68 mg , 95.66% pure by LCMS (fraction 2); and 70 mg, 93.86% pure by LCMS (fraction 3). The second fraction of the Boc-protected amide (68 mg) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (2.5 mL). The resulting mixture was stirred at 95°C for 12h, then cooled and submitted to reverse phase HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um, mobile phase: 20-40% 1-6 min water-methanol (NH 3 0.1%), flow rate: 30 ml/min) to give 25 mg of product (93.69% purity by LCMS) by reverse phase HPLC (column: SunFire C18 100*19mm 5um, mobile phase: 15-45% 1 -6min water-acetonitrile, flow rate: 30ml/min) was repurified again to give compound 555 as a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2R, 5S)-2-(4-Fluoro-3-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (18 mg, 46.58 μmol, 2.46% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.95-1.05(m,3H),1.24-1.35(m,1H),1.62-1.71(m,1H),1.80-1.91(m,1H),1.92-2.05(m,4H),2.05-2.13(m,1H),2.69-3.23(m,1H),3.43-4.06(m,1H),5.01-5.51(m,1H),5.55-5.69(m,2H),6.62-6.78(m,1H),6.80-6.96(m,1H),7.03-7.15(m,1H),7.40-7.50(m,1H),7.93-8.03(m,1H),9.57-10.06(m,1H),10.24-10.70(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.95-1.05(m,3H), 1.24-1.35(m,1H), 1.62-1.71(m,1H), 1.80-1.91(m,1H), 1.92- 2.05(m, 4H), 2.05-2.13(m, 1H), 2.69-3.23(m, 1H), 3.43-4.06(m, 1H), 5.01-5.51(m, 1H), 5.55-5.69(m, 2H ),6.62-6.78(m,1H),6.80-6.96(m,1H),7.03-7.15(m,1H),7.40-7.50(m,1H),7.93-8.03(m,1H),9.57-10.06 (m, 1H), 10.24-10.70 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值386.4；實測值387.2；Rt=1.948min。LCMS (ESI): [M+H] + m/z: calculated 386.4; found 387.2; Rt=1.948 min.

實例354. 外消旋N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物643)、rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(4-(甲基磺醯基)苯基)哌啶Example 354. Racemic N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(4-methylsulfonylbenzene yl)-1-piperidinyl]-2-oxoacetamide (Compound 643), rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2R, 5S)-5-methyl-2-(4-(methylsulfonyl)phenyl)piperidine -1-基)-2-側氧基乙醯胺(化合物976)及rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2S,5R)-5-甲基-2-(4-(甲基磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物938)之合成-1-yl)-2-oxyacetamide (compound 976) and rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2S,5R)-5 - Synthesis of methyl-2-(4-(methylsulfonyl)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 938)

Figure 110128222-A0202-12-1612-464
Figure 110128222-A0202-12-1612-464

步驟1：外消旋N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物643)之合成Step 1: Racemic N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(4-methylsulfonylbenzene) yl)-1-piperidinyl]-2-oxoacetamide (compound 643)

在25℃下，在0.5h內，向(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)哌啶(250mg，986.74μmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(291.37mg，986.74μmol)及三乙胺(998.48mg，9.87mmol，1.38mL)於DMF(5mL)中之正攪拌溶液中小批量添加HATU(412.71mg，1.09mmol)。將所得反應混合物在25℃下攪拌18h。在真空中濃縮反應混合物，將殘餘物溶解於二氯甲烷(10mL)中，且一次性添加於二噁烷中之4.0M氯化氫溶液(15.75g，60.04mmol，15mL，13.9%純度)。將所得混合物在25℃下攪拌3h，然後在真空中濃縮。藉由反相HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um，流動相：0-5min 20-70%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))純化殘餘物，以得到呈白色固體之化合物643 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-甲基磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(143 mg，332.16μmol，33.66%產率)。To (2R,5S)-5-methyl-2-(4-methylsulfonylphenyl)piperidine (250 mg, 986.74 μmol), 2-[[6- (Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (291.37 mg, 986.74 μmol) and triethylamine (998.48 mg, 9.87 mmol, 1.38 mL) to a stirring solution in DMF (5 mL) was added HATU (412.71 mg, 1.09 mmol) in small portions. The resulting reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in dichloromethane (10 mL), and a 4.0 M solution of hydrogen chloride in dioxane (15.75 g, 60.04 mmol, 15 mL, 13.9% purity) was added in one portion. The resulting mixture was stirred at 25 °C for 3 h, then concentrated in vacuo. By reverse phase HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um, mobile phase: 0-5min 20-70% water-methanol ( NH3 0.1%), flow rate 30ml/min (loading pump 4ml) /min methanol ( NH3 0.1%)), the residue was purified to give compound 643 as a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)- 5-Methyl-2-(4-methylsulfonylphenyl)-1-piperidinyl]-2-oxyacetamide (143 mg, 332.16 μmol, 33.66% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.34(m,1H),1.60(m,1H),1.89(m,1H),2.01(m,4H),2.23(m,2H),3.20(m,3H),3.68(m,1H),5.62(m,3H),7.46(m,1H),7.59(m,2H),7.95(m,3H),10.51(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.34(m, 1H), 1.60(m, 1H), 1.89(m, 1H), 2.01(m, 4H), 2.23(m, 2H), 3.20(m, 3H), 3.68(m, 1H), 5.62(m, 3H), 7.46(m, 1H), 7.59(m, 2H), 7.95(m, 3H), 10.51 (m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值430.2；實測值431.2；Rt=1.827min。LCMS (ESI): [M+H] + m/z: calculated 430.2; found 431.2; Rt=1.827 min.

步驟2：rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(4-(甲基磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物976 )及rel-N-(6-胺基-5-甲基吡啶-3-基)-2-((2S,5R)-5-甲基-2-(4-(甲基磺醯基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物938 )之合成Step 2: rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(4-(methylsulfonyl) Phenyl)piperidin-1-yl)-2-oxoacetamide ( compound 976 ) and rel-N-(6-amino-5-methylpyridin-3-yl)-2-((2S Synthesis of ,5R)-5-methyl-2-(4-(methylsulfonyl)phenyl)piperidin-1-yl)-2-oxyacetamide ( compound 938 )

在以下條件下分離鏡像異構物：管柱：Chiralpak IB(250 * 30mm，5mkm)；流動相：CO2-MeOH，60-40；流速：90mL/min；管柱溫度：40℃；波長：215nm。保留時間(化合物938 )=6.53min；保留時間(化合物643 )=10.14minEnantiomers were separated under the following conditions: Column: Chiralpak IB (250*30mm, 5mkm); Mobile Phase: CO2-MeOH, 60-40; Flow Rate: 90mL/min; Column Temperature: 40°C; Wavelength: 215nm . Retention time ( compound 938 )=6.53min; retention time ( compound 643 )=10.14min

在以下條件下另外自順式雜質純化化合物643 ：管柱：Chiralcel OJ-H(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，50-25-25；流速：10mL/min；管柱溫度：20℃；波長：205nm。保留時間(異構物A)=36.22min；保留時間(異構物B)=38.61min，以得到呈橙色固體之化合物976 (47.78mg，110.98μmol，41.99%產率)(RT(Chiralpak IB(250*4.6，5mkm)，己烷-IPA-MeOH，40-30-30，0.6ml/min)=21.522min)及呈黃色固體之化合物938 (47.82mg，111.08μmol，42.02%產率)(RT(Chiralpak IB(250*4.6，5mkm)，己烷-IPA-MeOH，40-30-30，0.6ml/min)=13.780min)。 Compound 643 was additionally purified from the cis impurity under the following conditions: Column: Chiralcel OJ-H (250*20mm, 5mkm); Mobile Phase: Hexane-IPA-MeOH, 50-25-25; Flow Rate: 10 mL/min; Column temperature: 20°C; wavelength: 205nm. Retention time (Isomer A) = 36.22 min; Retention time (Isomer B) = 38.61 min to give compound 976 (47.78 mg, 110.98 μmol, 41.99% yield) as an orange solid (RT (Chiralpak IB ( 250*4.6, 5mkm), hexane-IPA-MeOH, 40-30-30, 0.6ml/min)=21.522min) and compound 938 (47.82mg, 111.08μmol, 42.02% yield) as a yellow solid (RT) (Chiralpak IB (250*4.6, 5mkm), Hexane-IPA-MeOH, 40-30-30, 0.6ml/min)=13.780min).

化合物976： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.33(m,1H),1.62(m,1H),1.88(m,1H),1.99(m,3H),2.15(m,2H),3.19(m,4H),3.76(dd,1H),5.60(m,3H),7.45(m,1H),7.61(m,2H),7.91(m,2H),7.98(m,1H),10.51(s,1H)。 Compound 976: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.00 (m, 3H), 1.33 (m, 1H), 1.62 (m, 1H), 1.88 (m, 1H), 1.99 (m, 3H), 2.15(m, 2H), 3.19(m, 4H), 3.76(dd, 1H), 5.60(m, 3H), 7.45(m, 1H), 7.61(m, 2H), 7.91(m, 2H) ), 7.98(m, 1H), 10.51(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值430.2；實測值431.4；Rt=1.765min。LCMS (ESI): [M+H] + m/z: calculated 430.2; found 431.4; Rt=1.765 min.

RT(己烷-IPA-MeOH，40-30-30，0.6ml/min)=21.5222min。RT (Hexane-IPA-MeOH, 40-30-30, 0.6 ml/min) = 21.5222 min.

化合物938： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.33(m,1H),1.61(m,1H),1.87(m,1H),1.99(m,3H),2.15(m,2H),3.19(m,4H),3.76(dd,1H),5.60(m,3H),7.45(m,1H),7.58(dd,2H),7.91(m,2H),7.98(m,1H),10.51(m,1H)。 Compound 938: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.00 (m, 3H), 1.33 (m, 1H), 1.61 (m, 1H), 1.87 (m, 1H), 1.99 (m, 3H), 2.15(m, 2H), 3.19(m, 4H), 3.76(dd, 1H), 5.60(m, 3H), 7.45(m, 1H), 7.58(dd, 2H), 7.91(m, 2H ), 7.98 (m, 1H), 10.51 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值430.2；實測值431.4；Rt=1.750min。LCMS (ESI): [M+H] + m/z: calculated 430.2; found 431.4; Rt=1.750 min.

RT(己烷-IPA-MeOH，40-30-30，0.6ml/min)=13.7802min。RT (Hexane-IPA-MeOH, 40-30-30, 0.6 ml/min) = 13.7802 min.

實例355. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物662)之合成Example 355. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(4-aminosulfonylphenyl)-1 Synthesis of -piperidinyl]-2-oxoacetamide (compound 662)

Figure 110128222-A0202-12-1614-465
Figure 110128222-A0202-12-1614-465

步驟1：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(4-sulfamonophenyl)-1-piperidinyl]-2 -Synthesis of tert-butyl oxyacetyl]amino]-2-pyridyl]carbamate

向4-(5-甲基-2-哌啶基)苯磺醯胺(350mg，1.20mmol，HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(355.39mg，1.20mmol)及三乙胺(365.36mg，3.61mmol，503.25μL)於二甲基甲醯胺(4mL)中之經攪拌之混合物中添加HATU(503.38mg，1.32mmol)。將所得反應混合物在20℃下攪拌5h。然後，使其經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；40-55% 0-5min 0.1% NH3 -甲醇，流速：30ml/min)，得到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(97mg，182.46μmol，15.16%產率)。To 4-(5-methyl-2-piperidinyl)benzenesulfonamide (350 mg, 1.20 mmol, HCl), 2-[[6-(tertiary butoxycarbonylamino)-5-methyl- Stirred 3-pyridyl]amino]-2-side oxyacetic acid (355.39 mg, 1.20 mmol) and triethylamine (365.36 mg, 3.61 mmol, 503.25 μL) in dimethylformamide (4 mL) To the mixture was added HATU (503.38 mg, 1.32 mmol). The resulting reaction mixture was stirred at 20 °C for 5 h. Then, it was subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; 40-55% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min) to give N-[3-methyl-5-[ [2-[(2S,5R)-5-Methyl-2-(4-Sulfamonophenyl)-1-piperidinyl]-2-oxyacetyl]amino]-2- 3-butyl pyridyl]carbamate (97 mg, 182.46 μmol, 15.16% yield).

在下一個步驟前將兩種級分合併。The two fractions were combined before the next step.

LCMS(ESI)：[M+H]+ m/z：計算值531.2；實測值532.2；Rt=2.860min。LCMS (ESI): [M+H] + m/z: calculated 531.2; found 532.2; Rt=2.860 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物662 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(4-aminosulfonylphenyl)-1 Synthesis of -Piperidinyl]-2-Pendant Oxyacetamide ( Compound 662 )

將水(1.00g，55.51mmol，1mL)添加到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(97mg，182.46μmol)於二噁烷(2mL)中之溶液中。將所得混合物在95℃下攪拌36h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；0-5min 5-55%水-MeOH(NH3 0.1%)，流速30ml/min)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-胺磺醯基苯基)-1-哌啶基]-2-側氧基乙醯胺(27mg，62.57μmol，34.29%產率)。Water (1.00 g, 55.51 mmol, 1 mL) was added to N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(4-aminosulfonylphenyl) )-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (97 mg, 182.46 μmol) in dioxane (2 mL) . The resulting mixture was stirred at 95 °C for 36 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 0-5min 5-55% water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N-(6- Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(4-sulfamonophenyl)-1-piperidinyl]-2- Pendant oxyacetamide (27 mg, 62.57 μmol, 34.29% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.62(m,1H),1.86(m,1H),1.99(m,4H),2.22(m,1H),2.96(m,1H),3.67(m,1H),5.47(m,3H),7.32(m,2H),7.50(m,3H),7.80(m,2H),7.98(m,1H),10.50(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.32(m, 1H), 1.62(m, 1H), 1.86(m, 1H), 1.99(m, 4H), 2.22(m, 1H), 2.96(m, 1H), 3.67(m, 1H), 5.47(m, 3H), 7.32(m, 2H), 7.50(m, 3H), 7.80(m, 2H), 7.98 (m,1H),10.50(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值431.2；實測值432.2；Rt=1.645min。LCMS (ESI): [M+H] + m/z: calculated 431.2; found 432.2; Rt=1.645 min.

實例356. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物668)之合成Example 356. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl)benzene Synthesis of yl]-1-piperidinyl]-2-oxoacetamide (Compound 668)

Figure 110128222-A0202-12-1615-466
Figure 110128222-A0202-12-1615-466

步驟1：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidine Synthesis of tert-butyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamate

向N-甲基-4-(5-甲基-2-哌啶基)苯磺醯胺(370mg，1.38mmol，HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(407.11mg，1.38mmol)及三乙胺(418.52mg，4.14mmol，576.48μL)於二甲基甲醯胺(4mL) 中之經攪拌之混合物中添加HATU(576.63mg，1.52mmol)。將所得反應混合物在20℃下攪拌5h。然後，使其經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；40-70% 0-5min 0.1% NH3 -甲醇，流速：30ml/min)，得到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(140mg，256.57μmol，18.61%產率)。To N-methyl-4-(5-methyl-2-piperidinyl)benzenesulfonamide (370 mg, 1.38 mmol, HCl), 2-[[6-(tert-butoxycarbonylamino)- 5-Methyl-3-pyridyl]amino]-2-oxoacetic acid (407.11 mg, 1.38 mmol) and triethylamine (418.52 mg, 4.14 mmol, 576.48 μL) in dimethylformamide (4 mL) ) to the stirred mixture was added HATU (576.63 mg, 1.52 mmol). The resulting reaction mixture was stirred at 20 °C for 5 h. Then, it was subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; 40-70% 0-5min 0.1% NH3 -methanol, flow rate: 30ml/min) to give N-[3-methyl-5-[ [2-[(2S,5R)-5-Methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino ]- tert-butyl 2-pyridyl]carbamate (140 mg, 256.57 μmol, 18.61% yield).

LCMS(ESI)：[M+H]+ m/z：計算值545.3；實測值546.2；Rt=3.010min。LCMS (ESI): [M+H] + m/z: calculated 545.3; found 546.2; Rt=3.010 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物668 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl)benzene Synthesis of yl]-1-piperidinyl]-2-oxoacetamide ( compound 668 )

將水(1.00g，55.49mmol，1mL)添加到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(140mg，256.57μmol)於二噁烷(2mL)中之溶液中。將所得混合物在95℃下攪拌18h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mm，5um；0-5min 10-60%水-MeOH(NH3 0.1%)，流速30ml/min)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(甲基胺磺醯基)苯基]-1-哌啶基]-2-側氧基乙醯胺(85mg，190.78μmol，74.36%產率)。Water (1.00 g, 55.49 mmol, 1 mL) was added to N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl yl)phenyl]-1-piperidinyl]-2-oxoacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (140 mg, 256.57 μmol) in dioxane (2 mL) in the solution. The resulting mixture was stirred at 95 °C for 18 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mm, 5um; 0-5min 10-60% water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N-(6- Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(methylaminosulfonyl)phenyl]-1-piperidinyl ]-2-Oxyacetamide (85 mg, 190.78 μmol, 74.36% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.33(m,1H),1.62(m,1H),1.87(m,1H),1.99(m,3H),2.14(m,2H),2.39(m,3H),2.97(m,1H),3.76(m,1H),5.60(m,3H),7.43(m,1H),7.50(m,2H),7.56(m,1H),7.76(m,2H),7.98(m,1H),10.49(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 1.00 (m, 3H), 1.33 (m, 1H), 1.62 (m, 1H), 1.87 (m, 1H), 1.99 (m, 3H), 2.14(m, 2H), 2.39(m, 3H), 2.97(m, 1H), 3.76(m, 1H), 5.60(m, 3H), 7.43(m, 1H), 7.50(m, 2H), 7.56 (m, 1H), 7.76 (m, 2H), 7.98 (m, 1H), 10.49 (m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值445.2；實測值446.2；Rt=1.267min。LCMS (ESI): [M+H] + m/z: calculated 445.2; found 446.2; Rt=1.267 min.

實例357. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-噻唑并[5,4-b]吡啶-6-基-1-哌啶基]-2-側氧基乙醯胺(化合物685)之合成Example 357. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-thiazolo[5,4-b]pyridine-6 Synthesis of -yl-1-piperidinyl]-2-oxoacetamide (Compound 685)

Figure 110128222-A0202-12-1617-467
Figure 110128222-A0202-12-1617-467

步驟1：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-噻唑并[5,4-b]吡啶-6-基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-thiazolo[5,4-b]pyridin-6-yl-1-piperidine Synthesis of tert-butyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamate

在劇烈攪拌之情況下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(316.38mg，1.07mmol)、6-[(2S,5R)-5-甲基-2-哌啶基]噻唑并[5,4-b]吡啶(250.00mg，1.07mmol)、HATU(448.13mg，1.18mmol)及TEA(119.26mg，1.18mmol，164.27μL)混合於DMSO(2mL)中。將反應混合物用水處理且將所需產物用50ml EA萃取，經Na2 SO4 乾燥且在真空中濃縮，以得到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-噻唑并[5,4-b]吡啶-6-基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.45g，粗品)。With vigorous stirring, 2-[[6-(3-butoxycarbonylamino)-5-methyl-3-pyridinyl]amino]-2-pendoxoacetic acid (316.38 mg, 1.07 mmol), 6-[(2S,5R)-5-methyl-2-piperidinyl]thiazolo[5,4-b]pyridine (250.00 mg, 1.07 mmol), HATU (448.13 mg, 1.18 mmol) and TEA (119.26 mg, 1.18 mmol, 164.27 μL) was mixed in DMSO (2 mL). The reaction mixture was treated with water and the desired product was extracted with 50 ml EA, dried over Na 2 SO 4 and concentrated in vacuo to give N-[3-methyl-5-[[2-[(2S,5R)- 5-Methyl-2-thiazolo[5,4-b]pyridin-6-yl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Tributyl ester (0.45 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值510.2；實測值511.0；Rt=1.340min。LCMS (ESI): [M+H] + m/z: calculated 510.2; found 511.0; Rt=1.340 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-噻唑并[5,4-b]吡啶-6-基-1-哌啶基]-2-側氧基乙醯胺(化合物685 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-thiazolo[5,4-b]pyridine-6 Synthesis of -yl-1-piperidinyl]-2-oxoacetamide ( Compound 685 )

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-噻唑并[5,4-b]吡啶-6-基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(200.00mg，391.69μmol)溶解於二噁烷(3mL)中且添加H2 O(3mL)。在劇烈攪拌之情況下，將反應混合物在90℃下攪拌64h。將溶液在真空中濃縮，再溶解於4ml甲醇中且經歷HPLC。N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-thiazolo[5,4-b]pyridin-6-yl-1-piperidinyl] 3-Butyl-2-oxyacetoxy]amino]-2-pyridyl]carbamate (200.00 mg, 391.69 μmol) was dissolved in dioxane (3 mL) and H2O (3 mL) was added. The reaction mixture was stirred at 90 °C for 64 h with vigorous stirring. The solution was concentrated in vacuo, redissolved in 4 ml methanol and subjected to HPLC.

HPLC資料：2-10min 10-60%水/R1(裝載泵4ml R1)管柱：TRIART 100*20 5微米HPLC data: 2-10min 10-60% water/R1 (loading pump 4ml R1) Column: TRIART 100*20 5 microns

獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-噻唑并[5,4-b]吡啶-6-基-1-哌啶基]-2-側氧基乙醯胺(0.051g，124.24μmol，31.72%產率)。Obtained N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-thiazolo[5,4-b]pyridin-6-yl -1-Piperidinyl]-2-oxoacetamide (0.051 g, 124.24 μmol, 31.72% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.37(m,1H),1.72(m,1H),1.87(m,1H),1.99(m,3H),2.15(m,1H),2.31(m,1H),3.33(m,1H),3.75(m,1H),5.64(m,3H),7.44(m,1H),8.01(m,1H),8.39(m,1H),8.66(m,1H),9.56(m,1H),10.54(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.02(m, 3H), 1.37(m, 1H), 1.72(m, 1H), 1.87(m, 1H), 1.99(m, 3H), 2.15(m, 1H), 2.31(m, 1H), 3.33(m, 1H), 3.75(m, 1H), 5.64(m, 3H), 7.44(m, 1H), 8.01(m, 1H), 8.39 (m, 1H), 8.66 (m, 1H), 9.56 (m, 1H), 10.54 (m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值411.2；Rt=1.543min。LCMS (ESI): [M+H] + m/z: calculated 410.2; found 411.2; Rt=1.543 min.

實例358. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物871)之合成Example 358. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide (compound 871)

Figure 110128222-A0202-12-1618-468
Figure 110128222-A0202-12-1618-468

步驟1：N-[5-[[2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2- Synthesis of pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

在輕微加熱下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(287.67mg，974.21μmol)、(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基哌啶(223.33mg，974.21μmol)及dipea(377.73mg，2.92mmol，509.07μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(444.51mg，1.17mmol)。反應完成之後，藉由HPLC純化混合物，以得到N-[5-[[2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(80mg，157.94μmol，16.21%產率)2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (287.67 mg, 974.21 μmol) was added with gentle heating , (2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methylpiperidine (223.33 mg, 974.21 μmol) and dipea (377.73 mg, 2.92 mmol, 509.07 μL) were dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (444.51 mg, 1.17 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC to obtain N-[5-[[2-[(2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methyl- 1-Piperidinyl]-2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (80 mg, 157.94 μmol, 16.21% yield)

HPLC條件：(48% 0.5-6.5min水-乙腈；流速30ml/min；(裝載泵4ml/min乙腈)；目標質量506；管柱SunFireC18 100x19mm 5um(L))。HPLC conditions: (48% 0.5-6.5min water-acetonitrile; flow rate 30ml/min; (loading pump 4ml/min acetonitrile); target mass 506; column SunFire C18 100x19mm 5um(L)).

LCMS(ESI)：[M+H]+ m/z：計算值506.3；實測值507.2；Rt=3.521min。LCMS (ESI): [M+H] + m/z: calculated 506.3; found 507.2; Rt=3.521 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物871 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide ( compound 871 )

將N-[5-[[2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(80mg，157.94μmol)溶解於水(1mL)/二噁烷(1mL)之混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑及以HPLC(5-40% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量382；管柱SunFireC18 100x19mm 5um(R))之純化，產生N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-3,3-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31mg，76.28μmol，48.30%產率)N-[5-[[2-[(2S,5S)-3,3-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxygen tert-butylacetoxy]amino]-3-methyl-2-pyridinyl]carbamate (80 mg, 157.94 μmol) was dissolved in a mixture of water (1 mL)/dioxane (1 mL) and at reflux under stirring overnight. Aliquots showed complete consumption of starting material; solvent was evaporated under reduced pressure and analyzed by HPLC (5-40% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 382; Purification of column SunFire C18 100x19mm 5um(R)) to yield N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-3,3-difluoro-2- (4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (31 mg, 76.28 μmol, 48.30% yield)

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.08(m,3H),1.28-1.42(m,1H),1.57-1.70(m,1H),1.82-1.96(m,1H),2.03-2.19(m,1H),2.19-2.32(m,1H),2.70-3.24(m,1H),3.50-4.07(m,1H),5.22-5.76(m,1H),7.57-7.72(m,5H),8.08-8.19(m,1H),8.38-8.53(m,1H),8.67-8.78(m,1H),8.78-8.93(m,1H),11.29(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.08(m,3H), 1.28-1.42(m,1H), 1.57-1.70(m,1H), 1.82-1.96(m,1H), 2.03- 2.19(m,1H),2.19-2.32(m,1H),2.70-3.24(m,1H),3.50-4.07(m,1H),5.22-5.76(m,1H),7.57-7.72(m,5H ), 8.08-8.19(m, 1H), 8.38-8.53(m, 1H), 8.67-8.78(m, 1H), 8.78-8.93(m, 1H), 11.29(br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=2.294min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=2.294 min.

實例359. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物939)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3R,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物940)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3S,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物904)之合成Example 359. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,3R,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl yl-1-piperidinyl]-2-oxoacetamide (compound 939), N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,3R,5S )-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 940) and N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2R,3S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side Synthesis of Oxyacetamide (Compound 904)

Figure 110128222-A0202-12-1620-469
Figure 110128222-A0202-12-1620-469

步驟1：N-[5-[[2-[(2R,3R,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P1)、N-[5-[[2-[(2R,3S,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P2)、N-[5-[[2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P4)及N-[5-[[2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P3)之合成Step 1: N-[5-[[2-[(2R,3R,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P1), N-[5-[[2-[(2R,3S,5S)-3- Fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid Tributyl ester (P2), N-[5-[[2-[(2R,3R,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl] -2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P4) and N-[5-[[2-[(2R,3R,5R )-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl ] Synthesis of tertiary butyl carbamate (P3)

在輕微加熱下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(287.67mg，974.21μmol)、(2S,5S)-3-氟-2-(4-氟苯基)-5-甲基哌啶(205.80mg，974.21μmol)及dipea(377.73mg，2.92mmol，509.07μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(444.51mg，1.17mmol)。反應完成之後，藉由HPLC純化混合物，以得到N-[5-[[2-[(2R,3R,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲 酸第三丁酯P1(10mg，20.47μmol，2.10%產率)、N-[5-[[2-[(2R,3S,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(30mg，61.41μmol，6.30%產率)、N-[5-[[2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯P3(100mg，204.70μmol，21.01%產率)及N-[5-[[2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯P4(40mg，81.88μmol，8.40%產率)2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (287.67 mg, 974.21 μmol) was added with gentle heating , (2S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methylpiperidine (205.80 mg, 974.21 μmol) and dipea (377.73 mg, 2.92 mmol, 509.07 μL) were dissolved in DMSO ( 6mL). With vigorous stirring and occasional heating, HATU (444.51 mg, 1.17 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC to give N-[5-[[2-[(2R,3R,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1 -Piperidinyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]amine methyl tert-butyl acid P1 (10 mg, 20.47 μmol, 2.10% yield), N-[5-[[2-[(2R,3S,5S)-3-fluoro-2-(4-fluorophenyl)- 5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (30 mg, 61.41 μmol, 6.30% yield rate), N-[5-[[2-[(2R,3R,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester P3 (100 mg, 204.70 μmol, 21.01% yield) and N-[5-[[2-[( 2R,3R,5R)-3-Fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl -2-Pyridinyl]carbamic acid tert-butyl ester P4 (40 mg, 81.88 μmol, 8.40% yield)

HPLC條件：(48% 0.5-6.5min水-乙腈；流速30ml/min；(裝載泵4ml/min乙腈)；目標質量506；管柱SunFireC18 100x19mm 5um(L))HPLC conditions: (48% 0.5-6.5min water-acetonitrile; flow rate 30ml/min; (loading pump 4ml/min acetonitrile); target mass 506; column SunFireC18 100x19mm 5um (L))

P1： LCMS(ESI)：[M+H]+ m/z：計算值488.3；實測值489.4；Rt=3.580min。 P1: LCMS (ESI): [M+H] + m/z: calculated 488.3; found 489.4; Rt=3.580min.

P2： LCMS(ESI)：[M+H]+ m/z：計算值488.3；實測值489.0；Rt=3.350min。 P2: LCMS (ESI): [M+H] + m/z: calculated 488.3; found 489.0; Rt=3.350 min.

P3： LCMS(ESI)：[M+H]+ m/z：計算值488.3；實測值489.2；Rt=2.906min。 P3: LCMS (ESI): [M+H] + m/z: calculated 488.3; found 489.2; Rt=2.906 min.

P4： LCMS(ESI)：[M+H]+ m/z：計算值488.3；實測值489.4；Rt=3.379min。 P4: LCMS (ESI): [M+H] + m/z: calculated 488.3; found 489.4; Rt=3.379 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3R,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物940 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,3R,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 940 )

將N-[5-[[2-[(2R,3R,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯P1(10mg，20.47μmol)溶解於二噁烷(2mL)/H2 O(0.5mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑及以HPLC(32-36% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量388；管柱SunFireC18 100x19mm 5um(R))之純化，產生N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3R,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(5mg，12.87μmol，62.89%產率)。N-[5-[[2-[(2R,3R,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester P1 (10 mg, 20.47 μmol) was dissolved in a mixture of dioxane (2 mL)/H 2 O (0.5 mL) and Stir overnight at reflux. Aliquots showed complete consumption of starting material; solvent was evaporated under reduced pressure and HPLC (32-36% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 388; Purification on column SunFire C18 100x19mm 5um(R)) to yield N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,3R,5S)-3-fluoro-2-( 4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (5 mg, 12.87 μmol, 62.89% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.87(dd,3H),1.63(m,2H),2.00(m,4H),2.08(m,1H),2.72(m,1H),3.68(m,1H),5.03(m,1H),5.65(m,3H),7.20(m,2H), 7.46(m,2H),7.97(m,1H),10.51(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.87 (dd, 3H), 1.63 (m, 2H), 2.00 (m, 4H), 2.08 (m, 1H), 2.72 (m, 1H), 3.68(m, 1H), 5.03(m, 1H), 5.65(m, 3H), 7.20(m, 2H), 7.46(m, 2H), 7.97(m, 1H), 10.51(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.0；Rt=2.128min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.0; Rt=2.128 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3S,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物904 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,3S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxoacetamide ( compound 904 )

將N-[5-[[2-[(2R,3S,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯P2(30mg，61.41μmol)溶解於二噁烷(4mL)/H2 O(0.5mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑及以HPLC 32-36% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量388；管柱SunFireC18 100x19mm 5um(R))之純化，產生N-[5-[[2-[(2R,3S,5S)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(11mg，22.52μmol，36.67%產率)。N-[5-[[2-[(2R,3S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester P2 (30 mg, 61.41 μmol) was dissolved in a mixture of dioxane (4 mL)/H 2 O (0.5 mL) and Stir overnight at reflux. Aliquots showed complete consumption of starting material; solvent evaporated under reduced pressure and HPLC 32-36% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 388; tube Purification on column SunFire C18 100x19mm 5um(R)) to yield N-[5-[[2-[(2R,3S,5S)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1 -Piperidinyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (11 mg, 22.52 μmol, 36.67% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.05(m,3H),1.72(m,1H),1.87(m,2H),2.00(m,3H),3.01(m,1H),3.70(m,1H),5.60(m,4H),7.22(m,2H),7.43(m,3H),8.00(m,1H),10.51(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.05(m, 3H), 1.72(m, 1H), 1.87(m, 2H), 2.00(m, 3H), 3.01(m, 1H), 3.70 (m, 1H), 5.60 (m, 4H), 7.22 (m, 2H), 7.43 (m, 3H), 8.00 (m, 1H), 10.51 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=2.419min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=2.419 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物939 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,3R,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 939 )

將N-[5-[[2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P3(100mg，204.70μmol)溶解於二噁烷(2mL)/水(0.5mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑及以HPLC(32-36% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量388；管柱SunFireC18 100x19mm 5um(R))之純化，產生N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,3R,5R)-3-氟-2-(4-氟苯基)-5-甲 基-1-哌啶基]-2-側氧基乙醯胺(54mg，139.03μmol，67.92%產率)。N-[5-[[2-[(2R,3R,5R)-3-fluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P3 (100 mg, 204.70 μmol) was dissolved in a mixture of dioxane (2 mL)/water (0.5 mL) and in Stir overnight at reflux. Aliquots showed complete consumption of starting material; solvent was evaporated under reduced pressure and HPLC (32-36% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile) ; target mass 388; purification of column SunFire C18 100x19mm 5um(R)) to yield N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,3R,5R)-3- Fluoro-2-(4-fluorophenyl)-5-methyl yl-1-piperidinyl]-2-oxoacetamide (54 mg, 139.03 μmol, 67.92% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(d,3H),1.36(m,1H),2.03(m,4H),2.26(m,1H),3.53(m,1H),3.61(m,1H),5.26(m,2H),5.61(m,2H),7.18(m,2H),7.34(m,2H),7.45(s,1H),7.99(m,1H),10.37(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.02(d,3H), 1.36(m,1H), 2.03(m,4H), 2.26(m,1H), 3.53(m,1H), 3.61(m, 1H), 5.26(m, 2H), 5.61(m, 2H), 7.18(m, 2H), 7.34(m, 2H), 7.45(s, 1H), 7.99(m, 1H), 10.37 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值389.2；Rt=2.090min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 389.2; Rt=2.090 min.

實例360. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[1-(1H-吡唑-3-基)吡唑-4-基]-1-哌啶基]-2-側氧基乙醯胺(化合物793)之合成Example 360. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[1-(1H-pyrazol-3-yl ) Synthesis of pyrazol-4-yl]-1-piperidinyl]-2-side oxyacetamide (compound 793)

Figure 110128222-A0202-12-1623-470
Figure 110128222-A0202-12-1623-470

在25℃下，在0.5h時段內，將HATU(877.81mg，2.31mmol)小批量添加到(2R,5S)-5-甲基-2-[1-(1H-吡唑-3-基)吡唑-4-基]哌啶(1.1g，2.10mmol，3HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(619.74mg，2.10mmol)及三乙胺(2.12g，20.99mmol，2.93mL)於DMF(10mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後在真空中濃縮。將殘餘物溶解於二氯甲烷(10mL)且一次性添加於二噁烷中之4.0M氯化氫溶液(19.25g，73.39mmol，24.06mL，13.9%純度)。將所得混合物在25℃下攪拌3h，然後在真空中濃縮。藉由反相HPLC((管柱：YMC Triart C18 100x20mm，5um)，流動相：35-60% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30ml/min(裝載泵4ml/min甲醇)用於第1次HPLC，及35-50% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30ml/min(裝載泵4ml/min甲醇)用於第2次HPLC)純化殘餘物兩次，以得到呈白色固體之化合物793 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[1-(1H-吡唑-3-基)吡唑-4-基]-1-哌啶基]-2-側氧基乙醯胺(61mg，149.34μmol，7.12%產率)。HATU (877.81 mg, 2.31 mmol) was added in small batches to (2R,5S)-5-methyl-2-[1-(1H-pyrazol-3-yl) at 25°C over a period of 0.5h Pyrazol-4-yl]piperidine (1.1 g, 2.10 mmol, 3HCl), 2-[[6-(3-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]- In a stirred mixture of 2-pendoxoacetic acid (619.74 mg, 2.10 mmol) and triethylamine (2.12 g, 20.99 mmol, 2.93 mL) in DMF (10 mL). The resulting mixture was stirred at 25 °C for 18 h, then concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) and a 4.0 M solution of hydrogen chloride in dioxane (19.25 g, 73.39 mmol, 24.06 mL, 13.9% pure) was added in one portion. The resulting mixture was stirred at 25 °C for 3 h, then concentrated in vacuo. by reverse phase HPLC ((column: YMC Triart C18 100x20mm, 5um), mobile phase: 35-60% 0-5min H2O /MeOH/0.1% NH4OH, flow rate: 30ml/min (load pump 4ml/min methanol ) for the 1st HPLC, and 35-50% 0-5min H2O /MeOH/0.1% NH4OH, flow rate: 30ml/min (loading pump 4ml/min methanol) for the 2nd HPLC) purify the residue for two to obtain compound 793 as a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[1-(1H - Pyrazol-3-yl)pyrazol-4-yl]-1-piperidinyl]-2-oxyacetamide (61 mg, 149.34 μmol, 7.12% yield).

1 H NMR(dmso,600MHz)：δ(ppm)0.75-1.01(m,3H),1.18-1.39(m,1H),1.53-1.88(m,2H),1.89-1.98(m,1H),1.98-2.02(m,3H),2.02-2.10(m,1H),2.79-3.25(m,1H),3.36-4.00(m,1H),5.07-5.59(m,1H),5.59-5.64(m,2H),6.41-6.49(m,1H),7.42-7.53(m,1H),7.56-7.68(m,1H),7.73-7.84(m,1H),7.94-8.05(m,1H),8.09-8.20(m,1H),10.44-10.55(m,1H),12.71-12.85(m,1H) 1 H NMR (dmso, 600MHz): δ (ppm) 0.75-1.01 (m, 3H), 1.18-1.39 (m, 1H), 1.53-1.88 (m, 2H), 1.89-1.98 (m, 1H), 1.98 -2.02(m, 3H), 2.02-2.10(m, 1H), 2.79-3.25(m, 1H), 3.36-4.00(m, 1H), 5.07-5.59(m, 1H), 5.59-5.64(m, 2H), 6.41-6.49(m, 1H), 7.42-7.53(m, 1H), 7.56-7.68(m, 1H), 7.73-7.84(m, 1H), 7.94-8.05(m, 1H), 8.09- 8.20(m,1H),10.44-10.55(m,1H),12.71-12.85(m,1H)

LCMS(ESI)：[M+1]+ m/z：計算值408.2；實測值409.2；Rt=1.719min。LCMS (ESI): [M+1] + m/z: calculated 408.2; found 409.2; Rt=1.719 min.

實例361. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物969)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物941)之合成Example 361. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1H-pyrazol-4-yl)-1 -Piperidinyl]-2-oxoacetamide (Compound 969) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl Synthesis of yl-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-oxoacetamide (compound 941)

Figure 110128222-A0202-12-1624-471
Figure 110128222-A0202-12-1624-471

步驟1.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺Step 1. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)-1 -Piperidinyl]-2-oxyacetamide

在25℃下，在0.5h時段內，將HATU(456.61mg，1.20mmol)小批量添加到(2R,5S)-5-甲基-2-(1H-吡唑-4-基)哌啶(400mg，1.09mmol，2HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(370.73mg，1.26mmol)及三乙胺(883.77mg，8.73mmol，1.22mL)於DMF(10mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後在真空中濃縮。將殘餘物溶解於二氯甲烷(10mL)且一次性添加於二噁烷中之4.0M氯化氫溶液(10.50g，40.03mmol，10mL，13.9%純度)。將所得混合物在25℃下攪拌12h，然後在真空中濃縮。藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：25-55% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30ml/min(裝載泵4ml/min甲醇)純化殘餘物，以得到呈淡黃色膠狀物之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(227mg，662.98μmol，60.73%產率)，將其直接提交至製備型掌性HPLC。HATU (456.61 mg, 1.20 mmol) was added to (2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)piperidine (2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)piperidine ( 400 mg, 1.09 mmol, 2HCl), 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (370.73 mg, 1.26 mmol) and triethylamine (883.77 mg, 8.73 mmol, 1.22 mL) in a stirred mixture of DMF (10 mL). The resulting mixture was stirred at 25 °C for 18 h, then concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) and a 4.0 M solution of hydrogen chloride in dioxane (10.50 g, 40.03 mmol, 10 mL, 13.9% purity) was added in one portion. The resulting mixture was stirred at 25 °C for 12 h, then concentrated in vacuo. Purified by reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 25-55% 0-5min H2O /MeOH/0.1% NH4OH, flow rate: 30ml/min (load pump 4ml/min methanol) residue to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H- Pyrazol-4-yl)-1-piperidinyl]-2-oxoacetamide (227 mg, 662.98 μmol, 60.73% yield), which was submitted directly to preparative chiral HPLC.

LCMS(ESI)：[M+1]+ m/z：計算值342.4；實測值343.2；Rt=1.329min。LCMS (ESI): [M+1] + m/z: calculated 342.4; found 343.2; Rt=1.329 min.

步驟2.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物969 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物941 )之合成Step 2. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1H-pyrazol-4-yl)-1 -Piperidinyl]-2-oxyacetamide ( compound 969 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl Synthesis of base-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-oxoacetamide ( compound 941 )

將外消旋N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(227mg，662.98μmol)提交至製備型掌性HPLC(管柱：Chiralpak IC-II(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 60-20-20；流速：12mL/min)，以得到粗品第1級分(R.T.=27.732min，60mg)及化合物941 (第2級分)N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(54.8mg，160.05μmol，24.14%產率)(R.T.=39.160min)。藉由製備型掌性HPLC(管柱：Chiralcel OJ-H(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 80-10-10；流速：12mL/min)純化粗品第1級分(60mg)，以得到化合物969 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(42.7mg，124.71μmol，18.81%產率)(R.T.=25.846min)。The racemic N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)- 1-Piperidinyl]-2-oxyacetamide (227 mg, 662.98 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IC-II (250*20 mm, 5 mkm); mobile phase: hexane- IPA-MeOH 60-20-20; flow rate: 12 mL/min) to obtain crude product fraction 1 (RT=27.732 min, 60 mg) and compound 941 (fraction 2) N-(6-amino-5- Methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-side oxyacetyl Amine (54.8 mg, 160.05 μmol, 24.14% yield) (RT=39.160 min). Crude 1st fraction was purified by preparative chiral HPLC (column: Chiralcel OJ-H (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH 80-10-10; flow rate: 12 mL/min) (60 mg) to give compound 969 N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1H-pyrazole-4 -yl)-1-piperidinyl]-2-oxoacetamide (42.7 mg, 124.71 μmol, 18.81% yield) (RT=25.846 min).

化合物941： 1 H NMR(600MHz,DMSO-d 6 )δ 0.94-1.00(m,3H),1.29-1.39(m,1H),1.76-1.83(m,1H),1.84-1.94(m,2H),1.94-2.07(m,4H),2.72-3.24(m,1H),3.38-3.95(m,1H),4.98-5.57(m,1H),5.57-5.65(m,2H),7.22-7.80(m,3H),7.91-8.05(m,1H),10.28-10.53(m,1H),12.75(s,1H)。 Compound 941: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.94-1.00 (m, 3H), 1.29-1.39 (m, 1H), 1.76-1.83 (m, 1H), 1.84-1.94 (m, 2H) ,1.94-2.07(m,4H),2.72-3.24(m,1H),3.38-3.95(m,1H),4.98-5.57(m,1H),5.57-5.65(m,2H),7.22-7.80( m, 3H), 7.91-8.05 (m, 1H), 10.28-10.53 (m, 1H), 12.75 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值342.4；實測值343.4；Rt=1.388min。LCMS (ESI): [M+1] + m/z: calculated 342.4; found 343.4; Rt=1.388 min.

化合物969： 1 H NMR(600MHz,DMSO-d 6 )δ 0.94-0.99(m,3H),1.29-1.40(m, 1H),1.70-1.89(m,2H),1.89-1.99(m,2H),1.99-2.03(m,3H),2.74-3.22(m,1H),3.35-3.95(m,1H),4.96-5.57(m,1H),5.57-5.65(m,2H),7.31-7.71(m,3H),7.98(d,1H),10.30-10.51(m,1H),12.75(s,1H)。 Compound 969: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.94-0.99 (m, 3H), 1.29-1.40 (m, 1H), 1.70-1.89 (m, 2H), 1.89-1.99 (m, 2H) ,1.99-2.03(m,3H),2.74-3.22(m,1H),3.35-3.95(m,1H),4.96-5.57(m,1H),5.57-5.65(m,2H),7.31-7.71( m, 3H), 7.98 (d, 1H), 10.30-10.51 (m, 1H), 12.75 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值342.4；實測值343.4；Rt=1.379min。LCMS (ESI): [M+1] + m/z: calculated 342.4; found 343.4; Rt=1.379 min.

實例362. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物658)之合成Example 362. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(5-amino-2-pyridyl)-5-methyl-1-piperidinyl] - Synthesis of 2-oxoacetamide (Compound 658)

Figure 110128222-A0202-12-1626-472
Figure 110128222-A0202-12-1626-472

步驟1.N-[5-[[2-[2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1. N-[5-[[2-[2-(5-Amino-2-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of tert-butyl ]-3-methyl-2-pyridyl]carbamate

將DIPEA(787.83mg，6.10mmol，1.06mL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)及6-(5-甲基-2-哌啶基)吡啶-3-胺(194.32mg，735.53μmol，2HCl)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(424.92mg，1.12mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 2*100 5mkm管柱且以H2 O-MeCN為溶析液混合物)，以得到N-[5-[[2-[2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.11g，234.77μmol，23.11%產率)DIPEA (787.83 mg, 6.10 mmol, 1.06 mL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (0.3 g, 1.02 mmol) and 6-(5-methyl-2-piperidinyl)pyridin-3-amine (194.32 mg, 735.53 μmol, 2HCl) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (424.92 mg, 1.12 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 2*100 5mkm column with H2O -MeCN as eluent mixture) to give N-[5-[[2-[2-(5-amino -2-Pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.11 g, 234.77 μmol, 23.11% yield)

LCMS(ESI)：[M+1]+ m/z：計算值468.2；實測值369.2；Rt=2.265min。LCMS (ESI): [M+1] + m/z: calculated 468.2; found 369.2; Rt=2.265 min.

步驟2.N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物658 )Step 2. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(5-amino-2-pyridyl)-5-methyl-1-piperidinyl] -2-Pendant oxyacetamide ( compound 658 )

將N-[5-[[2-[2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.11g，234.77μmol)溶解於水(5mL)及二噁烷(2mL)之混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(5-胺基-2-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(3.9mg，10.59μmol，4.51%產率)。N-[5-[[2-[2-(5-amino-2-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]- 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (0.11 g, 234.77 μmol) was dissolved in a mixture of water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give pure N-(6-amino-5-methyl-3-pyridinyl)- 2-[2-(5-Amino-2-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (3.9 mg, 10.59 μmol, 4.51% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.75(m,3H),1.12(m,1H),1.64(m,3H),2.01(m,3H),2.63(m,1H),3.44(m,1H),4.27(m,1H),5.36(m,5H),6.98(m,2H),7.47(m,1H),7.89(m,1H),7.98(m,1H),10.43(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.75 (m, 3H), 1.12 (m, 1H), 1.64 (m, 3H), 2.01 (m, 3H), 2.63 (m, 1H), 3.44(m, 1H), 4.27(m, 1H), 5.36(m, 5H), 6.98(m, 2H), 7.47(m, 1H), 7.89(m, 1H), 7.98(m, 1H), 10.43 (m,1H)

LCMS(ESI)：[M+1]+ m/z：計算值368.2；實測值370.4；Rt=1.148min。LCMS (ESI): [M+1] + m/z: calculated 368.2; found 370.4; Rt=1.148 min.

實例363. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物701)之合成Example 363. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methan Synthesis of yl-1-piperidinyl]-2-oxoacetamide (Compound 701)

Figure 110128222-A0202-12-1627-473
Figure 110128222-A0202-12-1627-473

步驟1.N-[5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯之合成Step 1. N-[5-[[2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamate

在室溫下將HATU(4.50g，11.84mmol)分批添加到2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(3.66g，11.84mmol)、5-[(2R,5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(2.5g，10.76mmol)(中間物6LL)及TEA(6.53g，64.56mmol，9.00mL)於DMF(35mL)中之懸浮液中。將澄清溶液在20℃下攪拌32h且在真空中蒸發溶劑。將殘餘物溶解於EtOAc(300mL)中，用水(5x100mL)洗滌，在真空中蒸發且藉由矽膠急驟層析使用0至100% ACN-氯仿梯度溶析來純 化，以得到2.5g具有順式雜質之產物。藉由掌性HPLC(管柱：Chiralcel OJ(250*30，20mkm)，以CO2-MeOH，75-25，80ml/min補充流速-30ml/min為流動相)分離單獨的反式異構物，以得到N-[5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(1.94g，3.70mmol，34.43%產率)。藉由RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；以35-55% 0-5min H2 O/ACN/0.1% NH4OH，流速：30ml/min為流動相)純化經Boc去保護之產物，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.9g，2.12mmol，19.75%產率)。HATU (4.50 g, 11.84 mmol) was added portionwise to 2-[[6-(3-butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2- at room temperature Pendant oxyacetic acid (3.66 g, 11.84 mmol), 5-[(2R,5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (2.5 g, 10.76 mmol) (intermediate 6LL) and TEA (6.53 g, 64.56 mmol, 9.00 mL) in a suspension of DMF (35 mL). The clear solution was stirred at 20 °C for 32 h and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc (300 mL), washed with water (5×100 mL), evaporated in vacuo and purified by silica gel flash chromatography using a 0 to 100% ACN-chloroform gradient to give 2.5 g with cis impurity product of. Separate trans isomers by chiral HPLC (column: Chiralcel OJ (250*30, 20mkm) with CO2-MeOH, 75-25, 80ml/min supplemental flow - 30ml/min as mobile phase), to give N-[5-[[2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxygen ethylacetoxy]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester (1.94 g, 3.70 mmol, 34.43% yield). Purified by RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; with 35-55% 0-5min H2O /ACN/0.1% NH4OH, flow rate: 30ml/min as mobile phase) Product deprotected by Boc to give N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazole-5- (0.9 g, 2.12 mmol, 19.75% yield).

LCMS(ESI)：[M+1]+ m/z：計算值523.2；實測值524.2；Rt=1.288min。LCMS (ESI): [M+1] + m/z: calculated 523.2; found 524.2; Rt=1.288 min.

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值424.2；Rt=2.199min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 424.2; Rt=2.199 min.

Boc-中間物(99+ ee)之RT(OJ-H，CO2-MeOH，80-20，3.0mL/min)=2.859minRT of Boc-intermediate (99+ee) (OJ-H, CO2-MeOH, 80-20, 3.0 mL/min)=2.859min

步驟2.N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物701 )之合成Step 2. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 701 )

將N-[5-[[2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(1.94g，3.70mmol)於二噁烷(20mL)及水(10mL)中之溶液在85℃下攪拌12h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；以35-60% 0-5min H2 O/ACN/0.1% NH4OH，流速：30ml/min為流動相，然後另一管柱：Chromatorex 18 SMB 100-5T 100x19mm 5um；以30-60% 0-5min H2 O/MeOH/0.1% FA，流速：30ml/min為流動相)純化殘餘物，以得到0.8g具有溶劑之產物。將其溶解於15mL無水乙醇中，在真空中蒸發且在45℃下在真空中乾燥24h，以得到化合物701 N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.5g，1.18mmol，31.87%產率)。[α]21D=+135.0°(c=0.1 g/100mL EtOH)。1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.04(t,6H),1.36(m,1H),1.72(m,1H),1.87(m,1H),2.13(m,1H),2.35(m,2H),3.78(m,3H),4.33(s,1H),5.66(m,3H),7.43(d,1H),7.51(d,1H),8.00(d,1H),8.06(d,1H),8.17(m,1H),9.40(s,1H),10.56(m,1H)N-[5-[[2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester (1.94 g, 3.70 mmol) in dioxane (20 mL) and water (10 mL) at 85 °C Stir for 12 h and evaporate the solvent in vacuo. By RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; with 35-60% 0-5min H 2 O/ACN/0.1% NH4OH, flow rate: 30ml/min as mobile phase, then Another column: Chromatorex 18 SMB 100-5T 100x19mm 5um; the residue was purified with 30-60% 0-5min H2O /MeOH/0.1%FA, flow rate: 30ml/min as mobile phase) to give 0.8g with Solvent product. It was dissolved in 15 mL absolute ethanol, evaporated in vacuo and dried in vacuo at 45°C for 24 h to give compound 701 N-(6-amino-5-ethyl-3-pyridinyl)-2-[ (2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.5 g, 1.18 mmol, 31.87 %Yield). [α]21D=+135.0° (c=0.1 g/100 mL EtOH). 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.04(t, 6H), 1.36(m, 1H), 1.72(m, 1H), 1.87(m, 1H), 2.13(m, 1H), 2.35(m, 2H), 3.78(m, 3H), 4.33(s, 1H), 5.66(m, 3H), 7.43(d, 1H), 7.51(d, 1H), 8.00(d, 1H), 8.06 (d, 1H), 8.17 (m, 1H), 9.40 (s, 1H), 10.56 (m, 1H)

LCMS(ESI)：[M+1]+ m/z：計算值423.2；實測值424.2；Rt=2.082min。LCMS (ESI): [M+1] + m/z: calculated 423.2; found 424.2; Rt=2.082 min.

實例364. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物788)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物780)之合成Example 364. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b ]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide (Compound 788) and N-(6-amino-5-methyl-3-pyridyl)-2-[ (2S,5R)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide (compound 780) synthesis

Figure 110128222-A0202-12-1629-474
Figure 110128222-A0202-12-1629-474

步驟1.N-[3-甲基-5-[[2-[5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1. N-[3-Methyl-5-[[2-[5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl Synthesis of tert-butyl ]-2-oxyacetyl]amino]-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(327.67mg，1.11mmol)及5-(5-甲基-2-哌啶基)-1H-吡唑并[4,3-b]吡啶(0.24g，1.11mmol)混合於DMF(20mL)中。將反應懸浮液冷卻至0℃且添加HATU(506.31mg，1.33mmol)，隨後添加TEA(336.86mg，3.33mmol，464.00μL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發，以得到產物N-[3-甲基-5-[[2-[5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.7g，粗品)2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (327.67 mg, 1.11 mmol) and 5-(5 -Methyl-2-piperidinyl)-1H-pyrazolo[4,3-b]pyridine (0.24 g, 1.11 mmol) was mixed in DMF (20 mL). The reaction suspension was cooled to 0°C and HATU (506.31 mg, 1.33 mmol) was added followed by TEA (336.86 mg, 3.33 mmol, 464.00 μL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo to give the product N-[3-methyl-5-[[2-[5-methyl-2-(1H-pyrazolo[4,3-b]pyridine-5- (0.7 g, crude)

LCMS(ESI)：[M+H]+ m/z：計算值493.5；實測值494.2；Rt=1.214min。LCMS (ESI): [M+H] + m/z: calculated 493.5; found 494.2; Rt=1.214 min.

步驟2.N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 2. N-(6-Amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl )-1-piperidinyl]-2-side oxyacetamide synthesis

在室溫下將水(10mL)一次性添加到N-[3-甲基-5-[[2-[5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.7g，1.42mmol)於二噁烷(50mL)中之經攪拌之溶液中。將所得混合物在100℃下攪拌14h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用二氯甲烷(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發且藉由製備型(30-65% 0-5min H2 O/MeOH/0.1% NH4OH，流速30ml/min)純化0.45g所獲得之粗產物，以得到產物N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.082g，208.42μmol，14.70%產率)LCMS(ESI)：[M+1]+ m/z：計算值393.2；實測值394.2；Rt=2.082min。Water (10 mL) was added in one portion to N-[3-methyl-5-[[2-[5-methyl-2-(1H-pyrazolo[4,3-b]pyridine- 5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.7 g, 1.42 mmol) in dioxane (50 mL) in the stirred solution. The resulting mixture was stirred at 100 °C for 14 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo and 0.45 g obtained was purified by preparative (30-65% 0-5 min H2O /MeOH/0.1% NH4OH, flow rate 30 ml/min) crude product to give the product N-(6-amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-(1H-pyrazolo[4,3-b]pyridine- 5-yl)-1-piperidinyl]-2-oxyacetamide (0.082 g, 208.42 μmol, 14.70% yield) LCMS (ESI): [M+1] + m/z: calcd. 393.2 ; Measured value 394.2; Rt=2.082min.

步驟3.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物788 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物780 )之分離Step 3. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b ]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide ( compound 788 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[ (2S,5R)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2-oxoacetamide ( compound 780 ) separation

使N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.082g，208.42μmol)經歷掌性HPLC純化(管柱：OJ-H(250*20，5mkm)，溶析液：己烷-IPA-MeOH，70-15-15，流速：12mL/min)，以得到兩種單獨的鏡像異構物化合物788 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.0159g，40.41μmol，19.39%產率)及化合物780 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1H-吡唑并[4,3-b]吡啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.0189g，48.04μmol，23.05%產率)make N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridine -5-yl)-1-piperidinyl]-2-oxoacetamide (0.082 g, 208.42 μmol) was purified by chiral HPLC (column: OJ-H (250*20, 5 mkm), elution solution: hexane-IPA-MeOH, 70-15-15, flow rate: 12 mL/min) to obtain two separate enantiomers compound 788 N-(6-amino-5-methyl-3-pyridine yl)-2-[(2R,5S)-5-methyl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2-oxygen Ethylacetamide (0.0159 g, 40.41 μmol, 19.39% yield) and compound 780 N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl yl-2-(1H-pyrazolo[4,3-b]pyridin-5-yl)-1-piperidinyl]-2-oxyacetamide (0.0189 g, 48.04 μmol, 23.05% yield )

化合物788： 1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.07(m,3H),1.32-1.41(m, 1H),1.74-1.82(m,1H),1.81-1.92(m,1H),1.96-2.11(m,4H),2.53-2.56(m,1H),2.80-3.25(m,1H),3.44-4.10(m,1H),5.30-5.59(m,1H),5.59-5.75(m,2H),7.25-7.45(m,1H),7.45-7.51(m,1H),7.95-8.06(m,2H),8.24-8.32(m,1H),10.41-10.57(m,1H),13.30(s,1H)。 Compound 788: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.07 (m, 3H), 1.32-1.41 (m, 1H), 1.74-1.82 (m, 1H), 1.81-1.92 (m, 1H) ,1.96-2.11(m,4H),2.53-2.56(m,1H),2.80-3.25(m,1H),3.44-4.10(m,1H),5.30-5.59(m,1H),5.59-5.75( m,2H),7.25-7.45(m,1H),7.45-7.51(m,1H),7.95-8.06(m,2H),8.24-8.32(m,1H),10.41-10.57(m,1H), 13.30 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值393.2；實測值394.0；Rt=1.898min。LCMS (ESI): [M+1] + m/z: calculated 393.2; found 394.0; Rt=1.898 min.

化合物780： 1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.07(m,3H),1.32-1.41(m,1H),1.74-1.82(m,1H),1.81-1.92(m,1H),1.96-2.11(m,4H),2.53-2.56(m,1H),2.80-3.25(m,1H),3.44-4.10(m,1H),5.30-5.59(m,1H),5.59-5.75(m,2H),7.25-7.45(m,1H),7.45-7.51(m,1H),7.95-8.06(m,2H),8.24-8.32(m,1H),10.41-10.57(m,1H),13.30(s,1H)。 Compound 780: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.07 (m, 3H), 1.32-1.41 (m, 1H), 1.74-1.82 (m, 1H), 1.81-1.92 (m, 1H) ,1.96-2.11(m,4H),2.53-2.56(m,1H),2.80-3.25(m,1H),3.44-4.10(m,1H),5.30-5.59(m,1H),5.59-5.75( m,2H),7.25-7.45(m,1H),7.45-7.51(m,1H),7.95-8.06(m,2H),8.24-8.32(m,1H),10.41-10.57(m,1H), 13.30 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值393.2；實測值394.0；Rt=1.898min。LCMS (ESI): [M+1] + m/z: calculated 393.2; found 394.0; Rt=1.898 min.

實例365. 外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物671)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物762、化合物762)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(EN-TG-4743、化合物763)之合成Example 365. Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(2-oxy-1H-quinoline-6- yl)-1-piperidinyl]-2-oxoacetamide (Compound 671), rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R, 5S)-5-methyl-2-(2-oxo-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (compound 762, compound 762) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinoline-6 Synthesis of -yl)-1-piperidinyl]-2-side oxyacetamide (EN-TG-4743, compound 763)

Figure 110128222-A0202-12-1632-475
Figure 110128222-A0202-12-1632-475

步驟1：外消旋-N-[3-甲基-5-[[2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-methyl-5-[[2-[5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidine Synthesis of tert-butyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamate

將DIPEA(266.68mg，2.06mmol，359.41μL)添加到相應6-(5-甲基-2-哌啶基)-1H-喹啉-2-酮(0.2g，825.37μmol)及2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(243.72mg，825.37μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(345.21mg，907.91μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到N-[3-甲基-5-[[2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.21g，404.16μmol，48.97%產率)。DIPEA (266.68 mg, 2.06 mmol, 359.41 μL) was added to the corresponding 6-(5-methyl-2-piperidinyl)-1H-quinolin-2-one (0.2 g, 825.37 μmol) and 2-[[ A solution of 6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (243.72 mg, 825.37 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (345.21 mg, 907.91 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give N-[3-methyl-5-[[2-[5-methyl-2 -(2-Oxyoxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester ( 0.21 g, 404.16 μmol, 48.97% yield).

LCMS(ESI)：[M+H]+ m/z：計算值519.2；實測值520.4；Rt=2.748min。LCMS (ESI): [M+H] + m/z: calculated 519.2; found 520.4; Rt=2.748 min.

步驟2：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物671 )之合成Step 2: Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(2-oxy-1H-quinoline-6- Synthesis of yl)-1-piperidinyl]-2-oxoacetamide ( Compound 671 )

將N-[3-甲基-5-[[2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]-胺基]-2-吡啶基]胺甲酸第三丁酯(0.21g，404.16μmol)溶解於二噁 烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(121.9mg，290.60μmol，71.90%產率)。N-[3-methyl-5-[[2-[5-methyl-2-(2-side oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-side Oxyacetyl]-amino]-2-pyridyl]carbamic acid tert-butyl ester (0.21 g, 404.16 μmol) dissolved in dioxane in a mixture of alkane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give N-(6-amino-5-methyl-3-pyridinyl)-2- [5-Methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (121.9 mg, 290.60 μmol, 71.90% yield Rate).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.34(m,1H),1.69(m,1H),1.86(m,1H),2.01(m,4H),2.20(m,1H),2.90(m,1H),3.63(m,1H),5.59(m,3H),6.47(m,1H),7.29(m,1H),7.40(m,1H),7.48(m,1H),7.59(m,1H),7.87(m,1H),7.97(m,1H),10.46(m,1H),11.70(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.69(m, 1H), 1.86(m, 1H), 2.01(m, 4H), 2.20(m, 1H), 2.90(m, 1H), 3.63(m, 1H), 5.59(m, 3H), 6.47(m, 1H), 7.29(m, 1H), 7.40(m, 1H), 7.48 (m, 1H), 7.59 (m, 1H), 7.87 (m, 1H), 7.97 (m, 1H), 10.46 (m, 1H), 11.70 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值419.2；實測值420.2；Rt=1.670min。LCMS (ESI): [M+H] + m/z: calculated 419.2; found 420.2; Rt=1.670 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物762、化合物762 )及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(EN-TG-4743、化合物763 )之合成Step 3: rel-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-oxo-1H-quinoline Lin-6-yl)-1-piperidinyl]-2-oxoacetamide ( Compound 762, Compound 762 ) and rel-N-(6-amino-5-methyl-3-pyridyl) -2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide ( Synthesis of EN-TG-4743, compound 763 )

使用(Chiralpak IC(250* 20mm，5mm)管柱且以己烷-IPA-MeOH，50-25-25為流動相，流速：12mL/min；管柱溫度：24℃；波長：205nm，215nm，254nm)對外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(121.9mg，290.60μmol)進行掌性分離，得到化合物762(化合物762) rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(42.1mg，34.54%產率)及化合物763(化合物763) rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(52.29mg，42.90%產率)。保留時間(為A)=60.01min；保留時間(為B)=66.66min，保留時間(為C)=89.81A (Chiralpak IC (250 * 20mm, 5mm) column was used with hexane-IPA-MeOH, 50-25-25 as mobile phase, flow rate: 12mL/min; column temperature: 24°C; wavelength: 205nm, 215nm, 254nm) racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[5-methyl-2-(2-oxy-1H-quinolin-6-yl) )-1-piperidinyl]-2-oxyacetamide (121.9 mg, 290.60 μmol) chiral separation to give compound 762 (compound 762) rel-N-(6-amino-5-methyl) -3-Pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-side oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-side Oxyacetamide (42.1 mg, 34.54% yield) and Compound 763 (Compound 763) rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R) -5-Methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (52.29 mg, 42.90% yield). Retention time (for A)=60.01min; retention time (for B)=66.66min, retention time (for C)=89.81

化合物762(化合物762)： RT(IC(250*4.6，5mkm，IPA-MeOH，50-50，0.5mL/min) =28.057min。 Compound 762 (Compound 762): RT (IC(250*4.6, 5mkm, IPA-MeOH, 50-50, 0.5mL/min) = 28.057min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.02(m,3H),1.28-1.37(m,1H),1.66-1.73(m,1H),1.82-1.90(m,1H),1.96-2.03(m,3H),2.04-2.16(m,1H),2.18-2.26(m,1H),2.72-3.22(m,1H),3.42-4.02(m,1H),5.13-5.58(m,1H),5.58-5.65(m,2H),6.42-6.50(m,1H),7.24-7.32(m,1H),7.36-7.44(m,1H),7.44-7.51(m,1H),7.54-7.65(m,1H),7.82-7.90(m,1H),7.90-8.04(m,1H),10.35-10.57(m,1H),11.58-11.82(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.99-1.02(m,3H), 1.28-1.37(m,1H), 1.66-1.73(m,1H), 1.82-1.90(m,1H), 1.96- 2.03(m,3H), 2.04-2.16(m,1H), 2.18-2.26(m,1H), 2.72-3.22(m,1H), 3.42-4.02(m,1H), 5.13-5.58(m,1H) ),5.58-5.65(m,2H),6.42-6.50(m,1H),7.24-7.32(m,1H),7.36-7.44(m,1H),7.44-7.51(m,1H),7.54-7.65 (m, 1H), 7.82-7.90 (m, 1H), 7.90-8.04 (m, 1H), 10.35-10.57 (m, 1H), 11.58-11.82 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值419.2；實測值420.2；Rt=0.991min。LCMS (ESI): [M+H] + m/z: calculated 419.2; found 420.2; Rt=0.991 min.

化合物763(化合物763)： RT(IC(250*4.6，5mkm，IPA-MeOH，50-50，0.5mL/min)=20.804min。 Compound 763 (Compound 763): RT (IC (250*4.6, 5mkm, IPA-MeOH, 50-50, 0.5mL/min)=20.804min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.02(m,3H),1.28-1.37(m,1H),1.65-1.74(m,1H),1.81-1.90(m,1H),1.96-2.03(m,3H),2.04-2.16(m,1H),2.19-2.27(m,1H),2.70-3.23(m,1H),3.40-4.03(m,1H),5.10-5.58(m,1H),5.58-5.65(m,2H),6.42-6.51(m,1H),7.22-7.33(m,1H),7.35-7.42(m,1H),7.45-7.52(m,1H),7.54-7.65(m,1H),7.83-7.90(m,1H),7.90-8.05(m,1H),10.36-10.57(m,1H),11.70(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.02(m,3H), 1.28-1.37(m,1H), 1.65-1.74(m,1H), 1.81-1.90(m,1H), 1.96- 2.03(m,3H), 2.04-2.16(m,1H), 2.19-2.27(m,1H), 2.70-3.23(m,1H), 3.40-4.03(m,1H), 5.10-5.58(m,1H) ),5.58-5.65(m,2H),6.42-6.51(m,1H),7.22-7.33(m,1H),7.35-7.42(m,1H),7.45-7.52(m,1H),7.54-7.65 (m, 1H), 7.83-7.90 (m, 1H), 7.90-8.05 (m, 1H), 10.36-10.57 (m, 1H), 11.70 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值419.2；實測值420.2；Rt=0.988min。LCMS (ESI): [M+H] + m/z: calculated 419.2; found 420.2; Rt=0.988 min.

實例366. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物825、化合物825)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物819、化合物819)之合成Example 366. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-1H-quinoline Lin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 825, Compound 825) and rel-N-(6-amino-5-ethyl-3-pyridyl) -2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide ( Synthesis of compound 819, compound 819)

Figure 110128222-A0202-12-1635-476
Figure 110128222-A0202-12-1635-476

步驟1：外消旋-N-[3-乙基-5-[[2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-ethyl-5-[[2-[5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidine Synthesis of tert-butyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamate

將DIPEA(266.68mg，2.06mmol，359.41μL)添加到相應6-(5-甲基-2-哌啶基)-1H-喹啉-2-酮(0.2g，825.37μmol)及2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(255.30mg，825.37μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(345.21mg，907.91μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到N-[3-乙基-5-[[2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，374.80μmol，45.41%產率)。DIPEA (266.68 mg, 2.06 mmol, 359.41 μL) was added to the corresponding 6-(5-methyl-2-piperidinyl)-1H-quinolin-2-one (0.2 g, 825.37 μmol) and 2-[[ A solution of 6-(tert-butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-pendoxoacetic acid (255.30 mg, 825.37 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (345.21 mg, 907.91 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give N-[3-ethyl-5-[[2-[5-methyl-2 -(2-Oxyoxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester ( 0.2 g, 374.80 μmol, 45.41% yield).

LCMS(ESI)：[M+H]+ m/z：計算值533.2；實測值534.4；Rt=2.921min。LCMS (ESI): [M+H] + m/z: calculated 533.2; found 534.4; Rt=2.921 min.

步驟2：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[5-methyl-2-(2-oxy-1H-quinoline-6- Synthesis of )-1-piperidinyl]-2-side oxyacetamide

將N-[3-乙基-5-[[2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]-胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，374.80μmol)溶解於二噁 烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH+NH3 為溶析液混合物)，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(97.2mg，224.22μmol，59.82%產率)。N-[3-ethyl-5-[[2-[5-methyl-2-(2-side oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-side Oxyacetyl]-amino]-2-pyridyl]carbamic acid tert-butyl ester (0.2 g, 374.80 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH+ NH3 as eluent mixture) to give N-(6-amino-5-ethyl-3-pyridyl) -2-[5-Methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (97.2 mg, 224.22 μmol, 59.82% yield).

LCMS(ESI)：[M+H]+ m/z：計算值433.2；實測值434.2；Rt=1.882min。LCMS (ESI): [M+H] + m/z: calculated 433.2; found 434.2; Rt=1.882 min.

步驟3：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物825 、化合物825 )及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物819 、化合物819 )之合成Step 3: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxo-1H-quinoline) Lin-6-yl)-1-piperidinyl]-2-oxoacetamide ( Compound 825 , Compound 825 ) and rel-N-(6-amino-5-ethyl-3-pyridyl) -2-[(2S,5R)-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide ( Synthesis of compound 819 , compound 819 )

使用(Chiralpak IC-II(250*20mm，5mkm)管柱且以己烷-IPA-MeOH 50-25-25為流動相，流速：12mL/min)對外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(97.2mg，224.22μmol)進行掌性分離，得到化合物825 (化合物825 )rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(32.76mg，33.70%產率)及化合物819 (化合物819 )rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(28.39mg，29.21%產率)。Racemic-N-(6-amino- 5-ethyl-3-pyridyl)-2-[5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxy Chiral separation of acetamide (97.2 mg, 224.22 μmol) afforded compound 825 ( Compound 825 )rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S )-5-methyl-2-(2-oxy-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (32.76 mg, 33.70% yield) and compound 819 ( compound 819 ) rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-side oxygen -1H-Quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (28.39 mg, 29.21% yield).

化合物825(化合物825)： RT(OJ-H(250*4.6,5mkm)，Hex-IPA-MeOH，50-25-25，0.6mL/min)=30.120min。 Compound 825 (Compound 825): RT (OJ-H (250*4.6, 5mkm), Hex-IPA-MeOH, 50-25-25, 0.6mL/min)=30.120min.

1 H NMR(dmso,600MHz)：δ(ppm)0.97-1.03(m,3H),1.04-1.13(m,3H),1.28-1.40(m,1H),1.66-1.74(m,1H),1.80-1.93(m,1H),2.01-2.16(m,1H),2.18-2.28(m,1H),2.35-2.42(m,2H),2.72-3.21(m,1H),3.39-4.05(m,1H),5.09-5.59(m,1H),5.59-5.71(m,2H),6.45-6.51(m,1H),7.25-7.34(m,1H),7.38-7.43(m,1H), 7.45-7.51(m,1H),7.56-7.64(m,1H),7.84-7.90(m,1H),7.94-8.09(m,1H),10.24-10.70(m,1H),11.70(br s,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.97-1.03 (m, 3H), 1.04-1.13 (m, 3H), 1.28-1.40 (m, 1H), 1.66-1.74 (m, 1H), 1.80 -1.93(m, 1H), 2.01-2.16(m, 1H), 2.18-2.28(m, 1H), 2.35-2.42(m, 2H), 2.72-3.21(m, 1H), 3.39-4.05(m, 1H), 5.09-5.59(m, 1H), 5.59-5.71(m, 2H), 6.45-6.51(m, 1H), 7.25-7.34(m, 1H), 7.38-7.43(m, 1H), 7.45- 7.51(m,1H),7.56-7.64(m,1H),7.84-7.90(m,1H),7.94-8.09(m,1H),10.24-10.70(m,1H),11.70(br s,1H) .

LCMS(ESI)：[M+H]+ m/z：計算值433.2；實測值434.2；Rt=1.910min。LCMS (ESI): [M+H] + m/z: calculated 433.2; found 434.2; Rt=1.910 min.

化合物819(化合物819)： RT(OJ-H(250*4.6,5mkm)，Hex-IPA-MeOH，50-25-25，0.6mL/min)=12.280min。 Compound 819 (Compound 819): RT (OJ-H (250*4.6, 5mkm), Hex-IPA-MeOH, 50-25-25, 0.6mL/min)=12.280min.

1 H NMR(dmso,600MHz)：δ(ppm)0.99-1.03(m,3H),1.04-1.15(m,3H),1.29-1.38(m,1H),1.64-1.77(m,1H),1.81-1.91(m,1H),2.00-2.16(m,1H),2.18-2.30(m,1H),2.33-2.41(m,2H),2.76-3.21(m,1H),3.46-4.03(m,1H),5.11-5.59(m,1H),5.59-5.69(m,2H),6.43-6.50(m,1H),7.26-7.33(m,1H),7.39-7.43(m,1H),7.46-7.52(m,1H),7.55-7.64(m,1H),7.84-7.91(m,1H),7.95-8.08(m,1H),10.46(br s,1H),11.66(br s,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.99-1.03 (m, 3H), 1.04-1.15 (m, 3H), 1.29-1.38 (m, 1H), 1.64-1.77 (m, 1H), 1.81 -1.91(m, 1H), 2.00-2.16(m, 1H), 2.18-2.30(m, 1H), 2.33-2.41(m, 2H), 2.76-3.21(m, 1H), 3.46-4.03(m, 1H), 5.11-5.59(m, 1H), 5.59-5.69(m, 2H), 6.43-6.50(m, 1H), 7.26-7.33(m, 1H), 7.39-7.43(m, 1H), 7.46- 7.52 (m, 1H), 7.55-7.64 (m, 1H), 7.84-7.91 (m, 1H), 7.95-8.08 (m, 1H), 10.46 (br s, 1H), 11.66 (br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值433.2；實測值434.2；Rt=1.905min。LCMS (ESI): [M+H] + m/z: calculated 433.2; found 434.2; Rt=1.905 min.

實例367. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物756)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物784)之合成Example 367. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl) )-1-piperidinyl]-2-oxyacetamide (compound 756) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S )-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide (compound 784) synthesis

Figure 110128222-A0202-12-1637-477
Figure 110128222-A0202-12-1637-477

步驟1：rel-N-[3-乙基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙Step 1: rel-N-[3-ethyl-5-[[2-[5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxygen base 醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Synthesis of Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將DIPEA(522.29mg，4.04mmol，703.90μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(0.5g，1.62mmol)及2-甲基-5-(5-甲基-2-哌啶基)吡啶(307.59mg，1.62mmol)於DMF(15mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(676.09mg，1.78mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到rel-N-[3-乙基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(430.2mg，893.30μmol，55.26%產率)。DIPEA (522.29 mg, 4.04 mmol, 703.90 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-oxo acetic acid (0.5 g, 1.62 mmol) and 2-methyl-5-(5-methyl-2-piperidinyl)pyridine (307.59 mg, 1.62 mmol) in DMF (15 mL). The resulting mixture was stirred for 5 min before HATU (676.09 mg, 1.78 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give rel-N-[3-ethyl-5-[[2-[5-methyl -2-(6-Methyl-3-pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (430.2 mg, 893.30 μmol, 55.26% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值481.2；實測值483.2；Rt=2.306min。LCMS (ESI): [M+2H] + m/z: calculated 481.2; found 483.2; Rt=2.306 min.

步驟2：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[5-methyl-2-(6-methyl-3-pyridyl)-1-piperidine Synthesis of Radix]-2-Pendant Oxyacetamide

將Rel-N-[3-乙基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(430.2mg，893.30μmol)溶解於二噁烷(2mL)及水(5mL)混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN為溶析液混合物)，以得到rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(184.6mg，483.92μmol，54.17%產率)。Rel-N-[3-Ethyl-5-[[2-[5-methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (430.2 mg, 893.30 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN as eluent mixture) to give rel-N-(6-amino-5-ethyl-3-pyridyl)- 2-[5-Methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide (184.6 mg, 483.92 μmol, 54.17% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值381.2；實測值383.2；Rt=1.209min。LCMS (ESI): [M+2H] + m/z: calculated 381.2; found 383.2; Rt=1.209 min.

步驟3：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物756 )及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物 Step 3: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl) )-1-piperidinyl]-2-oxyacetamide ( compound 756 ) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S )-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide ( compound 784784 )之合成) synthesis

使用(Chiralpak IC-II(250 * 20mm，5mkm)管柱且以己烷-IPA-MeOH 60-20-20為流動相，流速：12mL/min)對rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(184.6mg，483.92μmol)進行掌性分離，得到化合物756 rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(72.55mg，39.30%產率)及化合物784 rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(71.94mg，38.97%產率)。Using (Chiralpak IC-II (250*20mm, 5mkm) column with hexane-IPA-MeOH 60-20-20 as mobile phase, flow rate: 12mL/min) for rel-N-(6-amino-5 -Ethyl-3-pyridyl)-2-[5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide (184.6 mg , 483.92 μmol) for chiral separation to obtain compound 756 rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-( 6-Methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide (72.55 mg, 39.30% yield) and compound 784 rel-N-(6-amino-5- Ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-side oxyethyl Amide (71.94 mg, 38.97% yield).

化合物756： RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=24.564min。 Compound 756: RT (Chiralpak IC (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 24.564 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.01(m,3H),1.05-1.12(m,3H),1.25-1.40(m,1H),1.57-1.67(m,1H),1.78-1.93(m,1H),1.94-2.14(m,1H),2.14-2.26(m,1H),2.37-2.45(m,5H),2.66-3.22(m,1H),3.40-4.03(m,1H),5.11-5.58(m,1H),5.58-5.66(m,2H),7.17-7.28(m,1H),7.41-7.51(m,1H),7.53-7.64(m,1H),7.95-8.07(m,1H),8.34-8.43(m,1H),10.43-10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.01(m,3H), 1.05-1.12(m,3H), 1.25-1.40(m,1H), 1.57-1.67(m,1H), 1.78- 1.93(m,1H),1.94-2.14(m,1H),2.14-2.26(m,1H),2.37-2.45(m,5H),2.66-3.22(m,1H),3.40-4.03(m,1H ), 5.11-5.58(m, 1H), 5.58-5.66(m, 2H), 7.17-7.28(m, 1H), 7.41-7.51(m, 1H), 7.53-7.64(m, 1H), 7.95-8.07 (m, 1H), 8.34-8.43 (m, 1H), 10.43-10.53 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值381.2；實測值383.4；Rt=1.211min。LCMS (ESI): [M+2H] + m/z: calculated 381.2; found 383.4; Rt=1.211 min.

化合物784： RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=34.051min。 Compound 784: RT (Chiralpak IC (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 34.051 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.02(m,3H),1.05-1.12(m,3H),1.28-1.38(m,1H),1.60-1.67(m,1H),1.82-1.91(m,1H),1.99-2.13(m,1H),2.16-2.26(m,1H),2.39-2.45(m,5H),2.69-3.19(m,1H),3.40-4.03(m,1H),5.14-5.59(m,1H),5.59-5.66(m,2H),7.23-7.27(m,1H),7.43-7.50(m,1H),7.54-7.64(m,1H),7.98-8.07(m,1H),8.35-8.41(m,1H),10.44-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.02(m,3H), 1.05-1.12(m,3H), 1.28-1.38(m,1H), 1.60-1.67(m,1H), 1.82- 1.91(m,1H),1.99-2.13(m,1H),2.16-2.26(m,1H),2.39-2.45(m,5H),2.69-3.19(m,1H),3.40-4.03(m,1H ), 5.14-5.59(m, 1H), 5.59-5.66(m, 2H), 7.23-7.27(m, 1H), 7.43-7.50(m, 1H), 7.54-7.64(m, 1H), 7.98-8.07 (m, 1H), 8.35-8.41 (m, 1H), 10.44-10.60 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值381.2；實測值383.4；Rt=1.217min。LCMS (ESI): [M+2H] + m/z: calculated 381.2; found 383.4; Rt=1.217 min.

實例368.N -(6-胺基-5-甲基吡啶-3-基)-2-(1',5-二甲基-[2,4'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物614)之合成Example 368. N- (6-amino-5-methylpyridin-3-yl)-2-(1',5-dimethyl-[2,4'-bipiperidin]-1-yl)- Synthesis of 2-Pendant Oxyacetamide (Compound 614)

Figure 110128222-A0202-12-1640-478
Figure 110128222-A0202-12-1640-478

步驟1：外消旋-(5-(2-((2R,5S)-1',5-二甲基-[2,4'-聯哌啶]-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-1',5-dimethyl-[2,4'-bipiperidin]-1-yl)-2-pendoxyl Synthesis of acetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

在室溫下將HATU(490.95mg，1.29mmol)分批添加到2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(381.28mg，1.29mmol)、1-甲基-4-[(2R,5S )-5-甲基-2-哌啶基]哌啶(298.24mg，1.29mmol)及DIPEA(1.00g，7.75mmol，1.35mL)於DMF(10mL)中之懸浮液中。將澄清溶液在25℃下攪拌18h且在真空中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以50-80% 0-5min水-MeOH(NH3 0.1%)，流速30ml/min為流動相)，以得到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(1-甲基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(206mg，434.96μmol，33.69%產率)。HATU (490.95 mg, 1.29 mmol) was added portionwise to 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2- at room temperature Pendant oxyacetic acid (381.28 mg, 1.29 mmol), 1-methyl-4-[( 2R,5S )-5-methyl-2-piperidinyl]piperidine (298.24 mg, 1.29 mmol) and DIPEA (1.00 g, 7.75 mmol, 1.35 mL) in DMF (10 mL). The clear solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; with 50-80% 0-5min water-MeOH ( NH3 0.1%), flow rate 30ml/min as mobile phase) to obtain N- [ 3-Methyl-5-[[2-[( 2R,5S )-5-methyl-2-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-side oxy Acetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (206 mg, 434.96 [mu]mol, 33.69% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.85(d,3H),1.12(m,2H),1.36(m,5H),1.48(s,9H),1.76(m,4H),2.12(m,2H),2.27(m,6H),2.96(m,1H),3.04(m,2H),4.12(m,1H),6.62(m,1H),8.03(m,1H),8.33(m,1H),9.36(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.85(d, 3H), 1.12(m, 2H), 1.36(m, 5H), 1.48(s, 9H), 1.76(m, 4H), 2.12( m, 2H), 2.27(m, 6H), 2.96(m, 1H), 3.04(m, 2H), 4.12(m, 1H), 6.62(m, 1H), 8.03(m, 1H), 8.33(m , 1H), 9.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值473.2；實測值474.2；Rt=2.046min。LCMS (ESI): [M] + m/z: calculated 473.2; found 474.2; Rt=2.046 min.

步驟2：N -(6-胺基-5-甲基吡啶-3-基)-2-(1',5-二甲基-[2,4'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物614 )之合成Step 2: N- (6-Amino-5-methylpyridin-3-yl)-2-(1',5-dimethyl-[2,4'-bipiperidin]-1-yl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 614 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(1.13g，4.35mmol，1.08mL，14%純度)小心添加到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(1-甲基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(206.00mg，434.96μmol) 於DCM(2mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以30-80% 1-6min水-MeOH(NH3 0.1%)，流速30ml/min為流動相)，以得到化合物614 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1-甲基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(114mg，305.23μmol，70.17%產率)。A 4.0 M solution of hydrogen chloride in dioxane (1.13 g, 4.35 mmol, 1.08 mL, 14% purity) was carefully added to N- [3-methyl-5-[[2-[( 2R, 5S )-5-methyl-2-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid A solution of tertiary butyl ester (206.00 mg, 434.96 [mu]mol) in DCM (2 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; 30-80% 1-6 min water-MeOH ( NH3 0.1%), flow rate 30 ml/min as mobile phase) to give compound 614N -(6-Amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(1-methyl-4-piperidinyl)-1-piperidine Peridyl]-2-Pendant oxyacetamide (114 mg, 305.23 μmol, 70.17% yield).

化合物614： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.91-0.96(m,3H),1.00-1.17(m,2H),1.21-1.32(m,1H),1.39-1.48(m,1H),1.51-1.66(m,3H),1.72-1.81(m,4H),1.81-1.96(m,2H),1.98-2.03(m,3H),2.07-2.14(m,3H),2.64-2.86(m,3H),3.47-4.11(m,1H),5.54-5.65(m,2H),7.41-7.48(m,1H),7.94-8.00(m,1H),10.16-10.38(m,1H)。 Compound 614: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.91-0.96 (m, 3H), 1.00-1.17 (m, 2H), 1.21-1.32 (m, 1H), 1.39-1.48 (m) ,1H),1.51-1.66(m,3H),1.72-1.81(m,4H),1.81-1.96(m,2H),1.98-2.03(m,3H),2.07-2.14(m,3H),2.64 -2.86(m, 3H), 3.47-4.11(m, 1H), 5.54-5.65(m, 2H), 7.41-7.48(m, 1H), 7.94-8.00(m, 1H), 10.16-10.38(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值373.2；實測值374.2；Rt=1.064min。LCMS (ESI): [M] + m/z: calculated 373.2; found 374.2; Rt=1.064 min.

實例369.N -(6-胺基-5-乙基吡啶-3-基)-2-(2-(3,4-二氫-2H -苯并[b ][1,4 ]噁嗪-7-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物870)之合成Example 369. N- (6-Amino-5-ethylpyridin-3-yl)-2-(2-(3,4-dihydro- 2H -benzo[ b ][ 1,4 ]oxazine- Synthesis of 7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 870)

Figure 110128222-A0202-12-1641-479
Figure 110128222-A0202-12-1641-479

步驟1：外消旋-(5-(2-((2R,5S)-2-(3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-乙基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5S)-2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)- Synthesis of 5-methylpiperidin-1-yl)-2-oxyacetamido)-3-ethylpyridin-2-yl)carbamic acid tert-butyl ester

將7-[(2R,5S )-5-甲基-2-哌啶基]-3,4-二氫-2H-1,4-苯并噁嗪(0.2g，860.88μmol)、TEA(871.12mg，8.61mmol，1.20mL)及2-[[6-(第三丁氧基 羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(266.28mg，860.88μmol)溶解於DMF(8.5mL)中且一次性添加HATU(491.00mg，1.29mmol)，將所得混合物在20℃下攪拌3h。將反應混合物倒入到水中且將水相用EtOAc萃取(3次)，然後將經合併之有機相用鹽水洗滌(3次)，經Na2 SO4 乾燥且在真空下濃縮。藉由反相HPLC (55-65% 2-10min；水-MeOH；流速30ml/min(裝載泵4ml/min MeOH)；管柱SunFireC18 100*19mm 5um)純化粗產物，以得到呈粉色固體之N -[5-[[2-[(2R,5S )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.096g，183.34μmol，21.30%產率)。該反應為成功的。分離呈粉色固體之所要N -[5-[[2-[(2R,5S )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.096g，183.34μmol，21.30%產率)。7-[( 2R,5S )-5-methyl-2-piperidinyl]-3,4-dihydro-2H-1,4-benzoxazine (0.2 g, 860.88 μmol), TEA (871.12 mg, 8.61 mmol, 1.20 mL) and 2-[[6-( tert- butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-oxoacetic acid (266.28 mg, 860.88 μmol) was dissolved in DMF (8.5 mL) and HATU (491.00 mg, 1.29 mmol) was added in one portion and the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (3 times), then the combined organic phases were washed with brine (3 times), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by reverse phase HPLC (55-65% 2-10 min; water-MeOH; flow rate 30 ml/min (loading pump 4 ml/min MeOH); column SunFire C18 100*19 mm 5um) to give N as a pink solid -[5-[[2-[( 2R,5S )-2-(3,4-dihydro- 2H -1,4-benzoxazin-7-yl)-5-methyl-1-piperidine (0.096 g, 183.34 [mu]mol, 21.30% yield). The reaction was successful. The desired N- [5-[[2-[( 2R,5S )-2-(3,4-dihydro- 2H -1,4-benzoxazin-7-yl)-5- was isolated as a pink solid Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert- butyl ester (0.096 g, 183.34 μmol, 21.30% yield ).

LCMS(ESI)：[M]+ m/z：計算值523.2；實測值524.2；Rt=1.377min。LCMS (ESI): [M] + m/z: calculated 523.2; found 524.2; Rt=1.377 min.

步驟2：N-(6-胺基-5-乙基吡啶-3-基)-2-(2-(3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物870 )之合成Step 2: N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-(3,4-dihydro-2H-benzo[b][1,4]oxazine- Synthesis of 7-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide ( Compound 870 )

將N -[5-[[2-[(2R,5S )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.096g，183.34μmol)溶解於二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空下濃縮反應混合物。藉由HPLC(35-55% MeCN/H2 O-2-10min流速：30ml/min；裝載泵4ml/min MeCN；管柱Sun Fire C18 100 x 19mm，5mk)純化粗產物，以得到呈白色固體之N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-(3,4-二氫-2H -1,4-苯并噁嗪-7-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.02g，47.22μmol，25.76%產率)。 N- [5-[[2-[( 2R,5S )-2-(3,4-dihydro- 2H -1,4-benzoxazin-7-yl)-5-methyl-1- Piperidinyl]-2-oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert- butyl ester (0.096 g, 183.34 μmol) was dissolved in dioxane (2 mL) and A mixture of water (2 mL) was then stirred at 100 °C for 12 h. The reaction mixture was concentrated under vacuum. The crude product was purified by HPLC (35-55% MeCN/ H2O -2-10min flow rate: 30ml/min; loading pump 4ml/min MeCN; column Sun Fire C18 100 x 19mm, 5mk) to give a white solid N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-(3,4-dihydro- 2H -1,4-benzoxazine- 7-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.02 g, 47.22 μmol, 25.76% yield).

化合物870： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94-1.04(m,3H),1.06-1.14(m,3H),1.23-1.34(m,1H),1.63-1.76(m,1H),1.77-1.87(m,1H),1.88-2.04(m,1H),2.04-2.13(m,1H),2.36-2.42(m,2H),2.70-3.16(m,1H),3.21-3.25(m,2H),3.35-3.96(m,1H),4.05-4.12(m,2H),4.89-5.58(m,1H),5.58-5.65(m,2H),5.66-5.71(m,1H),6.48-6.65(m,3H),7.43-7.53(m,1H),7.96-8.07(m,1H),10.38-10.55(m,1H)。 Compound 870: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.94-1.04 (m, 3H), 1.06-1.14 (m, 3H), 1.23-1.34 (m, 1H), 1.63-1.76 (m) ,1H),1.77-1.87(m,1H),1.88-2.04(m,1H),2.04-2.13(m,1H),2.36-2.42(m,2H),2.70-3.16(m,1H),3.21 -3.25(m, 2H), 3.35-3.96(m, 1H), 4.05-4.12(m, 2H), 4.89-5.58(m, 1H), 5.58-5.65(m, 2H), 5.66-5.71(m, 1H), 6.48-6.65 (m, 3H), 7.43-7.53 (m, 1H), 7.96-8.07 (m, 1H), 10.38-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值423.2；實測值424.2；Rt=1.004min。LCMS (ESI): [M] + m/z: calculated 423.2; found 424.2; Rt=1.004 min.

實例370. 1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-N ,5-二甲基-[2,3'-聯哌啶]-1'-甲醯胺(化合物814)之合成Example 370. 1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl) -N ,5-dimethyl-[2, Synthesis of 3'-bipiperidine]-1'-carboxamide (Compound 814)

Figure 110128222-A0202-12-1643-480
Figure 110128222-A0202-12-1643-480

步驟1：N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[1-(甲基胺甲醯基)-3-哌啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[1-(methylaminocarboxy)-3-piperidinyl]- Synthesis of 3-butyl 1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid

向N -甲基-3-[(2R,5S )-5-甲基-2-哌啶基]哌啶-1-甲醯胺(0.75g，2.72mmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(802.95mg，2.72mmol)及TEA(1.38g，13.60mmol，1.90mL)中之溶液中分批添加HATU(1.14g，2.99mmol)。將所得混合物在25℃下攪拌3h，溶解於水(50ml)中且用EtOAc(3*20ml)萃取。將經合併之有機層用鹽水(2*25ml)洗滌，經Na2 SO4 乾燥且移除溶劑，以得到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-[1-(甲基胺甲醯基)-3-哌啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(1.1g，2.13mmol，78.30%產率)。此化合物不經進一步純化即用於下一步驟。To N -methyl-3-[( 2R,5S )-5-methyl-2-piperidinyl]piperidin-1-carboxamide (0.75 g, 2.72 mmol, HCl), 2-[[6- ( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-side oxyacetic acid (802.95 mg, 2.72 mmol) and TEA (1.38 g, 13.60 mmol, 1.90 mL) To the solution was added HATU (1.14 g, 2.99 mmol) in portions. The resulting mixture was stirred at 25°C for 3h, dissolved in water (50ml) and extracted with EtOAc (3*20ml). The combined organic layers were washed with brine (2*25ml), dried over Na2SO4 and solvent removed to give N- [3-methyl-5-[[2-[( 2R,5S )-5 -Methyl-2-[1-(methylaminocarbamoyl)-3-piperidinyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl] tert -butyl carbamate (1.1 g, 2.13 mmol, 78.30% yield). This compound was used in the next step without further purification.

LCMS(ESI)：[M]+ m/z：計算值516.2；實測值517.2；Rt=1.147min。LCMS (ESI): [M] + m/z: calculated 516.2; found 517.2; Rt=1.147 min.

步驟2：1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-N,5-二甲基-[2,3'-聯哌啶]-1'-甲醯胺(化合物814 )之合成Step 2: 1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-N,5-dimethyl-[2, Synthesis of 3'-bipiperidine]-1'-carboxamide ( Compound 814 )

將N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-[1-(甲基胺甲醯基)-3-哌啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(1.1g，2.13mmol)及於二噁烷中之4.0M氯化氫溶液(8g，219.41mmol，10.00mL)於DCM(30mL)中之溶液在25℃下攪拌3h。移除溶劑且藉由HPLC(20-20-65% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)目標質量320 管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以獲得3-[(2R,5S )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N -甲基哌啶-1-甲醯胺(172mg，412.95μmol，19.39%產率)及(2S,5R )-2-[1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-3-哌啶基]-N ,5-二甲基哌啶-1-甲醯胺(111mg，266.50μmol，12.52%產率)。 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-[1-(methylaminocarboxy)-3-piperidinyl]-1- 3-butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (1.1 g, 2.13 mmol) and a 4.0 M solution of hydrogen chloride in dioxane (8 g, A solution of 219.41 mmol, 10.00 mL) in DCM (30 mL) was stirred at 25 °C for 3 h. The solvent was removed and by HPLC (20-20-65% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min (loading pump 4 ml/min MeOH) target mass 320 column: YMC Triart C18 100x20mm, 5um) to purify the residue to obtain 3-[( 2R,5S )-1-[2-[(6-amino-5-methyl-3-pyridyl)amino]-2- Pendant oxyacetyl]-5-methyl-2-piperidinyl] -N -methylpiperidine-1-carboxamide (172 mg, 412.95 μmol, 19.39% yield) and ( 2S,5R )- 2-[1-[2-[(6-Amino-5-methyl-3-pyridyl)amino]-2-oxyethanoyl]-3-piperidinyl] -N ,5- Dimethylpiperidine-1-carboxamide (111 mg, 266.50 μmol, 12.52% yield).

化合物814： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.78-0.94(m,3H),0.97-1.04(m,1H),1.23-1.33(m,2H),1.51-1.65(m,4H),1.78-1.88(m,2H),1.91-1.96(m,1H),1.99-2.04(m,3H),2.25-2.46(m,1H),2.51-2.54(m,3H),2.58-2.70(m,1H),2.81-3.26(m,1H),3.31-3.63(m,1H),3.67-3.74(m,1H),3.79-3.90(m,1H),3.94-4.22(m,1H),5.24-5.63(m,2H),6.32-6.42(m,1H),7.23-7.49(m,1H),7.87-8.01(m,1H),9.47-10.54(m,1H)。 Compound 814: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.78-0.94 (m, 3H), 0.97-1.04 (m, 1H), 1.23-1.33 (m, 2H), 1.51-1.65 (m) ,4H),1.78-1.88(m,2H),1.91-1.96(m,1H),1.99-2.04(m,3H),2.25-2.46(m,1H),2.51-2.54(m,3H),2.58 -2.70(m, 1H), 2.81-3.26(m, 1H), 3.31-3.63(m, 1H), 3.67-3.74(m, 1H), 3.79-3.90(m, 1H), 3.94-4.22(m, 1H), 5.24-5.63 (m, 2H), 6.32-6.42 (m, 1H), 7.23-7.49 (m, 1H), 7.87-8.01 (m, 1H), 9.47-10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值416.2；實測值417.2；Rt=1.427min。LCMS (ESI): [M] + m/z: calculated 416.2; found 417.2; Rt=1.427 min.

實例371.外消旋 -2-[(2R,5S )-2-(1-乙醯基-3-哌啶基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物757)之合成Example 371. Racemic -2-[( 2R,5S )-2-(1-acetyl-3-piperidinyl)-5-methyl - 1-piperidinyl]-N-(6-amine Synthesis of yl-5-methyl-3-pyridyl)-2-oxoacetamide (Compound 757)

Figure 110128222-A0202-12-1644-481
Figure 110128222-A0202-12-1644-481

步驟1：外消旋-N-[5-[[2-[(2R,5S)-2-(1-乙醯基-3-哌啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[5-[[2-[(2R,5S)-2-(1-acetyl-3-piperidinyl)-5-methyl-1-piperidinyl] Synthesis of tert-butyl-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid

向1-[3-[(2R,5S )-5-甲基-2-哌啶基]-1-哌啶基]乙酮(0.7g，2.68mmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(792.57mg，2.68mmol)及TEA(1.36g，13.42mmol，1.87mL)中之溶液中分批添加HATU(1.12g，2.95mmol)。將所得混合物在25℃下攪拌3h，溶解於水(50ml)中且用EtOAc(3*20ml)萃取。將經合併之有機層用鹽水(2*25ml)洗滌，經Na2 SO4 乾燥 且移除溶劑，以得到N -[5-[[2-[(2R,5S )-2-(1-乙醯基-3-哌啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1.2g，2.39mmol，89.13%產率)。此化合物不經進一步純化即用於下一步驟。To 1-[3-[( 2R,5S )-5-methyl-2-piperidinyl]-1-piperidinyl]ethanone (0.7 g, 2.68 mmol, HCl), 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridinyl]amino]-2-side oxyacetic acid (792.57 mg, 2.68 mmol) and TEA (1.36 g, 13.42 mmol, 1.87 mL) To this solution was added HATU (1.12 g, 2.95 mmol) in portions. The resulting mixture was stirred at 25°C for 3h, dissolved in water (50ml) and extracted with EtOAc (3*20ml). The combined organic layers were washed with brine (2*25ml), dried over Na2SO4 and solvent removed to give N- [5-[[2-[( 2R,5S )-2-(1-ethyl) Acrylo-3-piperidinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl Ester (1.2 g, 2.39 mmol, 89.13% yield). This compound was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.93(d,3H),1.12(m,3H),1.42(s,9H),1.62(m,4H),1.85(m,2H),1.97(s,3H),2.16(s,3H),2.66(m,5H),3.78(m,2H),4.21(m,1H),7.93(m,1H),8.41(m,1H),9.04(m,1H),10.86(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.93(d,3H), 1.12(m,3H), 1.42(s,9H), 1.62(m,4H), 1.85(m,2H), 1.97(s, 3H), 2.16(s, 3H), 2.66(m, 5H), 3.78(m, 2H), 4.21(m, 1H), 7.93(m, 1H), 8.41(m, 1H), 9.04 (m, 1H), 10.86 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值501.2；實測值502.2；Rt=1.286min。LCMS (ESI): [M] + m/z: calculated 501.2; found 502.2; Rt=1.286 min.

步驟2：外消旋-2-[(2R,5S)-2-(1-乙醯基-3-哌啶基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物757 )之合成Step 2: Racemic-2-[(2R,5S)-2-(1-acetyl-3-piperidinyl)-5-methyl-1-piperidinyl]-N-(6-amine Synthesis of yl-5-methyl-3-pyridyl)-2-oxoacetamide ( Compound 757 )

將N -[5-[[2-[(2R,5S )-2-(1-乙醯基-3-哌啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1.2g，2.39mmol)及於二噁烷中之4.0M氯化氫溶液(4g，109.71mmol，5.00mL)於DCM(25mL)中之溶液在25℃下攪拌12h。移除溶劑且藉由HPLC(25-50% 0.5-7.5min水-MeOH(NH3 0.1%)，流速30ml/min(裝載泵4ml/min MeOH)目標質量402)純化殘餘物，以獲得兩種2-[(2R,5S )-2-(1-乙醯基-3-哌啶基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(146mg，363.64μmol，15.20%產率)及2-[3-[(2R,5S )-1-乙醯基-5-甲基-2-哌啶基]-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(106mg，264.01μmol，11.04%產率)。藉由2D-NMR證明經氫化之產物之結構為反式。 藉由2D-NMR亦證明最終產物之結構。 N- [5-[[2-[( 2R,5S )-2-(1-acetyl-3-piperidinyl)-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (1.2 g, 2.39 mmol) and a 4.0 M solution of hydrogen chloride in dioxane (4 g, 109.71 mmol, 5.00 mL) ) in DCM (25 mL) was stirred at 25 °C for 12 h. The solvent was removed and the residue was purified by HPLC (25-50% 0.5-7.5 min water-MeOH ( NH3 0.1%), flow rate 30 ml/min (loading pump 4 ml/min MeOH) target mass 402) to obtain two 2-[( 2R,5S )-2-(1-Acetyl-3-piperidinyl)-5-methyl-1-piperidinyl]-N-(6-amino-5 - methyl- 3-Pyridinyl)-2-oxoacetamide (146 mg, 363.64 μmol, 15.20% yield) and 2-[3-[( 2R,5S )-1-acetyl-5-methyl-2 -Piperidinyl ]-1-Piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxyacetamide (106 mg, 264.01 μmol, 11.04% yield ). The structure of the hydrogenated product was confirmed to be trans by 2D-NMR. The structure of the final product was also confirmed by 2D-NMR.

化合物757： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.89-0.96(m,3H),1.05-1.16(m,1H),1.18-1.40(m,2H),1.51-1.70(m,4H),1.74-1.88(m,2H),1.89-1.95(m,2H),1.95-1.99(m,3H),1.99-2.02(m,3H),2.78-2.96(m,1H),2.97-3.27(m,1H),3.55-3.67(m,1H),3.68-4.00(m,1H),4.09-4.24(m,2H),5.53-5.63(m,2H),7.40-7.49(m,1H),7.94-8.02(m,1H),10.26-10.35(m,1H)。 Compound 757: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.89-0.96 (m, 3H), 1.05-1.16 (m, 1H), 1.18-1.40 (m, 2H), 1.51-1.70 (m ,4H),1.74-1.88(m,2H),1.89-1.95(m,2H),1.95-1.99(m,3H),1.99-2.02(m,3H),2.78-2.96(m,1H),2.97 -3.27(m, 1H), 3.55-3.67(m, 1H), 3.68-4.00(m, 1H), 4.09-4.24(m, 2H), 5.53-5.63(m, 2H), 7.40-7.49(m, 1H), 7.94-8.02 (m, 1H), 10.26-10.35 (m, 1H).

實例372. LCMS(ESI)：[M]Example 372. LCMS (ESI): [M] ++ m/z：計算值401.2；實測值402.2；Rt=1.517min。m/z: Calculated value 401.2; Measured value 402.2; Rt=1.517min. N -(6-胺基-5-甲基吡啶-3-基)-2-(1',5-二甲基-[2,3'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物832)之合成 N- (6-amino-5-methylpyridin-3-yl)-2-(1',5-dimethyl-[2,3'-bipiperidin]-1-yl)-2-side Synthesis of Oxyacetamide (Compound 832)

Figure 110128222-A0202-12-1646-482
Figure 110128222-A0202-12-1646-482

步驟1：外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1-甲基-3-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(1-methyl-3-piperidinyl)-1- Synthesis of tertiary butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate

向1-甲基-3-[(2R,5S )-5-甲基-2-哌啶基]哌啶(0.7g，2.60mmol，2HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(767.69mg，2.60mmol)及TEA(1.58g，15.60mmol，2.17mL)中之溶液中分批添加HATU(1.09g，2.86mmol)。將所得混合物在25℃下攪拌3h，溶解於水(50ml)中且用EtOAc(3*20ml)萃取。將經合併之有機層用鹽水(2*25ml)洗滌，經Na2 SO4 乾燥且移除溶劑，以得到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(1-甲基-3-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.95g，2.01mmol，77.16%產率)。此化合物不經進一步純化即用於下一步驟。To 1-methyl-3-[( 2R,5S )-5-methyl-2-piperidinyl]piperidine (0.7 g, 2.60 mmol, 2HCl), 2-[[6-( tert-butoxy Carbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (767.69 mg, 2.60 mmol) and TEA (1.58 g, 15.60 mmol, 2.17 mL) in portions in a solution HATU (1.09 g, 2.86 mmol) was added. The resulting mixture was stirred at 25°C for 3h, dissolved in water (50ml) and extracted with EtOAc (3*20ml). The combined organic layers were washed with brine (2*25ml), dried over Na2SO4 and solvent removed to give N- [3-methyl-5-[[2-[( 2R,5S )-5 -Methyl-2-(1-methyl-3-piperidinyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.95 g, 2.01 mmol, 77.16% yield). This compound was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.78(m,2H),0.93(d,3H),1.12(m,2H),1.42(s,9H),1.62(m,6H),2.56(m,2H),2.65(s,3H),2.86(m,6H),3.31(m,2H),7.46(m,1H),8.41(m,1H),9.04(m,1H),10.87(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.78(m, 2H), 0.93(d, 3H), 1.12(m, 2H), 1.42(s, 9H), 1.62(m, 6H), 2.56(m, 2H), 2.65(s, 3H), 2.86(m, 6H), 3.31(m, 2H), 7.46(m, 1H), 8.41(m, 1H), 9.04(m, 1H), 10.87 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值373.2；實測值374.2；Rt=1.080min。LCMS (ESI): [M-Boc] + m/z: calculated 373.2; found 374.2; Rt=1.080 min.

步驟2：N -(6-胺基-5-甲基吡啶-3-基)-2-(1',5-二甲基-[2,3'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物832 )之合成Step 2: N- (6-Amino-5-methylpyridin-3-yl)-2-(1',5-dimethyl-[2,3'-bipiperidin]-1-yl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 832 )

將N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(1-甲基-3-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.95g，2.01mmol)及於二噁烷中 之4.0M氯化氫溶液(5g，137.13mmol，6.25mL)於DCM(15mL)中之溶液在25℃下攪拌5h。移除溶劑且藉由HPLC(45-45-65% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)管柱：YMC Triart C18 100x20mm，5um)，且第二次：20-20-30% 0-1-6min H2 O/ACN/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)目標質量373.49管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1-甲基-3-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(24mg，64.26μmol，3.20%產率)。 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(1-methyl-3-piperidinyl)-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.95 g, 2.01 mmol) and a 4.0 M solution of hydrogen chloride in dioxane (5 g, 137.13 mmol, 6.25 mL) The solution in DCM (15 mL) was stirred at 25 °C for 5 h. The solvent was removed and analyzed by HPLC (45-45-65% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min (loading pump 4 ml/min MeOH) Column: YMC Triart C18 100x20mm, 5um), and second time: 20-20-30% 0-1-6min H2O /ACN/0.1% NH4OH , flow rate: 30ml/min (loading pump 4ml/min MeOH) target mass 373.49 tubes Column: YMC Triart C18 100x20mm, 5um) The residue was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2- (1-Methyl-3-piperidinyl)-1-piperidinyl]-2-oxoacetamide (24 mg, 64.26 μmol, 3.20% yield).

化合物832：Compound 832:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.73-0.89(m,1H),0.89-0.97(m,3H),1.22-1.31(m,1H),1.34-1.41(m,1H),1.42-1.56(m,3H),1.56-1.68(m,2H),1.70-1.79(m,1H),1.79-1.85(m,2H),1.86-1.98(m,1H),1.99-2.03(m,3H),2.05-2.09(m,2H),2.10-2.16(m,2H),2.61-2.70(m,1H),2.80-3.28(m,1H),3.32-4.29(m,2H),5.53-5.65(m,2H),7.39-7.48(m,1H),7.90-8.03(m,1H),10.23-10.35(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.73-0.89(m,1H), 0.89-0.97(m,3H), 1.22-1.31(m,1H), 1.34-1.41(m,1H) ,1.42-1.56(m,3H),1.56-1.68(m,2H),1.70-1.79(m,1H),1.79-1.85(m,2H),1.86-1.98(m,1H),1.99-2.03( m,3H),2.05-2.09(m,2H),2.10-2.16(m,2H),2.61-2.70(m,1H),2.80-3.28(m,1H),3.32-4.29(m,2H), 5.53-5.65 (m, 2H), 7.39-7.48 (m, 1H), 7.90-8.03 (m, 1H), 10.23-10.35 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值373.2；實測值374.2；Rt=0.703min。LCMS (ESI): [M] + m/z: calculated 373.2; found 374.2; Rt=0.703 min.

實例373.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-[2,3'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物744)之合成Example 373. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-[2,3'-bipiperidin]-1-yl)-2-oxygen Synthesis of Ethylacetamide (Compound 744)

Figure 110128222-A0202-12-1647-483
Figure 110128222-A0202-12-1647-483

步驟1：外消旋-3-((2R,5S)-1-(2-((6-((第三丁氧基羰基)胺基)-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)-5,6-二氫吡啶-1(2H)-甲酸苯甲酯之合成Step 1: Racemic-3-((2R,5S)-1-(2-((6-((3rd-butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino )-2-oxyethanoyl)-5-methylpiperidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid benzyl

向5-[(2R,5S )-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(10g，3.18mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(939.16mg，3.18mmol)及TEA(1.61g，15.90mmol，2.22mL)於DMF(50mL)中之溶液中分批添加HATU(1.33g，3.50mmol)。將所得混合物在25℃下攪拌3 h，溶解於水(300ml)中且用EtOAc(3*100ml)萃取。將經合併之有機層用鹽水(3*100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(11g)。藉由梯度層析(CHCl3 -MTBE)純化粗產物，以獲得5-[(2R,5S )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(1g，1.69mmol，53.14%產率)。To 5-[( 2R,5S )-5-methyl-2-piperidinyl]-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl (10 g, 3.18 mmol), 2-[[ 6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (939.16 mg, 3.18 mmol) and TEA (1.61 g, 15.90 mmol, 2.22 mL) in DMF (50 mL) was added portionwise HATU (1.33 g, 3.50 mmol). The resulting mixture was stirred at 25 °C for 3 h, dissolved in water (300 ml) and extracted with EtOAc (3*100 ml). The combined organic layers were washed with brine (3*100ml), dried over Na2SO4 and evaporated to obtain crude product (11 g). The crude product was purified by gradient chromatography ( CHCl3 -MTBE) to obtain 5-[( 2R,5S )-1-[2-[[6-( tert- butoxycarbonylamino)-5-methyl -3-Pyridinyl]amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl]-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester ( 1 g, 1.69 mmol, 53.14% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.90(d,3H),1.12(m,1H),1.42(s,9H),1.98(m,4H),2.22(m,2H),2.24(s,3H),2.78(m,4H),3.12(m,2H),3.78(m,4H),4.12(m,1H),4.56(m,1H),5.06(s,2H),7.32(m,5H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.90(d, 3H), 1.12(m, 1H), 1.42(s, 9H), 1.98(m, 4H), 2.22(m, 2H), 2.24(s, 3H), 2.78(m, 4H), 3.12(m, 2H), 3.78(m, 4H), 4.12(m, 1H), 4.56(m, 1H), 5.06(s, 2H), 7.32 (m, 5H).

LCMS(ESI)：[M]+ m/z：計算值591.2；實測值592.2；Rt=1.606min。LCMS (ESI): [M] + m/z: calculated 591.2; found 592.2; Rt=1.606 min.

步驟2：外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(3-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 2: Racemic-N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(3-piperidinyl)-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

向5-[(2R,5S )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(1g，1.69mmol)於MeOH(40mL)中之溶液中添加乾燥的487型鈀(10%於碳上)(0.5g，469.84μmol，10%純度)且將所得混合物在氫氣氣氛、40℃下攪拌72h。藉由LCMS控制轉化。過濾出催化劑且移除溶劑，以獲得粗產物順式異構物及反式異構物之混合物(在氫化期間，觀測到雙鍵之遷移)。藉由HPLC(50-50-80% 0-1-6min H2 O/MeOH/0.1% NH3 ，流速：30ml/min(裝載泵4ml/min MeOH)目標質量459管柱：YMC Triart C18 100x20mm，5um)純化粗產物，以獲得三種級分。純化各級分，以獲得兩種產物：N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(3-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(170mg，369.90μmol，21.89%產率)及N -[3-甲基-5-[[2-[(2S,5S )-5-甲基-2-(3-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(80mg，174.07μmol，10.30%產率)。藉由2D-NMR證明主要級分之結構為反式。 將此級分用於下一步驟。To 5-[( 2R,5S )-1-[2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-side oxyethyl Acyl]-5-methyl-2-piperidinyl]-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (1 g, 1.69 mmol) in MeOH (40 mL) was added to dry of palladium type 487 (10% on carbon) (0.5 g, 469.84 μmol, 10% purity) and the resulting mixture was stirred at 40 °C for 72 h under a hydrogen atmosphere. Conversion was controlled by LCMS. The catalyst was filtered off and the solvent was removed to obtain a crude mixture of cis and trans isomers (during hydrogenation, migration of double bonds was observed). By HPLC (50-50-80% 0-1-6 min H2O /MeOH/0.1% NH3 , flow rate: 30ml/min (loading pump 4ml/min MeOH) target mass 459 Column: YMC Triart C18 100x20mm, 5um) The crude product was purified to obtain three fractions. The fractions were purified to obtain two products: N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(3-piperidinyl)-1-piperidine Peridyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (170 mg, 369.90 μmol, 21.89% yield) and N- [3-methyl-5- [[2-[( 2S,5S )-5-methyl-2-(3-piperidinyl)-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl ] tert -butyl carbamate (80 mg, 174.07 μmol, 10.30% yield). The structure of the main fraction was confirmed to be trans by 2D-NMR. Use this fraction for the next step.

LCMS(ESI)：[M]+ m/z：計算值459.2；實測值460.2；Rt=1.620min。LCMS (ESI): [M] + m/z: calculated 459.2; found 460.2; Rt=1.620 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-[2,3'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物744 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-[2,3'-bipiperidin]-1-yl)-2-oxygen Synthesis of Ethylacetamide ( Compound 744 )

將N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(3-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(80mg，174.07μmol)於DCM(5mL)中之溶液在25℃下攪拌12h。移除溶劑且藉由HPLC(0-5min 30-80%水-MeOH(NH3 0.1%)，流速30ml/min(裝載泵4ml/min MeCN(NH3 0.1%))管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)純化殘餘物，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(11mg，30.60μmol，17.58%產率)及具有順式異構物雜質之其他級分29mg。 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(3-piperidinyl)-1-piperidinyl]-2-side oxyethyl A solution of acyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (80 mg, 174.07 [mu]mol) in DCM (5 mL) was stirred at 25&lt;0&gt;C for 12 h. The solvent was removed and by HPLC (0-5 min 30-80% water-MeOH ( NH3 0.1%), flow rate 30 ml/min (loading pump 4 ml/min MeCN ( NH3 0.1%)) Column: YMC-Actus Triart C18 100*20mml.DS-5um) purify the residue to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2- (3-Piperidinyl)-1-piperidinyl]-2-oxoacetamide (11 mg, 30.60 μmol, 17.58% yield) and other fractions with cis isomer impurity 29 mg.

化合物744： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.91-0.94(m,3H),1.19-1.33(m,2H),1.47-1.64(m,4H),1.73-2.00(m,6H),2.00-2.03(m,3H),2.15-2.28(m,2H),2.77-2.82(m,1H),2.87-2.99(m,1H),3.38-3.57(m,1H),3.98-4.34(m,1H),5.52-5.64(m,2H),7.40-7.50(m,1H),7.93-8.04(m,1H),10.18-10.42(m,1H)。 Compound 744: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.91-0.94 (m, 3H), 1.19-1.33 (m, 2H), 1.47-1.64 (m, 4H), 1.73-2.00 (m ,6H),2.00-2.03(m,3H),2.15-2.28(m,2H),2.77-2.82(m,1H),2.87-2.99(m,1H),3.38-3.57(m,1H),3.98 -4.34(m, 1H), 5.52-5.64(m, 2H), 7.40-7.50(m, 1H), 7.93-8.04(m, 1H), 10.18-10.42(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值359.2；實測值360.2；Rt=0.887min。LCMS (ESI): [M] + m/z: calculated 359.2; found 360.2; Rt=0.887 min.

實例374.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物887及化合物900)之合成Example 374. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidine-1- Synthesis of yl)-2-oxoacetamide (Compound 887 and Compound 900)

Figure 110128222-A0202-12-1649-484
Figure 110128222-A0202-12-1649-484

步驟1：(3-甲基-5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxyacetate Synthesis of tertiary butyl amino)pyridin-2-yl)carbamate

將DIPEA(656.52mg，5.08mmol，884.80μL)添加到相應2-((6-((第三丁氧基 羰基)胺基)-5-甲基吡啶-3-基)胺基)-2-側氧基乙酸(0.6g，2.03mmol)及5-(4-(5-甲基哌啶-2-基)苯基)噻唑(525.00mg，2.03mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(849.85mg，2.24mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH-水為溶析液混合物)，以得到(3-甲基-5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三 丁酯(119.4mg，222.90μmol，10.97%產率)。DIPEA (656.52 mg, 5.08 mmol, 884.80 μL) was added to the corresponding 2-((6-(( tertiary butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino)-2- Pendant oxyacetic acid (0.6 g, 2.03 mmol) and a solution of 5-(4-(5-methylpiperidin-2-yl)phenyl)thiazole (525.00 mg, 2.03 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (849.85 mg, 2.24 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH-water as eluent mixture) to give (3-methyl-5-(2-(5-methyl-2- (4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert -butyl ester (119.4 mg, 222.90 μmol, 10.97% yield).

LCMS(ESI)：[M]+ m/z：計算值535.2；實測值536.2；Rt=3.532min。LCMS (ESI): [M] + m/z: calculated 535.2; found 536.2; Rt=3.532 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidine-1- Synthesis of )-2-side oxyacetamide

將(3-甲基-5-(2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁 酯(119.4mg，222.90μmol)溶解於水(5mL)及二噁烷(2mL)之混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(46.5mg，106.76μmol，47.90%產率)。(3-methyl-5-(2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxyacetamide ) 3-butyl pyridin-2-yl)carbamate (119.4 mg, 222.90 [mu]mol) was dissolved in a mixture of water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give N- (6-amino-5-methylpyridin-3-yl)-2- (5-Methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxyacetamide (46.5 mg, 106.76 μmol, 47.90% yield).

LCMS(ESI)：[M]+ m/z：計算值435.2；實測值436.2；Rt=2.221min。LCMS (ESI): [M] + m/z: calculated 435.2; found 436.2; Rt=2.221 min.

步驟3：掌性分離(化合物887 及化合物900 )Step 3: Chiral separation ( compound 887 and compound 900 )

藉由掌性HPLC(管柱：YMC Chiral Art Cellulose-SC(250 * 20mm，5 mkm)，IPA-MeOH，50-50，10mL/min；215nm，管柱溫度：20℃；保留時間(異構物A)=17.69min；保留時間(異構物B)=18.70min；保留時間(異構物C)=23,65min；保留時間(異構物D)=33,10min)將N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(4-(噻唑-5-基)苯基)哌啶-1-基)-2-側氧基乙醯胺(46.5mg，106.76mmol)分成鏡像異構物。by chiral HPLC (column: YMC Chiral Art Cellulose-SC (250*20mm, 5 mkm), IPA-MeOH, 50-50, 10 mL/min; 215 nm, column temperature: 20°C; retention time (isomerization) Compound A)=17.69min; retention time (isomer B)=18.70min; retention time (isomer C)=23,65min; retention time (isomer D)=33,10min) N- (6 -Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(4-(thiazol-5-yl)phenyl)piperidin-1-yl)-2-oxygen Ethylacetamide (46.5 mg, 106.76 mmol) separated into the enantiomers.

化合物887 於分析條件下(管柱：IC，IPA-MeOH，50-50，0.5ml/min為流動相)之保留時間為48.43min且化合物900 之保留時間為25.41min。The retention time of compound 887 under analytical conditions (column: IC, IPA-MeOH, 50-50, 0.5 ml/min as mobile phase) was 48.43 min and the retention time of compound 900 was 25.41 min.

化合物887：保留時間：48.43minCompound 887: retention time: 48.43min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.34(m,1H),1.65(m,1H),1.87(m,1H),1.99(m,3H),2.19(m,2H),2.98(dd,1H),3.73(dd,1H),5.60(m,3H),7.36(d,1H),7.41(m,1H),7.48(s,1H),7.68(m,2H),7.99(m,1H),8.30(s,1H),9.06(s,1H),10.50(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.65(m, 1H), 1.87(m, 1H), 1.99(m, 3H), 2.19(m,2H),2.98(dd,1H),3.73(dd,1H),5.60(m,3H),7.36(d,1H),7.41(m,1H),7.48(s,1H),7.68 (m, 2H), 7.99 (m, 1H), 8.30 (s, 1H), 9.06 (s, 1H), 10.50 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值435.2；實測值436.2；Rt=0.858min。LCMS (ESI): [M] + m/z: calculated 435.2; found 436.2; Rt=0.858 min.

化合物900：保留時間：25.41minCompound 900: retention time: 25.41min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.34(m,1H),1.66(m,1H),1.86(m,1H),1.99(m,4H),2.18(m,1H),2.99(m,1H),3.83(m,1H),5.60(m,3H),7.41(m,3H),7.68(m,2H),7.99(m,1H),8.30(s,1H),9.06(s,1H),10.50(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.34(m, 1H), 1.66(m, 1H), 1.86(m, 1H), 1.99(m, 4H), 2.18(m, 1H), 2.99(m, 1H), 3.83(m, 1H), 5.60(m, 3H), 7.41(m, 3H), 7.68(m, 2H), 7.99(m, 1H), 8.30 (s, 1H), 9.06 (s, 1H), 10.50 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值435.2；實測值436.2；Rt=0.867min。LCMS (ESI): [M] + m/z: calculated 435.2; found 436.2; Rt=0.867 min.

實例375. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1069)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1049)之合成Example 375. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4,4 -Difluoro-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 1069) and N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 1049)

Figure 110128222-A0202-12-1652-485
Figure 110128222-A0202-12-1652-485

步驟1.N-[5-[[2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1. N-[5-[[2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5-methyl-1-piperidine Synthesis of 3-butyl pyridyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

將5-[(2R,5R)-4,4-二氟-5-甲基-2-哌啶基]-1,3-苯并噻唑(480mg，1.79mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(528.24mg，1.79mmol)、三乙胺(905.08mg，8.94mmol，1.25mL)混合於DMF(10mL)中，然後添加HATU(1.02g，2.68mmol)。將所得混合物在25℃下攪拌12h。蒸發溶劑且藉由HPLC(2-10min 60-65%甲醇30ml/min，裝載泵4ml/min甲醇，目標質量545，管柱：SunFire 100*19mm，5微米)純化粗品沉澱，以獲得N-[5-[[2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(69.2mg，126.83μmol，7.09%產率)LCMS(ESI)：[M+1]+ m/z：計算值545.2；實測值546.2；Rt=1.403min。5-[(2R,5R)-4,4-difluoro-5-methyl-2-piperidinyl]-1,3-benzothiazole (480 mg, 1.79 mmol), 2-[[6-( tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (528.24 mg, 1.79 mmol), triethylamine (905.08 mg, 8.94 mmol, 1.25 mL) ) in DMF (10 mL), then HATU (1.02 g, 2.68 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the crude precipitate was purified by HPLC (2-10 min 60-65% methanol 30 ml/min, loading pump 4 ml/min methanol, target mass 545, column: SunFire 100*19 mm, 5 microns) to obtain N-[ 5-[[2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (69.2 mg, 126.83 μmol, 7.09% yield) LCMS (ESI): [M+1] + m/z: Calculated value 545.2; Measured value 546.2; Rt=1.403min.

步驟2.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4 - Synthesis of difluoro-5-methyl-1-piperidinyl]-2-oxoacetamide

將N-[5-[[2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(56.8mg，104.11μmol)於二噁烷(2mL)及水(2mL)中之溶液在100℃下加熱12h。蒸發溶劑，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基 -1-哌啶基]-2-側氧基乙醯胺(44mg，粗品)。N-[5-[[2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5-methyl-1-piperidinyl ]-2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (56.8 mg, 104.11 μmol) in dioxane (2 mL) and water (2 mL) The solution was heated at 100°C for 12h. The solvent was evaporated to obtain N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4 ,4-Difluoro-5-methyl -1-Piperidinyl]-2-oxyacetamide (44 mg, crude).

LCMS(ESI)：[M+1]+ m/z：計算值445.2；實測值446.0；Rt=2.330min。LCMS (ESI): [M+1] + m/z: calculated 445.2; found 446.0; Rt=2.330 min.

步驟3.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1069 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1049 )之拆分Step 3. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4,4 -Difluoro-5-methyl-1-piperidinyl]-2-oxyacetamide ( Compound 1069 ) and N-(6-amino-5-methyl-3-pyridyl)-2- [(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 1049 ) Resolution

藉由掌性層析(Chiralpak IC-II(250*30mm，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)分離非鏡像異構物之混合物，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(15.7mg，35.24μmol，35.68%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(12.73mg，28.58μmol，28.93%產率)The mixture of diastereomers was separated by chiral chromatography (Chiralpak IC-II (250*30mm, 5mkm), hexane-IPA-MeOH, 60-20-20, 12ml/min) to obtain N-( 6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5- Methyl-1-piperidinyl]-2-oxyacetamide (15.7 mg, 35.24 μmol, 35.68% yield) and N-(6-amino-5-methyl-3-pyridyl)- 2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-side oxyethyl Amide (12.73 mg, 28.58 μmol, 28.93% yield)

製備型：化合物1069 之RT(Chiralpak IC-II(250*30mm，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)=31.414；化合物1049 之RT(Chiralpak IC-II(250*30mm，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)=37.133Preparation: RT of compound 1069 (Chiralpak IC-II (250*30mm, 5mkm), hexane-IPA-MeOH, 60-20-20, 12ml/min)=31.414; RT of compound 1049 (Chiralpak IC-II ( 250*30mm, 5mkm), Hexane-IPA-MeOH, 60-20-20, 12ml/min)=37.133

分析型：化合物1049 之RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6ml/min)=24.265；分析型：化合物1069 之RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6ml/min)=20.813Analytical type: RT of compound 1049 (Chiralpak IC (250*4.6, 5mkm), hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)=24.265; analytical type: RT of compound 1069 (Chiralpak IC ( 250*4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6ml/min)=20.813

化合物1049 1H NMR(600MHz,DMSO-d 6 )δ 1.09-1.14(m,3H),1.95-2.08(m,3H),2.15-2.30(m,1H),2.95-3.16(m,2H),3.38-3.56(m,1H),3.80-4.41(m,1H),5.54-5.69(m,2H),5.69-6.06(m,1H),7.38-7.56(m,2H),7.91-8.09(m,2H),8.11-8.21(m,1H),9.40(s,1H),10.51-10.75(m,1H)。 Compound 1049 1H NMR (600MHz, DMSO- d 6 )δ 1.09-1.14(m,3H), 1.95-2.08(m,3H), 2.15-2.30(m,1H), 2.95-3.16(m,2H), 3.38 -3.56(m,1H),3.80-4.41(m,1H),5.54-5.69(m,2H),5.69-6.06(m,1H),7.38-7.56(m,2H),7.91-8.09(m, 2H), 8.11-8.21 (m, 1H), 9.40 (s, 1H), 10.51-10.75 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值445.2；實測值446.0；Rt=2.330min。LCMS (ESI): [M+1] + m/z: calculated 445.2; found 446.0; Rt=2.330 min.

化合物1069 1H NMR(600MHz,DMSO-d 6 )δ 1.09-1.14(m,3H),1.95-2.08(m, 3H),2.15-2.30(m,1H),2.95-3.16(m,2H),3.38-3.56(m,1H),3.80-4.41(m,1H),5.54-5.69(m,2H),5.69-6.06(m,1H),7.38-7.56(m,2H),7.91-8.09(m,2H),8.11-8.21(m,1H),9.40(s,1H),10.51-10.75(m,1H)。 Compound 1069 1H NMR (600MHz, DMSO- d 6 )δ 1.09-1.14(m, 3H), 1.95-2.08(m, 3H), 2.15-2.30(m, 1H), 2.95-3.16(m, 2H), 3.38 -3.56(m,1H),3.80-4.41(m,1H),5.54-5.69(m,2H),5.69-6.06(m,1H),7.38-7.56(m,2H),7.91-8.09(m, 2H), 8.11-8.21 (m, 1H), 9.40 (s, 1H), 10.51-10.75 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值445.2；實測值446.0；Rt=2.330min。LCMS (ESI): [M+1] + m/z: calculated 445.2; found 446.0; Rt=2.330 min.

實例376. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-乙基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1032)之合成Example 376. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)-1 Synthesis of -Piperidinyl]-2-Pendant Oxyacetamide (Compound 1032)

Figure 110128222-A0202-12-1654-486
Figure 110128222-A0202-12-1654-486

向(2R,5S)-5-乙基-2-(1H-吡唑-4-基)哌啶(200mg，793.07μmol，2HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(245.90mg，832.73μmol)及三乙胺(401.26mg，3.97mmol，552.69μL)於二甲基甲醯胺(3mL)中之經攪拌之混合物中添加TATU(280.97mg，872.38μmol)。將所得反應混合物在25℃下攪拌4h。然後，使其經歷HPLC(40-40-75% 0-1-6min H2 O/MeOH，流速：30ml/min；管柱：Chromatorex 18 SMB 100-5T 100x19mm，5um)，得到N-[5-[[2-[(2R,5S)-5-乙基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(133mg，291.32μmol，36.73%產率)。To (2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)piperidine (200 mg, 793.07 μmol, 2HCl), 2-[[6-(tert-butoxycarbonylamino) )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (245.90 mg, 832.73 μmol) and triethylamine (401.26 mg, 3.97 mmol, 552.69 μL) in dimethylformamide To the stirred mixture in (3 mL) was added TATU (280.97 mg, 872.38 μmol). The resulting reaction mixture was stirred at 25 °C for 4 h. It was then subjected to HPLC (40-40-75% 0-1-6min H2O /MeOH, flow rate: 30ml/min; column: Chromatorex 18 SMB 100-5T 100x19mm, 5um) to give N-[5- [[2-[(2R,5S)-5-Ethyl-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-oxyacetyl]amino]-3 - tert-butyl methyl-2-pyridyl]carbamate (133 mg, 291.32 μmol, 36.73% yield).

LCMS(ESI)：[M+1]+ m/z：計算值456.2；實測值457.2；Rt=2.741min。LCMS (ESI): [M+1] + m/z: calculated 456.2; found 457.2; Rt=2.741 min.

將水(500.00mg，27.75mmol，0.5mL)添加到N-[5-[[2-[(2R,5S)-5-乙基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(133mg，291.32μmol)於二噁烷(1.5mL)中之溶液中。將所得混合物在100℃下攪拌16h。然後，使其經歷HPLC(30-75% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-乙基-2-(1H-吡唑-4-基)-1-哌啶基]-2-側氧基 乙醯胺(69mg，193.59μmol，66.45%產率)。Water (500.00 mg, 27.75 mmol, 0.5 mL) was added to N-[5-[[2-[(2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)-1- Piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (133 mg, 291.32 μmol) in dioxane (1.5 mL) in solution. The resulting mixture was stirred at 100 °C for 16 h. It was then subjected to HPLC (30-75% 0-5 min H2O /MeOH/0.1% NH4OH, flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) to give N-(6-amino- 5-Methyl-3-pyridyl)-2-[(2R,5S)-5-ethyl-2-(1H-pyrazol-4-yl)-1-piperidinyl]-2-side oxy Acetamide (69 mg, 193.59 μmol, 66.45% yield).

LCMS(ESI)：[M+1]+ m/z：計算值356.2；實測值357.2；Rt=2.161min。LCMS (ESI): [M+1] + m/z: calculated 356.2; found 357.2; Rt=2.161 min.

實例377. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物716)之合成Example 377. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazol-6-yl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxoacetamide (compound 716)

Figure 110128222-A0202-12-1655-487
Figure 110128222-A0202-12-1655-487

步驟1.N-[5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1. N-[5-[[2-[(2S,5R)-2-(1,3-benzothiazol-6-yl)-5-methyl-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(508.37mg，1.72mmol)及TEA(1.74g，17.22mmol，2.40mL)溶解於DMF(12mL)中且冷卻至0℃，添加HATU(981.90mg，2.58mmol)且在0℃下將混合物攪拌15min。添加6-[(2S,5R)-5-甲基-2-哌啶基]-1,3-苯并噻唑(0.4g，1.72mmol)且將混合物升溫至室溫且攪拌3h。添加10ml乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(2-10min 10-60%水/甲醇(裝載泵4ml甲醇)，管柱：TRIART 100*20 5微米)進行純化，以得到N-[5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.147g，288.45μmol，16.75%產率)2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (508.37 mg, 1.72 mmol) and TEA (1.74 g , 17.22 mmol, 2.40 mL) was dissolved in DMF (12 mL) and cooled to 0 °C, HATU (981.90 mg, 2.58 mmol) was added and the mixture was stirred at 0 °C for 15 min. 6-[(2S,5R)-5-methyl-2-piperidinyl]-1,3-benzothiazole (0.4 g, 1.72 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. 10 ml of ethyl acetate were added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product by HPLC (2-10 min 10-60% water/methanol (load pump 4 ml methanol), column : TRIART 100*20 5 μm) to give N-[5-[[2-[(2S,5R)-2-(1,3-benzothiazol-6-yl)-5-methyl- 1-Piperidinyl]-2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.147 g, 288.45 μmol, 16.75% yield)

LCMS(ESI)：[M+1]+ m/z：計算值509.2；實測值510.2；Rt=1.35min。LCMS (ESI): [M+1] + m/z: calculated 509.2; found 510.2; Rt=1.35 min.

步驟2.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物716 )之合成Step 2. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazol-6-yl)-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 716 )

將N-[5-[[2-[(2S,5R)-2-(1,3-苯并噻唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.147g，288.45μmol)溶解於 二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空、55℃下濃縮反應混合物，以得到粗產物，其藉由HPLC(2-10min 50-60%甲醇/H2 O 30ml/min(裝載泵4ml甲醇)，管柱：SunFire 100*19mm，5微米)進行純化，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1,3-苯并噻唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.04g，97.68μmol，33.86%產率)。N-[5-[[2-[(2S,5R)-2-(1,3-benzothiazol-6-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.147 g, 288.45 μmol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL), then added Stir at 100°C for 12h. The reaction mixture was concentrated under vacuum at 55°C to give crude product by HPLC (2-10min 50-60% methanol/ H2O 30ml/min (load pump 4ml methanol), column: SunFire 100*19mm, 5 microns) to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1,3-benzothiazol-6-yl) )-5-methyl-1-piperidinyl]-2-oxoacetamide (0.04 g, 97.68 μmol, 33.86% yield).

1H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.35(m,1H),1.71(m,1H),1.87(m,1H),1.99(m,3H),2.13(m,1H),2.29(m,1H),2.78(m,1H),3.76(m,1H),5.63(m,3H),7.45(m,2H),8.08(m,3H),9.36(s,1H),10.49(m,1H)1H NMR (DMSO-d6, 600MHz): δ (ppm) 1.01 (m, 3H), 1.35 (m, 1H), 1.71 (m, 1H), 1.87 (m, 1H), 1.99 (m, 3H), 2.13 (m,1H),2.29(m,1H),2.78(m,1H),3.76(m,1H),5.63(m,3H),7.45(m,2H),8.08(m,3H),9.36( s,1H),10.49(m,1H)

LCMS(ESI)：[M+1]+ m/z：計算值409.2；實測值410.2；Rt=1.745min。LCMS (ESI): [M+1] + m/z: calculated 409.2; found 410.2; Rt=1.745 min.

實例378. 2-[(2S ,5R )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2R ,5S )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物281及化合物296)之合成Example 378. 2-[( 2S , 5R )-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-N-(6-amino - 5-methyl 2-[(2 R ,5 S )-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidine [Synthesis of]-N-(6-amino - 5-methyl-3-pyridyl)-2-oxoacetamide (Compound 281 and Compound 296)

Figure 110128222-A0202-12-1656-488
Figure 110128222-A0202-12-1656-488

步驟1：外消旋-N-[5-[[2-[(2S,5R)-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[5-[[2-[(2S,5R)-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-2- Synthesis of pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向N -[4-(5-甲基-2-哌啶基)環己基]乙醯胺(0.5g，2.10mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(619.40mg，2.10mmol)及HATU(797.57mg，2.10mmol)於DMF(4mL)中之經攪拌之溶液中添加三乙胺(1.06g，10.49mmol，1.46mL)。將所得反應混合物在室溫下攪拌12小時。12小時之後，添加水(40mL)且用EtOAc(3 x 20mL)萃取。將經合併之有機層用鹽水(3 x 20mL)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以獲得粗產物，其藉由HPLC(溶析液：30-30-65%，0-1-5min，水-乙腈；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFireC18 100 x 19mm，5um)進行純化，以獲得呈淡黃色固體之外消旋 -N -[5-[[2-[(2S ,5R )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(220mg，426.65μmol，20.34%產率)。To N- [4-(5-methyl-2-piperidinyl)cyclohexyl]acetamide (0.5 g, 2.10 mmol), 2-[[6-( tert- butoxycarbonylamino)-5 To a stirred solution of -methyl-3-pyridyl]amino]-2-oxoacetic acid (619.40 mg, 2.10 mmol) and HATU (797.57 mg, 2.10 mmol) in DMF (4 mL) was added triethyl Amine (1.06 g, 10.49 mmol, 1.46 mL). The resulting reaction mixture was stirred at room temperature for 12 hours. After 12 hours, water (40 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude product by HPLC (eluent: 30-30-65%, 0 -1-5min, water-acetonitrile; flow rate: 30mL/min; loading pump: 4mL/min, acetonitrile; column: SunFireC18 100 x 19mm, 5um) for purification to obtain rac - N- as a pale yellow solid [5-[[2-[(2 S ,5 R )-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-2-oxoacetyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (220 mg, 426.65 [mu]mol, 20.34% yield).

LCMS(ESI)：[M+H]+ m/z：計算值515.4；實測值516.4；Rt=3.229min。LCMS (ESI): [M+H] + m/z: calculated 515.4; found 516.4; Rt=3.229 min.

步驟2：外消旋-(2-[(2S,5R)-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺之合成Step 2: Racemic-(2-[(2S,5R)-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-N-(6-amino- Synthesis of 5-methyl-3-pyridyl)-2-oxoacetamide

向外消旋 -N -[5-[[2-[(2S ,5R )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(220.00mg，426.65μmol)於DCM(10mL)中之經攪拌之溶液中添加於二噁烷中之4M氯化氫溶液(4.00g，109.71mmol，5mL)。將所得反應混合物在25℃下攪拌12小時。12小時之後，在真空中蒸發反應混合物且使粗產物經歷HPLC純化(溶析液：0-5min，30-40%，水-甲醇(0.1% NH3 )；流速：30mL/min；裝載泵：5mL/min，甲醇(0.1% NH3 )；管柱：YMC-Actus Triart C18 100 x 20mm，5um)，以得到呈白色固體之外消旋 -(2-[(2S ,5R )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(73mg，175.68μmol，41.18%產率)。 Racemic - N- [5-[[2-[( 2S , 5R )-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-2- To a stirred solution of pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (220.00 mg, 426.65 μmol) in DCM (10 mL) was added to dioxane 4M hydrogen chloride solution in alkane (4.00 g, 109.71 mmol, 5 mL). The resulting reaction mixture was stirred at 25°C for 12 hours. After 12 hours, the reaction mixture was evaporated in vacuo and the crude product was subjected to HPLC purification (eluent: 0-5 min, 30-40%, water-methanol (0.1% NH3 ); flow rate: 30 mL/min; loading pump: 5 mL/min, methanol (0.1% NH3 ); column: YMC-Actus Triart C18 100 x 20 mm, 5um) to give rac- (2-[(2S, 5R )-2 as a white solid -(4 - Acetamidocyclohexyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxoacetamide Amine (73 mg, 175.68 μmol, 41.18% yield).

LCMS(ESI)：[M+H]+ m/z：計算值415.3；實測值416.4；Rt=2.120min。LCMS (ESI): [M+H] + m/z: calculated 415.3; found 416.4; Rt=2.120 min.

步驟3：2-[(2S,5R)-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-Step 3: 2-[(2S,5R)-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl- 3- 吡啶基)-2-側氧基乙醯胺及2-[(2R,5S)-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物281 及化合物296 )之掌性分離Pyridyl)-2-oxyacetamide and 2-[(2R,5S)-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-N-( Chiral separation of 6-amino-5-methyl-3-pyridyl)-2-oxoacetamide ( compound 281 and compound 296 )

使外消旋 -(2-[(2S ,5R )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(73mg，175.68μmol)經歷掌性HPLC純化(管柱：Chiralpak OJ-H(250 x 20mm，5um)；流動相：己烷-IPA-MeOH，80-10-10；流速：12mL/min)，以得到呈白色固體之2-[(2S, 5R )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物281 ，21mg)及2-[(2R ,5S )-2-(4-乙醯胺基環己基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物296 ，39mg)。Make rac- (2-[( 2S , 5R )-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-N-(6 - amino- 5-Methyl-3-pyridyl)-2-oxyacetamide (73 mg, 175.68 μmol) was purified by chiral HPLC (column: Chiralpak OJ-H (250 x 20 mm, 5 um); mobile phase: hexane Alkane-IPA-MeOH, 80-10-10 ; flow rate: 12 mL/min) to give 2-[( 2S, 5R)-2-(4-acetamidocyclohexyl)-5 as a white solid -Methyl - 1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxyacetamide ( compound 281 , 21 mg) and 2-[(2 R ,5 S )-2-(4-acetamidocyclohexyl)-5-methyl-1-piperidinyl]-N-(6-amino - 5-methyl-3-pyridyl)- 2-Pendant oxyacetamide ( compound 296 , 39 mg).

化合物281： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.81-0.98(m,5H),1.02-1.24(m,3H),1.27-1.46(m,1H),1.54-1.68(m,3H),1.73-1.92(m,9H),2.00-2.08(m,3H),2.65-2.97(m,1H),3.40-3.47(m,1H),3.95-4.21(m,1H),5.61(s,2H),7.41-7.53(m,1H),7.63-7.73(m,1H),7.96-8.04(m,1H),10.25-10.37(m,1H)。 Compound 281: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.81-0.98 (m, 5H), 1.02-1.24 (m, 3H), 1.27-1.46 (m, 1H), 1.54-1.68 ( m,3H),1.73-1.92(m,9H),2.00-2.08(m,3H),2.65-2.97(m,1H),3.40-3.47(m,1H),3.95-4.21(m,1H), 5.61(s, 2H), 7.41-7.53(m, 1H), 7.63-7.73(m, 1H), 7.96-8.04(m, 1H), 10.25-10.37(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值415.3；實測值416.2；Rt=3.326min。LCMS (ESI): [M+H] + m/z: calculated 415.3; found 416.2; Rt=3.326 min.

掌性HPLC：Rt=23.08min(管柱：OJ-H；流動相：己烷-IPA-MeOH，80-10-10；流速：0.6mL/min)。Chiral HPLC: Rt=23.08 min (column: OJ-H; mobile phase: hexane-IPA-MeOH, 80-10-10; flow rate: 0.6 mL/min).

化合物296： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.81-0.98(m,5H),1.02-1.24(m,3H),1.27-1.46(m,1H),1.54-1.68(m,3H),1.73-1.92(m,9H),2.00-2.08(m,3H),2.65-2.97(m,1H),3.40-3.47(m,1H),3.95-4.21(m,1H),5.61(s,2H),7.41-7.53(m,1H),7.63-7.73(m,1H),7.96-8.04(m,1H),10.25-10.37(m,1H)。 Compound 296: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.81-0.98 (m, 5H), 1.02-1.24 (m, 3H), 1.27-1.46 (m, 1H), 1.54-1.68 ( m,3H),1.73-1.92(m,9H),2.00-2.08(m,3H),2.65-2.97(m,1H),3.40-3.47(m,1H),3.95-4.21(m,1H), 5.61(s, 2H), 7.41-7.53(m, 1H), 7.63-7.73(m, 1H), 7.96-8.04(m, 1H), 10.25-10.37(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值415.3；實測值416.2；Rt=3.375min。LCMS (ESI): [M+H] + m/z: calculated 415.3; found 416.2; Rt=3.375 min.

掌性HPLC：Rt=11.89min(管柱：OJ-H；流動相：己烷-IPA-MeOH，80-10-10；流速：0.6mL/min)。Chiral HPLC: Rt=11.89 min (column: OJ-H; mobile phase: hexane-IPA-MeOH, 80-10-10; flow rate: 0.6 mL/min).

實例379. 外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物861)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物959)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物972)之合成Example 379. Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl) )-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (compound 861), rel-N-(6-amino-5-methyl- 3-Pyridinyl)-2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl ]-2-Oxyacetamide (Compound 959) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl- Synthesis of 2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 972)

Figure 110128222-A0202-12-1659-489
Figure 110128222-A0202-12-1659-489

步驟1：外消旋-N-[3-甲基-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-methyl-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl Synthesis of 3-butyl ]-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(294.95mg，998.86μmol)及外消旋-5-(5-甲基-2-哌啶基)-2-(三氟甲基)-1,3-苯并噻唑(0.3g，998.86μmol)混合於DMF(15mL)中。將反應懸浮液冷卻至0℃且添加HATU(417.78mg，1.10mmol)，隨後添加TEA(202.15mg，2.00mmol，278.44μL)，且在環境溫度下攪拌12h。將反應混合物在真空中蒸發且倒入水(100ml)中且用EtOAc(2x40ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物外消旋-N-[3-甲基-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.42g，727.13μmol，72.80%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (294.95 mg, 998.86 μmol) and rac- 5-(5-Methyl-2-piperidinyl)-2-(trifluoromethyl)-1,3-benzothiazole (0.3 g, 998.86 μmol) was mixed in DMF (15 mL). The reaction suspension was cooled to 0°C and HATU (417.78 mg, 1.10 mmol) was added followed by TEA (202.15 mg, 2.00 mmol, 278.44 μL) and stirred at ambient temperature for 12 h. The reaction mixture was evaporated in vacuo and poured into water (100ml) and extracted with EtOAc (2x40ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo to give the product rac-N-[3-methyl-5-[[2-[5-methyl yl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridine tert-butyl]carbamate (0.42 g, 727.13 μmol, 72.80% yield).

LCMS(ESI)：[M+H]+ m/z：計算值577.2；實測值578.2；Rt=1.469min。LCMS (ESI): [M+H] + m/z: calculated 577.2; found 578.2; Rt=1.469 min.

步驟2：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物861 )之合成Step 2: Racemic-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl) )-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyacetamide ( compound 861 ) synthesis

在室溫下將二噁烷(20mL)添加到外消旋-N-[3-甲基-5-[[2-[5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.42g，727.13μmol)於水(10mL)中之經攪拌之溶液中。將所得混合物在100℃下攪拌12h，然後在真空中蒸發且藉由製備型(70-70-90% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min目標質量)純化0.3g所獲得之粗產物，以得到產物外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.148g，309.95μmol，42.63%產率)。Dioxane (20 mL) was added to rac-N-[3-methyl-5-[[2-[5-methyl-2-[2-(trifluoromethyl)-1 at room temperature ,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.42g, 727.13μmol) In a stirred solution in water (10 mL). The resulting mixture was stirred at 100 °C for 12 h, then evaporated in vacuo and purified by prep (70-70-90% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min target quality) 0.3 g of the obtained crude product was purified to obtain the product racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl -2-[2-(Trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (0.148 g, 309.95 μmol, 42.63% Yield).

1 H NMR(dmso,600MHz)：δ(ppm)0.89-1.12(m,3H),1.29-1.43(m,1H),1.63-1.75(m,1H),1.79-1.93(m,1H),1.94-2.05(m,3H),2.07-2.23(m,1H),2.27-2.35(m,1H),2.81-3.22(m,1H),3.48-4.06(m,1H),5.28-5.59(m,1H),5.59-5.82(m,2H),7.36-7.54(m,1H),7.60-7.73(m,1H),7.90-8.08(m,1H),8.14-8.24(m,1H),8.29-8.42(m,1H),10.42-10.77(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.89-1.12 (m, 3H), 1.29-1.43 (m, 1H), 1.63-1.75 (m, 1H), 1.79-1.93 (m, 1H), 1.94 -2.05(m, 3H), 2.07-2.23(m, 1H), 2.27-2.35(m, 1H), 2.81-3.22(m, 1H), 3.48-4.06(m, 1H), 5.28-5.59(m, 1H), 5.59-5.82(m, 2H), 7.36-7.54(m, 1H), 7.60-7.73(m, 1H), 7.90-8.08(m, 1H), 8.14-8.24(m, 1H), 8.29- 8.42 (m, 1H), 10.42-10.77 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值477.2；實測值478.4；Rt=2.825min。LCMS (ESI): [M+H] + m/z: calculated 477.2; found 478.4; Rt=2.825 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物959 )及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物972 )之合成Step 3: rel-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)- 1,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide ( compound 959 ) and rel-N-(6-amino-5-methyl-3- Pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide ( Compound 972 )

使外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.1155g，241.88μmol)經歷掌性HPLC純化(管柱：YMC ChiralArt(250 * 20mm，5mkm)；溶析液：己烷 -IPA-MeOH，50-25-25，流速：12mL/min)，以得到兩種單獨的鏡像異構物化合物959 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.05461g，114.37μmol，47.28%產率)及化合物972 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(43.86mg，91.85μmol，37.97%產率)。Make rac-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl)- 1,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (0.1155 g, 241.88 μmol) was subjected to chiral HPLC purification (column: YMC ChiralArt (250*20 mm) , 5mkm); eluent: hexane-IPA-MeOH, 50-25-25, flow rate: 12mL/min) to obtain two separate enantiomer compounds 959 rel-N-(6-amino- 5-Methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]- 1-Piperidinyl]-2-oxyacetamide (0.05461 g, 114.37 μmol, 47.28% yield) and compound 972 rel-N-(6-amino-5-methyl-3-pyridyl) -2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side Oxyacetamide (43.86 mg, 91.85 μmol, 37.97% yield).

化合物959： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=13.762min。 Compound 959: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 13.762 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.06(m,3H),1.29-1.44(m,1H),1.63-1.73(m,1H),1.80-1.92(m,1H),1.94-2.03(m,3H),2.08-2.21(m,1H),2.26-2.33(m,1H),2.76-3.20(m,1H),3.45-4.06(m,1H),5.27-5.59(m,1H),5.61-5.74(m,2H),7.37-7.51(m,1H),7.60-7.72(m,1H),7.91-8.04(m,1H),8.15-8.22(m,1H),8.30-8.37(m,1H),10.48-10.59(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.06(m,3H), 1.29-1.44(m,1H), 1.63-1.73(m,1H), 1.80-1.92(m,1H), 1.94- 2.03(m, 3H), 2.08-2.21(m, 1H), 2.26-2.33(m, 1H), 2.76-3.20(m, 1H), 3.45-4.06(m, 1H), 5.27-5.59(m, 1H) ), 5.61-5.74(m, 2H), 7.37-7.51(m, 1H), 7.60-7.72(m, 1H), 7.91-8.04(m, 1H), 8.15-8.22(m, 1H), 8.30-8.37 (m, 1H), 10.48-10.59 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值477.2；實測值478.2；Rt=2.884min。LCMS (ESI): [M+H] + m/z: calculated 477.2; found 478.2; Rt=2.884 min.

化合物972： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=21.265min。 Compound 972: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 21.265 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.05(m,3H),1.30-1.39(m,1H),1.63-1.72(m,1H),1.83-1.91(m,1H),1.94-2.03(m,3H),2.09-2.21(m,1H),2.22-2.34(m,1H),2.75-3.08(m,1H),3.45-4.07(m,1H),5.28-5.59(m,1H),5.60-5.75(m,2H),7.36-7.54(m,1H),7.59-7.72(m,1H),7.90-8.04(m,1H),8.15-8.23(m,1H),8.30-8.39(m,1H),10.49-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.00-1.05(m,3H), 1.30-1.39(m,1H), 1.63-1.72(m,1H), 1.83-1.91(m,1H), 1.94- 2.03(m, 3H), 2.09-2.21(m, 1H), 2.22-2.34(m, 1H), 2.75-3.08(m, 1H), 3.45-4.07(m, 1H), 5.28-5.59(m, 1H) ), 5.60-5.75(m, 2H), 7.36-7.54(m, 1H), 7.59-7.72(m, 1H), 7.90-8.04(m, 1H), 8.15-8.23(m, 1H), 8.30-8.39 (m, 1H), 10.49-10.60 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值477.2；實測值478.2；Rt=2.833min。LCMS (ESI): [M+H] + m/z: calculated 477.2; found 478.2; Rt=2.833 min.

實例380.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物743、化合物824及化合物826)之合成Example 380. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-( lH -thieno[ 3,2-c ]pyrazol-5-yl ) Piperidin-1-yl)-2-oxoacetamide (Compound 743, Compound 824 and Compound 826) Synthesis

Figure 110128222-A0202-12-1661-490
Figure 110128222-A0202-12-1661-490

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(1H-噻吩并[3,2-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(1H-thieno[3,2-c]pyrazol-5-yl )Piperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester synthesis

將DIPEA(765.94mg，5.93mmol，1.03mL)添加到相應2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.5g，1.69mmol)及5-(5-甲基-2-哌啶基)-1H -噻吩并[3,2-c ]吡唑(374.75mg，1.69mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(708.20mg，1.86mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH為溶析液混合物)，以得到N -[3-甲基-5-[[2-[5-甲基-2-(1H -噻吩并[3,2 -c]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(275.4mg，552.35μmol，32.62%產率)。DIPEA (765.94 mg, 5.93 mmol, 1.03 mL) was added to the corresponding 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (0.5 g, 1.69 mmol) and 5-(5-methyl-2-piperidinyl)-1H-thieno[ 3,2 -c ]pyrazole (374.75 mg, 1.69 mmol) in DMF (10 mL) in the solution. The resulting mixture was stirred for 5 min before HATU (708.20 mg, 1.86 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH as eluent mixture) to give N- [3-methyl-5-[[2-[5- Methyl-2-( 1H -thieno[ 3,2 -c]pyrazol-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl] tert -butyl carbamate (275.4 mg, 552.35 [mu]mol, 32.62% yield).

LCMS(ESI)：[M]+ m/z：計算值498.2；實測值499.2；Rt=2.933min。LCMS (ESI): [M] + m/z: calculated 498.2; found 499.2; Rt=2.933 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H-噻吩并[3,2-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物743 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(1H-thieno[3,2-c]pyrazol-5-yl ) synthesis of piperidin-1-yl)-2-oxoacetamide ( compound 743 )

將N -[3-甲基-5-[[2-[5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(275.40mg，552.35μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH(45-60%)+NH3 為溶析液混合物)，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(148.6mg，372.92μmol，67.51%產率)。 N- [3-methyl-5-[[2-[5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]- 3-Butyl 2-oxyacetoxy]amino]-2-pyridyl]carbamate ( 275.40 mg, 552.35 [mu]mol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH (45-60%)+ NH3 as eluent mixture) to give N- (6-amino- 5-Methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidine Peridyl]-2-Pendant oxyacetamide (148.6 mg, 372.92 μmol, 67.51% yield).

化合物743： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.00(m,3H),1.37-1.45(m,1H),1.80-1.98(m,3H),1.98-2.02(m,3H),2.07-2.21(m,1H),2.93-2.97(m, 0.4H),3.36-3.40(m,0.6H),3.45-4.08(m,1H),5.47-5.60(m,1H),5.61-5.82(m,2H),7.02-7.06(m,1H),7.48(s,1H),7.69-7.90(m,1H),8.01(d,1H),10.50(bs s,1H),13.05(br s,1H)。 Compound 743: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.97-1.00 (m, 3H), 1.37-1.45 (m, 1H), 1.80-1.98 (m, 3H), 1.98-2.02 (m) ,3H),2.07-2.21(m,1H),2.93-2.97(m,0.4H),3.36-3.40(m,0.6H),3.45-4.08(m,1H),5.47-5.60(m,1H) ,5.61-5.82(m,2H),7.02-7.06(m,1H),7.48(s,1H),7.69-7.90(m,1H),8.01(d,1H),10.50(bs s,1H), 13.05(br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=1.779min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=1.779 min.

步驟3：掌性分離(化合物824 及化合物826 )Step 3: Chiral separation ( compound 824 and compound 826 )

藉由以條件之掌性層析(管柱：Chiralpak IB(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 70-15-15；流速：12mL/min；m(化合物)=0,12g，進行5次注入，20mg/1次注入，V(級分)=3L，4,5小時。Rt(化合物826 )=24.57min及Rt(化合物824 )=33.68min)分離N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(148.60g，372.92mmol)，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(37.74mg，94.71μmol，2.54e-2%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(38.75mg，97.24μmol，2.61e-2%產率)。By chiral chromatography with conditions (column: Chiralpak IB (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH 70-15-15; flow rate: 12mL/min; m(compound)=0 , 12g, 5 injections, 20mg/1 injection, V(fraction)=3L, 4,5 hours. Rt( Compound 826 )=24.57min and Rt( Compound 824 )=33.68min) to separate N- (6 -amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl) -1-Piperidinyl]-2-oxyacetamide (148.60 g, 372.92 mmol) to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R ,5S )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyacetamide (37.74 mg, 94.71 μmol, 2.54e-2% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-( 1H- Thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyacetamide (38.75 mg, 97.24 μmol, 2.61e-2% yield).

化合物824 於分析條件下(管柱：IB，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為29.27min且化合物826 之保留時間為21.00min。The retention time of compound 824 under analytical conditions (column: IB, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 29.27 min and the retention time of compound 826 was 21.00 min.

化合物824：保留時間：29.27minCompound 824: retention time: 29.27min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.01(m,3H),1.37-1.45(m,1H),1.83-1.97(m,2H),1.97-2.03(m,3H),2.04-2.19(m,2H),2.92-2.97(m,0.4H),3.35-3.39(m,0.6H),3.43-4.08(m,1H),5.43-5.85(m,3H),6.95-7.13(m,1H),7.48(s,1H),7.69-7.97(m,1H),8.01(d,1H),10.38-10.61(m,1H),12.91-13.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.01(m,3H), 1.37-1.45(m,1H), 1.83-1.97(m,2H), 1.97-2.03(m,3H) ,2.04-2.19(m,2H),2.92-2.97(m,0.4H),3.35-3.39(m,0.6H),3.43-4.08(m,1H),5.43-5.85(m,3H),6.95- 7.13(m,1H), 7.48(s,1H), 7.69-7.97(m,1H), 8.01(d,1H), 10.38-10.61(m,1H), 12.91-13.34(m,1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=1.762min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=1.762 min.

化合物826：保留時間：21.00minCompound 826: retention time: 21.00min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.03(m,3H),1.37-1.47(m,1H),1.81-1.97(m,2H),1.98-2.03(m,3H),2.03-2.20(m,2H),2.92-2.97(m,0.4H),3.35-3.41(m,0.6H),3.43-4.08(m,1H),5.44-5.84(m,3H),6.97-7.12(m,1H),7.46-7.52(m,1H),7.67-7.99(m,1H),7.99-8.03(m,1H),10.47-10.55(m,1H),12.91-13.32(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.03(m,3H), 1.37-1.47(m,1H), 1.81-1.97(m,2H), 1.98-2.03(m,3H) ,2.03-2.20(m,2H),2.92-2.97(m,0.4H),3.35-3.41(m,0.6H),3.43-4.08(m,1H),5.44-5.84(m,3H),6.97- 7.12(m,1H),7.46-7.52(m,1H),7.67-7.99(m,1H),7.99-8.03(m,1H),10.47-10.55(m,1H),12.91-13.32(m,1H) ).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=1.752min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=1.752 min.

實例381.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物955及化合物967)之合成Example 381. N- (6-amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl ) Piperidin-1-yl)-2-oxoacetamide (Compound 955 and Compound 967) Synthesis

Figure 110128222-A0202-12-1664-491
Figure 110128222-A0202-12-1664-491

步驟1：(3-乙基-5-(2-(5-甲基-2-(1H-噻吩并[3,2-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-ethyl-5-(2-(5-methyl-2-(1H-thieno[3,2-c]pyrazol-5-yl)piperidin-1-yl)-2 -Synthesis of tert-butyl oxyacetamido)pyridin-2-yl)carbamate

在輕微加熱下，將2-[[6-(第三丁氧基 羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(349.40mg，1.13mmol)、5-[(2R,5S )-5-甲基-2-哌啶基]-1H -噻吩并[3,2-c ]吡唑(0.25,1.13mmol)及DIPEA(437.96mg，3.39mmol，590.24μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(515.40mg，1.36mmol)。反應完成之後，藉由HPLC(60% 0.5-6.5min水-MeOH；流速30ml/min(裝載泵4ml/min MeOH)；目標質量512；管柱SunFireC18 100x19mm 5um(R))純化混合物，以得到外消旋產物。在掌性HPLC(Chiral ART Cellulose-SC(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)之後，獲得N -[3-乙基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(32mg，62.42μmol，5.53%產率)及N -[3-乙基-5-[[2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(34mg，66.33μmol，5.87%產率)。2-[[6-( Third- butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-pendoxoacetic acid (349.40 mg, 1.13 mmol) was added with gentle heating , 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1H-thieno[ 3,2 -c ]pyrazole (0.25, 1.13 mmol) and DIPEA (437.96 mg, 3.39 mmol, 590.24 μL) in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (515.40 mg, 1.36 mmol) was added in small batches. After the reaction was complete, the mixture was purified by HPLC (60% 0.5-6.5min water-MeOH; flow rate 30ml/min (loading pump 4ml/min MeOH); target mass 512; column SunFire C18 100x19mm 5um(R)) to obtain external racemic product. After chiral HPLC (Chiral ART Cellulose-SC (250*20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 12ml/min), N- [3-ethyl-5-[[ 2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-side oxyacetyl tert -butyl ]amino]-2-pyridyl]carbamate (32 mg, 62.42 μmol, 5.53% yield) and N- [3-ethyl-5-[[2-[( 2R,5S )- 5-Methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridine tert -butyl ]carbamate (34 mg, 66.33 [mu]mol, 5.87% yield).

E1於分析條件下(管柱：IB，以己烷-IPA-MeOH，80-10-10，0.6ml/min為流動相)之保留時間為27.65min且E2之保留時間為24.09min。The retention time of E1 under analytical conditions (column: IB, with hexane-IPA-MeOH, 80-10-10, 0.6 ml/min as mobile phase) was 27.65 min and the retention time of E2 was 24.09 min.

E1：保留時間：27.65minE1: retention time: 27.65min

LCMS(ESI)：[M]+ m/z：計算值512.2；實測值513.2；Rt=3.142min。LCMS (ESI): [M] + m/z: calculated 512.2; found 513.2; Rt=3.142 min.

E2：保留時間：24.09minE2: retention time: 24.09min

LCMS(ESI)：[M]+ m/z：計算值512.2；實測值513.2；Rt=3.202min。LCMS (ESI): [M] + m/z: calculated 512.2; found 513.2; Rt=3.202 min.

步驟2：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(1H-噻吩并[3,2-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物955 及化合物967 )之合成Step 2: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1H-thieno[3,2-c]pyrazol-5-yl ) Piperidin-1-yl)-2-oxoacetamide ( Compound 955 and Compound 967 ) Synthesis

將N -[3-乙基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(32mg，62.42μmol)及N -[3-乙基-5-[[2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(32mg，62.42μmol)溶解於二噁烷(2mL)及H2 O(0.5mL)中。將所獲得之溶液在100℃下攪拌3h；反應完成之後，使混合物經歷HPLC(22% 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min MeCN)；目標質量412；管柱SunFire 100x19mm 5um(R))，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(15mg，36.36μmol，58.25%產率)及N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -噻吩并[3,2-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(15mg，36.36μmol，58.25%產率)。 N- [3-ethyl-5-[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1 -Piperidinyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (32 mg, 62.42 μmol) and N- [3-ethyl-5-[[2 -[( 2R,5S )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-side oxyethanoyl ]amino]-2-pyridyl]carbamic acid tert -butyl ester (32 mg, 62.42 [mu]mol) was dissolved in dioxane (2 mL) and H2O (0.5 mL). The obtained solution was stirred at 100°C for 3h; after completion of the reaction, the mixture was subjected to HPLC (22% 0.5-6.5min water-MeCN; flow rate 30ml/min (loading pump 4ml/min MeCN); target mass 412; column SunFire 100x19mm 5um(R)) to give N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-( 1H -thieno [ 3,2-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyacetamide (15 mg, 36.36 μmol, 58.25% yield) and N- (6-amino- 5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 3,2-c ]pyrazol-5-yl)-1-piperidine Peridyl]-2-Pendant oxyacetamide (15 mg, 36.36 μmol, 58.25% yield).

化合物955： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.02(m,3H),1.04-1.14(m,3H),1.36-1.47(m,1H),1.80-1.97(m,2H),2.01-2.20(m,2H),2.39(q,2H),2.92-3.40(m,1H),3.44-4.08(m,1H),5.43-5.87(m,3H),6.99-7.12(m,1H),7.42-7.53(m,1H),7.59-7.93(m,1H),8.02-8.09(m,1H),10.52(s,1H),13.03(s,1H)。 Compound 955: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.95-1.02 (m, 3H), 1.04-1.14 (m, 3H), 1.36-1.47 (m, 1H), 1.80-1.97 (m) ,2H),2.01-2.20(m,2H),2.39(q,2H),2.92-3.40(m,1H),3.44-4.08(m,1H),5.43-5.87(m,3H),6.99-7.12 (m, 1H), 7.42-7.53 (m, 1H), 7.59-7.93 (m, 1H), 8.02-8.09 (m, 1H), 10.52 (s, 1H), 13.03 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=1.018min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=1.018 min.

化合物967： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.80-1.01(m,3H),1.06-1.12(m,3H),1.37-1.45(m,1H),1.82-1.97(m,2H),2.02-2.20(m,2H),2.39(q,2H),2.91-3.40(m,1H),3.76(dd,1H),5.46-5.83(m,3H),6.95-7.09(m,1H),7.42-7.53(m,1H),7.59-7.98(m,1H),7.98-8.09(m,1H),10.52(s,1H),12.88-13.41(m,1H)。 Compound 967: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.80-1.01 (m, 3H), 1.06-1.12 (m, 3H), 1.37-1.45 (m, 1H), 1.82-1.97 (m) ,2H),2.02-2.20(m,2H),2.39(q,2H),2.91-3.40(m,1H),3.76(dd,1H),5.46-5.83(m,3H),6.95-7.09(m , 1H), 7.42-7.53(m, 1H), 7.59-7.98(m, 1H), 7.98-8.09(m, 1H), 10.52(s, 1H), 12.88-13.41(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=1.442min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=1.442 min.

實例382.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物815、化合物1085及化合物1086)之合成Example 382. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-( lH -thieno[ 2,3-c ]pyrazol-5-yl ) Piperidin-1-yl)-2-oxoacetamide (Compound 815, Compound 1085 and Compound 1086) Synthesis

Figure 110128222-A0202-12-1666-492
Figure 110128222-A0202-12-1666-492

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(1H-噻吩并[2,3-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(1H-thieno[2,3-c]pyrazol-5-yl )Piperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester synthesis

在輕微加熱下，將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(401.32mg，1.36mmol)、5-[(2S,5R )-5-甲基-2-哌啶基]-2H -噻吩并[2,3-c ]吡唑(300.79mg，1.36mmol)及DIPEA(526.94mg，4.08mmol，710.16μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(620.11mg，1.63mmol)。反應完成之後，藉由HPLC(40-90% 0.5-6.5min水-MeOH；流速30ml/min；(裝載泵4ml/min MeOH)；目標質量498；管柱SunFireC18 100x19mm 5um(L))純化混合物，以得到N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(80mg，160.45μmol，11.81%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (401.32 mg, 1.36 mmol) was added with gentle heating , 5-[( 2S,5R )-5-methyl-2-piperidinyl]-2H-thieno[ 2,3-c ]pyrazole ( 300.79 mg, 1.36 mmol) and DIPEA (526.94 mg, 4.08 mmol) , 710.16 μL) was dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (620.11 mg, 1.63 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC (40-90% 0.5-6.5 min water-MeOH; flow rate 30 ml/min; (loading pump 4 ml/min MeOH); target mass 498; column SunFire C18 100x19 mm 5um (L)), to give N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (80 mg, 160.45 [mu]mol, 11.81% yield).

LCMS(ESI)：[M]+ m/z：計算值498.2；實測值499.2；Rt=2.857min。LCMS (ESI): [M] + m/z: calculated 498.2; found 499.2; Rt=2.857 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H-噻吩并[2,3-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物815 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(1H-thieno[2,3-c]pyrazol-5-yl ) synthesis of piperidin-1-yl)-2-oxoacetamide ( compound 815 )

將N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(80mg，160.45μmol)溶解於二噁烷(2mL)及水(0.5mL)中。將所獲得之溶液在100℃下攪拌2h；反應完成之後，使混合物經歷HPLC(18% 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min MeCN)；目標質量398；管柱SunFireC18 100x19mm 5um(R))，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(40mg，100.38μmol，62.56%產率)。 N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1 -Piperidinyl]-2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (80 mg, 160.45 μmol) was dissolved in dioxane (2 mL) and water (0.5 mL) middle. The obtained solution was stirred at 100 °C for 2 h; after the reaction was complete, the mixture was subjected to HPLC (18% 0.5-6.5 min water-MeCN; flow rate 30 ml/min (loading pump 4 ml/min MeCN); target mass 398; column SunFire C18 100x19mm 5um(R)) to give N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S,5R )-5-methyl-2-( 1H -thieno [ 2,3-c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyacetamide (40 mg, 100.38 μmol, 62.56% yield).

化合物815： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.37-1.48(m,1H),1.83-1.96(m,2H),1.98-2.02(m,3H),2.02-2.17(m,2H),2.91-2.96(m,0.4H),3.34-3.39(m,0.6H),3.44-4.08(m,1H),5.40-5.81(m,3H),6.88-6.98(m,1H),7.46-7.51(m,1H),7.87-8.00(m,1H),8.01(s,1H),10.42-10.64(m,1H),13.29(s,1H)。 Compound 815: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98 (d, 3H), 1.37-1.48 (m, 1H), 1.83-1.96 (m, 2H), 1.98-2.02 (m, 3H) ), 2.02-2.17(m, 2H), 2.91-2.96(m, 0.4H), 3.34-3.39(m, 0.6H), 3.44-4.08(m, 1H), 5.40-5.81(m, 3H), 6.88 -6.98(m,1H), 7.46-7.51(m,1H), 7.87-8.00(m,1H), 8.01(s,1H), 10.42-10.64(m,1H), 13.29(s,1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=1.722min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=1.722 min.

步驟3：掌性分離(化合物1085 及化合物1086 )Step 3: Chiral separation ( compound 1085 and compound 1086 )

藉由掌性HPLC(Chiralpak IA(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)純化外消旋物，得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(8mg，20.08μmol，25.02%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(8mg，20.08μmol，25.02%產率)。The racemate was purified by chiral HPLC (Chiralpak IA (250*20, 5mkm), hexane-IPA-MeOH, 50-25-25, 12ml/min) to give N- (6-amino-5- Methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1-piperidinyl ]-2-Oxyacetamide (8 mg, 20.08 μmol, 25.02% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )- 5-Methyl-2-( 1H -thieno[2,3-c]pyrazol-5-yl)-1-piperidinyl]-2-oxoacetamide (8 mg, 20.08 μmol, 25.02% Yield).

化合物1085 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為65.80min且化合物1086 之保留時間為43.62min。The retention time of compound 1085 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 65.80 min and the retention time of compound 1086 was 43.62 min.

化合物1085：保留時間：65.80minCompound 1085: retention time: 65.80min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.39-1.44(m,1H),1.86 -1.96(m,2H),1.99-2.03(m,3H),2.04-2.19(m,2H),2.90-3.40(m,1H),3.45-4.09(m,1H),5.39-5.81(m,3H),6.89-7.00(m,1H),7.49(s,1H),7.95(s,1H),7.99-8.05(m,1H),10.43-10.53(m,1H),13.29(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.03(m,3H), 1.39-1.44(m,1H), 1.86-1.96(m,2H), 1.99-2.03(m,3H) ,2.04-2.19(m,2H),2.90-3.40(m,1H),3.45-4.09(m,1H),5.39-5.81(m,3H),6.89-7.00(m,1H),7.49(s, 1H), 7.95(s, 1H), 7.99-8.05(m, 1H), 10.43-10.53(m, 1H), 13.29(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=0.803min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=0.803 min.

化合物1086：保留時間：43.62minCompound 1086: retention time: 43.62min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.03(m,3H),1.38-1.45(m,1H),1.84-1.97(m,2H),1.99-2.18(m,5H),2.91-3.40(m,1H),3.44-4.07(m,1H),5.41-5.60(m,1H),5.61-5.79(m,2H),6.87-6.97(m,1H),7.45-7.52(m,1H),7.89-7.97(m,1H),8.02(d,1H),10.43-10.52(m,1H),13.29(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.03(m,3H), 1.38-1.45(m,1H), 1.84-1.97(m,2H), 1.99-2.18(m,5H) ,2.91-3.40(m,1H),3.44-4.07(m,1H),5.41-5.60(m,1H),5.61-5.79(m,2H),6.87-6.97(m,1H),7.45-7.52( m, 1H), 7.89-7.97 (m, 1H), 8.02 (d, 1H), 10.43-10.52 (m, 1H), 13.29 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=0.803min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=0.803 min.

實例383.N -(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1055及化合物1075)之合成Example 383. N- (6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl ) Piperidin-1-yl)-2-oxoacetamide (Compound 1055 and Compound 1075) Synthesis

Figure 110128222-A0202-12-1668-493
Figure 110128222-A0202-12-1668-493

步驟1：外消旋-(3-乙基-5-(2-((2R,5S)-5-甲基-2-(1H-噻吩并[2,3-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-ethyl-5-(2-((2R,5S)-5-methyl-2-(1H-thieno[2,3-c]pyrazol-5-yl )Piperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester synthesis

在輕微加熱下，將2-[[6-(第三丁氧基 羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(419.28mg，1.36mmol)、5-[(2R,5S )-5-甲基-2-哌啶基]-1H -噻吩并[3,2-c ]吡唑(0.3g，1.36mmol)及HATU(566.94mg，1.49mmol)溶解於DMSO(10mL)中。在劇烈攪拌及偶爾加熱下，小批量添加DIPEA(613.14mg，4.74mmol，826.34μL)。反應完成之後，藉由HPLC(37-39-56-70% 0.5-4.5-4.6-8min水-MeCN；流速30ml/min(裝載泵4ml/min MeCN)；目標質量512；管柱SunFireC18 100x19mm 5um(R))純化混合物，以得到N -[3-乙基-5-[[2-[(2R,5S )-5-甲基-2-(1H - 噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(33mg，64.37μmol，4.75%產率)及N -[5-[[2-[(2R,5S )-2-(2-第三丁基 噻吩并[2,3-c ]吡唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(190mg，334.08μmol，24.65%產率)。藉由2D-NMR光譜法證明第二產物之結構。N -[3-乙基-5-[[2-[(2R,5S )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(33mg，64.37μmol，4.75%產率)。2-[[6-( Third- butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-pendoxoacetic acid (419.28 mg, 1.36 mmol) was added with gentle heating , 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1H-thieno[ 3,2 -c ]pyrazole (0.3 g, 1.36 mmol) and HATU (566.94 mg, 1.49 mmol) ) was dissolved in DMSO (10 mL). With vigorous stirring and occasional heating, DIPEA (613.14 mg, 4.74 mmol, 826.34 μL) was added in small batches. After completion of the reaction, by HPLC (37-39-56-70% 0.5-4.5-4.6-8min water-MeCN; flow rate 30ml/min (loading pump 4ml/min MeCN); target mass 512; column SunFireC18 100x19mm 5um ( R)) Purify the mixture to give N- [3-ethyl-5-[[2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazole -5-yl)-1-piperidinyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (33 mg, 64.37 μmol, 4.75% yield) and N -[5-[[2-[( 2R,5S )-2-(2- tert-butylthieno [ 2,3-c ]pyrazol-5-yl)-5-methyl-1-piperidine [methyl]-2-oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert -butyl ester (190 mg, 334.08 [mu]mol, 24.65% yield). The structure of the second product was confirmed by 2D-NMR spectroscopy. N- [3-ethyl-5-[[2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1- 3 -Butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate (33 mg, 64.37 [mu]mol, 4.75% yield).

LCMS(ESI)：[M]+ m/z：計算值512.2；實測值513.2；Rt=3.221min。LCMS (ESI): [M] + m/z: calculated 512.2; found 513.2; Rt=3.221 min.

步驟2：N-(6-胺基-5-乙基吡啶-3-基)-2-(5-甲基-2-(1H-噻吩并[2,3-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1055 及化合物1075 )之合成Step 2: N-(6-Amino-5-ethylpyridin-3-yl)-2-(5-methyl-2-(1H-thieno[2,3-c]pyrazol-5-yl ) Piperidin-1-yl)-2-oxyacetamide ( Compound 1055 and Compound 1075 ) Synthesis

將N -[3-乙基-5-[[2-[(2R,5S )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(41.13mg，80.23μmol)溶解於二噁烷(3mL)/水(0.5mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑及以掌性HPLC(Chiralpak IA(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，14ml/min)之純化得到N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(9mg，21.82μmol，27.20%產率)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(7mg，16.97μmol，21.15%產率)。 N- [3-ethyl-5-[[2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1 -Piperidinyl]-2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (41.13 mg, 80.23 μmol) was dissolved in dioxane (3 mL)/water (0.5 mL) ) mixture and stirred at reflux overnight. An aliquot showed complete consumption of starting material; solvent was evaporated under reduced pressure and analyzed by chiral HPLC (Chiralpak IA (250*20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 14ml/min) was purified to give N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 2,3-c ] Pyrazol-5-yl)-1-piperidinyl]-2-oxoacetamide (9 mg, 21.82 μmol, 27.20% yield) and N-(6-amino-5-ethyl-3- Pyridyl)-2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 2,3-c ]pyrazol-5-yl)-1-piperidinyl]-2-side Oxyacetamide (7 mg, 16.97 μmol, 21.15% yield).

化合物1055 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為33.52min且化合物1075 之保留時間為50.94min。The retention time of compound 1055 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 33.52 min and the retention time of compound 1075 was 50.94 min.

化合物1055：保留時間：33.52minCompound 1055: retention time: 33.52min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00(d,3H),1.07-1.13(m,3H),1.38-1.48(m,1H),1.88-1.99(m,2H),2.02-2.06(m,1H),2.06-2.19(m,1H),2.38-2.43(m, 2H),2.93-2.98(m,0.3H),3.35-3.39(m,0.7H),3.44-4.10(m,1H),5.43-5.63(m,1H),5.63-5.79(m,2H),6.91-6.96(m,1H),7.47-7.53(m,1H),7.91-7.98(m,1H),8.05(s,1H),10.47-10.54(m,1H),13.29(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00(d,3H), 1.07-1.13(m,3H), 1.38-1.48(m,1H), 1.88-1.99(m,2H), 2.02 -2.06(m, 1H), 2.06-2.19(m, 1H), 2.38-2.43(m, 2H), 2.93-2.98(m, 0.3H), 3.35-3.39(m, 0.7H), 3.44-4.10( m,1H),5.43-5.63(m,1H),5.63-5.79(m,2H),6.91-6.96(m,1H),7.47-7.53(m,1H),7.91-7.98(m,1H), 8.05(s, 1H), 10.47-10.54(m, 1H), 13.29(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=0.838min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=0.838 min.

化合物1075：保留時間：50.94minCompound 1075: retention time: 50.94min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.02(m,3H),1.08-1.15(m,3H),1.39-1.46(m,1H),1.85-1.97(m,2H),2.02-2.17(m,2H),2.37-2.43(m,2H),2.93-2.98(m,0.3H),3.36-3.39(m,0.7H),3.48-4.11(m,1H),5.41-5.63(m,1H),5.63-5.81(m,2H),6.90-7.00(m,1H),7.46-7.58(m,1H),7.88-8.13(m,2H),10.44-10.57(m,1H),13.30(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.02(m,3H), 1.08-1.15(m,3H), 1.39-1.46(m,1H), 1.85-1.97(m,2H) ,2.02-2.17(m,2H),2.37-2.43(m,2H),2.93-2.98(m,0.3H),3.36-3.39(m,0.7H),3.48-4.11(m,1H),5.41- 5.63(m,1H),5.63-5.81(m,2H),6.90-7.00(m,1H),7.46-7.58(m,1H),7.88-8.13(m,2H),10.44-10.57(m,1H) ), 13.30(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值412.2；實測值413.2；Rt=0.837min。LCMS (ESI): [M] + m/z: calculated 412.2; found 413.2; Rt=0.837 min.

實例384.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H -吡唑-3-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1071及化合物1050)之合成Example 384. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-( 1H -pyrazol-3-yl)piperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide (Compound 1071 and Compound 1050)

Figure 110128222-A0202-12-1670-494
Figure 110128222-A0202-12-1670-494

步驟1：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H-吡唑-3-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(1H-pyrazol-3-yl)piperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide

在25℃下，在0.5h時段內，將HATU(1.10g，2.89mmol)小批量添加到(2R,5S )-5-甲基-2-(1H -吡唑-3-基)哌啶(530mg，2.63mmol，HCl)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(589.79mg，3.02mmol)及TEA(1.60g，15.77mmol，2.20mL)於DMF(5mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：35-50% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)，以得到430mg粗產物，其藉由反相HPLC(管柱：YMC Triart C18 100x20 mm，5um；流動相：35-40% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min甲醇)進行純化，以得到呈淡黃色膠狀物之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯胺(200mg，584.12μmol，22.23%產率)，將其直接提交至製備型掌性HPLC。HATU (1.10 g, 2.89 mmol) was added to ( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)piperidine ( 2R,5S )-5-methyl-2-(1H-pyrazol-3-yl)piperidine ( 530 mg, 2.63 mmol, HCl), 2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxoacetic acid (589.79 mg, 3.02 mmol) and TEA (1.60 g, 15.77 mmol, 2.20 mL) in a stirred mixture of DMF (5 mL). The resulting mixture was stirred at 25°C for 18h and then submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 35-50% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate : 30 ml/min (loading pump 4 ml/min MeOH) to give 430 mg of crude product by reverse phase HPLC (column: YMC Triart C18 100x20 mm, 5um; mobile phase: 35-40% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min (load pump 4ml/min methanol) was purified to give N- (6-amino-5-methyl-3-pyridine as a pale yellow gum yl)-2-[( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)-1-piperidinyl]-2-oxyacetamide (200 mg, 584.12 μmol , 22.23% yield), which was submitted directly to preparative chiral HPLC.

LCMS(ESI)：[M]+ m/z：計算值342.2；實測值343.2；Rt=1.020min。LCMS (ESI): [M] + m/z: calculated 342.2; found 343.2; Rt=1.020 min.

步驟2：掌性分離(化合物1071 及化合物1050 )Step 2: Chiral separation ( Compound 1071 and Compound 1050 )

將外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯胺(200mg，584.12μmol)提交至製備型掌性HPLC(管柱：Chiralpak IC-II(250*20，5mkm)；流動相：己烷-IPA-MeOH；流速：70-15-15，12ml/min；管柱溫度：24℃；波長：205nm、215nm、254nm)，以得到化合物1050 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯胺(38mg，110.98μmol，19.00%產率)(RT=37.07min)；及化合物1071 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -吡唑-3-基)-1-哌啶基]-2-側氧基乙醯胺(13.8mg，40.30μmol，6.90%產率)(RT=48.1min)。The racemic N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R,5S )-5-methyl-2-( 1H -pyrazol-3-yl)- 1-Piperidinyl]-2-oxyacetamide (200 mg, 584.12 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IC-II (250*20, 5 mkm); mobile phase: hexane- IPA-MeOH; flow rate: 70-15-15, 12ml/min; column temperature: 24°C; wavelengths: 205nm, 215nm, 254nm) to give compound 1050 N- (6-amino-5-methyl-3 -pyridyl)-2-[( 2S,5R )-5-methyl-2-( 1H -pyrazol-3-yl)-1-piperidinyl]-2-oxyacetamide (38 mg, 110.98 μmol, 19.00% yield) (RT=37.07 min); and compound 1071 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl -2-( 1H -pyrazol-3-yl)-1-piperidinyl]-2-oxyacetamide (13.8 mg, 40.30 μmol, 6.90% yield) (RT=48.1 min).

化合物1071 於分析條件下(管柱：IC，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為46.80min且化合物1050 之保留時間為37.45min。The retention time of compound 1071 under analytical conditions (column: IC, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 46.80 min and that of compound 1050 was 37.45 min.

化合物1071：保留時間：46.80minCompound 1071: retention time: 46.80min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.75-1.02(m,3H),1.25-1.40(m,1H),1.51-1.68(m,1H),1.78-1.87(m,1H),1.88-1.97(m,1H),1.99-2.04(m,3H),2.11-2.32(m,1H),2.69-3.22(m,1H),3.42-4.21(m,1H),5.14-5.66(m,3H),6.10-6.25(m,1H),7.21-7.49(m,1H),7.68(s,1H),7.96-8.03(m,1H),10.36-10.49(m,1H),12.60-12.72(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.75-1.02(m,3H), 1.25-1.40(m,1H), 1.51-1.68(m,1H), 1.78-1.87(m,1H) ,1.88-1.97(m,1H),1.99-2.04(m,3H),2.11-2.32(m,1H),2.69-3.22(m,1H),3.42-4.21(m,1H),5.14-5.66( m,3H),6.10-6.25(m,1H),7.21-7.49(m,1H),7.68(s,1H),7.96-8.03(m,1H),10.36-10.49(m,1H),12.60- 12.72 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值342.2；實測值343.2；Rt=1.854min。LCMS (ESI): [M] + m/z: calculated 342.2; found 343.2; Rt=1.854 min.

化合物1050：保留時間：37.45minCompound 1050: retention time: 37.45min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.72-0.96(m,3H),1.33(d,1H),1.52-1.62(m,1H),1.67-1.94(m,2H),1.99-2.04(m,3H),2.07-2.27(m,1H),2.73-3.20(m,1H),3.42-4.20(m,1H),5.14-5.64(m,3H),6.10-6.23(m,1H),7.46-7.51(m,1H),7.68(br s,1H),7.97-8.03(m,1H),10.36-10.46(m,1H),12.66(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.72-0.96(m,3H), 1.33(d,1H), 1.52-1.62(m,1H), 1.67-1.94(m,2H), 1.99 -2.04(m, 3H), 2.07-2.27(m, 1H), 2.73-3.20(m, 1H), 3.42-4.20(m, 1H), 5.14-5.64(m, 3H), 6.10-6.23(m, 1H), 7.46-7.51 (m, 1H), 7.68 (br s, 1H), 7.97-8.03 (m, 1H), 10.36-10.46 (m, 1H), 12.66 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值342.2；實測值343.2；Rt=1.859min。LCMS (ESI): [M] + m/z: calculated 342.2; found 343.2; Rt=1.859 min.

實例385. 2-(2-(1'H -[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物715、化合物789及化合物782)之合成Example 385. 2-(2-(1'H-[ 1,3' -bipyrazol]-3-yl)-5-methylpiperidin - 1-yl)-N-(6-amino-5 Synthesis of -methylpyridin-3-yl)-2-oxoacetamide (Compound 715, Compound 789 and Compound 782)

Figure 110128222-A0202-12-1672-495
Figure 110128222-A0202-12-1672-495

步驟1：2-(2-(1'H-[1,3'-聯吡唑]-3-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物715 )之合成Step 1: 2-(2-(1'H-[1,3'-bipyrazole]-3-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5 Synthesis of -methylpyridin-3-yl)-2-oxyacetamide ( compound 715 )

在25℃下，在0.5h時段內，將HATU(718.21mg，1.89mmol)小批量添加到(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]哌啶(900mg，1.72mmol，3HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(507.06mg，1.72mmol)及TEA(1.74g，17.17mmol，2.39mL)於DMF(10mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後在真空中濃縮。將殘餘物溶解於DCM(10mL)中且一次性添加於二噁烷中之4.0M氯化氫溶液(15.75g，60.04mmol，15mL，13.9%純度)。將所得混合物在25℃下攪拌3h，然後在真空中濃縮。藉由反相HPLC((管柱：YMC Triart C18 100x20mm，5um)，流動相：30-30-80% 0-1-6min H2 O/MeOH/0.1% NH3 ，流速：30ml/min(裝載泵4ml/min MeOH)用於第1次HPLC，及30-30-60% 0-1-6min H2 O/MeOH/0.1% NH3 ，流速：30ml/min(裝載泵4ml/min MeOH)用於第2次HPLC)純化殘餘物兩次，以得到呈 白色固體之化合物715 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-3-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯胺(112mg，274.20μmol，15.97%產率)。HATU (718.21 mg, 1.89 mmol) was added in small batches to ( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-3-yl) at 25°C over a period of 0.5 h Pyrazol-3-yl]piperidine (900 mg, 1.72 mmol, 3HCl), 2-[[6-( 3- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2 - Pendant oxyacetic acid (507.06 mg, 1.72 mmol) and TEA (1.74 g, 17.17 mmol, 2.39 mL) in a stirred mixture of DMF (10 mL). The resulting mixture was stirred at 25 °C for 18 h, then concentrated in vacuo. The residue was dissolved in DCM (10 mL) and a 4.0 M solution of hydrogen chloride in dioxane (15.75 g, 60.04 mmol, 15 mL, 13.9% pure) was added in one portion. The resulting mixture was stirred at 25 °C for 3 h, then concentrated in vacuo. by reverse phase HPLC ((column: YMC Triart C18 100x20mm, 5um), mobile phase: 30-30-80% 0-1-6 min H2O /MeOH/0.1% NH3 , flow rate: 30 ml/min (loading pump 4ml/min MeOH) for 1st HPLC, and 30-30-60% 0-1-6min H2O /MeOH/0.1% NH3 , flow rate: 30ml/min (load pump 4ml/min MeOH) with The residue was purified twice in 2nd HPLC) to give compound 715 as a white solid N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R,5S )-5- Methyl-2-[1-( 1H -pyrazol-3-yl)pyrazol-3-yl]-1-piperidinyl]-2-oxoacetamide (112 mg, 274.20 μmol, 15.97% yield Rate).

化合物715： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00(d,3H),1.37(m,1H),1.85(m,1H),1.93(m,1H),2.00(m,4H),2.16(m,1H),2.87(m,1H),3.74(m,1H),5.61(m,3H),6.38(m,2H),7.48(s,1H),7.78(m,1H),8.00(m,1H),8.16(d,1H),10.43(s,1H),12.77(s,1H)。 Compound 715: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.00 (d, 3H), 1.37 (m, 1H), 1.85 (m, 1H), 1.93 (m, 1H), 2.00 (m, 4H), 2.16(m, 1H), 2.87(m, 1H), 3.74(m, 1H), 5.61(m, 3H), 6.38(m, 2H), 7.48(s, 1H), 7.78(m, 1H) ), 8.00(m, 1H), 8.16(d, 1H), 10.43(s, 1H), 12.77(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值408.2；實測值409.2；Rt=1.753min。LCMS (ESI): [M] + m/z: calculated 408.2; found 409.2; Rt=1.753 min.

步驟2：掌性分離(化合物789 及化合物782 )Step 2: Chiral separation ( compound 789 and compound 782 )

使用(Chiralcel OJ-H(250*20，5mkm)管柱，己烷-IPA-MeOH，60-20-20為流動相；流速：12ml/min；24℃，波長：205nm，210nm)對N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[1-(1H -吡唑-5-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯胺(89.8mg，219.85μmol)進行掌性分離，得到呈黃色膠狀物之化合物782 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[1-(1H -吡唑-5-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯胺(26.64mg，65.22μmol，29.67%產率)(RT=14.5min)及呈米色固體之化合物789 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[1-(1H -吡唑-5-基)吡唑-3-基]-1-哌啶基]-2-側氧基乙醯胺(RT=22.2min)。Use (Chiralcel OJ-H (250*20, 5mkm) column, hexane-IPA-MeOH, 60-20-20 as mobile phase; flow rate: 12ml/min; 24°C, wavelength: 205nm, 210nm) for N- (6-Amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-[1-( 1H -pyrazol-5-yl)pyrazol-3 -yl]-1-piperidinyl]-2-oxoacetamide (89.8 mg, 219.85 μmol) was separated by chiral to give compound 782 as a yellow gum. N- (6-amino-5- Methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-[1-( 1H -pyrazol-5-yl)pyrazol-3-yl]-1-piperidine yl]-2-oxyacetamide (26.64 mg, 65.22 μmol, 29.67% yield) (RT=14.5 min) and compound 789 N- (6-amino-5-methyl-3 as a beige solid) -pyridyl)-2-[( 2R,5S )-5-methyl-2-[1-( 1H -pyrazol-5-yl)pyrazol-3-yl]-1-piperidinyl]-2 - Pendant oxyacetamide (RT=22.2 min).

化合物789 於分析條件下(管柱：OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為28.28min且化合物782 之保留時間為16.98min。The retention time of compound 789 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 28.28 min and the retention time of compound 782 was 16.98 min .

化合物789：保留時間：28.28minCompound 789: retention time: 28.28min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.01(m,3H),1.34-1.42(m,1H),1.81-1.87(m,1H),1.90-1.95(m,1H),1.96-2.10(m,4H),2.13-2.19(m,1H),2.85-2.89(m,0.4H),3.33-3.38(m,0.6H),3.43-4.06(m,1H),5.21-5.24(m,0.4H),5.57-5.62(m,2H),5.64-5.68(m,0.6H),6.33-6.45(m,2H),7.47-7.49(m,1H),7.76-7.81(m, 1H),7.99-8.02(m,1H),8.14-8.20(m,1H),10.44(s,1H),12.77(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.01(m,3H), 1.34-1.42(m,1H), 1.81-1.87(m,1H), 1.90-1.95(m,1H) ,1.96-2.10(m,4H),2.13-2.19(m,1H),2.85-2.89(m,0.4H),3.33-3.38(m,0.6H),3.43-4.06(m,1H),5.21- 5.24(m, 0.4H), 5.57-5.62(m, 2H), 5.64-5.68(m, 0.6H), 6.33-6.45(m, 2H), 7.47-7.49(m, 1H), 7.76-7.81(m , 1H), 7.99-8.02(m, 1H), 8.14-8.20(m, 1H), 10.44(s, 1H), 12.77(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值408.2；實測值409.2；Rt=1.722min。LCMS (ESI): [M] + m/z: calculated 408.2; found 409.2; Rt=1.722 min.

化合物782：保留時間：16.98minCompound 782: retention time: 16.98min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.01(m,3H),1.34-1.41(m,1H),1.80-1.87(m,1H),1.87-1.95(m,1H),1.95-2.10(m,4H),2.14-2.19(m,1H),2.85-2.89(m,0.4H),3.33-3.38(m,0.6H),3.42-4.05(m,1H),5.57-5.62(m,2H),5.63-5.67(m,1H),6.33-6.44(m,2H),7.48(d,1H),7.78(d,1H),7.96-8.02(m,1H),8.14-8.19(m,1H),10.44(s,1H),12.77(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.01(m,3H), 1.34-1.41(m,1H), 1.80-1.87(m,1H), 1.87-1.95(m,1H) ,1.95-2.10(m,4H),2.14-2.19(m,1H),2.85-2.89(m,0.4H),3.33-3.38(m,0.6H),3.42-4.05(m,1H),5.57- 5.62(m,2H),5.63-5.67(m,1H),6.33-6.44(m,2H),7.48(d,1H),7.78(d,1H),7.96-8.02(m,1H),8.14- 8.19(m, 1H), 10.44(s, 1H), 12.77(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值408.2；實測值409.2；Rt=1.723min。LCMS (ESI): [M] + m/z: calculated 408.2; found 409.2; Rt=1.723 min.

實例386.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,4S )-4-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物640)之合成Example 386. N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R , 4S )-4-methyl-2-phenyl-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide (Compound 640)

Figure 110128222-A0202-12-1674-496
Figure 110128222-A0202-12-1674-496

步驟1：N-[3-甲基-5-[[2-(4-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-(4-methyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]-2- Synthesis of tert-butyl pyridyl]carbamate

向2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.4g，1.35mmol)及4-甲基-2-苯基哌啶(237.42mg，1.35mmol)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(525.22mg，4.06mmol，707.84μL)。將所得混合物在20℃下攪拌5分鐘。5分鐘之後，添加HATU(566.56mg，1.49mmol)。在20℃下攪拌所得反應混合物。完成之後，在減壓下濃縮反應混合物且藉由HPLC純化粗產物，以獲得呈黃色固體之N -[3-甲基-5-[[2-(4-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(80.5mg，177.88μmol，13.13% 產率)。To 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridinyl]amino]-2-oxyacetic acid (0.4 g, 1.35 mmol) and 4-methyl To a stirred solution of -2-phenylpiperidine (237.42 mg, 1.35 mmol) in DMF (10 mL) was added DIPEA (525.22 mg, 4.06 mmol, 707.84 [mu]L). The resulting mixture was stirred at 20°C for 5 minutes. After 5 minutes, HATU (566.56 mg, 1.49 mmol) was added. The resulting reaction mixture was stirred at 20°C. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by HPLC to obtain N- [3-methyl-5-[[[2-(4-methyl-2-phenyl-1 as a yellow solid -Piperidinyl)-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert -butyl ester (80.5 mg, 177.88 μmol, 13.13% yield).

LCMS(ESI)：[M+H]+ m/z：計算值452.3；實測值453.4；Rt=3.209min。LCMS (ESI): [M+H] + m/z: calculated 452.3; found 453.4; Rt=3.209 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S)-4-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物640 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,4S)-4-methyl-2-phenyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 640 )

將N -[3-甲基-5-[[2-(4-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(38.9mg，85.96μmol)溶解於二噁烷(2mL)及水(5mL)中。然後將反應混合物在100℃下攪拌17小時。完成之後，在減壓下濃縮所得懸浮液。使所獲得之固體殘餘物經歷HPLC純化(溶析液：60-85% H2 O-CH3 CN；管柱：SunfireC18 20 x 100mm，5um)，以得到呈淡黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,4S )-4-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物640 ，13.7mg，38.87μmol，45.22%產率)。 N- [3-Methyl-5-[[2-(4-methyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]-2-pyridyl ] tert-butyl carbamate (38.9 mg, 85.96 μmol) was dissolved in dioxane (2 mL) and water (5 mL). The reaction mixture was then stirred at 100°C for 17 hours. After completion, the resulting suspension was concentrated under reduced pressure. The solid residue obtained was subjected to HPLC purification (eluent: 60-85% H2O - CH3CN ; column: Sunfire C18 20 x 100 mm, 5um) to give N- (6- as a pale yellow solid Amino-5-methyl-3-pyridyl)-2-[( 2R , 4S )-4-methyl-2-phenyl-1-piperidinyl]-2-oxyacetamide ( Compound 640 , 13.7 mg, 38.87 μmol, 45.22% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.84(m,3H),1.22(m,1H),1.78(m,2H),2.04(m,5H),3.40(m,1H),3.76(m,1H),5.15(m,1H),5.60(m,2H),7.33(m,6H),8.02(m,1H),10.43(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.84 (m, 3H), 1.22 (m, 1H), 1.78 (m, 2H), 2.04 (m, 5H), 3.40 (m, 1H) , 3.76 (m, 1H), 5.15 (m, 1H), 5.60 (m, 2H), 7.33 (m, 6H), 8.02 (m, 1H), 10.43 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.4；Rt=2.251min。LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.4; Rt=2.251 min.

實例387. 外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯胺(化合物923)之合成Example 387. Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(7-pendoxyl-6 Synthesis of ,8-dihydro-5H-1,8-naphthyridin-3-yl)-1-piperidinyl]-2-oxoacetamide (compound 923)

Figure 110128222-A0202-12-1675-497
Figure 110128222-A0202-12-1675-497

步驟1：外消旋-N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H Synthesis of -1,8-Naphthyridin-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將外消旋-6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-1,8-萘啶-2-酮(300mg，1.22mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側 氧基乙酸(361.11mg，1.22mmol)、三乙胺(618.72mg，6.11mmol，852.24μL)混合於DMF(5mL)中，然後添加HATU(697.47mg，1.83mmol)。將所得混合物在25℃下攪拌12h。蒸發溶劑且藉由HPLC(2-10min 20-45% MeCN/H2 O 30mL/min(裝載泵4mL MeCN)，管柱：SunFire 100*19mm，5微米)純化粗品沉澱，以獲得N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(80.8mg，154.61μmol，12.64%產率)。Racemic-6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-1,8-naphthyridin-2-one (300 mg, 1.22 mmol ), 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (361.11 mg, 1.22 mmol), triethylamine (618.72 mg, 6.11 mmol, 852.24 μL) was mixed in DMF (5 mL), then HATU (697.47 mg, 1.83 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the crude precipitate was purified by HPLC (2-10 min 20-45% MeCN/ H2O 30 mL/min (loading pump 4 mL MeCN), column: SunFire 100*19 mm, 5 microns) to obtain N-[3 -Methyl-5-[[2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1,8-naphthyridin-3-yl )-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (80.8 mg, 154.61 μmol, 12.64% yield).

LCMS(ESI)：[M+H]+ m/z：計算值522.2；實測值523.2；Rt=1.178min。LCMS (ESI): [M+H] + m/z: calculated 522.2; found 523.2; Rt=1.178 min.

步驟2：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯胺(化合物923 )之合成Step 2: Racemic-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(7-sideoxy-6 Synthesis of ,8-dihydro-5H-1,8-naphthyridin-3-yl)-1-piperidinyl]-2-side oxyacetamide ( compound 923 )

將外消旋-N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(80.8mg，154.61μmol)於二噁烷(2mL)及水(2mL)中之溶液在100℃下加熱11h。蒸發溶劑且藉由HPLC(35-55% MeCN/H20-2-10min流速：30mL/min；裝載泵4mL/min MeCN)純化所得沉澱，以獲得外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯胺(44.1mg，104.38μmol，67.51%產率)。rac-N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1 ,8-Naphthyridin-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (80.8 mg, 154.61 μmol) in A solution in dioxane (2 mL) and water (2 mL) was heated at 100 °C for 11 h. The solvent was evaporated and the resulting precipitate was purified by HPLC (35-55% MeCN/H 0-2-10 min flow rate: 30 mL/min; loading pump 4 mL/min MeCN) to obtain rac-N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1,8-naphthyridine-3 -yl)-1-piperidinyl]-2-oxoacetamide (44.1 mg, 104.38 μmol, 67.51% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.99(m,3H),1.33(m,1H),1.68(m,1H),1.87(m,1H),2.00(m,4H),2.18(m,1H),2.41(m,2H),3.04(m,3H),3.70(dd,1H),5.57(m,3H),7.48(m,2H),8.00(m,2H),10.47(m,2H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.99 (m, 3H), 1.33 (m, 1H), 1.68 (m, 1H), 1.87 (m, 1H), 2.00 (m, 4H), 2.18(m, 1H), 2.41(m, 2H), 3.04(m, 3H), 3.70(dd, 1H), 5.57(m, 3H), 7.48(m, 2H), 8.00(m, 2H), 10.47 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值422.2；實測值423.2；Rt=0.870min。LCMS (ESI): [M+H] + m/z: calculated 422.2; found 423.2; Rt=0.870 min.

實例388. 外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯胺(化合物916)之合成Example 388. Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(7-pendoxyl-6 Synthesis of ,8-dihydro-5H-1,8-naphthyridin-3-yl)-1-piperidinyl]-2-oxoacetamide (compound 916)

Figure 110128222-A0202-12-1677-498
Figure 110128222-A0202-12-1677-498

步驟1：外消旋-N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-Ethyl-5-[[2-[(2S,5R)-5-methyl-2-(7-pendoxyl-6,8-dihydro-5H Synthesis of -1,8-Naphthyridin-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將外消旋-6-[(2S,5R)-5-甲基-2-哌啶基]-3,4-二氫-1H-1,8-萘啶-2-酮(300mg，1.22mmol)、2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(378.26mg，1.22mmol)、三乙胺(618.72mg，6.11mmol，852.24μL)混合於DMF(5mL)中，然後添加HATU(697.47mg，1.83mmol)。將所得混合物在25℃下攪拌12h。蒸發溶劑且藉由HPLC(40-100% 2-10min；水-乙腈30mL/min；裝載泵乙腈4mL/min，目標質量536，管柱SunFire 19*100mm 5um)純化粗品沉澱，以獲得外消旋-N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(62.9mg，117.21μmol，9.59%產率)。Racemic-6-[(2S,5R)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-1,8-naphthyridin-2-one (300 mg, 1.22 mmol ), 2-[[6-(Third-butoxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-oxoacetic acid (378.26 mg, 1.22 mmol), triethylamine (618.72 mg, 6.11 mmol, 852.24 μL) was mixed in DMF (5 mL), then HATU (697.47 mg, 1.83 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the crude precipitate was purified by HPLC (40-100% 2-10 min; water-acetonitrile 30 mL/min; loading pump acetonitrile 4 mL/min, target mass 536, column SunFire 19*100 mm 5um) to obtain racemic -N-[3-Ethyl-5-[[2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1,8-naphthalene Perid-3-yl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (62.9 mg, 117.21 μmol, 9.59% yield) .

LCMS(ESI)：[M+H]+ m/z：計算值536.2；實測值537.2；Rt=0.993min。LCMS (ESI): [M+H] + m/z: calculated 536.2; found 537.2; Rt=0.993 min.

步驟2：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯胺(化合物916 )之合成Step 2: Racemic-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(7-pendoxyl-6 Synthesis of ,8-dihydro-5H-1,8-naphthyridin-3-yl)-1-piperidinyl]-2-oxoacetamide ( compound 916 )

將N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(62.9mg，117.21μmol)於二噁烷(2mL)及水(2mL)中之溶液在100℃下加熱12h。蒸發溶劑且藉由HPLC(35-55% MeCN-水2-10min流速：30mL/min；裝載泵4mL/min MeCN)純化所得沉澱，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(7-側氧基-6,8-二氫-5H-1,8-萘啶-3-基)-1-哌啶基]-2-側氧基乙醯胺(24mg， 54.98μmol，46.91%產率)。N-[3-ethyl-5-[[2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1,8-naphthalene Perid-3-yl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (62.9 mg, 117.21 μmol) in dioxane ( 2 mL) and water (2 mL) were heated at 100 °C for 12 h. The solvent was evaporated and the resulting precipitate was purified by HPLC (35-55% MeCN-water 2-10 min flow rate: 30 mL/min; loading pump 4 mL/min MeCN) to obtain N-(6-amino-5-ethyl-3 -Pyridinyl)-2-[(2S,5R)-5-methyl-2-(7-oxy-6,8-dihydro-5H-1,8-naphthyridin-3-yl)-1 -Piperidinyl]-2-oxyacetamide (24 mg, 54.98 μmol, 46.91% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.05(m,6H),1.33(m,1H),1.69(m,1H),1.87(m,1H),2.00(m,1H),2.16(m,1H),2.38(m,3H),3.01(m,4H),3.70(m,1H),5.59(m,3H),7.49(m,2H),8.01(m,2H),10.48(m,2H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.05(m, 6H), 1.33(m, 1H), 1.69(m, 1H), 1.87(m, 1H), 2.00(m, 1H), 2.16(m, 1H), 2.38(m, 3H), 3.01(m, 4H), 3.70(m, 1H), 5.59(m, 3H), 7.49(m, 2H), 8.01(m, 2H), 10.48 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=0.908min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=0.908 min.

實例389.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-胺基苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物997及化合物981)之合成Example 389. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(2-aminobenzo[ d ]thiazol-5-yl)-5-methylpiperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 997 and Compound 981)

Figure 110128222-A0202-12-1678-500
Figure 110128222-A0202-12-1678-500

步驟1：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-胺基苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-aminobenzo[d]thiazol-5-yl)-5-methylpiperidine Synthesis of -1-yl)-2-oxyacetamide

在25℃下，在0.5h時段內，將HATU(253.63mg，667.05μmol)小批量添加到到5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-胺(150mg，606.41μmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(205.93mg，697.37μmol)及TEA(245.45mg，2.43mmol，338.08μL)於DMF(5mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌18h，然後在真空中濃縮。將殘餘物溶解於DCM(10mL)中且一次性添加於二噁烷中之4.0M氯化氫溶液(10.50g，40.03mmol，10.00mL，13.9%純度)。將所得混合物在25℃下攪拌12h，然後在真空中濃縮。藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相：40-70% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)純化殘餘物，以得到呈淡黃色膠狀物之2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(131mg，308.59μmol，50.89%產率)，將其直接提交至製備型掌性HPLC。HATU (253.63 mg, 667.05 μmol) was added in small batches to 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3- Benzothiazol-2-amine (150 mg, 606.41 μmol), 2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendantoxy In a stirred mixture of acetic acid (205.93 mg, 697.37 μmol) and TEA (245.45 mg, 2.43 mmol, 338.08 μL) in DMF (5 mL). The resulting mixture was stirred at 25 °C for 18 h, then concentrated in vacuo. The residue was dissolved in DCM (10 mL) and a 4.0 M solution of hydrogen chloride in dioxane (10.50 g, 40.03 mmol, 10.00 mL, 13.9% purity) was added in one portion. The resulting mixture was stirred at 25 °C for 12 h, then concentrated in vacuo. by reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase: 40-70% 0-5min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min (load pump 4ml/min MeOH) ) purification of the residue to give 2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl)-5-methyl-1 as a pale yellow gum -Piperidinyl]-N-(6-amino - 5-methyl-3-pyridyl)-2-oxyacetamide (131 mg, 308.59 μmol, 50.89% yield), which was submitted directly to Preparative chiral HPLC.

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=1.719min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=1.719 min.

步驟2：掌性分離(化合物997 及化合物981 )Step 2: Chiral separation ( compound 997 and compound 981 )

將外消旋2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(131mg，308.59μmol)提交至製備型掌性HPLC(管柱：Chiralpak IA-II(250*20，5mkm)；流動相：IPA-MeOH，50-50；流速：9ml/min；管柱溫度：24℃；波長：205nm，215nm，254nm)，以得到化合物981 2-[(2S,5R )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(57mg，134.27μmol，43.51%產率)(RT=22.601min)及粗品第2級分(RT=35.267min)，藉由製備型掌性HPLC(管柱：Chiralpak IC-II(250*20，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min；管柱溫度：24℃；波長：205nm，215nm)再純化粗品第2級分，以得到化合物997 2-[(2R,5S )-2-(2-胺基-1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(51mg，120.14μmol，38.93%產率)(RT=45.230min)。The racemic 2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl)-5-methyl - 1-piperidinyl]-N-(6 - Amino-5-methyl-3-pyridyl)-2-oxoacetamide (131 mg, 308.59 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IA-II (250*20, 5mkm) ); mobile phase: IPA-MeOH, 50-50; flow rate: 9ml/min; column temperature: 24°C; wavelength: 205nm, 215nm, 254nm) to obtain compound 981 2-[( 2S,5R )-2- (2-Amino-1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-N-(6-amino - 5-methyl-3-pyridyl)- 2-Pendoxacetamide (57 mg, 134.27 μmol, 43.51% yield) (RT=22.601 min) and crude fraction 2 (RT=35.267 min) by preparative chiral HPLC (column: Chiralpak IC-II (250*20, 5mkm); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12ml/min; column temperature: 24°C; wavelength: 205nm, 215nm) and then purify the crude product. Fractions 2 to give compound 997 2-[( 2R,5S )-2-(2-amino-1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]- N- (6-amino-5-methyl-3-pyridyl)-2-oxyacetamide (51 mg, 120.14 μmol, 38.93% yield) (RT=45.230 min).

化合物997 於分析條件下(管柱：IA，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為30.40min且化合物981 之保留時間為18.36min。The retention time of compound 997 under analytical conditions (column: IA, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 30.40 min and the retention time of compound 981 was 18.36 min.

化合物997：保留時間：30.40minCompound 997: retention time: 30.40min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.02(m,3H),1.27-1.38(m,1H),1.65-1.73(m,1H),1.80-1.91(m,1H),1.95-2.02(m,3H),2.02-2.16(m,1H),2.17-2.27(m,1H),2.74-3.24(m,1H),3.41-4.03(m,1H),5.13-5.58(m,1H),5.58-5.64(m,2H),6.91-7.01(m,1H),7.22-7.30(m,1H),7.39-7.50(m,3H),7.58-7.64(m,1H),7.93-8.03(m,1H),10.39-10.56(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.02(m,3H), 1.27-1.38(m,1H), 1.65-1.73(m,1H), 1.80-1.91(m,1H) ,1.95-2.02(m,3H),2.02-2.16(m,1H),2.17-2.27(m,1H),2.74-3.24(m,1H),3.41-4.03(m,1H),5.13-5.58( m,1H),5.58-5.64(m,2H),6.91-7.01(m,1H),7.22-7.30(m,1H),7.39-7.50(m,3H),7.58-7.64(m,1H), 7.93-8.03 (m, 1H), 10.39-10.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=1.550min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=1.550 min.

化合物981：保留時間：18.36minCompound 981: retention time: 18.36min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.27-1.37(m,1H),1.66-1.75(m,1H),1.80-1.91(m,1H),1.96-2.02(m,3H),2.03-2.17(m,1H),2.18-2.28(m,1H),2.73-3.23(m,1H),3.43-4.03(m,1H),5.13-5.57(m,1H),5.58-5.65(m,2H),6.88-7.01(m,1H),7.21-7.31(m,1H),7.40-7.50(m,3H),7.58-7.64(m,1H),7.94-8.03(m,1H),10.39-10.68(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,3H), 1.27-1.37(m,1H), 1.66-1.75(m,1H), 1.80-1.91(m,1H) ,1.96-2.02(m,3H),2.03-2.17(m,1H),2.18-2.28(m,1H),2.73-3.23(m,1H),3.43-4.03(m,1H),5.13-5.57( m,1H),5.58-5.65(m,2H),6.88-7.01(m,1H),7.21-7.31(m,1H),7.40-7.50(m,3H),7.58-7.64(m,1H), 7.94-8.03 (m, 1H), 10.39-10.68 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=1.552min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=1.552 min.

實例390. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物953)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物961)之合成Example 390. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1-hydroxy-6-isoquinolinyl)-5- Methyl-1-piperidinyl]-2-oxoacetamide (compound 953) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R, Synthesis of 5S)-2-(1-hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 961)

Figure 110128222-A0202-12-1680-501
Figure 110128222-A0202-12-1680-501

步驟1：N-[5-[[2-[2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(1-Hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of tert-butyl]-3-methyl-2-pyridyl]carbamate

將DIPEA(133.34mg，1.03mmol，179.71μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(121.86mg，412.69μmol)及6-(5-甲基-2-哌啶基)異喹啉-1-酮(0.1g，412.69μmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(172.61mg，453.95μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸 浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN為溶析液混合物)，以得到N-[5-[[2-[2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(83.7mg，161.09μmol，39.03%產率)。DIPEA (133.34 mg, 1.03 mmol, 179.71 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (121.86 mg, 412.69 μmol) and 6-(5-methyl-2-piperidinyl)isoquinolin-1-one (0.1 g, 412.69 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (172.61 mg, 453.95 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction monitored by LCMS, the resulting suspension was The suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN as eluent mixture) to give N-[5-[[2-[2-(1-hydroxy-6-isoquinoline olinyl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (83.7 mg, 161.09 μmol, 39.03% yield).

LCMS(ESI)：[M+H]+ m/z：計算值519.2；實測值520.4；Rt=1.062min。LCMS (ESI): [M+H] + m/z: calculated 519.2; found 520.4; Rt=1.062 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[2-(1-hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl Synthesis of ]-2-oxyacetamide

將N-[5-[[2-[2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(83.7mg，161.09μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(60.8mg，144.94μmol，89.98%產率)。N-[5-[[2-[2-(1-Hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] - 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (83.7 mg, 161.09 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give N-(6-amino-5-methyl-3-pyridinyl)-2- [2-(1-Hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (60.8 mg, 144.94 μmol, 89.98% yield).

LCMS(ESI)：[M+H]+ m/z：計算值419.2；實測值420.2；Rt=0.747min。LCMS (ESI): [M+H] + m/z: calculated 419.2; found 420.2; Rt=0.747 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物953 )及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物961 )之合成Step 3: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(1-hydroxy-6-isoquinolinyl)-5- Methyl-1-piperidinyl]-2-oxyacetamide ( compound 953 ) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R, Synthesis of 5S)-2-(1-hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetamide ( compound 961 )

使用(Chiralcel OD-H 250*20mm管柱，以己烷-IPA-MeOH，50-25-25為流動相，流速30mL/min(Rt1=99,95min且Rt2=104,3min))對N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(60.8mg，144.94μmol)進行掌性分離，得到化合物953 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(10.55 mg，17.35%產率)及化合物961 rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(1-羥基-6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18.02mg，29.64%產率)。The N- (6-Amino-5-methyl-3-pyridyl)-2-[2-(1-hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-side Chiral separation of oxyacetamide (60.8 mg, 144.94 μmol) afforded compound 953 rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)- 2-(1-Hydroxy-6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (10.55 mg, 17.35% yield) and compound 961 rel-N -(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(1-hydroxy-6-isoquinolinyl)-5-methyl-1-piperidine Peridyl]-2-Pendant oxyacetamide (18.02 mg, 29.64% yield).

化合物953： RT(OD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=18.325min。 Compound 953: RT (OD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 18.325 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.03(m,3H),1.29-1.39(m,1H),1.61-1.70(m,1H),1.80-1.91(m,1H),1.95-2.03(m,3H),2.06-2.19(m,1H),2.23-2.32(m,1H),2.74-3.14(m,1H),3.47-4.07(m,1H),5.23-5.61(m,1H),5.61-5.69(m,2H),6.49-6.57(m,1H),7.08-7.20(m,1H),7.37-7.50(m,2H),7.52-7.61(m,1H),7.90-8.05(m,1H),8.11-8.18(m,1H),10.47-10.55(m,1H),11.15-11.24(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.03(m,3H), 1.29-1.39(m,1H), 1.61-1.70(m,1H), 1.80-1.91(m,1H), 1.95- 2.03(m,3H), 2.06-2.19(m,1H), 2.23-2.32(m,1H), 2.74-3.14(m,1H), 3.47-4.07(m,1H), 5.23-5.61(m,1H) ),5.61-5.69(m,2H),6.49-6.57(m,1H),7.08-7.20(m,1H),7.37-7.50(m,2H),7.52-7.61(m,1H),7.90-8.05 (m, 1H), 8.11-8.18 (m, 1H), 10.47-10.55 (m, 1H), 11.15-11.24 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值419.2；實測值420.2；Rt=0.729min。LCMS (ESI): [M+H] + m/z: calculated 419.2; found 420.2; Rt=0.729 min.

化合物961： RT(OD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=22.983min。 Compound 961: RT (OD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 22.983 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.04(m,3H),1.29-1.41(m,1H),1.61-1.70(m,1H),1.82-1.92(m,1H),1.95-2.04(m,3H),2.07-2.21(m,1H),2.23-2.34(m,1H),2.76-3.25(m,1H),3.47-4.07(m,1H),5.19-5.62(m,1H),5.65(s,2H),6.50-6.55(m,1H),7.10-7.18(m,1H),7.36-7.52(m,2H),7.52-7.63(m,1H),7.91-8.07(m,1H),8.10-8.18(m,1H),10.46-10.57(m,1H),11.15-11.22(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.04(m,3H), 1.29-1.41(m,1H), 1.61-1.70(m,1H), 1.82-1.92(m,1H), 1.95- 2.04(m,3H), 2.07-2.21(m,1H), 2.23-2.34(m,1H), 2.76-3.25(m,1H), 3.47-4.07(m,1H), 5.19-5.62(m,1H) ), 5.65(s, 2H), 6.50-6.55(m, 1H), 7.10-7.18(m, 1H), 7.36-7.52(m, 2H), 7.52-7.63(m, 1H), 7.91-8.07(m , 1H), 8.10-8.18 (m, 1H), 10.46-10.57 (m, 1H), 11.15-11.22 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值419.2；實測值420.2；Rt=0.730minLCMS(ESI): [M+H] + m/z: Calculated 419.2; Measured 420.2; Rt=0.730min

實例391. N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺鹽酸鹽(化合物1009)之合成Example 391. N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl-2-d) -Synthesis of 2-oxyacetamide hydrochloride (compound 1009)

Figure 110128222-A0202-12-1682-502
Figure 110128222-A0202-12-1682-502

步驟1：(5-(2-(2-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(4-Fluorophenyl)-5-methylpiperidin-1-yl-2-d)-2-oxyacetamido)-3-methyl Synthesis of tert-butyl pyridin-2-yl)carbamate

在0℃下，向2-((6-((第三丁氧基羰基)胺基)-5-甲基吡啶-3-基)胺基)-2-側氧基乙酸(167mg，0.57mmol)及2-(4-氟苯基)-5-甲基哌啶-2-d(110mg，0.57mmol)於DMF(0.2mL)中之經攪拌之溶液中添加HATU(215mg，0.57mmol)及三乙胺(237μL，1.70mmol)。將所得反應混合物在環境溫度下攪拌18小時。18小時之後，將反應混合物在減壓下濃縮且添加水。將水層用EtOAc(2x)萃取。將經合併之有機相用水(2x)洗滌，乾燥(Na2 SO4 )且在減壓下濃縮，以獲得粗產物。藉由矽膠管柱層析(己烷/乙酸乙酯10/0至0/10)純化殘餘物，得到呈白色固體之(5-(2-(2-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯)(170mg，64%)To 2-((6-((tertiary-butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino)-2-pendoxoacetic acid (167 mg, 0.57 mmol at 0 °C ) and 2-(4-fluorophenyl)-5-methylpiperidine-2-d (110 mg, 0.57 mmol) in DMF (0.2 mL) to a stirred solution of HATU (215 mg, 0.57 mmol) and Triethylamine (237 μL, 1.70 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure and water was added. The aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with water (2x), dried ( Na2SO4 ) and concentrated under reduced pressure to obtain crude product. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 10/0 to 0/10) to give (5-(2-(2-(4-fluorophenyl)-5-) as a white solid Methylpiperidin-1-yl-2-d)-2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester) (170 mg, 64%)

1 H NMR(DMSO-d6 ,400MHz)11.05(s,0.6H),10.98(s,0.4H),9.07(s,0.6H),9.03(s,0.4H),8.45(s,0.6H),8.38(s,0.4H),7.93(app d,0.6H),7.89(s,0.4H),7.44-7.32(m,2H),7.28-7.17(m,2H),3.46(d,J =13.7Hz,0.6H),3.24(dd,J =3.7,13.8Hz,0.6H),2.76(dd,J =3.7,13.4Hz,0.4H),2.26-1.99(m,4H),1.96-1.80(m,1H)1.74-1.61(m,1H),1.47-1.41(m,9H),1.07-0.99(m,3H)。 1 H NMR(DMSO-d 6 , 400MHz) 11.05(s, 0.6H), 10.98(s, 0.4H), 9.07(s, 0.6H), 9.03(s, 0.4H), 8.45(s, 0.6H) , 8.38(s, 0.4H), 7.93(app d, 0.6H), 7.89(s, 0.4H), 7.44-7.32(m, 2H), 7.28-7.17(m, 2H), 3.46(d, J = 13.7Hz, 0.6H), 3.24(dd, J =3.7, 13.8Hz, 0.6H), 2.76(dd, J =3.7, 13.4Hz, 0.4H), 2.26-1.99(m, 4H), 1.96-1.80( m, 1H) 1.74-1.61 (m, 1H), 1.47-1.41 (m, 9H), 1.07-0.99 (m, 3H).

19 F NMR(DMSO-d6 ,376MHz)δ -116.4,-116.5。 19 F NMR (DMSO-d 6 , 376 MHz) δ -116.4, -116.5.

LRMS(APCI+ )m/z(C25 H30 DFN4 O4 H)：理論值472.2，實驗值472.5。LRMS (APCI + ) m/z (C 25 H 30 DFN 4 O 4 H): theoretical 472.2, experimental 472.5.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺鹽酸鹽(化合物1009 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl-2-d) -Synthesis of 2-oxyacetamide hydrochloride ( compound 1009 )

向-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸酯(20mg，42μmol)之經攪拌之溶液中添加於二噁烷中之4M HCl(11mL，4.0mol，0.42mmol)。將所得反應混合物在環境溫度下攪拌，直到所有起始材料均消耗(3h)。在真空下濃縮揮發物且在醚中研磨固體殘餘物。過濾固體且用醚沖洗(將該操作重複1次)。過濾之後，獲得呈白色固體之N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基-2-d)-2-側氧基乙醯胺鹽酸鹽(化合物 1009 )(15mg，87%)To-(4-fluorophenyl)-5-methylpiperidin-1-yl-2-d)-2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid To a stirred solution of the ester (20 mg, 42 [mu]mol) was added 4M HCl in dioxane (11 mL, 4.0 mol, 0.42 mmol). The resulting reaction mixture was stirred at ambient temperature until all starting material was consumed (3 h). The volatiles were concentrated in vacuo and the solid residue was triturated in ether. The solids were filtered and rinsed with ether (this operation was repeated once). After filtration, N-(6-amino-5-methylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl was obtained as a white solid -2-d)-2-Oxyacetamide hydrochloride ( compound 1009 ) (15 mg, 87%)

1 H NMR(CD3 OD,400MHz)11.10(s,0.6H),11.04(s,0.4H),8.30(s,0.6H),8.24(s,0.4H),7.84(s,0.6H),7.82(s,0.4H),7.75-7.50(br s,2H),7.42-7.31(m,2H),7.28-7.18(m,2H),4.01(d,J =13.4Hz,0.4H),3.48(d,J =12.9Hz,0.6H),3.26-3.20(app d,0.6H),2.780-2.73(app d,0.4H),2.24-2.12(m,4H),2.12-1.82(m,2H)1.74-1.60(m,1H),1.40-1.27(m,1H),1.06-0.98(app t,3H)。 1 H NMR (CD 3 OD, 400MHz) 11.10(s, 0.6H), 11.04(s, 0.4H), 8.30(s, 0.6H), 8.24(s, 0.4H), 7.84(s, 0.6H), 7.82(s, 0.4H), 7.75-7.50(br s, 2H), 7.42-7.31(m, 2H), 7.28-7.18(m, 2H), 4.01(d, J =13.4Hz, 0.4H), 3.48 (d, J =12.9Hz, 0.6H), 3.26-3.20(app d, 0.6H), 2.780-2.73(app d, 0.4H), 2.24-2.12(m, 4H), 2.12-1.82(m, 2H ) 1.74-1.60 (m, 1H), 1.40-1.27 (m, 1H), 1.06-0.98 (app t, 3H).

LRMS(APCI+ )m/z(C20 H22 DFN4 O2 H)：理論值372.2，實驗值372.4。LRMS (APCI + ) m/z (C 20 H 22 DFN 4 O 2 H): theoretical 372.2, found 372.4.

實例392. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物356)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物357)之合成Example 392. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]- 2-Oxyacetamide (Compound 356) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S)-2-[3-(methylamino)benzene Synthesis of yl]-1-piperidinyl]-2-oxoacetamide (compound 357)

Figure 110128222-A0202-12-1684-503
Figure 110128222-A0202-12-1684-503

步驟1：N-[3-甲基-5-[[2-[2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino Synthesis of 3-butyl ]-2-pyridyl]carbamate

將DIPEA(273.55mg，2.12mmol，368.67μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.25g，846.62μmol)及 N-甲基-3-(2-哌啶基)苯胺(161.10mg，846.62μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(354.10mg，931.28μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10,in 85-100% H2 O-MeOH+NH3 ；裝載泵4.0mL MeOH+NH3 )；Triart C18 100* 20 5mkm管柱)，以得到純的N-[3-甲基-5-[[2-[2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.15g，320.82μmol，37.89%產率)。DIPEA (273.55 mg, 2.12 mmol, 368.67 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (0.25 g, 846.62 μmol) and N-methyl-3-(2-piperidinyl)aniline (161.10 mg, 846.62 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (354.10 mg, 931.28 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10, in 85-100% H2O -MeOH+ NH3 ; loading pump 4.0 mL MeOH+ NH3 ); Triart C18 100 * 20 5mkm column) to obtain pure N-[3-Methyl-5-[[2-[2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2 - tert-butyl pyridyl]carbamate (0.15 g, 320.82 μmol, 37.89% yield).

1 H NMR(400MHz,CDCl3 )δ 1.43(m,11H),1.82(m,1H),2.25(m,4H),2.41(m,1H),2.84(s,3H),3.20(m,1H),3.47(m,1H),4.72(m,1H),6.01(m,1H),6.41(m,2H),6.54(m,2H),7.20(m,1H),8.01(m,1H),8.30(m,1H),9.37(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.43(m,11H), 1.82(m,1H), 2.25(m,4H), 2.41(m,1H), 2.84(s,3H), 3.20(m,1H) ),3.47(m,1H),4.72(m,1H),6.01(m,1H),6.41(m,2H),6.54(m,2H),7.20(m,1H),8.01(m,1H) , 8.30 (m, 1H), 9.37 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值467.2；實測值469.2；Rt=2.998minLCMS(ESI): [M+2H] + m/z: Calculated 467.2; Measured 469.2; Rt=2.998min

步驟2：N-[3-甲基-5-[[2-[2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 2: N-[3-Methyl-5-[[2-[2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino Chiral separation of tert-butyl ]-2-pyridyl]carbamate

使用(IC-II(250* 20，5mkm)管柱；己烷-MeOH-IPA，50-25-25為流動相；流速12mL/min)進行N-[3-甲基-5-[[2-[2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之掌性分離，得到異構物2 N-[3-甲基-5-[[2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(46.5mg；31.0%產率；RT=)及異構物1 N-[3-甲基-5-[[2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(52.0mg，34.67%產率)。 N- [3-methyl-5-[[2 -[2-[3-(Methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester Isolated to give isomer 2 N-[3-methyl-5-[[2-[(2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-side Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (46.5 mg; 31.0% yield; RT=) and isomer 1 N-[3-methyl-5-[[ 2-[(2S)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid third Butyl ester (52.0 mg, 34.67% yield).

異構物1：Isomer 1:

RT(IC，CO2 -MeOH，50-50，2.0mL/min)=7.218min。RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 7.218 min.

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值469.2；Rt=4.512min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 469.2; Rt=4.512 min.

異構物2：Isomer 2:

RT(IC，CO2 -MeOH，50-50，2.0mL/min)=4.665min。RT (IC, CO2 -MeOH, 50-50, 2.0 mL/min) = 4.665 min.

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值468.2；Rt=4.512min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 468.2; Rt=4.512 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物356 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide ( Compound 356 )

將N-[3-甲基-5-[[2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物2(46.5mg，99.45μmol)溶解於水(5mL)及二噁烷(2mL)中。然後，將反應混合物在100℃下攪拌15h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min 0-70% MeOH-H2 O；流速30mL/min；裝載泵4mL MeOH；SunFire C18 100* 19mm，5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(14mg，38.10μmol，38.31%產率)。N-[3-Methyl-5-[[2-[(2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl] Amino]-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (46.5 mg, 99.45 μmol) was dissolved in water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 15 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 0-70% MeOH- H2O ; flow rate 30 mL/min; loading pump 4 mL MeOH; SunFire C18 100 * 19 mm, 5 mkm column) to give pure N-(6 -Amino-5-methyl-3-pyridyl)-2-[(2R)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-side oxyacetyl Amine (14 mg, 38.10 μmol, 38.31% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.40-1.52(m,2H),1.54-1.64(m,2H),1.71-1.88(m,1H),1.97-2.03(m,3H),2.32-2.36(m,1H),2.54-2.57(m,0.4H),2.61-2.67(m,3H),2.96-3.04(m,0.6H),3.56-4.33(m,1H),5.03-5.54(m,1H),5.54-5.63(m,3H),6.37-6.42(m,1H),6.43-6.46(m,1H),6.46-6.52(m,1H),7.04-7.11(m,1H),7.40-7.53(m,1H),7.94-8.05(m,1H),10.40-10.53(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.40-1.52 (m, 2H), 1.54-1.64 (m, 2H), 1.71-1.88 (m, 1H), 1.97-2.03 (m, 3H), 2.32- 2.36(m, 1H), 2.54-2.57(m, 0.4H), 2.61-2.67(m, 3H), 2.96-3.04(m, 0.6H), 3.56-4.33(m, 1H), 5.03-5.54(m ,1H),5.54-5.63(m,3H),6.37-6.42(m,1H),6.43-6.46(m,1H),6.46-6.52(m,1H),7.04-7.11(m,1H),7.40 -7.53(m, 1H), 7.94-8.05(m, 1H), 10.40-10.53(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.4；Rt=1.968min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.4; Rt=1.968 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物357 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S)-2-[3-(methylamino)phenyl]-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide ( Compound 357 )

將N-[3-甲基-5-[[2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物1(52mg，111.22μmol)溶解於二噁烷(2mL)及水(5mL)中。然後，將反應混合物在100℃下攪拌15h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min 0-70% MeOH-H2 O；流速30mL/min；裝載泵4mL MeOH；SunFire C18 100* 19 mm，5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(22.2mg，60.42μmol，54.32%產率)。N-[3-Methyl-5-[[2-[(2S)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl] Amino]-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (52 mg, 111.22 μmol) was dissolved in dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 15 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 0-70% MeOH- H2O ; flow rate 30 mL/min; loading pump 4 mL MeOH; SunFire C18 100 * 19 mm, 5 mkm column) to obtain pure N-( 6-Amino-5-methyl-3-pyridyl)-2-[(2S)-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-side oxyethyl Amide (22.2 mg, 60.42 μmol, 54.32% yield).

1 H NMR(600MHz,DMSO-d6 )δ 1.50(m,4H),1.79(m,1H),2.00(m,3H),2.32(m,1H),2.55(m,1H),2.63(m,3H),3.00(m,0.6H),3.41(m,0.4H),3.93(m,1H),5.37(m,1H),5.59(m,2H),6.39(m,1H),6.44(m,1H),6.48(m,1H),7.07(m,1H),7.47(m,1H),7.99(m,1H),10.46(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.50(m, 4H), 1.79(m, 1H), 2.00(m, 3H), 2.32(m, 1H), 2.55(m, 1H), 2.63(m ,3H),3.00(m,0.6H),3.41(m,0.4H),3.93(m,1H),5.37(m,1H),5.59(m,2H),6.39(m,1H),6.44( m, 1H), 6.48 (m, 1H), 7.07 (m, 1H), 7.47 (m, 1H), 7.99 (m, 1H), 10.46 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.4；Rt=1.967min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.4; Rt=1.967 min.

實例393.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺(化合物61、化合物336、化合物340)之合成Example 393. N- (6-amino-5-methylpyridin-3-yl)-2-(2-cyclopentylpiperidin-1-yl)-2-oxoacetamide (Compound 61, Synthesis of compound 336, compound 340)

Figure 110128222-A0202-12-1687-504
Figure 110128222-A0202-12-1687-504

步驟1：(5-(2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: tert-butyl (5-(2-(2-cyclopentylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridin-2-yl)carbamate synthesis

將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(352.94mg，1.02mmol)及2-環戊基哌啶(155.71mg，1.02mmol)混合於DMF(15mL)中。將反應懸浮液冷卻至0℃且添加HATU(386.29mg，1.02mmol)，隨後添加TEA(308.41mg，3.05mmol，424.81μL)。將澄清溶液在周圍溫度下攪拌5h，然後在減壓下蒸發揮發物，且使殘餘物(1g)經歷RP-HPLC(管柱：SunFire C18 100x19mm，5um；以60-60-90% 0-1-5min水-甲醇為流動相)，以得到N -[5-[[2-(2-環戊基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(264 mg，613.18μmol，60.36%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (352.94 mg, 1.02 mmol) and 2-cyclopenta Piperidine (155.71 mg, 1.02 mmol) was mixed in DMF (15 mL). The reaction suspension was cooled to 0°C and HATU (386.29 mg, 1.02 mmol) was added followed by TEA (308.41 mg, 3.05 mmol, 424.81 μL). The clear solution was stirred at ambient temperature for 5 h, then the volatiles were evaporated under reduced pressure and the residue (1 g) was subjected to RP-HPLC (column: SunFire C18 100x19 mm, 5 um; 0-1 at 60-60-90% 0-1 g). -5min water-methanol as mobile phase) to obtain N- [5-[[2-(2-cyclopentyl-1-piperidinyl)-2-side oxyacetyl]amino]-3- 3 -butyl methyl-2-pyridyl]carbamate (264 mg, 613.18 μmol, 60.36% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.43(s,9H),1.65(m,12H),2.17(s,3H),3.16(m,1H),3.53(m,1H),4.23(m,1H),7.91(m,1H),8.41(m,1H),9.05(m,1H),10.88(m,1H)。LCMS(ESI)：[M+1]+ m/z：計算值430.5；實測值431.2；Rt=3.533min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.43(s, 9H), 1.65(m, 12H), 2.17(s, 3H), 3.16(m, 1H), 3.53 (m, 1H), 4.23 (m, 1H), 7.91 (m, 1H), 8.41 (m, 1H), 9.05 (m, 1H), 10.88 (m, 1H). LCMS (ESI): [M+1] + m/z: calculated 430.5; found 431.2; Rt=3.533 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺(化合物61 )之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-cyclopentylpiperidin-1-yl)-2-oxoacetamide ( Compound 61 ) synthesis

在室溫下將於二噁烷中之4.0M氯化氫溶液(1.51g，5.81mmol，1.44mL，14%純度)小心添加到N -[5-[[2-(2-環戊基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(250mg，580.67μmol)於DCM(4mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑，以得到0.25g粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以50-60% 0-5min 0.1% NH3 -甲醇為流動相)，以得到化合物61 N -(6-胺基-5-甲基-3-吡啶基)-2-(2-環戊基-1-哌啶基)-2-側氧基乙醯胺(98mg，296.59μmol，51.08%產率)。A 4.0 M solution of hydrogen chloride in dioxane (1.51 g, 5.81 mmol, 1.44 mL, 14% purity) was carefully added to N- [5-[[2-(2-cyclopentyl-1- A solution of tert-butyl piperidinyl)-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate (250 mg, 580.67 [mu]mol) in DCM (4 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo to give 0.25 g of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; 50-60% 0-5min 0.1% NH3 -methanol as mobile phase) to give compound 61 N- (6-amino-5- Methyl-3-pyridyl)-2-(2-cyclopentyl-1-piperidinyl)-2-oxyacetamide (98 mg, 296.59 μmol, 51.08% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.12(m,2H),1.40(m,1H),1.55(m,6H),1.66(m,5H),2.03(s,3H),2.74(m,1H),3.14(m,1H),3.54(m,1H),4.21(m,1H),5.62(m,2H),7.48(m,1H),8.01(m,1H),10.26(m,1H)。LCMS(ESI)：[M+1]m/z：計算值330.5；實測值331.2；Rt=2.706min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.12(m, 2H), 1.40(m, 1H), 1.55(m, 6H), 1.66(m, 5H), 2.03(s, 3H), 2.74(m, 1H), 3.14(m, 1H), 3.54(m, 1H), 4.21(m, 1H), 5.62(m, 2H), 7.48(m, 1H), 8.01(m, 1H), 10.26 (m, 1H). LCMS (ESI): [M+1] m/z: calculated 330.5; found 331.2; Rt=2.706 min.

步驟3：掌性分離Step 3: Palm Separation

在體系CO2 -MeOH，90-10，2mL/min中在掌性管柱上進行純化。注入次數：1，注入體積：1mkl。自183.1mg外消旋物獲得71.84mg及60mg個別鏡像異構物。Purification was performed on a chiral column in system CO2-MeOH, 90-10, 2 mL/min. Injection times: 1, injection volume: 1mkl. 71.84 mg and 60 mg of individual enantiomers were obtained from 183.1 mg of racemate.

E1：保留時間：3.58min1 H NMR(400MHz,CDCl3 )δ(ppm)1.23(m,3H),1.47(s,9H),1.61(m,12H),2.14(s,3H),3.02(m,1H),4.43(m,1H),4.78(m,1H),7.08(m, 1H),8.08(s,1H),8.46(s,1H),9.51(m,1H)。LCMS(ESI)：[M+1]m/z：計算值430.2；實測值431.2；Rt=5.746min。E1: Retention time: 3.58 min 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.23 (m, 3H), 1.47 (s, 9H), 1.61 (m, 12H), 2.14 (s, 3H), 3.02 ( m, 1H), 4.43 (m, 1H), 4.78 (m, 1H), 7.08 (m, 1H), 8.08 (s, 1H), 8.46 (s, 1H), 9.51 (m, 1H). LCMS (ESI): [M+1]m/z: calculated 430.2; found 431.2; Rt=5.746 min.

保留時間：4.22min1 H NMR(400MHz,CDCl3 )δ(ppm)1.21(m,3H),1.48(s,9H),1.62(m,12H),2.14(s,3H),3.03(m,1H),4.42(m,1H),4.82(m,1H),6.98(m,1H),8.08(s,1H),8.42(s,1H),9.41(m,1H)。LCMS(ESI)：[M+1]m/z：計算值430.2；實測值431.2；Rt=5.757min。Retention time: 4.22 min 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.21 (m, 3H), 1.48 (s, 9H), 1.62 (m, 12H), 2.14 (s, 3H), 3.03 (m, 1H), 4.42(m, 1H), 4.82(m, 1H), 6.98(m, 1H), 8.08(s, 1H), 8.42(s, 1H), 9.41(m, 1H). LCMS (ESI): [M+1] m/z: calculated 430.2; found 431.2; Rt=5.757 min.

步驟4：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺(化合物336、化合物340 )之合成Step 4: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-cyclopentylpiperidin-1-yl)-2-oxoacetamide ( compound 336, Synthesis of compound 340 )

將N -[5-[[2-[(2S )-2-環戊基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.07184g，166.86μmol)及N -[5-[[2-[(2R )-2-環戊基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.06g，139.36μmol)於二噁烷/HCl(5mL)中之溶液在20℃下攪拌12h。使所得混合物經歷HPLC(管柱SunFire 19*100mm，以水-MeCN+HCl為流動相)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S )-2-環戊基-1-哌啶基]-2-側氧基乙醯胺(0.0329g，89.67μmol，53.74%產率，HCl)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R )-2-環戊基-1-哌啶基]-2-側氧基乙醯胺(0.0329，89.67μmol，64.35%產率，HCl)。 N- [5-[[2-[( 2S )-2-cyclopentyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl ] tert -butyl carbamate (0.07184 g, 166.86 μmol) and N- [5-[[2-[( 2R )-2-cyclopentyl-1-piperidinyl]-2-side oxyacetyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.06 g, 139.36 [mu]mol) in dioxane/HCl (5 mL) was stirred at 20&lt;0&gt;C for 12 h. The resulting mixture was subjected to HPLC (column SunFire 19*100 mm with water-MeCN+HCl as mobile phase) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S )-2-cyclopentyl-1-piperidinyl]-2-oxyacetamide (0.0329 g, 89.67 μmol, 53.74% yield, HCl) and N-(6-amino-5-methyl) -3-Pyridinyl)-2-[( 2R )-2-cyclopentyl-1-piperidinyl]-2-oxyacetamide (0.0329, 89.67 μmol, 64.35% yield, HCl).

化合物336： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(m,2H),1.37(m,1H),1.56(m,11H),2.16(s,3H),2.42(m,1H),3.05(m,1H),3.53(m,1H),4.19(m,1H),7.72(m,2H),7.82(m,1H),8.26(m,1H),10.93(m,1H),13.49(br s,1H)。LCMS(ESI)：[M+1]m/z：計算值330.2；實測值331.2；Rt=2.281min。 Compound 336: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.08 (m, 2H), 1.37 (m, 1H), 1.56 (m, 11H), 2.16 (s, 3H), 2.42 (m, 1H), 3.05(m, 1H), 3.53(m, 1H), 4.19(m, 1H), 7.72(m, 2H), 7.82(m, 1H), 8.26(m, 1H), 10.93(m, 1H) ), 13.49(br s, 1H). LCMS (ESI): [M+1] m/z: calculated 330.2; found 331.2; Rt=2.281 min.

化合物340： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.11(m,2H),1.36(m,1H),1.55(m,11H),2.16(s,3H),2.43(m,1H),2.94(m,1H),3.53(m,1H),4.19(m,1H),7.69(m,2H),7.81(m,1H),8.26(m,1H),10.92(m,1H),13.44(br s,1H)。LCMS(ESI)：[M+1]m/z：計算值330.2；實測值331.2；Rt=2.424min。 Compound 340: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.11 (m, 2H), 1.36 (m, 1H), 1.55 (m, 11H), 2.16 (s, 3H), 2.43 (m, 1H), 2.94(m, 1H), 3.53(m, 1H), 4.19(m, 1H), 7.69(m, 2H), 7.81(m, 1H), 8.26(m, 1H), 10.92(m, 1H) ), 13.44(br s, 1H). LCMS (ESI): [M+1] m/z: calculated 330.2; found 331.2; Rt=2.424 min.

實例394. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物390)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物384)之合成Example 394. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R)-2-[3-(dimethylamino)phenyl]-1-piperidinyl] -2-Oxyacetamide (Compound 390) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S)-2-[3-(dimethylamino) ) Phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 384) Synthesis

Figure 110128222-A0202-12-1690-505
Figure 110128222-A0202-12-1690-505

步驟1：N-[5-[[2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-[3-(Dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-3- Synthesis of tert-butyl methyl-2-pyridyl]carbamate

將DIPEA(262.61mg，2.03mmol，353.92μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.2g，677.30μmol)及N,N-二甲基-3-(2-哌啶基)苯胺(138.38mg，677.30μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(283.28mg，745.03μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min 35-60% H2 O-MeOH；裝載泵4mL MeOH；SunFire C18 100* 19mm 5mkm管柱)，以得到純的N-[5-[[2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.1g，207.65μmol，30.66%產率)DIPEA (262.61 mg, 2.03 mmol, 353.92 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo Ethylacetic acid (0.2 g, 677.30 μmol) and N,N-dimethyl-3-(2-piperidinyl)aniline (138.38 mg, 677.30 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (283.28 mg, 745.03 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 35-60% H2O -MeOH; loading pump 4mL MeOH; SunFire C18 100 * 19mm 5mkm column) to give pure N-[5-[[2-[ 2-[3-(Dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl Ester (0.1 g, 207.65 μmol, 30.66% yield)

1 H NMR(400MHz,DMSO-d6 )δ 1.42(m,9H),1.63(m,4H),2.18(m,2H),2.36(m, 2H),2.93(m,6H),3.22(m,3H),4.01(m,2H),6.64(m,3H),7.20(m,1H),7.94(m,1H),8.43(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.42(m, 9H), 1.63(m, 4H), 2.18(m, 2H), 2.36(m, 2H), 2.93(m, 6H), 3.22(m , 3H), 4.01 (m, 2H), 6.64 (m, 3H), 7.20 (m, 1H), 7.94 (m, 1H), 8.43 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值481.2；實測值482.2；Rt=3.235min。LCMS (ESI): [M+H] + m/z: calculated 481.2; found 482.2; Rt=3.235 min.

步驟2：N-[5-[[2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 2: N-[5-[[2-[2-[3-(Dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-3- Chiral separation of tert-butyl methyl-2-pyridyl]carbamate

使用(IC-II(250* 20，5mkm)管柱；己烷-MeOH-IPA，50-25-25為流動相；流速12mL/min)進行N-[5-[[2-[2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離，得到異構物1 N-[5-[[2-[(2R)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(29.4mg，29.40%產率；RT=39.731min)及異構物2 N-[5-[[2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(29.5mg，29.50%產率；RT=30.341min)。 N- [5-[[[2-[2-[ 3-(Dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester was isolated to give the isomer 1 N-[5-[[2-[(2R)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (29.4 mg, 29.40% yield; RT=39.731 min) and isomer 2 N-[5-[[2 -[(2S)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl ] tert-butyl carbamate (29.5 mg, 29.50% yield; RT=30.341 min).

異構物1： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=33.49min。 Isomer 1: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 33.49 min.

LCMS(ESI)：[M+H]+ m/z：計算值481.2；實測值482.2；Rt=4.733min。LCMS (ESI): [M+H] + m/z: calculated 481.2; found 482.2; Rt=4.733 min.

異構物2： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=25.16min。 Isomer 2: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 25.16 min.

LCMS(ESI)：[M+2H]+ m/z：計算值481.2；實測值483.2；Rt=4.742min。LCMS (ESI): [M+2H] + m/z: calculated 481.2; found 483.2; Rt=4.742 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物390 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R)-2-[3-(dimethylamino)phenyl]-1-piperidinyl] Synthesis of -2-oxoacetamide ( compound 390 )

將N-[5-[[2-[(2R)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物1(29.4mg，61.05μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min 0-60% H2 O-MeOH+NH3 ；裝載泵4mL MeOH+NH3 ；Triart 100* 20 5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R)-2-[3-(二甲胺基)苯 基]-1-哌啶基]-2-側氧基乙醯胺(16.1mg，42.21μmol，69.13%產率)N-[5-[[2-[(2R)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]- 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (29.4 mg, 61.05 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 0-60% H2O -MeOH+ NH3 ; loading pump 4 mL MeOH+ NH3 ; Triart 100 * 20 5mkm column) to give pure N-(6- Amino-5-methyl-3-pyridyl)-2-[(2R)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxoacetone Amine (16.1 mg, 42.21 μmol, 69.13% yield)

1 H NMR(600MHz,DMSO-d6 )δ 1.37-1.53(m,2H),1.53-1.64(m,2H),1.72-1.87(m,1H),1.96-2.04(m,3H),2.39-2.42(m,1H),2.54-2.56(m,0.3H),2.83-2.90(m,6H),2.99-3.06(m,0.7H),3.61-4.32(m,1H),5.03-5.58(m,1H),5.58-5.66(m,2H),6.55-6.63(m,3H),7.13-7.21(m,1H),7.42-7.53(m,1H),7.92-8.04(m,1H),10.45-10.56(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.37-1.53(m, 2H), 1.53-1.64(m, 2H), 1.72-1.87(m, 1H), 1.96-2.04(m, 3H), 2.39- 2.42(m, 1H), 2.54-2.56(m, 0.3H), 2.83-2.90(m, 6H), 2.99-3.06(m, 0.7H), 3.61-4.32(m, 1H), 5.03-5.58(m ,1H),5.58-5.66(m,2H),6.55-6.63(m,3H),7.13-7.21(m,1H),7.42-7.53(m,1H),7.92-8.04(m,1H),10.45 -10.56(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=1.900min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=1.900 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物384 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S)-2-[3-(dimethylamino)phenyl]-1-piperidinyl] Synthesis of -2-oxoacetamide ( compound 384 )

將N-[5-[[2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物2(29.5mg，61.26μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min 0-60% H2 O-MeOH+NH3 ；裝載泵4mL MeOH+NH3 ；Triart 100* 20 5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S)-2-[3-(二甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(16.2mg，42.47μmol，69.33%產率)。N-[5-[[2-[(2S)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]- 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (29.5 mg, 61.26 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 0-60% H2O -MeOH+ NH3 ; loading pump 4 mL MeOH+ NH3 ; Triart 100 * 20 5mkm column) to give pure N-(6- Amino-5-methyl-3-pyridyl)-2-[(2S)-2-[3-(dimethylamino)phenyl]-1-piperidinyl]-2-oxoacetone Amine (16.2 mg, 42.47 μmol, 69.33% yield).

1 H NMR(600MHz,DMSO-d6 )δ 1.35-1.53(m,2H),1.53-1.65(m,2H),1.72-1.90(m,1H),1.96-2.03(m,3H),2.38-2.43(m,1H),2.84-2.88(m,6H),2.98-3.27(m,1H),3.62-4.27(m,1H),5.06-5.64(m,3H),6.55-6.65(m,3H),7.13-7.22(m,1H),7.40-7.55(m,1H),7.90-8.08(m,1H),10.47-10.55(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 1.35-1.53(m, 2H), 1.53-1.65(m, 2H), 1.72-1.90(m, 1H), 1.96-2.03(m, 3H), 2.38- 2.43(m,1H),2.84-2.88(m,6H),2.98-3.27(m,1H),3.62-4.27(m,1H),5.06-5.64(m,3H),6.55-6.65(m,3H ), 7.13-7.22(m, 1H), 7.40-7.55(m, 1H), 7.90-8.08(m, 1H), 10.47-10.55(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=2.225min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=2.225 min.

實例395. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物449)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物Example 395. N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]- 1-Piperidinyl]-2-oxyacetamide (Compound 449) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5- Methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyacetamide (compound 450)之合成450) synthesis

Figure 110128222-A0202-12-1693-506
Figure 110128222-A0202-12-1693-506

步驟1：N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將DIPEA(765.94mg，5.93mmol，1.03mL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.5g，1.69mmol)及N-甲基-3-[(2S,5R)-5-甲基-2-哌啶基]苯胺(345.95mg，1.69mmol)於DMF(15mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(708.20mg，1.86mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min以35-100% MeCN-H2 O為流動相；流速30mL/min；裝載泵4mL MeCN；Sunfire C18 19* 100mm 5mkm管柱)，以得到純的N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.29g，602.18μmol，35.56%產率)。DIPEA (765.94 mg, 5.93 mmol, 1.03 mL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo Ethyl acetic acid (0.5 g, 1.69 mmol) and N-methyl-3-[(2S,5R)-5-methyl-2-piperidinyl]aniline (345.95 mg, 1.69 mmol) in DMF (15 mL) in solution. The resulting mixture was stirred for 5 min, then HATU solution (708.20 mg, 1.86 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 35-100% MeCN- H2O as mobile phase; flow rate 30 mL/min; loading pump 4 mL MeCN; Sunfire C18 19 * 100mm 5mkm column) to obtain pure N -[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxygen ethylacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.29 g, 602.18 μmol, 35.56% yield).

1 H NMR(400MHz,CDCl3 )δ 1.04(m,3H),1.32(m,2H),1.47(s,9H),2.12(m,6H),2.91(m,3H),3.41(m,3H),4.61(m,1H),6.67(m,3H),7.21(m,1H),8.05(m,1H),8.38(m,1H),9.41(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.04 (m, 3H), 1.32 (m, 2H), 1.47 (s, 9H), 2.12 (m, 6H), 2.91 (m, 3H), 3.41 (m, 3H) ), 4.61(m, 1H), 6.67(m, 3H), 7.21(m, 1H), 8.05(m, 1H), 8.38(m, 1H), 9.41(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值481.2；實測值482.2；Rt=1.297min。LCMS (ESI): [M+H] + m/z: calculated 481.2; found 482.2; Rt=1.297 min.

步驟2：N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 2: N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]- Chiral Separation of 2-Pendant Oxyacetyl]amino]-2-pyridyl]carbamic Acid 3-Butyl Ester

使用(IB(250* 20，5mkm)管柱，己烷-MeOH-IPA，50-25-25為流動相；流速12mL/min)進行N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之掌性分離，得到異構物1 N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(101.59mg，35.03%產率；RT=15.696min)及異構物2 N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(111.87mg，38.58%產率；RT=33.861min)。 N- [3-methyl-5-[[2-[ (2R,5S)-5-Methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl] Chiral separation of tert-butyl carbamate to give isomer 1 N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamine (101.59 mg, 35.03% yield; RT=15.696 min ) and isomer 2 N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidine [00108] tert-butyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamate (111.87 mg, 38.58% yield; RT=33.861 min).

異構物1： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=17.22min。 Isomer 1: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 17.22 min.

LCMS(ESI)：[M+H]+ m/z：計算值481.2；實測值482.2；Rt=2.964min。LCMS (ESI): [M+H] + m/z: calculated 481.2; found 482.2; Rt=2.964 min.

異構物2： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=42.79min。 Isomer 2: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 42.79 min.

LCMS(ESI)：[M+2H]+ m/z：計算值481.2；實測值483.2；Rt=2.961min。LCMS (ESI): [M+2H] + m/z: calculated 481.2; found 483.2; Rt=2.961 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物450 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[3-(methylamino)phenyl]- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 450 )

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物2(111.87mg，232.30μmol)溶解於水(5mL)及二噁烷(2mL)之混合物中。然後，將反應混合物在100℃下攪拌15h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min 35-100% MeCN-H2 O；流速30mL/min；裝載泵4mL MeCN；Sunfire C18 19* 100mm 5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(61.6mg，161.48μmol，69.52%產率)。N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-pyridyl]carbamate tert-butyl ester isomer 2 (111.87 mg, 232.30 μmol) was dissolved in a mixture of water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 15 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 35-100% MeCN- H2O ; flow rate 30 mL/min; loading pump 4 mL MeCN; Sunfire C18 19 * 100 mm 5mkm column) to obtain pure N-(6- Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2 - Pendant oxyacetamide (61.6 mg, 161.48 μmol, 69.52% yield).

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.02(m,3H),1.33(m,1H),1.68(m,1H),1.86(m,1H),2.03(m,3H),2.14(m,1H),2.66(m,3H),2.95(m,1H),3.65(m,1H),5.30(m,1H),5.61(m,3H),6.46(m,3H),6.52(d,1H),7.09(m,1H),7.48(m,1H),8.01(m,1H),10.45(m,1H)。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.02 (m, 3H), 1.33 (m, 1H), 1.68 (m, 1H), 1.86 (m, 1H), 2.03 (m, 3H) ,2.14(m,1H),2.66(m,3H),2.95(m,1H),3.65(m,1H),5.30(m,1H),5.61(m,3H),6.46(m,3H), 6.52 (d, 1H), 7.09 (m, 1H), 7.48 (m, 1H), 8.01 (m, 1H), 10.45 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=1.866minLCMS(ESI): [M+H] + m/z: Calculated 381.2; Found 382.2; Rt=1.866min

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物449 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 449 )

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物1(101.59mg，210.95μmol)溶解於水(5mL)及二噁烷(2mL)之混合物中。然後，將反應混合物在100℃下攪拌15h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min 35-100% MeCN-H2 O；流速30mL/min；裝載泵4mL MeCN；Sunfire C18 19* 100mm 5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[3-(甲胺基)苯基]-1-哌啶基]-2-側氧基乙醯胺(55.3mg，144.97μmol，68.72%產率)。N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (101.59 mg, 210.95 μmol) was dissolved in a mixture of water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 15 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min 35-100% MeCN- H2O ; flow rate 30 mL/min; loading pump 4 mL MeCN; Sunfire C18 19 * 100 mm 5mkm column) to obtain pure N-(6- Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[3-(methylamino)phenyl]-1-piperidinyl]-2 - Pendant oxyacetamide (55.3 mg, 144.97 μmol, 68.72% yield).

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.76(m,1H),2.03(m,3H),2.13(m,1H),2.66(m,5H),3.03(m,1H),3.74(m,1H),5.30(m,1H),5.61(m,3H),6.43(d,1H),6.50(m,2H),7.09(t,1H),7.49(m,1H),8.02(m,1H),10.45(m,1H)。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.02 (m, 3H), 1.34 (m, 1H), 1.76 (m, 1H), 2.03 (m, 3H), 2.13 (m, 1H) ,2.66(m,5H),3.03(m,1H),3.74(m,1H),5.30(m,1H),5.61(m,3H),6.43(d,1H),6.50(m,2H), 7.09 (t, 1H), 7.49 (m, 1H), 8.02 (m, 1H), 10.45 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.2；實測值382.2；Rt=1.831min。LCMS (ESI): [M+H] + m/z: calculated 381.2; found 382.2; Rt=1.831 min.

實例396. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基Example 396. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[3-(dimethylamino)phenyl]-5-methyl -1-哌啶基]-2-側氧基乙醯胺(化合物387)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物386)之合成-1-Piperidinyl]-2-oxyacetamide (Compound 387) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2 Synthesis of -[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 386)

Figure 110128222-A0202-12-1696-507
Figure 110128222-A0202-12-1696-507

步驟1：N-[5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxygen Synthesis of 3-butyl Acetyl]amino]-3-methyl-2-pyridyl]carbamate

將DIPEA(207.90mg，1.61mmol，280.19μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.19g，643.43μmol)及N,N-二甲基-3-[(2S,5R)-5-甲基-2-哌啶基]苯胺(140.49mg，643.43μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(269.12mg，707.78μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min以35-60% H2 O-MeCN為流動相；裝載泵4mL MeCN；Triart C18 100* 20mm 5mkm管柱)，以得到純的N-[5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(67mg，135.19μmol，21.01%產率)。DIPEA (207.90 mg, 1.61 mmol, 280.19 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo Ethyl acetate (0.19 g, 643.43 μmol) and N,N-dimethyl-3-[(2S,5R)-5-methyl-2-piperidinyl]aniline (140.49 mg, 643.43 μmol) in DMF (10 mL) ) in solution. The resulting mixture was stirred for 5 min, then HATU solution (269.12 mg, 707.78 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 35-60% H2O -MeCN as mobile phase; loading pump 4 mL MeCN; Triart C18 100 * 20mm 5mkm column) to obtain pure N-[5-[ [2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]- 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (67 mg, 135.19 μmol, 21.01% yield).

1 H NMR(400MHz,CDCl3 )δ 1.05(m,3H),1.37(m,2H),1.51(s,9H),2.12(m,6H),2.91(m,6H),3.48(s,3H),4.22(m,1H),5.78(m,1H),6.51(m,2H),7.20(m,1H),7.94(m,1H),8.31(m,1H),9.43(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.05(m, 3H), 1.37(m, 2H), 1.51(s, 9H), 2.12(m, 6H), 2.91(m, 6H), 3.48(s, 3H) ), 4.22(m, 1H), 5.78(m, 1H), 6.51(m, 2H), 7.20(m, 1H), 7.94(m, 1H), 8.31(m, 1H), 9.43(m, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值495.2；實測值496.2；Rt=1.398min。LCMS (ESI): [M+H] + m/z: calculated 495.2; found 496.2; Rt=1.398 min.

步驟2：N-[5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 2: N-[5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxygen Chiral Separation of 3-Butyl Acetyl]amino]-3-methyl-2-pyridyl]carbamate

使用(YMC(250* 20，5mkm)管柱，以己烷-MeOH-IPA，50-25-25為流動相；流速12mL/min)進行N-[5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離，得到異構物1 N-[5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(67.0g，29.55%；RT=14.517min)及異構物2 N-[5-[[2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(20.1mg，30.0%產率；RT=19.991min)。N-[5-[[2-[(2R,5S was carried out using (YMC (250 * 20, 5mkm) column with hexane-MeOH-IPA, 50-25-25 as mobile phase; flow rate 12mL/min) )-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridine Chiral separation of tert-butyl]carbamate to give isomer 1 N-[5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5 -Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (67.0 g, 29.55%; RT=14.517 min) and isomer 2 N-[5-[[2-[(2S,5R)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (20.1 mg, 30.0% yield; RT=19.991 min).

異構物1： RT(IC，己烷-IPA-MeOH，40-30-30，0.6mL/min)=15.76min。 Isomer 1: RT (IC, Hexane-IPA-MeOH, 40-30-30, 0.6 mL/min) = 15.76 min.

LCMS(ESI)：[M+H]+ m/z：計算值495.2；實測值496.4；Rt=1.315min。LCMS (ESI): [M+H] + m/z: calculated 495.2; found 496.4; Rt=1.315 min.

異構物2： RT(IC，己烷-IPA-MeOH，40-30-30，0.6mL/min)=25.50min。 Isomer 2: RT (IC, Hexane-IPA-MeOH, 40-30-30, 0.6 mL/min) = 25.50 min.

LCMS(ESI)：[M+H]+ m/z：計算值495.2；實測值496.4；Rt=1.316min。LCMS (ESI): [M+H] + m/z: calculated 495.2; found 496.4; Rt=1.316 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物386 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl Synthesis of -1-piperidinyl]-2-oxoacetamide ( compound 386 )

將N-[5-[[2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物1(19.8mg，39.95μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌15h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲 得之固體經歷HPLC(2-10min以45-60% H2 O-MeCN-NH3 為流動相；裝載泵4mL MeCN；Triart 100* 20mm 5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(7.5mg，18.96μmol，47.47%產率)。N-[5-[[2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (19.8 mg, 39.95 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL) . Then, the reaction mixture was stirred at 100 °C for 15 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 45-60% H2O -MeCN- NH3 as mobile phase; loading pump 4mL MeCN; Triart 100 * 20mm 5mkm column) to give pure N-(6 -Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl] -2-Pendant oxyacetamide (7.5 mg, 18.96 μmol, 47.47% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.96-1.02(m,3H),1.24-1.37(m,1H),1.59-1.75(m,1H),1.80-1.91(m,1H),1.95-2.02(m,3H),2.02-2.23(m,2H),2.75-2.79(m,0.4H),2.83-2.88(m,6H),3.24-3.27(m,0.6H),3.40-4.03(m,1H),5.03-5.53(m,1H),5.53-5.67(m,2H),6.55-6.67(m,3H),7.10-7.21(m,1H),7.41-7.55(m,1H),7.90-8.05(m,1H),10.43-10.60(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.96-1.02(m,3H), 1.24-1.37(m,1H), 1.59-1.75(m,1H), 1.80-1.91(m,1H), 1.95- 2.02(m, 3H), 2.02-2.23(m, 2H), 2.75-2.79(m, 0.4H), 2.83-2.88(m, 6H), 3.24-3.27(m, 0.6H), 3.40-4.03(m ,1H),5.03-5.53(m,1H),5.53-5.67(m,2H),6.55-6.67(m,3H),7.10-7.21(m,1H),7.41-7.55(m,1H),7.90 -8.05(m, 1H), 10.43-10.60(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=1.838min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=1.838 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物387 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[3-(dimethylamino)phenyl]-5-methyl Synthesis of -1-Piperidinyl]-2-Oxyacetamide ( Compound 387 )

將N-[5-[[2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物2(20.1mg，40.56μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌15h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min以45-60% H2 O-MeCN-NH3 為流動相；裝載泵4mL MeCN；Triart 100* 20mm 5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[3-(二甲胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(7mg，17.70μmol，43.64%產率)。N-[5-[[2-[(2S,5R)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (20.1 mg, 40.56 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL) . Then, the reaction mixture was stirred at 100 °C for 15 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 45-60% H2O -MeCN- NH3 as mobile phase; loading pump 4mL MeCN; Triart 100 * 20mm 5mkm column) to give pure N-(6 -Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[3-(dimethylamino)phenyl]-5-methyl-1-piperidinyl] -2-Pendant oxyacetamide (7 mg, 17.70 μmol, 43.64% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.96-1.02(m,3H),1.25-1.38(m,1H),1.63-1.75(m,1H),1.80-1.91(m,1H),1.97-2.02(m,3H),2.02-2.23(m,2H),2.75-2.79(m,0.4H),2.83-2.90(m,6H),3.24-3.27(m,0.6H),3.40-4.03(m,1H),5.04-5.54(m,1H),5.56-5.66(m,2H),6.55-6.64(m,3H),7.09-7.20(m,1H),7.41-7.52(m,1H), 7.92-8.03(m,1H),10.40-10.55(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.96-1.02(m,3H), 1.25-1.38(m,1H), 1.63-1.75(m,1H), 1.80-1.91(m,1H), 1.97- 2.02(m, 3H), 2.02-2.23(m, 2H), 2.75-2.79(m, 0.4H), 2.83-2.90(m, 6H), 3.24-3.27(m, 0.6H), 3.40-4.03(m ,1H),5.04-5.54(m,1H),5.56-5.66(m,2H),6.55-6.64(m,3H),7.09-7.20(m,1H),7.41-7.52(m,1H), 7.92 -8.03(m, 1H), 10.40-10.55(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.2；Rt=1.837min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.2; Rt=1.837 min.

實例397. 化合物148、化合物152、化合物175之合成Example 397. Synthesis of compound 148, compound 152, compound 175

Figure 110128222-A0202-12-1699-508
Figure 110128222-A0202-12-1699-508

步驟1：N-[5-[[2-(2-環己基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-(2-Cyclohexyl-5-methyl-1-piperidinyl)-2-oxyacetyl]amino]-3-methyl-2- Synthesis of tert-butyl pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(200mg，609.57μmol)及2-環己基-5-甲基哌啶(165.94mg，609.57μmol，HCl)混合於DMF(10mL)中。將反應懸浮液冷卻至0℃且添加HATU(231.78mg，609.57μmol)，隨後添加TEA(370.09mg，3.66mmol，509.77μL)。將澄清溶液在周圍溫度下攪拌12h。然後在減壓下蒸發揮發物且使殘餘物(1g)經歷RP-HPLC(管 柱：SunFire C18 100* 19mm，5um；以60-60-100% 0-1-6min水-甲醇為流動相)，以得到N-[5-[[2-(2-環己基-5-甲基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(88mg，191.89μmol，31.48%產率)及30mg經Boc去保護之產物(呈非鏡像異構物混合物)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (200 mg, 609.57 μmol) and 2-cyclohexyl- 5-Methylpiperidine (165.94 mg, 609.57 μmol, HCl) was mixed in DMF (10 mL). The reaction suspension was cooled to 0°C and HATU (231.78 mg, 609.57 μmol) was added followed by TEA (370.09 mg, 3.66 mmol, 509.77 μL). The clear solution was stirred at ambient temperature for 12 h. The volatiles were then evaporated under reduced pressure and the residue (1 g) was subjected to RP-HPLC (column: SunFire C18 100 * 19mm, 5um; 60-60-100% 0-1-6 min water-methanol as mobile phase) , to give N-[5-[[2-(2-cyclohexyl-5-methyl-1-piperidinyl)-2-oxyacetyl]amino]-3-methyl-2- 3-butyl pyridyl]carbamate (88 mg, 191.89 μmol, 31.48% yield) and 30 mg of the Boc deprotected product as a mixture of diastereomers.

1 H NMR(400MHz,CDCl3 )δ 0.93(m,6H),1.15(m,6H),1.56(m,16H),1.91(m,2H),2.28(s,3H),3.47(m,1H),6.60(s,1H),8.03(m,1H),8.32(s,1H),9.17(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.93(m,6H), 1.15(m,6H), 1.56(m,16H), 1.91(m,2H), 2.28(s,3H), 3.47(m,1H) ), 6.60(s, 1H), 8.03(m, 1H), 8.32(s, 1H), 9.17(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值458.2；實測值459.4；Rt=4.306min。LCMS (ESI): [M+H] + m/z: calculated 458.2; found 459.4; Rt=4.306 min.

步驟2：N-[5-[[2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯、N-[5-[[2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[(2R,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3 -Methyl-2-pyridyl]carbamic acid tert-butyl ester, N-[5-[[2-[(2R,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2S,5R)-2-cyclohexyl- Synthesis of 5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

藉由掌性HPLC(管柱：AD-H(I，250* 20，5mkm)，以CO2 -MeOH，80-20，50mL/min為流動相)分離非鏡像異構物，以得到順式鏡像異構物之混合物N-[5-[[2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(異構物3 )(13.3mg，29.00μmol，30.23%產率)，及兩種單獨的反式鏡像異構物N-[5-[[2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(異構物2 )(15.1mg，32.93μmol，68.64%產率)及N-[5-[[2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(異構物1 )(19.4mg，42.30μmol，88.18%產率)。Separation of the enantiomers by chiral HPLC (column: AD-H(1, 250 * 20, 5mkm) with CO2 -MeOH, 80-20, 50mL/min as mobile phase) to give cis Mixture of enantiomers ]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester ( isomer 3 ) (13.3 mg, 29.00 μmol, 30.23% yield), and two separate trans-enantiomers N- [5-[[2-[(2R,5S)-2-Cyclohexyl-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2 -Pyridinyl]carbamic acid tert-butyl ester ( isomer 2 ) (15.1 mg, 32.93 μmol, 68.64% yield) and N-[5-[[2-[(2S,5R)-2-cyclohexyl- 5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester ( Isomer 1 ) (19.4 mg , 42.30 μmol, 88.18% yield).

化合物1：Compound 1:

1 H NMR(500MHz,CDCl3 )δ 0.92(m,3H),1.17(m,4H),1.62(m,22H),2.28(s,3H),4.30(m,1H),4.81(m,1H),6.63(s,1H),8.02(m,1H),8.33(s,1H),9.22(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.92(m,3H), 1.17(m,4H), 1.62(m,22H), 2.28(s,3H), 4.30(m,1H), 4.81(m,1H) ), 6.63(s, 1H), 8.02(m, 1H), 8.33(s, 1H), 9.22(s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值458.2；實測值460.2；Rt=6.157min。LCMS (ESI): [M+2H] + m/z: calculated 458.2; found 460.2; Rt=6.157 min.

RT(AD-H，CO2-MeOH，70-30，3.0mL/min)=7.018min。RT (AD-H, CO2-MeOH, 70-30, 3.0 mL/min) = 7.018 min.

化合物2：Compound 2:

1 H NMR(400MHz,CDCl3 )δ 0.92(m,3H),1.17(m,4H),1.62(m,22H),2.28(s,3H),4.29(m,1H),4.76(m,1H),6.69(s,1H),8.02(m,1H),8.33(s,1H),9.28(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.92(m,3H), 1.17(m,4H), 1.62(m,22H), 2.28(s,3H), 4.29(m,1H), 4.76(m,1H) ), 6.69(s, 1H), 8.02(m, 1H), 8.33(s, 1H), 9.28(m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值458.2；實測值460.2；Rt=6.157min。LCMS (ESI): [M+2H] + m/z: calculated 458.2; found 460.2; Rt=6.157 min.

RT(AD-H，CO2-MeOH，70-30，3.0mL/min)=9.507min。RT (AD-H, CO2-MeOH, 70-30, 3.0 mL/min) = 9.507 min.

化合物3：Compound 3:

1 H NMR(500MHz,CDCl3 )δ 0.92(m,3H),1.17(m,4H),1.62(m,22H),2.28(s,3H),4.32(m,1H),4.81(m,1H),6.61(s,1H),8.01(s,1H),8.32(s,1H),9.14(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.92(m,3H), 1.17(m,4H), 1.62(m,22H), 2.28(s,3H), 4.32(m,1H), 4.81(m,1H) ), 6.61(s, 1H), 8.01(s, 1H), 8.32(s, 1H), 9.14(s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值458.2；實測值460.2；Rt=6.191min。LCMS (ESI): [M+2H] + m/z: calculated 458.2; found 460.2; Rt=6.191 min.

RT(AD-H，CO2-MeOH，70-30，3.0mL/min)=5.690min及6.463min(混合物)。RT (AD-H, CO2-MeOH, 70-30, 3.0 mL/min) = 5.690 min and 6.463 min (mixture).

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物148 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 148 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(110.17mg，423.03μmol，104.92μL，14%純度)小心添加到N-[5-[[2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物1(19.40mg，42.30μmol)於DCM(2mL)中之溶液中。然後將反應混合物在室溫下攪拌24h且在真空中蒸發溶劑，以得到15mg粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；以50-75%，0-5min，0.1% NH3 -甲醇為流動相)，以得到化合物148 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(9mg，25.11μmol，59.35%產率)。A 4.0 M solution of hydrogen chloride in dioxane (110.17 mg, 423.03 μmol, 104.92 μL, 14% purity) was carefully added to N-[5-[[2-[(2S,5R)-2- at room temperature Cyclohexyl-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl isomer 1 (19.40 mg, 42.30 μmol) in DCM (2 mL). The reaction mixture was then stirred at room temperature for 24 h and the solvent was evaporated in vacuo to give 15 mg of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; with 50-75%, 0-5 min, 0.1% NH3 -methanol as mobile phase) to give compound 148 N-(6-amine oxyacetamide (9 mg, 25.11 μmol, 59.35% yield).

1 H NMR(氯仿-d,400MHz)：δ(ppm)0.91(m,2H),1.01(m,3H),1.20(m,4H),1.49(m,1H),1.71(m,8H),1.97(m,2H),2.12(s,3H),3.09(m,1H),4.27(m,3H),4.73(m, 1H),7.71(m,1H),8.03(s,1H),9.07(m,1H)。 1 H NMR (chloroform-d, 400MHz): δ (ppm) 0.91 (m, 2H), 1.01 (m, 3H), 1.20 (m, 4H), 1.49 (m, 1H), 1.71 (m, 8H), 1.97(m, 2H), 2.12(s, 3H), 3.09(m, 1H), 4.27(m, 3H), 4.73(m, 1H), 7.71(m, 1H), 8.03(s, 1H), 9.07 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=1.166min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=1.166 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物152 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-cyclohexyl-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 152 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(85.75mg，329.27μmol，81.67μL，14%純度)小心添加到N-[5-[[2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物2(15.10mg，32.93μmol)於DCM(2mL)中之溶液中。然後將反應混合物在室溫下攪拌24h且在真空中蒸發溶劑，以得到15mg粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；以50-75%，0-5min，0.1% NH3 -甲醇為流動相)，以得到化合物152 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(8mg，22.32μmol，67.78%產率)。A 4.0 M solution of hydrogen chloride in dioxane (85.75 mg, 329.27 μmol, 81.67 μL, 14% purity) was carefully added to N-[5-[[2-[(2R,5S)-2- at room temperature Cyclohexyl-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl isomer 2 (15.10 mg, 32.93 μmol) in DCM (2 mL). The reaction mixture was then stirred at room temperature for 24 h and the solvent was evaporated in vacuo to give 15 mg of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; with 50-75%, 0-5 min, 0.1% NH3 -methanol as mobile phase) to give compound 152 N-(6-amine oxyacetamide (8 mg, 22.32 μmol, 67.78% yield).

1 H NMR(氯仿-d,400MHz)：δ(ppm)0.91(m,2H),1.02(m,3H),1.18(m,4H),1.74(m,9H),1.96(m,2H),2.12(s,3H),3.09(m,1H),4.29(m,3H),4.76(m,1H),7.72(m,1H),8.02(s,1H),9.02(m,1H)。 1 H NMR (chloroform-d, 400MHz): δ (ppm) 0.91 (m, 2H), 1.02 (m, 3H), 1.18 (m, 4H), 1.74 (m, 9H), 1.96 (m, 2H), 2.12(s, 3H), 3.09(m, 1H), 4.29(m, 3H), 4.76(m, 1H), 7.72(m, 1H), 8.02(s, 1H), 9.02(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=1.154min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=1.154 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物175 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 175 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(75.53mg，290.02μmol，71.93μL，14%純度)小心添加到N-[5-[[2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物3(13.3mg，29.00μmol)於DCM(2mL)中之溶液中。然後將反應混合物在室溫下攪拌24h且在真空中蒸發溶劑，以得到15mg粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100* 20mm，5um；以50-75%，0-5min，0.1% NH3 -甲醇為流動相)，以得到化合 物175 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2-環己基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(6.5mg，18.13μmol，62.52%產率)。A 4.0 M solution of hydrogen chloride in dioxane (75.53 mg, 290.02 μmol, 71.93 μL, 14% purity) was carefully added to N-[5-[[2-[(2R,5R)-2- at room temperature Cyclohexyl-5-methyl-1-piperidinyl]-2-oxoacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl isomer 3(13.3 mg, 29.00 μmol) in DCM (2 mL). The reaction mixture was then stirred at room temperature for 24 h and the solvent was evaporated in vacuo to give 15 mg of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100 * 20mm, 5um; with 50-75%, 0-5 min, 0.1% NH3 -methanol as mobile phase) to give compound 175 N-(6- Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2-cyclohexyl-5-methyl-1-piperidinyl]-2-oxyacetamide (6.5 mg, 18.13 μmol, 62.52% yield).

1 H NMR(氯仿-d,400MHz)：δ(ppm)0.91(m,5H),1.20(m,3H),1.67(m,9H),1.91(m,2H),2.13(s,3H),2.48(m,1H),4.32(m,1H),4.45(s,2H),4.77(m,1H),7.72(s,1H),8.03(s,1H),8.98(m,1H)。 1 H NMR (chloroform-d, 400MHz): δ(ppm) 0.91(m, 5H), 1.20(m, 3H), 1.67(m, 9H), 1.91(m, 2H), 2.13(s, 3H), 2.48(m,1H), 4.32(m,1H), 4.45(s,2H), 4.77(m,1H), 7.72(s,1H), 8.03(s,1H), 8.98(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=3.090min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=3.090 min.

實例398. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1081)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物461)之合成Example 398. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4-aminophenyl)-5-methyl-1-piperidine Iridinyl]-2-oxoacetamide (Compound 1081) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(4- Synthesis of aminophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 461)

Figure 110128222-A0202-12-1703-509
Figure 110128222-A0202-12-1703-509

步驟1：N-[5-[[2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetyl ]Amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

將DIPEA(765.94mg，5.93mmol，1.03mL)添加到2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.5g，1.69mmol)及4-[(2S,5R)-5-甲基-2-哌啶基]苯胺(322.20mg，1.69mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(708.20mg，1.86mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min以40-60%水/MeCN+NH3 為流動相；裝載泵4mL MeCN+NH3 ；管柱：TRIART 100* 20 5mkm)，以得到純的N-[5-[[2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲 基-2-吡啶基]胺甲酸第三丁酯(174mg，372.15μmol，21.98%產率)。DIPEA (765.94 mg, 5.93 mmol, 1.03 mL) was added to 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxyl A solution of acetic acid (0.5 g, 1.69 mmol) and 4-[(2S,5R)-5-methyl-2-piperidinyl]aniline (322.20 mg, 1.69 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (708.20 mg, 1.86 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeCN+ NH3 as mobile phase; loading pump 4 mL MeCN+ NH3 ; column: TRIART 100 * 20 5mkm) to obtain pure N- [5-[[2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]- 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (174 mg, 372.15 μmol, 21.98% yield).

1 H NMR(400MHz,CDCl3 )δ 1.12(m,3H),1.43(m,2H),1.52(d,9H),1.96(m,2H),2.18(m,5H),2.87(m,1H),3.32(m,1H),4.22(m,1H),4.62(m,1H),5.74(m,1H),6.62(m,2H),7.29(m,2H),8.11(s,1H),8.42(m,1H),9.41(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.12 (m, 3H), 1.43 (m, 2H), 1.52 (d, 9H), 1.96 (m, 2H), 2.18 (m, 5H), 2.87 (m, 1H) ),3.32(m,1H),4.22(m,1H),4.62(m,1H),5.74(m,1H),6.62(m,2H),7.29(m,2H),8.11(s,1H) , 8.42 (m, 1H), 9.41 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值468.2；Rt=1.018min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 468.2; Rt=1.018 min.

步驟2：N-[5-[[2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性拆分Step 2: N-[5-[[2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-pendant oxyacetyl ] Chiral resolution of tert-butyl amino]-3-methyl-2-pyridyl]carbamate

使用(IB(250* 20，5mkm)Chiralpak管柱；以己烷-MeOH-IPA，80-10-10為流動相；流速15mL/min；注入體積：900mkL)進行掌性分離，得到兩種異構物：(5-(2-((2R,5S)-2-(4-胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯異構物1(174.0mg，32.06%產率；RT(IB-3，己烷-IPA-MeOH，70-15-15，0.15mL/min)=8.93min))及(5-(2-((2S,5R)-2-(4-胺基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯異構物2(174.0mg，35.00%產率；RT(IB-3，己烷-IPA-MeOH，70-15-15，0.15mL/min)=14.96min)。Using (IB (250 * 20, 5mkm) Chiralpak column; hexane-MeOH-IPA, 80-10-10 as mobile phase; flow rate 15mL/min; injection volume: 900mkL) for chiral separation, two isotopes were obtained. Construct: (5-(2-((2R,5S)-2-(4-aminophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)- 3-Methylpyridin-2-yl)carbamic acid tert-butyl ester isomer 1 (174.0 mg, 32.06% yield; RT (IB-3, hexane-IPA-MeOH, 70-15-15, 0.15 mL) /min)=8.93min)) and (5-(2-((2S,5R)-2-(4-aminophenyl)-5-methylpiperidin-1-yl)-2-oxygen Acetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester isomer 2 (174.0 mg, 35.00% yield; RT(IB-3, hexane-IPA-MeOH, 70- 15-15, 0.15mL/min)=14.96min).

異構物1： RT(IB-3，己烷-IPA-MeOH，70-15-15，0.15mL/min)=8.93min Isomer 1: RT (IB-3, Hexane-IPA-MeOH, 70-15-15, 0.15 mL/min) = 8.93 min

LCMS(ESI)：[M+2H]+ m/z：計算值467.2；實測值469.2；Rt=4.211min。LCMS (ESI): [M+2H] + m/z: calculated 467.2; found 469.2; Rt=4.211 min.

異構物2： RT(IB-3，己烷-IPA-MeOH，70-15-15，0.15mL/min)=14.96min Isomer 2: RT (IB-3, Hexane-IPA-MeOH, 70-15-15, 0.15 mL/min) = 14.96 min

LCMS(ESI)：[M+2H]+ m/z：計算值467.2；實測值469.2；Rt=4.196min。LCMS (ESI): [M+2H] + m/z: calculated 467.2; found 469.2; Rt=4.196 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物461 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidine Synthesis of pyridyl]-2-oxoacetamide ( compound 461 )

將N-[5-[[2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物1(55.78mg，119.30μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16 h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min以40-60%水/MeCN+NH3 為流動相；裝載泵4mL；TRIART 100* 20 5微米管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(9.8mg，26.67μmol，22.36%產率)。N-[5-[[2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine [00109] tert-butyl]-3-methyl-2-pyridyl]carbamate isomer 1 (55.78 mg, 119.30 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeCN+ NH3 as mobile phase; loading pump 4 mL; TRIART 100 * 20 5 micron column) to give pure N-(6-amine yl-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxygen Acetamide (9.8 mg, 26.67 μmol, 22.36% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.94-1.04(m,3H),1.23-1.36(m,1H),1.65-1.75(m,1H),1.75-1.87(m,1H),1.87-1.98(m,1H),1.98-2.05(m,3H),2.06-2.15(m,1H),2.65-3.25(m,1H),3.35-3.97(m,1H),4.89-5.49(m,3H),5.54-5.64(m,2H),6.50-6.59(m,2H),6.88-7.00(m,2H),7.41-7.51(m,1H),7.92-8.08(m,1H),10.36-10.54(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.94-1.04(m,3H), 1.23-1.36(m,1H), 1.65-1.75(m,1H), 1.75-1.87(m,1H), 1.87- 1.98(m,1H),1.98-2.05(m,3H),2.06-2.15(m,1H),2.65-3.25(m,1H),3.35-3.97(m,1H),4.89-5.49(m,3H) ),5.54-5.64(m,2H),6.50-6.59(m,2H),6.88-7.00(m,2H),7.41-7.51(m,1H),7.92-8.08(m,1H),10.36-10.54 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=1.524min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=1.524 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1081 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4-aminophenyl)-5-methyl-1-piperidine Synthesis of pyridyl]-2-side oxyacetamide ( compound 1081 )

將N-[5-[[2-[(2S,5R)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物2(60.9mg，130.25μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min以40-60%水/MeCN+NH3 為流動相；裝載泵4mL；TRIART 100* 20 5微米管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(14.8mg，40.28μmol，30.92%產率)。N-[5-[[2-[(2S,5R)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine [00108] tert-butyl]-3-methyl-2-pyridyl]carbamate isomer 2 (60.9 mg, 130.25 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeCN+ NH3 as mobile phase; loading pump 4 mL; TRIART 100 * 20 5 micron column) to give pure N-(6-amine yl-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxygen Acetamide (14.8 mg, 40.28 μmol, 30.92% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.91-1.04(m,3H),1.20-1.37(m,1H),1.60-1.97(m,3H),1.97-2.04(m,3H),2.05-2.16(m,1H),2.63-3.24(m,1H),3.34-3.96(m,1H),4.94-5.48(m,3H),5.54-5.63(m,2H),6.48-6.56(m,2H),6.88-7.00(m,2H),7.41-7.52(m,1H),7.93-8.04(m,1H),10.36-10.54(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.91-1.04(m,3H), 1.20-1.37(m,1H), 1.60-1.97(m,3H), 1.97-2.04(m,3H), 2.05- 2.16(m,1H),2.63-3.24(m,1H),3.34-3.96(m,1H),4.94-5.48(m,3H),5.54-5.63(m,2H),6.48-6.56(m,2H) ), 6.88-7.00(m, 2H), 7.41-7.52(m, 1H), 7.93-8.04(m, 1H), 10.36-10.54(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=1.928min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=1.928 min.

實例399. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物499)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物506)之合成Example 399. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methane yl-1-piperidinyl]-2-oxyacetamide (compound 499) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)- Synthesis of 2-[4-(Methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 506)

Figure 110128222-A0202-12-1706-510
Figure 110128222-A0202-12-1706-510

步驟1：N-[5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate

向N-[5-[[2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(156.8mg，335.36μmol)於二噁烷(10mL)中之經預冷卻之溶液中添加吡啶(66.32mg，838.40μmol，67.81μL)。此後，在0℃下逐滴添加甲磺醯氯(42.26mg，368.89μmol，28.55μL)。然後，將反應混合物在室溫下攪拌12h。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min以40-60%水/MeCN+NH3 為流動相；裝載泵4mL；TRIART 100* 20 5微米管柱)，以得到純的N-[5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(74.6mg，136.72μmol，40.77%產率)。To N-[5-[[2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine To a precooled solution of tert-butyl]-3-methyl-2-pyridyl]carbamate (156.8 mg, 335.36 μmol) in dioxane (10 mL) was added pyridine (66.32 mg, 838.40 μmol, 67.81 μL). After this time, mesylate chloride (42.26 mg, 368.89 μmol, 28.55 μL) was added dropwise at 0°C. Then, the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeCN+ NH3 as mobile phase; loading pump 4 mL; TRIART 100 * 20 5 micron column) to obtain pure N-[5-[ [2-[(2R,5S)-2-[4-(Methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] - 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (74.6 mg, 136.72 μmol, 40.77% yield).

1 H NMR(400MHz,CDCl3 )δ 1.2(m,3H),1.34(m,2H),1.49(s,9H),2.1(m,9H),3.12(s,3H),3.62(m,1H),4.32(m,1H),6.02(m,1H),7.21(m,3H),8.12(m,1H),8.36(m,1H),9.52(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.2(m,3H), 1.34(m,2H), 1.49(s,9H), 2.1(m,9H), 3.12(s,3H), 3.62(m,1H) ), 4.32(m, 1H), 6.02(m, 1H), 7.21(m, 3H), 8.12(m, 1H), 8.36(m, 1H), 9.52(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值545.2；實測值546.2；Rt=3.362min。LCMS (ESI): [M+H] + m/z: calculated 545.2; found 546.2; Rt=3.362 min.

步驟2：N-[5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 2: N-[5-[[2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-side Chiral separation of tert-butyl oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate

使用(IC-II(250* 20，5mkm)管柱；以IPA-MeOH，50-50為流動相；流速12mL/min)進行N-[5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離；得到兩種異構物：N-[5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(異構物1：RT(IC管柱；MeOH-IPA，50-50，0.6mL/min)=19.14min；14.78mg，33.22%產率)及N-[5-[[2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(異構物1：RT(IC管柱；MeOH-IPA，50-50，0.6mL/min)=11.48min；23.98mg，32.14%產率)。N-[5-[[2-[(2R,5S)-2 was carried out using (IC-II (250 * 20, 5mkm) column; IPA-MeOH, 50-50 as mobile phase; flow rate 12mL/min) -[4-(Methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl] Chiral separation of tert-butyl carbamate; two isomers were obtained: N-[5-[[2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]- 5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (Isomer 1: RT (IC Column; MeOH-IPA, 50-50, 0.6 mL/min) = 19.14 min; 14.78 mg, 33.22% yield) and N-[5-[[2-[(2S,5R)-2-[4- (Methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid 3rd Butyl ester (Isomer 1: RT (IC column; MeOH-IPA, 50-50, 0.6 mL/min) = 11.48 min; 23.98 mg, 32.14% yield).

異構物1： RT(IC管柱；MeOH-IPA，50-50，0.6mL/min)=19.14min Isomer 1: RT (IC column; MeOH-IPA, 50-50, 0.6 mL/min) = 19.14 min

LCMS(ESI)：[M+H]+ m/z：計算值545.2；實測值546.2；Rt=1.270min。LCMS (ESI): [M+H] + m/z: calculated 545.2; found 546.2; Rt=1.270 min.

異構物2： RT(IC管柱；MeOH-IPA，50-50，0.6mL/min)=11.48min Isomer 2: RT (IC column; MeOH-IPA, 50-50, 0.6 mL/min) = 11.48 min

LCMS(ESI)：[M+H]+ m/z：計算值545.2；實測值546.2；Rt=1.270min。LCMS (ESI): [M+H] + m/z: calculated 545.2; found 546.2; Rt=1.270 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物499 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 499 )

將N-[5-[[2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物1(14.78mg，45.41μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃ 下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min，以25-70% MeCN-H2 O為流動相；流速：30mL/min；裝載泵4mL，MeCN；SunFire 100* 19mm，5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(13.6mg，30.53μmol，67.22%產率)。N-[5-[[2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (14.78 mg, 45.41 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL) middle. Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 25-70% MeCN- H2O as mobile phase; flow rate: 30 mL/min; loading pump 4 mL, MeCN; SunFire 100 * 19 mm, 5 mkm column) to obtain Pure N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(methylsulfonamido)phenyl]-5-methyl -1-Piperidinyl]-2-oxoacetamide (13.6 mg, 30.53 μmol, 67.22% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.95-1.04(m,3H),1.25-1.37(m,1H),1.60-1.72(m,1H),1.80-1.91(m,1H),1.96-2.07(m,4H),2.12-2.21(m,1H),2.68-2.74(m,0H),2.93-2.97(m,3H),3.16-3.21(m,1H),3.41-4.01(m,1H),5.04-5.55(m,1H),5.55-5.65(m,2H),7.15-7.21(m,2H),7.22-7.31(m,2H),7.40-7.51(m,1H),7.91-8.03(m,1H),9.66-9.76(m,1H),10.38-10.50(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.95-1.04(m,3H), 1.25-1.37(m,1H), 1.60-1.72(m,1H), 1.80-1.91(m,1H), 1.96- 2.07(m,4H), 2.12-2.21(m,1H), 2.68-2.74(m,0H), 2.93-2.97(m,3H), 3.16-3.21(m,1H), 3.41-4.01(m,1H) ),5.04-5.55(m,1H),5.55-5.65(m,2H),7.15-7.21(m,2H),7.22-7.31(m,2H),7.40-7.51(m,1H),7.91-8.03 (m, 1H), 9.66-9.76 (m, 1H), 10.38-10.50 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值445.3；實測值446.2；Rt=2.479min。LCMS (ESI): [M+H] + m/z: calculated 445.3; found 446.2; Rt=2.479 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物506 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-oxoacetamide ( Compound 506 )

將N-[5-[[2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物2(23.98mg，43.95μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min，以25-70% MeCN-H2 O為流動相；流速：30mL/min；裝載泵4mL，MeCN；SunFire 100* 19mm，5mkm管柱)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(甲磺醯胺基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(12mg，26.93μmol，61.29%產率)。N-[5-[[2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (23.98 mg, 43.95 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL) middle. Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 25-70% MeCN- H2O as mobile phase; flow rate: 30 mL/min; loading pump 4 mL, MeCN; SunFire 100 * 19 mm, 5 mkm column) to obtain Pure N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[4-(methylsulfonamido)phenyl]-5-methyl -1-Piperidinyl]-2-oxoacetamide (12 mg, 26.93 μmol, 61.29% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.03(m,3H),1.26-1.36(m,1H),1.60-1.72(m,1H),1.80-1.93(m,1H),1.96-2.09(m,4H),2.11-2.23(m,1H),2.68-2.73(m,0.4H),2.93-2.97(m,3H),3.17-3.20(m,0.6H),3.47-4.00(m,1H),5.05-5.55(m, 1H),5.56-5.66(m,2H),7.16-7.22(m,2H),7.23-7.32(m,2H),7.40-7.52(m,1H),7.94-8.05(m,1H),9.61-9.79(m,1H),10.40-10.50(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.97-1.03(m,3H), 1.26-1.36(m,1H), 1.60-1.72(m,1H), 1.80-1.93(m,1H), 1.96- 2.09(m, 4H), 2.11-2.23(m, 1H), 2.68-2.73(m, 0.4H), 2.93-2.97(m, 3H), 3.17-3.20(m, 0.6H), 3.47-4.00(m ,1H),5.05-5.55(m,1H),5.56-5.66(m,2H),7.16-7.22(m,2H),7.23-7.32(m,2H),7.40-7.52(m,1H),7.94 -8.05(m, 1H), 9.61-9.79(m, 1H), 10.40-10.50(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值445.3；實測值446.2；Rt=2.467min。LCMS (ESI): [M+H] + m/z: calculated 445.3; found 446.2; Rt=2.467 min.

實例400. 2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物527)及2-[(2S,5R)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物523)之合成Example 400. 2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl- 3-Pyridinyl)-2-oxyacetamide (Compound 527) and 2-[(2S,5R)-2-(4-acetamidophenyl)-5-methyl-1-piperidine [Synthesis of]-N-(6-amino-5-methyl-3-pyridyl)-2-oxoacetamide (Compound 523)

Figure 110128222-A0202-12-1709-511
Figure 110128222-A0202-12-1709-511

步驟1：N-[5-[[2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-2-pendoxoethyl Synthesis of Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向N-[5-[[2-[(2R,5S)-2-(4-胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(155mg，331.51μmol)於THF(15mL)中之經預冷卻之溶液中添加吡啶(65.56mg，828.77μmol，67.03μL)。此後，在0℃下逐滴添加乙醯氯(28.62mg，364.66μmol，22.19μL)。然後，將反應混合物在室溫下攪拌12h。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(2-10min以50-70% MeOH/H2 O為流動相；流速30mL/min；裝載泵4mL MeOH；SunFire 100* 19mm，5mkm管柱)，以得到純 的N-[5-[[2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(76mg，149.14μmol，44.99%產率)。To N-[5-[[2-[(2R,5S)-2-(4-aminophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine To a precooled solution of tert-butyl]-3-methyl-2-pyridyl]carbamate (155 mg, 331.51 μmol) in THF (15 mL) was added pyridine (65.56 mg, 828.77 μmol, 67.03 μL) . After this time, acetyl chloride (28.62 mg, 364.66 μmol, 22.19 μL) was added dropwise at 0°C. Then, the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 50-70% MeOH/H 2 O as mobile phase; flow rate 30 mL/min; loading pump 4 mL MeOH; SunFire 100 * 19 mm, 5 mkm column) to obtain pure N -[5-[[2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamido]amine tert-butyl]-3-methyl-2-pyridyl]carbamate (76 mg, 149.14 μmol, 44.99% yield).

LCMS(ESI)：[M+H]+ m/z：計算值509.2；實測值510.2；Rt=2.784min。LCMS (ESI): [M+H] + m/z: calculated 509.2; found 510.2; Rt=2.784 min.

步驟2：N-[5-[[2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 2: N-[5-[[2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-2-pendoxoethyl Chiral separation of tert-butyl acyl]amino]-3-methyl-2-pyridyl]carbamate

使用(IC-I(250*20，5mkm)管柱；IPA-MeOH，50-50為流動相；流速11mL/min)進行N-[5-[[2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離，得到兩種異構物：N-[5-[[2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物1(RT(IC管柱，MeOH-IPA，50-50，0.6mL/min)=10.07min；22.33mg，35.67%產率)及N-[5-[[2-[(2S,5R)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物2(RT(IC管柱，MeOH-IPA，50-50，0.6mL/min)=38.88min；53.20mg，29.38%產率)。N-[5-[[2-[(2R,5S)-2- (4-Acetylaminophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid 3rd Chiral separation of the butyl ester gave two isomers: N-[5-[[2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1- Piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester Isomer 1 (RT (IC column, MeOH-IPA, 50 -50, 0.6 mL/min) = 10.07 min; 22.33 mg, 35.67% yield) and N-[5-[[2-[(2S,5R)-2-(4-acetamidophenyl)- 5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (RT (IC tube Column, MeOH-IPA, 50-50, 0.6 mL/min) = 38.88 min; 53.20 mg, 29.38% yield).

異構物1： RT(IC管柱，MeOH-IPA，50-50，0.6mL/min)=10.07min Isomer 1: RT (IC column, MeOH-IPA, 50-50, 0.6 mL/min) = 10.07 min

LCMS(ESI)：[M+H]+ m/z：計算值509.2；實測值510.2；Rt=2.843min。LCMS (ESI): [M+H] + m/z: calculated 509.2; found 510.2; Rt=2.843 min.

異構物2： RT(IC管柱，MeOH-IPA，50-50，0.6mL/min)=38.88min Isomer 2: RT (IC column, MeOH-IPA, 50-50, 0.6 mL/min) = 38.88 min

LCMS(ESI)：[M+H]+ m/z：計算值509.2；實測值510.2；Rt=2.839min。LCMS (ESI): [M+H] + m/z: calculated 509.2; found 510.2; Rt=2.839 min.

步驟3：2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物527 )之合成Step 3: 2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl- Synthesis of 3-pyridyl)-2-oxoacetamide ( Compound 527 )

將N-[5-[[2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物1(22.33mg，43.82μmol)溶解於水(5mL)及二噁烷(2mL)混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得 之固體經歷HPLC(2-10min以40-60%水/MeOH為溶劑混合物；裝載泵4mL MeOH；以TRIART 100* 20 5微米為管柱)，以得到純的2-[(2R,5S)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(14.2mg，34.68μmol，79.14%產率)。N-[5-[[2-[(2R,5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-2-oxoacetyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (22.33 mg, 43.82 μmol) was dissolved in a mixture of water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeOH as solvent mixture; loading pump 4 mL MeOH; TRIART 100 * 20 5 micron column) to give pure 2-[(2R, 5S)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-side Oxyacetamide (14.2 mg, 34.68 μmol, 79.14% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.94-1.02(m,3H),1.24-1.38(m,1H),1.60-1.74(m,1H),1.76-1.91(m,1H),1.92-2.04(m,7H),2.10-2.23(m,1H),2.66-3.25(m,1H),3.38-3.99(m,1H),5.06-5.56(m,1H),5.56-5.69(m,2H),7.16-7.30(m,2H),7.40-7.49(m,1H),7.52-7.59(m,2H),7.92-8.05(m,1H),9.88-9.96(m,1H),10.36-10.53(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.94-1.02(m,3H), 1.24-1.38(m,1H), 1.60-1.74(m,1H), 1.76-1.91(m,1H), 1.92- 2.04(m, 7H), 2.10-2.23(m, 1H), 2.66-3.25(m, 1H), 3.38-3.99(m, 1H), 5.06-5.56(m, 1H), 5.56-5.69(m, 2H ),7.16-7.30(m,2H),7.40-7.49(m,1H),7.52-7.59(m,2H),7.92-8.05(m,1H),9.88-9.96(m,1H),10.36-10.53 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.4；Rt=1.894min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.4; Rt=1.894 min.

步驟4：2-[(2S,5R)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物523 )之合成Step 4: 2-[(2S,5R)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl- Synthesis of 3-pyridyl)-2-oxoacetamide ( Compound 523 )

將N-[5-[[2-[(2S,5R)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯異構物2(27.11mg，53.20μmol)溶解於水(5mL)及二噁烷(2mL)混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(2-10min以40-60%水/MeOH為溶劑混合物；裝載泵4mL MeOH；以TRIART 100* 20 5微米為管柱)，以得到純的2-[(2S,5R)-2-(4-乙醯胺基苯基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(17.5mg，42.74μmol，80.33%產率)。N-[5-[[2-[(2S,5R)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-2-oxoacetyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (27.11 mg, 53.20 μmol) was dissolved in a mixture of water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (2-10 min with 40-60% water/MeOH as solvent mixture; loading pump 4 mL MeOH; TRIART 100 * 20 5 micron column) to give pure 2-[(2S, 5R)-2-(4-acetamidophenyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-side Oxyacetamide (17.5 mg, 42.74 μmol, 80.33% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.92-1.03(m,3H),1.23-1.39(m,1H),1.58-1.73(m,1H),1.76-1.92(m,1H),1.94-2.06(m,7H),2.08-2.22(m,1H),2.66-3.21(m,1H),3.36-4.02(m,1H),5.06-5.56(m,1H),5.56-5.66(m,2H),7.16-7.29(m,2H),7.38-7.49(m,1H),7.51-7.60(m,2H),7.93-8.05(m,1H),9.88-9.98(m,1H),10.39 -10.50(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.92-1.03(m,3H), 1.23-1.39(m,1H), 1.58-1.73(m,1H), 1.76-1.92(m,1H), 1.94- 2.06(m,7H),2.08-2.22(m,1H),2.66-3.21(m,1H),3.36-4.02(m,1H),5.06-5.56(m,1H),5.56-5.66(m,2H ), 7.16-7.29(m, 2H), 7.38-7.49(m, 1H), 7.51-7.60(m, 2H), 7.93-8.05(m, 1H), 9.88-9.98(m, 1H), 10.39 -10.50 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.2；Rt=1.90min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.2; Rt=1.90 min.

實例401.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物397、化合物396)之合成Example 401. N- (6-amino-5-methylpyridin-3-yl)-2-(2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 397, Compound 396)

Figure 110128222-A0202-12-1712-512
Figure 110128222-A0202-12-1712-512

步驟1：(5-(2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(4-Hydroxyphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridine-2 -Synthesis of tertiary butyl carbamate

將4-(5-甲基-2-哌啶基)苯酚(300mg，895.80μmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(264.52mg，895.80μmol)及TEA(906.46mg，8.96mmol，1.25mL)於DMF(10mL)中之混合物在25℃下攪拌0.25h，然後在0.5h內小批量添加HATU(340.61mg，895.80μmol)。將反應混合物在25℃下攪拌2h，然後在真空中濃縮至5ml且提交至反相HPLC(管柱：XBridge C18 100x20mm，5um；流動相40-80% 0-5min 0.1% NH3 -MeOH，流速：30ml/min)，得到190mg外消旋醯胺，然後將其提交至製備型掌性HPLC(管柱：Chiralpak IC(250 *20mm，5mkm)；CO2 -MeOH，55-45.流速：35mL/min；管柱溫度：40℃；波長：215nm.)，以得到呈淡黃色膠狀物之N -[5-[[2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(49mg，104.58μmol，11.67%產率)(RT=5.47min)及N -[5-[[2-[(2R,5S )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(67mg，143.00μmol，15.96%產率)(RT=23.21min)，其直接用於下一步驟中。E1於分析條件下(管柱：IC，以CO2 -MeOH，50-50，2ml/min為流動相)之保留時間為8.40min且E2之保留時間為3.72min。4-(5-Methyl-2-piperidinyl)phenol (300 mg, 895.80 μmol, HCl), 2-[[6-( 3- butoxycarbonylamino)-5-methyl-3-pyridine A mixture of [methyl]amino]-2-pendoxoacetic acid (264.52 mg, 895.80 μmol) and TEA (906.46 mg, 8.96 mmol, 1.25 mL) in DMF (10 mL) was stirred at 25 °C for 0.25 h, then at 0.5 HATU (340.61 mg, 895.80 μmol) was added in small batches over h. The reaction mixture was stirred at 25°C for 2h, then concentrated in vacuo to 5ml and submitted to reverse phase HPLC (column: XBridge C18 100x20mm, 5um; mobile phase 40-80% 0-5min 0.1% NH3 -MeOH, flow rate : 30 ml/min) to give 190 mg of racemic amide, which was then submitted to preparative chiral HPLC (column: Chiralpak IC (250*20 mm, 5 mkm); CO2 -MeOH, 55-45. Flow rate: 35 mL /min; column temperature: 40°C; wavelength: 215nm.) to obtain N- [5-[[2-[( 2S,5R )-2-(4-hydroxyphenyl) as a pale yellow gum -5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E1 (49 mg, 104.58 μmol, 11.67 % yield) (RT=5.47 min) and N- [5-[[2-[( 2R,5S )-2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E2 (67 mg, 143.00 μmol, 15.96% yield) (RT=23.21 min), which was used directly in the next step. The retention time of E1 under analytical conditions (column: IC, with CO2-MeOH, 50-50, 2 ml/min as mobile phase) was 8.40 min and the retention time of E2 was 3.72 min.

E1：保留時間：8.40minE1: retention time: 8.40min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值468.5；實測值469.2；Rt=4.932min。LCMS (ESI): [M] + m/z: calculated 468.5; found 469.2; Rt=4.932 min.

E2：保留時間：3.72minE2: retention time: 3.72min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值468.5；實測值469.2；Rt=4.924min。LCMS (ESI): [M] + m/z: calculated 468.5; found 469.2; Rt=4.924 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物397 及化合物396 )Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl)-2-side Oxyacetamide ( Compound 397 and Compound 396 )

將N -[5-[[2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(49mg，104.58μmol)及N -[5-[[2-[(2R,5S )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(67mg，143.00μmol)於水(2mL)及1,4-二噁烷(1.5mL)之混合物中之溶液在95℃下攪拌18h，然後冷卻且提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相30-30-80% 0-1-6min 0.1%NH3 -MeOH，流速：30ml/min)，以得到呈白色固體之化合物397 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(25.7mg，69.76μmol，66.70%產率)及化合物396 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(33.5mg，90.93μmol，63.59%產率)。 N- [5-[[2-[( 2S,5R )-2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E1 (49 mg, 104.58 μmol) and N- [5-[[2-[( 2R,5S )-2-(4-hydroxyphenyl )-5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E2 (67 mg, 143.00 μmol) A solution in a mixture of water (2 mL) and 1,4-dioxane (1.5 mL) was stirred at 95 °C for 18 h, then cooled and submitted to reverse phase HPLC (column: YMC Triart C18 100x20 mm, 5 um; mobile phase 30-30-80% 0-1-6min 0.1% NH3 -MeOH, flow rate: 30ml/min) to give compound 397 as a white solid N- (6-amino-5-methyl-3-pyridinyl )-2-[( 2S,5R )-2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (25.7 mg, 69.76 μmol, 66.70% yield) and compound 396 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(4-hydroxyphenyl)-5-methyl-1 -Piperidinyl]-2-oxoacetamide (33.5 mg, 90.93 μmol, 63.59% yield).

化合物397：Compound 397:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.01(m,3H),1.26-1.36(m,1H),1.63-1.75(m,1H),1.78-1.89(m,1H),1.93-2.04(m,4H),2.11-2.19(m,1H),2.68-3.18(m,1H),3.37-3.96(m,1H),4.96-5.52(m,1H),5.53-5.66(m,2H),6.69-6.79(m,2H),7.04-7.15(m,2H),7.39-7.53(m,1H),7.91-8.06(m,1H),9.26-9.38(m,1H),10.40-10.51(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.01(m,3H), 1.26-1.36(m,1H), 1.63-1.75(m,1H), 1.78-1.89(m,1H) ,1.93-2.04(m,4H),2.11-2.19(m,1H),2.68-3.18(m,1H),3.37-3.96(m,1H),4.96-5.52(m,1H),5.53-5.66( m,2H),6.69-6.79(m,2H),7.04-7.15(m,2H),7.39-7.53(m,1H),7.91-8.06(m,1H),9.26-9.38(m,1H), 10.40-10.51 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值368.4；實測值369.2；Rt=2.013min。LCMS (ESI): [M] + m/z: calculated 368.4; found 369.2; Rt=2.013 min.

化合物396：Compound 396:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.01(m,3H),1.25-1.35(m,1H),1.61-1.75(m,1H),1.78-1.90(m,1H),1.91-2.03(m,4H),2.09-2.19(m,1H),2.65-3.22(m,1H),3.40-3.98(m,1H),4.98-5.52(m,1H),5.54-5.67(m,2H),6.71-6.77(m,2H),7.05-7.16(m,2H),7.42-7.50(m,1H),7.93-8.04(m,1H),9.08-9.49(m,1H),10.32-10.67(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.01(m,3H), 1.25-1.35(m,1H), 1.61-1.75(m,1H), 1.78-1.90(m,1H) ,1.91-2.03(m,4H),2.09-2.19(m,1H),2.65-3.22(m,1H),3.40-3.98(m,1H),4.98-5.52(m,1H),5.54-5.67( m,2H),6.71-6.77(m,2H),7.05-7.16(m,2H),7.42-7.50(m,1H),7.93-8.04(m,1H),9.08-9.49(m,1H), 10.32-10.67 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值368.4；實測值369.2；Rt=1.932min。LCMS (ESI): [M] + m/z: calculated 368.4; found 369.2; Rt=1.932 min.

實例402. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物713)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物735)之合成Example 402. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-phenyl-1- Piperidinyl]-2-oxoacetamide (Compound 713), N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-4,4- Synthesis of Difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxoacetamide (Compound 735)

Figure 110128222-A0202-12-1714-513
Figure 110128222-A0202-12-1714-513

步驟1：外消旋-N-[5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[5-[[2-[(2R,5R)-4,4-difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(503.22mg，1.70mmol)及TEA(1.72g，17.04mmol，2.38mL)溶解於DMF(8mL)中且冷卻至0℃，添加HATU(971.95mg，2.56mmol)且在0℃下將混合物攪拌15min。添加(2R,5R)-4,4-二氟-5-甲基-2-苯基哌啶(0.36g，1.70mmol)且將混合物升溫至室溫且攪拌3h。添加乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(2-10min 60-80%甲醇/H2 O 30ml/min(裝載泵4ml甲醇)，管柱：SunFire 100*19mm，5微米)進行純化，以得到N-[5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.095g，194.46μmol，11.41%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (503.22 mg, 1.70 mmol) and TEA (1.72 g , 17.04 mmol, 2.38 mL) was dissolved in DMF (8 mL) and cooled to 0 °C, HATU (971.95 mg, 2.56 mmol) was added and the mixture was stirred at 0 °C for 15 min. (2R,5R)-4,4-difluoro-5-methyl-2-phenylpiperidine (0.36 g, 1.70 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. Ethyl acetate was added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product, which was obtained by HPLC (2-10 min 60-80% methanol/H 2 O 30 ml/min (load pump 4 ml) methanol), column: SunFire 100*19mm, 5 microns) for purification to give N-[5-[[2-[(2R,5R)-4,4-difluoro-5-methyl-2-benzene tert-butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate (0.095 g, 194.46 μmol, 11.41% yield) .

LCMS(ESI)：[M+1]+ m/z：計算值488.2；實測值489.2；Rt=3.194minLCMS(ESI): [M+1] + m/z: Calculated 488.2; Measured 489.2; Rt=3.194min

步驟2：N-[5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[(2R,5R)-4,4-difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxoacetyl yl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2S,5S)-4,4-difluoro-5-methyl Synthesis of -2-Phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

使用(管柱：Chiralpak IA-II(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：12mL/min)進行掌性分離，以得到N-[5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.037g，75.74μmol，38.95%產率)及N-[5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.033g，67.55μmol，34.74%產率)。LCMS(ESI)：[M+1]+ m/z：計算值488.2；實測值489.2；Rt=3.194minChiral separation was performed using (column: Chiralpak IA-II (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH 50-25-25; flow rate: 12mL/min) to give N-[5- [[2-[(2R,5R)-4,4-Difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-3- tert-butyl methyl-2-pyridyl]carbamate (0.037 g, 75.74 μmol, 38.95% yield) and N-[5-[[2-[(2S,5S)-4,4-difluoro- 5-Methyl-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.033 g, 67.55 μmol, 34.74% yield). LCMS(ESI): [M+1] + m/z: Calculated 488.2; Measured 489.2; Rt=3.194min

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物735 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-4,4-difluoro-5-methyl-2-phenyl-1- Synthesis of piperidinyl]-2-oxoacetamide ( compound 735 )

將N-[5-[[2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.036g，73.69μmol)溶解於二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空、55℃下濃縮反應混合物，以得到粗產物，其藉由HPLC(6min 5-95% H2 O/MeCN 30ml/min(裝載泵4ml MeCN)，管柱：SunFire 100*19mm，5微米)進行純化，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.023g，59.22μmol，80.36%產率)。N-[5-[[2-[(2R,5R)-4,4-difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.036 g, 73.69 μmol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL), then stirred at 100 °C 12h. The reaction mixture was concentrated under vacuum at 55°C to give crude product by HPLC (6min 5-95% H2O /MeCN 30ml/min (load pump 4ml MeCN), column: SunFire 100*19mm, 5 microns ) to give N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5R)-4,4-difluoro-5-methyl-2-phenyl -1-Piperidinyl]-2-oxoacetamide (0.023 g, 59.22 μmol, 80.36% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.06(m,3H),2.00(m,3H),2.17(m,1H),2.91(m,2H),3.43(m,1H),3.97(m,1H),5.61(m,3H),7.31(m,5H),7.47(m,1H), 7.99(m,1H),10.56(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 1.06 (m, 3H), 2.00 (m, 3H), 2.17 (m, 1H), 2.91 (m, 2H), 3.43 (m, 1H), 3.97(m, 1H), 5.61(m, 3H), 7.31(m, 5H), 7.47(m, 1H), 7.99(m, 1H), 10.56(m, 1H)

LCMS(ESI)：[M+1]+ m/z：計算值388.2；實測值389.2；Rt=1.820minLCMS(ESI): [M+1] + m/z: Calculated 388.2; Measured 389.2; Rt=1.820min

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物713 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-phenyl-1- Synthesis of piperidinyl]-2-oxoacetamide ( compound 713 )

將N-[5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.033g，67.55μmol)溶解於二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空、55℃下濃縮反應混合物，以得到粗產物，其藉由HPLC(6min 5-95% H2 O/MeCN 30ml/min(裝載泵4ml MeCN)，管柱：SunFire 100*19mm，5微米)進行純化，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(0.022g，56.64μmol，83.85%產率)。N-[5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.033 g, 67.55 μmol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL), then stirred at 100 °C 12h. The reaction mixture was concentrated under vacuum at 55°C to give crude product by HPLC (6min 5-95% H2O /MeCN 30ml/min (load pump 4ml MeCN), column: SunFire 100*19mm, 5 microns ) to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-phenyl -1-Piperidinyl]-2-Pendant oxyacetamide (0.022 g, 56.64 μmol, 83.85% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.06(m,3H),2.00(m,3H),2.17(m,1H),2.91(m,2H),3.43(m,1H),3.97(m,1H),5.61(m,3H),7.31(m,5H),7.47(m,1H),7.99(m,1H),10.56(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 1.06 (m, 3H), 2.00 (m, 3H), 2.17 (m, 1H), 2.91 (m, 2H), 3.43 (m, 1H), 3.97(m, 1H), 5.61(m, 3H), 7.31(m, 5H), 7.47(m, 1H), 7.99(m, 1H), 10.56(m, 1H)

LCMS(ESI)：[M+1]+ m/z：計算值388.2；實測值389.2；Rt=1.820minLCMS(ESI): [M+1] + m/z: Calculated 388.2; Measured 389.2; Rt=1.820min

實例403. 2-(2-(1H -苯并[d ]咪唑-5-基)-5-甲基哌啶-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物408、化合物404)之合成Example 403. 2-(2-( 1H -benzo[ d ]imidazol-5-yl)-5-methylpiperidin - 1-yl)-N-(6-amino-5-methylpyridine-3 Synthesis of -yl)-2-side oxyacetamide (compound 408, compound 404)

Figure 110128222-A0202-12-1716-910
Figure 110128222-A0202-12-1716-910

步驟1：(5-(2-(2-(1H-苯并[d]咪唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(1H-benzo[d]imidazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)- Synthesis of 3-methylpyridin-2-yl)carbamic acid tert-butyl ester

在室溫下將HATU(353.22mg，928.96μmol)分批添加到2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(274.31mg，928.96μmol)、5-(5-甲基-2-哌啶基)-1H -苯并咪唑(250mg，928.96μmol)及TEA(564.01mg，5.57mmol，776.88μL)於DMF(9mL)中之懸浮液中。將澄清溶液在周圍溫度下攪拌108h且在真空中蒸發溶劑，以得到1g粗材料。使其經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以40-72% 0-5min 0.1% NH3 -MeOH為流動相)，以得到N -[5-[[2-[2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(65mg，131.96μmol，14.21%產率)。HATU (353.22 mg, 928.96 μmol) was added portionwise to 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2- at room temperature Pendant oxyacetic acid (274.31 mg, 928.96 μmol), 5-(5-methyl-2-piperidinyl)-1H-benzimidazole (250 mg, 928.96 μmol) and TEA (564.01 mg, 5.57 mmol, 776.88 μL) Suspension in DMF (9 mL). The clear solution was stirred at ambient temperature for 108 h and the solvent was evaporated in vacuo to give 1 g of crude material. It was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; 40-72% 0-5min 0.1% NH3 -MeOH as mobile phase) to give N- [5-[[2-[2- ( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl- 2 -pyridyl]carbamic acid Tributyl ester (65 mg, 131.96 [mu]mol, 14.21% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值492.2；實測值493.2；Rt=2.724min。LCMS (ESI): [M] + m/z: calculated 492.2; found 493.2; Rt=2.724 min.

步驟2：掌性分離Step 2: Palm Separation

藉由掌性HPLC(管柱：IA(250*20，5mkm)，以己烷-IPA-MeOH，50-25-25，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物N -[5-[[2-[(2S,5R )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(E1)(39mg，79.18μmol，70.91%產率)(保留時間=12.95min)及N -[5-[[2-[(2R,5S )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(E2)(35mg，71.06μmol，63.64%產率)(保留時間=16.57min)。The enantiomers were separated by chiral HPLC (column: IA (250*20, 5mkm) with hexane-IPA-MeOH, 50-25-25, 12ml/min as mobile phase) to give two separate The enantiomer of N- [5-[[2-[( 2S,5R )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (E1) (39 mg, 79.18 μmol, 70.91% yield) (retention time = 12.95 min) and N- [5-[[2-[( 2R,5S )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine tert -butyl]-3-methyl-2-pyridyl]carbamate (E2) (35 mg, 71.06 μmol, 63.64% yield) (retention time = 16.57 min).

E1：保留時間：12.95minE1: retention time: 12.95min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值492.5；實測值493.2；Rt=3.851min。LCMS (ESI): [M] + m/z: calculated 492.5; found 493.2; Rt=3.851 min.

E2：保留時間：16.57minE2: retention time: 16.57min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值492.5；實測值493.2；Rt=3.850min。LCMS (ESI): [M] + m/z: calculated 492.5; found 493.2; Rt=3.850 min.

步驟3：2-(2-(1H-苯并[d]咪唑-5-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物404 及化合物408 )之合成Step 3: 2-(2-(1H-Benzo[d]imidazol-5-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridine-3 Synthesis of -yl)-2-oxoacetamide ( Compound 404 and Compound 408 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(206.20mg，791.77μmol，196.38μL，14%純度)小心添加到N -[5-[[2-[(2S,5R )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(39mg，79.18μmol)及N -[5-[[2-[(2R,5S )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(35mg，71.06μmol)於DCM(0.5mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以30-70% 0-5min 0.1% NH3 -MeOH為流動相)，以得到呈固體材料之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺化合物404 (17mg，43.32μmol，54.71%產率)以及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(1H -苯并咪唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺化合物408 (15mg，38.22μmol，53.79%產率)。A 4.0 M solution of hydrogen chloride in dioxane (206.20 mg, 791.77 μmol, 196.38 μL, 14% purity) was carefully added to N- [5-[[2-[( 2S,5R )-2- at room temperature ( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl- 2 -pyridyl]carbamic acid Tributyl ester E1 (39 mg, 79.18 μmol) and N- [5-[[2-[( 2R,5S )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidine [00109] A solution of tert -butyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate E2 (35 mg, 71.06 [mu]mol) in DCM (0.5 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; 30-70% 0-5 min 0.1% NH3 -MeOH as mobile phase) to give N- (6-amino as a solid material -5-Methyl-3-pyridyl)-2-[( 2S,5R )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-side Oxyacetamide compound 404 (17 mg, 43.32 μmol, 54.71% yield) and N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-( 1H -benzimidazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide compound 408 (15 mg, 38.22 μmol, 53.79% yield).

化合物404：Compound 404:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.27-1.41(m,1H),1.69-1.81(m,1H),1.79-1.91(m,1H),1.96-2.03(m,3H),2.03-2.20(m,1H),2.22-2.34(m,1H),2.72-3.21(m,1H),3.43-4.05(m,1H),5.20-5.59(m,1H),5.59-5.74(m,2H),7.11-7.24(m,1H),7.38-7.52(m,2H),7.55-7.67(m,1H),7.92-8.07(m,1H),8.18(s,1H),10.40-10.59(m,1H),12.28-12.44(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.05(m,3H), 1.27-1.41(m,1H), 1.69-1.81(m,1H), 1.79-1.91(m,1H) ,1.96-2.03(m,3H),2.03-2.20(m,1H),2.22-2.34(m,1H),2.72-3.21(m,1H),3.43-4.05(m,1H),5.20-5.59( m,1H),5.59-5.74(m,2H),7.11-7.24(m,1H),7.38-7.52(m,2H),7.55-7.67(m,1H),7.92-8.07(m,1H), 8.18(s, 1H), 10.40-10.59(m, 1H), 12.28-12.44(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值392.4；實測值393.2；Rt=1.523min。LCMS (ESI): [M] + m/z: calculated 392.4; found 393.2; Rt=1.523 min.

化合物408：Compound 408:

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03-1.06(m,3H),1.29-1.45(m,1H),1.71-1.83(m,1H),1.82-1.94(m,1H),1.94-2.19(m,4H),2.20-2.35(m,1H),2.77-3.28 (m,1H),3.47-4.08(m,1H),5.23-5.62(m,1H),5.61-5.78(m,2H),7.12-7.27(m,1H),7.40-7.56(m,2H),7.59-7.68(m,1H),7.94-8.10(m,1H),8.18-8.24(m,1H),10.48-10.59(m,1H),12.33-12.47(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03-1.06(m,3H), 1.29-1.45(m,1H), 1.71-1.83(m,1H), 1.82-1.94(m,1H) ,1.94-2.19(m,4H),2.20-2.35(m,1H),2.77-3.28(m,1H),3.47-4.08(m,1H),5.23-5.62(m,1H),5.61-5.78( m,2H),7.12-7.27(m,1H),7.40-7.56(m,2H),7.59-7.68(m,1H),7.94-8.10(m,1H),8.18-8.24(m,1H), 10.48-10.59 (m, 1H), 12.33-12.47 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值392.4；實測值393.2；Rt=1.857min。LCMS (ESI): [M] + m/z: calculated 392.4; found 393.2; Rt=1.857 min.

實例404.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物677)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物678)之合成Example 404. N- (6-Amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )-5-methyl-2-(2-oxoindoline- 5-yl)-1-piperidinyl]-2-oxoacetamide (Compound 677) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2 R Synthesis of , 5S )-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyacetamide (compound 678)

Figure 110128222-A0202-12-1719-911
如對於化合物化合物373 之合成所述進行第一步驟
Figure 110128222-A0202-12-1719-911
 The first step was performed as described for the synthesis of compound compound 373

步驟2：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 2: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidine tert-butyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamate and N-[3-methyl-5-[[2-[(2R,5S)-5 -Methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid 3rd Palmar separation of butyl ester

使N -[3-甲基-5-[[2-[5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.2028g，399.54μmol)經歷掌性HPLC純化(管柱：Chiralpak IB(250 x 20mm，5um)；流動相：CO2 -MeOH，80-20；流速：50mL/min)，以獲得呈淡黃色固體之N -[3-甲基-5-[[2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.07683g，151.37μmol，37.88%產率)及N -[3-甲基-5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(74.80mg，147.37μmol，36.88%產率)。make N- [3-methyl-5-[[2-[5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl]-2-oxygen Acetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (0.2028 g, 399.54 μmol) was purified by chiral HPLC (column: Chiralpak IB (250 x 20 mm, 5 um); mobile phase: CO 2 -MeOH, 80-20; flow rate: 50 mL/min) to obtain N- [3-methyl-5-[[[2-[( 2S , 5R )-5-methyl-2 as a pale yellow solid -(2-Oxyindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.07683g , 151.37 μmol, 37.88% yield) and N- [3-methyl-5-[[2-[(2 R ,5 S )-5-methyl-2-(2-oxoindoline- 5-yl)-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (74.80 mg, 147.37 [mu]mol, 36.88% yield).

N -[3-甲基-5-[[2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯： N- [3-Methyl-5-[[2-[( 2S , 5R )-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester:

LCMS(ESI)：[M+H]+ m/z：計算值507.3；實測值508.4；Rt=3.951min。LCMS (ESI): [M+H] + m/z: calculated 507.3; found 508.4; Rt=3.951 min.

N -[3-甲基-5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯 N- [3-Methyl-5-[[2-[( 2R , 5S )-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester

LCMS(ESI)：[M+H]+ m/z：計算值507.3；實測值508.6；Rt=3.951min。LCMS (ESI): [M+H] + m/z: calculated 507.3; found 508.6; Rt=3.951 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物677 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-oxyindoline-5- Synthesis of yl)-1-piperidinyl]-2-oxoacetamide ( Compound 677 )

將N -[3-甲基-5-[[2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.07683g，151.37μmol)溶解於二噁烷(2.5mL)及水(2.5mL)中。將所得反應混合物在100℃下加熱隔夜。然後，在真空中濃縮反應混合物且藉由HPLC(溶析液：2-10min，30-55%，MeOH/H2 O；流速：30ml/min(裝載泵4ml MeOH)，管柱：SunFire 100 x 19mm，5um)純化殘餘物，以獲得呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物677， 0.031g，76.08μmol，50.26%產率)。 N- [3-methyl-5-[[2-[( 2S , 5R )-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidine ( 0.07683 g, 151.37 μmol) was dissolved in dioxane (2.5 mL) and water (2.5 mL) . The resulting reaction mixture was heated at 100°C overnight. Then, the reaction mixture was concentrated in vacuo and analyzed by HPLC (eluent: 2-10 min, 30-55%, MeOH/ H2O ; flow rate: 30 ml/min (loading pump 4 ml MeOH), column: SunFire 100 x 19mm, 5um), the residue was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )-5-methyl-2 as a white solid -(2-Pendant oxyindolin-5-yl)-1-piperidinyl]-2-pendant oxyacetamide ( compound 677, 0.031 g, 76.08 μmol, 50.26% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.30(m,1H),1.70(m,1H),1.84(m,1H),1.99(m,4H),2.14(m,1H),3.05(m,1H),3.43(m,3H),5.52(m,1H),5.59(m,2H),6.79(m,1H),7.13(m,2H),7.44(m,1H),7.98(m,1H),10.40(m,2H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.30 (m, 1H), 1.70 (m, 1H), 1.84 (m, 1H), 1.99 (m, 4H) ,2.14(m,1H),3.05(m,1H),3.43(m,3H),5.52(m,1H),5.59(m,2H),6.79(m,1H),7.13(m,2H), 7.44 (m, 1H), 7.98 (m, 1H), 10.40 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.0；Rt=1.634min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.0; Rt=1.634 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物678 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxyindoline-5- Synthesis of yl)-1-piperidinyl]-2-oxoacetamide ( Compound 678 )

將N -[3-甲基-5-[[2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(74.80mg，147.37μmol)溶解於二噁烷(2.5mL)及水(2.5mL)中。將所得反應混合物在100℃下加熱隔夜。然後，在真空中濃縮反應混合物且藉由HPLC(溶析液：2-10min，30-55%，MeOH/H2 O；流速：30ml/min(裝載泵4ml MeOH)，管柱：SunFire 100 x 19mm，5um)純化殘餘物，以獲得呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-5-甲基-2-(2-側氧基吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物678 ，0.042g，103.08μmol，69.95%產率)。 N- [3-methyl-5-[[2-[( 2R , 5S )-5-methyl-2-(2-oxyindolin-5-yl)-1-piperidine tert-butyl]-2-oxyacetyl]amino]-2-pyridyl] carbamate (74.80 mg, 147.37 μmol) was dissolved in dioxane (2.5 mL) and water (2.5 mL) . The resulting reaction mixture was heated at 100°C overnight. Then, the reaction mixture was concentrated in vacuo and analyzed by HPLC (eluent: 2-10 min, 30-55%, MeOH/ H2O ; flow rate: 30 ml/min (loading pump 4 ml MeOH), column: SunFire 100x 19mm, 5um), the residue was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R , 5S )-5-methyl-2 as a white solid -(2-Pendant oxyindolin-5-yl)-1-piperidinyl]-2-pendant oxyacetamide ( Compound 678 , 0.042 g, 103.08 μmol, 69.95% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.30(m,1H),1.70(m,1H),1.85(m,1H),1.99(m,4H),2.15(m,1H),3.04(m,1H),3.43(m,3H),5.56(m,3H),6.80(m,1H),7.10(m,2H),7.44(m,1H),7.98(m,1H),10.40(m,2H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.30 (m, 1H), 1.70 (m, 1H), 1.85 (m, 1H), 1.99 (m, 4H) ,2.15(m,1H),3.04(m,1H),3.43(m,3H),5.56(m,3H),6.80(m,1H),7.10(m,2H),7.44(m,1H), 7.98 (m, 1H), 10.40 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.0；Rt=1.634min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.0; Rt=1.634 min.

實例405. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物504)及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸酯(化合物503)之合成Example 405. N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1,2,3,4-tetrahydroquinoline Lin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 504) and N-[3-methyl-5-[[2-[(2R,5S)-5- Methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1-piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]amine Synthesis of Formate (Compound 503)

Figure 110128222-A0202-12-1722-912
Figure 110128222-A0202-12-1722-912

步驟1：N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)- Synthesis of 3-butyl 1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid

將於DMSO(4mL)中之6-[(2R,5S)-5-甲基-2-哌啶基]-1,2,3,4-四氫喹啉(0.3g，1.30mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(461.50mg，1.56mmol)、HATU(693.28mg，1.82mmol)及DIPEA(336.65mg，2.60mmol，453.70μL)在25℃下攪拌15h。反應混合物之HPLC顯示13%所要產物。將反應混合物提交至LCMS，以得到N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.077g，151.69μmol，11.65%產率)。6-[(2R,5S)-5-methyl-2-piperidinyl]-1,2,3,4-tetrahydroquinoline (0.3 g, 1.30 mmol), 2 -[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (461.50 mg, 1.56 mmol), HATU (693.28 mg, 1.82 mmol) and DIPEA (336.65 mg, 2.60 mmol, 453.70 μL) were stirred at 25 °C for 15 h. HPLC of the reaction mixture showed 13% of the desired product. The reaction mixture was submitted to LCMS to give N-[3-methyl-5-[[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinoline -6-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.077 g, 151.69 μmol, 11.65% yield).

HPLC資料：2-10min 0-70% MeCN/H2 O 30ml/min(裝載泵4mL MeCN；管柱：SunFire 100*19mm，5微米.HPLC profile: 2-10min 0-70% MeCN/ H2O 30ml/min (loading pump 4mL MeCN; column: SunFire 100*19mm, 5 micron.

LCMS(ESI)：[M+2H]+ m/z：計算值507.2；實測值509.2；Rt=1.107min。LCMS (ESI): [M+2H] + m/z: calculated 507.2; found 509.2; Rt=1.107 min.

步驟2：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-Step 2: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)- 1-Piperidinyl]-2- 側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester and N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2 -(1,2,3,4-Tetrahydroquinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl Synthesis of Esters

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.077g，147.14μmol)提交至掌性分離(樣品資訊：IC I(250*20mm，5mkm)IPA-MeOH，50-50，10ml/min；注入體積：900.000μl)，以得到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.022g，43.34μmol，29.46%產率)及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.021g，41.37μmol，28.12%產率)。N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1- Piperidinyl]-2-oxoacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.077 g, 147.14 μmol) was submitted to chiral separation (Sample information: IC I (250* 20mm, 5mkm) IPA-MeOH, 50-50, 10ml/min; injection volume: 900.000μl) to obtain N-[3-methyl-5-[[2-[(2S,5R)-5-methyl -2-(1,2,3,4-Tetrahydroquinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Tributyl ester (0.022 g, 43.34 μmol, 29.46% yield) and N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(1,2,3 ,4-Tetrahydroquinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.021 g, 41.37 μmol , 28.12% yield).

N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯：N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester:

RT(IC，MeOH-IPA，50-50，0.5mL/min)=11.391min。RT (IC, MeOH-IPA, 50-50, 0.5 mL/min) = 11.391 min.

LCMS(ESI)：[M+H]+ m/z：計算值507.2；實測值508.2；Rt=4.556min。LCMS (ESI): [M+H] + m/z: calculated 507.2; found 508.2; Rt=4.556 min.

N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯：N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1-piperidine Peridyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester:

RT(IC，MeOH-IPA，50-50，0.5mL/min)=36.735min。RT (IC, MeOH-IPA, 50-50, 0.5 mL/min) = 36.735 min.

LCMS(ESI)：[M+H]+ m/z：計算值507.2；實測值508.2；Rt=4.561min。LCMS (ESI): [M+H] + m/z: calculated 507.2; found 508.2; Rt=4.561 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物504 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1,2,3,4-tetrahydroquinoline Synthesis of Lin-6-yl)-1-piperidinyl]-2-oxoacetamide ( Compound 504 )

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.022g，43.34μmol)溶解於HCl於1,4-二噁烷中之溶液(10%)且在25℃下攪拌2h。在真空中濃縮反應混合 物且將粗材料提交至HPLC(HPLC資料：2-10min 40-60%水/MeOH+NH3 (裝載泵4ml MeOH)，管柱：TRIART 100* 20mm 5微米；注入體積4000.000)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.003g，7.36μmol，16.99%產率)。N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1- Piperidinyl]-2-oxoacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.022 g, 43.34 μmol) in HCl in 1,4-dioxane (10%) and stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo and crude material was submitted to HPLC (HPLC profile: 2-10 min 40-60% water/MeOH+ NH3 (load pump 4 ml MeOH), column: TRIART 100 * 20mm 5 microns; injection volume 4000.000 ) to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(1,2,3,4-tetrahydro Quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (0.003 g, 7.36 μmol, 16.99% yield).

1 H NMR(400MHz,CDCl3 )δ 1.06-1.17(m,3H),1.27-1.40(m,1H),1.88-2.05(m,5H),2.10-2.23(m,5H),2.69-2.81(m,2H),2.96-3.33(m,2H),3.33-3.86(m,1H),4.11-4.28(m,0.3H),4.40-4.61(m,2H),4.68-4.97(m,0.7H),5.63-6.35(m,1H),6.42-6.52(m,1H),6.80-6.97(m,2H),7.78(s,1H),8.00-8.18(m,1H),9.02-9.26(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.06-1.17 (m, 3H), 1.27-1.40 (m, 1H), 1.88-2.05 (m, 5H), 2.10-2.23 (m, 5H), 2.69-2.81 ( m,2H),2.96-3.33(m,2H),3.33-3.86(m,1H),4.11-4.28(m,0.3H),4.40-4.61(m,2H),4.68-4.97(m,0.7H ), 5.63-6.35(m, 1H), 6.42-6.52(m, 1H), 6.80-6.97(m, 2H), 7.78(s, 1H), 8.00-8.18(m, 1H), 9.02-9.26(m , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.2；Rt=1.74min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.2; Rt=1.74 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物503 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinoline Synthesis of Lin-6-yl)-1-piperidinyl]-2-oxyacetamide ( Compound 503 )

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.021g，41.37μmol)溶解於HCl於1,4-二噁烷中之溶液(10%)且在25℃下攪拌2h。在真空中濃縮反應混合物且將殘餘物提交至HPLC(HPLC資料：2-10min 40-60%水/MeOH+NH3 (裝載泵4ml MeOH)，管柱：TRIART 100*20 5微米)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(1,2,3,4-四氫喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.002g，4.91μmol，11.86%產率)。N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinolin-6-yl)-1- 3-Butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate (0.021 g, 41.37 μmol) in HCl in 1,4-dioxane (10%) and stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo and the residue was submitted to HPLC (HPLC profile: 2-10 min 40-60% water/MeOH+ NH3 (load pump 4 ml MeOH), column: TRIART 100*20 5 microns) to give N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(1,2,3,4-tetrahydroquinoline-6 -yl)-1-piperidinyl]-2-oxoacetamide (0.002 g, 4.91 μmol, 11.86% yield).

1 H NMR(400MHz,CDCl3 )δ 1.10(s,3H),1.35-1.40(m,1H),1.94-2.03(m,4H),2.14-2.22(m,5H),2.75-2.81(m,2H),3.29-3.35(m,2H),3.37-3.46(m,1H),4.21-4.87(m,3H),5.66-6.35(m,1H),6.45-6.51(m,1H),6.85-6.93(m,2H),7.28-7.30(m,1H),7.76-7.80(m,1H),8.03-8.14(m,1H),9.02-9.21(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.10(s, 3H), 1.35-1.40(m, 1H), 1.94-2.03(m, 4H), 2.14-2.22(m, 5H), 2.75-2.81(m, 2H), 3.29-3.35(m, 2H), 3.37-3.46(m, 1H), 4.21-4.87(m, 3H), 5.66-6.35(m, 1H), 6.45-6.51(m, 1H), 6.85- 6.93 (m, 2H), 7.28-7.30 (m, 1H), 7.76-7.80 (m, 1H), 8.03-8.14 (m, 1H), 9.02-9.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.2；Rt=1.738min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.2; Rt=1.738 min.

實例406. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物505)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物502)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物583)之合成Example 406. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-di Hydrogen-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 505), N-(6-amino-5-methyl-3-pyridyl) -2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2- Pendant oxyacetamide (compound 502) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-5-methyl-2-(2-pendant Synthesis of Oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 583)

Figure 110128222-A0202-12-1725-913
Figure 110128222-A0202-12-1725-913

步驟1：N-[3-甲基-5-[[2-[5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1 -Synthesis of tert-butyl-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將6-(5-甲基-2-哌啶基)-3,4-二氫-1H-喹啉-2-酮(0.5g，1.44mmol，HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(425.91mg，1.44mmol)、HATU(712.95mg，1.88mmol)及DIPEA(932.07mg，7.21mmol，1.26mL)之混合物在DMSO(5mL)中在25℃下攪拌16h。反應完成之後，將反應混合物倒入到水(10mL)中且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在真 空中濃縮。將粗材料提交至HPLC(2-10min 40-60%水/MeCN+NH3 (裝載泵4ml MeCN+NH3 )，管柱：TRIART 100* 20 5微米)，以得到呈兩種級分之N-[3-甲基-5-[[2-[5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.137g，262.65μmol，18.21%產率)：91mg(藉由LCMS為93%)及48mg(藉由LCMS為90%)。6-(5-Methyl-2-piperidinyl)-3,4-dihydro-1H-quinolin-2-one (0.5 g, 1.44 mmol, HCl), 2-[[6-(3rd Butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (425.91 mg, 1.44 mmol), HATU (712.95 mg, 1.88 mmol) and DIPEA (932.07 mg, A mixture of 7.21 mmol, 1.26 mL) was stirred in DMSO (5 mL) at 25 °C for 16 h. After the reaction was completed, the reaction mixture was poured into water (10 mL) and extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The crude material was submitted to HPLC (2-10 min 40-60% water/MeCN+ NH3 (load pump 4 ml MeCN+ NH3 ), column: TRIART 100 * 20 5 microns) to obtain N in two fractions -[3-Methyl-5-[[2-[5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.137 g, 262.65 μmol, 18.21% yield): 91 mg (93% by LCMS) and 48 mg (90% by LCMS).

LCMS(ESI)：[M-Boc]+ m/z：計算值421.2；實測值422.2；Rt=3.057min。LCMS (ESI): [M-Boc] + m/z: calculated 421.2; found 422.2; Rt=3.057 min.

步驟2：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline- 6-yl)-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester and N-[3-methyl-5-[[2 -[(2R,5S)-5-methyl-2-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxo Synthesis of 3-butyl Acetyl]amino]-2-pyridyl]carbamate

將N-[3-甲基-5-[[2-[5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.137g，262.65μmol)提交至掌性分離(IB(250* 20，5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min)，以得到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.05g，95.86μmol，36.50%產率)及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.047g，90.11μmol，34.31%產率)。N-[3-methyl-5-[[2-[5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidine Peridyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.137g, 262.65μmol) was submitted to chiral separation (IB (250 * 20, 5mkm), Hexane-IPA-MeOH, 70-15-15, 12 ml/min) to give N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(2 -Pendant oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamic acid Tributyl ester (0.05 g, 95.86 μmol, 36.50% yield) and N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(2-side oxy -3,4-Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester ( 0.047 g, 90.11 μmol, 34.31% yield).

N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯：N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl )-1-piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester:

RT(IB，己烷-IPA-MeOH，70-15-15，0.6ml/min)=17.300min。RT (IB, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 17.300 min.

LCMS(ESI)：[M+H]+ m/z：計算值521.2；實測值522.2；Rt=4.990min。LCMS (ESI): [M+H] + m/z: calculated 521.2; found 522.2; Rt=4.990 min.

N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯：N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl )-1-piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester:

RT(IB，己烷-IPA-MeOH，70-15-15，0.6ml/min)=15.437min。RT (IB, Hexane-IPA-MeOH, 70-15-15, 0.6 ml/min) = 15.437 min.

LCMS(ESI)：[M+H]+ m/z：計算值521.2；實測值；Rt=4.989min。LCMS (ESI): [M+H] + m/z: calculated 521.2; found; Rt=4.989 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物505 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(2-oxo-3,4-di Synthesis of Hydrogen-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide ( Compound 505 )

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.05g，92.98μmol)溶解於水(1.5mL)及1,4-二噁烷(0.5mL)之混合物中且在95℃下攪拌20h。在真空中濃縮反應混合物，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.036g，85.41μmol，91.86%產率)。N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6- (0.05 g, 92.98 μmol) was dissolved in water (1.5 mL) and 1 , 4-dioxane (0.5 mL) and stirred at 95 °C for 20 h. The reaction mixture was concentrated in vacuo to give N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(2-pendoxyl) -3,4-Dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (0.036 g, 85.41 μmol, 91.86% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.95-1.12(m,3H),1.24-1.36(m,1H),1.61-1.74(m,1H),1.78-1.90(m,1H),1.93-2.07(m,4H),2.09-2.22(m,1H),2.39-2.44(m,2H),2.72-2.76(m,0.4H),2.82-2.90(m,2H),3.17-3.24(m,0.6H),3.41-4.00(m,1H),4.99-5.53(m,1H),5.57-5.72(m,2H),6.79-6.86(m,1H),7.03-7.13(m,2H),7.37-7.57(m,1H),7.92-8.10(m,1H),10.03(s,1H),10.40-10.56(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.95-1.12(m,3H), 1.24-1.36(m,1H), 1.61-1.74(m,1H), 1.78-1.90(m,1H), 1.93- 2.07(m, 4H), 2.09-2.22(m, 1H), 2.39-2.44(m, 2H), 2.72-2.76(m, 0.4H), 2.82-2.90(m, 2H), 3.17-3.24(m, 0.6H), 3.41-4.00(m, 1H), 4.99-5.53(m, 1H), 5.57-5.72(m, 2H), 6.79-6.86(m, 1H), 7.03-7.13(m, 2H), 7.37 -7.57(m, 1H), 7.92-8.10(m, 1H), 10.03(s, 1H), 10.40-10.56(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.4；Rt=1.872min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.4; Rt=1.872 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物502 、化合物502 、化合物502 _3)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物583 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-oxo-3,4-di Hydrogen-1H-quinolin-6-yl)-1-piperidinyl]-2-side oxyacetamide ( compound 502 , compound 502 , compound 502-3) and N-(6-amino-5-methyl) yl-3-pyridyl)-2-[(2R,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1- Synthesis of piperidinyl]-2-oxoacetamide ( compound 583 )

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.047g，89.21μmol)溶解於水(1.5mL)及1,4-二噁烷(0.5mL)之混合物中且將反應混合物在95℃下攪拌16h。冷卻之後，在真空中濃縮反應混合物，以得到具有順式雜質之N-(6- 胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.032g，75.92μmol，85.11%產率)，在以下條件下對其進行純化：管柱：Chiralpak IA(250/20mm/5m)；流動相：己烷-IPA-MeOH，60-20-20；流速：12mL/min；管柱溫度：24℃；波長：205nm，210nm，308nm)，保留時間(異構物A)=70.02min；保留時間(異構物B)=77.91min，以得到20mg N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.032g，75.92μmol，85.11%產率)(化合物502) 及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.0015g，3.56μmol，3.99%產率)(化合物583 )。N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinoline-6- (0.047 g, 89.21 μmol) was dissolved in water (1.5 mL) and 1 , 4-dioxane (0.5 mL) and the reaction mixture was stirred at 95 °C for 16 h. After cooling, the reaction mixture was concentrated in vacuo to give N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl- with cis impurity 2-(2-Oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (0.032 g, 75.92 μmol, 85.11% Yield), it was purified under the following conditions: Column: Chiralpak IA (250/20mm/5m); Mobile Phase: Hexane-IPA-MeOH, 60-20-20; Flow Rate: 12 mL/min; Column temperature: 24°C; wavelength: 205nm, 210nm, 308nm), retention time (isomer A) = 70.02 min; retention time (isomer B) = 77.91 min to obtain 20 mg of N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)- 1-Piperidinyl]-2-oxyacetamide (0.032 g, 75.92 μmol, 85.11% yield) ( compound 502) and N-(6-amino-5-methyl-3-pyridyl) -2-[(2R,5R)-5-methyl-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)-1-piperidinyl]-2- Pendant oxyacetamide (0.0015 g, 3.56 μmol, 3.99% yield) ( compound 583 ).

化合物502：Compound 502:

1 H NMR(600MHz,DMSO-d6 )δ 0.98-1.20(m,3H),1.26-1.37(m,1H),1.63-1.75(m,1H),1.80-1.92(m,1H),1.95-2.07(m,4H),2.11-2.21(m,1H),2.40-2.43(m,2H),2.72-2.75(m,0.4H),2.83-2.89(m,2H),3.17-3.22(m,0.6H),3.42-3.99(m,1H),5.01-5.53(m,1H),5.57-5.66(m,2H),6.79-6.86(m,1H),7.04-7.13(m,2H),7.39-7.52(m,1H),7.91-8.07(m,1H),10.02(s,1H),10.41-10.52(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.98-1.20(m,3H), 1.26-1.37(m,1H), 1.63-1.75(m,1H), 1.80-1.92(m,1H), 1.95- 2.07(m, 4H), 2.11-2.21(m, 1H), 2.40-2.43(m, 2H), 2.72-2.75(m, 0.4H), 2.83-2.89(m, 2H), 3.17-3.22(m, 0.6H), 3.42-3.99(m, 1H), 5.01-5.53(m, 1H), 5.57-5.66(m, 2H), 6.79-6.86(m, 1H), 7.04-7.13(m, 2H), 7.39 -7.52(m, 1H), 7.91-8.07(m, 1H), 10.02(s, 1H), 10.41-10.52(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.4；Rt=1.868min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.4; Rt=1.868 min.

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=1.782min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=1.782 min.

化合物583：Compound 583:

1 H NMR(600MHz,DMSO-d6 )δ 0.70-0.98(m,3H),1.24-1.38(m,1H),1.60-1.67(m,1H),1.78-1.89(m,1H),1.95-2.07(m,4H),2.09-2.18(m,1H),2.42-2.44(m,2H),2.74-3.20(m,3H),3.34-4.20(m,1H),4.98-5.63(m,1H),5.87(br.s,2H),6.77-6.88(m,1H),7.03-7.13(m,2H),7.42-7.60(m,1H),7.95-8.10(m,1H),10.03(s,1H),10.48-10.64(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.70-0.98(m,3H), 1.24-1.38(m,1H), 1.60-1.67(m,1H), 1.78-1.89(m,1H), 1.95- 2.07(m, 4H), 2.09-2.18(m, 1H), 2.42-2.44(m, 2H), 2.74-3.20(m, 3H), 3.34-4.20(m, 1H), 4.98-5.63(m, 1H ),5.87(br.s,2H),6.77-6.88(m,1H),7.03-7.13(m,2H),7.42-7.60(m,1H),7.95-8.10(m,1H),10.03(s , 1H), 10.48-10.64 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=1.23min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=1.23 min.

實例407. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物864)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物876)之合成Example 407. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridine yl]-1-piperidinyl]-2-oxoacetamide (Compound 864) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S) Synthesis of -5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxoacetamide (compound 876)

Figure 110128222-A0202-12-1729-914
Figure 110128222-A0202-12-1729-914

步驟1：N-[3-甲基-5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-2-pyridyl]carbamate

將N-甲基-5-(5-甲基-2-哌啶基)吡啶-2-胺(0.5g，2.44mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(719.17mg，2.44mmol)及三乙胺(2.46g，24.35mmol，3.39mL)一起混合於DMF(10mL)中。添加HATU(1.39g，3.65mmol)且將所得混合物攪拌18h。在真空中濃縮反應混合物且藉由HPLC(50-75% MeOH-2-10min流速：30mL/min；裝載泵4mL/min MeOH；管柱Sun Fire 100* 19mm，5mkm)純化殘餘物，以獲得N-[3-甲基-5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.184g，381.29μmol，15.66%產率)。N-methyl-5-(5-methyl-2-piperidinyl)pyridin-2-amine (0.5 g, 2.44 mmol), 2-[[6-(tertiary butoxycarbonylamino)- 5-Methyl-3-pyridyl]amino]-2-pendoxoacetic acid (719.17 mg, 2.44 mmol) and triethylamine (2.46 g, 24.35 mmol, 3.39 mL) were mixed together in DMF (10 mL). HATU (1.39 g, 3.65 mmol) was added and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (50-75% MeOH-2-10 min flow rate: 30 mL/min; loading pump 4 mL/min MeOH; column Sun Fire 100 * 19 mm, 5 mkm) to obtain N -[3-Methyl-5-[[2-[5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxoacetyl tert-butyl]amino]-2-pyridyl]carbamate (0.184 g, 381.29 μmol, 15.66% yield).

LCMS(ESI)：[M+H]+ m/z：計算值482.2；實測值483.2；Rt=0.991min。LCMS (ESI): [M+H] + m/z: calculated 482.2; found 483.2; Rt=0.991 min.

步驟2：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidine tert-butyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamate and N-[3-methyl-5-[[2-[(2R,5S)-5 -Methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid 3rd Synthesis of Butyl Ester

對N-[3-甲基-5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.184g，381.29μmol)進行掌性分離(管柱：Chiralpak ICII(250* 20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：12mL/min；9次注入，20mg/注入，11h)，以獲得N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物1(0.05273g，109.27μmol，28.66%產率；保留時間=28.35)及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物2(0.06791g，140.72μmol，36.91%產率；保留時間=54.813)。p-N-[3-Methyl-5-[[2-[5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-side oxy Acetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.184 g, 381.29 μmol) for chiral separation (column: Chiralpak ICII (250 * 20 mm, 5 mkm); mobile phase: hexane- IPA-MeOH 50-25-25; flow rate: 12 mL/min; 9 injections, 20 mg/injection, 11 h) to obtain N-[3-methyl-5-[[2-[(2S,5R)-5 -Methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid 3rd Butyl ester isomer 1 (0.05273 g, 109.27 μmol, 28.66% yield; retention time = 28.35) and N-[3-methyl-5-[[2-[(2R,5S)-5-methyl- 2-[6-(Methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester isomerization Compound 2 (0.06791 g, 140.72 μmol, 36.91% yield; retention time=54.813).

第1種異構物： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=28.386min。 Isomer 1: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 28.386 min.

LCMS(ESI)：[M+2H]+ m/z：計算值482.2；實測值484.2；Rt=2.009min。LCMS (ESI): [M+2H] + m/z: calculated 482.2; found 484.2; Rt=2.009 min.

第2種異構物： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=56.615min。 Isomer 2: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 56.615 min.

LCMS(ESI)：[M+2H]+ m/z：計算值482.2；實測值484.2；Rt=2.002min。LCMS (ESI): [M+2H] + m/z: calculated 482.2; found 484.2; Rt=2.002 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物864 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridine Synthesis of yl]-1-piperidinyl]-2-oxoacetamide ( compound 864 )

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物1(0.05273g，109.27μmol)溶解於二噁烷(1mL)及水(1mL)之混合物中且將所得混合物在100℃下加熱18h。在真空中濃縮反應混合物且藉由HPLC(35-55% MeOH/H2 O+NH3 -2-10 min，流速：30ml/min；裝載泵4ml/min MeOH+NH3 ；目標質量382)純化殘餘物，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(0.0281g，73.47μmol，67.24%產率)。N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl] -2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (0.05273 g, 109.27 μmol) was dissolved in dioxane (1 mL) and water (1 mL) into the mixture and the resulting mixture was heated at 100 °C for 18 h. The reaction mixture was concentrated in vacuo and purified by HPLC (35-55% MeOH/ H2O + NH3-2-10 min, flow rate: 30 ml/min; loading pump 4 ml/min MeOH+ NH3 ; target mass 382) residue to obtain N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3 -Pyridinyl]-1-piperidinyl]-2-oxoacetamide (0.0281 g, 73.47 μmol, 67.24% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.95-1.03(m,3H),1.24-1.40(m,1H),1.65-1.77(m,1H),1.77-1.89(m,1H),1.89-1.98(m,1H),1.98-2.03(m,3H),2.06-2.15(m,1H),2.71-2.74(m,3H),2.77-3.18(m,1H),3.39-3.95(m,1H),4.95-5.50(m,1H),5.54-5.66(m,2H),6.38-6.46(m,2H),7.24-7.38(m,1H),7.42-7.50(m,1H),7.89-7.94(m,1H),7.95-8.03(m,1H),10.32-10.65(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.95-1.03 (m, 3H), 1.24-1.40 (m, 1H), 1.65-1.77 (m, 1H), 1.77-1.89 (m, 1H) ,1.89-1.98(m,1H),1.98-2.03(m,3H),2.06-2.15(m,1H),2.71-2.74(m,3H),2.77-3.18(m,1H),3.39-3.95( m,1H),4.95-5.50(m,1H),5.54-5.66(m,2H),6.38-6.46(m,2H),7.24-7.38(m,1H),7.42-7.50(m,1H), 7.89-7.94 (m, 1H), 7.95-8.03 (m, 1H), 10.32-10.65 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值382.2；實測值384.2；Rt=0.684min。LCMS (ESI): [M+2H] + m/z: calculated 382.2; found 384.2; Rt=0.684 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物876 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridine Synthesis of yl]-1-piperidinyl]-2-oxoacetamide ( compound 876 )

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物2(0.06791g，140.72μmol)溶解於二噁烷(1mL)及水(1mL)之混合物中且將所得混合物在100℃下加熱18h。在真空中濃縮反應混合物且藉由HPLC(35-55% MeOH/H2 O+NH3 -2-10min，流速：30mL/min；裝載泵4mL/min MeOH+NH3 ；目標質量382)純化殘餘物，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(0.0368g，96.22μmol，68.37%產率)。N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl] -2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (0.06791 g, 140.72 μmol) was dissolved in dioxane (1 mL) and water (1 mL) into the mixture and the resulting mixture was heated at 100 °C for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (35-55% MeOH/ H2O + NH3-2-10 min, flow rate: 30 mL/min; loading pump 4 mL/min MeOH+ NH3 ; target mass 382) to obtain N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3- Pyridinyl]-1-piperidinyl]-2-oxoacetamide (0.0368 g, 96.22 μmol, 68.37% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.94-1.01(m,3H),1.26-1.36(m,1H),1.65-1.78(m,1H),1.78-1.97(m,2H),1.97-2.03(m,3H),2.06-2.15(m,1H),2.72(s,3H),2.75-3.20(m,1H),3.38-3.95(m,1H),4.92-5.50(m,1H),5.56-5.66(m,2H),6.37-6.47(m,2H),7.23-7.40(m,1H),7.42-7.50(m,1H),7.92(s,1H),7.95-8.02(m,1H),10.44(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.94-1.01 (m, 3H), 1.26-1.36 (m, 1H), 1.65-1.78 (m, 1H), 1.78-1.97 (m, 2H) ,1.97-2.03(m,3H),2.06-2.15(m,1H),2.72(s,3H),2.75-3.20(m,1H),3.38-3.95(m,1H),4.92-5.50(m, 1H), 5.56-5.66(m, 2H), 6.37-6.47(m, 2H), 7.23-7.40(m, 1H), 7.42-7.50(m, 1H), 7.92(s, 1H), 7.95-8.02( m, 1H), 10.44 (s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值382.2；實測值384.2；Rt=0.681min。LCMS (ESI): [M+2H] + m/z: calculated 382.2; found 384.2; Rt=0.681 min.

實例408. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物865)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物878)之合成Example 408. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridine yl]-1-piperidinyl]-2-oxoacetamide (Compound 865) and N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S) Synthesis of -5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (compound 878)

Figure 110128222-A0202-12-1732-915
Figure 110128222-A0202-12-1732-915

步驟1：N-[3-乙基-5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Ethyl-5-[[2-[5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-2-pyridyl]carbamate

將N-甲基-5-(5-甲基-2-哌啶基)吡啶-2-胺(0.4g，1.95mmol)、2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(602.67mg，1.95mmol)及三乙胺(1.97g，19.48mmol，2.72mL)一起混合於DMF(10mL)中。向其中添加HATU(1.11g，2.92mmol)，且將所得混合物攪拌18h。在真空中濃縮反應混合物且藉由HPLC(50-75% MeOH 2-10min流速：30mL/min；裝載泵4mL/min MeOH；管柱Sun Fire 100* 19mm，5mkm)純化殘餘物，以獲得N-[3-乙基-5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.1351g，272.05μmol，13.96%產率)N-methyl-5-(5-methyl-2-piperidinyl)pyridin-2-amine (0.4 g, 1.95 mmol), 2-[[6-(tertiary butoxycarbonylamino)- 5-Ethyl-3-pyridyl]amino]-2-pendoxoacetic acid (602.67 mg, 1.95 mmol) and triethylamine (1.97 g, 19.48 mmol, 2.72 mL) were mixed together in DMF (10 mL). To this was added HATU (1.11 g, 2.92 mmol) and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (50-75% MeOH 2-10 min flow rate: 30 mL/min; loading pump 4 mL/min MeOH; column Sun Fire 100 * 19 mm, 5 mkm) to obtain N- [3-Ethyl-5-[[2-[5-Methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl ]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.1351 g, 272.05 μmol, 13.96% yield)

LCMS(ESI)：[M+H]+ m/z：計算值496.2；實測值497.2；Rt=1.023min。LCMS (ESI): [M+H] + m/z: calculated 496.2; found 497.2; Rt=1.023 min.

步驟2：N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[3-Ethyl-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidine tert-butyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate and N-[3-ethyl-5-[[2-[(2R,5S)-5 -Methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid 3rd Synthesis of Butyl Ester

對N-[3-乙基-5-[[2-[5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.1351g，272.05μmol)進行掌性分離(管柱：Chiralpak ICII(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：12mL/min；7次注入，20mg/注入，7.5h)，以獲得N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物1(0.04623g，93.09μmol，34.22%產率；保留時間=28.48)及N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物2(0.0479g，96.46μmol，35.46%產率；保留時間=51.36)p-N-[3-Ethyl-5-[[2-[5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-side oxy Acetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.1351 g, 272.05 μmol) for chiral separation (column: Chiralpak ICII (250*20 mm, 5 mkm); mobile phase: hexane- IPA-MeOH 50-25-25; flow rate: 12 mL/min; 7 injections, 20 mg/injection, 7.5 h) to obtain N-[3-ethyl-5-[[2-[(2S,5R)- 5-Methyl-2-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Tributyl ester isomer 1 (0.04623 g, 93.09 μmol, 34.22% yield; retention time = 28.48) and N-[3-ethyl-5-[[2-[(2R,5S)-5-methyl -2-[6-(Methylamino)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester iso Construct 2 (0.0479 g, 96.46 μmol, 35.46% yield; retention time = 51.36)

第1種異構物： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=27.861min。 Isomer 1: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 27.861 min.

LCMS(ESI)：[M+2H]+ m/z：計算值496.2；實測值497.2；Rt=2.178min。LCMS (ESI): [M+2H] + m/z: calculated 496.2; found 497.2; Rt=2.178 min.

第2種異構物： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=52.672min。 Isomer 2: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 52.672 min.

LCMS(ESI)：[M+2H]+ m/z：計算值496.2；實測值497.2；Rt=2.173min。LCMS (ESI): [M+2H] + m/z: calculated 496.2; found 497.2; Rt=2.173 min.

步驟3：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物865 )之合成Step 3: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridine Synthesis of yl]-1-piperidinyl]-2-oxoacetamide ( compound 865 )

將N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物1(0.04623g，93.09μmol)溶解於二噁烷(1mL)及水(1mL)之混合物中且將所得混合物在100℃下加熱18h。在真空中濃縮反應混合物且藉由HPLC(35-55% MeOH/H2 O+NH3 2-10min，流速：30mL/min；裝載泵4mL/min MeOH+NH3 )純化殘餘物，以獲得N-(6- 胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(0.0251g，63.31μmol，68.00%產率)。N-[3-ethyl-5-[[2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl] -2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester isomer 1 (0.04623 g, 93.09 μmol) was dissolved in dioxane (1 mL) and water (1 mL) into the mixture and the resulting mixture was heated at 100 °C for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (35-55% MeOH/ H2O + NH3 2-10 min, flow rate: 30 mL/min; loading pump 4 mL/min MeOH+ NH3 ) to obtain N -(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1 -Piperidinyl]-2-oxoacetamide (0.0251 g, 63.31 μmol, 68.00% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.96-1.02(m,3H),1.06-1.13(m,3H),1.25-1.36(m,1H),1.67-1.77(m,1H),1.79-1.91(m,1H),1.92-2.05(m,1H),2.06-2.18(m,1H),2.36-2.42(m,2H),2.73(s,3H),2.77-3.17(m,1H),3.40-3.96(m,1H),4.96-5.50(m,1H),5.55-5.65(m,2H),6.37-6.46(m,2H),7.24-7.38(m,1H),7.43-7.49(m,1H),7.92(s,1H),7.97-8.06(m,1H),10.44(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.96-1.02 (m, 3H), 1.06-1.13 (m, 3H), 1.25-1.36 (m, 1H), 1.67-1.77 (m, 1H) ,1.79-1.91(m,1H),1.92-2.05(m,1H),2.06-2.18(m,1H),2.36-2.42(m,2H),2.73(s,3H),2.77-3.17(m, 1H), 3.40-3.96(m, 1H), 4.96-5.50(m, 1H), 5.55-5.65(m, 2H), 6.37-6.46(m, 2H), 7.24-7.38(m, 1H), 7.43- 7.49(m, 1H), 7.92(s, 1H), 7.97-8.06(m, 1H), 10.44(s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值396.2；實測值398.2；Rt=0.719min。LCMS (ESI): [M+2H] + m/z: calculated 396.2; found 398.2; Rt=0.719 min.

步驟4：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物878 )之合成Step 4: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridine Synthesis of yl]-1-piperidinyl]-2-oxoacetamide ( compound 878 )

將N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯異構物2(0.0479g，96.46μmol)溶解於二噁烷(1mL)及水(1mL)之混合物中且將所得混合物在100℃下加熱18h。在真空中濃縮反應混合物且藉由HPLC(35-55% MeOH/H2 O+NH3 2-10min，流速：30mL/min；裝載泵4mL/min MeOH+NH3 )純化殘餘物，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(0.0248g，62.55μmol，64.85%產率)。N-[3-ethyl-5-[[2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1-piperidinyl] -2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester isomer 2 (0.0479 g, 96.46 μmol) was dissolved in dioxane (1 mL) and water (1 mL) into the mixture and the resulting mixture was heated at 100 °C for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (35-55% MeOH/ H2O + NH3 2-10 min, flow rate: 30 mL/min; loading pump 4 mL/min MeOH+ NH3 ) to obtain N -(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(methylamino)-3-pyridyl]-1 -Piperidinyl]-2-oxoacetamide (0.0248 g, 62.55 μmol, 64.85% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.95-1.02(m,3H),1.07-1.12(m,3H),1.25-1.36(m,1H),1.65-1.77(m,1H),1.79-1.91(m,1H),1.92-2.05(m,1H),2.06-2.14(m,1H),2.36-2.41(m,2H),2.73(s,3H),2.82-3.19(m,1H),3.42-3.97(m,1H),4.94-5.51(m,1H),5.56-5.65(m,2H),6.37-6.46(m,2H),7.23-7.39(m,1H),7.41-7.52(m,1H),7.92(s,1H),7.98-8.06(m,1H),10.45(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.95-1.02 (m, 3H), 1.07-1.12 (m, 3H), 1.25-1.36 (m, 1H), 1.65-1.77 (m, 1H) ,1.79-1.91(m,1H),1.92-2.05(m,1H),2.06-2.14(m,1H),2.36-2.41(m,2H),2.73(s,3H),2.82-3.19(m, 1H), 3.42-3.97(m, 1H), 4.94-5.51(m, 1H), 5.56-5.65(m, 2H), 6.37-6.46(m, 2H), 7.23-7.39(m, 1H), 7.41- 7.52(m, 1H), 7.92(s, 1H), 7.98-8.06(m, 1H), 10.45(s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值396.2；實測值398.2；Rt=0.723min。LCMS (ESI): [M+2H] + m/z: calculated 396.2; found 398.2; Rt=0.723 min.

實例409.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3,4-二氟苯基)-5-甲基哌啶-1-Example 409. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(3,4-difluorophenyl)-5-methylpiperidine-1- 基)-2-側氧基乙醯胺(化合物472、化合物458)之合成Synthesis of yl)-2-oxoacetamide (Compound 472, Compound 458)

Figure 110128222-A0202-12-1735-916
Figure 110128222-A0202-12-1735-916

步驟1：(5-(2-(2-(3,4-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(3,4-Difluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methyl Synthesis of tert-butyl pyridin-2-yl)carbamate

將DIPEA(525.22mg，4.06mmol，707.84μL)添加到相應2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.4g，1.35mmol)及(2S,5R )-2-(3,4-二氟苯基)-5-甲基哌啶(286.16mg，1.35mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(566.56mg，1.49mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(管柱：Triart 100*20，5mkl；以MeOH+NH3 為溶析液混合物)，以得到純的N -[5-[[2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(370mg，757.38μmol，55.91%產率)。DIPEA (525.22 mg, 4.06 mmol, 707.84 μL) was added to the corresponding 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo A solution of acetic acid (0.4 g, 1.35 mmol) and ( 2S,5R )-2-(3,4-difluorophenyl)-5-methylpiperidine (286.16 mg, 1.35 mmol) in DMF (10 mL) middle. The resulting mixture was stirred for 5 min, then HATU solution (566.56 mg, 1.49 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (column: Triart 100*20, 5mkl; with MeOH+ NH3 as eluent mixture) to obtain pure N- [5-[[2-[( 2R,5S )- 2-(3,4-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid Tertiary butyl ester (370 mg, 757.38 [mu]mol, 55.91% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm) 1 H NMR (400MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值488.2；實測值489.2；Rt=4.078min。LCMS (ESI): [M] + m/z: calculated 488.2; found 489.2; Rt=4.078 min.

步驟2：掌性分離Step 2: Palm Separation

使用(Chiralpak IC 250*20，5mkm管柱；以CO2 -MeOH，70-30為流動相；流速50mL/min；注入體積：900mkl)分離N -[5-[[2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(370 mg，757.38μmol)；得到呈米色固體之E1N -[5-[[2-[(2S,5R )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(142.29mg，291.26μmol，38.46%產率)(RT(IC，CO2 -MeOH，60-40，2ml/min)=5.93min)及呈米色固體之E2N -[5-[[2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(111.93mg，229.12μmol，30.25%產率)(RT(IC，CO2 -MeOH，60-40，2ml/min)=4.83min)。 N- [5-[[2-[( 2R,5S was separated using (Chiralpak IC 250*20, 5mkm column; CO 2 -MeOH, 70-30 as mobile phase; flow rate 50mL/min; injection volume: 900mkl) )-2-(3,4-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl] tert -butyl carbamate (370 mg, 757.38 μmol); E1 N- [5-[[2-[( 2S,5R )-2-(3,4-difluorophenyl)-5 was obtained as a beige solid -Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (142.29 mg, 291.26 μmol, 38.46% yield rate) (RT(IC, CO2 -MeOH, 60-40, 2ml/min)=5.93min) and E2N- [5-[[2-[( 2R,5S )-2-(3 as a beige solid ,4-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (111.93 mg, 229.12 μmol, 30.25% yield) (RT (IC, CO2-MeOH, 60-40, 2 ml/min)=4.83 min).

E1：保留時間：5.93minE1: retention time: 5.93min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm) 1 H NMR (600MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值488.2；實測值489.2；Rt=5.938min。LCMS (ESI): [M] + m/z: calculated 488.2; found 489.2; Rt=5.938 min.

E2：保留時間：4.83minE2: retention time: 4.83min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm) 1 H NMR (600MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值488.2；實測值489.2；Rt=5.939min。LCMS (ESI): [M] + m/z: calculated 488.2; found 489.2; Rt=5.939 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3,4-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物472 及化合物458 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3,4-difluorophenyl)-5-methylpiperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 472 and Compound 458 )

將N -[5-[[2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(111.93mg，229.12μmol)及N -[5-[[2-[(2S,5R )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(142.29mg，291.26μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(管柱：Triart 100*20，5mkl；以MeCN+NH3 為溶析液混合物)，以得到純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物458 )(67.1mg，172.76μmol，75.40%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3,4-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物 472 )(87.2mg，224.51μmol，77.08%產率)。 N- [5-[[2-[( 2R,5S )-2-(3,4-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetoxy ] amino]-3-methyl-2-pyridyl] carbamic acid tert- butyl ester E2 (111.93 mg, 229.12 μmol) and N- [5-[[2-[( 2S,5R )-2-(3 ,4-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E1 (142.29 mg, 291.26 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (column: Triart 100*20, 5mkl; with MeCN+ NH3 as eluent mixture) to obtain pure N- (6-amino-5-methyl-3-pyridine yl)-2-[( 2R,5S )-2-(3,4-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide ( Compound 458 )( 67.1 mg, 172.76 μmol, 75.40% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(3,4-difluorobenzene yl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 472 ) (87.2 mg, 224.51 μmol, 77.08% yield).

化合物472： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94-1.02(m,3H),1.25-1.38(m,1H),1.57-1.68(m,1H),1.80-1.92(m,1H),1.95-2.07(m,4H),2.12-2.23(m,1H),2.67-3.23(m,1H),3.38-4.05(m,1H),5.07-5.54(m,1H),5.56-5.65(m,2H),7.10-7.21(m,1H),7.31-7.40(m,1H),7.40-7.49(m,2H),7.93-8.04(m,1H),10.45-10.64(m,1H)。 Compound 472: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.94-1.02 (m, 3H), 1.25-1.38 (m, 1H), 1.57-1.68 (m, 1H), 1.80-1.92 (m ,1H),1.95-2.07(m,4H),2.12-2.23(m,1H),2.67-3.23(m,1H),3.38-4.05(m,1H),5.07-5.54(m,1H),5.56 -5.65(m, 2H), 7.10-7.21(m, 1H), 7.31-7.40(m, 1H), 7.40-7.49(m, 2H), 7.93-8.04(m, 1H), 10.45-10.64(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.875min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.875min.

化合物458： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.00(m,3H),1.25-1.36(m,1H),1.57-1.67(m,1H),1.80-1.92(m,1H),1.96-2.03(m,4H),2.12-2.24(m,1H),2.68-3.22(m,1H),3.41-4.03(m,1H),5.08-5.52(m,1H),5.58-5.63(m,2H),7.09-7.20(m,1H),7.30-7.40(m,1H),7.41-7.49(m,2H),7.93-8.03(m,1H),10.47-10.53(m,1H)。 Compound 458: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.97-1.00 (m, 3H), 1.25-1.36 (m, 1H), 1.57-1.67 (m, 1H), 1.80-1.92 (m ,1H),1.96-2.03(m,4H),2.12-2.24(m,1H),2.68-3.22(m,1H),3.41-4.03(m,1H),5.08-5.52(m,1H),5.58 -5.63(m, 2H), 7.09-7.20(m, 1H), 7.30-7.40(m, 1H), 7.41-7.49(m, 2H), 7.93-8.03(m, 1H), 10.47-10.53(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.882min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.882 min.

實例410.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物478、化合物487)之合成Example 410. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl )-2-oxyacetamide (Compound 478, Compound 487) Synthesis

Figure 110128222-A0202-12-1737-917
Figure 110128222-A0202-12-1737-917

步驟1：(3-甲基-5-(2-(5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-(5-methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl)-2-oxoacetamide Synthesis of tert-butyl)pyridin-2-yl)carbamate

將DIPEA(459.56mg，3.56mmol，619.36μL)添加到相應2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)及5-甲 基-2-(3,4,5-三氟苯基)哌啶(232.90mg，1.02mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(424.92mg，1.12mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(管柱：Triart 100*20,5mkl；以MeOH+NH3 為溶析液混合物)，以得到純的N -[3-甲基-5-[[2-[5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.21g，414.60μmol，40.81%產率)。DIPEA (459.56 mg, 3.56 mmol, 619.36 μL) was added to the corresponding 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (0.3 g, 1.02 mmol) and 5-methyl-2-(3,4,5-trifluorophenyl)piperidine (232.90 mg, 1.02 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (424.92 mg, 1.12 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (column: Triart 100*20,5mkl; with MeOH+ NH3 as eluent mixture) to obtain pure N- [3-methyl-5-[[[2-[5 -Methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.21 g, 414.60 μmol, 40.81% yield).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=4.196min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=4.196 min.

步驟2：掌性分離Step 2: Palm Separation

使用(Chiralpak AD 250*30，5mkm管柱；CO2 -MeOH，60-40為流動相；流速30mL/min；注入體積：900mkl)分離N -[3-甲基-5-[[2-[5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(57mg，149.04μmol)；得到呈黃色固體之E1N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(66.11mg，130.52μmol，31.48%產率)(RT(AD-H，CO2 -MeOH，60-40，2ml/min)=9.02min)及呈黃色固體之E2N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(70.13mg，138.46μmol，33.40%產率)(RT(AD-H，CO2 -MeOH，60-40，2ml/min)=5.75min)。 N- [ 3 -methyl-5-[[[2-[ 5-Methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (57 mg, 149.04 μmol); E1 N- [3-methyl-5-[[[2-[( 2S,5R )-5-methyl-2-(3,4,5-tris) was obtained as a yellow solid Fluorophenyl)-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (66.11 mg, 130.52 μmol, 31.48% yield) (RT (AD-H, CO2 -MeOH, 60-40, 2ml/min)=9.02min) and E2N- [3-methyl-5-[[2-[( 2R,5S )-5 as a yellow solid -Methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (70.13 mg, 138.46 μmol, 33.40% yield) (RT (AD-H, CO2-MeOH, 60-40, 2 ml/min)=5.75 min).

E1：保留時間：9.02minE1: retention time: 9.02min

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=6.118min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=6.118 min.

E2：保留時間：5.75minE2: retention time: 5.75min

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=6.118min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=6.118 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物487 及化合物478 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl )-2-oxyacetamide ( Compound 487 and Compound 478 ) Synthesis

將N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯E1(66.11mg，130.52μmol)及N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯E2(70.13mg，138.46μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(管柱：Triart 100*20，5mkl；以MeOH+NH3 為溶析液混合物)，以得到純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物487 )(34.9mg，85.88μmol，65.80%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物478 )(44.3mg，109.01μmol，78.73%產率)。 N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester E1 (66.11 mg, 130.52 μmol) and N- [3-methyl-5-[[2-[( 2R, 5S )-5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid The tertiary butyl ester E2 (70.13 mg, 138.46 [mu]mol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (column: Triart 100*20, 5mkl; with MeOH+ NH3 as eluent mixture) to obtain pure N- (6-amino-5-methyl-3-pyridine base)-2-[( 2S,5R )-5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxoacetamide ( Compound 487 ) (34.9 mg, 85.88 μmol, 65.80% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-( 3,4,5-Trifluorophenyl)-1-piperidinyl]-2-oxoacetamide ( Compound 478 ) (44.3 mg, 109.01 μmol, 78.73% yield).

化合物487： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.02(m,3H),1.24-1.36(m,1H),1.57-1.67(m,1H),1.79-1.91(m,1H),1.97-2.06(m,4H),2.12-2.24(m,1H),2.70-3.25(m,1H),3.39-4.03(m,1H),5.05-5.50(m,1H),5.56-5.68(m,2H),7.17-7.33(m,2H),7.41-7.52(m,1H),7.91-8.06(m,1H),10.40-10.67(m,1H)。 Compound 487: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.95-1.02 (m, 3H), 1.24-1.36 (m, 1H), 1.57-1.67 (m, 1H), 1.79-1.91 (m) ,1H),1.97-2.06(m,4H),2.12-2.24(m,1H),2.70-3.25(m,1H),3.39-4.03(m,1H),5.05-5.50(m,1H),5.56 -5.68(m, 2H), 7.17-7.33(m, 2H), 7.41-7.52(m, 1H), 7.91-8.06(m, 1H), 10.40-10.67(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=2.170min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=2.170 min.

化合物478： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.01(m,3H),1.23-1.36(m,1H),1.55-1.68(m,1H),1.80-1.92(m,1H),1.95-2.04(m,4H),2.13-2.24(m,1H),2.70-3.24(m,1H),3.40-4.05(m,1H),5.06-5.48(m,1H),5.58-5.65(m,2H),7.19-7.32(m,2H),7.40-7.51(m,1H),7.91-8.06(m,1H),10.45-10.64(m,1H)。 Compound 478: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.96-1.01 (m, 3H), 1.23-1.36 (m, 1H), 1.55-1.68 (m, 1H), 1.80-1.92 (m ,1H),1.95-2.04(m,4H),2.13-2.24(m,1H),2.70-3.24(m,1H),3.40-4.05(m,1H),5.06-5.48(m,1H),5.58 -5.65(m, 2H), 7.19-7.32(m, 2H), 7.40-7.51(m, 1H), 7.91-8.06(m, 1H), 10.45-10.64(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=2.169min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=2.169 min.

實例411.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(4-羥基環己基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物423、化合物436、化合物431及化合物434)之合成Example 411. N- (6-amino-5-methylpyridin-3-yl)-2-(2-(4-hydroxycyclohexyl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 423, Compound 436, Compound 431 and Compound 434)

Figure 110128222-A0202-12-1740-918
Figure 110128222-A0202-12-1740-918

步驟1：(5-(2-(2-(4-羥基環己基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(4-Hydroxycyclohexyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridine-2 -Synthesis of tertiary butyl carbamate

將4-(5-甲基-2-哌啶基)環己醇(500mg，2.53mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(748.27mg，2.53mmol)及TEA(2.56g，25.34mmol，3.53mL)於DMF(20mL)中之混合物在25℃下攪拌0.25h，然後在0.5h內小批量添加HATU(963.50mg，2.53mmol)。將反應混合物在25℃下攪拌2h，然後在真空中濃縮至5ml且提交至反相HPLC(管柱：SunFireC18 100x19mm 5um，流動相：20-65% 0-5min水-MeOH+FA，流速：30ml/min)，得到呈淡黃色膠狀物之N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(260mg，547.84μmol，21.62%產率)及N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(240mg，505.70μmol，19.96%產率)，將其直接提交至製備型掌性HPLC。4-(5-Methyl-2-piperidinyl)cyclohexanol (500 mg, 2.53 mmol), 2-[[6-( 3- butoxycarbonylamino)-5-methyl-3-pyridine A mixture of [methyl]amino]-2-oxoacetic acid (748.27 mg, 2.53 mmol) and TEA (2.56 g, 25.34 mmol, 3.53 mL) in DMF (20 mL) was stirred at 25 °C for 0.25 h, then at 0.5 HATU (963.50 mg, 2.53 mmol) was added in small batches over h. The reaction mixture was stirred at 25°C for 2h, then concentrated in vacuo to 5ml and submitted to reverse phase HPLC (column: SunFire C18 100x19mm 5um, mobile phase: 20-65% 0-5min water-MeOH+FA, flow rate: 30ml /min) to obtain N- [5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (260 mg, 547.84 μmol, 21.62% yield) and N- [5-[[2- [( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridine tert -butyl ]carbamate (240 mg, 505.70 [mu]mol, 19.96% yield), which was submitted directly to preparative chiral HPLC.

D1： LCMS(ESI)：[M]+ m/z：計算值474.2；實測值475.2；Rt=2.953min。 D1: LCMS (ESI): [M] + m/z: calculated 474.2; found 475.2; Rt=2.953 min.

D2： CMS(ESI)：[M]+ m/z：計算值474.2；實測值475.2；Rt=3.100min。 D2: CMS (ESI): [M] + m/z: calculated 474.2; found 475.2; Rt=3.100 min.

步驟2：掌性分離Step 2: Palm Separation

將外消旋N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(240mg，505.70μmol)提交至製備型掌性HPLC(管柱：Chiralpak IC(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，40-30-30；流速：11mL/min；管柱溫度：21℃；波長：205nm)，以得到含有痕量溶劑之粗品N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(121mg，254.96μmol，50.42%產率)E2(R.T.=14.766min)及N -[5-[[2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(119mg，250.74μmol，49.58%產率)E1(R.T.=24.933min)，其直接用於下一步驟中。The racemic N- [5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (240 mg, 505.70 μmol) was submitted to preparative chiral HPLC (column: Chiralpak IC (250*20 mm, 5 mkm); mobile phase : hexane-IPA-MeOH, 40-30-30; flow rate: 11 mL/min; column temperature: 21 °C; wavelength: 205 nm) to obtain crude N- [5-[[2-[ ( 2S,5R )-2-(4-Hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl ] tert -butyl carbamate (121 mg, 254.96 μmol, 50.42% yield) E2 (RT=14.766 min) and N- [5-[[2-[( 2R,5S )-2-(4-hydroxycyclohexyl) )-3-butyl-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (119 mg, 250.74 μmol, 49.58 % yield) E1 (RT=24.933 min), which was used directly in the next step.

將外消旋N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(260mg，547.84μmol)提交至製備型掌性HPLC(管柱：IB(250*30，5mkm)，流動相：己烷-IPA-MeOH，80-10-10，流速12ml/min)，以得到含有痕量溶劑之粗品N -[5-[[2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(117mg，246.53μmol，45.00%產率)E4(R.T.=14.531min)及N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E3(114mg，240.21μmol，43.85%產率)(R.T.=29.070min)，其直接用於下一步驟中。The racemic N- [5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (260 mg, 547.84 μmol) was submitted to preparative chiral HPLC (column: IB (250*30, 5 mkm), mobile phase: Hexane-IPA-MeOH, 80-10-10, flow rate 12 ml/min) to give crude N- [5-[[2-[( 2R,5S )-2-(4-hydroxy ring with traces of solvent Hexyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (117 mg, 246.53 μmol, 45.00% yield) E4 (RT=14.531 min) and N- [5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl] -2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E3 (114 mg, 240.21 μmol, 43.85% yield) (RT=29.070 min), which used directly in the next step.

E1：保留時間：24.93minE1: retention time: 24.93min

LCMS(ESI)：[M]+ m/z：計算值474.5；實測值475.2；Rt=4.856min。LCMS (ESI): [M] + m/z: calculated 474.5; found 475.2; Rt=4.856 min.

E2：保留時間：14.76minE2: retention time: 14.76min

LCMS(ESI)：[M]+ m/z：計算值474.5；實測值475.2；Rt=4.854min。LCMS (ESI): [M] + m/z: calculated 474.5; found 475.2; Rt=4.854 min.

E3：保留時間：29.07minE3: retention time: 29.07min

LCMS(ESI)：[M]+ m/z：計算值474.5；實測值475.2；Rt=4.621min。LCMS (ESI): [M] + m/z: calculated 474.5; found 475.2; Rt=4.621 min.

E4：保留時間：14.53minE4: retention time: 14.53min

LCMS(ESI)：[M]+ m/z：計算值474.5；實測值475.2；Rt=4.622min。LCMS (ESI): [M] + m/z: calculated 474.5; found 475.2; Rt=4.622 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(4-羥基環己基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物423 、化合物436 及化合物431 、化合物434)之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(4-hydroxycyclohexyl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide ( Compound 423 , Compound 436 , Compound 431 , Compound 434)

將N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(121mg，254.96μmol)、N -[5-[[2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(119mg，250.74μmol)、N -[5-[[2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E4(117.00mg，246.53μmol)及N -[5-[[2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E3(114mg，240.21μmol)於水(2mL)及1.4-二噁烷(2mL)之混合物中之溶液在95℃下攪拌12h，然後冷卻且提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相40-40-65% 0-1-5min 0.1%NH3 -MeOH，流速：30ml/min)，以得到呈白色固體之化合物436 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(48mg，128.18μmol，50.27%產率)、化合物423 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(47.8mg，127.65μmol，50.91%產率)、化合物434 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(57.7mg，154.08μmol，62.50%產率)及化合物431 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(4-羥基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(52.5mg，140.20μmol，58.36%產率)。 N- [5-[[2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E2 (121 mg, 254.96 μmol), N- [5-[[2-[( 2R,5S )-2-(4-hydroxycyclohexyl )-5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E1 (119 mg, 250.74 μmol) , N- [5-[[2-[( 2R,5S )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E4 (117.00 mg, 246.53 μmol) and N- [5-[[2-[( 2S,5R )-2-(4-hydroxy ring Hexyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E3 (114 mg, 240.21 μmol ) in a mixture of water (2 mL) and 1.4-dioxane (2 mL) was stirred at 95°C for 12 h, then cooled and submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase 40- 40-65% 0-1-5min 0.1% NH3 -MeOH, flow rate: 30ml/min) to give compound 436 as a white solid N- (6-amino-5-methyl-3-pyridinyl)- 2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (48 mg, 128.18 μmol, 50.27% yield) , compound 423 N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidine N- (6- amino -5-methyl-3-pyridyl)-2-[( 2R ,5S )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (57.7 mg, 154.08 μmol, 62.50% yield) and compound 431 N -(6-Amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(4-hydroxycyclohexyl)-5-methyl-1-piperidinyl]-2 - Pendant oxyacetamide (52.5 mg, 140.20 μmol, 58.36% yield).

化合物423： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.92-0.98(m,3H),1.11-1.32(m,4H),1.33-1.51(m,4H),1.59-1.65(m,3H),1.81-1.95(m,3H),1.99-2.05(m, 3H),2.85-3.22(m,1H),3.36-3.61(m,1H),3.72-3.79(m,1H),3.98-4.29(m,2H),5.53-5.63(m,2H),7.42-7.54(m,1H),7.96-8.10(m,1H),10.24-10.38(m,1H)。 Compound 423: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.92-0.98 (m, 3H), 1.11-1.32 (m, 4H), 1.33-1.51 (m, 4H), 1.59-1.65 (m) ,3H),1.81-1.95(m,3H),1.99-2.05(m,3H),2.85-3.22(m,1H),3.36-3.61(m,1H),3.72-3.79(m,1H),3.98 -4.29(m, 2H), 5.53-5.63(m, 2H), 7.42-7.54(m, 1H), 7.96-8.10(m, 1H), 10.24-10.38(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值374.4；實測值375.2；Rt=2.217min。LCMS (ESI): [M] + m/z: calculated 374.4; found 375.2; Rt=2.217 min.

化合物436： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.90-1.01(m,3H),1.13-1.33(m,4H),1.33-1.51(m,4H),1.58-1.66(m,3H),1.80-1.96(m,3H),1.99-2.08(m,3H),2.81-3.31(m,1H),3.33-3.59(m,1H),3.72-3.78(m,1H),3.97-4.28(m,2H),5.56-5.65(m,2H),7.44-7.51(m,1H),7.99-8.06(m,1H),10.24-10.33(m,1H)。 Compound 436: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.90-1.01 (m, 3H), 1.13-1.33 (m, 4H), 1.33-1.51 (m, 4H), 1.58-1.66 (m ,3H),1.80-1.96(m,3H),1.99-2.08(m,3H),2.81-3.31(m,1H),3.33-3.59(m,1H),3.72-3.78(m,1H),3.97 -4.28(m, 2H), 5.56-5.65(m, 2H), 7.44-7.51(m, 1H), 7.99-8.06(m, 1H), 10.24-10.33(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值374.4；實測值375.2；Rt=2.125min。LCMS (ESI): [M] + m/z: calculated 374.4; found 375.2; Rt=2.125 min.

化合物431： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.72-0.90(m,2H),0.91-1.00(m,3H),1.05-1.19(m,2H),1.22-1.29(m,1H),1.56(d,3H),1.63-2.01(m,7H),2.01-2.14(m,3H),2.82-3.27(m,1H),3.42-4.02(m,1H),4.03-4.13(m,1H),4.46-4.51(m,1H),5.52-5.67(m,2H),7.43-7.50(m,1H),7.96-8.03(m,1H),10.25-10.33(m,1H)。 Compound 431: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.72-0.90 (m, 2H), 0.91-1.00 (m, 3H), 1.05-1.19 (m, 2H), 1.22-1.29 (m ,1H),1.56(d,3H),1.63-2.01(m,7H),2.01-2.14(m,3H),2.82-3.27(m,1H),3.42-4.02(m,1H),4.03-4.13 (m,1H),4.46-4.51(m,1H),5.52-5.67(m,2H),7.43-7.50(m,1H),7.96-8.03(m,1H),10.25-10.33(m,1H) .

LCMS(ESI)：[M]+ m/z：計算值374.4；實測值375.2；Rt=1.941min。LCMS (ESI): [M] + m/z: calculated 374.4; found 375.2; Rt=1.941 min.

化合物434： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.75-0.90(m,2H),0.91-1.01(m,3H),1.05-1.17(m,2H),1.21-1.30(m,1H),1.41-1.62(m,3H),1.64-2.00(m,7H),2.00-2.13(m,3H),2.82-3.27(m,1H),3.41-4.02(m,1H),4.03-4.13(m,1H),4.46-4.53(m,1H),5.55-5.68(m,2H),7.43-7.51(m,1H),7.98-8.06(m,1H),10.23-10.31(m,1H)。 Compound 434: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 0.75-0.90 (m, 2H), 0.91-1.01 (m, 3H), 1.05-1.17 (m, 2H), 1.21-1.30 (m ,1H),1.41-1.62(m,3H),1.64-2.00(m,7H),2.00-2.13(m,3H),2.82-3.27(m,1H),3.41-4.02(m,1H),4.03 -4.13(m, 1H), 4.46-4.53(m, 1H), 5.55-5.68(m, 2H), 7.43-7.51(m, 1H), 7.98-8.06(m, 1H), 10.23-10.31(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值374.4；實測值375.2；Rt=2.105min。LCMS (ESI): [M] + m/z: calculated 374.4; found 375.2; Rt=2.105 min.

實例412.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯-5-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物682及化合物659)之合成Example 412. N- (6-amino-5-methylpyridin-3-yl)-2-(2-(3-chloro-5-fluorophenyl)-5-methylpiperidin-1-yl) - Synthesis of 2-oxoacetamide (Compound 682 and Compound 659)

Figure 110128222-A0202-12-1744-919
Figure 110128222-A0202-12-1744-919

步驟1：(5-(2-(2-(3-氯-5-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(3-Chloro-5-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methyl Synthesis of tert-butyl pyridin-2-yl)carbamate

將DIPEA(393.91mg，3.05mmol，530.88μL)添加到相應2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)及2-(3-氯-5-氟苯基)-5-甲基哌啶(231.34mg，1.02mmol)於DMF(15mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(424.92mg，1.12mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Suniire C18 19*100 5mkm管柱且以H2 O-MeOH為溶析液混合物)，以得到純的N -[5-[[2-[2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.32g，633.69μmol，62.37%產率)。DIPEA (393.91 mg, 3.05 mmol, 530.88 μL) was added to the corresponding 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen acetic acid (0.3 g, 1.02 mmol) and 2-(3-chloro-5-fluorophenyl)-5-methylpiperidine (231.34 mg, 1.02 mmol) in DMF (15 mL). The resulting mixture was stirred for 5 min before HATU (424.92 mg, 1.12 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Suniire C18 19*100 5mkm column with H2O -MeOH as eluent mixture) to give pure N- [5-[[2-[2-(3- Chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.32 g, 633.69 μmol, 62.37% yield).

LCMS(ESI)：[M]+ m/z：計算值504.2；實測值505.2；Rt=3.569min。LCMS (ESI): [M] + m/z: calculated 504.2; found 505.2; Rt=3.569 min.

步驟2：掌性分離Step 2: Palm Separation

藉由掌性HPLC(管柱：IC-II(250*20，5mkm)，以己烷-MeOH-IPA，80-15-15，12ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物E1N -[5-[[2-[(2S,5R )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(116.9mg，231.49μmol，36.53%產率)及E2N -[5-[[2-[(2R,5S )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(109.4mg，216.64μmol，34.19%產率)。The enantiomers were separated by chiral HPLC (column: IC-II (250*20, 5mkm) with hexane-MeOH-IPA, 80-15-15, 12ml/min as mobile phase) to give two an individual enantiomer E1 N- [5-[[2-[( 2S,5R )-2-(3-chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (116.9 mg, 231.49 μmol, 36.53% yield) and E2 N- [5-[[ 2-[( 2R,5S )-2-(3-Chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3- 3 -butyl methyl-2-pyridyl]carbamate (109.4 mg, 216.64 [mu]mol, 34.19% yield).

E1於分析條件下(管柱：IC，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為20.40min且E2之保留時間為29.38min。The retention time of E1 under analytical conditions (column: IC, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 20.40 min and that of E2 was 29.38 min.

E1： LCMS(ESI)：[M]+ m/z：計算值504.2；實測值505.2；Rt=1.227min。 E1: LCMS (ESI): [M] + m/z: calculated 504.2; found 505.2; Rt=1.227 min.

E2： LCMS(ESI)：[M]+ m/z：計算值504.2；實測值505.2；Rt=1.224min。 E2: LCMS (ESI): [M] + m/z: calculated 504.2; found 505.2; Rt=1.224 min.

步驟3：(5-(2-(2-(3-氯-5-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯(化合物659 及化合物682 )之合成Step 3: (5-(2-(2-(3-Chloro-5-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methyl Synthesis of tert-butyl pyridin-2-yl)carbamate ( Compound 659 and Compound 682 )

將N -[5-[[2-[(2R,5S )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(109.4mg，216.64μmol)及N -[5-[[2-[(2S,5R )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(116.9mg，231.49μmol)溶解於二噁烷(2mL)及水(5mL)混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH(45-60%)+NH3 為溶析液混合物)，以得到純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(68.6mg，169.44μmol，78.21%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3-氯-5-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(48.8mg，120.53μmol，52.07%產率)。 N- [5-[[2-[( 2R,5S )-2-(3-chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetyl (109.4 mg, 216.64 μmol) and N- [5-[[2-[( 2S,5R )-2-( 3-Chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid third Butyl ester E1 (116.9 mg, 231.49 [mu]mol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH (45-60%)+ NH3 as eluent mixture) to give pure N- (6-amine) yl-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(3-chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetamide (68.6 mg, 169.44 μmol, 78.21% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-( 3-Chloro-5-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (48.8 mg, 120.53 μmol, 52.07% yield).

化合物659： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.30(m,1H),1.61(m,1H),1.86(m,1H),2.00(m,4H),2.16(m,1H),2.97(m,1H),3.64(m,1H),5.31(m,1H),5.61(m,2H),7.14(m,2H),7.34(m,1H),7.45(m,1H),7.97(m,1H),10.54(m,1H)。 Compound 659: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.99 (m, 3H), 1.30 (m, 1H), 1.61 (m, 1H), 1.86 (m, 1H), 2.00 (m, 4H), 2.16(m, 1H), 2.97(m, 1H), 3.64(m, 1H), 5.31(m, 1H), 5.61(m, 2H), 7.14(m, 2H), 7.34(m, 1H) ), 7.45(m, 1H), 7.97(m, 1H), 10.54(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值404.2；實測值405.2；Rt=2.525min。LCMS (ESI): [M] + m/z: calculated 404.2; found 405.2; Rt=2.525min.

化合物682： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.30(m,1H),1.60(m,1H),1.88(m,1H),2.00(m,4H),2.17(m,1H),2.98(m,1H),3.73(m,1H),5.31 (m,1H),5.61(m,2H),7.14(m,2H),7.34(m,1H),7.45(d,1H),7.97(m,1H),10.54(m,1H)。 Compound 682: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.99 (m, 3H), 1.30 (m, 1H), 1.60 (m, 1H), 1.88 (m, 1H), 2.00 (m, 4H), 2.17(m, 1H), 2.98(m, 1H), 3.73(m, 1H), 5.31(m, 1H), 5.61(m, 2H), 7.14(m, 2H), 7.34(m, 1H) ), 7.45(d, 1H), 7.97(m, 1H), 10.54(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值404.2；實測值405.2；Rt=2.494min。LCMS (ESI): [M] + m/z: calculated 404.2; found 405.2; Rt=2.494 min.

實例413.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯-4-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物689、化合物703)之合成Example 413. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chloro-4-(trifluoromethyl)phenyl)-5-methylpiperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 689, Compound 703)

Figure 110128222-A0202-12-1746-920
Figure 110128222-A0202-12-1746-920

步驟1：(5-(2-(2-(3-氯-4-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(3-Chloro-4-(trifluoromethyl)phenyl)-5-methylpiperidin-1-yl)-2-oxoacetamido )-3-methylpyridin-2-yl) synthesis of tert-butyl carbamate

向(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基哌啶(0.9g，3.24mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(1.15g，3.89mmol，HCl)及DIPEA(1.05g，8.10mmol，1.41mL)於DMSO(5mL)中之經攪拌之溶液中添加HATU(1.48g，3.89mmol)。將所得反應混合物在20℃下攪拌13h。完成之後，將反應混合物提交至反相HPLC(管柱：SunFire 19*100mm，5mkl；MeOH為溶析液混合物)，以得到呈淡黃色固體之N -[5-[[2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.32g，576.59μmol，17.79%產率)。To ( 2R,5S )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methylpiperidine (0.9 g, 3.24 mmol), 2-[[6-( tertiary butyl Oxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-side oxyacetic acid (1.15 g, 3.89 mmol, HCl) and DIPEA (1.05 g, 8.10 mmol, 1.41 mL) in DMSO To the stirred solution in (5 mL) was added HATU (1.48 g, 3.89 mmol). The resulting reaction mixture was stirred at 20 °C for 13 h. After completion, the reaction mixture was submitted to reverse phase HPLC (column: SunFire 19*100mm, 5mkl; MeOH was the eluent mixture) to give N- [5-[[2-[( 2R, 5S )-2-[3-Chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl tert -butyl -2-pyridyl]carbamate (0.32 g, 576.59 [mu]mol, 17.79% yield).

LCMS(ESI)：[M]+ m/z：計算值554.2；實測值555.2；Rt=1.445min。LCMS (ESI): [M] + m/z: calculated 554.2; found 555.2; Rt=1.445 min.

步驟2：掌性分離Step 2: Palm Separation

將N -[5-[[2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.32g，576.59μmol)提交 至掌性分離(IA-I(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/min)，以得到N -[5-[[2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.12g，216.22μmol，37.50%產率)及N -[5-[[2-[(2S,5R )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.1g，180.18μmol，31.25%產率)。 N- [5-[[2-[( 2R,5S )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.32g, 576.59μmol) was submitted to chiral separation (IA-I (250*20, 5mkm) , hexane-IPA-MeOH, 60-20-20, 12 ml/min) to give N- [5-[[2-[( 2R,5S )-2-[3-chloro-4-(trifluoromethyl) (0.12 g ) , 216.22 μmol, 37.50% yield) and N- [5-[[2-[( 2S,5R )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methyl- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.1 g, 180.18 [mu]mol, 31.25% yield).

E1於分析條件下(管柱：IA，以己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為20.78min且E2之保留時間為15.01min。The retention time of E1 under analytical conditions (column: IA, with hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 20.78 min and that of E2 was 15.01 min.

E1：保留時間：20.78minE1: retention time: 20.78min

LCMS(ESI)：[M]+ m/z：計算值554.2；實測值555.2；Rt=5.656min。LCMS (ESI): [M] + m/z: calculated 554.2; found 555.2; Rt=5.656 min.

E2：保留時間：15.01minE2: retention time: 15.01min

LCMS(ESI)：[M]+ m/z：計算值554.2；實測值555.2；Rt=6.191min。LCMS (ESI): [M] + m/z: calculated 554.2; found 555.2; Rt=6.191 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯-4-(三氟甲基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物703 及化合物689 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chloro-4-(trifluoromethyl)phenyl)-5-methylpiperidine Synthesis of -1-yl)-2-oxyacetamide ( Compound 703 and Compound 689 )

將N -[5-[[2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.11g，198.20μmol)及N -[5-[[2-[(2S,5R )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.1g，180.18μmol)添加到水(0.7mL)及1,4-二噁烷(2mL)之混合物中且將反應混合物在80℃下攪拌16h。冷卻之後，在減壓下濃縮溶液且將殘餘物提交至反相HPLC(管柱：SunFire 19*100mm，5mkl；以水-MeOH為溶析液混合物)，以得到呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.037g，81.34μmol，41.04%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-[3-氯-4-(三氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.04g，87.94μmol，48.80%產率)。 N- [5-[[2-[( 2R,5S )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.11 g, 198.20 μmol) and N- [5-[[2-[( 2S,5R ) -2-[3-Chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl- 3- Butyl 2-pyridyl]carbamate (0.1 g, 180.18 μmol) was added to a mixture of water (0.7 mL) and 1,4-dioxane (2 mL) and the reaction mixture was stirred at 80 °C for 16 h. After cooling, the solution was concentrated under reduced pressure and the residue was submitted to reverse phase HPLC (column: SunFire 19*100mm, 5mkl; water-MeOH as eluent mixture) to give N- (6 as a white solid -Amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[3-chloro-4-(trifluoromethyl)phenyl]-5-methyl-1- Piperidinyl]-2-oxyacetamide (0.037 g, 81.34 μmol, 41.04% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S ,5R )-2-[3-Chloro-4-(trifluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (0.04 g, 87.94 μmol, 48.80% yield).

化合物689： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.31(m,1H),1.61(m,1H),1.88(m,1H),2.00(m,3H),2.14(m,2H),3.01(m,1H),3.65(m,1H),5.59(m,3H),7.45(m,2H),7.61(m,1H),7.85(m,1H),7.97(m,1H),10.53(m,1H)。 Compound 689: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.99 (m, 3H), 1.31 (m, 1H), 1.61 (m, 1H), 1.88 (m, 1H), 2.00 (m, 3H), 2.14(m, 2H), 3.01(m, 1H), 3.65(m, 1H), 5.59(m, 3H), 7.45(m, 2H), 7.61(m, 1H), 7.85(m, 1H) ), 7.97 (m, 1H), 10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值454.2；實測值455.2；Rt=2.501min。LCMS (ESI): [M] + m/z: calculated 454.2; found 455.2; Rt=2.501 min.

化合物703： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.31(m,1H),1.62(m,1H),1.87(m,1H),2.00(m,3H),2.13(m,2H),3.00(m,1H),3.75(m,1H),5.58(m,3H),7.45(m,2H),7.61(m,1H),7.85(m,1H),7.97(m,1H),10.53(m,1H)。 Compound 703: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.99 (m, 3H), 1.31 (m, 1H), 1.62 (m, 1H), 1.87 (m, 1H), 2.00 (m, 3H), 2.13(m, 2H), 3.00(m, 1H), 3.75(m, 1H), 5.58(m, 3H), 7.45(m, 2H), 7.61(m, 1H), 7.85(m, 1H) ), 7.97 (m, 1H), 10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值454.2；實測值455.2；Rt=2.481min。LCMS (ESI): [M] + m/z: calculated 454.2; found 455.2; Rt=2.481 min.

實例414. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物806)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物802)之合成Example 414. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(hydroxymethyl)phenyl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide (Compound 806) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- Synthesis of [4-(Hydroxymethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 802)

Figure 110128222-A0202-12-1748-921
Figure 110128222-A0202-12-1748-921

步驟1：N-[5-[[2-[(2R,5S)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P1)及N-[5-[[2-[(2S,5R)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P2)之合成Step 1: N-[5-[[2-[(2R,5S)-2-[4-(hydroxymethyl)phenyl]-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P1) and N-[5-[[2-[(2S,5R)-2-[4-( Hydroxymethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester ( Synthesis of P2)

在輕微加熱下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺 基]-2-側氧基乙酸(287.67mg，974.21μmol)、[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]甲醇(0.2g，974.21μmol)及dipea(377.73mg，2.92mmol，509.07μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(444.51mg，1.17mmol)。反應完成之後，藉由HPLC純化混合物，以得到外消旋產物，使其經歷掌性HPLC，以得到N-[5-[[2-[(2R,5S)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(30mg，62.17μmol，6.38%產率)及N-[5-[[2-[(2S,5R)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(39mg，80.82μmol，8.30%產率)Under gentle heating, 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridinyl]amine [4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]methanol (0.2 g, 974.21 μmol) and dipea (377.73 mg, 2.92 mmol, 509.07 μL) was dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (444.51 mg, 1.17 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC to give the racemic product, which was subjected to chiral HPLC to give N-[5-[[2-[(2R,5S)-2-[4-(hydroxymethyl yl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (30 mg, 62.17 μmol, 6.38% yield) and N-[5-[[2-[(2S,5R)-2-[4-(hydroxymethyl)phenyl]-5-methyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (39 mg, 80.82 μmol, 8.30% yield)

HPLC條件：(32-36% 0.9-6min水-乙腈；流速30ml/min；(裝載泵4ml/min乙腈)；目標質量482；管柱SunFireC18 100x19mm 5um(R))HPLC conditions: (32-36% 0.9-6min water-acetonitrile; flow rate 30ml/min; (loading pump 4ml/min acetonitrile); target mass 482; column SunFireC18 100x19mm 5um(R))

掌性製備型HPLC條件：Chiralcel OJ-H(250*20，5mkm)，流動相：己烷-IPA-MeOH，80-10-10；流速：12ml/min。24℃，波長：205nm，215nm，保留時間(異構物1(SR))=19.9，保留時間(異構物2(RS))=33.28Chiral preparative HPLC conditions: Chiralcel OJ-H (250*20, 5 mkm), mobile phase: hexane-IPA-MeOH, 80-10-10; flow rate: 12 ml/min. 24℃, wavelength: 205nm, 215nm, retention time (isomer 1(SR))=19.9, retention time (isomer 2(RS))=33.28

P1： LCMS(ESI)：[M+H]+ m/z：計算值482.6；實測值483.2；Rt=5.045min。 P1: LCMS (ESI): [M+H] + m/z: calculated 482.6; found 483.2; Rt=5.045min.

RT(己烷-IPA-MeOH，80-10-10，12ml/min)=11.3442min。RT (Hexane-IPA-MeOH, 80-10-10, 12 ml/min) = 11.3442 min.

P2： LCMS(ESI)：[M+H]+ m/z：計算值482.6；實測值483.2；Rt=5.043min。 P2: LCMS (ESI): [M+H] + m/z: calculated 482.6; found 483.2; Rt=5.043 min.

RT(己烷-IPA-MeOH，80-10-10，12ml/min)=19.8252min。RT (hexane-IPA-MeOH, 80-10-10, 12 ml/min) = 19.8252 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物806 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(hydroxymethyl)phenyl]-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 806 )

將N-[5-[[2-[(2R,5S)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(30mg，62.17μmol)溶解於水(1mL)/二噁烷(1mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑且藉由HPLC(5-50% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量382；管柱SunFireC18 100x19mm 5um(R))純 化，產生N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(20mg，52.29μmol，84.12%產率)。N-[5-[[2-[(2R,5S)-2-[4-(Hydroxymethyl)phenyl]-5-methyl-1-piperidinyl]-2-side oxyacetyl tert-butyl]amino]-3-methyl-2-pyridyl]carbamate (30 mg, 62.17 μmol) was dissolved in a mixture of water (1 mL)/dioxane (1 mL) and stirred at reflux overnight. Aliquots showed complete consumption of starting material; solvent was evaporated under reduced pressure and analyzed by HPLC (5-50% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 382 ; String SunFireC18 100x19mm 5um(R)) Pure , resulting in N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(hydroxymethyl)phenyl]-5-methyl- 1-Piperidinyl]-2-oxoacetamide (20 mg, 52.29 μmol, 84.12% yield).

LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.4；Rt=1.541min。LCMS (ESI): [M+H] + m/z: calculated 382.2; found 383.4; Rt=1.541 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物802 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[4-(hydroxymethyl)phenyl]-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 802 )

將N-[5-[[2-[(2S,5R)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(38mg，78.74μmol)溶解於水(1mL)/二噁烷(1mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑且藉由HPLC(5-40% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量382；管柱SunFireC18 100x19mm 5um(R))純化，產生N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(羥基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(10mg，26.15μmol，33.20%產率)。N-[5-[[2-[(2S,5R)-2-[4-(Hydroxymethyl)phenyl]-5-methyl-1-piperidinyl]-2-side oxyacetyl tert-butyl]amino]-3-methyl-2-pyridyl]carbamate (38 mg, 78.74 μmol) was dissolved in a mixture of water (1 mL)/dioxane (1 mL) and stirred at reflux overnight. Aliquots showed complete consumption of starting material; solvent was evaporated under reduced pressure and analyzed by HPLC (5-40% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 382 ; column SunFire C18 100x19mm 5um(R)) purification to yield N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[4-(hydroxymethyl) )phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (10 mg, 26.15 μmol, 33.20% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.98-1.03(m,3H),1.27-1.36(m,1H),1.61-1.69(m,1H),1.80-1.91(m,1H),1.97-2.02(m,3H),2.02-2.14(m,1H),2.16-2.27(m,1H),2.68-3.19(m,1H),3.41-4.05(m,1H),4.42-4.50(m,2H),5.09-5.57(m,2H),5.57-5.65(m,2H),7.21-7.24(m,1H),7.24-7.34(m,3H),7.42-7.54(m,1H),7.88-8.05(m,1H),10.41-10.52(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.98-1.03 (m, 3H), 1.27-1.36 (m, 1H), 1.61-1.69 (m, 1H), 1.80-1.91 (m, 1H) ,1.97-2.02(m,3H),2.02-2.14(m,1H),2.16-2.27(m,1H),2.68-3.19(m,1H),3.41-4.05(m,1H),4.42-4.50( m,2H),5.09-5.57(m,2H),5.57-5.65(m,2H),7.21-7.24(m,1H),7.24-7.34(m,3H),7.42-7.54(m,1H), 7.88-8.05 (m, 1H), 10.41-10.52 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.4；Rt=1.752min。LCMS (ESI): [M+H] + m/z: calculated 382.2; found 383.4; Rt=1.752 min.

實例415.外消旋 -N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物145)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物260)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物290)之合成Example 415. Racemic - N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )-2-(4-tert -butylcyclohexyl )- 5-Methyl-1-piperidinyl]-2-oxoacetamide (Compound 145), N-(6-amino-5-methyl-3-pyridyl)-2-[(2 S ,5 R )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 260) and N-(6-amino) -5-Methyl-3-pyridyl)-2-[(2 R ,5 S )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 290)

Figure 110128222-A0202-12-1751-922
Figure 110128222-A0202-12-1751-922

步驟1：N-[5-[[2-[2-(4-第三丁基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(4-tert-butylcyclohexyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] Synthesis of -3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(621.87mg，2.11mmol)、2-(4-第三丁基 環己基)-5-甲基哌啶(0.5g，2.11mmol)及HATU(880.82mg，2.32mmol)於DMF(1.5mL)中之經攪拌之溶液中添加三乙胺(852.40mg，8.42mmol，1.17mL)。將所得反應混合物在25℃下攪拌4小時。4小時之後，將反應混合物在減壓下濃縮且藉由反相HPLC(溶析液：70-70-100%，0-1-6min，水-甲醇；流速：30mL/min；裝載泵：4mL/min，甲醇；管柱：SunFireC18 100 x19mm，5um)純化所獲得之粗產物，以得到呈白色固體之N -[5-[[2-[2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.25g，485.72μmol，23.06%產率)。To 2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (621.87 mg, 2.11 mmol), 2-(4 - tert-butylcyclohexyl )-5-methylpiperidine (0.5 g, 2.11 mmol) and HATU (880.82 mg, 2.32 mmol) in DMF (1.5 mL) was added triethylamine (852.40 g) to a stirred solution of mg, 8.42 mmol, 1.17 mL). The resulting reaction mixture was stirred at 25°C for 4 hours. After 4 hours, the reaction mixture was concentrated under reduced pressure and analyzed by reverse phase HPLC (eluent: 70-70-100%, 0-1-6 min, water-methanol; flow rate: 30 mL/min; loading pump: 4 mL /min, methanol; column: SunFire C18 100 x 19 mm, 5 um) to purify the crude product obtained to give N- [5-[[2-[2-(4-tert -butylcyclohexyl )- 5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.25 g, 485.72 μmol, 23.06% Yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值514.4；實測值515.4；Rt=4.992min。LCMS (ESI): [M+Boc] + m/z: calculated 514.4; found 515.4; Rt=4.992 min.

步驟2：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-第三丁基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物145 )之合成Step 2: Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(4-tert-butylcyclohexyl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide ( compound 145 )

將N -[5-[[2-[2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯 基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.1g，194.29μmol)於二噁烷中之4.0M HCl(70.84mg，1.94mmol，88.55μL)中之溶液在25℃下攪拌2小時。2小時之後，在減壓下濃縮反應混合物且藉由反相HPLC(溶析液：0-5min，65-85%，水-甲醇(0.1% NH3 )；流速：30mL/min；裝載泵：4mL/min，甲醇(0.1% NH3 )；管柱：YMC-Actus Triart C18 100*20mm，5um)純化粗產物，以獲得呈白色固體之外消旋 -N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物145 ,42mg，101.31μmol，52.14%產率)。 N- [5-[[2-[2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3 - A solution of tert-butyl methyl-2-pyridyl] carbamate (0.1 g, 194.29 μmol) in 4.0 M HCl in dioxane (70.84 mg, 1.94 mmol, 88.55 μL) was stirred at 25 °C for 2 Hour. After 2 hours, the reaction mixture was concentrated under reduced pressure and analyzed by reverse phase HPLC (eluent: 0-5 min, 65-85%, water-methanol (0.1% NH3 ); flow rate: 30 mL/min; loading pump: 4 mL/min, methanol (0.1% NH3 ); column: YMC-Actus Triart C18 100*20mm, 5um) The crude product was purified to obtain rac - N- (6-amino-5- as a white solid Methyl-3-pyridyl)-2-[(2 S ,5 R )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-side oxy Acetamide ( Compound 145 , 42 mg, 101.31 μmol, 52.14% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.82(m,11H),0.94(m,6H),1.28(m,1H),1.62(m,2H),1.76(m,5H),1.85(m,2H),2.03(s,3H),2.84(m,1H),3.45(d,1H),4.04(m,1H),5.60(m,2H),7.47(m,1H),8.08(m,1H),10.26(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.82 (m, 11H), 0.94 (m, 6H), 1.28 (m, 1H), 1.62 (m, 2H), 1.76 (m, 5H) ,1.85(m,2H),2.03(s,3H),2.84(m,1H),3.45(d,1H),4.04(m,1H),5.60(m,2H),7.47(m,1H), 8.08 (m, 1H), 10.26 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值414.4；實測值415.4；Rt=3.779min。LCMS (ESI): [M+H] + m/z: calculated 414.4; found 415.4; Rt=3.779 min.

步驟3：N-[5-[[2-[(2R,5S)-2-(4-第三丁基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2S,5R)-2-(4-第三丁基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 3: N-[5-[[2-[(2R,5S)-2-(4-tert-butylcyclohexyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2S,5R)-2-(4-tert-butyl ring Chiral isolation of tert-butyl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

藉由掌性HPLC(溶析液：己烷-IPA-MeOH，60-20-20；管柱：IC，250*20mm，5um；流速：12mL/min)純化外消旋 -N -[5-[[2-[(2R ,5S )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(90mg，174.86μmol)，以得到呈白色固體之N -[5-[[2-[(2R ,5S )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(34mg，66.06μmol，37.78%產率)及N -[5-[[2-[(2S ,5R )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(26mg，50.52μmol，28.89%產率)。Purification of Racemic - N- [5- [[2-[(2 R ,5 S )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] -3-Methyl-2-pyridyl]carbamic acid tert- butyl ester (90 mg, 174.86 μmol) to give N- [5-[[2-[( 2R ,5S)-2- as a white solid (4- tert-butylcyclohexyl )-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tertiary Butyl ester (34 mg, 66.06 μmol, 37.78% yield) and N- [5-[[2-[( 2S , 5R )-2-(4-tert -butylcyclohexyl )-5-methyl- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (26 mg, 50.52 [mu]mol, 28.89% yield).

N -[5-[[2-[(2R ,5S )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺 基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯： LCMS(ESI)：[M+H]+ m/z：計算值514.4；實測值515.4；Rt=7.292min。掌性HPLC：Rt=7.76min(溶析液：CO2 -MeOH，60-40；管柱：IC；流速：2mL/min)。 N -[5-[[2-[(2 R ,5 S )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-side oxyacetyl [M+H ] + m/z: calcd. 514.4; found 515.4; Rt= 7.292min . Chiral HPLC: Rt=7.76 min (eluent: CO2 -MeOH, 60-40; column: IC; flow rate: 2 mL/min).

N -[5-[[2-[(2R ,5S )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯： LCMS(ESI)：[M+H]+ m/z：計算值514.4；實測值515.2；Rt=7.368min；掌性HPLC：Rt=6.39min(溶析液：CO2 -MeOH，60-40；管柱：IC；流速：2mL/min)。 N -[5-[[2-[(2 R ,5 S )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-side oxyacetyl [M+H] + m/z: calcd. 514.4; found 515.2; Rt= 7.368min ; chiral HPLC: Rt=6.39 min (eluent: CO 2 -MeOH, 60-40; column: IC; flow rate: 2 mL/min).

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(4-第三丁基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物260 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-(4-tert-butylcyclohexyl)-5-methyl-1 Synthesis of -Piperidinyl]-2-oxyacetamide ( Compound 260 )

向N -[5-[[2-[(2S ,5R )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(26mg，50.52μmol)於DCM(3mL)中之經攪拌之溶液中添加於二噁烷中之4.0M HCl(18.42mg，505.15μmol，23.02μL)。將所得反應混合物在25℃下攪拌2小時。2小時之後，在減壓下濃縮反應混合物且藉由反相HPLC(溶析液：0-5min，65-100%，水-甲醇(0.1% NH3 )；流速：30mL/min；裝載泵：4mL/min，甲醇；管柱：YMC-Actus Triart C18 100*20mm，5um)純化粗產物，以獲得呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物260 ,15mg，36.18μmol，71.62%產率)。To N- [5-[[2-[(2 S ,5 R )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (26 mg, 50.52 μmol) in DCM (3 mL) was added to a stirred solution of 4.0 M in dioxane HCl (18.42 mg, 505.15 μmol, 23.02 μL). The resulting reaction mixture was stirred at 25°C for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and analyzed by reverse phase HPLC (eluent: 0-5 min, 65-100%, water-methanol (0.1% NH3 ); flow rate: 30 mL/min; loading pump: 4mL/min, methanol; column: YMC-Actus Triart C18 100*20mm, 5um) The crude product was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2 as a white solid -[( 2S , 5R )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-oxyacetamide ( compound 260 , 15 mg, 36.18 μmol, 71.62% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.65-0.78(m,2H),0.78-0.82(m,9H),0.82-0.91(m,3H),0.91-0.95(m,3H),0.95-1.04(m,1H),1.20-1.30(m,1H),1.52-1.63(m,2H),1.65-1.77(m,4H),1.78-1.97(m,3H),1.98-2.04(m,3H),2.78-3.27(m,1H),3.44-4.09(m,1H),5.53-5.66(m,2H),7.39-7.48(m,1H),7.95-8.02(m,1H),10.21-10.32(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.65-0.78 (m, 2H), 0.78-0.82 (m, 9H), 0.82-0.91 (m, 3H), 0.91-0.95 (m, 3H) ),0.95-1.04(m,1H),1.20-1.30(m,1H),1.52-1.63(m,2H),1.65-1.77(m,4H),1.78-1.97(m,3H),1.98-2.04 (m,3H), 2.78-3.27(m,1H), 3.44-4.09(m,1H), 5.53-5.66(m,2H), 7.39-7.48(m,1H), 7.95-8.02(m,1H) , 10.21-10.32 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值414.4；實測值415.4；Rt=3.275min。LCMS (ESI): [M+H] + m/z: calculated 414.4; found 415.4; Rt=3.275 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(4-第三丁基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物290 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(4-tert-butylcyclohexyl)-5-methyl-1 Synthesis of -Piperidinyl]-2-oxyacetamide ( Compound 290 )

向N -[5-[[2-[(2R ,5S )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(34mg，66.06μmol)於DCM(3mL)中之經攪拌之溶液中添加於二噁烷中之4.0M HCl(24.09mg，660.58μmol，30.11μL)。將所得反應混合物在25℃下攪拌2小時。2小時之後，在減壓下濃縮反應混合物且藉由反相HPLC(溶析液：0-5min，65-100%，水-甲醇(0.1% NH3 )；流速：30mL/min；裝載泵：4mL/min，甲醇；管柱：YMC-Actus Triart C18 100*20mm，5um)純化粗產物，以獲得呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-2-(4-第三丁基 環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物290 ,15mg，36.18μmol，54.77%產率)。To N- [5-[[2-[(2 R ,5 S )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridinyl]carbamic acid tert- butyl ester (34 mg, 66.06 μmol) in DCM (3 mL) was added to a stirred solution of 4.0 M in dioxane HCl (24.09 mg, 660.58 μmol, 30.11 μL). The resulting reaction mixture was stirred at 25°C for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and analyzed by reverse phase HPLC (eluent: 0-5 min, 65-100%, water-methanol (0.1% NH3 ); flow rate: 30 mL/min; loading pump: 4mL/min, methanol; column: YMC-Actus Triart C18 100*20mm, 5um) The crude product was purified to obtain N- (6-amino-5-methyl-3-pyridyl)-2 as a white solid -[( 2R , 5S )-2-(4-tert -butylcyclohexyl )-5-methyl-1-piperidinyl]-2-oxyacetamide ( compound 290 , 15mg, 36.18 μmol, 54.77% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.65-0.78(m,2H),0.78-0.82(m,9H),0.82-0.91(m,3H),0.91-0.95(m,3H),0.95-1.04(m,1H),1.20-1.30(m,1H),1.52-1.63(m,2H),1.65-1.77(m,4H),1.78-1.97(m,3H),1.98-2.04(m,3H),2.78-3.27(m,1H),3.44-4.09(m,1H),5.53-5.66(m,2H),7.39-7.48(m,1H),7.95-8.02(m,1H),10.21-10.32(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.65-0.78 (m, 2H), 0.78-0.82 (m, 9H), 0.82-0.91 (m, 3H), 0.91-0.95 (m, 3H) ),0.95-1.04(m,1H),1.20-1.30(m,1H),1.52-1.63(m,2H),1.65-1.77(m,4H),1.78-1.97(m,3H),1.98-2.04 (m,3H), 2.78-3.27(m,1H), 3.44-4.09(m,1H), 5.53-5.66(m,2H), 7.39-7.48(m,1H), 7.95-8.02(m,1H) , 10.21-10.32 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值414.4；實測值415.4；Rt=3.926min。LCMS (ESI): [M+H] + m/z: calculated 414.4; found 415.4; Rt=3.926 min.

實例416.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯胺(化合物158)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2,5-二甲基-1-哌啶基]-2-側氧基乙醯胺(化合物168) 之合成Example 416. N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R , 5R )-2,5-dimethyl-1-piperidinyl]-2- Pendant oxyacetamide (compound 158) and N- (6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2,5-dimethyl-1-piperidine Synthesis of pyridyl]-2-oxoacetamide (compound 168)

Figure 110128222-A0202-12-1754-923
Figure 110128222-A0202-12-1754-923

步驟1：N-[5-[[2-[(2R,5R)-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2S,5R)-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,5R)-2,5-Dimethyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl 3-butyl-2-pyridyl]carbamate and N-[5-[[2-[(2S,5R)-2,5-dimethyl-1-piperidinyl]-2-oxygen Synthesis of Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向2,5-二甲基哌啶(0.08g，706.71μmol)及2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(208.69mg，706.71μmol)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(228.34mg，1.77mmol，307.74μL)。將所得混合物攪拌5分鐘。5分鐘之後，添加HATU(282.15mg，742.05μmol)於DMF(2mL)中之溶液。將反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液。使所獲得之粗產物經歷HPLC純化(管柱：Waters SunFire C18 19*100mm，5um；溶析液：40-60% CH3 CN)，以得到呈淡黃色固體之N -[5-[[2-[(2R ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(53.9mg，138.04μmol，19.53%產率)及N -[5-[[2-[(2S ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(16.6mg，42.51μmol，6.02%產率)。To 2,5-dimethylpiperidine (0.08 g, 706.71 μmol) and 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2 - To a stirred solution of oxyacetic acid (208.69 mg, 706.71 μmol) in DMF (10 mL) was added DIPEA (228.34 mg, 1.77 mmol, 307.74 μL). The resulting mixture was stirred for 5 minutes. After 5 minutes, a solution of HATU (282.15 mg, 742.05 μmol) in DMF (2 mL) was added. The reaction mixture was stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure. The crude product obtained was subjected to HPLC purification (column: Waters SunFire C18 19*100mm, 5um; eluent: 40-60% CH3CN ) to give N- [5-[[2 as a pale yellow solid -[(2 R ,5 R )-2,5-dimethyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid Tertiary butyl ester (53.9 mg, 138.04 μmol, 19.53% yield) and N- [5-[[2-[( 2S , 5R )-2,5-dimethyl-1-piperidinyl]- 2-Pendant oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (16.6 mg, 42.51 [mu]mol, 6.02% yield).

N -[5-[[2-[(2R ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯： LCMS(ESI)：[M+Boc]+ m/z：計算值390.3；實測值391.2；Rt=3.340min。 N -[5-[[2-[(2 R ,5 R )-2,5-dimethyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl 3-butyl -2-pyridyl]carbamate: LCMS (ESI): [M+Boc] + m/z: calcd. 390.3; found 391.2; Rt=3.340 min.

N -[5-[[2-[(2S ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯： LCMS(ESI)：[M+Boc]+ m/z：計算值390.3；實測值391.2；Rt=3.389min。 N -[5-[[2-[(2 S ,5 R )-2,5-dimethyl-1-piperidinyl]-2-oxyacetoxy]amino]-3-methyl 3-butyl -2-pyridyl]carbamate: LCMS (ESI): [M+Boc] + m/z: calcd. 390.3; found 391.2; Rt=3.389 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-2,5-二甲基-1-哌啶基]-2-側氧基乙醯胺(化合物158 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-2,5-dimethyl-1-piperidinyl]-2-oxygen Synthesis of Ethylacetamide ( Compound 158 )

將N -[5-[[2-[(2R ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(53.9mg，138.04μmol)溶解於水(5mL)及二噁烷 (5mL)中。將反應混合物在100℃下攪拌17小時。完成之後，在減壓下濃縮所得懸浮液。使所獲得之粗產物經歷HPLC純化，以得到呈淡黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯胺(化合物158 ，18.5mg，63.71μmol，46.16%產率)。 N- [5-[[2-[(2 R ,5 R )-2,5-dimethyl-1-piperidinyl]-2-oxoacetyl]amino]-3-methyl tert-butyl-2-pyridyl]carbamate (53.9 mg, 138.04 μmol) was dissolved in water (5 mL) and dioxane (5 mL). The reaction mixture was stirred at 100°C for 17 hours. After completion, the resulting suspension was concentrated under reduced pressure. The crude product obtained was subjected to HPLC purification to give N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R , 5R )-2,5 as a pale yellow solid -Dimethyl-1-piperidinyl]-2-oxoacetamide ( Compound 158 , 18.5 mg, 63.71 μmol, 46.16% yield).

1H NMR(CDCl3 ,400MHz)：δ(ppm)1.01(m,3H),1.23(m,4H),1.35(m,2H),1.95(m,4H),2.14(s,3H),3.35(m,1H),4.81(m,3H),7.73(m,1H),8.05(m,1H),9.01(m,1H)。1H NMR (CDCl 3 , 400MHz): δ(ppm) 1.01(m, 3H), 1.23(m, 4H), 1.35(m, 2H), 1.95(m, 4H), 2.14(s, 3H), 3.35( m, 1H), 4.81 (m, 3H), 7.73 (m, 1H), 8.05 (m, 1H), 9.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值290.2；實測值291.4；Rt=2.008min。LCMS (ESI): [M+H] + m/z: calculated 290.2; found 291.4; Rt=2.008 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2,5-二甲基-1-哌啶基]-2-側氧基乙醯胺(化合物168 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2,5-dimethyl-1-piperidinyl]-2-oxygen Synthesis of Ethylacetamide ( Compound 168 )

將N -[5-[[2-[(2S ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(16mg，40.98μmol)溶解於水(5mL)及二噁烷(2mL)中。將反應混合物在100℃下攪拌17小時。完成之後，在減壓下濃縮所得懸浮液。使所獲得之粗產物經歷HPLC純化(溶析液：2-10min，50-70%水-CH3 CN(以甲酸為添加劑)；裝載泵：4mL/min，CH3 CN；管柱：Sunfire C18 100 x 20mm，5um)且冷凍乾燥，以得到呈淡黃色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2,5-二甲基-1-哌啶基]-2-側氧基乙醯胺(化合物168 ，3.5mg，12.05μmol，29.42%產率)。 N- [5-[[2-[(2 S ,5 R )-2,5-dimethyl-1-piperidinyl]-2-oxyacetoxy]amino]-3-methyl tert -butyl -2-pyridyl]carbamate (16 mg, 40.98 [mu]mol) was dissolved in water (5 mL) and dioxane (2 mL). The reaction mixture was stirred at 100°C for 17 hours. After completion, the resulting suspension was concentrated under reduced pressure. The crude product obtained was subjected to HPLC purification (eluent: 2-10 min, 50-70% water- CH3CN (with formic acid as additive); loading pump: 4 mL/min, CH3CN ; column: Sunfire C18 100 x 20mm, 5um) and freeze-dried to give N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S , 5R )-2,5 as a pale yellow solid -Dimethyl-1-piperidinyl]-2-oxoacetamide ( compound 168 , 3.5 mg, 12.05 μmol, 29.42% yield).

LCMS(ESI)：[M+H]+ m/z：計算值290.2；實測值291.2；Rt=2.240min。LCMS (ESI): [M+H] + m/z: calculated 290.2; found 291.2; Rt=2.240 min.

實例417.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物380)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,4S )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物399)之合成Example 417. N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 4R )-4-cyano-2-phenyl-1-piperidinyl]- 2-Pendant oxyacetamide (compound 380) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R , 4S )-4-cyano-2- Synthesis of phenyl-1-piperidinyl]-2-oxoacetamide (compound 399)

Figure 110128222-A0202-12-1757-924
Figure 110128222-A0202-12-1757-924

步驟1：N-[5-[[2-[(2S,4R)-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2R,4S)-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2S,4R)-4-cyano-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3 -Methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2R,4S)-4-cyano-2-phenyl-1-piperidinyl]-2 -Synthesis of tert-butyl oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate

向2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)及(2R ,4S )-2-苯基哌啶-4-甲腈(226.27mg，1.02mmol，鹽酸鹽)於DMF(10mL)中之經攪拌之溶液中添加DIPEA(525.22mg，4.06mmol，707.84μL)。將所得反應混合物攪拌5分鐘。5分鐘之後，添加HATU(424.92mg，1.12mmol)。然後將所得反應混合物在室溫下攪拌隔夜。完成之後，在減壓下濃縮所得懸浮液且藉由反相HPLC純化粗產物，以得到呈淡黃色固體之外消旋 -N -[5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.11g，237.31μmol，23.36%產率)。使所獲得之純產物經歷掌性HPLC純化(管柱：IB(250 x 20，5um)；溶析液：己烷-MeOH-IPA，70-15-15：流速：12mL/min)，以得到呈淡黃色固體之N -[5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(36.1mg)及N -[5-[[2-[(2R ,4S )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(36.8mg)。To 2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (0.3 g, 1.02 mmol) and ( 2R , To a stirred solution of 4S )-2-phenylpiperidine-4-carbonitrile (226.27 mg, 1.02 mmol, hydrochloride) in DMF (10 mL) was added DIPEA (525.22 mg, 4.06 mmol, 707.84 μL) . The resulting reaction mixture was stirred for 5 minutes. After 5 minutes, HATU (424.92 mg, 1.12 mmol) was added. The resulting reaction mixture was then stirred at room temperature overnight. After completion, the resulting suspension was concentrated under reduced pressure and the crude product was purified by reverse phase HPLC to give rac - N- [5-[[2-[( 2S , 4R )- as a pale yellow solid 4-Cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.11 g, 237.31 μmol, 23.36% yield). The pure product obtained was subjected to chiral HPLC purification (column: IB (250 x 20, 5um); eluent: hexane-MeOH-IPA, 70-15-15: flow rate: 12 mL/min) to obtain N- [5-[[2-[( 2S , 4R )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amine as pale yellow solid tert -butyl]-3-methyl-2-pyridyl]carbamate (36.1 mg) and N- [5-[[2-[( 2R , 4S )-4-cyano-2-benzene tert -butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate (36.8 mg).

N -[5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯： LCMS(ESI)：[M+Boc]+ m/z：計算值463.2：實測值464.4；Rt=3.389min。 N -[5-[[2-[(2 S ,4 R )-4-cyano-2-phenyl-1-piperidinyl]-2-oxoacetyl]amino]-3- 3 -butyl methyl-2-pyridyl]carbamate: LCMS (ESI): [M+Boc] + m/z: calculated 463.2: found 464.4; Rt=3.389 min.

掌性HPLC：Rt=36.62min(管柱：IB；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=36.62 min (column: IB; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

N -[5-[[2-[(2R ,4S )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯： LCMS(ESI)：[M+Boc]+ m/z：計算值463.2；實測值464.4；Rt=3.390min。 N -[5-[[2-[(2 R ,4 S )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3- 3 -butyl methyl-2-pyridyl]carbamate: LCMS (ESI): [M+Boc] + m/z: calcd. 463.2; found 464.4; Rt=3.390 min.

掌性HPLC：Rt=23.36min(管柱：IB；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=23.36 min (column: IB; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S)-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物399 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,4S)-4-cyano-2-phenyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 399 )

將N -[5-[[2-[(2R ,4S )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(36.8mg，79.39μmol)溶解於二噁烷(2mL)及水(5mL)中。將所得反應混合物在100℃下攪拌15小時。完成之後，在減壓下濃縮所得懸浮液。藉由HPLC純化所獲得之粗產物，以得到呈白色固體之純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,4S )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物399 ，16.9mg，46.50μmol，58.58%產率)。 N- [5-[[2-[(2 R ,4 S )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3 -Methyl-2-pyridyl]carbamic acid tert- butyl ester (36.8 mg, 79.39 [mu]mol) was dissolved in dioxane (2 mL) and water (5 mL). The resulting reaction mixture was stirred at 100°C for 15 hours. After completion, the resulting suspension was concentrated under reduced pressure. The crude product obtained was purified by HPLC to give pure N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R , 4S )-4- as a white solid Cyano-2-phenyl-1-piperidinyl]-2-oxoacetamide ( Compound 399 , 16.9 mg, 46.50 μmol, 58.58% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.82-1.87(m,1H),1.93-1.97(m,1H),1.97-2.04(m,3H),2.16-2.23(m,1H),2.60-3.06(m,1H),3.18-3.24(m,1H),3.36-3.47(m,1H),3.79-4.50(m,1H),5.29-5.53(m,1H),5.54-5.69(m,2H),7.21-7.28(m,1H),7.30-7.36(m,4H),7.36-7.54(m,1H),7.84-8.11(m,1H),10.34-10.62(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.82-1.87 (m, 1H), 1.93-1.97 (m, 1H), 1.97-2.04 (m, 3H), 2.16-2.23 (m, 1H) ), 2.60-3.06(m, 1H), 3.18-3.24(m, 1H), 3.36-3.47(m, 1H), 3.79-4.50(m, 1H), 5.29-5.53(m, 1H), 5.54-5.69 (m,2H),7.21-7.28(m,1H),7.30-7.36(m,4H),7.36-7.54(m,1H),7.84-8.11(m,1H),10.34-10.62(m,1H) .

LCMS(ESI)：[M+H]+ m/z：計算值363.2；實測值364.2；Rt=2.235min。LCMS (ESI): [M+H] + m/z: calculated 363.2; found 364.2; Rt=2.235 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R)-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物380 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,4R)-4-cyano-2-phenyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 380 )

將N -[5-[[2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺 基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(36.1mg，77.88μmol)溶解於水(5mL)及二噁烷(2mL)中。然後將反應混合物在100℃下攪拌15小時。完成之後，在減壓下濃縮所得懸浮液。藉由HPLC純化所獲得之粗產物，以得到呈白色固體之純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,4R )-4-氰基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物380 ，18.8mg，51.73μmol，66.42%產率)。 N- [5-[[2-[(2 S ,4 R )-4-cyano-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3 -Methyl-2-pyridyl]carbamic acid tert- butyl ester (36.1 mg, 77.88 [mu]mol) was dissolved in water (5 mL) and dioxane (2 mL). The reaction mixture was then stirred at 100°C for 15 hours. After completion, the resulting suspension was concentrated under reduced pressure. The obtained crude product was purified by HPLC to give pure N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S , 4R )-4- as a white solid Cyano-2-phenyl-1-piperidinyl]-2-oxoacetamide ( Compound 380 , 18.8 mg, 51.73 μmol, 66.42% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.82-1.87(m,1H),1.95-2.03(m,4H),2.15-2.25(m,1H),2.64-3.05(m,1H),3.18-3.24(m,1H),3.35-3.45(m,1H),3.81-4.44(m,1H),5.31-5.54(m,1H),5.55-5.67(m,2H),7.18-7.27(m,1H),7.31-7.53(m,5H),7.83-8.10(m,1H),10.32-10.63(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.82-1.87 (m, 1H), 1.95-2.03 (m, 4H), 2.15-2.25 (m, 1H), 2.64-3.05 (m, 1H) ), 3.18-3.24(m, 1H), 3.35-3.45(m, 1H), 3.81-4.44(m, 1H), 5.31-5.54(m, 1H), 5.55-5.67(m, 2H), 7.18-7.27 (m, 1H), 7.31-7.53 (m, 5H), 7.83-8.10 (m, 1H), 10.32-10.63 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值363.2；實測值364.2；Rt=2.262min。LCMS (ESI): [M+H] + m/z: calculated 363.2; found 364.2; Rt=2.262 min.

實例418. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物566)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物567)、N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[(1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物568)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物559)之合成Example 418. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl yl-1-piperidinyl]-2-oxoacetamide (compound 566), N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)- 2-[(1R,3S)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 567), N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2R,5S)-2-[(1R,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side Oxyacetamide (Compound 568) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[(1S,3S)-3-hydroxyl Synthesis of cyclohexyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 559)

Figure 110128222-A0202-12-1760-925
Figure 110128222-A0202-12-1760-925

步驟1：N-[5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯、N-[5-[[2-[(2R,5S)-2-[(1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯、N-[5-[[2-[(2S,5R)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2R,5S)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester, N-[5-[[2-[(2R,5S)-2-[(1R,3R )-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester , N-[5-[[2-[(2S,5R)-2-[(1R,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2R,5S)-2-[(1S,3R)- Synthesis of 3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

將3-(5-甲基-2-哌啶基)環己醇(550mg，2.79mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(823.09mg，2.79mmol)及三乙胺(2.82g，27.87mmol，3.89mL)於DMF(20mL)中之混合物在25℃下攪拌0.25h，然後在0.5h內小批量添加HATU(1.06g，2.79mmol)。將反應混合物在25℃ 下攪拌2h，然後在真空中濃縮至5ml且提交至反相HPLC(管柱：SunFireC18 100x19mm 5um，流動相：50-50-80% 0-1-6min水-甲醇，流速：30ml/min)，得到呈無色膠狀物之產物之兩種級分：259mg(第1級分)及337mg(第2級分)。然後將HPLC之後之第1級分(259mg)提交至製備型掌性HPLC(管柱：IC-II(250*20，5mkm)，流動相：己烷-IPA-MeOH,70-15-15，流速：12ml/min)，以得到呈無色膠狀物之N-[5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(89mg，187.53μmol，6.73%產率)(R.T.=30.039min)及N-[5-[[2-[(2R,5S)-2-[(1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(70mg，147.50μmol，5.29%產率)(R.T.=34.388min)，其含有痕量溶劑。將HPLC之後之第2級分(337mg)提交至製備型掌性HPLC(管柱：IC-II(250* 20，5mkm)，流動相：己烷-IPA-MeOH,70-15-15，流速：12ml/min)，以得到呈無色膠狀物之N-[5-[[2-[(2S,5R)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(119mg，250.74μmol，9.00%產率)(R.T.=38.496min)及N-[5-[[2-[(2R,5S)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(83mg，174.89μmol，6.27%產率)(R.T.=47.540min)，其含有痕量溶劑。所有產物均直接用於後續步驟中。3-(5-Methyl-2-piperidinyl)cyclohexanol (550 mg, 2.79 mmol), 2-[[6-(3-butoxycarbonylamino)-5-methyl-3-pyridine A mixture of [methyl]amino]-2-pendoxoacetic acid (823.09 mg, 2.79 mmol) and triethylamine (2.82 g, 27.87 mmol, 3.89 mL) in DMF (20 mL) was stirred at 25 °C for 0.25 h, then HATU (1.06 g, 2.79 mmol) was added in small batches over 0.5 h. The reaction mixture was stirred at 25°C for 2h, then concentrated in vacuo to 5ml and submitted to reverse phase HPLC (column: SunFire C18 100x19mm 5um, mobile phase: 50-50-80% 0-1-6min water-methanol, flow rate : 30 ml/min) to give two fractions of the product as a colorless gum: 259 mg (fraction 1) and 337 mg (fraction 2). Fraction 1 after HPLC (259 mg) was then submitted to preparative chiral HPLC (column: IC-II (250*20, 5 mkm), mobile phase: Hexane-IPA-MeOH, 70-15-15, Flow rate: 12ml/min) to obtain N-[5-[[2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl as a colorless gum tert-butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate (89 mg, 187.53 μmol, 6.73% yield) ( RT=30.039min) and N-[5-[[2-[(2R,5S)-2-[(1R,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (70 mg, 147.50 μmol, 5.29% yield) (RT=34.388 min) with traces amount of solvent. Fraction 2 (337 mg) after HPLC was submitted to preparative chiral HPLC (column: IC-II (250 * 20, 5 mkm), mobile phase: Hexane-IPA-MeOH, 70-15-15, flow rate : 12ml/min) to obtain N-[5-[[2-[(2S,5R)-2-[(1R,3S)-3-hydroxycyclohexyl]-5-methyl as a colorless gum -1-Piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (119 mg, 250.74 μmol, 9.00% yield) (RT =38.496min) and N-[5-[[2-[(2R,5S)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (83 mg, 174.89 μmol, 6.27% yield) (RT=47.540 min) containing traces solvent. All products were used directly in subsequent steps.

第1級分： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=15.559min。 Fraction 1: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 15.559 min.

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.2；Rt=4.558min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.2; Rt=4.558 min.

第2級分： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=17.928min。 Fraction 2: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 17.928 min.

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.2；Rt=4.558min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.2; Rt=4.558 min.

第3級分： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=20.008min。 Fraction 3: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 20.008 min.

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.2；Rt=4.896min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.2; Rt=4.896 min.

第4級分： RT(IC，己烷-IPA-MeOH，50-25-25，0.6mL/min)=23.341min。 Fraction 4: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 23.341 min.

LCMS(ESI)：[M+H]+ m/z：計算值474.2；實測值475.2；Rt=4.894min。LCMS (ESI): [M+H] + m/z: calculated 474.2; found 475.2; Rt=4.894 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物559 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 559 )

將N-[5-[[2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(89mg，187.53μmol)溶解於1,4-二噁烷(2mL)及水(2.5mL)之混合物中。將所得溶液在95℃下攪拌12h，然後冷卻且提交至反相HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um，流動相：30-45% 1-6min水-甲醇(NH3 0.1%)，流速：30ml/min)，以得到呈白色固體之化合物559 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[(1S,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(51.7mg，138.06μmol，73.62%產率)。N-[5-[[2-[(2S,5R)-2-[(1S,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (89 mg, 187.53 μmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (2.5 mL) middle. The resulting solution was stirred at 95°C for 12h, then cooled and submitted to reverse phase HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um, mobile phase: 30-45% 1-6 min water-methanol (NH 3 0.1%), flow rate: 30 ml/min) to obtain compound 559 as a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- [(1S,3S)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (51.7 mg, 138.06 μmol, 73.62% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.57-0.67(m,1H),0.73-0.89(m,1H),0.91-0.95(m,3H),0.95-1.05(m,1H),1.11-1.19(m,1H),1.21-1.30(m,1H),1.42-1.51(m,1H),1.52-1.62(m,2H),1.62-1.68(m,1H),1.74-1.96(m,6H),1.99-2.05(m,3H),2.78-3.24(m,1H),3.37-3.52(m,1H),3.93-4.14(m,1H),4.44-4.55(m,1H),5.54-5.62(m,2H),7.39-7.47(m,1H),7.94-8.03(m,1H),10.23-10.32(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.57-0.67(m,1H), 0.73-0.89(m,1H), 0.91-0.95(m,3H), 0.95-1.05(m,1H), 1.11- 1.19(m,1H),1.21-1.30(m,1H),1.42-1.51(m,1H),1.52-1.62(m,2H),1.62-1.68(m,1H),1.74-1.96(m,6H) ),1.99-2.05(m,3H),2.78-3.24(m,1H),3.37-3.52(m,1H),3.93-4.14(m,1H),4.44-4.55(m,1H),5.54-5.62 (m, 2H), 7.39-7.47 (m, 1H), 7.94-8.03 (m, 1H), 10.23-10.32 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值374.2；實測值375.2；Rt=1.588min。LCMS (ESI): [M+H] + m/z: calculated 374.2; found 375.2; Rt=1.588 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[(1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物568 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[(1R,3R)-3-hydroxycyclohexyl]-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 568 )

將N-[5-[[2-[(2R,5S)-2-[(1R,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(70mg，147.50μmol)溶解於1,4-二噁烷(2mL)及水(2.5mL)之混合物中。將所得溶液在95℃下攪拌12h，然後冷卻且提交至反相HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um，流動相：35-60% 1-6min水-甲醇(NH3 0.1%)，流速：30ml/min)，以得到呈白色固體之化合物568 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[(1R,3R)-3-羥基環己 基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(33mg，88.12μmol，59.75%產率)。N-[5-[[2-[(2R,5S)-2-[(1R,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (70 mg, 147.50 μmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (2.5 mL) middle. The resulting solution was stirred at 95°C for 12h, then cooled and submitted to reverse phase HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um, mobile phase: 35-60% 1-6 min water-methanol (NH 3 0.1%), flow rate: 30 ml/min) to give compound 568 as a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2- [(1R,3R)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (33 mg, 88.12 μmol, 59.75% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.54-0.78(m,2H),0.89-0.94(m,3H),0.95-1.04(m,1H),1.11-1.20(m,1H),1.21-1.30(m,1H),1.39-1.51(m,1H),1.51-1.63(m,2H),1.63-1.70(m,1H),1.71-1.99(m,6H),1.99-2.05(m,3H),2.78-3.25(m,1H),3.37-3.51(m,1H),3.94-4.14(m,1H),4.45-4.56(m,1H),5.55-5.61(m,2H),7.40-7.49(m,1H),7.97(s,1H),10.17-10.35(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ 0.54-0.78 (m, 2H), 0.89-0.94 (m, 3H), 0.95-1.04 (m, 1H), 1.11-1.20 (m, 1H), 1.21- 1.30(m,1H),1.39-1.51(m,1H),1.51-1.63(m,2H),1.63-1.70(m,1H),1.71-1.99(m,6H),1.99-2.05(m,3H ), 2.78-3.25(m, 1H), 3.37-3.51(m, 1H), 3.94-4.14(m, 1H), 4.45-4.56(m, 1H), 5.55-5.61(m, 2H), 7.40-7.49 (m, 1H), 7.97 (s, 1H), 10.17-10.35 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值374.2；實測值375.2；Rt=1.717min。LCMS (ESI): [M+H] + m/z: calculated 374.2; found 375.2; Rt=1.717 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物567 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[(1R,3S)-3-hydroxycyclohexyl]-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 567 )

將N-[5-[[2-[(2S,5R)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(119mg，250.74μmol)溶解於1,4-二噁烷(2mL)及水(2.5mL)之混合物中。將所得溶液在95℃下攪拌12h，然後冷卻且提交至反相HPLC(管柱：YMC-Actus Triart C18 100* 20mml.D.S-5um，流動相：40-60% 1-6min水-甲醇(NH3 0.1%)，流速：30ml/min)，以得到呈白色固體之化合物567 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[(1R,3S)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(59mg，157.55μmol，62.83%產率)。N-[5-[[2-[(2S,5R)-2-[(1R,3S)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (119 mg, 250.74 μmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (2.5 mL) middle. The resulting solution was stirred at 95°C for 12h, then cooled and submitted to reverse phase HPLC (column: YMC-Actus Triart C18 100 * 20mml. DS-5um, mobile phase: 40-60% 1-6 min water-methanol (NH 3 0.1%), flow rate: 30 ml/min) to give compound 567 as a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- [(1R,3S)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (59 mg, 157.55 μmol, 62.83% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.54-0.78(m,2H),0.87-1.04(m,4H),1.15-1.29(m,2H),1.54-1.62(m,2H),1.62-1.72(m,2H),1.72-1.83(m,3H),1.84-1.98(m,2H),1.99-2.04(m,3H),2.79-3.28(m,1H),3.36-3.57(m,1H),3.92-4.16(m,1H),4.38-4.50(m,1H),5.55-5.63(m,2H),7.38-7.51(m,1H),7.92-8.02(m,1H),10.20-10.38(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.54-0.78 (m, 2H), 0.87-1.04 (m, 4H), 1.15-1.29 (m, 2H), 1.54-1.62 (m, 2H), 1.62- 1.72(m, 2H), 1.72-1.83(m, 3H), 1.84-1.98(m, 2H), 1.99-2.04(m, 3H), 2.79-3.28(m, 1H), 3.36-3.57(m, 1H ),3.92-4.16(m,1H),4.38-4.50(m,1H),5.55-5.63(m,2H),7.38-7.51(m,1H),7.92-8.02(m,1H),10.20-10.38 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值374.2；實測值375.2；Rt=1.929min。LCMS (ESI): [M+H] + m/z: calculated 374.2; found 375.2; Rt=1.929 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物566 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-oxoacetamide ( Compound 566 )

將N-[5-[[2-[(2R,5S)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(83mg，174.89μmol)溶解於1,4-二噁烷(2mL)及水(2.5mL)之混合物中。將所得溶液在95℃下攪拌12h，然後冷卻且提交至反相HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um，流動相：40-60% 1-6min水-甲醇(NH3 0.1%)，流速：30ml/min)，以得到呈白色固體之化合物566 N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[(1S,3R)-3-羥基環己基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(52mg，138.86μmol，79.40%產率)。N-[5-[[2-[(2R,5S)-2-[(1S,3R)-3-hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (83 mg, 174.89 μmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (2.5 mL) middle. The resulting solution was stirred at 95°C for 12h, then cooled and submitted to reverse phase HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um, mobile phase: 40-60% 1-6 min water-methanol (NH 3 0.1%), flow rate: 30 ml/min) to obtain compound 566 as a white solid N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2- [(1S,3R)-3-Hydroxycyclohexyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (52 mg, 138.86 μmol, 79.40% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.52-0.79(m,2H),0.90-0.95(m,3H),0.95-1.03(m,1H),1.14-1.29(m,2H),1.54-1.62(m,2H),1.62-1.71(m,2H),1.71-1.83(m,3H),1.83-1.98(m,2H),1.99-2.05(m,3H),2.79-3.27(m,1H),3.36-3.57(m,1H),3.94-4.14(m,1H),4.39-4.49(m,1H),5.54-5.62(m,2H),7.42-7.50(m,1H),7.96-8.02(m,1H),10.16-10.36(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.52-0.79(m, 2H), 0.90-0.95(m, 3H), 0.95-1.03(m, 1H), 1.14-1.29(m, 2H), 1.54- 1.62(m,2H),1.62-1.71(m,2H),1.71-1.83(m,3H),1.83-1.98(m,2H),1.99-2.05(m,3H),2.79-3.27(m,1H ),3.36-3.57(m,1H),3.94-4.14(m,1H),4.39-4.49(m,1H),5.54-5.62(m,2H),7.42-7.50(m,1H),7.96-8.02 (m, 1H), 10.16-10.36 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值374.2；實測值375.2；Rt=1.940min。LCMS (ESI): [M+H] + m/z: calculated 374.2; found 375.2; Rt=1.940 min.

實例419. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物545)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物538)之合成Example 419. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(2-methoxy-4-pyridyl)-5-methyl -1-Piperidinyl]-2-oxyacetamide (Compound 545) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2 Synthesis of -(2-Methoxy-4-pyridyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 538)

Figure 110128222-A0202-12-1765-926
Figure 110128222-A0202-12-1765-926

步驟1：N-[5-[[2-[2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(2-Methoxy-4-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of tert-butyl]-3-methyl-2-pyridyl]carbamate

將DIPEA(525.22mg，4.06mmol，707.84μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.4g，1.35mmol)及2-甲氧基-4-(5-甲基-2-哌啶基)吡啶(279.43mg，1.35mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU溶液(566.56mg，1.49mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到N-[5-[[2-[2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.34g，703.12μmol，51.91%產率)。DIPEA (525.22 mg, 4.06 mmol, 707.84 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (0.4 g, 1.35 mmol) and 2-methoxy-4-(5-methyl-2-piperidinyl)pyridine (279.43 mg, 1.35 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then HATU solution (566.56 mg, 1.49 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to obtain N-[5-[[2-[2-(2-methoxy-4-pyridinyl)-5-methyl-1-piperidinyl]-2-side Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.34 g, 703.12 μmol, 51.91% yield).

LCMS(ESI)：[M+H]+ m/z：計算值483.3；實測值484.4；Rt=3.696min。LCMS (ESI): [M+H] + m/z: calculated 483.3; found 484.4; Rt=3.696 min.

步驟2：N-[5-[[2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P1)及N-[5-[[2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P2)之合成Step 2: N-[5-[[2-[(2S,5R)-2-(2-methoxy-4-pyridyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P1) and N-[5-[[2-[(2R,5S)-2-(2- Methoxy-4-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl Synthesis of Esters (P2)

使用(IC(100*20，5mkm)Chiralpak管柱，以IPA-MeOH，50-50為流動相，流速10mL/min)對N-[5-[[2-[2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(330.0mg，682.44μmol)進行掌性分離，得到P1 N-[5-[[2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(79.26mg，24.02%產率)及P2 N-[5-[[2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(119.89mg，36.33%產率)。Use (IC (100*20, 5mkm) Chiralpak column, with IPA-MeOH, 50-50 as mobile phase, flow rate 10mL/min) to N-[5-[[2-[2-(2-methoxyl -4-Pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (330.0 mg, 682.44 μmol) for chiral separation to give P1 N-[5-[[2-[(2S,5R)-2-(2-methoxy-4-pyridyl)-5-methyl-1- Piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (79.26 mg, 24.02% yield) and P2 N-[5- [[2-[(2R,5S)-2-(2-Methoxy-4-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] - 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (119.89 mg, 36.33% yield).

P1： LCMS(ESI)：[M+H]+ m/z：計算值483.6；實測值484.6；Rt=5.139min。 P1: LCMS (ESI): [M+H] + m/z: calculated 483.6; found 484.6; Rt=5.139 min.

RT(IC，IPA-MeOH，50-50，0.6mL/min)=56.1162min。RT (IC, IPA-MeOH, 50-50, 0.6 mL/min) = 56.1162 min.

P2： LCMS(ESI)：[M+H]+ m/z：計算值483.6；實測值484.6；Rt=5.140min。 P2: LCMS (ESI): [M+H] + m/z: calculated 483.6; found 484.6; Rt=5.140 min.

RT(IC，IPA-MeOH，50-50，0.6mL/min)=14.6942min。RT (IC, IPA-MeOH, 50-50, 0.6 mL/min) = 14.6942 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物545 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(2-methoxy-4-pyridyl)-5-methyl Synthesis of -1-piperidinyl]-2-oxoacetamide ( Compound 545 )

將N-[5-[[2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(119.89mg，247.93μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(67.7mg，176.56μmol，71.21%產率)。N-[5-[[2-[(2R,5S)-2-(2-methoxy-4-pyridyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (119.89 mg, 247.93 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(2-methoxy-4 -Pyridinyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (67.7 mg, 176.56 μmol, 71.21% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.89-1.05(m,3H),1.25-1.36(m,1H),1.44-1.65(m,1H),1.79-1.91(m,1H),1.97-2.02(m,3H),2.10-2.20(m,1H),2.49-2.49(m,1H),2.68-3.23(m,1H),3.40-4.06(m,4H),5.06-5.51(m,1H),5.54-5.70(m,2H),6.63-6.76(m,1H),6.88-6.99(m,1H),7.39-7.53(m,1H),7.92-8.04(m,1H),8.11-8.21(m,1H),10.44-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.89-1.05(m,3H), 1.25-1.36(m,1H), 1.44-1.65(m,1H), 1.79-1.91(m,1H), 1.97- 2.02(m, 3H), 2.10-2.20(m, 1H), 2.49-2.49(m, 1H), 2.68-3.23(m, 1H), 3.40-4.06(m, 4H), 5.06-5.51(m, 1H) ),5.54-5.70(m,2H),6.63-6.76(m,1H),6.88-6.99(m,1H),7.39-7.53(m,1H),7.92-8.04(m,1H),8.11-8.21 (m, 1H), 10.44-10.61 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.2；Rt=1.929min。LCMS (ESI): [M+H] + m/z: calculated 383.2; found 384.2; Rt=1.929 min.

步驟4： N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物538 )之合成 Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(2-methoxy-4-pyridyl)-5-methyl Synthesis of -1-piperidinyl]-2-oxoacetamide ( Compound 538 )

將N-[5-[[2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(79.26mg，163.91μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(2-甲氧基-4-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(43.7mg，113.97μmol，69.53%產率)。N-[5-[[2-[(2S,5R)-2-(2-methoxy-4-pyridinyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (79.26 mg, 163.91 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(2-methoxy-4 -Pyridinyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (43.7 mg, 113.97 μmol, 69.53% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.88-1.03(m,3H),1.25-1.38(m,1H),1.49-1.62(m,1H),1.78-1.91(m,1H),1.91-2.13(m,4H),2.13-2.22(m,1H),2.67-3.23(m,1H),3.40-4.10(m,4H),5.02-5.52(m,1H),5.54-5.73(m,2H),6.63-6.74(m,1H),6.86-6.97(m,1H),7.39-7.51(m,1H),7.93-8.04(m,1H),8.09-8.20(m,1H),10.46-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.88-1.03(m,3H), 1.25-1.38(m,1H), 1.49-1.62(m,1H), 1.78-1.91(m,1H), 1.91- 2.13(m, 4H), 2.13-2.22(m, 1H), 2.67-3.23(m, 1H), 3.40-4.10(m, 4H), 5.02-5.52(m, 1H), 5.54-5.73(m, 2H ),6.63-6.74(m,1H),6.86-6.97(m,1H),7.39-7.51(m,1H),7.93-8.04(m,1H),8.09-8.20(m,1H),10.46-10.57 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.2；Rt=1.933mLCMS(ESI): [M+H] + m/z: Calculated 383.2; Measured 384.2; Rt=1.933m

實例420. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物777)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物786)之合成Example 420. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5- Methyl-1-piperidinyl]-2-oxoacetamide (Compound 777) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R) Synthesis of -4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 786)

Figure 110128222-A0202-12-1768-927
Figure 110128222-A0202-12-1768-927

步驟1：外消旋-(5-(2-((2R,5R)-2-(3,4-二氟苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2R,5R)-2-(3,4-difluorophenyl)-4,4-difluoro-5-methylpiperidin-1-yl )-2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

將(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基哌啶(0.6g，2.62mmol)、TEA(2.65g，26.17mmol，3.65mL)及2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(772.88mg，2.62mmol)溶解於DMF(26mL)中且一次性添加HATU(1.49g，3.93mmol)，將所得混合物在20℃下攪拌3h。將反應混合物倒入到水中且將水相用EA萃取(3次)，然後將經合併之有機相用鹽水洗滌(3次)，經Na2 SO4 乾燥且在真空上濃縮。藉由反相HPLC(45-60% 2-10min；水-乙腈；30ml/min；裝載泵4ml/min乙腈，管柱SunFire 19*100mm)純化粗產物。該反應為成功的。分離呈棕色固體之所要產物(N-[5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.23g，454.08μmol，17.35%產率))。(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methylpiperidine (0.6 g, 2.62 mmol), TEA (2.65 g, 26.17 mmol, 3.65 mL) and 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (772.88 mg, 2.62 mmol) was dissolved in DMF (26 mL) HATU (1.49 g, 3.93 mmol) was added in one portion and the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water and the aqueous phase was extracted with EA (3 times), then the combined organic phases were washed with brine (3 times), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by reverse phase HPLC (45-60% 2-10 min; water-acetonitrile; 30 ml/min; loading pump 4 ml/min acetonitrile, column SunFire 19*100 mm). The reaction was successful. The desired product (N-[5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidine was isolated as a brown solid (0.23 g, 454.08 μmol, 17.35% yield)).

LCMS(ESI)：[M+1]+ m/z：計算值506.2；實測值507.2；Rt=1.471min。LCMS (ESI): [M+1] + m/z: calculated 506.2; found 507.2; Rt=1.471 min.

步驟2：N-[5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性拆分Step 2: N-[5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2S,5S)-4,4-difluoro -2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid 3rd Palmar resolution of butyl ester

使用(管柱：Chiralpak IC-II(250*20，5mkm)；流動相：己烷-IPA-MeOH，60-20-20，流速：12mL/min；管柱溫度：24℃；波長：205nm， 258nm，290nm)，以得到N-[5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.097g，191.50μmol，42.17%產率)(保留時間為11.162min)及N-[5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.089g，175.71μmol，38.70%產率)(保留時間為15.271min)。Use (column: Chiralpak IC-II (250*20, 5mkm); mobile phase: hexane-IPA-MeOH, 60-20-20, flow rate: 12mL/min; column temperature: 24°C; wavelength: 205nm, 258nm, 290nm) to give N-[5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl ]-2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.097g, 191.50μmol, 42.17% yield) (retention time 11.162min) and N-[5-[[2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxygen ethylacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.089 g, 175.71 μmol, 38.70% yield) (retention time 15.271 min).

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物777 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide ( compound 777 )

將N-[5-[[2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.089g，175.71μmol)溶解於二噁烷(3mL)及水(3mL)之混合物中，然後在100℃下攪拌12h。在真空下濃縮反應混合物。N-[5-[[2-[(2S,5S)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxygen tert-butylacetoxy]amino]-3-methyl-2-pyridyl]carbamate (0.089 g, 175.71 μmol) was dissolved in a mixture of dioxane (3 mL) and water (3 mL), then Stir at 100°C for 12h. The reaction mixture was concentrated under vacuum.

藉由HPLC(10-65% 2-10min；水/MeCN+TFA；30ml/min；裝載泵4ml/min MeCN；管柱SunFire 19*100mm)純化粗產物。獲得呈淡黃色固體之所要產物(N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.04g，98.42μmol，56.02%產率))。The crude product was purified by HPLC (10-65% 2-10 min; water/MeCN+TFA; 30 ml/min; loading pump 4 ml/min MeCN; column SunFire 19*100 mm). The desired product (N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-2-(4-fluoro) was obtained as a pale yellow solid Phenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (0.04 g, 98.42 μmol, 56.02% yield)).

1 H NMR(600MHz,DMSO-d 6 )δ 1.07(d,3H),1.96-2.05(m,3H),2.12-2.26(m,1H),2.37-2.46(m,1H),2.80-2.89(m,1H),2.95-3.01(m,0H),3.38-3.48(m,1H),3.73-4.36(m,1H),5.49-5.63(m,1H),5.63-5.86(m,2H),7.13-7.28(m,2H),7.33-7.41(m,2H),7.41-7.55(m,1H),7.91-8.11(m,1H),10.46-10.68(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.07(d,3H), 1.96-2.05(m,3H), 2.12-2.26(m,1H), 2.37-2.46(m,1H), 2.80-2.89( m,1H),2.95-3.01(m,0H),3.38-3.48(m,1H),3.73-4.36(m,1H),5.49-5.63(m,1H),5.63-5.86(m,2H), 7.13-7.28(m, 2H), 7.33-7.41(m, 2H), 7.41-7.55(m, 1H), 7.91-8.11(m, 1H), 10.46-10.68(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值406.2；實測值407.2；Rt=2.740min。LCMS (ESI): [M+1] + m/z: calculated 406.2; found 407.2; Rt=2.740 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物786 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide ( compound 786 )

將N-[5-[[2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.097g，191.50μmol)溶解於 二噁烷(3mL)及水(3mL)之混合物中，然後在100℃下攪拌12h。在真空下濃縮反應混合物。N-[5-[[2-[(2R,5R)-4,4-difluoro-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxygen ethylacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.097 g, 191.50 μmol) was dissolved in A mixture of dioxane (3 mL) and water (3 mL) was then stirred at 100 °C for 12 h. The reaction mixture was concentrated under vacuum.

藉由HPLC(10-65% 2-10min；水/MeCN+TFA；30ml/min；裝載泵4ml/min MeCN；管柱SunFire 19*100mm)純化粗產物。獲得呈淡黃色固體之所要產物(N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.046g，113.19μmol，59.11%產率)。The crude product was purified by HPLC (10-65% 2-10 min; water/MeCN+TFA; 30 ml/min; loading pump 4 ml/min MeCN; column SunFire 19*100 mm). The desired product (N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-4,4-difluoro-2-(4-fluoro) was obtained as a pale yellow solid Phenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (0.046 g, 113.19 μmol, 59.11% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.07(d,3H),1.96-2.05(m,3H),2.12-2.26(m,1H),2.37-2.46(m,1H),2.80-2.89(m,1H),2.95-3.01(m,0H),3.38-3.48(m,1H),3.73-4.36(m,1H),5.49-5.63(m,1H),5.63-5.86(m,2H),7.13-7.28(m,2H),7.33-7.41(m,2H),7.41-7.55(m,1H),7.91-8.11(m,1H),10.46-10.68(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.07(d,3H), 1.96-2.05(m,3H), 2.12-2.26(m,1H), 2.37-2.46(m,1H), 2.80-2.89( m,1H),2.95-3.01(m,0H),3.38-3.48(m,1H),3.73-4.36(m,1H),5.49-5.63(m,1H),5.63-5.86(m,2H), 7.13-7.28(m, 2H), 7.33-7.41(m, 2H), 7.41-7.55(m, 1H), 7.91-8.11(m, 1H), 10.46-10.68(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值406.2；實測值407.2；Rt=2.740min。LCMS (ESI): [M+1] + m/z: calculated 406.2; found 407.2; Rt=2.740 min.

實例421. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物681)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物660)之合成Example 421. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide (Compound 681) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-( Synthesis of 3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 660)

Figure 110128222-A0202-12-1770-928
Figure 110128222-A0202-12-1770-928

步驟1.N-[5-[[2-[2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1. N-[5-[[2-[2-(3,5-Dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]amino] Synthesis of -3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向2-[2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.88g，2.67mmol)於MeOH(10mL)中之溶液中添加羥基鈉(106.59mg，2.67mmol，50.04μL)且將所得混合物攪拌1h。然後，蒸發溶劑且將殘餘物與EtOH一起再蒸發。此後，將固體溶解於DMF中且添加HATU(1.01g，2.67mmol)，隨後添加N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(595.02mg，2.67mmol)且將所得混合物攪拌12h。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(60-85% 2-7min水-乙腈；流速30ml/min(裝載泵4ml/min；乙腈)；管柱SunFireC18 100x19mm 5um(R))。獲得呈灰白色固體之N-[5-[[2-[2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(920mg，1.76mmol，66.20%產率)。To methyl 2-[2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetate (0.88 g, 2.67 mmol) in MeOH (10 mL) To the solution was added sodium hydroxy (106.59 mg, 2.67 mmol, 50.04 μL) and the resulting mixture was stirred for 1 h. Then, the solvent was evaporated and the residue was re-evaporated with EtOH. After this time, the solid was dissolved in DMF and HATU (1.01 g, 2.67 mmol) was added followed by 3-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (595.02 mg, 2.67 mmol) mmol) and the resulting mixture was stirred for 12 h. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (60-85% 2-7 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min; acetonitrile); column SunFire C18 100x19mm 5um(R)). N-[5-[[2-[2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-oxoethanoyl]amine was obtained as an off-white solid tert-butyl]-3-methyl-2-pyridyl]carbamate (920 mg, 1.76 mmol, 66.20% yield).

1 H NMR(500MHz,CDCl3 )δ 1.09(m,3H),1.44(m,1H),1.51(s,9H),1.91-2.18(m,4H),2.34(m,3H),2.97-3.38(m,1H),4.26-4.86(m,1H),5.59-6.42(m,1H),6.91(m,1H),7.16(m,2H),7.26(m,1H),8.08(m,1H),8.39(m,1H),9.47(m,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.09 (m, 3H), 1.44 (m, 1H), 1.51 (s, 9H), 1.91-2.18 (m, 4H), 2.34 (m, 3H), 2.97-3.38 (m,1H),4.26-4.86(m,1H),5.59-6.42(m,1H),6.91(m,1H),7.16(m,2H),7.26(m,1H),8.08(m,1H ), 8.39 (m, 1H), 9.47 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值521.2；實測值522.2；Rt=4.140min。LCMS (ESI): [M+H] + m/z: calculated 521.2; found 522.2; Rt=4.140 min.

步驟2.N-[5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之分離Step 2. N-[5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2R,5S)-2-(3,5-dichlorobenzene Isolation of tert-butyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

掌性拆分第一次：分離P1與順式1雜質及P2(未與順式2雜質分離)(IC-II(250*20，5mkm)，己烷-IPA-MeOH，80-10-10，12ml/min)，第二次：分離P2與順式2雜質(AD-H(250*20，5mkm)，己烷-EtOH，80-20，12ml/min)，P1之RT=31.454min(IC，己烷-IPA-MeOH，80-10-10，0.6ml/min)，P2之RT=44.868min(IC，己烷-IPA-MeOH，80-10-10，0.6ml/min)。The first chiral resolution: separation of P1 and cis-1 impurities and P2 (not separated from cis-2 impurities) (IC-II (250*20, 5mkm), hexane-IPA-MeOH, 80-10-10 , 12ml/min), the second time: separation of P2 and cis-2 impurities (AD-H (250*20, 5mkm), hexane-EtOH, 80-20, 12ml/min), RT of P1=31.454min ( IC, hexane-IPA-MeOH, 80-10-10, 0.6 ml/min), RT for P2 = 44.868 min (IC, hexane-IPA-MeOH, 80-10-10, 0.6 ml/min).

步驟3.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物681 )之合成Step 3. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1 Synthesis of -Piperidinyl]-2-Pendant Oxyacetamide ( Compound 681 )

在21℃下，向N-[5-[[2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(271.36mg，520.41μmol)於二噁烷(3mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(94.87mg，2.60mmol，118.59μL)。使將所得混合物攪拌8h。將所得混合物蒸發至乾且經歷HPLC(50% 0.5-6min水-乙腈+NH3 ；流速30ml/min(裝載泵4ml/min；乙腈)；管柱Tiart 100x19mm 5um(R))。獲得呈灰白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(152.5mg，361.96μmol，69.55%產率)。旋光能力：+136.15°(C=0.2g/100mL；21℃)。RT=36.109min(IC，己烷-IPA-MeOH，80-10-10，0.6ml/min)。To N-[5-[[2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-side at 21 °C Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (271.36 mg, 520.41 μmol) in dioxane (3 mL) was added in dioxane 4.0 M hydrogen chloride solution (94.87 mg, 2.60 mmol, 118.59 μL). The resulting mixture was allowed to stir for 8 h. The resulting mixture was evaporated to dryness and subjected to HPLC (50% 0.5-6 min water-acetonitrile + NH3 ; flow rate 30 ml/min (loading pump 4 ml/min; acetonitrile); column Tiart 100x19 mm 5um (R)). N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3,5-dichlorophenyl)-5-methyl was obtained as an off-white solid -1-Piperidinyl]-2-oxoacetamide (152.5 mg, 361.96 μmol, 69.55% yield). Optical activity: +136.15° (C=0.2g/100mL; 21°C). RT=36.109 min (IC, Hexane-IPA-MeOH, 80-10-10, 0.6 ml/min).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.99(m,3H),1.30(m,1H),1.60(m,1H),1.87(m,1H),2.01(m,4H),2.16(m,1H),2.90(m,1H),3.73(m,1H),5.30(m,1H),5.61(m,2H),7.33(m,2H),7.47(m,2H),7.97(m,1H),10.55(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.99(m, 3H), 1.30(m, 1H), 1.60(m, 1H), 1.87(m, 1H), 2.01(m, 4H), 2.16(m, 1H), 2.90(m, 1H), 3.73(m, 1H), 5.30(m, 1H), 5.61(m, 2H), 7.33(m, 2H), 7.47(m, 2H), 7.97 (m,1H),10.55(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=2.679min。LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=2.679 min.

步驟4.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物660 )之合成Step 4. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1 Synthesis of -Piperidinyl]-2-oxyacetamide ( Compound 660 )

在21℃下，向N-[5-[[2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(297.59mg，570.71μmol)於二噁烷(3mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(104.04mg，2.85mmol，130.05μL)。使將所得混合物攪拌8h。將所得混合物蒸發至乾且經歷HPLC(50% 0.5-6min水-乙腈+NH3 ；流速30ml/min(裝載泵4ml/min；乙腈)；管柱Tiart 100x19mm 5um(R))。獲得呈灰白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(176.9mg， 419.87μmol，73.57%產率)。To N-[5-[[2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl-1-piperidinyl]-2-side at 21 °C Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (297.59 mg, 570.71 μmol) in dioxane (3 mL) was added in dioxane 4.0 M hydrogen chloride solution (104.04 mg, 2.85 mmol, 130.05 μL). The resulting mixture was allowed to stir for 8 h. The resulting mixture was evaporated to dryness and subjected to HPLC (50% 0.5-6 min water-acetonitrile + NH3 ; flow rate 30 ml/min (loading pump 4 ml/min; acetonitrile); column Tiart 100x19 mm 5um (R)). N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methyl was obtained as an off-white solid -1-Piperidinyl]-2-oxyacetamide (176.9 mg, 419.87 μmol, 73.57% yield).

旋光能力：-139.95°(C=0.2g/100mL；21℃)Optical rotation ability: -139.95°(C=0.2g/100mL; 21℃)

RT=30.522min(IC，己烷-IPA-MeOH，80-10-10，0.6ml/min)RT=30.522min (IC, Hexane-IPA-MeOH, 80-10-10, 0.6ml/min)

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.99(m,3H),1.30(m,1H),1.60(m,1H),1.87(m,1H),2.01(m,4H),2.16(m,1H),2.90(m,1H),3.73(m,1H),5.30(m,1H),5.61(m,2H),7.33(m,2H),7.47(m,2H),7.97(m,1H),10.55(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.99(m, 3H), 1.30(m, 1H), 1.60(m, 1H), 1.87(m, 1H), 2.01(m, 4H), 2.16(m, 1H), 2.90(m, 1H), 3.73(m, 1H), 5.30(m, 1H), 5.61(m, 2H), 7.33(m, 2H), 7.47(m, 2H), 7.97 (m,1H),10.55(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=2.679min。LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=2.679 min.

實例422. 外消旋N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物758)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1002)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1000)之合成Example 422. Racemic N-(6-amino-5-methyl-3-pyridyl)-2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl] -2-Oxyacetamide (Compound 758), rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(6-iso Quinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 1002) and rel-N-(6-amino-5-methyl-3-pyridyl) Synthesis of -2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1000)

Figure 110128222-A0202-12-1773-929
Figure 110128222-A0202-12-1773-929

步驟1：(5-(2-(2-(異喹啉-6-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(isoquinolin-6-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridine Synthesis of 3-butyl-2-yl)carbamate

將6-(5-甲基-2-哌啶基)異喹啉(0.32g，1.41mmol)溶解於DMF(5mL)中且添加三乙胺(1.43g，14.14mmol，1.97mL)，隨後添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(417.53mg，1.41mmol)。然後逐滴添加HATU(806.44mg，2.12mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化6-(5-Methyl-2-piperidinyl)isoquinoline (0.32 g, 1.41 mmol) was dissolved in DMF (5 mL) and triethylamine (1.43 g, 14.14 mmol, 1.97 mL) was added followed by 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (417.53 mg, 1.41 mmol). HATU (806.44 mg, 2.12 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC

LCMS(ESI)：[M+H]+ m/z：計算值503.2；實測值504.4；Rt=1.137min。LCMS (ESI): [M+H] + m/z: calculated 503.2; found 504.4; Rt=1.137 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物758 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 758 )

將N-[5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.142g，281.97μmol)溶解於二噁烷(1.5mL)及水(1.5mL)中且在100℃下攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0264g，65.43μmol，23.20%產率)。N-[5-[[2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl 3-butyl-2-pyridyl]carbamate (0.142 g, 281.97 μmol) was dissolved in dioxane (1.5 mL) and water (1.5 mL) and stirred at 100 °C overnight. The next day, it was evaporated in vacuo and purified by HPLC to give N-(6-amino-5-methyl-3-pyridinyl)-2-[2-(6-isoquinolinyl)- 5-Methyl-1-piperidinyl]-2-oxoacetamide (0.0264 g, 65.43 μmol, 23.20% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.04(m,3H),1.31-1.47(m,1H),1.66-1.85(m,2H),1.86-1.97(m,2H),1.98-2.09(m,3H),2.09-2.21(m,1H),2.21-2.34(m,1H),2.77-3.27(m,1H),3.48-4.09(m,2H),5.31-5.75(m,1H),5.84-6.16(m,1H),7.57-7.69(m,1H),7.77-7.85(m,1H),7.87-8.04(m,1H),8.10-8.15(m,1H),8.43-8.53(m,1H),9.24-9.31(m,1H),10.56-10.67(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.04 (m, 3H), 1.31-1.47 (m, 1H), 1.66-1.85 (m, 2H), 1.86-1.97 (m, 2H), 1.98- 2.09(m,3H), 2.09-2.21(m,1H), 2.21-2.34(m,1H), 2.77-3.27(m,1H), 3.48-4.09(m,2H), 5.31-5.75(m,1H) ), 5.84-6.16(m, 1H), 7.57-7.69(m, 1H), 7.77-7.85(m, 1H), 7.87-8.04(m, 1H), 8.10-8.15(m, 1H), 8.43-8.53 (m, 1H), 9.24-9.31 (m, 1H), 10.56-10.67 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值403.2；實測值405.2；Rt=0.834min。LCMS (ESI): [M+2H] + m/z: calculated 403.2; found 405.2; Rt=0.834 min.

步驟3：rel-N-[5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及rel-N-(5-{2-[(2R,5S)-2-(異喹啉-6-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 3: rel-N-[5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and rel-N-(5-{2-[(2R,5S)-2-(isoquinoline-6- Synthesis of tert-butyl)-5-methylpiperidin-1-yl]-2-oxyacetamido}-3-methylpyridin-2-yl)carbamate

對N-[5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺 基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.14g，278.00μmol)進行掌性分離(管柱：Chiralpak IA-II(250*20mm，5mkm)管柱且以己烷-IPA-MeOH，60-20-20為流動相，流速：12mL/min；管柱溫度：24℃；波長：205nm，220mn，258nm)，以獲得異構物B N-[5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(55.74mg，110.69μmol，39.81%產率；保留時間=38.79min)及異構物A rel-N-(5-{2-[(2R,5S)-2-(異喹啉-6-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}-3-甲基吡啶-2-基)胺甲酸第三丁酯(0.06222g，123.55μmol，44.44%產率；保留時間=28.38min)p-N-[5-[[2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine 3-butyl]-3-methyl-2-pyridyl]carbamate (0.14 g, 278.00 μmol) for chiral separation (column: Chiralpak IA-II (250*20 mm, 5 mkm) Alkane-IPA-MeOH, 60-20-20 as mobile phase, flow rate: 12mL/min; column temperature: 24°C; wavelength: 205nm, 220mn, 258nm) to obtain isomer B N-[5-[[ 2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl- 2-Pyridinyl]carbamic acid tert-butyl ester (55.74 mg, 110.69 μmol, 39.81% yield; retention time=38.79 min) and isomer A rel-N-(5-{2-[(2R,5S) -2-(Isoquinolin-6-yl)-5-methylpiperidin-1-yl]-2-oxyacetamido}-3-methylpyridin-2-yl)carbamic acid third Butyl ester (0.06222 g, 123.55 μmol, 44.44% yield; retention time = 28.38 min)

異構物B： RT(IA，己烷-IPA-MeOH，60-20-20，0.6mL/min)=34.111min。 Isomer B: RT (IA, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 34.111 min.

LCMS(ESI)：[M+2H]+ m/z：計算值503.2；實測值505.2；Rt=2.360min。LCMS (ESI): [M+2H] + m/z: calculated 503.2; found 505.2; Rt=2.360 min.

異構物A： RT(IA，己烷-IPA-MeOH，60-20-20，0.6mL/min)=26.066min。 Isomer A: RT (IA, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 26.066 min.

LCMS(ESI)：[M+H]+ m/z：計算值503.2；實測值504.2；Rt=2.358min。LCMS (ESI): [M+H] + m/z: calculated 503.2; found 504.2; Rt=2.358 min.

步驟4：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1000 )之合成Step 4: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1 Synthesis of -Piperidinyl]-2-oxyacetamide ( Compound 1000 )

將N-[5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.06222g，123.55μmol)溶解於二噁烷(1mL)及H2 O(1mL)中且在100℃下攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0108g，26.77μmol，21.66%產率)。N-[5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine tert-butyl]-3-methyl-2-pyridyl]carbamate (0.06222 g, 123.55 μmol) was dissolved in dioxane (1 mL) and H2O (1 mL) and stirred at 100 °C overnight. The next day, it was evaporated in vacuo and purified by HPLC to obtain N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-(6- Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (0.0108 g, 26.77 μmol, 21.66% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值403.2；實測值405.2；Rt=0.774min。LCMS (ESI): [M+2H] + m/z: calculated 403.2; found 405.2; Rt=0.774 min.

步驟5：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1002 )之合成Step 5: rel-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1 Synthesis of -Piperidinyl]-2-oxyacetamide ( Compound 1002 )

將N-[5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(55.74mg，110.68μmol)溶解於二噁烷 (1mL)及H2 O(1mL)中且在100℃下攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0115g，28.50μmol，25.75%產率)。N-[5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine tert-butyl]-3-methyl-2-pyridyl]carbamate (55.74 mg, 110.68 μmol) was dissolved in dioxane (1 mL) and H 2 O (1 mL) and stirred at 100° C. overnight. The next day, it was evaporated in vacuo and purified by HPLC to give N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(6- Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (0.0115 g, 28.50 μmol, 25.75% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值403.2；實測值405.2；Rt=0.775min。LCMS (ESI): [M+2H] + m/z: calculated 403.2; found 405.2; Rt=0.775 min.

實例423. rel-N-[3-乙基-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸酯(化合物919)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物929)之合成Example 423. rel-N-[3-ethyl-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-2-pyridyl]carbamate (compound 919) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[ Synthesis of (2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 929)

Figure 110128222-A0202-12-1776-930
Figure 110128222-A0202-12-1776-930

步驟1：N-[3-乙基-5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Ethyl-5-[[2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxoethanoyl] Synthesis of tertiary butyl amino]-2-pyridyl]carbamate

將6-(5-甲基-2-哌啶基)異喹啉(0.5g，2.21mmol)溶解於DMF(10mL)中且添加三乙胺(2.24g，22.09mmol，3.08mL)，隨後添加2-[[6-(第三丁氧基羰 基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(683.37mg，2.21mmol)。然後逐滴添加HATU(1.26g，3.31mmol)且將反應混合物攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得N-[3-乙基-5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.13g，251.15μmol，11.37%產率)。6-(5-Methyl-2-piperidinyl)isoquinoline (0.5 g, 2.21 mmol) was dissolved in DMF (10 mL) and triethylamine (2.24 g, 22.09 mmol, 3.08 mL) was added followed by 2-[[6-(Tertiary butoxycarbonyl amino)-5-ethyl-3-pyridyl]amino]-2-pendoxoacetic acid (683.37 mg, 2.21 mmol). HATU (1.26 g, 3.31 mmol) was then added dropwise and the reaction mixture was stirred overnight. The next day, it was evaporated in vacuo and purified by HPLC to obtain N-[3-ethyl-5-[[2-[2-(6-isoquinolinyl)-5-methyl-1- Piperidinyl]-2-Pendant oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.13 g, 251.15 μmol, 11.37% yield).

LCMS(ESI)：[M+H]+ m/z：計算值517.2；實測值518.2；Rt=0.971min。LCMS (ESI): [M+H] + m/z: calculated 517.2; found 518.2; Rt=0.971 min.

步驟2：rel-N-[3-乙基-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及rel-N-[3-乙基-5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 2: rel-N-[3-ethyl-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester and rel-N-[3-ethyl-5-[[2-[(2R,5S)-2-( Synthesis of 6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

對N-[3-乙基-5-[[2-[2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.13g，251.15μmol)進行掌性分離(管柱：Chiralpak AD-H(250*20mm，5m)；流動相：己烷-IPA-MeOH，70-15-15；流速：12mL/min；管柱溫度：24℃；波長：210nm，225nm，254nm，以獲得N-[3-乙基-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.04g，77.28μmol，30.77%產率；保留時間=22.46min；異構物A)及N-[3-乙基-5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.0497g，96.02μmol，38.23%產率；保留時間=26.31min；異構物B)。p-N-[3-Ethyl-5-[[2-[2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino ]-2-Pyridinyl]carbamic acid tert-butyl ester (0.13 g, 251.15 μmol) for chiral separation (column: Chiralpak AD-H (250*20 mm, 5 m); mobile phase: Hexane-IPA-MeOH, 70-15-15; flow rate: 12mL/min; column temperature: 24°C; wavelengths: 210nm, 225nm, 254nm to obtain N-[3-ethyl-5-[[2-[(2S,5R)- 2-(6-Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.04g , 77.28 μmol, 30.77% yield; retention time=22.46 min; Isomer A) and N-[3-ethyl-5-[[2-[(2R,5S)-2-(6-isoquinoline (0.0497 g, 96.02 μmol, 38.23% yield ; retention time=26.31 min; Isomer B).

異構物A：RT(AD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=19.622min。Isomer A: RT (AD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 19.622 min.

LCMS(ESI)：[M+2H]+ m/z：計算值517.2；實測值519.2；Rt=1.167min。LCMS (ESI): [M+2H] + m/z: calculated 517.2; found 519.2; Rt=1.167 min.

異構物B： RT(AD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=27.358min。 Isomer B: RT (AD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 27.358 min.

LCMS(ESI)：[M+2H]+ m/z：計算值517.2；實測值519.2；Rt=1.166min。LCMS (ESI): [M+2H] + m/z: calculated 517.2; found 519.2; Rt=1.166 min.

步驟3：rel-N-[3-乙基-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基Step 3: rel-N-[3-ethyl-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2 - pendant oxygen 乙醯基]胺基]-2-吡啶基]胺甲酸酯(化合物919 )之合成Synthesis of Acetyl]amino]-2-pyridyl]carbamate ( Compound 919 )

將N-[3-乙基-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.04g，77.28μmol)溶解於H2 O(1mL)及二噁烷(1mL)中且在100℃下攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得rel-N-[3-乙基-5-[[2-[(2S,5R)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸酯(0.0214g，51.26μmol，66.33%產率)。N-[3-Ethyl-5-[[2-[(2S,5R)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]-2-pyridinyl]carbamic acid tert-butyl ester (0.04 g, 77.28 μmol) was dissolved in H2O (1 mL) and dioxane (1 mL) and stirred at 100 °C overnight. The next day, it was evaporated in vacuo and purified by HPLC to obtain rel-N-[3-ethyl-5-[[2-[(2S,5R)-2-(6-isoquinolinyl) -5-Methyl-1-piperidinyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamate (0.0214 g, 51.26 μmol, 66.33% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.07(m,6H),1.37(m,1H),1.71(m,1H),1.89(m,1H),2.38(m,4H),3.03(m,1H),3.80(m,1H),5.67(m,3H),7.45(m,1H),7.64(m,1H),7.81(m,1H),8.01(m,3H),8.48(m,1H),9.27(m,1H),10.55(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.07(m, 6H), 1.37(m, 1H), 1.71(m, 1H), 1.89(m, 1H), 2.38(m, 4H), 3.03(m, 1H), 3.80(m, 1H), 5.67(m, 3H), 7.45(m, 1H), 7.64(m, 1H), 7.81(m, 1H), 8.01(m, 3H), 8.48 (m, 1H), 9.27 (m, 1H), 10.55 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=1.528min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=1.528 min.

步驟4：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物929 )之合成Step 4: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1 Synthesis of -Piperidinyl]-2-Pendant Oxyacetamide ( Compound 929 )

將N-[3-乙基-5-[[2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.0497g，96.02μmol)溶解於H2 O(1mL)及二噁烷(1mL)中且在100℃下攪拌隔夜。次日，將其在真空中蒸發且藉由HPLC純化，以獲得rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-異喹啉基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0249g，59.64μmol，62.11%產率)。N-[3-Ethyl-5-[[2-[(2R,5S)-2-(6-isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.0497 g, 96.02 μmol) was dissolved in H2O (1 mL) and dioxane (1 mL) and stirred at 100 °C overnight. The next day, it was evaporated in vacuo and purified by HPLC to obtain rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-( 6-Isoquinolinyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.0249 g, 59.64 μmol, 62.11% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.07(m,6H),1.37(m,1H),1.72(m,1H),1.87(m,1H),2.14(m,1H),2.36(m,3H),2.95(m,1H),3.80(m,1H),5.65(m,3H),7.45(m,1H),7.64(dd,1H),7.81(m,1H),7.90(m,1H),8.03(m,1H),8.12(m,1H),8.48(m,1H),9.27(m,1H),10.54(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.07(m, 6H), 1.37(m, 1H), 1.72(m, 1H), 1.87(m, 1H), 2.14(m, 1H), 2.36(m,3H),2.95(m,1H),3.80(m,1H),5.65(m,3H),7.45(m,1H),7.64(dd,1H),7.81(m,1H),7.90 (m, 1H), 8.03 (m, 1H), 8.12 (m, 1H), 8.48 (m, 1H), 9.27 (m, 1H), 10.54 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.2；Rt=1.502min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.2; Rt=1.502 min.

實例424. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物707)及rel-N-(6-胺基-5-甲基-3-吡啶Example 424. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl) )-1-piperidinyl]-2-oxyacetamide (compound 707) and rel-N-(6-amino-5-methyl-3-pyridine) 基)-2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物687)之合成yl)-2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide (Compound 687) synthesis

Figure 110128222-A0202-12-1779-931
Figure 110128222-A0202-12-1779-931

步驟1：N-[3-甲基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-pendoxoethyl Synthesis of Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將DIPEA(547.10mg，4.23mmol，737.33μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.5g，1.69mmol)及2-甲基-5-(5-甲基-2-哌啶基)吡啶(322.20mg，1.69mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(708.20mg，1.86mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH為溶析液混合物)，以得到N-[3-甲基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(329.8mg，705.37μmol，41.66%產率)。DIPEA (547.10 mg, 4.23 mmol, 737.33 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (0.5 g, 1.69 mmol) and 2-methyl-5-(5-methyl-2-piperidinyl)pyridine (322.20 mg, 1.69 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (708.20 mg, 1.86 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH as eluent mixture) to give N-[3-methyl-5-[[2-[5-methyl-2 -(6-Methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (329.8 mg, 705.37 μmol , 41.66% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值467.2；實測值469.2；Rt=2.087min。LCMS (ESI): [M+2H] + m/z: calculated 467.2; found 469.2; Rt=2.087 min.

步驟2：rel-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(P1)及rel-N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(P2)之合成Step 2: rel-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (P1) and rel-N-[3-methyl-5-[[2-[(2S, 5R)-5-Methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Synthesis of Tributyl Ester (P2)

使用(Chiralpak IC-II(250*30mm，5mkm)管柱且以己烷-IPA-MeOH，60-20-20為流動相，流速12mL/min)對N-[3-甲基-5-[[2-[5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(329.8mg，705.37μmol)進行掌性分離，得到呈米色固體之rel-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(119.4mg，36.20%產率；P1)及亦呈米色固體之rel-N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(110.77mg，33.59%產率；P2)。N-[3-methyl-5-[ [2-[5-Methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Chiral separation of tert-butyl ester (329.8 mg, 705.37 μmol) afforded rel-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2 as a beige solid -(6-Methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (119.4 mg, 36.20% Yield; P1) and rel-N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridine also as a beige solid yl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (110.77 mg, 33.59% yield; P2).

P1： RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，60-20-20，0.6mL/min)=60.357min。 P1: RT (Chiralpak IC (250*4.6, 5mkm), Hexane-IPA-MeOH, 60-20-20, 0.6mL/min)=60.357min.

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值468.2；Rt=2.151min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 468.2; Rt=2.151 min.

P2： RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，60-20-20，0.6mL/min)=48.066min。 P2: RT (Chiralpak IC (250*4.6, 5mkm), Hexane-IPA-MeOH, 60-20-20, 0.6mL/min)=48.066min.

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值468.2；Rt=2.168min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 468.2; Rt=2.168 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物707 )之合成Step 3: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl) )-1-piperidinyl]-2-side oxyacetamide ( compound 707 ) synthesis

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]-胺基]-2-吡啶基]胺甲酸第三丁酯(119.14mg，254.81μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。 在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN+NH3 為溶析液混合物)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(74.4mg，202.48μmol，79.46%產率)。N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]-amino]-2-pyridyl]carbamic acid tert-butyl ester (119.14 mg, 254.81 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN+ NH3 as eluent mixture) to give N-(6-amino-5-methyl-3-pyridyl) -2-[(2R,5S)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide (74.4 mg, 202.48 μmol , 79.46% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.33(m,1H),1.65(m,1H),1.86(m,1H),2.00(m,4H),2.10(m,1H),2.19(m,1H),2.43(m,3H),3.03(m,1H),3.71(dd,1H),5.59(m,3H),7.24(m,1H),7.45(d,1H),7.59(dd,1H),7.97(m,1H),8.39(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.33(m, 1H), 1.65(m, 1H), 1.86(m, 1H), 2.00(m, 4H), 2.10(m, 1H), 2.19(m, 1H), 2.43(m, 3H), 3.03(m, 1H), 3.71(dd, 1H), 5.59(m, 3H), 7.24(m, 1H), 7.45 (d, 1H), 7.59 (dd, 1H), 7.97 (m, 1H), 8.39 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值367.2；實測值369.2；Rt=1.071min。LCMS (ESI): [M+2H] + m/z: calculated 367.2; found 369.2; Rt=1.071 min.

步驟4：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物687 )之合成Step 4: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl) )-1-piperidinyl]-2-side oxyacetamide ( compound 687 ) synthesis

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]-胺基]-2-吡啶基]胺甲酸第三丁酯(110.77mg，236.91μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeCN+NH3 為溶析液混合物)，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(58.1mg，158.12μmol，66.74%產率)。N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]-amino]-2-pyridyl]carbamic acid tert-butyl ester (110.77 mg, 236.91 μmol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeCN+ NH3 as eluent mixture) to give N-(6-amino-5-methyl-3-pyridyl) -2-[(2S,5R)-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide (58.1 mg, 158.12 μmol , 66.74% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.98(m,3H),1.32(m,1H),1.63(m,1H),1.86(m,1H),2.00(m,4H),2.19(m,1H),2.43(m,3H),2.94(m,1H),3.71(dd,1H),5.59(m,3H),7.25(m,1H),7.45(m,1H),7.59(m,1H),7.97(m,1H),8.39(m,1H),10.49(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.98(m, 3H), 1.32(m, 1H), 1.63(m, 1H), 1.86(m, 1H), 2.00(m, 4H), 2.19(m,1H),2.43(m,3H),2.94(m,1H),3.71(dd,1H),5.59(m,3H),7.25(m,1H),7.45(m,1H),7.59 (m, 1H), 7.97 (m, 1H), 8.39 (m, 1H), 10.49 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值367.2；實測值369.4；Rt=1.073min。LCMS (ESI): [M+2H] + m/z: calculated 367.2; found 369.4; Rt=1.073 min.

實例425.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌Example 425. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(1-oxyisoindolin-5-yl)piperidine 啶-1-基)-2-側氧基乙醯胺(化合物591及化合物581)之合成Synthesis of pyridin-1-yl)-2-oxoacetamide (Compound 591 and Compound 581)

Figure 110128222-A0202-12-1782-932
Figure 110128222-A0202-12-1782-932

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(1-oxyisoindolin-5-yl)piperidine- Synthesis of 1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester

將N -[3-甲基-5-(草醯胺醯基胺基)-2-吡啶基]胺甲酸第三丁 酯(511.16mg，1.74mmol)及TEA(1.76g，17.37mmol，2.42mL)溶解於DMF(12mL)中且冷卻至0℃，添加HATU(990.59mg，2.61mmol)且在0℃下將混合物攪拌15min。添加5-[(2R ,5S )-5-甲基-2-哌啶基]異吲哚啉-1-酮(0.4g，1.74mmol)且將混合物升溫至室溫且攪拌3h。添加10ml乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(90%水-MeOH，2-10min，流速：30ml/min(裝載泵4ml/min MeOH)管柱：TSunFire 100*19mm，5微米)進行純化，以得到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.28g，551.64μmol，31.76%產率)。Combine N- [3-methyl-5-(oxamidoamino)-2-pyridyl]carbamic acid tert- butyl ester (511.16 mg, 1.74 mmol) and TEA (1.76 g, 17.37 mmol, 2.42 mL) ) was dissolved in DMF (12 mL) and cooled to 0 °C, HATU (990.59 mg, 2.61 mmol) was added and the mixture was stirred at 0 °C for 15 min. 5-[( 2R , 5S )-5-methyl-2-piperidinyl]isoindolin-1-one (0.4 g, 1.74 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. 10 ml of ethyl acetate were added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product, which was obtained by HPLC (90% water-MeOH, 2-10 min, flow rate: 30 ml/min (load pump 4 ml) /min MeOH) column: TSunFire 100*19mm, 5 microns) for purification to give N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(1 - Pendant oxyisoindolin-5-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.28g, 551.64 g μmol, 31.76% yield).

LCMS(ESI)：[M]+ m/z：計算值507.2；實測值508.2；Rt=1.254min。LCMS (ESI): [M] + m/z: calculated 507.2; found 508.2; Rt=1.254 min.

步驟2：掌性分離Step 2: Palm Separation

使用(管柱：Chiralpak IC-I(250 * 20mm，5mkm)；流動相：IPA-MeOH 50-50流速：10mL/min)進行掌性分離，以得到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.068g，133.97μmol，24.29%產率)及N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.089g，175.34μmol，31.79%產率)。Chiral separation was performed using (column: Chiralpak IC-I (250*20mm, 5mkm); mobile phase: IPA-MeOH 50-50 flow rate: 10 mL/min) to give N- [3-methyl-5-[ [2-[( 2R,5S )-5-methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amine tert -butyl ]-2-pyridyl]carbamate (0.068 g, 133.97 μmol, 24.29% yield) and N- [3-methyl-5-[[2-[( 2S,5R )-5- Methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid third Butyl ester (0.089 g, 175.34 [mu]mol, 31.79% yield).

E1於分析條件下(管柱：IC，以IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為46.83min且E2之保留時間為22.80min。The retention time of E1 under analytical conditions (column: IC, with IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 46.83 min and the retention time of E2 was 22.80 min.

E1：保留時間：46.83minE1: retention time: 46.83min

LCMS(ESI)：[M]+ m/z：計算值507.2；實測值508.2；Rt=2.851min。LCMS (ESI): [M] + m/z: calculated 507.2; found 508.2; Rt=2.851 min.

E2：保留時間：22.80minE2: retention time: 22.80min

LCMS(ESI)：[M]+ m/z：計算值507.2；實測值508.2；Rt=2.856min。LCMS (ESI): [M] + m/z: calculated 507.2; found 508.2; Rt=2.856 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1-側氧基異吲哚啉-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物581 及化合物591 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(1-oxyisoindolin-5-yl)piperidine- Synthesis of 1-yl)-2-oxyacetamide ( Compound 581 and Compound 591 )

將N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.068g，133.97μmol)及N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.089g，175.34μmol)溶解於二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空、55℃下濃縮反應混合物，以得到粗產物，其藉由HPLC(0-60% MeCN-水，2-10min，流速30ml/min(裝載泵4ml/min MeCN)，管柱：SUNFIRE 100*19mm)進行純化，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.03g，73.63μmol，54.96%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1-側氧基異吲哚啉-5-基)-1-哌啶基]-2-側氧基乙醯胺(0.034g，83.44μmol，47.59%產率)。 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (0.068g, 133.97μmol) and N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxyacetyl]amino]-2- 3-Butyl pyridyl]carbamate (0.089 g, 175.34 μmol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL), then stirred at 100 °C for 12 h. The reaction mixture was concentrated under vacuum at 55°C to give crude product by HPLC (0-60% MeCN-water, 2-10 min, flow rate 30 ml/min (loading pump 4 ml/min MeCN), column: SUNFIRE 100 *19mm) was purified to give N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R,5S )-5-methyl-2-(1-side oxyiso Indolin-5-yl)-1-piperidinyl]-2-oxyacetamide (0.03 g, 73.63 μmol, 54.96% yield) and N-(6-amino-5-methyl- 3-Pyridinyl)-2-[( 2S,5R )-5-methyl-2-(1-oxyisoindolin-5-yl)-1-piperidinyl]-2-oxygen Acetamide (0.034 g, 83.44 μmol, 47.59% yield).

化合物581： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,3H),1.27-1.36(m,1H),1.61-1.69(m,1H),1.82-1.90(m,1H),1.96-2.03(m,3H),2.05-2.15(m, 1H),2.19-2.27(m,1H),2.76-3.24(m,1H),3.33-4.06(m,1H),4.32-4.39(m,2H),5.18-5.60(m,1H),5.60-5.65(m,2H),7.38-7.46(m,1H),7.46-7.56(m,2H),7.61-7.70(m,1H),7.90-8.04(m,1H),8.50(s,1H),10.41-10.54(m,1H)。 Compound 581: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.99-1.03 (m, 3H), 1.27-1.36 (m, 1H), 1.61-1.69 (m, 1H), 1.82-1.90 (m ,1H),1.96-2.03(m,3H),2.05-2.15(m,1H),2.19-2.27(m,1H),2.76-3.24(m,1H),3.33-4.06(m,1H),4.32 -4.39(m, 2H), 5.18-5.60(m, 1H), 5.60-5.65(m, 2H), 7.38-7.46(m, 1H), 7.46-7.56(m, 2H), 7.61-7.70(m, 1H), 7.90-8.04 (m, 1H), 8.50 (s, 1H), 10.41-10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值407.2；實測值408.2；Rt=1.669min。LCMS (ESI): [M] + m/z: calculated 407.2; found 408.2; Rt=1.669 min.

化合物591： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.04(m,3H),1.27-1.40(m,1H),1.57-1.73(m,1H),1.77-1.94(m,1H),1.94-2.14(m,4H),2.14-2.31(m,1H),2.74-3.26(m,1H),3.47-4.04(m,1H),4.32-4.38(m,2H),5.19-5.59(m,1H),5.60-5.67(m,2H),7.34-7.54(m,3H),7.61-7.71(m,1H),7.87-8.09(m,1H),8.43-8.53(m,1H),10.40-10.53(m,1H)。 Compound 591: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.97-1.04 (m, 3H), 1.27-1.40 (m, 1H), 1.57-1.73 (m, 1H), 1.77-1.94 (m) ,1H),1.94-2.14(m,4H),2.14-2.31(m,1H),2.74-3.26(m,1H),3.47-4.04(m,1H),4.32-4.38(m,2H),5.19 -5.59(m, 1H), 5.60-5.67(m, 2H), 7.34-7.54(m, 3H), 7.61-7.71(m, 1H), 7.87-8.09(m, 1H), 8.43-8.53(m, 1H), 10.40-10.53 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值407.2；實測值408.2；Rt=0.921min。LCMS (ESI): [M] + m/z: calculated 407.2; found 408.2; Rt=0.921 min.

實例426. 乙酸4-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)苯酯(化合物1087及化合物597)之合成Example 426. Acetate 4-(1-(2-((6-amino-5-methylpyridin-3-yl)amino)-2-oxyacetoxy)-5-methylpiperidine- Synthesis of 2-yl)phenylester (Compound 1087 and Compound 597)

Figure 110128222-A0202-12-1784-933
Figure 110128222-A0202-12-1784-933

步驟1：乙酸外消旋-4-((2R,5S)-1-(2-((6-((第三丁氧基羰基)胺基)-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)苯酯之合成Step 1: Acetic Acid Racemic-4-((2R,5S)-1-(2-((6-((3-butoxycarbonyl)amino)-5-methylpyridin-3-yl)amine Synthesis of phenyl)-2-oxyacetyl)-5-methylpiperidin-2-yl)phenyl ester

將N -[3-甲基-5-(草醯胺醯基胺基)-2-吡啶基]胺甲酸第三丁 酯(446.56mg，1.52mmol)及TEA(1.54g，15.17mmol，2.11mL)溶解於DMF(10mL)中且冷卻至0℃，添加HATU(865.40mg，2.28mmol)且在0℃下將混合物攪拌15min。添加乙酸[4-[(2S,5R )-5-甲基-2-哌啶基]苯]酯(0.354g，1.52mmol)且將混合物升溫 至室溫且攪拌3h。添加10ml EtOAc且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(55-80%水/MeOH，2-10min，(裝載泵4ml MeOH)，管柱：TRIART 100*20)進行純化，以得到乙酸[4-[(2S,5R )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.177g，346.66μmol，22.85%產率)。Combine N- [3-methyl-5-(oxamidoamino)-2-pyridyl]carbamic acid tert- butyl ester (446.56 mg, 1.52 mmol) and TEA (1.54 g, 15.17 mmol, 2.11 mL) ) was dissolved in DMF (10 mL) and cooled to 0 °C, HATU (865.40 mg, 2.28 mmol) was added and the mixture was stirred at 0 °C for 15 min. [4-[( 2S,5R )-5-methyl-2-piperidinyl]phenyl]acetate (0.354 g, 1.52 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. 10 ml EtOAc was added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45°C to give crude product by HPLC (55-80% water/MeOH, 2-10 min, (loading pump 4 ml MeOH), Column: TRIART 100*20) for purification to give [4-[( 2S,5R )-1-[2-[[6-( tert- butoxycarbonylamino)-5-methyl-3 acetate -Pyridinyl]amino]-2-oxyacetyl]-5-methyl-2-piperidinyl]phenyl]ester (0.177 g, 346.66 μmol, 22.85% yield).

LCMS(ESI)：[M]+ m/z：計算值510.2；實測值511.2；Rt=1.238min。LCMS (ESI): [M] + m/z: calculated 510.2; found 511.2; Rt=1.238 min.

步驟2：掌性分離 使用(管柱：Chiralpak OJ-H-I(250*20，5mkm)；流動相：己烷-MeOH-IPA，60-20-20，流速：12mL/min)進行掌性分離，以得到乙酸[4-[(2S,5R )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.048g，94.01μmol，27.12%產率)及乙酸[4-[(2R,5S )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.047g，92.05μmol，26.55%產率)。 Step 2: chiral separation (column: Chiralpak OJ-HI (250*20, 5mkm); mobile phase: hexane-MeOH-IPA, 60-20-20, flow rate: 12mL/min) for chiral separation, to give [4-[( 2S,5R )-1-[2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-side acetate Oxyacetyl]-5-methyl-2-piperidinyl]phenyl]ester (0.048 g, 94.01 μmol, 27.12% yield) and [4-[( 2R,5S )-1-[2-acetic acid] [[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl] Phenyl]ester (0.047 g, 92.05 μmol, 26.55% yield).

E1於分析條件下(管柱：OJ-H，以己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為14.46min且E2之保留時間為32.46min。The retention time of E1 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 14.46 min and that of E2 was 32.46 min.

E1：保留時間：14.46minE1: retention time: 14.46min

LCMS(ESI)：[M]+ m/z：計算值510.2；實測值511.2；Rt=3.486min。LCMS (ESI): [M] + m/z: calculated 510.2; found 511.2; Rt=3.486 min.

E2：保留時間：32.46minE2: retention time: 32.46min

LCMS(ESI)：[M]+ m/z：計算值510.2；實測值511.2；Rt=3.488min。LCMS (ESI): [M] + m/z: calculated 510.2; found 511.2; Rt=3.488 min.

步驟3：乙酸4-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)苯酯(化合物1087 及化合物597 )之合成Step 3: Acetate 4-(1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-5-methylpiperidine- Synthesis of 2-yl)phenylester ( Compound 1087 and Compound 597 )

將乙酸[4-[(2S,5R )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.048g，94.01μmol)及乙酸[4-[(2R,5S )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯 基]-5-甲基-2-哌啶基]苯]酯(0.047g，92.05μmol)溶解於二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空、55℃下濃縮反應混合物，以得到粗產物，其藉由HPLC(50-60% MeCN-水，2-10min，流速30ml/min(裝載泵4ml/min MeCN)，管柱：SUNFIRE 100*19mm)進行純化，以得到粗產物：乙酸[4-[(2S,5R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.009g，粗品)及乙酸[4-[(2R,5S )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]苯]酯(0.014g，34.11μmol，37.05%產率)。Acetate [4-[( 2S,5R )-1-[2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxygen Acetyl]-5-methyl-2-piperidinyl]phenyl]ester (0.048g, 94.01μmol) and [4-[( 2R,5S )-1-[2-[[6-( th ) acetate Tributoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-oxyethanoyl]-5-methyl-2-piperidinyl]phenyl]ester (0.047g , 92.05 μmol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL), then stirred at 100 °C for 12 h. The reaction mixture was concentrated under vacuum at 55°C to give crude product by HPLC (50-60% MeCN-water, 2-10 min, flow rate 30 ml/min (loading pump 4 ml/min MeCN), column: SUNFIRE 100 *19mm) was purified to give crude product: [4-[( 2S,5R )-1-[2-[(6-amino-5-methyl-3-pyridyl)amino]-2-acetic acid Pendant oxyacetyl]-5-methyl-2-piperidinyl]phenyl]ester (0.009g, crude) and [4-[( 2R,5S )-1-[2-[(6-amine acetate) (0.014 g, 34.11 μmol, 37.05% yield) Rate).

化合物1087： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.28-1.38(m,1H),1.62-1.71(m,1H),1.82-1.93(m,1H),1.96-2.05(m,4H),2.10-2.20(m,1H),2.23-2.26(m,3H),2.67-3.22(m,1H),3.42-4.04(m,1H),5.11-5.57(m,1H),5.57-5.69(m,2H),7.10-7.14(m,2H),7.30-7.39(m,2H),7.43-7.50(m,1H),7.92-8.03(m,1H),10.42-10.55(m,1H)。 Compound 1087: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98-1.03 (m, 3H), 1.28-1.38 (m, 1H), 1.62-1.71 (m, 1H), 1.82-1.93 (m) ,1H),1.96-2.05(m,4H),2.10-2.20(m,1H),2.23-2.26(m,3H),2.67-3.22(m,1H),3.42-4.04(m,1H),5.11 -5.57(m,1H),5.57-5.69(m,2H),7.10-7.14(m,2H),7.30-7.39(m,2H),7.43-7.50(m,1H),7.92-8.03(m, 1H), 10.42-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=1.104min。LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=1.104 min.

化合物597： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.28-1.38(m,1H),1.62-1.71(m,1H),1.82-1.93(m,1H),1.96-2.05(m,4H),2.10-2.20(m,1H),2.23-2.26(m,3H),2.67-3.22(m,1H),3.42-4.04(m,1H),5.11-5.57(m,1H),5.57-5.69(m,2H),7.10-7.14(m,2H),7.30-7.39(m,2H),7.43-7.50(m,1H),7.92-8.03(m,1H),10.42-10.55(m,1H)。 Compound 597: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98-1.03 (m, 3H), 1.28-1.38 (m, 1H), 1.62-1.71 (m, 1H), 1.82-1.93 (m) ,1H),1.96-2.05(m,4H),2.10-2.20(m,1H),2.23-2.26(m,3H),2.67-3.22(m,1H),3.42-4.04(m,1H),5.11 -5.57(m,1H),5.57-5.69(m,2H),7.10-7.14(m,2H),7.30-7.39(m,2H),7.43-7.50(m,1H),7.92-8.03(m, 1H), 10.42-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=2.323min。LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=2.323 min.

實例427. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物816)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物820)之合成Example 427. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl) )-1-piperidinyl]-2-oxyacetamide (compound 816) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S )-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxoacetamide (compound 820) synthesis

Figure 110128222-A0202-12-1787-934
Figure 110128222-A0202-12-1787-934

步驟1：外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidine Synthesis of 3-butyl pyridyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamate

向2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]噻唑(0.3g，1.16mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(342.85mg，1.16mmol)及DIPEA(300.12mg，2.32mmol，404.48μL)於DMSO(7mL)中之經攪拌之溶液中添加HATU(529.77mg，1.39mmol)。將所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物提交至反相HPLC，以得到外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，373.37μmol，32.16%產率)。To 2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]thiazole (0.3 g, 1.16 mmol), 2-[[6-(tert-butoxycarbonylamine (342.85 mg, 1.16 mmol) and DIPEA (300.12 mg, 2.32 mmol, 404.48 μL) in DMSO (7 mL) To the stirred solution was added HATU (529.77 mg, 1.39 mmol). The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was submitted to reverse phase HPLC to give rac-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazole -2-ylphenyl)-1-piperidinyl]-2-oxoacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.2 g, 373.37 μmol, 32.16% yield ).

HPLC資料：2-10min 60-90% MeCN/H2 O；30mL/min(裝載泵4mL MeCN)，管柱：HILIC，5微米HPLC profile: 2-10 min 60-90% MeCN/H 2 O; 30 mL/min (loading pump 4 mL MeCN), column: HILIC, 5 micron

LCMS(ESI)：[M+H]+ m/z：計算值535.2；實測值536.2；Rt=1.415min。LCMS (ESI): [M+H] + m/z: calculated 535.2; found 536.2; Rt=1.415 min.

步驟2：rel-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲醯第三丁酯(P1)及rel-N-[3-甲基Step 2: rel-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamoyl tert-butyl ester (P1) and rel-N-[3-methyl -5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(P2)之合成-5-[[2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of tert-butyl]-2-pyridyl]carbamate (P2)

將外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，373.37μmol)提交至掌性分離，以得到P1 rel-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.085g，158.68μmol，42.50%產率)及P2 rel-N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.072g，134.41μmol，36.00%產率)。rac-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.2 g, 373.37 μmol) was submitted to chiral separation to give P1 rel-N-[3-methyl] Alkyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl] Amino]-2-pyridyl]carbamic acid tert-butyl ester (0.085 g, 158.68 μmol, 42.50% yield) and P2 rel-N-[3-methyl-5-[[2-[(2S,5R )-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid third Butyl ester (0.072 g, 134.41 μmol, 36.00% yield).

分離資料：管柱：Chiralcel OD-H(250*30，5mkm)，流動相：己烷-IPA-MeOH，70-15-15；流速：28ml/min。24℃，波長：205nm，215nm，保留時間P1=13.24；保留時間P2=17.67Separation data: column: Chiralcel OD-H (250*30, 5mkm), mobile phase: hexane-IPA-MeOH, 70-15-15; flow rate: 28ml/min. 24℃, wavelength: 205nm, 215nm, retention time P1=13.24; retention time P2=17.67

P1： RT(OD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=12.231min。 P1: RT (OD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 12.231 min.

LCMS(ESI)：[M+H]+ m/z：計算值535.2；實測值536.2；Rt=5.623min。LCMS (ESI): [M+H] + m/z: calculated 535.2; found 536.2; Rt=5.623 min.

P2： RT(OD-H，己烷-IPA-MeOH，50-25-25，0.6mL/min)=9.621min。 P2: RT (OD-H, Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 9.621 min.

LCMS(ESI)：[M+H]+ m/z：計算值535.2；實測值536.2；Rt=5.621min。LCMS (ESI): [M+H] + m/z: calculated 535.2; found 536.2; Rt=5.621 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物820 )之合成：Step 3: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl) )-1-piperidinyl]-2-side oxyacetamide ( compound 820 ) synthesis:

將rel-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯P1(0.085g，158.68μmol)溶解於1,4-二噁烷(2mL)及水(1mL)之混合物中且將混合物在80℃下攪拌17h。完成之後，在減壓下濃縮反應混合物且將殘餘物提交至反相HPLC，以得到rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(0.033g，75.77μmol，47.75%產率)。rel-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester P1 (0.085 g, 158.68 μmol) was dissolved in 1,4-dioxane (2 mL) and water (1 mL) and the mixture was stirred at 80 °C for 17 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was submitted to reverse phase HPLC to give rel-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S )-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyacetamide (0.033 g, 75.77 μmol, 47.75% yield).

HPLC資料：50-75% MeOH-2-10min流速：30mL/min；裝載泵4mL/min MeOH，管柱Sun Fire 100 x 19mm，5mkmHPLC profile: 50-75% MeOH-2-10min Flow rate: 30mL/min; loading pump 4mL/min MeOH, column Sun Fire 100 x 19mm, 5mkm

1 H NMR(dmso,600MHz)：δ(ppm)0.98-1.04(m,3H),1.29-1.41(m,1H),1.61-1.73(m,1H),1.80-1.93(m,1H),1.96-2.03(m,3H),2.04-2.18(m,1H),2.18-2.29(m,1H),2.76-3.24(m,1H),3.44-4.06(m,1H),5.17-5.59(m,1H),5.59-5.66(m,2H),7.40-7.47(m,2H),7.47-7.50(m,1H),7.75-7.78(m,1H),7.88-7.91(m,1H),7.91-7.96(m,2H),7.96-8.03(m,1H),10.45-10.55(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.98-1.04 (m, 3H), 1.29-1.41 (m, 1H), 1.61-1.73 (m, 1H), 1.80-1.93 (m, 1H), 1.96 -2.03(m, 3H), 2.04-2.18(m, 1H), 2.18-2.29(m, 1H), 2.76-3.24(m, 1H), 3.44-4.06(m, 1H), 5.17-5.59(m, 1H), 5.59-5.66(m, 2H), 7.40-7.47(m, 2H), 7.47-7.50(m, 1H), 7.75-7.78(m, 1H), 7.88-7.91(m, 1H), 7.91- 7.96 (m, 2H), 7.96-8.03 (m, 1H), 10.45-10.55 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=1.052min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=1.052 min.

步驟4：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物816 )之合成Step 4: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl) )-1-piperidinyl]-2-side oxyacetamide ( compound 816 ) synthesis

將rel-N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯P2(0.072g，134.41μmol)溶解於1,4-二噁烷及水之混合物中且將混合物在80℃下攪拌17h。完成之後，在減壓下濃縮反應混合物且將殘餘物提交至反相HPLC，以得到rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(0.031g，71.18μmol，52.95%產率)。rel-N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Pendant oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester P2 (0.072 g, 134.41 μmol) was dissolved in a mixture of 1,4-dioxane and water and the mixture was placed in Stir at 80°C for 17h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was submitted to reverse phase HPLC to give rel-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R )-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyacetamide (0.031 g, 71.18 μmol, 52.95% yield).

HPLC資料：50-75% MeOH-2-10min流速：30mL/min；裝載泵4mL/min MeOH，管柱Sun Fire 100 x 19mm，5mkmHPLC profile: 50-75% MeOH-2-10min Flow rate: 30mL/min; loading pump 4mL/min MeOH, column Sun Fire 100 x 19mm, 5mkm

1 H NMR(dmso,600MHz)：δ(ppm)0.97-1.05(m,3H),1.28-1.40(m,1H),1.63-1.71(m,1H),1.82-1.94(m,1H),1.96-2.04(m,3H),2.04-2.17(m,1H),2.19-2.29(m,1H),2.77-3.27(m,1H),3.45-4.06(m,1H),5.18-5.59(m,1H),5.59-5.68(m,2H),7.40-7.47(m,2H),7.47-7.50(m,1H),7.75-7.78(m,1H),7.89-7.91(m,1H),7.92-7.96(m,2H),7.96-8.04(m,1H),10.40-10.64(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.97-1.05 (m, 3H), 1.28-1.40 (m, 1H), 1.63-1.71 (m, 1H), 1.82-1.94 (m, 1H), 1.96 -2.04(m, 3H), 2.04-2.17(m, 1H), 2.19-2.29(m, 1H), 2.77-3.27(m, 1H), 3.45-4.06(m, 1H), 5.18-5.59(m, 1H), 5.59-5.68(m, 2H), 7.40-7.47(m, 2H), 7.47-7.50(m, 1H), 7.75-7.78(m, 1H), 7.89-7.91(m, 1H), 7.92- 7.96 (m, 2H), 7.96-8.04 (m, 1H), 10.40-10.64 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=1.052min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=1.052 min.

實例428. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物822)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物813)之合成Example 428. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl) )-1-piperidinyl]-2-oxyacetamide (compound 822) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R )-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxoacetamide (compound 813) synthesis

Figure 110128222-A0202-12-1790-935
Figure 110128222-A0202-12-1790-935

步驟1：外消旋-N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[3-ethyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidine Synthesis of 3-butyl pyridyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamate

將外消旋-2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]噻唑(0.25g，967.56μmol)、2-[[6-(第三丁氧基羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(299.28mg，967.56μmol)、HATU(441.48mg，1.16mmol)及DIPEA(250.10mg，1.94mmol，337.06μL)混合於DMSO(7mL)中且將反應混合物在室溫下攪拌隔夜。完成之後，將反應混合物提交至反相HPLC，以得到外消旋-N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，363.85μmol，37.60%產率)。Racemic-2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]thiazole (0.25 g, 967.56 μmol), 2-[[6-(tertiary butyl Oxycarbonylamino)-5-ethyl-3-pyridyl]amino]-2-oxoacetic acid (299.28 mg, 967.56 μmol), HATU (441.48 mg, 1.16 mmol) and DIPEA (250.10 mg, 1.94 mmol, 337.06 μL) in DMSO (7 mL) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was submitted to reverse phase HPLC to give rac-N-[3-ethyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazole -2-ylphenyl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.2 g, 363.85 μmol, 37.60% yield ).

HPLC資料；60-95%(MeCN)-2-10min流速：30mL/min；裝載泵4mL/min MeCN，管柱Sun Fire 100 x 19mm，5mkmHPLC profile; 60-95% (MeCN)-2-10min flow rate: 30mL/min; loading pump 4mL/min MeCN, column Sun Fire 100 x 19mm, 5mkm

LCMS(ESI)：[M+H]+ m/z：計算值459.2；實測值550.2；Rt=1.502min。LCMS (ESI): [M+H] + m/z: calculated 459.2; found 550.2; Rt=1.502 min.

步驟2：rel-N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(P1)及rel-N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(P2)之合成Step 2: rel-N-[3-ethyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (P1) and rel-N-[3-ethyl-5-[[2-[(2S, 5R)-5-Methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Synthesis of Tributyl Ester (P2)

將外消旋-N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2g，363.85μmol)提交至掌性分離，以得到rel-N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯P1(0.067g，121.89μmol，33.50%產率)及rel-N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯P2(0.077g，140.08μmol，38.50%產率)。rac-N-[3-ethyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.2 g, 363.85 μmol) was submitted to chiral isolation to give rel-N-[3-ethyl -5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amine tert-butyl]-2-pyridyl]carbamate P1 (0.067 g, 121.89 μmol, 33.50% yield) and rel-N-[3-ethyl-5-[[2-[(2S,5R) -5-Methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl Ester P2 (0.077 g, 140.08 μmol, 38.50% yield).

製備型分離：樣品資訊：IC(250*20，5mkm)，IPA-MeOH，50-25-25，10mL/minPreparative separation: Sample information: IC (250*20, 5mkm), IPA-MeOH, 50-25-25, 10mL/min

P1： RT(IC，IPA-MeOH，50-50，0.6mL/min)=34.861min。LCMS(ESI)：[M+H]+ m/z：計算值549.2；實測值550.4；Rt=1.403min。 P1: RT (IC, IPA-MeOH, 50-50, 0.6 mL/min) = 34.861 min. LCMS (ESI): [M+H] + m/z: calculated 549.2; found 550.4; Rt=1.403 min.

P2： RT(IC，IPA-MeOH，50-50，0.6mL/min)=16.318min。LCMS(ESI)：[M+H]+ m/z：計算值549.2；實測值550.4；Rt=1.405min。 P2: RT (IC, IPA-MeOH, 50-50, 0.6 mL/min) = 16.318 min. LCMS (ESI): [M+H] + m/z: calculated 549.2; found 550.4; Rt=1.405 min.

步驟3：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物822 )之合成：Step 3: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl) )-1-piperidinyl]-2-side oxyacetamide ( compound 822 ) synthesis:

將rel-N-[3-乙基-5-[[2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯P1(0.067g，121.89μmol)溶解於1,4-二噁烷(2mL)及水(1mL)之混合物中且將混合物在80℃下攪拌16h。 完成之後，在減壓下濃縮反應混合物且將殘餘物提交至反相HPLC，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(0.0335g，74.52μmol，61.13%產率)。rel-N-[3-ethyl-5-[[2-[(2R,5S)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester P1 (0.067 g, 121.89 μmol) was dissolved in 1,4-dioxane (2 mL) and water (1 mL) and the mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was submitted to reverse phase HPLC to give N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)- 5-Methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyacetamide (0.0335 g, 74.52 μmol, 61.13% yield).

HPLC資料：50-75% MeOH-2-10min流速：30mL/min；裝載泵4mL/min MeOH，管柱Sun Fire 100 x 19mm，5mkmHPLC profile: 50-75% MeOH-2-10min Flow rate: 30mL/min; loading pump 4mL/min MeOH, column Sun Fire 100 x 19mm, 5mkm

1 H NMR(dmso,600MHz)：δ(ppm)0.99-1.04(m,3H),1.04-1.13(m,3H),1.30-1.40(m,1H),1.62-1.71(m,1H),1.82-1.96(m,1H),2.01-2.17(m,1H),2.18-2.30(m,1H),2.36-2.43(m,2H),2.73-3.24(m,1H),3.39-4.09(m,1H),5.17-5.60(m,1H),5.60-5.67(m,2H),7.40-7.47(m,2H),7.47-7.51(m,1H),7.76-7.78(m,1H),7.89-7.92(m,1H),7.92-7.97(m,2H),7.98-8.07(m,1H),10.45-10.59(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.4；Rt=2.493min。 1 H NMR (dmso, 600MHz): δ (ppm) 0.99-1.04 (m, 3H), 1.04-1.13 (m, 3H), 1.30-1.40 (m, 1H), 1.62-1.71 (m, 1H), 1.82 -1.96(m, 1H), 2.01-2.17(m, 1H), 2.18-2.30(m, 1H), 2.36-2.43(m, 2H), 2.73-3.24(m, 1H), 3.39-4.09(m, 1H), 5.17-5.60(m, 1H), 5.60-5.67(m, 2H), 7.40-7.47(m, 2H), 7.47-7.51(m, 1H), 7.76-7.78(m, 1H), 7.89- 7.92 (m, 1H), 7.92-7.97 (m, 2H), 7.98-8.07 (m, 1H), 10.45-10.59 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.4; Rt=2.493 min.

步驟4：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(化合物813 )之合成：Step 4: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl) )-1-piperidinyl]-2-side oxyacetamide ( compound 813 ) synthesis:

將rel-N-[3-乙基-5-[[2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯P2(0.077g，140.08μmol)溶解於1,4-二噁烷(2mL)及水(1mL)之混合物中且將混合物在80℃下攪拌16h。完成之後，在減壓下濃縮反應混合物且將殘餘物提交至反相HPLC，以得到tel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(4-噻唑-2-基苯基)-1-哌啶基]-2-側氧基乙醯胺(0.0364g，80.97μmol，57.80%產率)。rel-N-[3-ethyl-5-[[2-[(2S,5R)-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]- 2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester P2 (0.077 g, 140.08 μmol) was dissolved in 1,4-dioxane (2 mL) and water (1 mL) and the mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was submitted to reverse phase HPLC to give tel-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5R )-5-methyl-2-(4-thiazol-2-ylphenyl)-1-piperidinyl]-2-oxyacetamide (0.0364 g, 80.97 μmol, 57.80% yield).

HPLC資料：50-75% MeOH-2-10min流速：30mL/min；裝載泵4mL/min MeOH，管柱Sun Fire 100 x 19mm，5mkmHPLC profile: 50-75% MeOH-2-10min Flow rate: 30mL/min; loading pump 4mL/min MeOH, column Sun Fire 100 x 19mm, 5mkm

1 H NMR(dmso,600MHz)：δ(ppm)1.00-1.04(m,3H),1.04-1.15(m,3H),1.29-1.40(m,1H),1.60-1.75(m,1H),1.82-1.94(m,1H),2.03-2.16(m,1H),2.19-2.29(m,1H),2.36-2.43(m,2H),2.72-3.24(m,1H),3.46-4.08(m,1H),5.18-5.60(m, 1H),5.60-5.68(m,2H),7.40-7.47(m,2H),7.47-7.51(m,1H),7.75-7.78(m,1H),7.88-7.92(m,1H),7.92-7.97(m,2H),7.98-8.08(m,1H),10.52(s,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 1.00-1.04 (m, 3H), 1.04-1.15 (m, 3H), 1.29-1.40 (m, 1H), 1.60-1.75 (m, 1H), 1.82 -1.94(m, 1H), 2.03-2.16(m, 1H), 2.19-2.29(m, 1H), 2.36-2.43(m, 2H), 2.72-3.24(m, 1H), 3.46-4.08(m, 1H), 5.18-5.60(m, 1H), 5.60-5.68(m, 2H), 7.40-7.47(m, 2H), 7.47-7.51(m, 1H), 7.75-7.78(m, 1H), 7.88- 7.92 (m, 1H), 7.92-7.97 (m, 2H), 7.98-8.08 (m, 1H), 10.52 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值449.2；實測值450.4；Rt=min。LCMS (ESI): [M+H] + m/z: calculated 449.2; found 450.4; Rt=min.

實例429. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物1005)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物982)之合成Example 429. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(5-methyl-2-pyridyl)- 1-Piperidinyl]-2-oxyacetamide (Compound 1005) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-5- Synthesis of methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2-oxyacetamide (compound 982)

Figure 110128222-A0202-12-1793-936
Figure 110128222-A0202-12-1793-936

步驟1：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-甲基-5-[[2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester and N-[3-methyl-5-[[2-[(2R,5R)-5-methyl -Synthesis of tert-butyl 2-(5-methyl-2-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(625.09mg，1.58mmol，N(C2H5)3)、5-甲基-2-(5-甲基-2-哌啶基)吡啶(300mg，1.58mmol)、HATU(659.41mg，1.73mmol)及TEA(175.49mg，1.73mmol，241.72μL)混合於DMSO(4mL)中且在20℃下攪拌2h。使反應混合物經歷HPLC。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (625.09 mg, 1.58 mmol, N(C2H5)3 ), 5-methyl-2-(5-methyl-2-piperidinyl)pyridine (300 mg, 1.58 mmol), HATU (659.41 mg, 1.73 mmol) and TEA (175.49 mg, 1.73 mmol, 241.72 μL) were mixed Stir in DMSO (4 mL) at 20 °C for 2 h. The reaction mixture was subjected to HPLC.

HPLC資料：2-10min20-45% MeCN/H2 O 30mL/min(裝載泵4mL MeCN)，管柱：SunFire 100*19mm，5微米HPLC profile: 2-10min 20-45% MeCN/H 2 O 30mL/min (loading pump 4mL MeCN), column: SunFire 100*19mm, 5 microns

獲得N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(90mg，粗品)。Obtained N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2- Pendant oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (90 mg, crude).

獲得N-[3-甲基-5-[[2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(367mg，784.93μmol，49.79%產率)(主要為順式)Obtained N-[3-methyl-5-[[2-[(2R,5R)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (367 mg, 784.93 μmol, 49.79% yield) (mainly cis)

LCMS(ESI)：[M+2H]+ m/z：計算值467.2；實測值469.2；Rt=3.031min。LCMS (ESI): [M+2H] + m/z: calculated 467.2; found 469.2; Rt=3.031 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物1005 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物982 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(5-methyl-2-pyridyl)- 1-Piperidinyl]-2-oxyacetamide ( Compound 1005 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5R)-5- Synthesis of methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2-oxyacetamide ( compound 982 )

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(90mg，192.49μmol)溶解於二噁烷(1.5mL)及水(0.5mL)中且在90℃下攪拌隔夜。使反應混合物經歷HPLC。N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-(5-methyl-2-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (90 mg, 192.49 μmol) was dissolved in dioxane (1.5 mL) and water (0.5 mL) and stirred at 90 °C overnight. The reaction mixture was subjected to HPLC.

HPLC資料：2-10min 10-50% MeCN+TFA，30mL/min(裝載泵4mL MeCN)，管柱：SunFire 100*19mm，5微米HPLC profile: 2-10min 10-50% MeCN+TFA, 30mL/min (loading pump 4mL MeCN), column: SunFire 100*19mm, 5 microns

獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(5-甲基-2-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(17.3mg，47.08μmol，24.46%產率)。Obtained N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(5-methyl-2-pyridyl)-1- Piperidinyl]-2-oxoacetamide (17.3 mg, 47.08 μmol, 24.46% yield).

化合物1005： 1 H NMR(600MHz,DMSO-d 6 )δ 0.97-1.04(m,3H),1.26-1.35(m,1H),1.56-1.66(m,1H),1.78-1.88(m,1H),1.88-1.96(m,1H),1.97-2.04(m,3H),2.24-2.29(m,3H),2.40-2.43(m,1H),2.77-2.97(m,1H),3.52-4.07(m,1H),5.13-5.54(m,1H),5.55-5.63(m,2H),7.15-7.34(m,1H),7.40-7.49(m,1H),7.58-7.64(m,1H),7.93-8.03(m,1H),8.36-8.42(m,1H),10.32-10.54(m,1H)。 Compound 1005: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.97-1.04 (m, 3H), 1.26-1.35 (m, 1H), 1.56-1.66 (m, 1H), 1.78-1.88 (m, 1H) ,1.88-1.96(m,1H),1.97-2.04(m,3H),2.24-2.29(m,3H),2.40-2.43(m,1H),2.77-2.97(m,1H),3.52-4.07( m,1H),5.13-5.54(m,1H),5.55-5.63(m,2H),7.15-7.34(m,1H),7.40-7.49(m,1H),7.58-7.64(m,1H), 7.93-8.03 (m, 1H), 8.36-8.42 (m, 1H), 10.32-10.54 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=1.730min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=1.730 min.

化合物982： 1 H NMR(600MHz,DMSO-d 6 )δ 0.67-0.81(m,3H),0.96-1.06(m,1H),1.54-1.70(m,2H),1.72-1.90(m,1H),1.99-2.07(m,3H),2.24-2.29(m,3H), 2.59-2.72(m,2H),3.61-4.25(m,1H),5.14-5.61(m,1H),5.67-6.29(m,2H),7.16-7.31(m,1H),7.48-7.58(m,1H),7.59-7.64(m,1H),7.97-8.09(m,1H),8.36-8.42(m,1H),10.49-10.75(m,1H)。 Compound 982: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.67-0.81 (m, 3H), 0.96-1.06 (m, 1H), 1.54-1.70 (m, 2H), 1.72-1.90 (m, 1H) ,1.99-2.07(m,3H),2.24-2.29(m,3H), 2.59-2.72(m,2H),3.61-4.25(m,1H),5.14-5.61(m,1H),5.67-6.29( m,2H),7.16-7.31(m,1H),7.48-7.58(m,1H),7.59-7.64(m,1H),7.97-8.09(m,1H),8.36-8.42(m,1H), 10.49-10.75 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=1.846min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=1.846 min.

實例430.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1074及化合物1045)之合成Example 430. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chlorophenyl)-4,4-difluoro-5-methylpiperidine-1 Synthesis of -yl)-2-oxoacetamide (Compound 1074 and Compound 1045)

Figure 110128222-A0202-12-1795-937
Figure 110128222-A0202-12-1795-937

步驟1：外消旋-(5-(2-((2S,5R)-2-(3-氯苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(5-(2-((2S,5R)-2-(3-chlorophenyl)-4,4-difluoro-5-methylpiperidin-1-yl)-2 -Synthesis of tert-butyl oxyacetamido)-3-methylpyridin-2-yl)carbamate

將(2R,5R )-2-(3-氯苯基)-4,4-二氟-5-甲基哌啶(300mg，1.22mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(360.56mg，1.22mmol)、TEA(370.67mg，3.66mmol，510.56μL)混合於DMF(6mL)中，然後添加HATU(696.40mg，1.83mmol)。將所得混合物在25℃下攪拌12h。蒸發溶劑且藉由HPLC(45-90% 2-10min；水-MeOH 30ml/min；裝載泵MeOH 4ml/min，目標質量511，管柱SunFire 19*100mm 5um)純化粗品沉澱，以獲得N -[5-[[2-[(2R,5R )-2-(3-氯苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(102.8mg，196.57μmol，16.10%產率)。( 2R,5R )-2-(3-chlorophenyl)-4,4-difluoro-5-methylpiperidine (300 mg, 1.22 mmol), 2-[[6-( tert- butoxycarbonyl Amino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (360.56 mg, 1.22 mmol), TEA (370.67 mg, 3.66 mmol, 510.56 μL) were mixed in DMF (6 mL) , then HATU (696.40 mg, 1.83 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the crude precipitate was purified by HPLC (45-90% 2-10min; water-MeOH 30ml/min; loading pump MeOH 4ml/min, target mass 511, column SunFire 19*100mm 5um) to obtain N- [ 5-[[2-[( 2R,5R )-2-(3-chlorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxoacetoxy ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (102.8 mg, 196.57 [mu]mol, 16.10% yield).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=1.372min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=1.372 min.

步驟2：掌性分離Step 2: Palm Separation

藉由掌性層析(IA-II(250*20，5mkm)，IPA-MeOH，50-50，12ml/min)分離非鏡像異構物之混合物，以獲得N -[5-[[2-[(2S,5R )-2-(3-氯苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(33.06mg，63.22μmol，31.55%產率)(其中RT=15.17min)及N -[5-[[2-[(2R,5S )-2-(3-氯苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(38.78mg，74.15μmol，37.72%產率)(其中RT=21.89min)。The mixture of diastereomers was separated by chiral chromatography (IA-II (250*20, 5mkm), IPA-MeOH, 50-50, 12ml/min) to obtain N- [5-[[2- [( 2S,5R )-2-(3-Chlorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3 -Methyl-2-pyridyl]carbamic acid tert- butyl ester E1 (33.06 mg, 63.22 μmol, 31.55% yield) (wherein RT=15.17 min) and N- [5-[[2-[( 2R,5S )-2-(3-Chlorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2 - tert -butyl pyridyl]carbamate E2 (38.78 mg, 74.15 μmol, 37.72% yield) (wherein RT=21.89 min).

E1於分析條件下(管柱：IC，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為15.08min且E2之保留時間為23.16min。The retention time of E1 under analytical conditions (column: IC, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 15.08 min and the retention time of E2 was 23.16 min.

E1：保留時間：15.08minE1: retention time: 15.08min

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=3.820min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=3.820 min.

E2：保留時間：23.16minE2: retention time: 23.16min

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=3.818min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=3.818 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3-氯苯基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1074 及化合物1045 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3-chlorophenyl)-4,4-difluoro-5-methylpiperidine-1 Synthesis of -yl)-2-oxoacetamide ( Compound 1074 and Compound 1045 )

將N -[5-[[2-[(2S,5R )-2-(3-氯苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E1(33.06mg，63.22μmol)及N -[5-[[2-[(2R,5S )-2-(3-氯苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯E2(38.78mg，74.15μmol)於水(2mL)及二噁烷(2mL)中之溶液在100℃下加熱12h。蒸發溶劑且藉由HPLC(2-10min 55-65% MeOH 30ml/min，裝載泵4ml/min MeOH，目標質量422，管柱：SunFire 100*19mm，5微米)純化所得沉澱，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3-氯苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(19.4mg，45.88μmol，72.57%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(3-氯苯基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(22.7mg，53.68μmol，72.39%產率)。 N- [5-[[2-[( 2S,5R )-2-(3-chlorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester E1 (33.06 mg, 63.22 μmol) and N- [5-[[2-[( 2R,5S )- 2-(3-Chlorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridine A solution of tert -butyl ]carbamate E2 (38.78 mg, 74.15 [mu]mol) in water (2 mL) and dioxane (2 mL) was heated at 100&lt;0&gt;C for 12 h. The solvent was evaporated and the resulting precipitate was purified by HPLC (2-10 min 55-65% MeOH 30 ml/min, loading pump 4 ml/min MeOH, target mass 422, column: SunFire 100*19 mm, 5 microns) to obtain N- ( 6-Amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(3-chlorophenyl)-4,4-difluoro-5-methyl-1-piperidine Peridyl]-2-oxyacetamide (19.4 mg, 45.88 μmol, 72.57% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R, 5S )-2-(3-chlorophenyl)-4,4-difluoro-5-methyl-1-piperidinyl]-2-oxyacetamide (22.7 mg, 53.68 μmol, 72.39% yield Rate).

化合物1074： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(d,3H),2.05(s,3H),2.20(m,1H),2.45(m,1H),2.87(m,1H),3.42(m,1H),4.02(m,1H),5.62(m,1H),5.82(m,2H),7.37(m,4H),7.52(m,1H),8.05(m,1H),10.67(m,1H)。 Compound 1074: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.08 (d, 3H), 2.05 (s, 3H), 2.20 (m, 1H), 2.45 (m, 1H), 2.87 (m, 1H), 3.42(m, 1H), 4.02(m, 1H), 5.62(m, 1H), 5.82(m, 2H), 7.37(m, 4H), 7.52(m, 1H), 8.05(m, 1H) ), 10.67(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=1.127min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=1.127 min.

化合物1045： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.08(d,3H),2.05(s,3H),2.22(m,1H),2.42(m,1H),2.87(m,1H),3.44(m,1H),4.02(m,1H),5.62(m,1H),5.82(m,2H),7.37(m,4H),7.52(m,1H),8.05(m,1H),10.67(m,1H)。 Compound 1045: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.08 (d, 3H), 2.05 (s, 3H), 2.22 (m, 1H), 2.42 (m, 1H), 2.87 (m, 1H), 3.44(m, 1H), 4.02(m, 1H), 5.62(m, 1H), 5.82(m, 2H), 7.37(m, 4H), 7.52(m, 1H), 8.05(m, 1H) ), 10.67(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=1.127min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=1.127 min.

實例431. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物593)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物608)之合成Example 431. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-4-pyridyl)- 1-Piperidinyl]-2-oxyacetamide (Compound 593) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5- Synthesis of methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]-2-oxyacetamide (compound 608)

Figure 110128222-A0202-12-1797-938
Figure 110128222-A0202-12-1797-938

步驟1.外消旋-N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1. Racemic-N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidine Synthesis of 3-butyl pyridyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamate

將DIPEA(525.22mg，4.06mmol，707.84μL)添加到相應2-[[6-(第三 丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)及2-甲基-4-[(2R,5S)-5-甲基-2-哌啶基]吡啶(193.32mg，1.02mmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(424.92mg，1.12mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以H2 O-MeCN為溶析液混合物)，以得到純的N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.24g，513.30μmol，50.52%產率)。DIPEA (525.22 mg, 4.06 mmol, 707.84 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo acetic acid (0.3 g, 1.02 mmol) and 2-methyl-4-[(2R,5S)-5-methyl-2-piperidinyl]pyridine (193.32 mg, 1.02 mmol) in DMF (5 mL) in solution. The resulting mixture was stirred for 5 min before HATU (424.92 mg, 1.12 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with H2O -MeCN as eluent mixture) to give pure N-[3-methyl-5-[[2-[ (2S,5R)-5-Methyl-2-(2-methyl-4-pyridinyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl] tert-butyl carbamate (0.24 g, 513.30 μmol, 50.52% yield).

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值468.2；Rt=1.845min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 468.2; Rt=1.845 min.

步驟2.N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯及N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 2. N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester and N-[3-methyl-5-[[2-[(2R,5S)-5-methyl -Synthesis of 3-butyl 2-(2-methyl-4-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

在以下條件下分離鏡像異構物：管柱：Chiral ART纖維素-SC(250*20，5mkm)；流動相：己烷-IPA-MeOH，50-25-25，流速：12mL/min；管柱溫度：24℃；波長：205nm，256nm，290nm)，保留時間(順式異構物)=21.53；保留時間(反式異構物)=23.03min；保留時間(順式異構物)=31.75min；保留時間(反式異構物)=39.93minEnantiomers were separated under the following conditions: Column: Chiral ART Cellulose-SC (250*20, 5mkm); Mobile Phase: Hexane-IPA-MeOH, 50-25-25, Flow Rate: 12 mL/min; Tube Column temperature: 24°C; wavelength: 205nm, 256nm, 290nm), retention time (cis isomer)=21.53; retention time (trans isomer)=23.03min; retention time (cis isomer)= 31.75min; retention time (trans isomer)=39.93min

分析資料：儀器：反相及梯度：CO2-MeOH,60-40,2ml/min，管柱：IC，反式異構物1之保留時間=11.60min；反式異構物2之保留時間=23.98min；Analytical data: Instrument: reverse phase and gradient: CO2-MeOH, 60-40, 2ml/min, column: IC, retention time of trans isomer 1=11.60min; retention time of trans isomer 2= 23.98min;

步驟3A.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物593 )之合成Step 3A. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-4-pyridyl)- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 593 )

將N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(103.22mg，220.76μmol， 異構物 2 )溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH(50-60%)為溶析液混合物)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(48.6mg，132.27μmol，59.91%產率)。N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (103.22 mg, 220.76 μmol, isomer 2 ) was dissolved in a mixture of dioxane (2 mL) and water (5 mL) . Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH (50-60%) as eluent mixture) to give pure N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]-2-side oxy Acetamide (48.6 mg, 132.27 μmol, 59.91% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.94-1.03(m,3H),1.26-1.39(m,1H),1.50-1.63(m,1H),1.80-1.92(m,1H),1.97-2.03(m,3H),2.03-2.13(m,1H),2.13-2.23(m,1H),2.49-2.53(m,3H),2.71-3.18(m,1H),3.45-4.08(m,1H),5.08-5.53(m,1H),5.54-5.67(m,2H),7.04-7.13(m,1H),7.13-7.22(m,1H),7.37-7.53(m,1H),7.91-8.06(m,1H),8.35-8.46(m,1H),10.46-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.94-1.03(m,3H), 1.26-1.39(m,1H), 1.50-1.63(m,1H), 1.80-1.92(m,1H), 1.97- 2.03(m, 3H), 2.03-2.13(m, 1H), 2.13-2.23(m, 1H), 2.49-2.53(m, 3H), 2.71-3.18(m, 1H), 3.45-4.08(m, 1H ), 5.08-5.53(m, 1H), 5.54-5.67(m, 2H), 7.04-7.13(m, 1H), 7.13-7.22(m, 1H), 7.37-7.53(m, 1H), 7.91-8.06 (m, 1H), 8.35-8.46 (m, 1H), 10.46-10.61 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.4；Rt=1.035min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.4; Rt=1.035 min.

步驟3B.N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物608 )之合成Step 3B. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-methyl-4-pyridyl)- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 608 )

將N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(88.45mg，189.17μmol， 異構物1 )溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH(50-60%)為溶析液混合物)，以得到純的N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-甲基-4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(50.6mg，137.71μmol，72.79%產率)N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]-2- Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (88.45 mg, 189.17 μmol, isomer 1 ) was dissolved in a mixture of dioxane (2 mL) and water (5 mL) . Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH (50-60%) as eluent mixture) to give pure N-(6-amino-5 -Methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-methyl-4-pyridyl)-1-piperidinyl]-2-pendoxyl Acetamide (50.6 mg, 137.71 μmol, 72.79% yield)

1 H NMR(600MHz,DMSO-d 6 )δ 0.94-1.03(m,3H),1.26-1.39(m,1H),1.50-1.63(m,1H),1.80-1.92(m,1H),1.97-2.03(m,3H),2.03-2.13(m,1H),2.13-2.23(m, 1H),2.49-2.53(m,3H),2.71-3.18(m,1H),3.45-4.08(m,1H),5.08-5.53(m,1H),5.54-5.67(m,2H),7.04-7.13(m,1H),7.13-7.22(m,1H),7.37-7.53(m,1H),7.91-8.06(m,1H),8.35-8.46(m,1H),10.46-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.94-1.03(m,3H), 1.26-1.39(m,1H), 1.50-1.63(m,1H), 1.80-1.92(m,1H), 1.97- 2.03(m,3H),2.03-2.13(m,1H),2.13-2.23(m,1H),2.49-2.53(m,3H),2.71-3.18(m,1H),3.45-4.08(m,1H ), 5.08-5.53(m, 1H), 5.54-5.67(m, 2H), 7.04-7.13(m, 1H), 7.13-7.22(m, 1H), 7.37-7.53(m, 1H), 7.91-8.06 (m, 1H), 8.35-8.46 (m, 1H), 10.46-10.61 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.4；Rt=1.035min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.4; Rt=1.035 min.

實例432.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(吡啶-4-基)哌啶-1-基)-2-側氧基乙醯胺(化合物609及化合物592)之合成Example 432. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(pyridin-4-yl)piperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 609 and Compound 592)

Figure 110128222-A0202-12-1800-939
Figure 110128222-A0202-12-1800-939

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(吡啶-4-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-methyl-5-(2-((2R,5S)-5-methyl-2-(pyridin-4-yl)piperidin-1-yl)-2-side Synthesis of tert-butyl oxyacetamido)pyridin-2-yl)carbamate

將DIPEA(525.22mg，4.06mmol，707.84μL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(0.3g，1.02mmol)及4-[(2S,5R )-5-甲基-2-哌啶基]吡啶(179.07mg，1.02mmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(424.92mg，1.12mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(管柱：Triart 100*20*5mm，水-MeOH為溶析液混合物)，以得到純的N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.24g，529.18μmol，52.09%產率)。DIPEA (525.22 mg, 4.06 mmol, 707.84 μL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxo Ethylacetic acid (0.3 g, 1.02 mmol) and 4-[( 2S,5R )-5-methyl-2-piperidinyl]pyridine (179.07 mg, 1.02 mmol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (424.92 mg, 1.12 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (column: Triart 100*20*5 mm, water-MeOH as eluent mixture) to obtain pure N- [3-methyl-5-[[2-[( 2S, 5R )-5-methyl-2-(4-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.24 g, 529.18 μmol, 52.09% yield).

1 H NMR(400MHz,DMSO-d 6 δ(ppm)0.98(d,3H),1.32(m,1H),1.42(s,9H),1.58(m,1H),1.88(m,1H),2.12(m,1H),2.24(s,3H),3.22(m,1H),3.51(m,1H),4.08(m, 1H),5.48(m,1H),7.32(d,2H),7.92(m,1H),8.41(m,1H),8.56(d,2H),9.04(m,1H),11.11(m,1H)。 1 H NMR (400MHz, DMSO- d 6 δ(ppm) 0.98(d, 3H), 1.32(m, 1H), 1.42(s, 9H), 1.58(m, 1H), 1.88(m, 1H), 2.12 (m, 1H), 2.24(s, 3H), 3.22(m, 1H), 3.51(m, 1H), 4.08(m, 1H), 5.48(m, 1H), 7.32(d, 2H), 7.92( m, 1H), 8.41 (m, 1H), 8.56 (d, 2H), 9.04 (m, 1H), 11.11 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.889min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.889 min.

步驟2：掌性分離Step 2: Palm Separation

使外消旋 -(3-甲基-5-(2-((2R,5S )-5-甲基-2-(吡啶-4-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯(240.00mg，529.18μmol)經歷掌性HPLC純化(管柱：ID-H-III(250*20，5mkm)，溶析液：己烷-IPA-MeOH，60-20-20，流速：12mL/min)，以得到兩種單獨的鏡像異構物E1N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(71.45mg，157.54μmol，29.77%產率)及E2N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(82mg，180.80μmol，34.17%產率)。make rac- (3-methyl-5-(2-(( 2R,5S )-5-methyl-2-(pyridin-4-yl)piperidin-1-yl)-2-pendoxyl Acetamido)pyridin-2-yl)carbamic acid tert-butyl ester (240.00 mg, 529.18 μmol) was purified by chiral HPLC (column: ID-H-III (250*20, 5 mkm), eluent: Hexane-IPA-MeOH, 60-20-20, flow rate: 12 mL/min) to give two separate enantiomers E1 N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-(4-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (71.45mg , 157.54 μmol, 29.77% yield) and E2 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(4-pyridyl)-1-piperidine tert-butyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate (82 mg, 180.80 [mu]mol, 34.17% yield).

E1於分析條件下(管柱：IC，以IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為21.25min且E2之保留時間為55.10min。The retention time of E1 under analytical conditions (column: IC, with IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 21.25 min and that of E2 was 55.10 min.

E1：保留時間：38.91minE1: retention time: 38.91min

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.849min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.849 min.

E2：保留時間：55.10minE2: retention time: 55.10min

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.842min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.842 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(吡啶-4-基)哌啶-1-基)-2-側氧基乙醯胺(化合物609 及化合物592 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(pyridin-4-yl)piperidin-1-yl)-2-side Synthesis of Oxyacetamide ( Compound 609 and Compound 592 )

將N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(71.45mg，157.54μmol)及N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(82mg，180.80μmol)溶解於二噁烷(2mL)及水(5mL)之混合物 中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(管柱：Triart 100*20*5mm，水-MeCN為溶析液混合物)，以得到純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(44.1mg，124.78μmol，79.21%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(4-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(43.8mg，123.93μmol，68.55%產率)。 N- [3-Methyl-5-[[2-[( 2S,5R )-5-methyl-2-(4-pyridyl)-1-piperidinyl]-2-oxoacetyl N- [ 3 -methyl-5-[[2-[( 2R,5S )-5-methyl -2-(4-Pyridinyl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert- butyl ester (82 mg, 180.80 μmol) was dissolved in in a mixture of oxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (column: Triart 100*20*5 mm, water-MeCN as eluent mixture) to obtain pure N- (6-amino-5-methyl-3-pyridyl) -2-[( 2S,5R )-5-methyl-2-(4-pyridyl)-1-piperidinyl]-2-oxyacetamide (44.1 mg, 124.78 μmol, 79.21% yield ) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(4-pyridyl)-1-piperidinyl] -2-Pendant oxyacetamide (43.8 mg, 123.93 μmol, 68.55% yield).

化合物609： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.25-1.41(m,1H),1.51-1.59(m,1H),1.76-1.91(m,1H),1.92-2.10(m,4H),2.11-2.25(m,1H),2.65-3.24(m,1H),3.41-4.08(m,1H),5.15-5.57(m,1H),5.57-5.69(m,2H),7.25-7.38(m,2H),7.42-7.53(m,1H),7.91-8.05(m,1H),8.51-8.60(m,2H),10.44-10.65(m,1H)。 Compound 609: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98-1.04 (m, 3H), 1.25-1.41 (m, 1H), 1.51-1.59 (m, 1H), 1.76-1.91 (m ,1H),1.92-2.10(m,4H),2.11-2.25(m,1H),2.65-3.24(m,1H),3.41-4.08(m,1H),5.15-5.57(m,1H),5.57 -5.69(m, 2H), 7.25-7.38(m, 2H), 7.42-7.53(m, 1H), 7.91-8.05(m, 1H), 8.51-8.60(m, 2H), 10.44-10.65(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值353.2；實測值354.2；Rt=0.590min。LCMS (ESI): [M] + m/z: calculated 353.2; found 354.2; Rt=0.590 min.

化合物592： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.26-1.40(m,1H),1.46-1.61(m,1H),1.80-1.92(m,1H),1.97-2.13(m,4H),2.15-2.27(m,1H),2.68-3.21(m,1H),3.44-4.07(m,1H),5.15-5.56(m,1H),5.57-5.69(m,2H),7.28-7.36(m,2H),7.42-7.51(m,1H),7.91-8.03(m,1H),8.52-8.59(m,2H),10.48-10.67(m,1H)。 Compound 592: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98-1.04 (m, 3H), 1.26-1.40 (m, 1H), 1.46-1.61 (m, 1H), 1.80-1.92 (m ,1H),1.97-2.13(m,4H),2.15-2.27(m,1H),2.68-3.21(m,1H),3.44-4.07(m,1H),5.15-5.56(m,1H),5.57 -5.69(m, 2H), 7.28-7.36(m, 2H), 7.42-7.51(m, 1H), 7.91-8.03(m, 1H), 8.52-8.59(m, 2H), 10.48-10.67(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值353.2；實測值354.2；Rt=0.591min。LCMS (ESI): [M] + m/z: calculated 353.2; found 354.2; Rt=0.591 min.

實例433. rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物944)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物973)之合成Example 433. rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6- Methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide (compound 944) and rel-N-(6-amino-5-methyl-3-pyridyl)- 2-[(2R,5R)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 973)

Figure 110128222-A0202-12-1803-940
Figure 110128222-A0202-12-1803-940

步驟1：外消旋-N-[5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: Racemic-N-[5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridinyl)-1 -Synthesis of tert-butyl-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向5-[(2S,5S)-4,4-二氟-5-甲基-2-哌啶基]-2-甲基吡啶(0.4g，1.77mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(574.23mg，1.94mmol)及三乙胺(894.44mg，8.84mmol，1.23mL)中之溶液中分批添加HATU(806.62mg，2.12mmol)。將所得混合物在25℃下攪拌12h，溶解於水(50mL)中且用EtOAc(3*20mL)萃取。將經合併之有機層用鹽水(2*25mL)洗滌，經Na2 SO4 乾燥且移除溶劑，以得到N-[5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.7g，1.39mmol，78.64%產率)。To 5-[(2S,5S)-4,4-difluoro-5-methyl-2-piperidinyl]-2-methylpyridine (0.4 g, 1.77 mmol), 2-[[6-(th Tributoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-side oxyacetic acid (574.23 mg, 1.94 mmol) and triethylamine (894.44 mg, 8.84 mmol, 1.23 mL) To the solution was added HATU (806.62 mg, 2.12 mmol) in portions. The resulting mixture was stirred at 25 °C for 12 h, dissolved in water (50 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were washed with brine (2*25 mL), dried over Na2SO4 and solvent removed to give N-[5-[[2-[(2S,5S)-4,4-difluoro -5-Methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl] tert-butyl carbamate (0.7 g, 1.39 mmol, 78.64% yield).

此化合物不經進一步純化即用於下一步驟。This compound was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值503.2；實測值504.2；Rt=0.950min。LCMS (ESI): [M+H] + m/z: calculated 503.2; found 504.2; Rt=0.950 min.

步驟2：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: Racemic-N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-( Synthesis of 6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide

將N-[5-[[2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.7g，1.39mmol)及於二噁烷中之4.0M氯化氫溶液(10g，274.27mmol，12.50mL)於DCM(10mL)中之溶液在25℃下攪拌24h。移除溶劑且藉由HPLC(15-65% 0-5min H2 O/MeOH/0.1% NH4OH，流速：30mL/min(裝載泵4mL/min甲醇)目標質量 403.44管柱：YMC Triart C18 100x20mm，5um)，以獲得N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(0.34g，842.78μmol，60.63%產率)。N-[5-[[2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.7 g, 1.39 mmol) and a 4.0 M solution of hydrogen chloride in dioxane (10 g, A solution of 274.27 mmol, 12.50 mL) in DCM (10 mL) was stirred at 25 °C for 24 h. Solvent was removed and analyzed by HPLC (15-65% 0-5 min H2O /MeOH/0.1% NH4OH, flow rate: 30 mL/min (load pump 4 mL/min methanol) target mass 403.44 Column: YMC Triart C18 100x20mm, 5um ) to obtain N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl) (0.34 g, 842.78 μmol, 60.63% yield).

此化合物不經HNMR即用於掌性拆分。This compound was used for chiral resolution without HNMR.

LCMS(ESI)：[M+H]+ m/z：計算值403.2；實測值404.2；Rt=1.203min。LCMS (ESI): [M+H] + m/z: calculated 403.2; found 404.2; Rt=1.203 min.

步驟3：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物944 )及rel-N-(6-胺基-5-甲基3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物973 )之合成Step 3: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6- Methyl-3-pyridyl)-1-piperidinyl]-2-oxyacetamide ( compound 944 ) and rel-N-(6-amino-5-methyl 3-pyridyl)-2 -[(2R,5R)-4,4-Difluoro-5-methyl-2-(6-methyl-3-pyridyl)-1-piperidinyl]-2-oxoacetamide ( Synthesis of compound 973 )

對外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(0.34g，842.78μmol)進行掌性分離(Chiralpak IA(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)，以獲得rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(50mg，123.94μmol，29.41%產率)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R)-4,4-二氟-5-甲基-2-(6-甲基-3-吡啶基)-1-哌啶基]-2-側氧基乙醯胺(65mg，161.12μmol，38.24%產率)。Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-difluoro-5-methyl-2-(6-methyl) chiral separation (Chiralpak IA (250*20, 5mkm), hexane-IPA- MeOH, 50-25-25, 12 mL/min) to obtain rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-4,4-di Fluoro-5-methyl-2-(6-methyl-3-pyridinyl)-1-piperidinyl]-2-oxyacetamide (50 mg, 123.94 μmol, 29.41% yield) and rel- N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5R)-4,4-difluoro-5-methyl-2-(6-methyl-3- Pyridinyl)-1-piperidinyl]-2-oxoacetamide (65 mg, 161.12 μmol, 38.24% yield).

化合物944： RT(IC，己烷-IPA-MeOH，50-25-25，0.15mL/min)=10.430min。 Compound 944: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 10.430 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.02-1.10(m,3H),1.93-2.04(m,3H),2.10-2.24(m,1H),2.37-2.45(m,4H),2.66-3.17(m,2H),3.75-4.30(m,1H),5.52-5.87(m,3H),7.16-7.29(m,1H),7.40-7.54(m,1H),7.56-7.64(m,1H),7.90-8.07(m,1H),8.36-8.42(m,1H),10.46-10.68(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.02-1.10 (m, 3H), 1.93-2.04 (m, 3H), 2.10-2.24 (m, 1H), 2.37-2.45 (m, 4H), 2.66- 3.17(m, 2H), 3.75-4.30(m, 1H), 5.52-5.87(m, 3H), 7.16-7.29(m, 1H), 7.40-7.54(m, 1H), 7.56-7.64(m, 1H) ), 7.90-8.07(m, 1H), 8.36-8.42(m, 1H), 10.46-10.68(m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值403.2；實測值405.4；Rt=1.144min。LCMS (ESI): [M+2H] + m/z: calculated 403.2; found 405.4; Rt=1.144 min.

化合物973： RT(IC，己烷-IPA-MeOH，50-25-25，0.15mL/min)=13.589min。 Compound 973: RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.15 mL/min) = 13.589 min.

1 H NMR(600MHz,DMSO-d 6 )δ 1.03-1.09(m,3H),1.93-2.04(m,3H),2.11-2.22 (m,1H),2.38-2.44(m,4H),2.80-3.22(m,2H),3.69-4.30(m,1H),5.53-5.62(m,1H),5.62-5.86(m,2H),7.16-7.28(m,1H),7.40-7.54(m,1H),7.54-7.63(m,1H),7.91-8.06(m,1H),8.34-8.42(m,1H),10.44-10.67(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.03-1.09 (m, 3H), 1.93-2.04 (m, 3H), 2.11-2.22 (m, 1H), 2.38-2.44 (m, 4H), 2.80- 3.22(m, 2H), 3.69-4.30(m, 1H), 5.53-5.62(m, 1H), 5.62-5.86(m, 2H), 7.16-7.28(m, 1H), 7.40-7.54(m, 1H) ), 7.54-7.63(m, 1H), 7.91-8.06(m, 1H), 8.34-8.42(m, 1H), 10.44-10.67(m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值403.2；實測值405.4：Rt=1.145min。LCMS (ESI): [M+2H] + m/z: calculated 403.2; found 405.4: Rt=1.145min.

實例434.N -(6-胺基-5-乙基吡啶-3-基)-2-(4,4-二氟-2-(1H -吲唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1357及化合物 1148)之合成 Example 434. N- (6-Amino-5-ethylpyridin-3-yl)-2-(4,4-difluoro-2-( 1H -indazol-5-yl)-5-methylpiperin Synthesis of pyridin-1-yl)-2-oxoacetamide (Compound 1357 and Compound 1148 )

Figure 110128222-A0202-12-1805-941
Figure 110128222-A0202-12-1805-941

步驟4：外消旋-(5-(2-((2R,5R)-4,4-二氟-2-(1H-吲唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-乙基吡啶-2-基)胺甲酸第三丁酯之合成 將 5-[(2S,5R )-4,4-二氟-5-甲基-2-哌啶基]-1H -吲唑(0.42g，1.67mmol)、TEA(1.69g，16.71mmol，2.33mL)及2-[[6-(第三丁氧基 羰基胺基)-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(517.02mg，1.67mmol)溶解於DMF(18mL)中且一次性添加HATU(953.32mg，2.51mmol)，將所得混合物在20℃下攪拌3h。將反應混合物倒入到水中且將水相用EtOAc(3次)萃取，然後將經合併之有機相用鹽水洗滌(3次)，經Na2 SO4 乾燥且在真空中濃縮。藉由反相HPLC(2-10min 55-70% MeOH 30ml/min，裝載泵4ml/min MeOH，目標質量542，管柱：SunFire 19*100mm，5微米)純化粗反應混合物。分離呈淡黃色固體之所要產物N -[5-[[2-[(2S,5R )-4,4-二氟-2-(1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.071g，130.86umol，7.83%產率)。 Step 4: Racemic-(5-(2-((2R,5R)-4,4-difluoro-2-(1H-indazol-5-yl)-5-methylpiperidin-1-yl )-2-oxyacetamido)-3-ethylpyridin-2-yl)carbamic acid tert-butyl ester Methyl-2-piperidinyl] -1H -indazole (0.42 g, 1.67 mmol), TEA (1.69 g, 16.71 mmol, 2.33 mL) and 2-[[6-( tert- butoxycarbonylamino) -5-ethyl-3-pyridyl]amino]-2-pendoxoacetic acid (517.02 mg, 1.67 mmol) was dissolved in DMF (18 mL) and HATU (953.32 mg, 2.51 mmol) was added in one portion and the resulting The mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (3 times), then the combined organic phases were washed with brine (3 times), dried over Na 2 SO 4 and concentrated in vacuo. The crude reaction mixture was purified by reverse phase HPLC (2-10 min 55-70% MeOH 30 ml/min, loading pump 4 ml/min MeOH, target mass 542, column: SunFire 19*100 mm, 5 microns). The desired product N- [5-[[2-[( 2S,5R )-4,4-difluoro-2-( 1H -indazol-5-yl)-5-methyl-1 was isolated as a pale yellow solid -Piperidinyl]-2-Pendant oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert -butyl ester (0.071 g, 130.86 umol, 7.83% yield).

LCMS(ESI)：[M]+ m/z：計算值542.2；實測值543.2；Rt=1.365min。LCMS (ESI): [M] + m/z: calculated 542.2; found 543.2; Rt=1.365 min.

步驟5：掌性分離Step 5: Palm Separation

Figure 110128222-A0202-12-1806-942
Figure 110128222-A0202-12-1806-942

使用(管柱：Chiralpak IB(250*20，5mkm)；流動相：己烷-IPA-MeOH，70-15-15，流速：12mL/min；管柱溫度：24℃；波長：205nm，258nm，290nm)進行掌性分離，以得到N -[5-[[2-[(2S,5R)-4,4-二氟-2-(1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.018g，33.18umol，25.35%產率)(RT為12.445min)及N -[5-[[2-[(2R,5S)-4,4-二氟-2-(1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.02g，36.86umol，28.17%產率)(RT為13.865min)。Use (column: Chiralpak IB (250*20, 5mkm); mobile phase: hexane-IPA-MeOH, 70-15-15, flow rate: 12mL/min; column temperature: 24°C; wavelength: 205nm, 258nm, 290 nm) for chiral separation to give N- [5-[[2-[(2S,5R)-4,4-difluoro-2-( 1H -indazol-5-yl)-5-methyl- 1-Piperidinyl]-2-oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert- butyl ester (0.018 g, 33.18 umol, 25.35% yield) (RT for 12.445min) and N- [5-[[2-[(2R,5S)-4,4-difluoro-2-( 1H -indazol-5-yl)-5-methyl-1-piperidine (0.02 g, 36.86 umol, 28.17% yield) (RT: 13.865 min) .

E1於分析條件下(管柱：IB，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為15.37min且E2之保留時間為18.40min。The retention time of E1 under analytical conditions (column: IB, with hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 15.37 min and the retention time of E2 was 18.40 min.

E1：E1:

保留時間：15.37minRetention time: 15.37min

LCMS(ESI)：[M]+ m/z：計算值542.2；實測值543.2；Rt=1.306min。LCMS (ESI): [M] + m/z: calculated 542.2; found 543.2; Rt=1.306 min.

E2：E2:

保留時間：18.40minRetention time: 18.40min

LCMS(ESI)：[M]+ m/z：計算值542.2；實測值543.2；Rt=1.307min。LCMS (ESI): [M] + m/z: calculated 542.2; found 543.2; Rt=1.307 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-(4,4-二氟-2-(1H-吲唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1148及化合物1357)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-(4,4-difluoro-2-(1H-indazol-5-yl)-5-methylpiperin Synthesis of pyridin-1-yl)-2-oxoacetamide (Compound 1148 and Compound 1357)

將N -[5-[[2-[(2R,5R )-4,4-二氟-2-(1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.018g，33.18umol)及N -[5-[[2-[(2S,5S )-4,4-二氟-2-(1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基] 胺基]-3-乙基-2-吡啶基]胺甲酸第三丁 酯(0.02g，36.86umol)溶解於二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空下濃縮反應混合物。藉由HPLC(2-10min 45-60% MeOH 30ml/min，裝載泵4ml/min MeOH，目標質量442，管柱：SunFire 100*19mm，5微米)純化粗反應混合物。獲得呈淡黃色固體之所要產物N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-4,4-二氟-2-(1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.009g，20.34umol，61.31%產率)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-4,4-二氟-2-(1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.01g，22.60umol，61.31%產率)。 N- [5-[[2-[( 2R,5R )-4,4-difluoro-2-( 1H -indazol-5-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert -butyl ester (0.018g, 33.18umol) and N- [5-[[2-[( 2S, 5S )-4,4-Difluoro-2-( 1H -indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3- Ethyl-2-pyridyl]carbamic acid tert -butyl ester (0.02 g, 36.86 umol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL), then stirred at 100 °C for 12 h. The reaction mixture was concentrated under vacuum. The crude reaction mixture was purified by HPLC (2-10 min 45-60% MeOH 30 ml/min, loading pump 4 ml/min MeOH, target mass 442, column: SunFire 100*19 mm, 5 microns). The desired product, N- (6-amino-5-ethyl-3-pyridinyl)-2-[( 2S,5R )-4,4-difluoro-2-( 1H -indazole, was obtained as a pale yellow solid -5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (0.009 g, 20.34 umol, 61.31% yield) and N-(6-amino-5-ethyl) yl-3-pyridyl)-2-[( 2R,5S )-4,4-difluoro-2-( 1H -indazol-5-yl)-5-methyl-1-piperidinyl]-2 - Pendant oxyacetamide (0.01 g, 22.60 umol, 61.31% yield).

化合物1357：Compound 1357:

LCMS(ESI)：[M]+ m/z：計算值442.2；實測值443.2；Rt=0.986min。LCMS (ESI): [M] + m/z: calculated 442.2; found 443.2; Rt=0.986 min.

化合物1148：Compound 1148:

LCMS(ESI)：[M]+ m/z：計算值442.2；實測值443.2；Rt=0.987min。LCMS (ESI): [M] + m/z: calculated 442.2; found 443.2; Rt=0.987 min.

實例435. N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(7-氟-1H-吲唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1350及化合物1191)之合成Example 435. N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(7-fluoro-1H-indazol-5-yl)-5-methylpiperidine-1 Synthesis of -yl)-2-oxoacetamide (Compound 1350 and Compound 1191)

Figure 110128222-A0202-12-1807-943
Figure 110128222-A0202-12-1807-943

步驟1：(5-(2-(2-(7-氟-1H-吲唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(7-Fluoro-1H-indazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)- Synthesis of 3-methylpyridin-2-yl)carbamic acid tert-butyl ester

將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸 (1.09g，3.69mmol)及7-氟-5-(5-甲基-2-哌啶基)-1H -吲唑(0.86g，3.69mmol)混合於DMF(50mL)中。將反應懸浮液冷卻至0℃且添加HATU(1.54g，4.06mmol)，隨後添加TEA(746.07mg，7.37mmol，1.03mL)且在室溫下攪拌14h。將反應混合物在真空中蒸發且倒入到水(100ml)中且用EtOAc(2x50ml)萃取。將經合併之有機萃取物用水洗滌(2*30ml)，經硫酸鈉乾燥且在真空中蒸發，以得到產物N -[5-[[2-[2-(7-氟-1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1.42g，2.78mmol，75.44%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridinyl]amino]-2-oxoacetic acid (1.09 g, 3.69 mmol) and 7-fluoro- 5-(5-Methyl-2-piperidinyl) -lH -indazole (0.86 g, 3.69 mmol) was mixed in DMF (50 mL). The reaction suspension was cooled to 0 °C and HATU (1.54 g, 4.06 mmol) was added followed by TEA (746.07 mg, 7.37 mmol, 1.03 mL) and stirred at room temperature for 14 h. The reaction mixture was evaporated in vacuo and poured into water (100ml) and extracted with EtOAc (2x50ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo to give the product N- [5-[[2-[2-(7-fluoro- lH -indazole- 5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (1.42 g, 2.78 mmol, 75.44% yield).

LCMS(ESI)：[M]+ m/z：計算值510.2；實測值511.2；Rt=1.284min。LCMS (ESI): [M] + m/z: calculated 510.2; found 511.2; Rt=1.284 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(7-氟-1H-吲唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(7-fluoro-1H-indazol-5-yl)-5-methylpiperidine-1 -Base)-2-Side Oxyacetamide Synthesis

在室溫下將水(10mL)添加到N -[5-[[2-[2-(7-氟-1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1.42g，2.78mmol)於二噁烷(30mL)中之經攪拌之溶液中。將所得混合物在100℃下攪拌15h，然後在真空中蒸發且藉由製備型(35-75% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min)純化0.9g所獲得之粗產物，以得到產物N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(7-氟-1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.400g，974.55umol，35.04%產率)。Water (10 mL) was added to N- [5-[[2-[2-(7-fluoro- 1H -indazol-5-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (1.42 g, 2.78 mmol) in a stirred solution of dioxane (30 mL) . The resulting mixture was stirred at 100 °C for 15 h, then evaporated in vacuo and 0.9 g of the resulting mixture was purified by preparative (35-75% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min) The crude product was obtained to give the product N- (6-amino-5-methyl-3-pyridyl)-2-[2-(7-fluoro- 1H -indazol-5-yl)-5-methyl yl-1-piperidinyl]-2-oxoacetamide (0.400 g, 974.55 umol, 35.04% yield).

LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=2.340min。LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=2.340 min.

步驟3：掌性分離(化合物1350及化合物1191)Step 3: Chiral separation (compound 1350 and compound 1191)

對外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[2-(7-氟-1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.400g，974.55umol)進行掌性分離(管柱：Chiralcel OD-H(250*20，5um)，溶析液：己烷-IPA-MeOH，50-25-25，流速：12mL/min)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(7-氟-1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(110.40mg，268.98umol，27.60%產率)及N-(6-胺基-5-甲 基-3-吡啶基)-2-[(2S,5R )-2-(7-氟-1H -吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.1061g，258.50umol，26.53%產率)。Racemic N- (6-amino-5-methyl-3-pyridyl)-2-[2-(7-fluoro- 1H -indazol-5-yl)-5-methyl-1-piperidine pyridyl]-2-oxyacetamide (0.400g, 974.55umol) for chiral separation (column: Chiralcel OD-H (250*20, 5um), elution solution: hexane-IPA-MeOH, 50-25-25, flow rate: 12 mL/min) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-(7-fluoro- 1H -Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (110.40 mg, 268.98 umol, 27.60% yield) and N-(6-amino) -5-Methyl-3-pyridyl)-2-[( 2S,5R )-2-(7-fluoro- 1H -indazol-5-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetamide (0.1061 g, 258.50 umol, 26.53% yield).

化合物1350於分析條件下(管柱：OD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為17.08min且化合物1191之保留時間為8.00min。The retention time of compound 1350 under analytical conditions (column: OD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 17.08 min and the retention time of compound 1191 was 8.00 min .

化合物1350：Compound 1350:

保留時間：17.08minRetention time: 17.08min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.07(m,3H),1.29-1.40(m,1H),1.69-1.81(m,1H),1.82-1.92(m,1H),1.95-2.04(m,3H),2.06-2.21(m,1H),2.22-2.31(m,1H),2.74-3.28(m,1H),3.43-4.04(m,1H),5.15-5.69(m,3H),7.06-7.26(m,1H),7.40-7.52(m,1H),7.52-7.59(m,1H),7.92-8.05(m,1H),8.15(s,1H),10.47-10.58(m,1H),13.60(s,1H)。LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=2.486min。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.07(m,3H), 1.29-1.40(m,1H), 1.69-1.81(m,1H), 1.82-1.92(m,1H) ,1.95-2.04(m,3H),2.06-2.21(m,1H),2.22-2.31(m,1H),2.74-3.28(m,1H),3.43-4.04(m,1H),5.15-5.69( m,3H),7.06-7.26(m,1H),7.40-7.52(m,1H),7.52-7.59(m,1H),7.92-8.05(m,1H),8.15(s,1H),10.47- 10.58 (m, 1H), 13.60 (s, 1H). LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=2.486 min.

化合物1191：Compound 1191:

保留時間：8.00minRetention time: 8.00min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.06(m,3H),1.29-1.41(m,1H),1.69-1.80(m,1H),1.82-1.92(m,1H),1.96-2.04(m,3H),2.06-2.20(m,1H),2.23-2.31(m,1H),2.74-3.28(m,1H),3.43-4.04(m,1H),5.13-5.69(m,3H),7.05-7.25(m,1H),7.37-7.52(m,1H),7.52-7.59(m,1H),7.90-8.05(m,1H),8.16(s,1H),10.49-10.59(m,1H),13.60(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.06(m,3H), 1.29-1.41(m,1H), 1.69-1.80(m,1H), 1.82-1.92(m,1H) ,1.96-2.04(m,3H),2.06-2.20(m,1H),2.23-2.31(m,1H),2.74-3.28(m,1H),3.43-4.04(m,1H),5.13-5.69( m,3H),7.05-7.25(m,1H),7.37-7.52(m,1H),7.52-7.59(m,1H),7.90-8.05(m,1H),8.16(s,1H),10.49- 10.59 (m, 1H), 13.60 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=2.482min。LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=2.482 min.

實例436.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H -噻吩并[2,3 -c ]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1392及化合物1120)之合成Example 436. N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-2-( lH -thieno[ 2,3 - c ]pyrazol-5-yl ) Piperidin-1-yl)-2-oxoacetamide (Compound 1392 and Compound 1120) Synthesis

Figure 110128222-A0202-12-1810-944
Figure 110128222-A0202-12-1810-944

步驟1：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(1H-噻吩并[2,3-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(1H-thieno[2,3-c]pyrazol-5-yl )Piperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester synthesis

在輕微加熱下，將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(401.32mg，1.36mmol)、5-[(2S,5R )-5-甲基-2-哌啶基]-2H -噻吩并[2,3 -c ]吡唑(300.79mg，1.36mmol)及DIPEA(526.94mg，4.08mmol，710.16uL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(620.11mg，1.63mmol)。反應完成之後，藉由HPLC(40-90% 0.5-6.5min水-MeOH：流速30ml/min；(裝載泵4ml/min MeOH)；目標質量498；管柱SunFireC18 100x19mm 5um(L))純化混合物，以得到N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3 -c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(80mg，160.45umol，11.81%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (401.32 mg, 1.36 mmol) was added with gentle heating , 5-[( 2S,5R )-5-methyl-2-piperidinyl]-2H-thieno[ 2,3 - c ]pyrazole ( 300.79 mg, 1.36 mmol) and DIPEA (526.94 mg, 4.08 mmol) , 710.16 uL) was dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (620.11 mg, 1.63 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC (40-90% 0.5-6.5 min water-MeOH: flow rate 30 ml/min; (loading pump 4 ml/min MeOH); target mass 498; column SunFire C18 100x19mm 5um (L)), to give N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 2,3 - c ]pyrazol-5-yl)- 1-Piperidinyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (80 mg, 160.45 umol, 11.81% yield).

LCMS(ESI)：[M]+ m/z：計算值498.2；實測值499.2；Rt=2.857min。LCMS (ESI): [M] + m/z: calculated 498.2; found 499.2; Rt=2.857 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(1H-噻吩并[2,3-c]吡唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(1H-thieno[2,3-c]pyrazol-5-yl ) Synthesis of piperidin-1-yl)-2-side oxyacetamide

將N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3 -c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(80mg，160.45umol)溶解於二噁烷(2mL)及水(0.5mL)中。將所獲得之溶液在100℃下攪拌2h；反應完成之後，使混合物經歷HPLC(18% 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min MeCN)；目標質量398；管柱SunFireC18 100x19mm 5um(R))，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3 -c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(40mg，100.38umol，62.56%產率)。 N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-( 1H -thieno[ 2,3 - c ]pyrazol-5-yl)-1 -Piperidinyl]-2-Oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (80 mg, 160.45 umol) was dissolved in dioxane (2 mL) and water (0.5 mL) middle. The obtained solution was stirred at 100 °C for 2 h; after the reaction was complete, the mixture was subjected to HPLC (18% 0.5-6.5 min water-MeCN; flow rate 30 ml/min (loading pump 4 ml/min MeCN); target mass 398; column SunFire C18 100x19mm 5um(R)) to give N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S,5R )-5-methyl-2-( 1H -thieno [ 2,3 - c ]pyrazol-5-yl)-1-piperidinyl]-2-oxyacetamide (40 mg, 100.38 umol, 62.56% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.37-1.48(m,1H),1.83-1.96 (m,2H),1.98-2.02(m,3H),2.02-2.17(m,2H),2.91-2.96(m,0.4H),3.34-3.39(m,0.6H),3.44-4.08(m,1H),5.40-5.81(m,3H),6.88-6.98(m,1H),7.46-7.51(m,1H),7.87-8.00(m,1H),8.01(s,1H),10.42-10.64(m,1H),13.29(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98(d,3H), 1.37-1.48(m,1H), 1.83-1.96 (m,2H), 1.98-2.02(m,3H), 2.02 -2.17(m, 2H), 2.91-2.96(m, 0.4H), 3.34-3.39(m, 0.6H), 3.44-4.08(m, 1H), 5.40-5.81(m, 3H), 6.88-6.98( m, 1H), 7.46-7.51 (m, 1H), 7.87-8.00 (m, 1H), 8.01 (s, 1H), 10.42-10.64 (m, 1H), 13.29 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=1.722min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=1.722 min.

步驟3：掌性分離(化合物1392及化合物1120)Step 3: Chiral separation (compound 1392 and compound 1120)

藉由掌性HPLC(Chiralpak IA(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)純化外消旋物，得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(1H -噻吩并[2,3 -c ]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(8mg，20.08umol，25.02%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(1H -噻吩并[2,3-c]吡唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(8mg，20.08umol，25.02%產率)。化合物1392 於分析條件下(管柱：IA，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為65.80min且化合物1120 之保留時間為43.62min。The racemate was purified by chiral HPLC (Chiralpak IA (250*20, 5mkm), hexane-IPA-MeOH, 50-25-25, 12ml/min) to give N- (6-amino-5- Methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-( 1H -thieno[ 2,3 - c ]pyrazol-5-yl)-1-piperidinyl ]-2-Oxyacetamide (8 mg, 20.08 umol, 25.02% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )- 5-Methyl-2-( 1H -thieno[2,3-c]pyrazol-5-yl)-1-piperidinyl]-2-oxyacetamide (8 mg, 20.08 umol, 25.02% Yield). The retention time of compound 1392 under analytical conditions (column: IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 65.80 min and the retention time of compound 1120 was 43.62 min.

化合物1392：Compound 1392:

保留時間：65.80minRetention time: 65.80min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.39-1.44(m,1H),1.86-1.96(m,2H),1.99-2.03(m,3H),2.04-2.19(m,2H),2.90-3.40(m,1H),3.45-4.09(m,1H),5.39-5.81(m,3H),6.89-7.00(m,1H),7.49(s,1H),7.95(s,1H),7.99-8.05(m,1H),10.43-10.53(m,1H),13.29(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.03(m,3H), 1.39-1.44(m,1H), 1.86-1.96(m,2H), 1.99-2.03(m,3H) ,2.04-2.19(m,2H),2.90-3.40(m,1H),3.45-4.09(m,1H),5.39-5.81(m,3H),6.89-7.00(m,1H),7.49(s, 1H), 7.95(s, 1H), 7.99-8.05(m, 1H), 10.43-10.53(m, 1H), 13.29(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=0.803min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=0.803 min.

化合物1120：Compound 1120:

保留時間：43.62minRetention time: 43.62min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.03(m,3H),1.38-1.45(m,1H),1.84-1.97(m,2H),1.99-2.18(m,5H),2.91-3.40(m,1H),3.44-4.07(m,1H),5.41-5.60 (m,1H),5.61-5.79(m,2H),6.87-6.97(m,1H),7.45-7.52(m,1H),7.89-7.97(m,1H),8.02(d,1H),10.43-10.52(m,1H),13.29(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.03(m,3H), 1.38-1.45(m,1H), 1.84-1.97(m,2H), 1.99-2.18(m,5H) ,2.91-3.40(m,1H),3.44-4.07(m,1H),5.41-5.60(m,1H),5.61-5.79(m,2H),6.87-6.97(m,1H),7.45-7.52( m, 1H), 7.89-7.97 (m, 1H), 8.02 (d, 1H), 10.43-10.52 (m, 1H), 13.29 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=0.803min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=0.803 min.

實例437. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1103)之合成Example 437. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(4-methylpiperazine-1 Synthesis of -yl)-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (Compound 1103)

Figure 110128222-A0202-12-1812-945
Figure 110128222-A0202-12-1812-945

步驟1：N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-Tertibutoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[6-(4-methylpiperazine-1 -Synthesis of tert-butyl)-3-pyridyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

向1-甲基-4-[5-[(5S)-5-甲基-2-哌啶基]-2-吡啶基]哌嗪(40mg，0.146mmol)、2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(60mg，0.146mmol)及DCM(2mL)之混合物中添加HATU(70mg，0.184mmol)及DIPEA(0.1mL，0.574mmol)且將混合物在25℃下攪拌2小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(10mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL * 2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速：30mL/min)進行純化，以得到呈黃色油狀物之N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(80mg，82.4%產率)。LCMS(ESI)[M+H]+ m/z：計算值666.3，實測值666.3。To 1-methyl-4-[5-[(5S)-5-methyl-2-piperidinyl]-2-pyridyl]piperazine (40 mg, 0.146 mmol), 2-[[6-[bis To a mixture of (tertiary butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2-oxoacetic acid (60 mg, 0.146 mmol) and DCM (2 mL) was added HATU (70 mg) , 0.184 mmol) and DIPEA (0.1 mL, 0.574 mmol) and the mixture was stirred at 25 °C for 2 h. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash Purification by analysis ( ISCO® ; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc, where EtOAc was 0-20%, flow rate: 30 mL/min) to give N-tertidine as a yellow oil Oxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridyl ]-1-Piperidinyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (80 mg, 82.4% yield). LCMS (ESI) [M+H] + m/z: calcd 666.3, found 666.3.

步驟2：N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(5S)-5-methyl-2-[6-(4-methylpiperazin-1-yl )-3-pyridyl]-1-piperidinyl]-2-side oxyacetamide synthesis

向N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(80mg，0.120mmol)及DCM(1mL)之混合物中添加TFA(1mL，13.0mmol)且將混合物在20℃下攪拌1小時。過濾混合物且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ，管柱：SepaFlash® Sphercial C18，25g，40-60μm，120Å；MeCN/水(0.5%NH3 -H2 O)，其中MeCN為0-45%，25mL/min，220nm)進行純化，以得到呈白色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(35mg，62.6%產率)。LCMS(ESI)[M+H]+ m/z：計算值466.2，實測值466.2。To N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[6-(4-methylpiperazin-1-yl )-3-Pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (80 mg, 0.120 mmol) and DCM (1 mL) To the mixture was added TFA (1 mL, 13.0 mmol) and the mixture was stirred at 20°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® , column: SepaFlash® Sphercial C18, 25 g, 40-60 μm, 120 Å; MeCN/water (0.5% NH3 -H) 2 O) with 0-45% MeCN, 25 mL/min, 220 nm) was purified to give N-(6-amino-5-ethyl-3-pyridinyl)-2-[( as a white solid 5S)-5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-1-piperidinyl]-2-oxoacetamide (35 mg, 62.6% yield). LCMS (ESI) [M+H] + m/z: calcd 466.2, found 466.2.

步驟3：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1103)之合成Step 3: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[6-(4-methylpiperazine-1 Synthesis of -yl)-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (Compound 1103)

藉由掌性SFC(儀器：Berger，Multigr AM-II；管柱：Daicel Chiralcel OD-H(250mm * 30mm，5μm)；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=50/50；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(30mg，64.4umol)，以得到化合物1103 (峰2，保留時間=5.269min)。N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(21mg，具有反式相對化學之單一已知鏡像異構物，峰2，保留時間=5.269min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.22(s,1 H),8.08(br d,J =17.1Hz,2 H),7.44-7.56(m,2 H),6.81(d,J =8.8Hz,1 H),5.36(br s,3 H),3.46-3.57(m,5 H),2.40-2.49(m,7 H),2.28(s,3 H),2.02-2.13(m,2 H),1.72-1.96(m,2 H),1.35(br d,J =13.3Hz,1 H),1.16(t,J =7.4Hz,3 H),1.05(d,J =6.8Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值466.2，實測值466.2。by chiral SFC (instrument: Berger, Multigr AM-II; column: Daicel Chiralcel OD-H (250 mm*30 mm, 5 μm); mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=50/50; flow rate: 80mL/min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; dresser temperature: 25°C; wavelength: 220nm ) purified N-(6-amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-[6-(4-methylpiperazin-1-yl) -3-Pyridinyl]-1-piperidinyl]-2-oxoacetamide (30 mg, 64.4 umol) to give compound 1103 (peak 2, retention time = 5.269 min). N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(4-methylpiperazin-1-yl) -3-Pyridinyl]-1-piperidinyl]-2-oxoacetamide (21 mg, single known enantiomer with trans relative chemistry, peak 2, retention time = 5.269 min, white solid ). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.22 (s, 1 H), 8.08 (br d, J =17.1 Hz, 2 H), 7.44-7.56 (m, 2 H), 6.81 (d, J =8.8Hz,1H),5.36(br s,3H),3.46-3.57(m,5H),2.40-2.49(m,7H),2.28(s,3H),2.02-2.13(m ,2 H),1.72-1.96(m,2 H),1.35(br d, J =13.3Hz,1 H),1.16(t, J =7.4Hz,3 H),1.05(d, J =6.8Hz ,3 H); LCMS (ESI) [M+H] + m/z: calcd 466.2, found 466.2.

HPLC：在220nm下為100%，在254nm下為100%；100%ee。HPLC: 100% at 220 nm, 100% at 254 nm; 100% ee.

實例438.N -(6-胺基-5-環丙基吡啶-3-基)-2-(2-(咪唑并[1,5 -a ]吡啶-6-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1336及化合物1205)之合成Example 438. N- (6-Amino-5-cyclopropylpyridin-3-yl)-2-(2-(imidazo[ 1,5 - a ]pyridin-6-yl)-5-methylpiperidine Synthesis of pyridin-1-yl)-2-oxoacetamide (Compound 1336 and Compound 1205)

Figure 110128222-A0202-12-1814-946
Figure 110128222-A0202-12-1814-946

步驟1：N-(6-胺基-5-環丙基吡啶-3-基)-2-(2-(咪唑并[1,5-a]吡啶-6-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-cyclopropylpyridin-3-yl)-2-(2-(imidazo[1,5-a]pyridin-6-yl)-5-methylpiperin Synthesis of pyridin-1-yl)-2-oxoacetamide

在21℃下，將2-[(6-胺基-5-環丙基-3-吡啶基)胺基]-2-側氧基乙酸鈉(225.92mg，464.48umol)、HATU(229.59mg，603.83umol)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加6-(5-甲基-2-哌啶基)咪唑并[1,5-a]吡啶(100mg，464.48umol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(20-40 0.5-6.5min水-MeCN；流速30ml/min(裝載泵5ml/min MeCN)；管柱SunFire 100x19mm 5um(R))。獲得兩種級分之N -(6-胺基-5-環丙基-3-吡啶基)-2-(2-咪唑并[1,5 -a ]吡啶-6-基-5-甲基-1-哌啶基)-2-側氧基乙醯胺(56.7mg，135.49umol，29.17%產率)：第1級分-17mg(藉由LCMS為91.41%)，第2級分-39.7mg(藉由LCMS為100%)。At 21 °C, sodium 2-[(6-amino-5-cyclopropyl-3-pyridyl)amino]-2-oxoacetate (225.92 mg, 464.48 umol), HATU (229.59 mg, 603.83 umol) in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added 6-(5-methyl-2-piperidinyl)imidazo[1,5-a]pyridine (100 mg, 464.48 umol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (20-40 0.5-6.5min water-MeCN; flow rate 30ml/min (loading pump 5ml/min MeCN); column SunFire 100x19mm 5um(R)). Two fractions of N- (6-amino-5-cyclopropyl-3-pyridinyl)-2-(2-imidazo[ 1,5 - a ]pyridin-6-yl-5-methyl were obtained -1-Piperidinyl)-2-oxyacetamide (56.7 mg, 135.49 umol, 29.17% yield): Fraction 1 - 17 mg (91.41% by LCMS), Fraction 2 - 39.7 mg (100% by LCMS).

LCMS(ESI)：[M]+ m/z：計算值418.2；實測值419.2；Rt=1.973min。LCMS (ESI): [M] + m/z: calculated 418.2; found 419.2; Rt=1.973 min.

步驟2：掌性分離(化合物1336及化合物1205)Step 2: Chiral separation (compound 1336 and compound 1205)

對外消旋N -(6-胺基-5-環丙基吡啶-3-基)-2-(2-(咪唑并[1,5 -a ]吡啶-6-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(56.7mg，135.49umol)進行掌性分離(管柱：Chiralpak IB(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)，以獲得N -(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S )-2-咪唑并[1,5 -a ]吡啶-6-基-5-甲 基-1-哌啶基]-2-側氧基乙醯胺(15.21mg，36.34umol，26.83%產率)(RT=21.13min)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R )-2-咪唑并[1,5 -a ]吡啶-6-基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(16.15mg，38.59umol，28.48%產率)(RT=10.23min)。化合物1336於分析條件下(管柱：IB，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為12.98min且化合物1205之保留時間為30.65min。Racemic N- (6-amino-5-cyclopropylpyridin-3-yl)-2-(2-(imidazo[ 1,5 - a ]pyridin-6-yl)-5-methylpiperidine Chiral separation (column: Chiralpak IB (250*20mm, 5mkm), Hexane-IPA-MeOH, 50-25 -25, 12ml/min) to obtain N- (6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2R,5S )-2-imidazo[ 1,5 - a ] Pyridin-6-yl-5-methyl-1-piperidinyl]-2-oxyacetamide (15.21 mg, 36.34 umol, 26.83% yield) (RT=21.13 min) and N-(6- Amino-5-cyclopropyl-3-pyridyl)-2-[( 2S,5R )-2-imidazo[ 1,5 - a ]pyridin-6-yl-5-methyl-1-piperidine yl]-2-oxyacetamide (16.15 mg, 38.59 umol, 28.48% yield) (RT=10.23 min). The retention time of compound 1336 under analytical conditions (column: IB, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 12.98 min and that of compound 1205 was 30.65 min.

化合物1336：Compound 1336:

保留時間：12.98minRetention time: 12.98min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.44(m,2H),0.87(m,2H),1.01(m,3H),1.35(m,1H),1.65(m,1H),1.99(m,4H),2.82(m,1H),3.76(dd,1H),5.35(m,1H),5.75(m,2H),6.74(m,1H),7.32(m,2H),7.54(m,1H),8.02(m,1H),8.31(m,2H),10.47(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.44(m, 2H), 0.87(m, 2H), 1.01(m, 3H), 1.35(m, 1H), 1.65(m, 1H), 1.99(m, 4H), 2.82(m, 1H), 3.76(dd, 1H), 5.35(m, 1H), 5.75(m, 2H), 6.74(m, 1H), 7.32(m, 2H), 7.54 (m, 1H), 8.02 (m, 1H), 8.31 (m, 2H), 10.47 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值418.2；實測值419.2；Rt=1.654min。LCMS (ESI): [M] + m/z: calculated 418.2; found 419.2; Rt=1.654 min.

化合物1205：Compound 1205:

保留時間：30.65minRetention time: 30.65min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.44(m,2H),0.87(m,2H),1.01(m,3H),1.35(m,1H),1.65(m,1H),1.97(m,4H),2.82(m,1H),3.76(dd,1H),5.75(m,3H),6.71(m,1H),7.32(m,2H),7.54(m,1H),8.02(m,1H),8.31(m,2H),10.47(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.44(m, 2H), 0.87(m, 2H), 1.01(m, 3H), 1.35(m, 1H), 1.65(m, 1H), 1.97(m, 4H), 2.82(m, 1H), 3.76(dd, 1H), 5.75(m, 3H), 6.71(m, 1H), 7.32(m, 2H), 7.54(m, 1H), 8.02 (m, 1H), 8.31 (m, 2H), 10.47 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值418.2；實測值419.2；Rt=1.663min。LCMS (ESI): [M] + m/z: calculated 418.2; found 419.2; Rt=1.663 min.

實例439. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1400)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1153)之合成Example 439. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(1,2-benzothiazol-5-yl)-5- Methyl-1-piperidinyl]-2-oxyacetamide (Compound 1400) and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S )-2-(1,2-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 1153) synthesis

Figure 110128222-A0202-12-1816-947
Figure 110128222-A0202-12-1816-947

步驟1：6-(1,2-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(1,2-benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鈉(812mg，7.66mmol，321μL)添加到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,2-苯并噻唑(1.00g，3.83mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.45g，4.21mmol)於二噁烷(15.0mL)及水(5.00mL)中之溶液中。將所獲得之混合物抽真空，然後用Ar回填。添加Pd(dppf)Cl2 *DCM(125mg，153μmol)。將所得混合物在90℃、惰性氣氛下攪拌16h。將所獲得之混合物在減壓下濃縮。將殘餘物用MTBE(40.0mL)萃取。透過短矽膠墊過濾所獲得之混合物且在減壓下濃縮，以得到呈棕色油狀物之6-(1,2-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.24g，3.76mmol，98.2%產率)。Sodium carbonate (812 mg, 7.66 mmol, 321 μL) was added to 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1, 2-benzothiazole (1.00 g, 3.83 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.45 g, 4.21 mmol) in dioxane (15.0 mL) and water (5.00 mL). The obtained mixture was evacuated and then backfilled with Ar. Pd(dppf)Cl2*DCM (125 mg , 153 μmol) was added. The resulting mixture was stirred at 90 °C under an inert atmosphere for 16 h. The obtained mixture was concentrated under reduced pressure. The residue was extracted with MTBE (40.0 mL). The resulting mixture was filtered through a short pad of silica gel and concentrated under reduced pressure to give 6-(1,2-benzothiazol-5-yl)-3-methyl-3,4-di as a brown oil Hydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.24 g, 3.76 mmol, 98.2% yield).

LCMS(ESI)：[M+H]+ m/z：計算值331.17；實測值331.2；Rt=1.529。LCMS (ESI): [M+H] + m/z: calculated 331.17; found 331.2; Rt=1.529.

步驟2：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,2-苯并噻唑之合成Step 2: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,2-benzothiazole

將三氟乙酸(4.29g，37.6mmol，2.90mL)添加到6-(1,2-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.24g，3.76mmol)於二氯甲烷(20.0mL)中之溶液中。將所得混合物在25℃下攪拌14h。將所獲得之混合物在減壓下濃縮。將殘餘物用水(40.0mL)稀釋且過濾出。將濾液用固體K2 CO3 鹼化至pH

Figure 110128222-A0202-12-1816-89
10。將所得混合物用DCM(2x20.0mL)萃取。將有機層分離，經Na2 SO4 乾燥且在真空中濃縮，以得到呈黃色膠狀物之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,2-苯并噻唑(540mg，2.34mmol，62.4%產率)。Trifluoroacetic acid (4.29 g, 37.6 mmol, 2.90 mL) was added to 6-(1,2-benzothiazol-5-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1 - A solution of tert-butyl formate (1.24 g, 3.76 mmol) in dichloromethane (20.0 mL). The resulting mixture was stirred at 25 °C for 14 h. The obtained mixture was concentrated under reduced pressure. The residue was diluted with water (40.0 mL) and filtered off. The filtrate was basified to pH with solid K2CO3
Figure 110128222-A0202-12-1816-89
10. The resulting mixture was extracted with DCM (2x20.0 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)- as a yellow gum 1,2-benzothiazole (540 mg, 2.34 mmol, 62.4% yield).

LCMS(ESI)：[M+H]+ m/z：計算值231.11；實測值231.0；Rt=0.700。LCMS (ESI): [M+H] + m/z: calculated 231.11; found 231.0; Rt=0.700.

步驟3：5-[(2R,5S)-5-甲基-2-哌啶基]-1,2-苯并噻唑之合成Step 3: Synthesis of 5-[(2R,5S)-5-methyl-2-piperidinyl]-1,2-benzothiazole

向5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1,2-苯并噻唑(540mg，2.34mmol)於甲醇(30.0mL)中之正攪拌溶液中分批添加硼氫化鈉(133mg，3.52mmol，124μL)。將所得混合物在20℃下攪拌1.5h。將所獲得之混合物在減壓下濃縮。將殘餘物分配於水(30.0mL)與DCM(40.0mL)之間。將有機層分離，經Na2 SO4 乾燥且在真空中濃縮，以得到呈黃色油狀物之5-[(2R,5S)-5-甲基-2-哌啶基]-1,2-苯并噻唑(460mg，1.98mmol，84.5%產率)。To a positively stirring solution of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,2-benzothiazole (540 mg, 2.34 mmol) in methanol (30.0 mL) Sodium borohydride (133 mg, 3.52 mmol, 124 μL) was added portionwise. The resulting mixture was stirred at 20 °C for 1.5 h. The obtained mixture was concentrated under reduced pressure. The residue was partitioned between water (30.0 mL) and DCM (40.0 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo to give 5-[(2R,5S)-5-methyl-2-piperidinyl]-1,2- as a yellow oil Benzothiazole (460 mg, 1.98 mmol, 84.5% yield).

LCMS(ESI)：[M+H]+ m/z：計算值233.13；實測值233.2；Rt=0.785。LCMS (ESI): [M+H] + m/z: calculated 233.13; found 233.2; Rt=0.785.

步驟4：N-[5-[[2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[5-[[2-[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-3-cyclopropyl-2-pyridyl]carbamate

向5-[(2R,5S)-5-甲基-2-哌啶基]-1,2-苯并噻唑(230mg，990μmol)、2-[[6-(第三丁氧基羰基胺基)-5-環丙基-3-吡啶基]胺基]-2-側氧基乙酸(318mg，990μmol)及三乙胺(250mg，2.47mmol，345μL)於二甲基甲醯胺(3.00mL)中之經攪拌之混合物中添加HATU(414mg，1.09mmol)。將所得反應混合物在25℃下攪拌4h。使所獲得之混合物經歷HPLC(0-5min 40-65%水-ACN；流速：30mL/min，管柱：Chromatorex 18 SMB100-5T，100x19mm，5μm)，以得到呈白色固體之N-[5-[[2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯(74.0mg，138μmol，13.9%產率)。To 5-[(2R,5S)-5-methyl-2-piperidinyl]-1,2-benzothiazole (230 mg, 990 μmol), 2-[[6-(tert-butoxycarbonylamino )-5-cyclopropyl-3-pyridyl]amino]-2-oxoacetic acid (318 mg, 990 μmol) and triethylamine (250 mg, 2.47 mmol, 345 μL) in dimethylformamide (3.00 mL) ) was added HATU (414 mg, 1.09 mmol) to the stirred mixture. The resulting reaction mixture was stirred at 25 °C for 4 h. The obtained mixture was subjected to HPLC (0-5 min 40-65% water-ACN; flow rate: 30 mL/min, column: Chromatorex 18 SMB100-5T, 100 x 19 mm, 5 μm) to give N-[5- as a white solid [[2-[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-Cyclopropyl-2-pyridyl]carbamic acid tert-butyl ester (74.0 mg, 138 μmol, 13.9% yield).

LCMS(ESI)：[M+H]+ m/z：計算值536.26；實測值536；Rt=3.898。LCMS (ESI): [M+H] + m/z: calculated 536.26; found 536; Rt=3.898.

步驟5：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 5: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5- Synthesis of methyl-1-piperidinyl]-2-oxoacetamide

將水(1.00g，55.5mmol，1.00mL)添加到N-[5-[[2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯(74.0mg，138μmol)於二噁烷(2.00mL)中之溶液中。將所得混合物在 90℃下攪拌16h。使所獲得之混合物經歷HPLC(0-5min 40-90%水-甲醇，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：YMC-Actus Triart C18，100x20mm，5μm)，以得到呈白色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(44.0mg，101μmol，73.1%產率)。Water (1.00 g, 55.5 mmol, 1.00 mL) was added to N-[5-[[2-[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5-methyl -1-Piperidinyl]-2-Oxyacetyl]amino]-3-cyclopropyl-2-pyridyl]carbamic acid tert-butyl ester (74.0 mg, 138 μmol) in dioxane (2.00 mL) in the solution. The resulting mixture was stirred at 90 °C for 16 h. The obtained mixture was subjected to HPLC (0-5 min 40-90% water-methanol, + 0.1 vol% 25% NH3 in water, 30 mL/min, column: YMC-Actus Triart C18, 100x20 mm, 5 μm) to obtain a N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5-white solid Methyl-1-piperidinyl]-2-oxyacetamide (44.0 mg, 101 μmol, 73.1% yield).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值436.2；Rt=2.413。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 436.2; Rt=2.413.

步驟6：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(1,2-benzothiazol-5-yl)-5- Methyl-1-piperidinyl]-2-oxyacetamide and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2- Synthesis of (1,2-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide

使N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(44.0mg，101μmol)經歷掌性HPLC(體系：管柱：Chiralpak IB(250*20mm，5mkm)，流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min。24℃，波長：205nm，215nm)，以得到呈白色固體之化合物1400 N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(16.9mg，38.8μmol，76.8%產率；保留時間=11.112min(分析型)，13.9min(製備型))及化合物1153 N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(23.0mg，粗品；保留時間=19.536min(分析型)，23.5min(製備型))。make N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5-methyl -1-Piperidinyl]-2-oxyacetamide (44.0 mg, 101 μmol) was subjected to chiral HPLC (system: column: Chiralpak IB (250*20 mm, 5 mkm), mobile phase: hexane-IPA- MeOH, 50-25-25; flow rate: 12 mL/min. 24°C, wavelength: 205 nm, 215 nm) to give compound 1400 as a white solid N-(6-amino-5-cyclopropyl-3-pyridyl )-2-[(2S,5R)-2-(1,2-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxoacetamide (16.9 mg , 38.8 μmol, 76.8% yield; retention time = 11.112 min (analytical type), 13.9 min (preparative type) and compound 1153 N-(6-amino-5-cyclopropyl-3-pyridyl)-2 -[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (23.0 mg, crude; Retention time = 19.536 min (analytical), 23.5 min (preparative)).

(化合物1400)：(Compound 1400):

N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(1,2-benzothiazol-5-yl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide

1H NMR(600MHz,DMSO-d6 )δ 10.53-10.43(m,1H),9.12-9.08(m,1H),8.26-8.19(m,1H),8.18-8.13(m,1H),8.09-7.96(m,1H),7.65-7.51(m,1H),7.38-7.24(m,1H),5.79-5.27(m,3H),4.07-3.49(m,1H),3.28-2.78(m,1H),2.35-2.26(m,1H),2.23-2.07(m,1H),1.93-1.84(m,1H),1.75-1.60(m,2H),1.41-1.30(m,1H), 1.04-1.00(m,3H),0.91-0.82(m,2H),0.48-0.38(m,2H)。1H NMR (600MHz, DMSO-d 6 )δ 10.53-10.43(m,1H), 9.12-9.08(m,1H), 8.26-8.19(m,1H), 8.18-8.13(m,1H), 8.09-7.96 (m,1H),7.65-7.51(m,1H),7.38-7.24(m,1H),5.79-5.27(m,3H),4.07-3.49(m,1H),3.28-2.78(m,1H) ,2.35-2.26(m,1H),2.23-2.07(m,1H),1.93-1.84(m,1H),1.75-1.60(m,2H),1.41-1.30(m,1H), 1.04-1.00( m, 3H), 0.91-0.82 (m, 2H), 0.48-0.38 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值436.2；Rt=1.041。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 436.2; Rt=1.041.

(化合物1153)：(Compound 1153):

N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(1,2-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(1,2-benzothiazol-5-yl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide

1H NMR(600MHz,DMSO-d6 )δ 10.52-10.44(m,1H),9.12-9.07(m,1H),8.26-8.19(m,1H),8.19-8.13(m,1H),8.08-7.95(m,1H),7.64-7.52(m,1H),7.41-7.22(m,1H),5.79-5.28(m,3H),4.07-3.49(m,1H),3.27-2.78(m,1H),2.33-2.26(m,1H),2.23-2.08(m,1H),1.93-1.84(m,1H),1.76-1.61(m,2H),1.40-1.32(m,1H),1.03-1.01(m,3H),0.90-0.82(m,2H),0.49-0.38(m,2H)。1H NMR (600MHz, DMSO-d 6 )δ 10.52-10.44(m,1H), 9.12-9.07(m,1H), 8.26-8.19(m,1H), 8.19-8.13(m,1H), 8.08-7.95 (m,1H),7.64-7.52(m,1H),7.41-7.22(m,1H),5.79-5.28(m,3H),4.07-3.49(m,1H),3.27-2.78(m,1H) ,2.33-2.26(m,1H),2.23-2.08(m,1H),1.93-1.84(m,1H),1.76-1.61(m,2H),1.40-1.32(m,1H),1.03-1.01( m, 3H), 0.90-0.82 (m, 2H), 0.49-0.38 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值436.2；Rt=1.060。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 436.2; Rt=1.060.

實例440. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1222)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1201)之合成Example 440. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4- Piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1222) and N-(6-amino-5-cyclopropane) yl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazole-5- [Synthesis of]-1-piperidinyl]-2-oxoacetamide (Compound 1201)

Figure 110128222-A0202-12-1819-948
Figure 110128222-A0202-12-1819-948

步驟1：N-第三丁氧基羰基-N-[3-甲基-5-[[2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-Step 1: N-tert-butoxycarbonyl-N-[3-methyl-5-[[2-[5-methyl-2-[2-(1-methyl-4-piperidinyl)- 1,3- 苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Synthesis of benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

向2-(1-甲基-4-哌啶基)-5-(5-甲基-2-哌啶基)-1,3-苯并噻唑(150mg，0.46mmol)、2-[[6-[雙(第三丁氧基羰基)胺基]-5-環丙基-3-吡啶基]胺基]-2-側氧基乙酸(191mg，0.45mmol)於DMF(5mL)中之混合物中添加DIPEA(371mg，2.87mmol)及HATU(225mg，0.59mmol)且將混合物在20℃下攪拌12小時。將混合物用EtOAc(50mL)稀釋，用鹽水(20mL * 3)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物。藉由急驟層析(ISCO；24g AgelaFlash二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~50%，流速=30mL/min，254nm)純化粗產物，以得到呈淡黃色固體之N-第三丁氧基羰基-N-[3-甲基-5-[[2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(150mg，46.6%產率)。LCMS(ESI)[M+H]+ m/z：計算值733.3，實測值733.4。To 2-(1-methyl-4-piperidinyl)-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole (150 mg, 0.46 mmol), 2-[[6 A mixture of -[bis(tert-butoxycarbonyl)amino]-5-cyclopropyl-3-pyridyl]amino]-2-pendoxoacetic acid (191 mg, 0.45 mmol) in DMF (5 mL) DIPEA (371 mg, 2.87 mmol) and HATU (225 mg, 0.59 mmol) were added and the mixture was stirred at 20°C for 12 hours. The mixture was diluted with EtOAc (50 mL), washed with brine (20 mL* 3 ), dried over Na2SO4 , filtered and concentrated under reduced pressure to give crude product. The crude product was purified by flash chromatography (ISCO; 24g AgelaFlash silica flash column, petroleum ether/EtOAc with 0-50% EtOAc, flow = 30 mL/min, 254 nm) to give N as a pale yellow solid -Third-butoxycarbonyl-N-[3-methyl-5-[[2-[5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3- Benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (150 mg, 46.6% yield). LCMS (ESI) [M+H]+ m/z: calculated 733.3, found 733.4.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-[2-(1-methyl-4-piperidinyl)-1, Synthesis of 3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide

將N-第三丁氧基羰基-N-[3-甲基-5-[[2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(145mg，0.21mmol)於TFA(7.25mL，94.1mmol)及DCM(2mL)中之溶液在20℃下攪拌1小時。在減壓下濃縮混合物，以得到呈棕色油狀物之粗產物。藉由製備型HPLC純化(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Durashell 150×25mm×5μm；流動相A：水(0.05% NH3 H2 O+10mM NH4 HCO3 )；流動相A：MeCN；梯度：在7.8min內36%至66% B，保持100% B達2.0min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)進一步純化粗產物，以得到呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基 -2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(64mg，61.6%產率)。LCMS(ESI)[M+H]+ m/z：計算值533.2，實測值533.2。N-tert-butoxycarbonyl-N-[3-methyl-5-[[2-[5-methyl-2-[2-(1-methyl-4-piperidinyl)-1, 3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (145 mg, 0.21 mmol) in TFA (7.25 mL, 94.1 mmol) and a solution in DCM (2 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give the crude product as a brown oil. Purification by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Durashell 150 x 25 mm x 5 μm; mobile phase A: water (0.05% NH3H2O ) +10 mM NH 4 HCO 3 ); mobile phase A: MeCN; gradient: 36% to 66% B in 7.8 min, hold 100% B for 2.0 min; flow rate: 25 mL/min; column temperature: 30°C; wavelength: 220 nm, 254 nm) the crude product was further purified to give N-(6-amino-5-methyl-3-pyridinyl)-2-[5-methyl-2-[2-(1- Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (64 mg, 61.6% yield). LCMS (ESI) [M+H] + m/z: calcd 533.2, found 533.2.

步驟3：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1222)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1201)之合成Step 3: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4- Piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1222) and N-(6-amino-5-cyclopropane) yl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazole-5- [Synthesis of]-1-piperidinyl]-2-oxoacetamide (Compound 1201)

將N-(6-胺基-5-環丙基-3-吡啶基)-2-[5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(50mg，0.094mmol)送至SFC純化(儀器：Berger，Multigr AM-II；管柱：Chiralpak AD 250×30mm I.D.5μm；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=65/35；流速：70mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)，以得到化合物1222 (峰1，保留時間=5.166min)及化合物1201 (峰2，保留時間=5.951min)。N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3 - Benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (50 mg, 0.094 mmol) was sent to SFC purification (instrument: Berger, Multigr AM-II; column: Chiralpak AD 250×30mm ID5μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=65/35; flow rate: 70 mL/min; column temperature: 38°C; nozzle temperature: 100 bar ; Nozzle temperature: 60°C; Evaporator temperature: 20°C; Dresser temperature: 25°C; Wavelength: 220 nm) to obtain compound 1222 (peak 1, retention time=5.166 min) and compound 1201 (peak 2, retention time= 5.951min).

化合物1222 ：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(23.1mg，具有反式相對化學之單一未知鏡像異構物，峰1，保留時間=5.166min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.77-8.15(m,3 H),7.34-7.62(m,1 H),7.21-7.64(m,1 H),5.42-5.98(m,1 H),3.68-3.87(m,1 H),3.67-4.16(m,1 H),3.36-3.59(m,1 H),3.24(br s,1 H),2.84-2.97(m,1 H),2.77-3.23(m,2 H),2.61-2.83(m,1 H),2.20-2.41(m,4 H),1.78-2.05(m,4 H),1.38-1.75(m,2 H),1.16(br d,J =6.9Hz,3 H),0.81-1.03(m,2 H),0.41-0.70(m,2 H)；LCMS(ESI)[M+H]+ m/z：計算值533.1，實測值533.2；HPLC：在254nm下為100%；100.0%ee。 Compound 1222 : N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4- piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (23.1 mg, single unknown enantiomer with trans relative chemistry, Peak 1, retention time = 5.166 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.77-8.15 (m, 3 H), 7.34-7.62 (m, 1 H), 7.21-7.64 (m, 1 H), 5.42-5.98 (m, 1 H), 3.68-3.87 (m, 1 H), 3.67-4.16 (m, 1 H), 3.36-3.59 (m, 1 H), 3.24 (br s, 1 H), 2.84-2.97 (m, 1 H) ), 2.77-3.23(m, 2 H), 2.61-2.83(m, 1 H), 2.20-2.41(m, 4 H), 1.78-2.05(m, 4 H), 1.38-1.75(m, 2 H) ), 1.16(br d, J =6.9Hz, 3 H), 0.81-1.03(m, 2 H), 0.41-0.70(m, 2 H); LCMS(ESI)[M+H] + m/z: Calculated 533.1, found 533.2; HPLC: 100% at 254 nm; 100.0% ee.

化合物1201 ：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(22.4mg，具有反式相對 化學之單一未知鏡像異構物，峰2，保留時間=5.951min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.12(br s,1 H),7.72-8.15(m,2 H),7.58(br s,1 H),7.20-7.65(m,1 H),5.85(br s,1 H),5.38-5.56(m,1 H),3.72-4.15(m,1 H),3.40-3.52(m,1 H),3.03(br d,J =11.1Hz,1 H),2.86-3.24(m,2 H),2.17-2.40(m,8 H),1.82-2.09(m,3 H),1.56-1.76(m,1 H),1.37-1.55(m,1 H),1.07-1.30(m,3 H),0.83-1.04(m,2 H),0.46-0.72(m,2 H)；LCMS(ESI)[M+H]+ m/z：計算值533.1，實測值533.2；HPLC：在254nm下為98.82%：100%ee。 Compound 1201 : N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[2-(1-methyl-4- piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (22.4 mg, single unknown enantiomer with trans relative chemistry, Peak 2, retention time = 5.951 min, white solid). 1 H NMR (400MHz, methanol- d 4 ) δ ppm 8.12(br s,1 H), 7.72-8.15(m, 2 H), 7.58(br s, 1 H), 7.20-7.65(m, 1 H) , 5.85(br s, 1 H), 5.38-5.56(m, 1 H), 3.72-4.15(m, 1 H), 3.40-3.52(m, 1 H), 3.03(br d, J =11.1Hz, 1 H), 2.86-3.24(m, 2 H), 2.17-2.40(m, 8 H), 1.82-2.09(m, 3 H), 1.56-1.76(m, 1 H), 1.37-1.55(m, 1 H), 1.07-1.30 (m, 3 H), 0.83-1.04 (m, 2 H), 0.46-0.72 (m, 2 H); LCMS (ESI) [M+H] + m/z: calculated 533.1, found 533.2; HPLC: 98.82% at 254 nm: 100% ee.

實例441. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1258)之合成Example 441. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5S)-5-methyl-2-(2-tetrahydropyran-4-yl Synthesis of -1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (compound 1258)

Figure 110128222-A0202-12-1822-949
Figure 110128222-A0202-12-1822-949

步驟9：N-第三丁氧基羰基-N-[3-環丙基-5-[[2-[(5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 9: N-tert-butoxycarbonyl-N-[3-cyclopropyl-5-[[2-[(5S)-5-methyl-2-(2-tetrahydropyran-4-yl Synthesis of -1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

向5-((5S)-5-甲基-2-哌啶基)-2-四氫哌喃-4-基-1,3-苯并噻唑(70mg，0.198mmol，HCl)、[2-[[6-[雙(第三丁氧基羰基)胺基]-5-環丙基-3-吡啶基]胺基]-2-側氧基乙醯基]氧基鈉(89.8mg，0.202mmol)、HATU(80mg，0.210mmol)及DMF (3mL)之混合物中添加DIPEA(0.1mL，0.574mmol)且將混合物在20℃下攪拌12小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL * 2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；12g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~68%，流速：30mL/min，254nm)進行純化，以得到呈黃色固體之N-第三丁氧基羰基-N-[3-環丙基-5-[[2-[(5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(110mg，77.0%產率)。To 5-((5S)-5-methyl-2-piperidinyl)-2-tetrahydropyran-4-yl-1,3-benzothiazole (70 mg, 0.198 mmol, HCl), [2- [[6-[Bis(tert-butoxycarbonyl)amino]-5-cyclopropyl-3-pyridyl]amino]-2-oxyacetoxy]oxysodium sodium (89.8 mg, 0.202 To a mixture of mmol), HATU (80 mg, 0.210 mmol) and DMF (3 mL) was added DIPEA (0.1 mL, 0.574 mmol) and the mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash (ISCO®; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-68% EtOAc, flow rate: 30 mL/min, 254 nm) for purification to give N-tertidine as a yellow solid Oxycarbonyl-N-[3-cyclopropyl-5-[[2-[(5S)-5-methyl-2-(2-tetrahydropyran-4-yl-1,3-benzothiazole -5-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (110 mg, 77.0% yield).

步驟10：N-第三丁氧基羰基-N-[3-環丙基-5-[[2-[(5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 10: N-tert-butoxycarbonyl-N-[3-cyclopropyl-5-[[2-[(5S)-5-methyl-2-(2-tetrahydropyran-4-yl Synthesis of -1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將N-第三丁氧基羰基-N-[3-環丙基-5-[[2-[(5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(110mg，0.153mmol)及4M MeOH/HCl(4mL，16mmol)之混合物在20℃下攪拌2小時。向混合物中添加NH3 -H2 O(1mL)且在減壓下濃縮，以得到殘餘物，其藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Waters Xbridge 150×25mm×5μm；流動相A：具有0.05% NH3 -H2 O(v%)之H2 O；流動相B：MeCN；梯度：在7.8min內35%至65% B，保持100% B達2.5min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)進行純化，以得到呈白色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(40mg，50.4%產率)。The N-tert-butoxycarbonyl-N-[3-cyclopropyl-5-[[2-[(5S)-5-methyl-2-(2-tetrahydropyran-4-yl-1 and A mixture of 4M MeOH/HCl (4 mL, 16 mmol) was stirred at 20°C for 2 hours. To the mixture was added NH3 - H2O (1 mL) and concentrated under reduced pressure to give a residue which was analyzed by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detection device; column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase A: H 2 O with 0.05% NH 3 -H 2 O (v%); mobile phase B: MeCN; gradient: 35% to 0.05% in 7.8 min 65% B, hold 100% B for 2.5 min; flow rate: 25 mL/min; column temperature: 30 °C; wavelength: 220 nm, 254 nm) for purification to obtain N-(6-amino-5- as a white solid) Cyclopropyl-3-pyridyl)-2-[(5S)-5-methyl-2-(2-tetrahydropyran-4-yl-1,3-benzothiazol-5-yl)-1 -Piperidinyl]-2-oxoacetamide (40 mg, 50.4% yield).

步驟11：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1258)之合成Step 11: N-(6-Amino-5-cyclopropyl-3-pyridinyl)-2-[(2S,5S)-5-methyl-2-(2-tetrahydropyran-4-yl Synthesis of -1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxoacetamide (compound 1258)

藉由SFC儀器(Thar 800Q；Daicel Chiralpak IG(250mm * 30mm，10μm)；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=60/40；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離N-(6-胺基-5-環丙基-3-吡啶基)-2-[(5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(40mg，77.0μmol)，以得到N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-1-哌啶基]-2-側氧基乙醯胺(25mg，具有反式相對化學之單一已知鏡像異構物，峰2，保留時間=5.211min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.73-8.17(m,3 H),7.18-7.63(m,2 H),5.46-5.89(m,1 H),4.00-4.17(m,2 H),3.53-3.80(m,2 H),3.44(br d,J =11.6Hz,2 H),2.93-3.28(m,1 H),1.87-2.40(m,8 H),1.57-1.76(m,1 H),1.49(br d,J =11.9Hz,1 H),1.16(br d,J =6.9Hz,3 H),0.84-1.04(m,2 H),0.49-0.69(m,2 H)；LCMS(ESI)[M+H]+ m/z：計算值520.2，實測值520.2；HPLC：在220nm下為100%，在254nm下為100%；100%ee。By SFC instrument (Thar 800Q; Daicel Chiralpak IG (250mm*30mm, 10μm); mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=60/40; flow rate: 80 mL/ min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; dresser temperature: 25°C; wavelength: 220nm) separation of N-(6-amino-5- Cyclopropyl-3-pyridyl)-2-[(5S)-5-methyl-2-(2-tetrahydropyran-4-yl-1,3-benzothiazol-5-yl)-1 -Piperidinyl]-2-oxyacetamide (40 mg, 77.0 μmol) to give N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5S )-5-methyl-2-(2-tetrahydropyran-4-yl-1,3-benzothiazol-5-yl)-1-piperidinyl]-2-oxyacetamide ( 25 mg, single known enantiomer with trans relative chemistry, peak 2, retention time = 5.211 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.73-8.17 (m, 3 H), 7.18-7.63 (m, 2 H), 5.46-5.89 (m, 1 H), 4.00-4.17 (m, 2 H), 3.53-3.80 (m, 2 H), 3.44 (br d, J = 11.6 Hz, 2 H), 2.93-3.28 (m, 1 H), 1.87-2.40 (m, 8 H), 1.57-1.76 (m, 1 H), 1.49(br d, J =11.9Hz, 1 H), 1.16(br d, J =6.9Hz, 3 H), 0.84-1.04(m, 2 H), 0.49-0.69(m , 2 H); LCMS (ESI) [M+H] + m/z: calculated 520.2, found 520.2; HPLC: 100% at 220 nm, 100% at 254 nm; 100% ee.

實例442. rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1169)及rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1119)之合成Example 442. rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide (Compound 1169) and rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)- Synthesis of 2-(3-Chlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1119)

Figure 110128222-A0202-12-1824-950
Figure 110128222-A0202-12-1824-950

步驟1：N-[5-[[2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-(3-Chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3- Synthesis of 3-butyl cyclopropyl-2-pyridyl]carbamate

Figure 110128222-A0202-12-1825-951
Figure 110128222-A0202-12-1825-951

在室溫下將2-(3-氯苯基)-5-甲基哌啶(150mg，715.26umol)及HATU(326.36mg，858.31umol)混合於無水DMF(5mL)中且將所得混合物攪拌5min。向其中添加HATU(326.36mg，858.31umol)且將所得混合物在室溫下攪拌15min。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-100% 0.5-6.5min水-乙腈+FA；流速30mL/min(裝載泵；4mL/min乙腈)；管柱SunFireC18 100x19mm 5um(R)。獲得呈帶棕色膠狀物之N-[5-[[2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯(287.9mg，561.18umol，78.46%產率)。2-(3-Chlorophenyl)-5-methylpiperidine (150 mg, 715.26 umol) and HATU (326.36 mg, 858.31 umol) were mixed in dry DMF (5 mL) at room temperature and the resulting mixture was stirred for 5 min . To this was added HATU (326.36 mg, 858.31 umol) and the resulting mixture was stirred at room temperature for 15 min. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-100% 0.5-6.5 min water-acetonitrile+FA; flow rate 30 mL/min (loading pump; 4 mL/min acetonitrile); column SunFire C18 100x19 mm 5um (R). Obtained as a brownish gum N-[5-[[2-[2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-cyclopropane tert-butyl-2-pyridyl]carbamate (287.9 mg, 561.18 umol, 78.46% yield).

LCMS(ESI)：[M+H]+ m/z：計算值513.2；實測值513.2；Rt=3.883min。LCMS (ESI): [M+H] + m/z: calculated 513.2; found 513.2; Rt=3.883 min.

步驟2：N-(6-胺基-5-環丙基-3-吡啶基)-2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide

Figure 110128222-A0202-12-1825-952
Figure 110128222-A0202-12-1825-952

將N-[5-[[2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯(287.9mg，561.18umol)溶解於水(2mL)/二噁烷(2mL)混合物中且在90℃下加熱隔夜。將所得混合物蒸發至乾，以得到呈黃色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.22g，532.80umol，94.94%產率)。N-[5-[[2-[2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-cyclopropane tert-butyl-2-pyridyl]carbamate (287.9 mg, 561.18 umol) was dissolved in a mixture of water (2 mL)/dioxane (2 mL) and heated at 90°C overnight. The resulting mixture was evaporated to dryness to give N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[2-(3-chlorophenyl)-5-methyl as a yellow solid -1-Piperidinyl]-2-Pendant oxyacetamide (0.22 g, 532.80 umol, 94.94% yield).

LCMS(ESI)：[M+H]+ m/z：計算值413.2；實測值413.4；Rt=3.124min。LCMS (ESI): [M+H] + m/z: calculated 413.2; found 413.4; Rt=3.124 min.

步驟3：rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1169)及rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1119)之合成Step 3: rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1 -Piperidinyl]-2-oxyacetamide (Compound 1169) and rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)- Synthesis of 2-(3-Chlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1119)

藉由掌性層析在以下兩次運行中分離非鏡像異構物之混合物：第1次運行(Chiralpak IC-III(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12mL/min)及第2次運行(Chiralpak AD-H-III(250*20mm，5mkm)，己烷-IPA-MeOH，70-15-15，12mL/min)，以獲得N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(51.72mg，125.26umol，21.55%產率)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(44.25mg，107.17umol，18.44%產率)。A mixture of diastereomers was separated by chiral chromatography in the following two runs: Run 1 (Chiralpak IC-III (250*20, 5mkm), Hexane-IPA-MeOH, 60-20-20 , 12mL/min) and a second run (Chiralpak AD-H-III (250*20mm, 5mkm), Hexane-IPA-MeOH, 70-15-15, 12mL/min) to obtain N-(6- Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxygen Ethylacetamide (51.72 mg, 125.26 umol, 21.55% yield) and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(3 -Chlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (44.25 mg, 107.17 umol, 18.44% yield).

製備型：Preparation:

第1次運行：1st run:

化合物1169之RT(Chiralpak IC-III(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12mL/min)=18.792min；(連同其順式雜質)RT of compound 1169 (Chiralpak IC-III (250*20, 5mkm), hexane-IPA-MeOH, 60-20-20, 12mL/min)=18.792min; (together with its cis impurity)

化合物1119之RT(Chiralpak IC-III(250*20，5mkm)，己烷-IPA-MeOH，60-20-20，12mL/min)=25.119min。RT for compound 1119 (Chiralpak IC-III (250*20, 5 mkm), hexane-IPA-MeOH, 60-20-20, 12 mL/min) = 25.119 min.

製備型：Preparation:

第2次運行：2nd run:

化合物1169之RT(Chiralpak AD-H-III(250*20mm，5mkm)，己烷-IPA-MeOH，70-15-15，12mL/min)=41.448min；(連同其順式雜質)RT of compound 1169 (Chiralpak AD-H-III (250*20mm, 5mkm), hexane-IPA-MeOH, 70-15-15, 12mL/min)=41.448min; (together with its cis impurity)

化合物1169：Compound 1169:

產率：51.72mg(21.55%)Yield: 51.72 mg (21.55%)

RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，60-20-20，0.6mL/min)=17.466min。RT (Chiralpak IC (250*4.6, 5mkm), Hexane-IPA-MeOH, 60-20-20, 0.6mL/min)=17.466min.

1 H NMR(500MHz,dmso)δ 0.40-0.50(m,2H),0.84-0.90(m,2H),0.96-1.05(m,3H),1.24-1.37(m,1H),1.59-1.69(m,2H),1.79-1.91(m,1H),1.99-2.10(m,1H),2.14-2.25(m,1H),2.68-3.25(m,1H),3.45-4.04(m,1H),5.13-5.57(m,1H),5.71-5.80(m,2H),7.23-7.37(m,4H),7.39-7.47(m,1H),7.96-8.10(m,1H),10.46-10.58(m,1H)。 1 H NMR(500MHz,dmso)δ 0.40-0.50(m,2H),0.84-0.90(m,2H),0.96-1.05(m,3H),1.24-1.37(m,1H),1.59-1.69(m ,2H),1.79-1.91(m,1H),1.99-2.10(m,1H),2.14-2.25(m,1H),2.68-3.25(m,1H),3.45-4.04(m,1H),5.13 -5.57(m, 1H), 5.71-5.80(m, 2H), 7.23-7.37(m, 4H), 7.39-7.47(m, 1H), 7.96-8.10(m, 1H), 10.46-10.58(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值413.2；實測值413.2；Rt=2.535min。LCMS (ESI): [M+H] + m/z: calculated 413.2; found 413.2; Rt=2.535 min.

化合物1119：Compound 1119:

產率：44.25mg(18.44%)Yield: 44.25 mg (18.44%)

RT(Chiralpak IC(250*4.6，5mkm)，己烷-IPA-MeOH，60-20-20，0.6mL/min)=22.691min。RT (Chiralpak IC (250*4.6, 5 mkm), Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 22.691 min.

1 H NMR(500MHz,dmso)δ 0.40-0.50(m,2H),0.82-0.90(m,2H),0.96-1.04(m,3H),1.24-1.38(m,1H),1.54-1.73(m,2H),1.80-1.92(m,1H),1.96-2.08(m,1H),2.11-2.26(m,1H),2.69-3.26(m,1H),3.44-4.06(m,1H),5.13-5.59(m,1H),5.70-5.82(m,2H),7.24-7.37(m,4H),7.38-7.44(m,1H),7.94-8.06(m,1H),10.43-10.57(m,1H)。 1 H NMR(500MHz,dmso)δ 0.40-0.50(m,2H),0.82-0.90(m,2H),0.96-1.04(m,3H),1.24-1.38(m,1H),1.54-1.73(m ,2H),1.80-1.92(m,1H),1.96-2.08(m,1H),2.11-2.26(m,1H),2.69-3.26(m,1H),3.44-4.06(m,1H),5.13 -5.59(m, 1H), 5.70-5.82(m, 2H), 7.24-7.37(m, 4H), 7.38-7.44(m, 1H), 7.94-8.06(m, 1H), 10.43-10.57(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值413.2；實測值413.2；Rt=2.553min。LCMS (ESI): [M+H] + m/z: calculated 413.2; found 413.2; Rt=2.553 min.

實例443. rel-N-(6-胺基-5-環丙基吡啶-3-基)-2-((2R,5R)-2-(苯并[d]噻唑-5-基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1307)及rel-N-(6-胺基-5-環丙基吡啶-3-基)-2-((2R,5R)-2-(苯并[d]噻唑-5-基)-4,4-二氟-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1207)之合成Example 443. rel-N-(6-amino-5-cyclopropylpyridin-3-yl)-2-((2R,5R)-2-(benzo[d]thiazol-5-yl)-4 ,4-Difluoro-5-methylpiperidin-1-yl)-2-oxyacetamide (Compound 1307) and rel-N-(6-amino-5-cyclopropylpyridine-3- yl)-2-((2R,5R)-2-(benzo[d]thiazol-5-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-2-oxygen Synthesis of Ethylacetamide (Compound 1207)

Figure 110128222-A0202-12-1828-953
Figure 110128222-A0202-12-1828-953

將N-[5-[[2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯(1.5g，2.62mmol)於二噁烷(15mL)及水(15mL)中之溶液在100℃下加熱12h。蒸發溶劑且藉由HPLC(2-10min；20-55%乙腈，30mL/min(裝載泵4mL MeCN)，管柱：SunFire 100*19mm，5微米)純化粗材料，以獲得外消旋混合物。藉由掌性層析(Chiralpak AS-H(250*20mm，5mkm)，己烷-IPA-MeOH,60-20-20，12mL/min)純化所得混合物。在管柱上觀測到外消旋。獲得N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5R)-2-(1,3-苯并噻唑-5-基)-4,4-二氟-5-甲基-1-哌啶基]-2-側氧基乙醯胺(60.28mg，127.84umol，4.87%產率)之非鏡像異構物比率不同(12%/88%-16.23mg及65%/35%-44.05mg)的兩種級分。N-[5-[[2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4-difluoro-5-methyl-1-piperidinyl ]-2-Oxyacetyl]amino]-3-cyclopropyl-2-pyridyl]carbamic acid tert-butyl ester (1.5 g, 2.62 mmol) in dioxane (15 mL) and water (15 mL) ) was heated at 100°C for 12h. The solvent was evaporated and the crude material was purified by HPLC (2-10 min; 20-55% acetonitrile, 30 mL/min (loading pump 4 mL MeCN), column: SunFire 100*19 mm, 5 microns) to obtain a racemic mixture. The resulting mixture was purified by chiral chromatography (Chiralpak AS-H (250*20 mm, 5 mkm), hexane-IPA-MeOH, 60-20-20, 12 mL/min). Racemization was observed on the column. Obtained N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5R)-2-(1,3-benzothiazol-5-yl)-4,4- Difluoro-5-methyl-1-piperidinyl]-2-oxyacetamide (60.28 mg, 127.84 umol, 4.87% yield) had different ratios of diastereoisomers (12%/88%- 16.23 mg and 65%/35%-44.05 mg) in two fractions.

化合物1307：Compound 1307:

產率：16.23mg(26.92%)Yield: 16.23 mg (26.92%)

RT(Chiralpak AS-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=11.576min(12%)，16.249min(88%)。RT (Chiralpak AS-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 11.576 min (12%), 16.249 min (88%).

1 H NMR(600MHz,dmso)δ 0.37-0.54(m,2H),0.81-0.94(m,2H),1.10(d,3H),1.55-1.73(m,1H),2.14-2.27(m,1H),2.82-3.21(m,2H),3.40-3.58(m,1H),3.84-4.37(m,1H),5.71-6.06(m,3H),7.25-7.43(m,1H),7.47(d,1H),7.97-8.20(m,3H),9.40(s,1H),10.49-10.72(m,1H)。 1 H NMR(600MHz, dmso)δ 0.37-0.54(m, 2H), 0.81-0.94(m, 2H), 1.10(d, 3H), 1.55-1.73(m, 1H), 2.14-2.27(m, 1H) ), 2.82-3.21(m, 2H), 3.40-3.58(m, 1H), 3.84-4.37(m, 1H), 5.71-6.06(m, 3H), 7.25-7.43(m, 1H), 7.47(d , 1H), 7.97-8.20 (m, 3H), 9.40 (s, 1H), 10.49-10.72 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值472.2；實測值472.2；Rt=2.795min。LCMS (ESI): [M+H] + m/z: calculated 472.2; found 472.2; Rt=2.795 min.

化合物1207：Compound 1207:

產率：44.05mg(73.07%)Yield: 44.05 mg (73.07%)

RT(Chiralpak AS-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=11.576min(65%)，16.249min(35%)。RT (Chiralpak AS-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 11.576 min (65%), 16.249 min (35%).

1 H NMR(600MHz,dmso)δ 0.53-0.66(m,2H),0.95-1.03(m,2H),1.10(d,3H),1.68-1.82(m,1H),2.19-2.27(m,1H),2.61-3.02(m,2H),3.15-3.58(m,1H),3.93-4.36(m,1H),5.75-6.01(m,1H),7.39-7.73(m,4H),8.01(s,1H),8.11-8.19(m,1H),8.19-8.35(m,1H),9.40(s,1H),10.85-11.19(m,1H)。 1 H NMR(600MHz,dmso)δ 0.53-0.66(m,2H),0.95-1.03(m,2H),1.10(d,3H),1.68-1.82(m,1H),2.19-2.27(m,1H) ),2.61-3.02(m,2H),3.15-3.58(m,1H),3.93-4.36(m,1H),5.75-6.01(m,1H),7.39-7.73(m,4H),8.01(s , 1H), 8.11-8.19(m, 1H), 8.19-8.35(m, 1H), 9.40(s, 1H), 10.85-11.19(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值472.2；實測值472.2；Rt=2.803min。LCMS (ESI): [M+H] + m/z: calculated 472.2; found 472.2; Rt=2.803 min.

實例444. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1143)之合成Example 444. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Synthesis of pyridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1143)

Figure 110128222-A0202-12-1829-954
Figure 110128222-A0202-12-1829-954

步驟1：(5S)-5-甲基-2-[2-(1-甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯之合成Step 1: (5S)-5-Methyl-2-[2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl Synthesis of 3-butyl piperidine-1-carboxylate

將(5S)-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(1.2g，2.92mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H-吡啶(700mg，3.14mmol)、K2 CO3 (1.20g，8.68mmol)、鈀；三苯基磷烷(360mg，0.312mmol)、EtOH(10mL)及H2 O(2mL)之混合物在95℃下攪拌1.5小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(20mL * 3)萃取。將經合併之 有機層用飽和NH4 Cl水溶液(10mL * 2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱，DCM/MeOH，其中MeOH為0~20%，流速：30mL/min，254nm)進行純化，以得到呈黃色固體之(5S)-5-甲基-2-[2-(1-甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(1.1g，88.2%產率)。Combine (5S)-2-(2-bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.92 mmol), 1-methyl yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro-2H-pyridine (700 mg, A mixture of 3.14 mmol), K 2 CO 3 (1.20 g, 8.68 mmol), palladium; triphenylphosphine (360 mg, 0.312 mmol), EtOH (10 mL) and H 2 O (2 mL) was stirred at 95 °C for 1.5 h . The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash (ISCO®; 24 g AgelaFlash® silica flash column, DCM/MeOH with 0~20% MeOH, flow rate: 30 mL/min, 254 nm) for purification to give (5S)-5- as a yellow solid Methyl-2-[2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid third Butyl ester (1.1 g, 88.2% yield).

步驟2：(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯之合成Step 2: (5S)-5-Methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid 3rd Synthesis of Butyl Ester

在H2 氣氛(15psi)下，將(5S)-5-甲基-2-[2-(1-甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(1.10g，2.57mmol)、Pd/C(1g，具有50重量%水之10重量% Pd)及MeOH(5mL)之混合物在20℃下攪拌12小時。過濾混合物且在減壓下濃縮，以得到呈黑色油狀物之(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(1g，90.5%產率)。(5S)-5-methyl-2-[2-(1-methyl-3,6-dihydro-2H - pyridin-4-yl)-1,3- A mixture of benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (1.10 g, 2.57 mmol), Pd/C (1 g, 10 wt % Pd with 50 wt % water) and MeOH (5 mL) Stir at 20°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give (5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzo as a black oil Thiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (1 g, 90.5% yield).

步驟3：2-(1-甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 3: Synthesis of 2-(1-Methyl-4-piperidinyl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole

將(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(1g，2.33mmol)、TFA(2mL，26.0mmol)及DCM(10mL)之混合物在20℃下攪拌2小時。在減壓下濃縮混合物，以得到殘餘物，將其與Na2 CO3 固體及MeOH混合且將混合物在20℃下攪拌1小時.在減壓下濃縮混合物，以得到殘餘物，將其用DCM(100mL)研磨。過濾混合物且在減壓下濃縮濾液，以得到呈黃色油狀物之2-(1-甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(700mg，91.3%產率)(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester A mixture of (1 g, 2.33 mmol), TFA (2 mL, 26.0 mmol) and DCM (10 mL) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue which was mixed with Na2CO3 solid and MeOH and the mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give a residue which was taken up with DCM (100 mL) triturated. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(1-methyl-4-piperidinyl)-5-[(5S)-5-methyl-2-piperidinyl as a yellow oil ]-1,3-benzothiazole (700 mg, 91.3% yield)

步驟4：N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidine Synthesis of 3-butyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基 乙酸(130mg，0.317mmol)、2-(1-甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(105mg，0.319mmol)、HATU(130mg，0.342mmol)、DIPEA(0.2mL，1.15mmol)及DCM(20mL)之混合物在20℃下攪拌2小時。過濾混合物且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱DCM/MeOH，其中MeOH為0~20%，流速：30mL/min，254nm)進行純化，以得到呈黃色油狀物之N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(150mg，65.5%產率)。2-[[6-[Bis(tert-butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2-side oxy Acetic acid (130 mg, 0.317 mmol), 2-(1-methyl-4-piperidinyl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole ( A mixture of 105 mg, 0.319 mmol), HATU (130 mg, 0.342 mmol), DIPEA (0.2 mL, 1.15 mmol) and DCM (20 mL) was stirred at 20 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash chromatography (ISCO®; 24 g AgelaFlash® silica flash column DCM/MeOH with 0-20% MeOH, flow rate: 30 mL/min , 254 nm) was purified to give N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[ as a yellow oil 2-(1-Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetyl]amino]-2- 3-butyl pyridyl]carbamate (150 mg, 65.5% yield).

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 5: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl) )-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyacetamide synthesis

將N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(150mg，0.208mmol)、TFA(1mL，13.0mmol)及DCM(2mL)之混合物在20℃下攪拌2小時。在減壓下濃縮混合物，以得到殘餘物，其藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Waters Xbridge 150×25mm×5μm；流動相A：具有0.05% NH3 -H2 O(v%)之H2 O；流動相B：MeCN；梯度：在7.8min內28%至58% B，保持100% B達2.5min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)進行純化，以得到呈白色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(100mg，92.3%產率)。N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl )-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (150 mg, 0.208 mmol), TFA (1 mL, 13.0 mmol) and DCM (2 mL) was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was analyzed by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile Phase A: H2O with 0.05% NH3 - H2O (v%); Mobile Phase B: MeCN; Gradient: 28% to 58% B in 7.8 min, hold 100% B for 2.5 min; flow rate : 25 mL/min; column temperature: 30 °C; wavelength: 220 nm, 254 nm) for purification to obtain N-(6-amino-5-ethyl-3-pyridyl)-2-[( 5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxygen Ethylacetamide (100 mg, 92.3% yield).

步驟6：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1143)之合成Step 6: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2S,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Synthesis of pyridyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1143)

將N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(50mg，96.0μmol)藉由掌性 SFC(儀器：Thar 800Q；Daicel Chiralpak IG(250mm * 30mm，10μm)；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=55/45；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(30mg，具有反式相對化學之單一已知鏡像異構物，峰2，保留時間=5.155min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.88-8.29(m,3 H),7.20-7.88(m,2 H),5.44-5.90(m,1 H),3.70-4.20(m,1 H),3.36-3.52(m,1 H),3.17(br s,1 H),3.03(br d,J =11.3Hz,2 H),2.12-2.62(m,9 H),1.99(br d,J =11.8Hz,4 H),1.41-1.56(m,1 H),1.04-1.37(m,6 H)；LCMS(ESI)[M+H]+ m/z：計算值521.3，實測值521.3；HPLC：在220nm下為99.11%，在254nm下為100%；100%ee。N-(6-amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)- 1,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (50 mg, 96.0 μmol) was purified by chiral SFC (instrument: Thar 800Q; Daicel Chiralpak IG (250 mm) * 30mm, 10μm); mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=55/45; flow rate: 80mL/min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) separation to give N-(6-amino-5-ethyl-3-pyridyl)-2 -[(2S,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl] -2-Oxyacetamide (30 mg, single known enantiomer with trans relative chemistry, peak 2, retention time = 5.155 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.88-8.29 (m, 3 H), 7.20-7.88 (m, 2 H), 5.44-5.90 (m, 1 H), 3.70-4.20 (m, 1 H), 3.36-3.52(m, 1 H), 3.17(br s, 1 H), 3.03(br d, J =11.3Hz, 2 H), 2.12-2.62(m, 9 H), 1.99(br d , J =11.8Hz,4H),1.41-1.56(m,1H),1.04-1.37(m,6H); LCMS(ESI)[M+H] + m/z: calculated 521.3, found 521.3; HPLC: 99.11% at 220 nm, 100% at 254 nm; 100% ee.

實例445. rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1370)及rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1241)之合成Example 445. rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl )-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 1370) and rel-N-(6-amino-5-cyclopropyl-3 -Pyridinyl)-2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]- Synthesis of 2-Pendant Oxyacetamide (Compound 1241)

Figure 110128222-A0202-12-1832-955
Figure 110128222-A0202-12-1832-955

步驟7：外消旋-N-[5-[[2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯之合成Step 7: Racemic-N-[5-[[2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl- Synthesis of 3-butyl 1-piperidinyl]-2-oxyacetyl]amino]-3-cyclopropyl-2-pyridyl]carbamic acid

Figure 110128222-A0202-12-1833-956
Figure 110128222-A0202-12-1833-956

在室溫下將5-[(2S,5S)-4-甲氧基-5-甲基-2-哌啶基]-1,3-苯并噻唑(0.2g，669.28umol，HCl)、TEA(338.62mg，3.35mmol，466.42uL)及HATU(305.37mg，803.13umol)混合於無水DMF(5mL)中且將所得混合物攪拌15min.向其中添加2-[[6-(第三丁氧基羰基胺基)-5-環丙基-3-吡啶基]胺基]-2-側氧基乙酸(219.70mg，669.28umol，Li)且將所得混合物在室溫下攪拌12h。將所得混合物蒸發至乾，以獲得N-[5-[[2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯(670mg，粗品)。5-[(2S,5S)-4-methoxy-5-methyl-2-piperidinyl]-1,3-benzothiazole (0.2 g, 669.28 umol, HCl), TEA (338.62 mg, 3.35 mmol, 466.42 uL) and HATU (305.37 mg, 803.13 umol) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added 2-[[6-(tert-butoxycarbonyl amino)-5-cyclopropyl-3-pyridyl]amino]-2-pendoxoacetic acid (219.70 mg, 669.28 umol, Li) and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was evaporated to dryness to obtain N-[5-[[2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methane tert-butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-cyclopropyl-2-pyridyl]carbamic acid tert-butyl ester (670 mg, crude).

LCMS(ESI)：[M+H]+ m/z：計算值566.2；實測值566.2；Rt=1.373min。LCMS (ESI): [M+H] + m/z: calculated 566.2; found 566.2; Rt=1.373 min.

步驟8：外消旋-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 8: Racemic-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl )-4-methoxy-5-methyl-1-piperidinyl]-2-side oxyacetamide synthesis

將外消旋-N-[5-[[2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-環丙基-2-吡啶基]胺甲酸第三丁酯(670mg，1.18mmol)於二噁烷(5mL)及水(5mL)中之溶液在100℃下加熱12h。蒸發溶劑且藉由HPLC(2-10min 30-55%甲醇+NH3 ，30mL/min(裝載泵4mL甲醇)，管柱：SunFire 100*19mm，5微米)純化所得沉澱，以獲得外消旋-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(33.8mg，粗品)。rac-N-[5-[[2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1- Piperidinyl]-2-oxoacetyl]amino]-3-cyclopropyl-2-pyridyl]carbamic acid tert-butyl ester (670 mg, 1.18 mmol) in dioxane (5 mL) and water The solution in (5 mL) was heated at 100 °C for 12 h. The solvent was evaporated and the resulting precipitate was purified by HPLC (2-10 min 30-55% methanol + NH3 , 30 mL/min (loading pump 4 mL methanol), column: SunFire 100*19 mm, 5 microns) to obtain rac- N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy -5-Methyl-1-piperidinyl]-2-oxyacetamide (33.8 mg, crude).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=0.923min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=0.923 min.

步驟9：rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-Step 9: rel-N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[(2R,4S,5R)-2-(1,3-benzothiazol-5-yl )-4- 甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1370)及rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1241)之合成Methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (Compound 1370) and rel-N-(6-amino-5-cyclopropyl-3-pyridyl) -2-[(2S,4R,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxygen Synthesis of Acetamide (Compound 1241)

Figure 110128222-A0202-12-1834-957
Figure 110128222-A0202-12-1834-957

對外消旋-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(33.8mg，72.60umol)進行掌性分離(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，80-10-10，12mL/min)，以獲得化合物1241 rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,4R,5S)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(8.75mg，18.79umol，25.89%產率)及化合物1370 rel-N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,4S,5R)-2-(1,3-苯并噻唑-5-基)-4-甲氧基-5-甲基-1-哌啶基]-2-側氧基乙醯胺(12.9mg，27.71umol，38.17%產率)。Racemic-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5S)-2-(1,3-benzothiazol-5-yl)-4 -Methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (33.8mg, 72.60umol) was chiral separation (Chiralcel OD-H (250*20, 5mkm), hexane alkane-IPA-MeOH, 80-10-10, 12 mL/min) to obtain compound 1241 rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,4R ,5S)-2-(1,3-benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxoacetamide (8.75 mg, 18.79umol, 25.89% yield) and compound 1370 rel-N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,4S,5R)-2-(1,3 - benzothiazol-5-yl)-4-methoxy-5-methyl-1-piperidinyl]-2-oxyacetamide (12.9 mg, 27.71 umol, 38.17% yield).

製備型：Preparation:

化合物1241之RT(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，80-10-10，12mL/min)=58.183min。RT for compound 1241 (Chiralcel OD-H (250*20, 5 mkm), hexane-IPA-MeOH, 80-10-10, 12 mL/min) = 58.183 min.

化合物1370之RT(Chiralcel OD-H(250*20，5mkm)，己烷-IPA-MeOH，80-10-10，12mL/min)=46.633min。RT for compound 1370 (Chiralcel OD-H (250*20, 5 mkm), hexane-IPA-MeOH, 80-10-10, 12 mL/min) = 46.633 min.

化合物1241：Compound 1241:

產率：8.75mg(25.89%)Yield: 8.75 mg (25.89%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，60-20-20，0.6mL/min)=18.234min。RT (Chiralcel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 18.234 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.41(m,2H),0.85(m,2H),1.03(d,3H),1.63(m,1H),1.91(m,1H),2.25(m,1H),3.05(m,3H),3.21(m,2H),3.50(m,1H),3.70(m,1H),5.64(m,3H),7.44(m,2H),8.05(m,3H),9.36(m,1H),10.39(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.41 (m, 2H), 0.85 (m, 2H), 1.03 (d, 3H), 1.63 (m, 1H), 1.91 (m, 1H) ,2.25(m,1H),3.05(m,3H),3.21(m,2H),3.50(m,1H),3.70(m,1H),5.64(m,3H),7.44(m,2H), 8.05 (m, 3H), 9.36 (m, 1H), 10.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=0.938min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=0.938 min.

化合物1370：Compound 1370:

產率：12.9mg(38.17%)Yield: 12.9 mg (38.17%)

RT(Chiralcel OD-H(250*4.6，5mkm)，己烷-IPA-MeOH，60-20-20，0.6mL/min)=15.314min。RT (Chiralcel OD-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 15.314 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.41(m,2H),0.85(m,2H),1.03(d,3H),1.63(m,1H),1.91(m,1H),2.25(m,1H),3.05(m,3H),3.20(m,2H),3.50(m,1H),3.71(m,1H),5.64(m,3H),7.44(m,2H),8.05(m,3H),9.36(m,1H),10.39(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.41 (m, 2H), 0.85 (m, 2H), 1.03 (d, 3H), 1.63 (m, 1H), 1.91 (m, 1H) ,2.25(m,1H),3.05(m,3H),3.20(m,2H),3.50(m,1H),3.71(m,1H),5.64(m,3H),7.44(m,2H), 8.05 (m, 3H), 9.36 (m, 1H), 10.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值466.2；Rt=0.929min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 466.2; Rt=0.929 min.

實例446. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1264)之合成Example 446. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-3,4-di Synthesis of Hydrogen-1H-isoquinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 1264)

Figure 110128222-A0202-12-1835-958
Figure 110128222-A0202-12-1835-958

步驟3：(3S)-3-甲基-6-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: (3S)-3-Methyl-6-(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-3,4-dihydro-2H-pyridine-1 -Synthesis of tert-butyl formate

Figure 110128222-A0202-12-1836-959
Figure 110128222-A0202-12-1836-959

將(5S)-5-甲基-2-(三氟甲基磺醯基氧基)哌啶-1-甲酸第三丁酯(4.07g，11.71mmol)、2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-1H-異喹啉(3.2g，11.71mmol)及碳酸鈉(3.72g，35.14mmol，1.47mL)添加到二噁烷(30mL)及水(10mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(478.30mg，585.70umol)。將反應混合物在氬氣、70℃下攪拌16h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20mL)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之(3S)-3-甲基-6-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，11.68mmol，99.71%產率)，其不經純化即用於下一步驟中。Combine (5S)-5-methyl-2-(trifluoromethylsulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (4.07 g, 11.71 mmol), 2-methyl-6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-1H-isoquinoline (3.2 g, 11.71 mmol) and sodium carbonate (3.72 g, 35.14 mmol, 1.47 mL) were added to a mixture of dioxane (30 mL) and water (10 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM ( 478.30 mg, 585.70 umol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 16 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20 mL) and discarded. The filtrate was evaporated in vacuo to give (3S)-3-methyl-6-(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-3 as a brown oil , 3-butyl 4-dihydro-2H-pyridine-1-carboxylate (4 g, 11.68 mmol, 99.71% yield) was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值343.2；實測值343.2；Rt=1.050min。LCMS (ESI): [M+H] + m/z: calculated 343.2; found 343.2; Rt=1.050 min.

步驟4：2-甲基-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]-3,4-二氫-1H-異喹啉之合成Step 4: 2-Methyl-6-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-3,4-dihydro-1H-isoquinoline synthesis

將(3S)-3-甲基-6-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4g，11.68mmol)於TFA(19.98g，175.20mmol，13.50mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之2-甲基-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]-3,4-二氫-1H-異喹啉(2.3g，9.49mmol，81.25%產率)，其直接用於下一步驟中。(3S)-3-methyl-6-(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid A solution of tert-butyl ester (4 g, 11.68 mmol) in TFA (19.98 g, 175.20 mmol, 13.50 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-methyl-6-[(3S)-3-methyl-2,3,4,5- as a brown oil Tetrahydropyridin-6-yl]-3,4-dihydro-lH-isoquinoline (2.3 g, 9.49 mmol, 81.25% yield), which was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值243.2；實測值243.2；Rt=0.219min。LCMS (ESI): [M+H] + m/z: calculated 243.2; found 243.2; Rt=0.219 min.

步驟5：2-甲基-6-[(5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-異喹啉之合成Step 5: Synthesis of 2-methyl-6-[(5S)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-isoquinoline

在0℃下，將硼氫化鈉(718.07mg，18.98mmol，671.09uL)一次性添加到2-甲基-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]-3,4-二氫-1H-異喹啉(2.3g，9.49mmol)於MeOH(20mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌15h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用EtOAc(2*40mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以MeCN為溶析液混合物)，以得到2-甲基-6-[(5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-異喹啉(0.4g，1.64mmol，17.25%產率)。At 0 °C, sodium borohydride (718.07 mg, 18.98 mmol, 671.09 uL) was added in one portion to 2-methyl-6-[(3S)-3-methyl-2,3,4,5-tetrahydro Pyridin-6-yl]-3,4-dihydro-lH-isoquinoline (2.3 g, 9.49 mmol) in a stirred solution of MeOH (20 mL). The resulting mixture was stirred at 25 °C for 15 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2*40 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The oil obtained was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with MeCN as eluent mixture) to give 2-methyl-6-[(5S)-5-methyl-2- Piperidinyl]-3,4-dihydro-1H-isoquinoline (0.4 g, 1.64 mmol, 17.25% yield).

LCMS(ESI)：[M+H]+ m/z：計算值245.2；實測值245.2；Rt=0.322min。LCMS (ESI): [M+H] + m/z: calculated 245.2; found 245.2; Rt=0.322 min.

步驟6：N-[3-環丙基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 6: N-[3-Cyclopropyl-5-[[2-[(2R,5S)-5-methyl-2-(2-methyl-3,4-dihydro-1H-isoquinoline Synthesis of -6-yl)-1-piperidinyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

Figure 110128222-A0202-12-1837-960
Figure 110128222-A0202-12-1837-960

將DIPEA(180.74mg，1.40mmol，243.59uL)添加到相應2-[[6-(第三丁氧基羰基胺基)-5-環丙基-3-吡啶基]胺基]-2-側氧基乙酸鹽(182.93mg，559.39umol，Li+)及2-甲基-6-[(5S)-5-甲基-2-哌啶基]-3,4-二氫-1H-異喹啉(136.7mg，559.39umol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(233.97mg，615.33umol)。然後，在室溫下在Ar下將反應混合物攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以MeOH+NH3為溶析液混合物)，以得到N-[3-環丙基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基-3,4-二氫-1H-異喹啉-6- 基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(106.4mg，194.27μmol，34.73%產率)。DIPEA (180.74 mg, 1.40 mmol, 243.59 uL) was added to the corresponding 2-[[6-(tert-butoxycarbonylamino)-5-cyclopropyl-3-pyridyl]amino]-2-side Oxyacetic acid salt (182.93mg, 559.39umol, Li+) and 2-methyl-6-[(5S)-5-methyl-2-piperidinyl]-3,4-dihydro-1H-isoquinoline (136.7 mg, 559.39 umol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (233.97 mg, 615.33 umol) was added. The reaction mixture was then stirred under Ar at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with MeOH+NH as eluent mixture) to give N-[3-cyclopropyl-5-[[2-[(2R, 5S)-5-methyl-2-(2-methyl-3,4-dihydro-1H-isoquinoline-6- yl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (106.4 mg, 194.27 μmol, 34.73% yield).

LCMS(ESI)：[M+H]+ m/z：計算值548.2；實測值548.4；Rt=2.229min。LCMS (ESI): [M+H] + m/z: calculated 548.2; found 548.4; Rt=2.229 min.

步驟7：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(化合物1264)之合成Step 7: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-3,4-di Synthesis of Hydrogen-1H-isoquinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (Compound 1264)

Figure 110128222-A0202-12-1838-961
Figure 110128222-A0202-12-1838-961

將N-[3-環丙基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(106.4mg，194.27μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以水-MeCN+NH3 為溶析液混合物)，以得到N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(10.3mg，23.01μmol，11.85%產率)。N-[3-Cyclopropyl-5-[[2-[(2R,5S)-5-methyl-2-(2-methyl-3,4-dihydro-1H-isoquinoline-6 -yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (106.4 mg, 194.27 μmol) was dissolved in dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with water-MeCN+ NH3 as eluent mixture) to give N-(6-amino-5-cyclopropyl-3- Pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-1-piperidinyl] -2-Pendant oxyacetamide (10.3 mg, 23.01 μmol, 11.85% yield).

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.41-0.46(m,2H),0.84-1.01(m,5H),1.22-1.35(m,2H),1.61-1.67(m,2H),1.81-2.31(m,7H),2.54-2.57(m,2H),2.73-2.80(m,2H),3.43-3.45(m,2H),5.09-5.75(m,4H),7.01-7.08(m,3H),7.29-7.36(m,1H),10.41-10.47(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.41-0.46 (m, 2H), 0.84-1.01 (m, 5H), 1.22-1.35 (m, 2H), 1.61-1.67 (m, 2H) ),1.81-2.31(m,7H),2.54-2.57(m,2H),2.73-2.80(m,2H),3.43-3.45(m,2H),5.09-5.75(m,4H),7.01-7.08 (m, 3H), 7.29-7.36 (m, 1H), 10.41-10.47 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值448.2；實測值448.4；Rt=1.372min。LCMS (ESI): [M+H] + m/z: calculated 448.2; found 448.4; Rt=1.372 min.

實例447. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-[(3S)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1311)及N-(6-Example 447. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-[(3S)-1-methyl Pyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1311) and N-(6- 胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-[(3R)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1308)之合成Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-[(3R)-1-methylpyrrolidin-3-yl]- Synthesis of 1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1308)

Figure 110128222-A0202-12-1839-962
Figure 110128222-A0202-12-1839-962

步驟1：N-(5-溴-2-氟苯基)-1-甲基-吡咯啶-3-甲醯胺之合成Step 1: Synthesis of N-(5-bromo-2-fluorophenyl)-1-methyl-pyrrolidine-3-carboxamide

向1-甲基吡咯啶-3-甲酸(1g，7.74mmol)、5-溴-2-氟苯胺(1.47g，7.74mmol)、2-氯-1-甲基吡啶-1-鎓；碘化物(2.4g，9.39mmol)及DCM(12mL)中之混合物中添加DIPEA(3g，23.2mmol)且將混合物在20℃下攪拌12小時。在減壓下濃縮混合物。藉由急驟層析(ISCO®；40g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速：30mL/min)純化殘餘物，以得到呈黃色油狀物之N-(5-溴-2-氟苯基)-1-甲基-吡咯啶-3-甲醯胺(1.8g，77.2%產率)。LCMS(ESI)[M+H]+ m/z：計算值284.0，實測值302.9(M+H2 O)。To 1-methylpyrrolidine-3-carboxylic acid (1 g, 7.74 mmol), 5-bromo-2-fluoroaniline (1.47 g, 7.74 mmol), 2-chloro-1-methylpyridine-1-onium; iodide To a mixture in (2.4 g, 9.39 mmol) and DCM (12 mL) was added DIPEA (3 g, 23.2 mmol) and the mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® silica flash column, petroleum ether/EtOAc, where EtOAc was 0-20%, flow rate: 30 mL/min) to give as a yellow oil. N-(5-Bromo-2-fluorophenyl)-1-methyl-pyrrolidine-3-carboxamide (1.8 g, 77.2% yield). LCMS (ESI) [M+H] + m/z: calcd 284.0, found 302.9 (M+ H2O ).

步驟2：5-溴-2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑之合成Step 2: Synthesis of 5-bromo-2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazole

向N-(5-溴-2-氟苯基)-1-甲基-吡咯啶-3-甲醯胺(1.8g，5.98mmol)、勞森試劑(Lawessons reagent)(1.46g，3.61mmol)及DMF(20mL)之混合物中添加Cs2 CO3 (4.93g，15.1mmol)且將混合物在100℃下攪拌24小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和 NH4 Cl水溶液(100mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~100%，流速：30mL/min)進行純化，以得到粗產物，其藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX C18 75 * 30mm * 3μm；流動相A：具有10mM NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在7.8min內31%至61% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)進行進一步純化，以得到呈黃色固體之5-溴-2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑(350mg，21.2%產率)。LCMS(ESI)[M+H]+ m/z：計算值299.0，實測值299.0。To N-(5-bromo-2-fluorophenyl)-1-methyl-pyrrolidine-3-carboxamide (1.8 g, 5.98 mmol), Lawessons reagent (1.46 g, 3.61 mmol) To a mixture of and DMF (20 mL) was added Cs 2 CO 3 (4.93 g, 15.1 mmol) and the mixture was stirred at 100° C. for 24 hours. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (100 mL*2), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product, which was purified by flash purification (ISCO®; 24g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-100% EtOAc, flow rate: 30 mL/min) to obtain the crude product, which was purified by preparative HPLC (instrument : Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Phenomenex Gemini-NX C18 75*30mm*3μm; Mobile Phase A: H2O (v% ) with 10mM NH4HCO3 ); Mobile Phase B: MeCN; Gradient: 31% to 61% B in 7.8min, hold 100% B for 2min; Flow Rate: 25mL/min; Column Temperature: 30°C; Wavelength: 220nm, 254nm) for further purification , to give 5-bromo-2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazole (350 mg, 21.2% yield) as a yellow solid. LCMS (ESI) [M+H] + m/z: Calculated 299.0, found 299.0.

步驟3：2-(1-甲基吡咯啶-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑之合成Step 3: 2-(1-Methylpyrrolidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Base)-1,3-Benzothiazole Synthesis

將5-溴-2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑(330mg，1.11mmol)、KOAc(630mg，2.23mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(430mg，1.69mmol)、環戊基(二苯基)磷烷；二氯化鈀；鐵(80mg，0.109mmol)及二噁烷(8mL)之混合物在100℃下攪拌12小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO®；80g AgelaFlash®二氧化矽急驟管柱，EtOAc/MeOH，其中MeOH為0~5%，流速：30mL/min)純化殘餘物，以得到呈棕色固體之2-(1-甲基吡咯啶-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(240mg，62.8%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.30(s,1H),7.96(d,J =8.0Hz,1H),7.75(d,J =8.0Hz,1H),4.01-4.10(m,1H),3.35-3.40(m,1H),3.24-3.28(m,1H),3.02-3.10(m,2H),2.64(s,3H),2.54-2.62(m, 1H),2.29-2.38(m,1H),1.38(s,12H)；LCMS(ESI)[M+H]+ m/z：計算值345.2，實測值345.2。5-Bromo-2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazole (330 mg, 1.11 mmol), KOAc (630 mg, 2.23 mmol), 4,4,5,5- Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A mixture of cyclopentane (430 mg, 1.69 mmol), cyclopentyl(diphenyl)phosphine; palladium dichloride; iron (80 mg, 0.109 mmol) and dioxane (8 mL) was stirred at 100°C for 12 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g AgelaFlash® silica flash column, EtOAc/MeOH with 0-5% MeOH, flow rate: 30 mL/min) to give 2-( as a brown solid 1-Methylpyrrolidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3 - benzothiazole (240 mg, 62.8% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.30 (s, 1H), 7.96 (d, J =8.0 Hz, 1H), 7.75 (d, J =8.0 Hz, 1H), 4.01-4.10 (m, 1H), 3.35-3.40(m, 1H), 3.24-3.28(m, 1H), 3.02-3.10(m, 2H), 2.64(s, 3H), 2.54-2.62(m, 1H), 2.29-2.38( m, 1H), 1.38 (s, 12H); LCMS (ESI) [M+H] + m/z: calculated 345.2, found 345.2.

步驟4：(3S)-3-甲基-6-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 4: (3S)-3-Methyl-6-[2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazol-5-yl]-3,4-dihydro- Synthesis of 2H-pyridine-1-carboxylic acid tert-butyl ester

向2-(1-甲基吡咯啶-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(200mg，0.581mmol)、(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(300mg，0.869mmol)於二噁烷(1.5mL)及H2 O(0.5mL)中之混合物中添加Pd(dppf)Cl2 -DCM(47mg，0.0576mmol)及Cs2 CO3 (280mg，0.859mmol)。將所得混合物密封且在真空下除氣且用N2 吹掃三次，然後在100℃下於微波中加熱1小時。所得混合物藉由添加水(30mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO®；12g AgelaFlash®二氧化矽急驟管柱，DCM/MeOH，其中MeOH為0~10%，流速=30mL/min)純化殘餘物，以得到呈黃色固體之(3S)-3-甲基-6-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(200mg，83.2%產率)。To 2-(1-methylpyrrolidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) -1,3-benzothiazole (200 mg, 0.581 mmol), (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1 - To a mixture of tert-butyl formate (300 mg, 0.869 mmol) in dioxane (1.5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 - DCM (47 mg , 0.0576 mmol) and Cs2 CO3 (280 mg, 0.859 mmol). The resulting mixture was sealed and degassed under vacuum and purged with N2 three times, then heated in microwave at 100 °C for 1 hour. The resulting mixture was quenched by adding water (30 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL), brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12g AgelaFlash® silica flash column, DCM/MeOH with 0~10% MeOH, flow rate = 30 mL/min) to give (3S) as a yellow solid -3-Methyl-6-[2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H-pyridine-1- 3-Butyl formate (200 mg, 83.2% yield).

步驟5：5-[(5S)-5-甲基-2-哌啶基]-2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑之合成Step 5: Synthesis of 5-[(5S)-5-methyl-2-piperidinyl]-2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazole

將(3S)-3-甲基-6-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(200mg，0.484mmol)、DCM(3mL)及TFA(2mL，26.0mmol)之混合物在20℃下攪拌2小時。在減壓下濃縮所得混合物。將殘餘物用MeOH(5mL)稀釋且用飽和Na2 CO3 調節至pH=6，然後在0℃下將NaBH4 (30mg，0.793mmol)緩慢添加到混合物中。將所得混合物在0℃下攪拌1小時。在減壓下濃縮混合物。藉由急驟層析(管柱：SepaFlash® Sphercial C18，40g，40-60μm，120Å；MeCN/水(0.05v% NH3 -H2 O)，其中MeCN為0-50%，25mL/min，220 nm)純化殘餘物，以得到呈白色固體之5-[(5S)-5-甲基-2-哌啶基]-2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑(70mg，45.9%產率)。LCMS(ESI)[M+H]+ m/z：計算值316.2，實測值316.2。(3S)-3-methyl-6-[2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H- A mixture of tert-butyl pyridine-1-carboxylate (200 mg, 0.484 mmol), DCM (3 mL) and TFA (2 mL, 26.0 mmol) was stirred at 20 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with MeOH (5 mL) and adjusted to pH= 6 with saturated Na2CO3 , then NaBH4 (30 mg, 0.793 mmol) was slowly added to the mixture at 0 °C. The resulting mixture was stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure. by flash chromatography (column: SepaFlash® Sphercial C18, 40g, 40-60μm, 120Å; MeCN/water (0.05v% NH3 - H2O ) with MeCN 0-50%, 25mL/min, 220 nm) purification of the residue to give 5-[(5S)-5-methyl-2-piperidinyl]-2-(1-methylpyrrolidin-3-yl)-1,3- as a white solid Benzothiazole (70 mg, 45.9% yield). LCMS (ESI) [M+H] + m/z: calcd 316.2, found 316.2.

步驟6：N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 6: N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(1-methylpyrrolidine-3 -yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

將2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(90mg，0.220mmol)、5-[(5S)-5-甲基-2-哌啶基]-2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑(70.0mg，0.222mmol)、HATU(100mg，0.263mmol)及DIPEA(0.11mL，0.632mmol)於DCM(5mL)中之混合物在20℃下攪拌2小時。所得混合物藉由添加水(50mL)來淬滅且用DCM(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；4g AgelaFlash® 二氧化矽急驟管柱，DCM/MeOH，其中MeOH為0~20%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(130mg，83.7%產率)。LCMS(ESI)[M+H]+ m/z：計算值707.4，實測值707.4。2-[[6-[Bis(tert-butoxycarbonyl)amino]-5-ethyl-3-pyridinyl]amino]-2-side oxyacetic acid (90 mg, 0.220 mmol), 5- [(5S)-5-methyl-2-piperidinyl]-2-(1-methylpyrrolidin-3-yl)-1,3-benzothiazole (70.0 mg, 0.222 mmol), HATU (100 mg , 0.263 mmol) and DIPEA (0.11 mL, 0.632 mmol) in DCM (5 mL) was stirred at 20 °C for 2 h. The resulting mixture was quenched by adding water (50 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL), brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 4g AgelaFlash® silica flash column, DCM/MeOH with 0-20% MeOH, flow rate = 30 mL/min, 254 nm) to give a yellow oil N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(1-methylpyrrolidin-3-yl )-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (130 mg, 83.7 %Yield). LCMS (ESI) [M+H] + m/z: calcd 707.4, found 707.4.

步驟7：N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 7: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(5S)-5-methyl-2-[2-(1-methylpyrrolidin-3-yl )-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyacetamide synthesis

將N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(130mg，0.184mmol)、DCM(3mL)及TFA(2mL，26.0mmol)之混合物在20℃下攪拌2小時。將所得混合物用28重量% NH3 -H2 O調節至pH=8，然後在減壓下濃縮混合物，以得到粗產物，其藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80 * 40mm * 3μm；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內27%至57% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)進行純化，以得到呈白色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(60mg，64.4%產率)。LCMS(ESI)[M+H]+ m/z：計算值507.2，實測值507.3；HPLC：在254nm下為96.24%；在254nm下為100%。N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(1-methylpyrrolidin-3-yl )-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (130 mg, 0.184 mmol), DCM (3 mL) and TFA (2 mL, 26.0 mmol) was stirred at 20 °C for 2 h. The resulting mixture was adjusted to pH=8 with 28 wt% NH3 - H2O , then the mixture was concentrated under reduced pressure to give crude product, which was analyzed by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV detector; Column: Phenomenex Gemini-NX 80*40mm*3μm; Mobile Phase A : H2O (v%) with 10 mmol NH4HCO3 ; Mobile Phase B: MeCN; Gradient: In 27% to 57% B in 9.5min, hold 100% B for 2min; flow rate: 25mL/min; column temperature: 30°C; wavelength: 220nm, 254nm) for purification to obtain N-(6- Amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-[2-(1-methylpyrrolidin-3-yl)-1,3-benzo Thiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (60 mg, 64.4% yield). LCMS (ESI) [M+H] + m/z: calcd 507.2, found 507.3; HPLC: 96.24% at 254 nm; 100% at 254 nm.

步驟8：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 8: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methylpyrrolidine-3 -yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyacetamide synthesis

藉由SFC(儀器：Berger，Multigr AM-II；管柱：Daicel Chiralcel OJ 250mm×30mm×10μm；流動相：超臨界CO2 /EtOH(0.1% NH3- H2 O,v%)=70/30；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(50mg，0.0987mmol)。將級分在減壓下濃縮，然後凍乾隔夜，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(45mg，90.0%產率，峰2，保留時間：3.415min，兩種非鏡像異構物之混合物，白色固體，遞送2.1mg)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.11(br s,1H),7.87-8.00(m,2H),7.65(br s,1H),7.44(br s,1H),5.43-5.90(m,1H),3.88-4.13(m,1H),3.41-3.81(m,1H),3.10-3.21(m,1H),2.92(br s,1H),2.81(br s,2H),2.21-2.59(m,10H),1.95(br s,2H),1.47(br d,J =12.5Hz,1H),1.10-1.29(m,6H)；LCMS(ESI)[M+H]+ m/z：計算值507.2，實測值507.3；HPLC：在220nm下為100%，在254nm下為100%。By SFC (instrument: Berger, Multigr AM-II; column: Daicel Chiralcel OJ 250 mm×30 mm×10 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3- H 2 O, v%)=70/ 30; flow rate: 80 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; dresser temperature: 25 °C; wavelength: 220 nm) purification of N-(6 -Amino-5-ethyl-3-pyridyl)-2-[(5S)-5-methyl-2-[2-(1-methylpyrrolidin-3-yl)-1,3-benzene Thiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (50 mg, 0.0987 mmol). Fractions were concentrated under reduced pressure, then lyophilized overnight to give N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2 -[2-(1-Methylpyrrolidin-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (45 mg, 90.0% Yield, peak 2, retention time: 3.415 min, mixture of two diastereoisomers, white solid, delivering 2.1 mg). 1 H NMR (400MHz, methanol- d 4 ) δ ppm 8.11(br s,1H),7.87-8.00(m,2H),7.65(br s,1H),7.44(br s,1H),5.43-5.90( m,1H),3.88-4.13(m,1H),3.41-3.81(m,1H),3.10-3.21(m,1H),2.92(br s,1H),2.81(br s,2H),2.21- 2.59(m, 10H), 1.95(br s, 2H), 1.47(br d, J =12.5Hz, 1H), 1.10-1.29(m, 6H); LCMS(ESI)[M+H] + m/z : Calculated value 507.2, found value 507.3; HPLC: 100% at 220 nm, 100% at 254 nm.

步驟9：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-[(3S)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1311)及N-(6-胺基-5-乙基3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-[(3R)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1308)之合成Step 9: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-[(3S)-1-methyl Pyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1311) and N-(6-amino-5 -Ethyl 3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-[(3R)-1-methylpyrrolidin-3-yl]-1,3-benzene Synthesis of Thiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1308)

藉由掌性SFC(儀器：Berger，Multigr AM-II；管柱：Daicel Chiralcel OJ 250mm×10mm×10μm；流動相：超臨界CO2 /EtOH(0.1% NH3- H2 O,v%)=70/30；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(40mg，0.0790mmol)，以得到化合物1311及化合物1308 。By chiral SFC (instrument: Berger, Multigr AM-II; column: Daicel Chiralcel OJ 250mm×10mm×10μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)= 70/30; flow rate: 80mL/min; column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; dresser temperature: 25°C; wavelength: 220nm) to separate N- (6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methylpyrrolidin-3-yl)-1 , 3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (40 mg, 0.0790 mmol) to give compound 1311 and compound 1308 .

化合物1311 ：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-[(3S)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(17.2mg，具有反式相對化學之單一未知鏡像異構物，峰1，保留時間：6.269min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.12(br s,1H),7.91-8.01(m,2H),7.65(br s,1H),7.38-7.54(m,1H),5.46-5.87(m,1H),3.93-4.17(m,1H),3.39-3.84(m,1H),3.14(br d,J =5.3Hz,1H),2.97(br d,J =5.8Hz,2H),2.20-2.72(m,10H),1.92(br d,J =12.3Hz,2H),1.47(br d,J =11.8Hz,1H),1.08-1.31(m,6H)；LCMS(ESI)[M+H]+ m/z：計算值507.2，實測值507.3；HPLC：在254nm下為98.34%，在254nm下為99.43%；96.9%ee。 Compound 1311 : N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-[(3S)-1-methyl Pyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (17.2 mg, single unknown mirror isomeric with trans relative chemistry Construct, peak 1, retention time: 6.269 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.12 (br s, 1H), 7.91-8.01 (m, 2H), 7.65 (br s, 1H), 7.38-7.54 (m, 1H), 5.46-5.87 (m,1H),3.93-4.17(m,1H),3.39-3.84(m,1H),3.14(br d, J =5.3Hz,1H),2.97(br d, J =5.8Hz,2H), 2.20-2.72(m, 10H), 1.92(br d, J =12.3Hz, 2H), 1.47(br d, J =11.8Hz, 1H), 1.08-1.31(m, 6H); LCMS(ESI)[M +H] + m/z: calculated 507.2, found 507.3; HPLC: 98.34% at 254 nm, 99.43% at 254 nm; 96.9% ee.

化合物1308 ：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-[(3R)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(16.8mg，具有反式相對化學之單一未知鏡像異構物，峰2，保留時間：7.179min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.11(br s,1H),7.90-8.01(m,2H),7.65(br s,1H),7.40- 7.53(m,1H),5.44-5.87(m,1H),3.93(br s,1H),3.41-3.82(m,1H),3.12-3.22(m,1H),2.92(br s,1H),2.76-2.86(m,2H),2.08-2.64(m,10H),1.94(br s,2H),1.47(br d,J =12.5Hz,1H),1.14(br d,J =7.0Hz,6H)；LCMS(ESI)[M+H]+ m/z：計算值507.2，實測值507.3；HPLC：在254nm下為97.87%，在254nm下為97.79%；93.2%ee。 Compound 1308 : N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-[(3R)-1-methyl Pyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (16.8 mg, single unknown mirror isomeric with trans relative chemistry Construct, peak 2, retention time: 7.179 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.11(br s, 1H), 7.90-8.01(m, 2H), 7.65(br s, 1H), 7.40-7.53(m, 1H), 5.44-5.87 (m,1H),3.93(br s,1H),3.41-3.82(m,1H),3.12-3.22(m,1H),2.92(br s,1H),2.76-2.86(m,2H),2.08 -2.64(m, 10H), 1.94(br s, 2H), 1.47(br d, J =12.5Hz, 1H), 1.14(br d, J =7.0Hz, 6H); LCMS(ESI)[M+H ] + m/z: calculated 507.2, found 507.3; HPLC: 97.87% at 254 nm, 97.79% at 254 nm; 93.2% ee.

實例448. N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1382)、N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(化合物1131)、N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺 (化合物1373)、N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(化合物1227)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(化合物1098)之合成 Example 448. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(5S)-2-[2-(1,3-dimethyl-4-piperidinyl)- 1,3-Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1382), N-(6-amino-5-ethyl) -3-Pyridinyl)-2-oxo-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R,4R)-1,3 -Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide (Compound 1131), N-(6-amino-5-ethyl) yl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S,4S)-1, 3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide (compound 1373 ), N-(6-amino-5- Ethyl-3-pyridyl)-2-oxo-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S,4R)-1 ,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide (Compound 1227) and N-(6-amino-5 -Ethyl-3-pyridyl)-2-oxo-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R,4S)- Synthesis of 1,3-Dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide (Compound 1098)

Figure 110128222-A0202-12-1845-963
Figure 110128222-A0202-12-1845-963

步驟1：(1,3-二甲基-3,6-二氫-2H-吡啶-4-基)三氟甲磺酸酯之合成Step 1: Synthesis of (1,3-Dimethyl-3,6-dihydro-2H-pyridin-4-yl)trifluoromethanesulfonate

將1,3-二甲基哌啶-4-酮(1.5g，0.0118mol)於THF(10mL)中之混合物密封且在真空中除氣且用N2 吹掃三次，然後在-78℃下逐滴添加1M鋰；雙(三甲基矽基)氮烷(azanide)/THF(17mL，17.0mmol)，將混合物在-78℃下攪拌1小時，然後添加THF(10mL)中之PhNTf2 (6.3g，0.176mol)。將溶液在20℃下攪拌12小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL * 2)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；24g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~80%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之(1,3-二甲基-3,6-二氫-2H-吡啶-4-基)三氟甲磺酸酯(2g，65.4%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 5.83(br s,1 H),3.21-3.28(m,1 H),3.06-3.21(m,1 H),2.99(br dd,J =11.5,5.3Hz,1 H),2.80(br s,1 H),2.36-2.48(m,4 H),1.16(d,J =7.0Hz,3 H)。LCMS(ESI)[M+H]+ m/z：計算值260.0，實測值260.0。A mixture of 1,3-dimethylpiperidin-4-one (1.5 g, 0.0118 mol) in THF (10 mL) was sealed and degassed in vacuo and purged with N 3 times, then at -78 °C 1M Lithium; bis(trimethylsilyl)azanide/THF (17 mL, 17.0 mmol) was added dropwise, the mixture was stirred at -78 °C for 1 h, then PhNTf in THF (10 mL) was added ( 6.3 g, 0.176 mol). The solution was stirred at 20°C for 12 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL*2), brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 24g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-80% EtOAc, flow = 30 mL/min, 254 nm) to give a yellow oil (1,3-Dimethyl-3,6-dihydro-2H-pyridin-4-yl)trifluoromethanesulfonate (2 g, 65.4% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 5.83 (br s, 1 H), 3.21-3.28 (m, 1 H), 3.06-3.21 (m, 1 H), 2.99 (br dd, J =11.5 , 5.3 Hz, 1 H), 2.80 (br s, 1 H), 2.36-2.48 (m, 4 H), 1.16 (d, J = 7.0 Hz, 3 H). LCMS (ESI) [M+H] + m/z: Calculated 260.0, found 260.0.

步驟2：1,3-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H-吡啶之合成Step 2: 1,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6- Synthesis of Dihydro-2H-pyridine

向(1,3-二甲基-3,6-二氫-2H-吡啶-4-基)三氟甲磺酸酯(2g，7.71mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.43g，9.56mmol)、環戊基(二苯基)磷烷；二氯甲烷；二氯化鈀；鐵(650mg，0.796mmol)於二噁烷(20mL)中之溶液中添加CH3 COOK(2.29g，0.0233mol)。將所得混合物密封且在真空中除氣且用N2 吹掃三次，然後在90℃、N2 下攪拌12小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL * 2)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；24g AgelaFlash® 二氧化矽急驟管柱，EtOAc/MeOH，其中MeOH為0~20%，流速=30mL/min， 254nm)純化殘餘物，以得到呈棕色固體之1,3-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H-吡啶(1g，54.7%產率)。LCMS(ESI)[M+H]+ m/z：計算值238.2，實測值238.1。To (1,3-dimethyl-3,6-dihydro-2H-pyridin-4-yl)trifluoromethanesulfonate (2 g, 7.71 mmol), 4,4,5,5-tetramethyl- 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane ( 2.43 g, 9.56 mmol), cyclopentyl(diphenyl)phosphine; dichloromethane; palladium dichloride; iron (650 mg, 0.796 mmol) in dioxane (20 mL) was added CH3COOK ( 2.29 g, 0.0233 mol). The resulting mixture was sealed and degassed in vacuo and purged with N 2 three times, then stirred at 90 °C under N 2 for 12 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL*2), brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 24g AgelaFlash® silica flash column, EtOAc/MeOH with 0-20% MeOH, flow = 30 mL/min, 254 nm) to give 1 as a brown solid ,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro-2H - Pyridine (1 g, 54.7% yield). LCMS (ESI) [M+H]+ m/z: calculated 238.2, found 238.1.

步驟3：(5S)-2-[2-(1,3-二甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 3: (5S)-2-[2-(1,3-Dimethyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]- Synthesis of 3-butyl 5-methylpiperidine-1-carboxylate

將(5S)-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(300mg，0.729mmol)、1,3-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H-吡啶(300mg，1.27mmol)、K2 CO3 (300mg，2.17mmol)及Pd(PPh3 )4 (120mg，0.104mmol)溶解到微波管中之EtOH(10mL)及H2 O(1mL)中。將密封管在90℃下於微波中加熱1小時。所得混合物藉由添加水(20mL)來淬滅且用EtOAc(20mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(20mL * 2)、鹽水(20mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；24g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~100%，流速=30mL/min，254nm)純化殘餘物，以得到呈棕色油狀物之(5S)-2-[2-(1,3-二甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(300mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值442.2，實測值442.2。(5S)-2-(2-Bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.729 mmol), 1,3- Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro-2H-pyridine ( 300 mg, 1.27 mmol), K2CO3 ( 300 mg , 2.17 mmol) and Pd( PPh3 ) 4 (120 mg, 0.104 mmol) were dissolved in EtOH (10 mL) and H2O (1 mL) in a microwave tube. The sealed tube was heated in the microwave at 90°C for 1 hour. The resulting mixture was quenched by adding water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (20 mL*2), brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 24g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-100% EtOAc, flow = 30 mL/min, 254 nm) to give a brown oil (5S)-2-[2-(1,3-dimethyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]-5 - tert-butyl methylpiperidine-1-carboxylate (300 mg, crude). LCMS (ESI) [M+H]+ m/z: calculated 442.2, found 442.2.

步驟4：(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: (5S)-2-[2-(1,3-Dimethyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-5-methylpiperidine-1- Synthesis of tert-butyl formate

向(5S)-2-[2-(1,3-二甲基-3,6-二氫-2H-吡啶-4-基)-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(300mg，0.679mmol)於MeOH(4mL)中之溶液中添加Pd/C(300mg，具有50重量%水之10重量% Pd/C)。將所得混合物密封且在真空下除氣且用H2 吹掃三次，然後在20℃、H2 (在氣球中)下攪拌18小時。過濾所得混合物且在減壓下濃縮，以得到呈黃色油狀物之(5S)-2-[2-(1,3-二甲基-4-哌 啶基)-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(250mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值442.2，實測值444.3。To (5S)-2-[2-(1,3-dimethyl-3,6-dihydro-2H-pyridin-4-yl)-1,3-benzothiazol-5-yl]-5- To a solution of tert-butyl methylpiperidine-1-carboxylate (300 mg, 0.679 mmol) in MeOH (4 mL) was added Pd/C (300 mg, 10 wt % Pd/C with 50 wt % water). The resulting mixture was sealed and degassed under vacuum and purged with H2 three times, then stirred at 20°C under H2 (in a balloon) for 18 hours. The resulting mixture was filtered and concentrated under reduced pressure to give (5S)-2-[2-(1,3-dimethyl-4-piperidinyl)-1,3-benzothiazole as a yellow oil -5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (250 mg, crude). LCMS (ESI) [M+H]+ m/z: calculated 442.2, found 444.3.

步驟5：2-(1,3-二甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 5: Synthesis of 2-(1,3-Dimethyl-4-piperidinyl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole

向(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(250mg，0.564mmol)於DCM(6mL)中之溶液中添加TFA(0.8mL，10.4mmol)。將混合物在20℃下攪拌12小時。將所得混合物在減壓下濃縮，以得到呈黃色油狀物之2-(1,3-二甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(150mg，77.5%產率)。To (5S)-2-[2-(1,3-dimethyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-5-methylpiperidine-1-carboxylic acid To a solution of tributyl ester (250 mg, 0.564 mmol) in DCM (6 mL) was added TFA (0.8 mL, 10.4 mmol). The mixture was stirred at 20°C for 12 hours. The resulting mixture was concentrated under reduced pressure to give 2-(1,3-dimethyl-4-piperidinyl)-5-[(5S)-5-methyl-2-piperidine as a yellow oil Peridyl]-1,3-benzothiazole (150 mg, 77.5% yield).

步驟6：N-第三丁氧基羰基-N-[5-[[2-[(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯之合成Step 6: N-Tertibutoxycarbonyl-N-[5-[[2-[(5S)-2-[2-(1,3-dimethyl-4-piperidinyl)-1,3 -Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl Synthesis of Esters

向2-(1,3-二甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(150mg，0.437mmol)、2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(170mg，0.415mmol)、HATU(225mg，0.592mmol)於DCM(4mL)中之溶液中添加N-乙基-N-異丙基丙-2-胺(0.4mL，2.30mmol)。將混合物在20℃下攪拌2小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，EtOAc/MeOH，其中MeOH為0~20%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之N-第三丁氧基羰基-N-[5-[[2-[(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(200mg，68.9%產率)。LCMS(ESI)[M+H]+ m/z：計算值735.4，實測值735.4。To 2-(1,3-dimethyl-4-piperidinyl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (150 mg, 0.437 mmol ), 2-[[6-[bis(tert-butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2-side oxyacetic acid (170 mg, 0.415 mmol), HATU (225 mg, 0.592 mmol) in DCM (4 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.4 mL, 2.30 mmol). The mixture was stirred at 20°C for 2 hours. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL*2), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, EtOAc/MeOH with 0-20% MeOH, flow = 30 mL/min, 254 nm) to give a yellow oil N-tert-butoxycarbonyl-N-[5-[[2-[(5S)-2-[2-(1,3-dimethyl-4-piperidinyl)-1,3-benzene Thiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester ( 200 mg, 68.9% yield). LCMS (ESI) [M+H]+ m/z: calculated 735.4, found 735.4.

步驟7：N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并Step 7: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(5S)-2-[2-(1,3-dimethyl-4-piperidinyl)- 1,3-Benzo 噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1382)之合成Synthesis of Thiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1382)

向N-第三丁氧基羰基-N-[5-[[2-[(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-乙基-2-吡啶基]胺甲酸第三丁酯(200mg，0.272mmol)於DCM(4mL)中之溶液中添加TFA(0.02mL，0.272mmol)。將混合物在20℃下攪拌12小時。在減壓下濃縮所得混合物。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80×40mm×3μm；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內35%至65% B，保持100% B達1min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈白色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(50mg，34.4%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.88-8.17(m,3 H),7.36-7.71(m,2 H),5.43-5.91(m,1 H),3.67-4.20(m,1 H),3.43(br s,1 H),2.72-3.20(m,3 H),1.82-2.63(m,15 H),1.20-1.52(m,3 H),1.15(br d,J =6.8Hz,3 H),0.84-0.97(m,3 H)；LCMS(ESI)[M+H]+ m/z：計算值535.3，實測值535.3；HPLC：在220nm下為100%，在254nm下為100%。To N-tert-butoxycarbonyl-N-[5-[[2-[(5S)-2-[2-(1,3-dimethyl-4-piperidinyl)-1,3-benzene Thiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-ethyl-2-pyridyl]carbamic acid tert-butyl ester ( 200 mg, 0.272 mmol) in DCM (4 mL) was added TFA (0.02 mL, 0.272 mmol). The mixture was stirred at 20°C for 12 hours. The resulting mixture was concentrated under reduced pressure. by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex Gemini-NX 80×40 mm×3 μm; mobile phase A: with 10 mmol of NH 4 HCO 3 H 2 O (v%); mobile phase B: MeCN; gradient: 35% to 65% B in 9.5 min, hold 100% B for 1 min; flow rate: 25 mL/min; column temperature: 30 °C; wavelength: 220 nm , 254 nm), the residue was purified to give N-(6-amino-5-ethyl-3-pyridinyl)-2-[(5S)-2-[2-(1,3-diol) as a white solid Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (50 mg, 34.4% yield ). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.88-8.17 (m, 3 H), 7.36-7.71 (m, 2 H), 5.43-5.91 (m, 1 H), 3.67-4.20 (m, 1 H), 3.43(br s, 1 H), 2.72-3.20(m, 3 H), 1.82-2.63(m, 15 H), 1.20-1.52(m, 3 H), 1.15(br d, J =6.8 Hz, 3 H), 0.84-0.97 (m, 3 H); LCMS (ESI) [M+H] + m/z: calcd 535.3, found 535.3; HPLC: 100% at 220 nm, at 254 nm is 100%.

步驟8：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(化合物1131)、N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(化合物1373)、N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(化合物1227)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(化合物Step 8: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 -[racemic-(3R,4R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide ( Compound 1131), N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[ 2-[Rac-(3S,4S)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide (Compound 1373), N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2- [2-[Rac-(3S,4R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetone Amine (Compound 1227) and N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2 -[2-[Rac-(3R,4S)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]ethyl Amide (compound 1098)之合成1098) synthesis

藉由掌性SFC(儀器：Thar800Q；管柱：daicel chiralcel OJ 250×30mm I.D.10μm；流動相：超臨界CO2 /EtOH(0.1% NH3、 H2 O，v%)=75/25；流速：70mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化N-(6-胺基-5-乙基-3-吡啶基)-2-[(5S)-2-[2-(1,3-二甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(50mg，0.0935mmol)，以得到兩種產物。By chiral SFC (instrument: Thar800Q; column: daicel chiralcel OJ 250×30 mm ID 10 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 , H 2 O, v%)=75/25; flow rate: 70mL/min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; conditioner temperature: 25°C; wavelength: 220nm) purification of N-(6-amino- 5-Ethyl-3-pyridyl)-2-[(5S)-2-[2-(1,3-dimethyl-4-piperidinyl)-1,3-benzothiazol-5-yl ]-5-methyl-1-piperidinyl]-2-oxoacetamide (50 mg, 0.0935 mmol) to give two products.

藉由掌性SFC(儀器：ACSSH-CO；管柱：daicel chiralcel IC 250×30mm * 5μm；流動相：超臨界己烷/IPA(0.1% NH3- H2 O，v%)=70/30；流速：25mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)進一步純化峰1，以得到化合物1131 及化合物1373。 By chiral SFC (instrument: ACSSH-CO; column: daicel chiralcel IC 250×30 mm*5 μm; mobile phase: supercritical hexane/IPA (0.1% NH3 - H2O , v%)=70/30 ; flow rate: 25 mL/min; column temperature: 38 °C; nozzle temperature: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; Compound 1131 and compound 1373 were obtained.

化合物1131： N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(峰1，保留時間=4.028min，單一未知鏡像異構物，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.41-8.81(m,1 H),7.86-8.11(m,3 H),7.35-7.51(m,1 H),5.44-5.91(m,1 H),3.39-4.20(m,7 H),3.14(br d,J =11.5Hz,1 H),3.00(br d,J =12.0Hz,2 H),2.13-2.61(m,14 H),1.98(br d,J =12.0Hz,5 H),1.47(br d,J =12.0Hz,1 H),1.14(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值535.3，實測值535.3；HPLC：在220nm下為96.51%，在254nm下為96.00%；96.7%ee。 Compound 1131: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 -[racemic-(3R,4R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide ( Peak 1, retention time = 4.028 min, single unknown enantiomer, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.41-8.81 (m, 1 H), 7.86-8.11 (m, 3 H), 7.35-7.51 (m, 1 H), 5.44-5.91 (m, 1 H), 3.39-4.20(m, 7 H), 3.14(br d, J =11.5Hz, 1 H), 3.00(br d, J =12.0Hz, 2 H), 2.13-2.61(m, 14 H) ,1.98(br d, J =12.0Hz,5 H),1.47(br d, J =12.0Hz,1 H),1.14(d, J =7.0Hz,3 H); LCMS(ESI)[M+H ] + m/z: calculated 535.3, found 535.3; HPLC: 96.51% at 220 nm, 96.00% at 254 nm; 96.7% ee.

化合物1373： N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(峰2，保留時間=4.169min，單一未知鏡像異構物，白色固體)。1 H NMR(400MHz,甲醇-d 4 )δ ppm 8.41-8.81(m,1 H),7.86-8.11(m,3 H),7.35-7.51(m,1 H),5.44-5.91(m,1 H),3.39-4.20(m,7 H),3.14(br d,J =11.5Hz,1 H),3.00(br d,J =12.0 Hz,2 H),2.13-2.61(m,14 H),1.98(br d,J =12.0Hz,5 H),1.47(br d,J =12.0Hz,1 H),1.14(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值535.3，實測值535.3；HPLC：在220nm下為96.75%，在254nm下為96.89%；74.6%ee。 Compound 1373: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 -[racemic-(3S,4S)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide ( Peak 2, retention time = 4.169 min, single unknown enantiomer, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.41-8.81 (m, 1 H), 7.86-8.11 (m, 3 H), 7.35-7.51 (m, 1 H), 5.44-5.91 (m, 1 H), 3.39-4.20 (m, 7 H), 3.14 (br d, J = 11.5 Hz, 1 H), 3.00 (br d, J =12.0 Hz, 2 H), 2.13-2.61 (m, 14 H) ,1.98(br d, J =12.0Hz,5 H),1.47(br d, J =12.0Hz,1 H),1.14(d, J =7.0Hz,3 H); LCMS(ESI)[M+H ] + m/z: calculated 535.3, found 535.3; HPLC: 96.75% at 220 nm, 96.89% at 254 nm; 74.6% ee.

藉由掌性SFC(儀器：Berger，Multigr AM-II；管柱：daicel chiralcel AD 250×30mm * 10μm；流動相：超臨界CO2 /EtOH(0.1% NH3- H2 O，v%)=50/50；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)進一步純化峰2，以得到化合物1227及化合物1098。 By chiral SFC (instrument: Berger, Multigr AM-II; column: daicel chiralcel AD 250×30 mm*10 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3- H 2 O, v%)= 50/50; flow rate: 80 mL/min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220nm) to further purify the peaks 2, to obtain compound 1227 and compound 1098.

化合物1227： N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S,4R)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(峰3，保留時間=4.648min，單一未知鏡像異構物，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.90-8.21(m,3 H),7.29-7.78(m,2 H),5.84(br s,1 H),3.67-4.19(m,1 H),3.37-3.55(m,1 H),2.72-3.18(m,2 H),1.80-2.61(m,12 H),1.47(br d,J =11.3Hz,1 H),1.07-1.35(m,6 H),0.92(br s,3 H)；LCMS(ESI)[M+H]+ m/z：計算值535.3，實測值535.3；HPLC：在220nm下為97.75%，在254nm下為100%；98.8%ee。 Compound 1227: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 -[racemic-(3S,4R)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide ( Peak 3, retention time = 4.648 min, single unknown enantiomer, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.90-8.21 (m, 3 H), 7.29-7.78 (m, 2 H), 5.84 (br s, 1 H), 3.67-4.19 (m, 1 H) ), 3.37-3.55(m, 1 H), 2.72-3.18(m, 2 H), 1.80-2.61(m, 12 H), 1.47(br d, J =11.3Hz, 1 H), 1.07-1.35( m, 6 H), 0.92 (br s, 3 H); LCMS (ESI) [M+H] + m/z: calcd 535.3, found 535.3; HPLC: 97.75% at 220 nm, 254 nm 100%; 98.8%ee.

化合物1098： N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R,4S)-1,3-二甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(峰4，保留時間=4.689min，單一未知鏡像異構物，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.86-8.17(m,3 H),7.32-7.72(m,2 H),5.45-5.90(m,1 H),3.69-4.18(m,1 H),3.37-3.49(m,1 H),2.95-3.20(m,1 H),2.82(br d,J =9.5Hz,1 H),1.88-2.59(m,14 H),1.47(br d,J =12.0Hz,1 H),1.22-1.31(m,2 H),1.15(d,J =6.8Hz,3 H),0.93(br d,J =5.5Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值535.3，實測值535.3；HPLC：在220nm下為96.27%，在254nm下為100%； 100%ee。 Compound 1098: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 -[racemic-(3R,4S)-1,3-dimethyl-4-piperidinyl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide ( Peak 4, retention time = 4.689 min, single unknown enantiomer, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.86-8.17 (m, 3 H), 7.32-7.72 (m, 2 H), 5.45-5.90 (m, 1 H), 3.69-4.18 (m, 1 H), 3.37-3.49(m, 1 H), 2.95-3.20(m, 1 H), 2.82(br d, J =9.5Hz, 1 H), 1.88-2.59(m, 14 H), 1.47(br d d, J =12.0Hz,1H),1.22-1.31(m,2H),1.15(d, J =6.8Hz,3H),0.93(br d, J =5.5Hz,3H); LCMS( ESI) [M+H] + m/z: calcd 535.3, found 535.3; HPLC: 96.27% at 220 nm, 100% at 254 nm; 100% ee.

實例449. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1187)之合成Example 449. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(8-methyl-8-nitrogen Synthesis of Heterobicyclo[3.2.1]oct-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1187)

Figure 110128222-A0202-12-1852-964
Figure 110128222-A0202-12-1852-964

步驟1：(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)三氟甲磺酸酯之合成Step 1: Synthesis of (8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)trifluoromethanesulfonate

將8-甲基-8-氮雜雙環[3.2.1]辛-3-酮(1g，7.18mmol)於THF(20mL)中之混合物密封且在真空下除氣且用N2 吹掃三次，然後在-78℃下逐滴添加1M LiHMDS/THF(13mL，13.0mmol)，且將混合物在-78℃下攪拌1小時。然後添加PhNTf2 (3.85g，10.8mmol)於THF(20mL)中之溶液。將溶液在25℃下攪拌12小時。藉由添加飽和NH4 Cl水溶液(100mL)淬滅所得混合物且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；25g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~60%，流速=60mL/min，I2 )純化殘餘物，以得到呈棕色油狀物之(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)三氟 甲磺酸酯(1.6g，82.1%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 5.95(br d,J =5.4Hz,1H),3.52(t,J =5.7Hz,1H),3.44(br dd,J =6.1,4.9Hz,1H),2.85(br dd,J =17.5,3.1Hz,1H),2.40(s,3H),2.15-2.26(m,1H),1.95-2.12(m,3H),1.68(ddd,J =12.9,9.2,6.5Hz,1H)；LCMS(ESI)[M+H]+ m/z：計算值272.0，實測值272.0。A mixture of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1 g, 7.18 mmol) in THF (20 mL) was sealed and degassed under vacuum and purged with N 3 times, Then 1M LiHMDS/THF (13 mL, 13.0 mmol) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. Then a solution of PhNTf2 (3.85 g, 10.8 mmol) in THF (20 mL) was added. The solution was stirred at 25°C for 12 hours. The resulting mixture was quenched by addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 25g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-60% EtOAc, flow = 60 mL/min, I2 ) to give a brown oil (8-Methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)trifluoromethanesulfonate (1.6 g, 82.1% yield) was obtained. 1 H NMR (400MHz, methanol- d 4 ) δ ppm 5.95(br d, J =5.4Hz, 1H), 3.52(t, J =5.7Hz, 1H), 3.44(br dd, J =6.1, 4.9Hz, 1H), 2.85(br dd, J =17.5, 3.1Hz, 1H), 2.40(s, 3H), 2.15-2.26(m, 1H), 1.95-2.12(m, 3H), 1.68(ddd, J =12.9 , 9.2, 6.5 Hz, 1H); LCMS (ESI) [M+H] + m/z: calculated 272.0, found 272.0.

步驟2：(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)硼酸之合成Step 2: Synthesis of (8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)boronic acid

向(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)三氟甲磺酸酯(1.6g，5.90mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.86g，7.31mmol)、環戊基(二苯基)磷烷；二氯甲烷；二氯化鈀；鐵(430mg，0.527mmol)於二噁烷(20mL)中之溶液中添加CH3 COOK(1.75g，17.8mmol)。將所得混合物密封且在真空下除氣且用N2 吹掃三次。然後在90℃、N2 氣氛下將混合物攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之水層在減壓下濃縮，以得到粗產物，將其溶解於DCM/MeOH(10：1)(100mL)中。然後，過濾溶液且在減壓下濃縮濾液，以得到呈黃色固體之(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)硼酸(2g，粗品)。LCMS(ESI)[M+H]+ m/z：計算值168.1，實測值168.1。To (8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)trifluoromethanesulfonate (1.6 g, 5.90 mmol), 4,4,5,5-tetrafluoromethane Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane Pentane (1.86 g, 7.31 mmol), cyclopentyl(diphenyl)phosphine; dichloromethane; palladium dichloride; iron (430 mg, 0.527 mmol) in dioxane (20 mL) was added CH 3COOK (1.75 g, 17.8 mmol). The resulting mixture was sealed and degassed under vacuum and purged with N2 three times. The mixture was then stirred for 12 hours at 90°C under N2 atmosphere. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined aqueous layers were concentrated under reduced pressure to give the crude product, which was dissolved in DCM/MeOH (10:1) (100 mL). Then, the solution was filtered and the filtrate was concentrated under reduced pressure to give (8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)boronic acid (2 g, crude) as a yellow solid . LCMS (ESI) [M+H] + m/z: calcd 168.1, found 168.1.

步驟3：(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯之合成Step 3: (5S)-5-Methyl-2-[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)-1,3-benzo Synthesis of Thiazol-5-yl]piperidine-1-carboxylate tert-butyl ester

向(5S)-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(300mg，0.729mmol)、(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)硼酸(1.5g，8.98mmol)於EtOH(6mL)及H2 O(2mL)中之混合物中添加Pd(PPh3 )4 (80mg，0.0692mmol)及K2 CO3 (300mg，2.17mmol)。將所得混合物在90℃下於微波中加熱1小時。在減壓下濃縮所得混合物。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，EtOAc/MeOH，其中MeOH為0~20%，流速=60mL/min，254nm)純化殘餘物，以得到呈棕色油狀物之(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯 -3-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(300mg，90.7%產率)。LCMS(ESI)[M+H]+ m/z：計算值454.2，實測值454.2。To (5S)-2-(2-bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.729 mmol), (8-methylpiperidine) To a mixture of yl-8-azabicyclo[3.2.1]oct-3-en-3-yl)boronic acid (1.5 g, 8.98 mmol) in EtOH (6 mL) and H 2 O (2 mL) was added Pd(PPh 3 ) 4 (80 mg, 0.0692 mmol) and K2CO3 ( 300 mg , 2.17 mmol). The resulting mixture was heated in the microwave at 90°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, EtOAc/MeOH with 0-20% MeOH, flow rate=60 mL/min, 254 nm) to give a brown oil (5S)-5-methyl-2-[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)-1,3-benzothiazole- 5-yl]piperidine-1-carboxylic acid tert-butyl ester (300 mg, 90.7% yield). LCMS (ESI) [M+H] + m/z: calcd 454.2, found 454.2.

步驟4：(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯之合成Step 4: (5S)-5-Methyl-2-[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3-benzothiazole-5- Synthesis of tert-butyl]piperidine-1-carboxylate

在氫氣下(在氣球中)，將(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-烯-3-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(300mg，0.661mmol)、Pd/C(50mg，具有50重量%水之10重量% Pd)及MeOH(10mL)中之混合物在20℃下攪拌12小時。過濾所得混合物且在減壓下濃縮。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Welch Xtimate C18 150 * 25mm * 5μm；流動相A：具有0.225% FA之H2 O(v%)；流動相B：MeOH；梯度：在9.5min內45%至75% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈白色固體之(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(150mg，49.8%產率)。LCMS(ESI)[M+H]+ m/z：計算值456.3，實測值456.2。Under hydrogen (in a balloon), (5S)-5-methyl-2-[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl) -1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.661 mmol), Pd/C (50 mg, 10 wt % Pd with 50 wt % water) and MeOH ( The mixture in 10 mL) was stirred at 20°C for 12 hours. The resulting mixture was filtered and concentrated under reduced pressure. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Welch Xtimate C18 150*25mm*5μm; mobile phase A: H2O with 0.225% FA (v%); Mobile Phase B: MeOH; Gradient: 45% to 75% B in 9.5min, hold 100% B for 2min; Flow Rate: 25mL/min; Column Temperature: 30°C; Wavelength: 220nm, 254nm) The residue was purified to give (5S)-5-methyl-2-[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3 as a white solid - benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (150 mg, 49.8% yield). LCMS (ESI) [M+H] + m/z: calcd 456.3, found 456.2.

步驟5：2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑之合成Step 5: 2-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3 -Synthesis of benzothiazole

將(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(150mg，0.329mmol)、MeOH(3mL)及4M HCl/MeOH(3mL，12.0mmol)之混合物在20℃下攪拌2小時。將所得混合物在減壓下濃縮，以得到呈白色固體之2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(110mg，粗品，HCl)。LCMS(ESI)[M+H]+ m/z：計算值356.2，實測值356.1。(5S)-5-methyl-2-[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3-benzothiazol-5-yl] A mixture of tert-butyl piperidine-1-carboxylate (150 mg, 0.329 mmol), MeOH (3 mL) and 4M HCl/MeOH (3 mL, 12.0 mmol) was stirred at 20 °C for 2 h. The resulting mixture was concentrated under reduced pressure to give 2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-[(5S)-5-methyl as a white solid yl-2-piperidinyl]-1,3-benzothiazole (110 mg, crude, HCl). LCMS (ESI) [M+H] + m/z: calcd 356.2, found 356.1.

步驟6：N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙Step 6: N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(8-methyl-8-nitrogen heterodouble 環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Cyclo[3.2.1]oct-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl ] Synthesis of tertiary butyl carbamate

向2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(110mg，0.281mmol，HCl)、2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(120mg，0.293mmol)於DCM(5mL)中之混合物中添加HATU(130mg，0.342mmol)及DIPEA(0.25mL，1.44mmol)。將所得混合物在20℃下攪拌2小時。在減壓下濃縮反應所得混合物。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，EtOAc/MeOH，其中MeOH為0~40%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(200mg，95.4%產率)。LCMS(ESI)[M+H]+ m/z：計算值747.4，實測值747.5。To 2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzene Thiazole (110 mg, 0.281 mmol, HCl), 2-[[6-[bis(tert-butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2-pendantoxy To a mixture of acetic acid (120 mg, 0.293 mmol) in DCM (5 mL) was added HATU (130 mg, 0.342 mmol) and DIPEA (0.25 mL, 1.44 mmol). The resulting mixture was stirred at 20°C for 2 hours. The resulting mixture of the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, EtOAc/MeOH with 0-40% MeOH, flow = 30 mL/min, 254 nm) to give a yellow oil N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(8-methyl-8-azabicyclo [3.2.1]Oct-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetyl]amino]-2-pyridyl] tert-butyl carbamate (200 mg, 95.4% yield). LCMS (ESI) [M+H] + m/z: calcd 747.4, found 747.5.

步驟7：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1187)之合成Step 7: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[2-(8-methyl-8-nitrogen Synthesis of Heterobicyclo[3.2.1]oct-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1187)

將N-第三丁氧基羰基-N-[3-乙基-5-[[2-[(5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(200mg，0.268mmol)、DCM(3mL)及TFA(3mL，38.9mmol)之混合物在20℃下攪拌2小時。將所得混合物用飽和NaHCO3 溶液調節至pH=9，然後在減壓下濃縮混合物。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80 * 40mm * 3μm；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內22%至52% B，保持100% B達1min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈白色固體之N-(6- 胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(39.4mg，26.9%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.01-8.21(m,1H),7.86-8.01(m,2H),7.61-7.85(m,1H),7.37-7.51(m,1H),5.44-5.86(m,1H),3.69-4.13(m,1H),3.54(br s,1H),3.33-3.46(m,3H),2.51(br d,J =6.9Hz,2H),2.38(s,5H),2.17-2.25(m,2H),1.99-2.15(m,4H),1.78-1.96(m,4H),1.40-1.55(m,1H),1.17-1.33(m,3H),1.14(br d,J =6.9Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值547.3，實測值547.3；HPLC：在220nm下為100%，在254nm下為99.11%；96.8%ee。N-tert-butoxycarbonyl-N-[3-ethyl-5-[[2-[(5S)-5-methyl-2-[2-(8-methyl-8-azabicyclo [3.2.1]Oct-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetyl]amino]-2-pyridyl] A mixture of tert-butyl carbamate (200 mg, 0.268 mmol), DCM (3 mL) and TFA (3 mL, 38.9 mmol) was stirred at 20 °C for 2 h. The resulting mixture was adjusted to pH=9 with saturated NaHCO 3 solution, then the mixture was concentrated under reduced pressure. by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex Gemini-NX 80*40mm* 3 μm; mobile phase A: with 10 mmol of NH4HCO3 H 2 O (v%); mobile phase B: MeCN; gradient: 22% to 52% B in 9.5 min, hold 100% B for 1 min; flow rate: 25 mL/min; column temperature: 30 °C; wavelength: 220 nm , 254 nm), the residue was purified to give N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2 as a white solid -(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side oxyethyl Amide (39.4 mg, 26.9% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.01-8.21 (m, 1H), 7.86-8.01 (m, 2H), 7.61-7.85 (m, 1H), 7.37-7.51 (m, 1H), 5.44 -5.86(m,1H),3.69-4.13(m,1H),3.54(br s,1H),3.33-3.46(m,3H),2.51(br d, J =6.9Hz,2H),2.38(s ,5H),2.17-2.25(m,2H),1.99-2.15(m,4H),1.78-1.96(m,4H),1.40-1.55(m,1H),1.17-1.33(m,3H),1.14 (br d, J =6.9Hz,3H); LCMS(ESI)[M+H] + m/z: calculated 547.3, found 547.3; HPLC: 100% at 220nm, 99.11% at 254nm; 96.8%ee.

實例450. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[4-[外消旋-(3aS,7aS)-5-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-2-基]苯基]-1-哌啶基]乙醯胺(化合物1167)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[4-[外消旋-(3aR,7aR)-5-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-2-基]苯基]-1-哌啶基]乙醯胺(化合物1287)之合成Example 450. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[4 -[Rac-(3aS,7aS)-5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl]benzene yl]-1-piperidinyl]acetamide (Compound 1167) and N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-( 2R,5S)-5-methyl-2-[4-[racemic-(3aR,7aR)-5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo Synthesis of [3,4-c]pyridin-2-yl]phenyl]-1-piperidinyl]acetamide (Compound 1287)

Figure 110128222-A0202-12-1856-965
Figure 110128222-A0202-12-1856-965

藉由掌性SFC(儀器：Berger，Multigr AM-II；管柱：Daicel chiralpak AS(250mm * 30mm * 5μm)；流動相：超臨界己烷-IPA(0.1% NH3 ，MeOH v%)=60/40；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[4-(5-甲基-3,3a,4,6,7,7a-六 氫-1H-吡咯并[3,4-c]吡啶-2-基)苯基]-1-哌啶基]乙醯胺(50mg，0.0991mmol)。將級分在減壓下濃縮，然後凍乾隔夜，以得到化合物1167及化合物1287 。By chiral SFC (instrument: Berger, Multigr AM-II; column: Daicel chiralpak AS (250mm*30mm*5μm); mobile phase: supercritical hexane-IPA (0.1% NH3 , MeOH v%)=60 /40; flow rate: 80 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; dresser temperature: 25 °C; wavelength: 220 nm) purified N-( 6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[4-(5-methyl) -3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)phenyl]-1-piperidinyl]acetamide (50 mg, 0.0991 mmol). The fractions were concentrated under reduced pressure and then lyophilized overnight to give compound 1167 and compound 1287 .

化合物1167 ：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[4-[外消旋-(3aS,7aS)-5-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-2-基]苯基]-1-哌啶基]乙醯胺(11mg，單一未知鏡像異構物，峰2，保留時間：1.337min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.93-8.13(m,1H),7.49-7.69(m,1H),7.16(br d,J =8.3Hz,2H),6.48-6.60(m,2H),5.58-5.74(m,1H),3.60-4.00(m,1H),3.23(br s,3H),2.40-2.64(m,7H),2.28(s,6H),1.91(br d,J =10.5Hz,3H),1.72(br s,2H),1.23-1.44(m,5H),1.11(br d,J =6.9Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值505.3，實測值505.4；HPLC：在220nm下為98.69%，在254nm下為99.23%；100%ee。 Compound 1167 : N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[4 -[Rac-(3aS,7aS)-5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl]benzene yl]-1-piperidinyl]acetamide (11 mg, single unknown enantiomer, peak 2, retention time: 1.337 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.93-8.13 (m, 1H), 7.49-7.69 (m, 1H), 7.16 (br d, J =8.3Hz, 2H), 6.48-6.60 (m, 2H), 5.58-5.74(m, 1H), 3.60-4.00(m, 1H), 3.23(br s, 3H), 2.40-2.64(m, 7H), 2.28(s, 6H), 1.91(br d, J =10.5Hz,3H),1.72(br s,2H),1.23-1.44(m,5H),1.11(br d, J =6.9Hz,3H); LCMS(ESI)[M+H] + m/ z: Calculated 505.3, found 505.4; HPLC: 98.69% at 220 nm, 99.23% at 254 nm; 100% ee.

化合物1287 ：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[4-[外消旋-(3aR,7aR)-5-甲基-3,3a,4,6,7,7a-六氫-1H-吡咯并[3,4-c]吡啶-2-基]苯基]-1-哌啶基]乙醯胺(13.2mg，單一未知鏡像異構物，峰3，保留時間：2.427min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.92-8.19(m,1H),7.43-7.69(m,1H),7.08-7.23(m,2H),6.31-6.64(m,2H),5.12-5.74(m,1H),3.55-4.26(m,1H),3.08-3.27(m,3H),2.35-2.75(m,8H),2.17-2.33(m,5H),1.90(br d,J =7.8Hz,3H),1.70(br d,J =8.8Hz,2H),1.18-1.48(m,5H),1.11(br d,J =6.8Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值505.3，實測值505.3；HPLC：在254nm下為100%，在254nm下為99.05%；98.6%ee。 Compound 1287 : N-(6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[4 -[Rac-(3aR,7aR)-5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl]benzene yl]-1-piperidinyl]acetamide (13.2 mg, single unknown enantiomer, peak 3, retention time: 2.427 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.92-8.19 (m, 1H), 7.43-7.69 (m, 1H), 7.08-7.23 (m, 2H), 6.31-6.64 (m, 2H), 5.12 -5.74(m, 1H), 3.55-4.26(m, 1H), 3.08-3.27(m, 3H), 2.35-2.75(m, 8H), 2.17-2.33(m, 5H), 1.90(br d, J =7.8Hz,3H),1.70(br d, J =8.8Hz,2H),1.18-1.48(m,5H),1.11(br d, J =6.8Hz,3H); LCMS(ESI)[M+H ] + m/z: calculated 505.3, found 505.3; HPLC: 100% at 254 nm, 99.05% at 254 nm; 98.6% ee.

實例451. N-(6-胺基-5-環丙基吡啶-3-基)-2-((2S,5R)-5-甲基-2-(2-甲基-2H -吲唑-6-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1043)之合成Example 451. N-(6-Amino-5-cyclopropylpyridin-3-yl)-2-((2S,5R)-5-methyl-2-(2-methyl- 2H -indazole Synthesis of -6-yl)piperidin-1-yl)-2-oxoacetamide (compound 1043)

Figure 110128222-A0202-12-1858-966
Figure 110128222-A0202-12-1858-966

步驟1：N-[3-環丙基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Cyclopropyl-5-[[2-[(2R,5S)-5-methyl-2-(2-methylindazol-6-yl)-1-piperidinyl Synthesis of tert-butyl ]-2-oxyacetyl]amino]-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-環丙基-3-吡啶基]胺基]-2-側氧基乙酸(0.32g，996μmol)添加到2-甲基-6-[(2R,5S)-5-甲基-2-哌啶基]吲唑(228mg，996μmol)及三乙胺(504mg，4.98mmol，694μL)於DMFA(4.00mL)之混合物中。將所得混合物攪拌10min。添加HATU(454mg，1.20mmol)且在25℃下繼續攪拌17h。將所獲得之混合物在真空中濃縮。使殘餘物經歷HPLC(0-5min 40-90%水-MeOH；流速：30mL/min，管柱：Chromatorex 18 SMB100-5T，100x19mm，5μm)，以得到呈黃色固體之N-[3-環丙基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.164g，粗品)。2-[[6-(Third-butoxycarbonylamino)-5-cyclopropyl-3-pyridyl]amino]-2-oxoacetic acid (0.32 g, 996 μmol) was added to 2-methyl yl-6-[(2R,5S)-5-methyl-2-piperidinyl]indazole (228 mg, 996 μmol) and triethylamine (504 mg, 4.98 mmol, 694 μL) in DMFA (4.00 mL) . The resulting mixture was stirred for 10 min. HATU (454 mg, 1.20 mmol) was added and stirring was continued for 17 h at 25 °C. The obtained mixture was concentrated in vacuo. The residue was subjected to HPLC (0-5 min 40-90% water-MeOH; flow rate: 30 mL/min, column: Chromatorex 18 SMB100-5T, 100x19 mm, 5 μm) to give N-[3-cyclopropane as a yellow solid Alkyl-5-[[2-[(2R,5S)-5-methyl-2-(2-methylindazol-6-yl)-1-piperidinyl]-2-oxyethanoyl ]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.164 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值533.32；實測值533.2；Rt=3.460。LCMS (ESI): [M+H] + m/z: calculated 533.32; found 533.2; Rt=3.460.

步驟2：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methylindazol-6-yl) )-1-piperidinyl]-2-side oxyacetamide synthesis

將N-[3-環丙基-5-[[2-[(2R,5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.12g，225μmol)溶解於水(2.00mL)及二噁烷(2.00mL)之混合物中。使所得混合物在100℃下攪拌20h。使所獲得之混合物經歷HPLC(0-5min 30-80%水-甲醇，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：YMC-Actus Triart C18,100x20mm，5μm)，以得到呈黃色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基吲唑-6- 基)-1-哌啶基]-2-側氧基乙醯胺(0.04g，90.2μmol，40.0%產率)。N-[3-Cyclopropyl-5-[[2-[(2R,5S)-5-methyl-2-(2-methylindazol-6-yl)-1-piperidinyl]- 2-Pendant oxyacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.12 g, 225 μmol) was dissolved in a mixture of water (2.00 mL) and dioxane (2.00 mL). The resulting mixture was stirred at 100 °C for 20 h. The obtained mixture was subjected to HPLC (0-5 min 30-80% water-methanol, + 0.1 vol% 25% NH 3 in water, 30 mL/min, column: YMC-Actus Triart C18, 100 x 20 mm, 5 μm) to obtain a N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methylindazol-6-yl) as a yellow solid )-1-piperidinyl]-2-oxoacetamide (0.04 g, 90.2 μmol, 40.0% yield).

LCMS(ESI)：[M+H]+ m/z：計算值433.26；實測值433.4；Rt=2.443。LCMS (ESI): [M+H] + m/z: calculated 433.26; found 433.4; Rt=2.443.

步驟3：N-(6-胺基-5-環丙基吡啶-3-基)-2-((2S,5R)-5-甲基-2-(2-甲基-2H-吲唑-6-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 3: N-(6-Amino-5-cyclopropylpyridin-3-yl)-2-((2S,5R)-5-methyl-2-(2-methyl-2H-indazole- Synthesis of 6-yl)piperidin-1-yl)-2-oxoacetamide

使N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-甲基吲唑-6-基)-1-哌啶基]-2-側氧基乙醯胺(0.04g，90.2μmol)經歷掌性層析(Chiralpak As-H(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)，以得到N-(6-胺基-5-環丙基吡啶-3-基)-2-((2S,5R)-5-甲基-2-(2-甲基-2H -吲唑-6-基)哌啶-1-基)-2-側氧基乙醯胺(0.01786g，41.29μmol，4.47%產率)make N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(2-methylindazol-6-yl)- 1-Piperidinyl]-2-oxyacetamide (0.04 g, 90.2 μmol) was subjected to chiral chromatography (Chiralpak As-H (250*20, 5 mkm), Hexane-IPA-MeOH, 50-25 -25, 12 mL/min) to give N-(6-amino-5-cyclopropylpyridin-3-yl)-2-((2S,5R)-5-methyl-2-(2-methyl) yl- 2H -indazol-6-yl)piperidin-1-yl)-2-oxyacetamide (0.01786 g, 41.29 μmol, 4.47% yield)

製備型：Preparation:

鏡像異構化合物1403 之RT(Chiralpak As-H(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)=10.623RT of enantiomer 1403 (Chiralpak As-H (250*20, 5mkm), hexane-IPA-MeOH, 50-25-25, 12mL/min)=10.623

化合物1403 之RT(Chiralpak As-H(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min)=15.580。RT for compound 1403 (Chiralpak As-H (250*20, 5 mkm), hexane-IPA-MeOH, 50-25-25, 12 mL/min) = 15.580.

分析型：化合物1403 之RT(Chiralpak As-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=9.495。Analytical: RT for compound 1403 (Chiralpak As-H (250*4.6, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=9.495.

1H NMR(600MHz,DMSO-d6 )δ 0.35-0.51(m,2H),0.81-0.92(m,2H),0.96-1.08(m,3H),1.29-1.42(m,1H),1.61-1.80(m,2H),1.82-1.94(m,1H),1.98-2.19(m,1H),2.20-2.36(m,1H),2.75-3.25(m,1H),3.45-4.05(m,1H),4.14(s,3H),5.14-5.66(m,1H),5.67-5.79(m,2H),6.89-7.08(m,1H),7.27-7.43(m,1H),7.44-7.53(m,1H),7.63-7.74(m,1H),7.95-8.09(m,1H),8.28(s,1H),10.40-10.57(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 0.35-0.51(m, 2H), 0.81-0.92(m, 2H), 0.96-1.08(m, 3H), 1.29-1.42(m, 1H), 1.61-1.80 (m,2H),1.82-1.94(m,1H),1.98-2.19(m,1H),2.20-2.36(m,1H),2.75-3.25(m,1H),3.45-4.05(m,1H) ,4.14(s,3H),5.14-5.66(m,1H),5.67-5.79(m,2H),6.89-7.08(m,1H),7.27-7.43(m,1H),7.44-7.53(m, 1H), 7.63-7.74 (m, 1H), 7.95-8.09 (m, 1H), 8.28 (s, 1H), 10.40-10.57 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值433.26；實測值433.2；Rt=0.955。LCMS (ESI): [M+H] + m/z: calculated 433.26; found 433.2; Rt=0.955.

分析型：鏡像異構化合物1403 之RT(Chiralpak As-H(250*4.6，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=13.320。Analytical: RT for enantiomer 1403 (Chiralpak As-H (250*4.6, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 13.320.

1H NMR(600MHz,dmso)δ 0.39-0.50(m,2H),0.82-0.91(m,2H),0.99-1.05(m,3H),1.31-1.42(m,1H),1.61-1.81(m,2H),1.82-1.93(m,1H),2.01-2.21(m,1H),2.23-2.33(m,1H),2.78-3.25(m,1H),3.46-4.03(m,1H),4.14(s,3H),5.20-5.67(m,1H),5.69-5.79(m,2H),6.91-7.08(m,1H),7.26-7.40(m,1H),7.46-7.53(m,1H),7.63-7.71(m,1H),7.97-8.09(m,1H),8.28(s,1H),10.40-10.57(m,1H)。1H NMR(600MHz,dmso)δ 0.39-0.50(m,2H),0.82-0.91(m,2H),0.99-1.05(m,3H),1.31-1.42(m,1H),1.61-1.81(m, 2H), 1.82-1.93(m, 1H), 2.01-2.21(m, 1H), 2.23-2.33(m, 1H), 2.78-3.25(m, 1H), 3.46-4.03(m, 1H), 4.14( s,3H),5.20-5.67(m,1H),5.69-5.79(m,2H),6.91-7.08(m,1H),7.26-7.40(m,1H),7.46-7.53(m,1H), 7.63-7.71(m,1H), 7.97-8.09(m,1H), 8.28(s,1H), 10.40-10.57(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值433.26：實測值433.2；Rt=0.955。LCMS (ESI): [M+H] + m/z: calculated 433.26: found 433.2; Rt=0.955.

實例452. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1156)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1156)之合成Example 452. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-[2-[2-(dimethylamino)ethyl]indium Azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1156) and N-(6-amino-5-cyclopropyl-3-pyridyl) )-2-[(2R,5S)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Enantiomer 1156)

Figure 110128222-A0202-12-1860-967
Figure 110128222-A0202-12-1860-967

步驟1：N-[3-環丙基-5-[[2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Cyclopropyl-5-[[2-[(2R,5S)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]- Synthesis of 3-butyl 5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid

向N,N-二甲基-2-[5-[(2R,5S)-5-甲基-2-哌啶基]吲唑-2-基]乙胺(200mg，505μmol，3鹽酸鹽)、2-[[6-(第三丁氧基羰基胺基)-5-環丙基-3-吡啶基]胺基]-2-側氧基乙酸鹽(174mg，531μmol，Li+鹽)及三乙胺(256mg，2.53mmol，352μL)於二甲基甲醯胺(2.50mL)中之經攪拌之混合物中添加HATU(211mg，556μmol)。將反應混合物在20℃下攪拌4h。使所獲得之混合物經歷HPLC(0-5min 50-100%水-ACN；流速：30mL/min，管柱：Chromatorex 18 SMB100-5T，100x19mm，5μm)，以得到呈淡黃色固體之N-[3-環丙基-5-[[2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(179mg，303μmol，60.1%產率)。To N,N-dimethyl-2-[5-[(2R,5S)-5-methyl-2-piperidinyl]indazol-2-yl]ethanamine (200 mg, 505 μmol, 3 hydrochloride ), 2-[[6-(Third-butoxycarbonylamino)-5-cyclopropyl-3-pyridyl]amino]-2-oxoacetate (174mg, 531μmol, Li+ salt) and To a stirred mixture of triethylamine (256 mg, 2.53 mmol, 352 μL) in dimethylformamide (2.50 mL) was added HATU (211 mg, 556 μmol). The reaction mixture was stirred at 20 °C for 4 h. The obtained mixture was subjected to HPLC (0-5 min 50-100% water-ACN; flow rate: 30 mL/min, column: Chromatorex 18 SMB100-5T, 100x19 mm, 5 μm) to give N-[3 as a pale yellow solid -Cyclopropyl-5-[[2-[(2R,5S)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1- 3-Butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate (179 mg, 303 μmol, 60.1% yield).

LCMS(ESI)：[M-H]+ m/z：計算值588.39；實測值588.0；Rt=2.360。LCMS (ESI): [MH] + m/z: calculated 588.39; found 588.0; Rt=2.360.

步驟2：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[2-[2-(dimethylamino)ethyl]indium Synthesis of azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

將水(1.00g，55.5mmol，1.00mL)添加到N-[3-環丙基-5-[[2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(179mg，304μmol)於二噁烷(2.00mL)中之溶液中。將所得混合物在95℃下攪拌15h。使所獲得之混合物經歷HPLC(0-1-6min 40-40-85%水-甲醇，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：XBridge BEH C18，100x20mm，5μm)，以得到呈白色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(101mg，206μmol，67.9%產率)。Water (1.00 g, 55.5 mmol, 1.00 mL) was added to N-[3-cyclopropyl-5-[[2-[(2R,5S)-2-[2-[2-(dimethylamino) Ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (179 mg, 304 μmol) in dioxane (2.00 mL). The resulting mixture was stirred at 95 °C for 15 h. The obtained mixture was subjected to HPLC (0-1-6 min 40-40-85% water-methanol, + 0.1 vol% 25% NH3 in water, 30 mL/min, column: XBridge BEH C18, 100x20 mm, 5 μm) to N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[(2R,5S)-2-[2-[2-(dimethylamino)ethyl was obtained as a white solid ]Indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (101 mg, 206 μmol, 67.9% yield).

LCMS(ESI)：[M-H]+ m/z：計算值488.33；實測值488.2；Rt=1.773。LCMS (ESI): [MH] + m/z: calculated 488.33; found 488.2; Rt=1.773.

步驟3：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 3: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-[2-[2-(dimethylamino)ethyl]indium Azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide and N-(6-amino-5-cyclopropyl-3-pyridyl)-2- [(2R,5S)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2-side oxyethyl Synthesis of Amide

使N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(101mg，206μmol)經歷掌性HPLC(管柱：CHIRALCEL OJ-H 250*20，5um，流)相：己烷-IPA-MeOH，50-25-25，流速：10mL/min，10mg/注入，10次注入，V=4L)，以得到：呈白色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(38.0mg，77.6μmol，75.3%產率)化合物1156(其中保留時間=13.490min(分析型)，16.023min(製備型))及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙 醯胺(34.0mg，69.4μmol，67.3%產率)鏡像異構化合物1156(其中保留時間=25.422min(分析型)，29.223min(製備型))。Make N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[2-[2-(dimethylamino)ethyl]indazole- 5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (101 mg, 206 μmol) was subjected to chiral HPLC (column: CHIRALCEL OJ-H 250*20, 5um, stream) Phase: Hexane-IPA-MeOH, 50-25-25, flow rate: 10 mL/min, 10 mg/injection, 10 injections, V=4L) to give: N-(6-amino-5 as a white solid -Cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-[2-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide (38.0 mg, 77.6 μmol, 75.3% yield) compound 1156 (wherein retention time = 13.490 min (analytical), 16.023 min (preparative)) and N -(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[2-[2-(dimethylamino)ethyl]indazole-5- yl]-5-methyl-1-piperidinyl]-2-side oxyethyl Amide (34.0 mg, 69.4 μmol, 67.3% yield) enantiomer 1156 (where retention time = 25.422 min (analytical), 29.223 min (preparative)).

(化合物1156)： N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 (Compound 1156): N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-[2-[2-(dimethylamino)ethyl ]Indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

1H NMR(600MHz,DMSO-d6 )δ 0.37-0.49(m,2H),0.81-0.90(m,2H),1.00-1.07(m,3H),1.29-1.43(m,1H),1.58-1.70(m,1H),1.72-1.82(m,1H),1.82-1.95(m,1H),2.01-2.14(m,1H),2.16(s,6H),2.21-2.31(m,1H),2.76(t,2H),2.78-3.26(m,1H),3.45-4.07(m,1H),4.48(t,2H),5.16-5.67(m,1H),5.67-5.80(m,2H),7.05-7.25(m,1H),7.28-7.42(m,1H),7.54-7.69(m,2H),7.97-8.10(m,1H),8.25-8.37(m,1H),10.47(br s,1H)。1H NMR (600MHz, DMSO-d 6 )δ 0.37-0.49(m, 2H), 0.81-0.90(m, 2H), 1.00-1.07(m, 3H), 1.29-1.43(m, 1H), 1.58-1.70 (m,1H),1.72-1.82(m,1H),1.82-1.95(m,1H),2.01-2.14(m,1H),2.16(s,6H),2.21-2.31(m,1H),2.76 (t,2H),2.78-3.26(m,1H),3.45-4.07(m,1H),4.48(t,2H),5.16-5.67(m,1H),5.67-5.80(m,2H),7.05 -7.25(m,1H),7.28-7.42(m,1H),7.54-7.69(m,2H),7.97-8.10(m,1H),8.25-8.37(m,1H),10.47(br s,1H ).

LCMS(ESI)：[M+H]+ m/z：計算值490.33；實測值490.2；Rt=1.640。LCMS (ESI): [M+H] + m/z: calculated 490.33; found 490.2; Rt=1.640.

(鏡像異構化合物1156)： N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[2-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 (Enantiomer 1156): N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[2-[2-(dimethylamino) ) ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

1H NMR(600MHz,DMSO-d6 )δ 0.37-0.49(m,2H),0.81-0.91(m,2H),0.96-1.06(m,3H),1.30-1.39(m,1H),1.61-1.70(m,1H),1.72-1.82(m,1H),1.82-1.96(m,1H),2.00-2.13(m,1H),2.17(s,6H),2.22-2.33(m,1H),2.74-2.82(m,2H),2.88-3.26(m,1H),3.44-4.04(m,1H),4.49(t,2H),5.13-5.68(m,1H),5.68-5.87(m,2H),7.10-7.27(m,1H),7.27-7.44(m,1H),7.50-7.64(m,2H),7.97-8.15(m,1H),8.25-8.37(m,1H),10.41-10.54(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 0.37-0.49(m, 2H), 0.81-0.91(m, 2H), 0.96-1.06(m, 3H), 1.30-1.39(m, 1H), 1.61-1.70 (m,1H),1.72-1.82(m,1H),1.82-1.96(m,1H),2.00-2.13(m,1H),2.17(s,6H),2.22-2.33(m,1H),2.74 -2.82(m, 2H), 2.88-3.26(m, 1H), 3.44-4.04(m, 1H), 4.49(t, 2H), 5.13-5.68(m, 1H), 5.68-5.87(m, 2H) ,7.10-7.27(m,1H),7.27-7.44(m,1H),7.50-7.64(m,2H),7.97-8.15(m,1H),8.25-8.37(m,1H),10.41-10.54( m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值490.33；實測值490.2；Rt=1.641。LCMS (ESI): [M+H] + m/z: calculated 490.33; found 490.2; Rt=1.641.

實例453. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1249)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1249)之合成Example 453. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indium Azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1249) and N-(6-amino-5-cyclopropyl-3-pyridyl) )-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Enantiomer Compound 1249)

Figure 110128222-A0202-12-1863-968
Figure 110128222-A0202-12-1863-968

步驟1：N-[3-環丙基-5-[[2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Cyclopropyl-5-[[2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]- Synthesis of 3-butyl 5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid

向N,N-二甲基-2-[5-[(2R,5S)-5-甲基-2-哌啶基]吲唑-1-基]乙胺(200mg，505μmol，3鹽酸鹽)、2-[[6-(第三丁氧基羰基胺基)-5-環丙基-3-吡啶基]胺基]-2-側氧基乙酸鹽(174mg，531μmol，Li+)及三乙胺(256mg，2.53mmol，352μL)於二甲基甲醯胺(2.50mL)中之經攪拌之混合物中添加HATU(211mg，556μmol)。將反應混合物在20℃下攪拌4h。使所獲得之混合物經歷HPLC(0-5min 50-50-80%水-甲醇，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：YMC-Actus Triart C18，100x20mm，5μm)，以得到呈淡黃色固體之N-[3-環丙基-5-[[2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(220mg，373μmol，73.8%產率)。To N,N-dimethyl-2-[5-[(2R,5S)-5-methyl-2-piperidinyl]indazol-1-yl]ethanamine (200 mg, 505 μmol, 3 hydrochloride ), 2-[[6-(Third-butoxycarbonylamino)-5-cyclopropyl-3-pyridyl]amino]-2-side oxyacetate (174mg, 531μmol, Li+) and tris To a stirred mixture of ethylamine (256 mg, 2.53 mmol, 352 μL) in dimethylformamide (2.50 mL) was added HATU (211 mg, 556 μmol). The reaction mixture was stirred at 20 °C for 4 h. The obtained mixture was subjected to HPLC (0-5 min 50-50-80% water-methanol, + 0.1 vol% 25% NH3 in water, 30 mL/min, column: YMC-Actus Triart C18, 100x20 mm, 5 μm) to N-[3-cyclopropyl-5-[[2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazole-5- was obtained as a pale yellow solid yl]-5-methyl-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (220 mg, 373 μmol, 73.8% yield).

LCMS(ESI)：[M+H]+ m/z：計算值590.39：實測值590.2；Rt=2.586。LCMS (ESI): [M+H] + m/z: calculated 590.39: found 590.2; Rt=2.586.

步驟2：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indium Synthesis of azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

將水(1.00g，55.5mmol，1.00mL)添加到N-[3-環丙基-5-[[2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(220mg，373μmol)於二噁烷(2.00mL)中之溶液中。將所得混合物在95℃下攪拌15h。使所獲得之混合物經歷HPLC(0-5min 50-90%水-甲醇，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：YMC-Actus Triart C18，100x20mm，5μm)，以得到呈白色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(126mg，257μmol，68.9%產率)。Water (1.00 g, 55.5 mmol, 1.00 mL) was added to N-[3-cyclopropyl-5-[[2-[(2R,5S)-2-[1-[2-(dimethylamino) Ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (220 mg, 373 μmol) in dioxane (2.00 mL). The resulting mixture was stirred at 95 °C for 15 h. The obtained mixture was subjected to HPLC (0-5 min 50-90% water-methanol, +0.1 vol% 25% NH3 in water, 30 mL/min, column: YMC-Actus Triart C18, 100x20 mm, 5 μm) to obtain a N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indium as a white solid Azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (126 mg, 257 μmol, 68.9% yield).

LCMS(ESI)：[M+H]+ m/z：計算值490.33；實測值490.2；Rt=2.033。LCMS (ESI): [M+H] + m/z: calculated 490.33; found 490.2; Rt=2.033.

步驟3：N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1249)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(鏡像異構化合物1249)之合成Step 3: N-(6-Amino-5-cyclopropyl-3-pyridinyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indium Azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1249) and N-(6-amino-5-cyclopropyl-3-pyridyl) )-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Enantiomer Compound 1249)

使N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(126mg，257μmol)經歷掌性HPLC(Chiralcel OJ-H 250*20，5-I己烷-IPA-MeOH，60-20-20，12mL/min，0.36L(15mg)/注入，8次注入)，以得到呈白色固體之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(48.0mg，98.0μmol，76.2%產率)化合物1249(其中保留時間=12.828min(分析型)，16,18min(製備型))及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(29.0mg，59.2μmol，46.0%產率)鏡像異構化合物1249(其中保留時間=18.201min(分析型)，22.28min(製備型))。Make N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazole- 5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (126 mg, 257 μmol) was subjected to chiral HPLC (Chiralcel OJ-H 250*20, 5-1 hexane-IPA -MeOH, 60-20-20, 12 mL/min, 0.36 L (15 mg)/injection, 8 injections) to give N-(6-amino-5-cyclopropyl-3-pyridyl as a white solid )-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetamide (48.0 mg, 98.0 μmol, 76.2% yield) compound 1249 (where retention time = 12.828 min (analytical), 16, 18 min (preparative)) and N-(6-amino-5 -Cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl]indazol-5-yl]-5-methyl- 1-Piperidinyl]-2-oxyacetamide (29.0 mg, 59.2 μmol, 46.0% yield) enantiomer 1249 (wherein retention time = 18.201 min (analytical), 22.28 min (preparative) ).

化合物1249： N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 Compound 1249: N-(6-amino-5-cyclopropyl-3-pyridinyl)-2-[(2S,5R)-2-[1-[2-(dimethylamino)ethyl]indium Azol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

1H NMR(600MHz,DMSO-d6 )δ 0.37-0.51(m,2H),0.82-0.93(m,2H),1.00-1.05(m,3H),1.30-1.41(m,1H),1.60-1.71(m,1H),1.72-1.82(m,1H),1.83-1.93(m,1H),2.01-2.13(m,1H),2.14(s,6H),2.25-2.35(m,1H),2.64-2.71(m,2H),2.77-3.27(m,1H),3.44-4.06(m,1H),4.39-4.52(m,2H),5.18-5.70(m,1H),5.70-5.82 (m,2H),7.25-7.34(m,1H),7.34-7.44(m,1H),7.64-7.70(m,2H),7.98-8.10(m,2H),10.44-10.60(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 0.37-0.51 (m, 2H), 0.82-0.93 (m, 2H), 1.00-1.05 (m, 3H), 1.30-1.41 (m, 1H), 1.60-1.71 (m,1H),1.72-1.82(m,1H),1.83-1.93(m,1H),2.01-2.13(m,1H),2.14(s,6H),2.25-2.35(m,1H),2.64 -2.71(m, 2H), 2.77-3.27(m, 1H), 3.44-4.06(m, 1H), 4.39-4.52(m, 2H), 5.18-5.70(m, 1H), 5.70-5.82 (m, 2H), 7.25-7.34(m, 1H), 7.34-7.44(m, 1H), 7.64-7.70(m, 2H), 7.98-8.10(m, 2H), 10.44-10.60(m, 1H).

LCMS(ESI)：[M-H]+ m/z：計算值488.33；實測值488.2；Rt=1.801。LCMS (ESI): [MH] + m/z: calculated 488.33; found 488.2; Rt=1.801.

鏡像異構化合物1249： N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-[1-[2-(二甲胺基)乙基]吲唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 Enantiomer 1249: N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-[1-[2-(dimethylamino)ethyl yl]indazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide

1H NMR(600MHz,DMSO-d6 )δ 0.38-0.48(m,2H),0.82-0.91(m,2H),0.98-1.07(m,3H),1.29-1.43(m,1H),1.60-1.76(m,2H),1.83-1.92(m,1H),2.05-2.19(m,1H),2.25-2.33(m,1H),2.49-2.57(m,6H),2.70-2.96(m,1H),2.99-3.20(m,2H),3.43-4.05(m,1H),4.62(s,2H),5.21-5.71(m,1H),5.71-5.83(m,2H),7.26-7.46(m,2H),7.67-7.77(m,2H),7.96-8.12(m,2H),10.44-10.56(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 0.38-0.48(m, 2H), 0.82-0.91(m, 2H), 0.98-1.07(m, 3H), 1.29-1.43(m, 1H), 1.60-1.76 (m,2H),1.83-1.92(m,1H),2.05-2.19(m,1H),2.25-2.33(m,1H),2.49-2.57(m,6H),2.70-2.96(m,1H) ,2.99-3.20(m,2H),3.43-4.05(m,1H),4.62(s,2H),5.21-5.71(m,1H),5.71-5.83(m,2H),7.26-7.46(m, 2H), 7.67-7.77 (m, 2H), 7.96-8.12 (m, 2H), 10.44-10.56 (m, 1H).

LCMS(ESI)：[M-H]+ m/z：計算值488.33；實測值488.2；Rt=1.812。LCMS (ESI): [MH] + m/z: calculated 488.33; found 488.2; Rt=1.812.

實例454. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1142)之合成Example 454. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[3-[2-(dimethylamino)ethyl]benzo Synthesis of Thiophen-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1142)

Figure 110128222-A0202-12-1866-969
Figure 110128222-A0202-12-1866-969

步驟1：2-(5-溴苯并噻吩-3-基)乙酸甲酯之合成Step 1: Synthesis of methyl 2-(5-bromobenzothiophen-3-yl)acetate

將2-(5-溴苯并噻吩-3-基)乙酸(0.50g，1.84mmol)溶解於無水甲醇(20.0mL)中且添加硫酸(1.00g，10.2mmol)。將反應混合物在75℃下加熱12h。將所獲得之混合物在真空中濃縮。將殘餘物用水處理且過濾。將沉澱溶解於EA(50.0mL)中，用NaHCO3 水溶液洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到呈黃色固體之2-(5-溴苯并噻吩-3-基)乙酸甲酯(0.60g，粗品)。2-(5-Bromobenzothiophen-3-yl)acetic acid (0.50 g, 1.84 mmol) was dissolved in dry methanol (20.0 mL) and sulfuric acid (1.00 g, 10.2 mmol) was added. The reaction mixture was heated at 75 °C for 12 h. The obtained mixture was concentrated in vacuo. The residue was treated with water and filtered. The precipitate was dissolved in EA (50.0 mL), washed with aqueous NaHCO 3 , dried over Na 2 SO 4 and concentrated in vacuo to give 2-(5-bromobenzothiophen-3-yl)acetic acid as a yellow solid Methyl ester (0.60 g, crude).

1 H NMR(500MHz,DMSO-d6 )δ 3.62(s,3H),3.97(s,2H),7.49-7.52(m,1H),7.68(s,1H),7.68-7.72(m,2H)。 1 H NMR (500MHz, DMSO-d 6 )δ 3.62(s, 3H), 3.97(s, 2H), 7.49-7.52(m, 1H), 7.68(s, 1H), 7.68-7.72(m, 2H) .

步驟2：2-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并噻吩-3-基]乙酸甲酯之合成Step 2: Methyl 2-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)benzothiophen-3-yl]acetate Synthesis of Esters

向2-(5-溴苯并噻吩-3-基)乙酸甲酯(0.39g，1.35mmol)及 4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧雜硼雜環戊烷e)(326mg，1.29mmol)於DME(25.0mL)中之經攪拌之溶液中添加乙酸鉀(266mg，2.71mmol，169μL)。將所得懸浮液抽真空且用氬氣回填。將反應混合物在50℃下攪拌1h。添加[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II)(99.1mg，135μmol)。將反應混合物在80℃下攪拌6h。將所獲得之混合物在減壓下濃縮。將殘餘物溶解於CHCl3 中，透過矽膠墊過濾且在真空中濃縮濾液，以得到呈淡黃色膠狀物之2-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并噻吩-3-基]乙酸甲酯(170mg，512μmol，37.8%產率)。To methyl 2-(5-bromobenzothiophen-3-yl)acetate (0.39 g, 1.35 mmol) and 4,4,4',4',5,5,5',5'-octamethyl- To a stirred solution of 2,2'-bis(1,3,2-dioxaborolane) (326 mg, 1.29 mmol) in DME (25.0 mL) was added potassium acetate (266 mg, 2.71 mmol) , 169 μL). The resulting suspension was evacuated and backfilled with argon. The reaction mixture was stirred at 50 °C for 1 h. [1,1'-Bis(diphenylphosphino)ferrocene]dichloride palladium(II) (99.1 mg, 135 μmol) was added. The reaction mixture was stirred at 80 °C for 6 h. The obtained mixture was concentrated under reduced pressure. The residue was dissolved in CHCl3 , filtered through a pad of silica gel and the filtrate was concentrated in vacuo to give 2-[5-(4,4,5,5-tetramethyl-1,3 as a pale yellow gum , 2-dioxaborol-2-yl)benzothiophen-3-yl]acetic acid methyl ester (170 mg, 512 μmol, 37.8% yield).

LCMS(ESI)：[M+H]+ m/z：計算值333.15；實測值-；Rt=4.046。LCMS (ESI): [M+H] + m/z: calculated 333.15; found -; Rt=4.046.

步驟3：6-[3-(2-甲氧基-2-側氧基乙基)苯并噻吩-5-基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: 6-[3-(2-Methoxy-2-pendoxethyl)benzothiophen-5-yl]-3-methyl-3,4-dihydro-2H-pyridine-1- Synthesis of tert-butyl formate

向2-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并噻吩-3-基]乙酸甲酯(19.3g，34.8mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(11.8g，34.1mmol)於水(100mL)及二噁烷(250mL)中之經攪拌之溶液中添加碳酸鈉(7.37g，69.5mmol，2.91mL)。將所得懸浮液抽真空，然後用氬氣回填。將所獲得之混合物在50℃下攪拌1h。添加[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II)(1.27g，1.74mmol)。將反應混合物在80℃下攪拌18h。將所獲得之混合物在減壓下濃縮，溶解於CHCl3 中，經Na2 SO4 乾燥，透過矽膠墊過濾且在真空中濃縮濾液，以得到呈棕色膠狀物之6-[3-(2-甲氧基-2-側氧基乙基)苯并噻吩-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(15.4g，粗品)。to methyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzothiophen-3-yl]acetate ( 19.3 g, 34.8 mmol) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (11.8 g, 34.1 To a stirred solution of mmol) in water (100 mL) and dioxane (250 mL) was added sodium carbonate (7.37 g, 69.5 mmol, 2.91 mL). The resulting suspension was evacuated and backfilled with argon. The obtained mixture was stirred at 50 °C for 1 h. [1,1'-Bis(diphenylphosphino)ferrocene]dichloride palladium(II) (1.27 g, 1.74 mmol) was added. The reaction mixture was stirred at 80 °C for 18 h. The obtained mixture was concentrated under reduced pressure, dissolved in CHCl 3 , dried over Na 2 SO 4 , filtered through a pad of silica gel and the filtrate was concentrated in vacuo to give 6-[3-(2 as a brown gum -Methoxy-2-oxyethyl)benzothiophen-5-yl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (15.4 g, Crude).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值-；Rt=4.557。LCMS (ESI): [M+H] + m/z: calculated 402.2; found -; Rt=4.557.

步驟4：2-[5-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯并噻吩-3-基]乙酸之合成Step 4: Synthesis of 2-[5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)benzothiophen-3-yl]acetic acid

將6-[3-(2-甲氧基-2-側氧基乙基)苯并噻吩-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(15.4g，24.9mmol)於二噁烷(150mL)及氯化氫20%(100 mL)中之溶液在21℃下攪拌15h。在真空中濃縮反應混合物，以得到呈棕色膠狀物之2-[5-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯并噻吩-3-基]乙酸(12.7g，粗品，鹽酸鹽)。6-[3-(2-Methoxy-2-oxyethyl)benzothiophen-5-yl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid A solution of tert-butyl ester (15.4 g, 24.9 mmol) in dioxane (150 mL) and hydrogen chloride 20% (100 mL) was stirred at 21 °C for 15 h. The reaction mixture was concentrated in vacuo to give 2-[5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)benzothiophen-3-yl] as a brown gum Acetic acid (12.7 g, crude, hydrochloride).

LCMS(ESI)：[M+H]+ m/z：計算值288.10；實測值288.2；Rt=2.133。LCMS (ESI): [M+H] + m/z: calculated 288.10; found 288.2; Rt=2.133.

步驟5：2-[5-(1-第三丁氧基羰基-5-甲基-2-哌啶基)苯并噻吩-3-基]乙酸之合成Step 5: Synthesis of 2-[5-(1-tert-butoxycarbonyl-5-methyl-2-piperidinyl)benzothiophen-3-yl]acetic acid

向2-[5-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯并噻吩-3-基]乙酸(12.5g，23.9mmol，鹽酸鹽)於MeOH(250mL)中之冰冷溶液中添加硼氫化鈉(1.81g，47.9mmol，1.69mL)。使所得混合物在室溫下攪拌隔夜將所獲得之混合物用1N HCl酸化至pH=3-4。添加於MeOH(250mL)及水(50.0mL)中之氫氧化鈉珠粒(1.91g，47.9mmol，899μL)，隨後添加二碳酸二-第三丁酯(5.22g，23.9mmol，5.49mL)。使反應混合物攪拌隔夜。將所獲得之混合物在真空中濃縮。將殘餘物用EtOAc/水進行分配。將所獲得之混合物用EtOAc(100mL)萃取。將水酸化至pH=1且用DCM萃取兩次。將經合併之有機物用鹽水洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到呈米色固體之2-[5-(1-第三丁氧基羰基-5-甲基-2-哌啶基)苯并噻吩-3-基]乙酸(9.15g，23.5mmol，98.2%產率)。To 2-[5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)benzothiophen-3-yl]acetic acid (12.5 g, 23.9 mmol, hydrochloride) in MeOH To the ice-cold solution in (250 mL) was added sodium borohydride (1.81 g, 47.9 mmol, 1.69 mL). The resulting mixture was allowed to stir at room temperature overnight and the resulting mixture was acidified to pH=3-4 with 1N HCl. Sodium hydroxide beads (1.91 g, 47.9 mmol, 899 μL) in MeOH (250 mL) and water (50.0 mL) were added, followed by di-tert-butyl dicarbonate (5.22 g, 23.9 mmol, 5.49 mL). The reaction mixture was allowed to stir overnight. The obtained mixture was concentrated in vacuo. The residue was partitioned with EtOAc/water. The obtained mixture was extracted with EtOAc (100 mL). The water was acidified to pH=1 and extracted twice with DCM. The combined organics were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give 2-[5-(1-tert-butoxycarbonyl-5-methyl-2-piperidine as a beige solid Peridyl)benzothiophen-3-yl]acetic acid (9.15 g, 23.5 mmol, 98.2% yield).

LCMS(ESI)：[M-boc]+ m/z：計算值290.2；實測值290.2；Rt=4.087。LCMS (ESI): [M-boc] + m/z: calculated 290.2; found 290.2; Rt=4.087.

步驟6：2-[3-[2-(二甲胺基)-2-側氧基乙基]苯并噻吩-5-基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 6: Compound of 2-[3-[2-(dimethylamino)-2-oxyethyl]benzothiophen-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester synthesis

在室溫下將2-[5-(1-第三丁氧基羰基-5-甲基-2-哌啶基)苯并噻吩-3-基]乙酸(1.00g，2.57mmol)、HATU(1.17g，3.08mmol)及TEA(779mg，7.70mmol，1.07mL)混合於無水DCM(25.0mL)中。將所得混合物攪拌15min。添加二甲胺(419mg，5.13mmol，540μL，鹽酸鹽)。將所得混合物在室溫下攪拌隔夜。將所獲得之混合物用水、鹽水洗滌且在真空中濃縮，以得到呈棕色膠狀物之2-[3-[2-(二甲胺基)-2-側氧基乙基]苯并噻吩-5-基]-5-甲基哌啶-1-甲酸第三丁酯 (1.30g，粗品)。2-[5-(1-Third-butoxycarbonyl-5-methyl-2-piperidinyl)benzothiophen-3-yl]acetic acid (1.00 g, 2.57 mmol), HATU ( 1.17 g, 3.08 mmol) and TEA (779 mg, 7.70 mmol, 1.07 mL) were mixed in dry DCM (25.0 mL). The resulting mixture was stirred for 15 min. Dimethylamine (419 mg, 5.13 mmol, 540 μL, hydrochloride) was added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was washed with water, brine and concentrated in vacuo to give 2-[3-[2-(dimethylamino)-2-pendoxoethyl]benzothiophene- 5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.30 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值417.26；實測值-；Rt=4.352。LCMS (ESI): [M+H] + m/z: calculated 417.26; found -; Rt=4.352.

步驟7：2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 7: Synthesis of 2-[3-[2-(dimethylamino)ethyl]benzothiophen-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在惰性氣氛中，向2-[3-[2-(二甲胺基)-2-側氧基乙基]苯并噻吩-5-基]-5-甲基哌啶-1-甲酸第三丁酯(1.10g，2.64mmol)於THF(25.0mL)中之溶液中添加雙(2-甲氧基乙氧基)氫化鋁鈉(3.05g，10.6mmol，3.02mL，70%純度)。在室溫下攪拌12h之後，將所得混合物用1N NaOH萃取，用MTBE(2x25.0mL)萃取，乾燥且在真空中濃縮至乾，以得到呈帶棕色膠狀物之2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基哌啶-1-甲酸第三丁酯(1.10g，粗品)。In an inert atmosphere, add 2-[3-[2-(dimethylamino)-2-oxyethyl]benzothiophen-5-yl]-5-methylpiperidine-1-carboxylic acid to the third To a solution of butyl ester (1.10 g, 2.64 mmol) in THF (25.0 mL) was added sodium bis(2-methoxyethoxy)aluminum hydride (3.05 g, 10.6 mmol, 3.02 mL, 70% purity). After stirring at room temperature for 12 h, the resulting mixture was extracted with 1 N NaOH, extracted with MTBE (2 x 25.0 mL), dried and concentrated to dryness in vacuo to give 2-[3-[2 as a brownish gum -(Dimethylamino)ethyl]benzothiophen-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.10 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值403.29；實測值403.2；Rt=3.089。LCMS (ESI): [M+H] + m/z: calculated 403.29; found 403.2; Rt=3.089.

步驟8：N,N-二甲基-2-[5-(5-甲基-2-哌啶基)苯并噻吩-3-基]乙胺之合成Step 8: Synthesis of N,N-dimethyl-2-[5-(5-methyl-2-piperidinyl)benzothiophen-3-yl]ethanamine

在21℃下，向2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基哌啶-1-甲酸第三丁酯(1.21g，3.01mmol)於MeOH(25.0mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(4.00g，110mmol，5.00mL)。將所得混合物攪拌12h。將所獲得之混合物在真空中濃縮，以得到呈米色固體之N,N-二甲基-2-[5-(5-甲基-2-哌啶基)苯并噻吩-3-基]乙胺(0.90g，2.40mmol，79,2%)。To 2-[3-[2-(dimethylamino)ethyl]benzothiophen-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.21 g, 3.01 mmol) in MeOH (25.0 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (4.00 g, 110 mmol, 5.00 mL). The resulting mixture was stirred for 12 h. The obtained mixture was concentrated in vacuo to give N,N-dimethyl-2-[5-(5-methyl-2-piperidinyl)benzothiophen-3-yl]ethane as a beige solid Amine (0.90 g, 2.40 mmol, 79, 2%).

LCMS(ESI)：[M+H]+ m/z：計算值303.23；實測值303.2；Rt=1.129。LCMS (ESI): [M+H] + m/z: calculated 303.23; found 303.2; Rt=1.129.

步驟9：N-[5-[[2-[2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 9: N-[5-[[2-[2-[3-[2-(dimethylamino)ethyl]benzothiophen-5-yl]-5-methyl-1-piperidinyl] Synthesis of tert-butyl-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid

在室溫下將N,N-二甲基-2-[5-(5-甲基-2-哌啶基)苯并噻吩-3-基]乙胺(0.45g，1.20mmol，2鹽酸鹽)、HATU(456mg，1.20mmol)及TEA(607mg，5.99mmol，835μL)混合於無水DMF(5.00mL)中。將所得混合物攪拌15min。向其中添加2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(354 mg，1.20mmol)且在室溫下繼續攪拌隔夜。將所獲得之混合物倒入到水中且用EtOAc萃取3次。將經合併之有機物用水、鹽水洗滌且在真空中濃縮。使殘餘物經歷HPLC(0.5-6.5min 63%水-乙腈+NH3 ，30mL/min(裝載泵4mL；乙腈)，管柱：YMC-ACTUS TRIART C18 100*20 5微米)，以得到呈米色固體之N-[5-[[2-[2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(159mg，274μmol，22.9%產率)。N,N-Dimethyl-2-[5-(5-methyl-2-piperidinyl)benzothiophen-3-yl]ethanamine (0.45 g, 1.20 mmol, 2 hydrochloric acid) at room temperature salt), HATU (456 mg, 1.20 mmol) and TEA (607 mg, 5.99 mmol, 835 μL) were mixed in dry DMF (5.00 mL). The resulting mixture was stirred for 15 min. To this was added 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (354 mg, 1.20 mmol) and in room Continue stirring overnight at room temperature. The obtained mixture was poured into water and extracted 3 times with EtOAc. The combined organics were washed with water, brine and concentrated in vacuo. The residue was subjected to HPLC (0.5-6.5 min 63% water-acetonitrile + NH3 , 30 mL/min (loading pump 4 mL; acetonitrile), column: YMC-ACTUS TRIART C18 100*20 5 microns) to give a beige solid N-[5-[[2-[2-[3-[2-(dimethylamino)ethyl]benzothiophen-5-yl]-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (159 mg, 274 μmol, 22.9% yield).

LCMS(ESI)：[M+H]+ m/z：計算值580.34；實測值580.4；Rt=3.059。LCMS (ESI): [M+H] + m/z: calculated 580.34; found 580.4; Rt=3.059.

步驟10：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1141)之合成Step 10: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[3-[2-(dimethylamino)ethyl]benzo Synthesis of Thiophen-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1141)

將N-[5-[[2-[2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(159mg，274μmol)溶解於水(2.00mL)/二噁烷(2.00mL)中。將反應混合物在90℃下加熱隔夜。將所獲得之混合物在真空中濃縮至乾。使殘餘物經歷HPLC(第1次運行：45-70% 0.5-6.5min水-乙腈+NH3 ；流速30mL/min(裝載泵4ml/min乙腈)；管柱xbridgeC18 100x19mm 5um(R)；第2次運行：10-40% 0.5-6.5min水-ACN+FA；流速30ml/min(裝載泵4mL/min acn)；管柱SunFireC18 100x19mm 5um(R))，以得到呈米色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[3-[2-(二甲胺基)乙基]苯并噻吩-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(61.4mg，128μmol，46.7%產率)。N-[5-[[2-[2-[3-[2-(dimethylamino)ethyl]benzothiophen-5-yl]-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (159 mg, 274 μmol) was dissolved in water (2.00 mL)/dioxane (2.00 mL). The reaction mixture was heated at 90°C overnight. The obtained mixture was concentrated to dryness in vacuo. The residue was subjected to HPLC (run 1: 45-70% 0.5-6.5 min water-acetonitrile + NH3 ; flow rate 30 mL/min (load pump 4 ml/min acetonitrile); column xbridge C18 100x19 mm 5um(R); 2 Sub-runs: 10-40% 0.5-6.5min water-ACN+FA; flow rate 30ml/min (loading pump 4mL/min acn); column SunFireC18 100x19mm 5um(R)) to give N-(6 as a beige solid -Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[3-[2-(dimethylamino)ethyl]benzothiophen-5-yl]- 5-Methyl-1-piperidinyl]-2-oxoacetamide (61.4 mg, 128 μmol, 46.7% yield).

1H NMR(600MHz,DMSO-d6 )δ 1.01-1.06(m,3H),1.32-1.42(m,1H),1.66-1.79(m,1H),1.81-1.92(m,1H),1.95-2.04(m,3H),2.06-2.18(m,1H),2.22-2.26(m,6H),2.27-2.34(m,1H),2.58-2.65(m,2H),2.93-3.00(m,2H),3.28-3.30(m,1H),3.65-4.11(m,1H),5.25-5.60(m,1H),5.59-5.77(m,2H),7.28-7.39(m,1H),7.39-7.53(m,2H),7.67-7.73(m,1H),7.92-8.07(m,2H),10.46-10.59(m,1H)。1H NMR (600MHz, DMSO-d 6 )δ 1.01-1.06(m,3H), 1.32-1.42(m,1H), 1.66-1.79(m,1H), 1.81-1.92(m,1H), 1.95-2.04 (m,3H), 2.06-2.18(m,1H), 2.22-2.26(m,6H), 2.27-2.34(m,1H), 2.58-2.65(m,2H), 2.93-3.00(m,2H) ,3.28-3.30(m,1H),3.65-4.11(m,1H),5.25-5.60(m,1H),5.59-5.77(m,2H),7.28-7.39(m,1H),7.39-7.53( m, 2H), 7.67-7.73 (m, 1H), 7.92-8.07 (m, 2H), 10.46-10.59 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值480.28；實測值480.4；Rt=2.171。LCMS (ESI): [M+H] + m/z: calculated 480.28; found 480.4; Rt=2.171.

方案D.式4化合物之合成Scheme D. Synthesis of compounds of formula 4

式4化合物為式(I)、(Ia)及(Ib)化合物，其中R1 為H，R2 為-C(=O)NH2 ，R3 、R4 及R8 為H，R7 為-MeThe compound of formula 4 is the compound of formula (I), (Ia) and (Ib), wherein R 1 is H, R 2 is -C(=O)NH 2 , R 3 , R 4 and R 8 are H, and R 7 is -Me

一般程序4General Procedure 4

Figure 110128222-A0202-12-1871-970
Figure 110128222-A0202-12-1871-970

步驟1： 將化合物1 (1.0當量)、相應硼酸(1.25當量)、碳酸鈉(3當量)、Pd(dppf)Cl2* DCM(0.04當量)、水(1mL)及1,4-二噁烷(2mL)置於8ml小瓶中且在手套箱中裝入Ar。將反應混合物在75℃下攪拌12h。冷卻至室溫之後，將水(4mL)添加到小瓶中且將混合物用DCM萃取。將經分離之有機層濃縮，以得到粗化合物2 ，其不經另外純化即用於下一步驟中。 Step 1: Compound 1 (1.0 equiv), corresponding boronic acid (1.25 equiv), sodium carbonate (3 equiv), Pd(dppf)Cl2 * DCM (0.04 equiv), water (1 mL) and 1,4-dioxane were combined (2 mL) was placed in an 8 ml vial and the glove box was loaded with Ar. The reaction mixture was stirred at 75 °C for 12 h. After cooling to room temperature, water (4 mL) was added to the vial and the mixture was extracted with DCM. The separated organic layer was concentrated to give crude compound 2 , which was used in the next step without further purification.

步驟2： 向粗化合物2 於DCM(0.5mL)中之溶液中添加TFA(0.5mL)。將反應混合物在室溫下攪拌30min。然後，將所得混合物蒸發且將殘餘物溶解於DCM(5mL)中。將有機層用NaOH水溶液洗滌兩次且在減壓下濃縮，以得到粗化合物3 ，其不經純化即用於下一步驟。 Step 2: To a solution of crude compound 2 in DCM (0.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 30 min. Then, the resulting mixture was evaporated and the residue was dissolved in DCM (5 mL). The organic layer was washed twice with aqueous NaOH and concentrated under reduced pressure to give crude compound 3 , which was used in the next step without purification.

步驟3 ： 將NaBH4 (1.1當量)一次性添加到粗化合物3 (1當量)於甲醇(4mL)中之溶液中。將反應混合物攪拌隔夜且蒸發。將殘餘物溶解於DCM(5mL)中且用水洗滌兩次。將有機層在真空中濃縮，以得到粗胺A1 ，其不經純化即用於下一步驟中。 Step 3 : NaBH4 (1.1 equiv) was added in one portion to a solution of crude compound 3 (1 equiv) in methanol (4 mL). The reaction mixture was stirred overnight and evaporated. The residue was dissolved in DCM (5 mL) and washed twice with water. The organic layer was concentrated in vacuo to give crude amine A1 which was used in the next step without purification.

示範性偶合程序1： 將胺A1 (約1當量)、2-((5-胺甲醯基吡啶-3-基)胺基)-2-側氧基乙酸三乙基銨鹽(約1.1當量)、HATU(1.1當量)、DIPEA(1.5當量)在DMSO中攪拌隔夜。在LCMS確認所要產物存在之後，將反應混合物提交至HPLC(Sunfire C18 19* 100 5mkm管柱，以H2 O-MeOH為流動相，流速15ml/min，運行時間5min)，以得到純的式4 化合物。 Exemplary Coupling Procedure 1: Combine Amine Al (about 1 equiv.), 2-((5-aminocarboxypyridin-3-yl)amino)-2-oxoacetic acid triethylammonium salt (about 1.1 equiv. ), HATU (1.1 equiv), DIPEA (1.5 equiv) were stirred in DMSO overnight. After LCMS confirmed the presence of the desired product, the reaction mixture was submitted to HPLC (Sunfire C18 19 * 100 5mkm column with H2O -MeOH as mobile phase, flow rate 15ml/min, run time 5min) to give pure formula 4 compound.

示範性偶合程序2 ：在21℃下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(約1當量)、HATU(約1.1當量)及三乙胺(約3當量)混合於無水DMF中且將所得混合物攪拌12h。向其中添加胺A1(約1當量)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(0-5min 20-70%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)，提供式4化合物。Exemplary Coupling Procedure 2 : 2-[(5-Aminocarboxy-3-pyridinyl)amino]-2-pendoxoacetic acid (about 1 equiv.), HATU (about 1.1 equiv.) at 21 °C and triethylamine (about 3 equiv.) were mixed in dry DMF and the resulting mixture was stirred for 12 h. To this was added amine A1 (about 1 equiv.) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (0-5 min 20-70% water-methanol ( NH3 0.1%), flow rate 30 ml/min (load pump 4 ml/min methanol ( NH3 0.1%)), column: YMC-Actus Triart C18 100*20mml.DS-5um), providing the compound of formula 4.

在以上程序之後，產生起始材料變化文庫。使在該等系列之各反應中之試劑及反應條件之莫耳比保持相同。在以下頁中呈現最終產物之產率及LC-MS及NMR描述。所有硼酸及頻哪醇酯均為商業烯胺儲備液。Following the above procedure, a library of starting material changes is generated. The molar ratios of the reagents and reaction conditions in each reaction of the series were kept the same. Yields and LC-MS and NMR descriptions of the final products are presented on the following pages. All boronic acids and pinacol esters are commercial enamine stock solutions.

實例455. 外消旋-5-{2-[(2R,5S)-2-(4-氟-3-甲基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物131)之合成Example 455. Racemic-5-{2-[(2R,5S)-2-(4-fluoro-3-methylphenyl)-5-methylpiperidin-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 131)

Figure 110128222-A0202-12-1872-971
Figure 110128222-A0202-12-1872-971

藉由一般程序1製備。產率：12.8mg，9.18%1 H NMR(500MHz,CDCl3 )δ 1.11(m,3H),1.40(m,2H),1.89(m,1H),2.00(m,2H),2.18(m,2H),2.28(m,3H), 3.40(m,1H),5.97(m,1H),7.00(m,1H),7.08(m,2H),8.92(m,2H),9.53(m,1H)。Prepared by General Procedure 1. Yield: 12.8 mg, 9.18% 1 H NMR (500 MHz, CDCl 3 ) δ 1.11 (m, 3H), 1.40 (m, 2H), 1.89 (m, 1H), 2.00 (m, 2H), 2.18 (m, 2H), 2.28(m, 3H), 3.40(m, 1H), 5.97(m, 1H), 7.00(m, 1H), 7.08(m, 2H), 8.92(m, 2H), 9.53(m, 1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值398.2；實測值399.2；Rt=3.381min。LCMS (ESI): [M+H] + m/z: calculated 398.2; found 399.2; Rt=3.381 min.

實例456. 外消旋-5-{2-[(2R,5S)-2-(6-甲氧基吡啶-3-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物128)之合成Example 456. Racemic-5-{2-[(2R,5S)-2-(6-methoxypyridin-3-yl)-5-methylpiperidin-1-yl]-2-oxygen Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 128)

Figure 110128222-A0202-12-1873-972
Figure 110128222-A0202-12-1873-972

藉由一般程序1製備。產率：6.1mg，4.38%1 H NMR(500MHz,CDCl3 )δ 1.12(m,3H),1.45(m,1H),1.98(m,2H),2.23(m,2H),3.36(m,1H),3.96(m,3H),4.57(m,1H),6.34(m,1H),6.79(m,1H),7.54(m,1H),8.16(s,1H),8.69(s,1H),8.90(s,1H),8.99(s,1H),9.74(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值398.2；Rt=2.770min。Prepared by General Procedure 1. Yield: 6.1 mg, 4.38% 1 H NMR (500 MHz, CDCl 3 ) δ 1.12 (m, 3H), 1.45 (m, 1H), 1.98 (m, 2H), 2.23 (m, 2H), 3.36 (m, 1H), 3.96(m, 3H), 4.57(m, 1H), 6.34(m, 1H), 6.79(m, 1H), 7.54(m, 1H), 8.16(s, 1H), 8.69(s, 1H) ), 8.90(s, 1H), 8.99(s, 1H), 9.74(m, 1H). LCMS (ESI): [M+H] + m/z: calculated 397.2; found 398.2; Rt=2.770 min.

實例457. 外消旋-5-{2-[(2R,5S)-2-(3,5-二甲基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物118)之合成Example 457. Racemic-5-{2-[(2R,5S)-2-(3,5-dimethylphenyl)-5-methylpiperidin-1-yl]-2-pendoxyl Synthesis of Acetamido}pyridine-3-carbamoylamine (Compound 118)

Figure 110128222-A0202-12-1873-973
Figure 110128222-A0202-12-1873-973

藉由一般程序1製備。產率：5.2mg，3.77%1 H NMR(500MHz,CDCl3 )δ 1.12(m,3H),1.39(m,1H),1.99(m,3H),2.23(m,2H),2.33(m,6H),3.44(m,1H),4.83(m,1H),6.03(m,2H),6.90(m,3H),8.69(m,1H),8.94(m,2H),9.79(m,1H)。Prepared by General Procedure 1. Yield: 5.2 mg, 3.77% 1 H NMR (500 MHz, CDCl 3 ) δ 1.12 (m, 3H), 1.39 (m, 1H), 1.99 (m, 3H), 2.23 (m, 2H), 2.33 (m, 6H), 3.44(m, 1H), 4.83(m, 1H), 6.03(m, 2H), 6.90(m, 3H), 8.69(m, 1H), 8.94(m, 2H), 9.79(m, 1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.4；Rt=3.518min。LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.4; Rt=3.518 min.

實例458. 外消旋-5-{2-[(2R,5S)-2-(3,4-二氟苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物263)之合成Example 458. Racemic-5-{2-[(2R,5S)-2-(3,4-difluorophenyl)-5-methylpiperidin-1-yl]-2-side oxyethyl Synthesis of amido}pyridine-3-carboxamide (compound 263)

Figure 110128222-A0202-12-1874-974
Figure 110128222-A0202-12-1874-974

藉由一般程序1製備。產率：8.3mg，5.89%1 H NMR(600MHz,DMSO-d6 )δ 0.96-1.07(m,3H),1.26-1.38(m,1H),1.59-1.69(m,1H),1.81-1.94(m,1H),2.00-2.14(m,1H),2.14-2.29(m,1H),2.78-3.26(m,1H),3.45-4.05(m,1H),5.06-5.65(m,1H),7.10-7.23(m,1H),7.33-7.50(m,2H),7.51-7.68(m,1H),8.10-8.23(m,1H),8.42-8.53(m,1H),8.70-8.80(m,1H),8.81-8.93(m,1H),11.17-11.33(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值403.2；Rt=3.123min。Prepared by General Procedure 1. Yield: 8.3 mg, 5.89% 1 H NMR (600 MHz, DMSO-d 6 ) δ 0.96-1.07 (m, 3H), 1.26-1.38 (m, 1H), 1.59-1.69 (m, 1H), 1.81-1.94 (m,1H),2.00-2.14(m,1H),2.14-2.29(m,1H),2.78-3.26(m,1H),3.45-4.05(m,1H),5.06-5.65(m,1H) ,7.10-7.23(m,1H),7.33-7.50(m,2H),7.51-7.68(m,1H),8.10-8.23(m,1H),8.42-8.53(m,1H),8.70-8.80( m, 1H), 8.81-8.93 (m, 1H), 11.17-11.33 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 402.2; found 403.2; Rt=3.123 min.

實例459. 外消旋-5-{2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物338)之合成Example 459. Racemic-5-{2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methylpiperidin-1-yl]-2-pendoxyl Synthesis of Acetamido}pyridine-3-carbamoylamine (Compound 338)

Figure 110128222-A0202-12-1874-975
Figure 110128222-A0202-12-1874-975

藉由一般程序1製備。產率：1.7mg，1.16% LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.308minPrepared by General Procedure 1. Yield: 1.7 mg, 1.16% LCMS (ESI): [M+H] + m/z: calcd 418.2; found 419.2; Rt=1.308 min

實例460. 外消旋-5-{2-[(2R,5S)-2-[4-氟-3-(三氟甲基)苯基]-5-甲基哌啶-1-基]-2-Example 460. Racemic-5-{2-[(2R,5S)-2-[4-fluoro-3-(trifluoromethyl)phenyl]-5-methylpiperidin-1-yl]- 2- 側氧基乙醯胺基}吡啶-3-甲醯胺(化合物255)之合成Synthesis of Pendant Oxyacetamido}Pyridine-3-Carboxamide (Compound 255)

Figure 110128222-A0202-12-1875-976
Figure 110128222-A0202-12-1875-976

藉由一般程序1製備。產率：17.7mg，11.18%1 H NMR(600MHz,DMSO-d6 )δ 0.86-1.07(m,3H),1.21-1.42(m,1H),1.60-1.71(m,1H),1.84-1.98(m,1H),2.04-2.31(m,2H),2.73-3.28(m,1H),3.45-4.04(m,1H),5.15-5.71(m,1H),7.48-7.72(m,4H),8.07-8.22(m,1H),8.39-8.56(m,1H),8.72-8.80(m,1H),8.80-8.97(m,1H),11.17-11.36(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值452.2；實測值453.2；Rt=1.281min。Prepared by General Procedure 1. Yield: 17.7 mg, 11.18% 1 H NMR (600 MHz, DMSO-d 6 ) δ 0.86-1.07 (m, 3H), 1.21-1.42 (m, 1H), 1.60-1.71 (m, 1H), 1.84-1.98 (m,1H), 2.04-2.31(m,2H), 2.73-3.28(m,1H), 3.45-4.04(m,1H), 5.15-5.71(m,1H), 7.48-7.72(m,4H) , 8.07-8.22(m, 1H), 8.39-8.56(m, 1H), 8.72-8.80(m, 1H), 8.80-8.97(m, 1H), 11.17-11.36(m, 1H). LCMS (ESI): [M+H] + m/z: calculated 452.2; found 453.2; Rt=1.281 min.

實例461. 外消旋-5-{2-[(2R,5S)-2-[4-(二氟甲氧基)苯基]-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物271)之合成Example 461. Racemic-5-{2-[(2R,5S)-2-[4-(difluoromethoxy)phenyl]-5-methylpiperidin-1-yl]-2-side Synthesis of Oxyacetamido}pyridine-3-carbamoylamine (Compound 271)

Figure 110128222-A0202-12-1875-977
Figure 110128222-A0202-12-1875-977

藉由一般程序1製備。產率：13.3mg，8.79%1 H R(600MHz,DMSO-d6 )δ 0.96-1.04(m,3H),1.28-1.40(m,1H),1.62-1.69(m,1H),1.82-1.95(m,1H),2.02-2.14(m,1H),2.16-2.29(m,1H),2.75-3.24(m,1H),3.46-4.04(m,1H),5.10-5.60(m,1H),7.06-7.33(m,3H),7.34-7.41(m,2H),7.53-7.65(m,1H),8.10-820(m,1H),8.42-8.51(m,1H),8.70-8.80(m,1H),8.81-8.93(m,1H),11.13-11.35(m, 1H)。LCMS(ESI)：[M+H]+ m/z：計算值432.2；實測值433.2；Rt=3.218min。Prepared by General Procedure 1. Yield: 13.3 mg, 8.79% 1 HR (600 MHz, DMSO-d 6 ) δ 0.96-1.04 (m, 3H), 1.28-1.40 (m, 1H), 1.62-1.69 (m, 1H), 1.82-1.95 ( m,1H), 2.02-2.14(m,1H), 2.16-2.29(m,1H), 2.75-3.24(m,1H), 3.46-4.04(m,1H), 5.10-5.60(m,1H), 7.06-7.33(m, 3H), 7.34-7.41(m, 2H), 7.53-7.65(m, 1H), 8.10-820(m, 1H), 8.42-8.51(m, 1H), 8.70-8.80(m , 1H), 8.81-8.93 (m, 1H), 11.13-11.35 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 432.2; found 433.2; Rt=3.218 min.

實例462. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[4-(環氧乙烷-4-基氧基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物269)之合成Example 462. Racemic-5-{2-[(2R,5S)-5-methyl-2-[4-(oxiran-4-yloxy)phenyl]piperidin-1-yl Synthesis of ]-2-oxyacetamido}pyridine-3-carboxamide (Compound 269)

Figure 110128222-A0202-12-1876-978
Figure 110128222-A0202-12-1876-978

藉由一般程序製備。產率：8.1mg，4.96%1 H NMR(600MHz,DMSO-d6 )δ 0.98-1.03(m,3H),1.27-1.36(m,1H),1.49-1.57(m,2H),1.65-1.73(m,1H),1.79-1.89(m,1H),1.90-1.97(m,2H),1.98-2.12(m,1H),2.14-2.22(m,1H),2.79-3.21(m,1H),3.40-3.49(m,3H),3.80-3.98(m,2H),4.48-4.59(m,1H),5.02-5.60(m,1H),6.92-7.00(m,2H),7.18-7.28(m,2H),7.55-7.66(m,1H),8.10-8.21(m,1H),8.41-8.53(m,1H),8.67-8.80(m,1H),8.81-8.93(m,1H),11.08-11.35(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值467.2；Rt=3.057min。Prepared by general procedure. Yield: 8.1 mg, 4.96% 1 H NMR (600 MHz, DMSO-d 6 ) δ 0.98-1.03 (m, 3H), 1.27-1.36 (m, 1H), 1.49-1.57 (m, 2H), 1.65-1.73 (m,1H),1.79-1.89(m,1H),1.90-1.97(m,2H),1.98-2.12(m,1H),2.14-2.22(m,1H),2.79-3.21(m,1H) ,3.40-3.49(m,3H),3.80-3.98(m,2H),4.48-4.59(m,1H),5.02-5.60(m,1H),6.92-7.00(m,2H),7.18-7.28( m,2H),7.55-7.66(m,1H),8.10-8.21(m,1H),8.41-8.53(m,1H),8.67-8.80(m,1H),8.81-8.93(m,1H), 11.08-11.35 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 466.2; found 467.2; Rt=3.057 min.

實例463. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[4-(氧戊環-3-基氧基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物264)之合成Example 463. Racemic-5-{2-[(2R,5S)-5-methyl-2-[4-(oxolan-3-yloxy)phenyl]piperidin-1-yl] Synthesis of -2-oxoacetamido}pyridine-3-carboxamido (Compound 264)

Figure 110128222-A0202-12-1876-979
Figure 110128222-A0202-12-1876-979

藉由一般程序1製備。產率：5.4mg，3.41%1 H NMR(600MHz,DMSO-d6 )δ 0.98-1.04(m,3H),1.28-1.38(m,1H),1.63-1.73(m,1H),1.82-1.95(m,2H),1.97-2.13(m,1H),2.15-2.23(m,2H),2.77-3.23(m,1H),3.40-3.70(m,1H),3.73-4.00(m,4H),4.95-5.04(m,1H),5.05-5.63(m,1H),6.87-6.94(m,2H),7.19-7.26(m,2H),7.55-7.64(m,1H),8.11-8.20(m,1H),8.40-8.51(m,1H),8.71-8.80(m,1H),8.81-8.94(m,1H),11.13-11.28(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值452.2；實測值453.2；Rt=2.921min。Prepared by General Procedure 1. Yield: 5.4 mg, 3.41% 1 H NMR (600 MHz, DMSO-d 6 ) δ 0.98-1.04 (m, 3H), 1.28-1.38 (m, 1H), 1.63-1.73 (m, 1H), 1.82-1.95 (m,2H),1.97-2.13(m,1H),2.15-2.23(m,2H),2.77-3.23(m,1H),3.40-3.70(m,1H),3.73-4.00(m,4H) ,4.95-5.04(m,1H),5.05-5.63(m,1H),6.87-6.94(m,2H),7.19-7.26(m,2H),7.55-7.64(m,1H),8.11-8.20( m, 1H), 8.40-8.51 (m, 1H), 8.71-8.80 (m, 1H), 8.81-8.94 (m, 1H), 11.13-11.28 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 452.2; found 453.2; Rt=2.921 min.

實例464. 外消旋-5-{2-[(2R,5S)-2-(6-氟吡啶-3-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物276)之合成Example 464. Racemic-5-{2-[(2R,5S)-2-(6-fluoropyridin-3-yl)-5-methylpiperidin-1-yl]-2-side oxyethyl Synthesis of amido}pyridine-3-carboxamide (compound 276)

Figure 110128222-A0202-12-1877-980
Figure 110128222-A0202-12-1877-980

藉由一般程序1製備。產率：14.9mg，11.05%1 H NMR(600MHz,DMSO-d6 )δ 0.80-1.07(m,3H),1.28-1.41(m,1H),1.62-1.70(m,1H),1.81-1.96(m,1H),1.99-2.15(m,1H),2.15-2.27(m,1H),2.70-3.25(m,1H),3.48-4.23(m,1H),5.21-5.78(m,1H),7.15-7.30(m,1H),7.49-7.64(m,1H),7.87-8.00(m,1H),8.07-8.26(m,2H),8.36-8.52(m,1H),8.65-8.78(m,1H),8.78-8.94(m,1H),11.21(br s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值385.3；實測值386.2；Rt=2.738min。Prepared by General Procedure 1. Yield: 14.9 mg, 11.05% 1 H NMR (600 MHz, DMSO-d 6 ) δ 0.80-1.07 (m, 3H), 1.28-1.41 (m, 1H), 1.62-1.70 (m, 1H), 1.81-1.96 (m,1H),1.99-2.15(m,1H),2.15-2.27(m,1H),2.70-3.25(m,1H),3.48-4.23(m,1H),5.21-5.78(m,1H) ,7.15-7.30(m,1H),7.49-7.64(m,1H),7.87-8.00(m,1H),8.07-8.26(m,2H),8.36-8.52(m,1H),8.65-8.78( m, 1H), 8.78-8.94 (m, 1H), 11.21 (br s, 1H). LCMS (ESI): [M+H] + m/z: calculated 385.3; found 386.2; Rt=2.738 min.

實例465. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[4-(三氟甲氧基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物250)之合成Example 465. Racemic-5-{2-[(2R,5S)-5-methyl-2-[4-(trifluoromethoxy)phenyl]piperidin-1-yl]-2-side Synthesis of Oxyacetamido}pyridine-3-carbamoylamine (Compound 250)

Figure 110128222-A0202-12-1878-981
Figure 110128222-A0202-12-1878-981

藉由一般程序1製備。產率：10.3mg，6.53%1 H NMR(600MHz,DMSO-d6 )δ 0.97-1.11(m,3H),1.27-1.41(m,1H),1.57-1.70(m,1H),1.82-1.98(m,1H),1.98-2.14(m,1H),2.14-2.29(m,1H),2.79-3.20(m,1H),3.38-4.08(m,1H),5.09-5.71(m,1H),7.34-7.40(m,2H),7.42-7.49(m,2H),7.54-7.65(m,1H),8.08-8.20(m,1H),8.41-8.51(m,1H),8.72-8.79(m,1H),8.81-8.92(m,1H),11.13-11.31(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值450.2；實測值451.2；Rt=1.299min。Prepared by General Procedure 1. Yield: 10.3 mg, 6.53% 1 H NMR (600 MHz, DMSO-d 6 ) δ 0.97-1.11 (m, 3H), 1.27-1.41 (m, 1H), 1.57-1.70 (m, 1H), 1.82-1.98 (m,1H),1.98-2.14(m,1H),2.14-2.29(m,1H),2.79-3.20(m,1H),3.38-4.08(m,1H),5.09-5.71(m,1H) ,7.34-7.40(m,2H),7.42-7.49(m,2H),7.54-7.65(m,1H),8.08-8.20(m,1H),8.41-8.51(m,1H),8.72-8.79( m, 1H), 8.81-8.92 (m, 1H), 11.13-11.31 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 450.2; found 451.2; Rt=1.299 min.

實例466. 外消旋-5-{2-[(2R,5S)-2-[4-(環丙基甲基)苯基]-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物273)之合成Example 466. Racemic-5-{2-[(2R,5S)-2-[4-(cyclopropylmethyl)phenyl]-5-methylpiperidin-1-yl]-2-side Synthesis of Oxyacetamido}pyridine-3-carbamoylamine (Compound 273)

Figure 110128222-A0202-12-1878-982
Figure 110128222-A0202-12-1878-982

藉由一般程序1製備。產率：12.4mg，8.42%1 H NMR(600MHz,DMSO-d 6 )δ 0.14-0.19(m,2H),0.41-0.47(m,2H),0.88-0.97(m,1H),0.97-1.06(m,3H),1.23-1.38(m,1H),1.60-1.72(m,1H),1.77-1.95(m,1H),1.98-2.16(m,1H),2.16-2.29(m,1H),2.43-2.45(m,1H),2.49-2.52(m,1H),2.74-3.20(m,1H),3.45-4.04(m,1H),5.08-5.63(m,1H),7.19-7.27(m,4H),7.49-7.64(m,1H),8.05 -8.28(m,1H),8.38-8.54(m,1H),8.68-8.79(m,1H),8.80-8.93(m,1H),11.22(br s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.4；Rt=3.738min。Prepared by General Procedure 1. Yield: 12.4 mg, 8.42% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.14-0.19 (m, 2H), 0.41-0.47 (m, 2H), 0.88-0.97 (m, 1H), 0.97-1.06 (m,3H),1.23-1.38(m,1H),1.60-1.72(m,1H),1.77-1.95(m,1H),1.98-2.16(m,1H),2.16-2.29(m,1H) ,2.43-2.45(m,1H),2.49-2.52(m,1H),2.74-3.20(m,1H),3.45-4.04(m,1H),5.08-5.63(m,1H),7.19-7.27( m,4H),7.49-7.64(m,1H),8.05-8.28(m,1H),8.38-8.54(m,1H),8.68-8.79(m,1H),8.80-8.93(m,1H), 11.22(br s, 1H). LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.4; Rt=3.738 min.

實例467. 外消旋-5-{2-[(2R,5S)-2-(4-氰基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物246)之合成Example 467. Racemic-5-{2-[(2R,5S)-2-(4-cyanophenyl)-5-methylpiperidin-1-yl]-2-oxoacetamide Synthesis of yl}pyridine-3-carboxamide (Compound 246)

Figure 110128222-A0202-12-1879-983
Figure 110128222-A0202-12-1879-983

藉由一般程序1製備。產率：8.0mg，5.34%1 H NMR(600MHz,DMSO-d 6 )δ 0.87-1.06(m,3H),1.26-1.41(m,1H),1.56-1.65(m,1H),1.66-1.89(m,1H),1.89-2.13(m,1H),2.15-2.28(m,1H),2.73-3.25(m,1H),3.47-4.31(m,1H),5.22-5.77(m,1H),7.50-7.56(m,2H),7.56-7.64(m,1H),7.83-7.89(m,2H),8.11-8.21(m,1H),8.42-8.53(m,1H),8.72-8.79(m,1H),8.81-8.92(m,1H),11.18-11.32(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值391.2；實測值392.2；Rt=1.017min。Prepared by General Procedure 1. Yield: 8.0 mg, 5.34% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.87-1.06 (m, 3H), 1.26-1.41 (m, 1H), 1.56-1.65 (m, 1H), 1.66-1.89 (m,1H),1.89-2.13(m,1H),2.15-2.28(m,1H),2.73-3.25(m,1H),3.47-4.31(m,1H),5.22-5.77(m,1H) ,7.50-7.56(m,2H),7.56-7.64(m,1H),7.83-7.89(m,2H),8.11-8.21(m,1H),8.42-8.53(m,1H),8.72-8.79( m, 1H), 8.81-8.92 (m, 1H), 11.18-11.32 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 391.2; found 392.2; Rt=1.017 min.

實例468. 外消旋-5-{2-[(2R,5S)-2-[4-氯-3-(三氟甲基)苯基]-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物337)之合成Example 468. Racemic-5-{2-[(2R,5S)-2-[4-chloro-3-(trifluoromethyl)phenyl]-5-methylpiperidin-1-yl]- Synthesis of 2-Oxyacetamido}pyridine-3-carbamoylamine (Compound 337)

Figure 110128222-A0202-12-1879-984
Figure 110128222-A0202-12-1879-984

藉由一般程序1製備。產率：14.7mg，8.96%1 H NMR(600MHz,DMSO-d 6 )δ 1.03(m,3H),1.35(m,3H),1.72(m,1H),1.86(m,1H),2.01(m,1H), 2.14(m,1H),2.74(m,1H),3.00(m,1H),3.42(m,2H),4.22(m,1H),4.87(m,1H),5.27(m,1H),6.69(m,1H),7.02(m,1H),7.14(m,1H),7.59(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.85(m,1H),11.17(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值468.2；實測值469.2；Rt=3.388min。Prepared by General Procedure 1. Yield: 14.7 mg, 8.96% 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.03 (m, 3H), 1.35 (m, 3H), 1.72 (m, 1H), 1.86 (m, 1H), 2.01 ( m, 1H), 2.14(m, 1H), 2.74(m, 1H), 3.00(m, 1H), 3.42(m, 2H), 4.22(m, 1H), 4.87(m, 1H), 5.27(m ,1H),6.69(m,1H),7.02(m,1H),7.14(m,1H),7.59(m,1H),8.14(m,1H),8.46(m,1H),8.75(m, 1H), 8.85 (m, 1H), 11.17 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 468.2; found 469.2; Rt=3.388 min.

實例469. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[4-(1H-吡唑-1-基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物256)之合成Example 469. Racemic-5-{2-[(2R,5S)-5-methyl-2-[4-(1H-pyrazol-1-yl)phenyl]piperidin-1-yl]- Synthesis of 2-Pendant oxyacetamido}pyridine-3-carbamoylamine (Compound 256)

Figure 110128222-A0202-12-1880-985
Figure 110128222-A0202-12-1880-985

藉由一般程序1製備。產率：10.8mg，7.2%1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.08(m,3H),1.29-1.44(m,1H),1.64-1.75(m,1H),1.84-1.96(m,1H),2.04-2.19(m,1H),2.20-2.32(m,1H),2.77-3.17(m,1H),3.47-4.06(m,1H),5.17-5.74(m,1H),6.50-6.55(m,1H),7.41-7.49(m,2H),7.55-7.64(m,1H),7.67-7.75(m,1H),7.80-7.87(m,2H),8.10-8.21(m,1H),8.43-8.53(m,2H),8.71-8.80(m,1H),8.83-8.94(m,1H),11.05-11.39(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值432.2；實測值433.2；Rt=3.037min。Prepared by General Procedure 1. Yield: 10.8 mg, 7.2% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.08 (m, 3H), 1.29-1.44 (m, 1H), 1.64-1.75 (m, 1H), 1.84-1.96 (m,1H), 2.04-2.19(m,1H), 2.20-2.32(m,1H), 2.77-3.17(m,1H), 3.47-4.06(m,1H), 5.17-5.74(m,1H) ,6.50-6.55(m,1H),7.41-7.49(m,2H),7.55-7.64(m,1H),7.67-7.75(m,1H),7.80-7.87(m,2H),8.10-8.21( m, 1H), 8.43-8.53 (m, 2H), 8.71-8.80 (m, 1H), 8.83-8.94 (m, 1H), 11.05-11.39 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 432.2; found 433.2; Rt=3.037 min.

實例470. 外消旋-5-{2-[(2R,5S)-2-(4-氰基-3-環丙基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物244)之合成Example 470. Racemic-5-{2-[(2R,5S)-2-(4-cyano-3-cyclopropylphenyl)-5-methylpiperidin-1-yl]-2- Synthesis of Pendant Oxyacetamido}Pyridine-3-Carboxamide (Compound 244)

Figure 110128222-A0202-12-1881-986
Figure 110128222-A0202-12-1881-986

藉由一般程序1製備。產率：2.9mg，1.93%1 H NMR(600MHz,DMSO-d 6 )δ 0.75-0.84(m,2H),0.97-1.15(m,5H),1.23-1.38(m,1H),1.51-1.63(m,1H),1.81-1.93(m,1H),1.99-2.27(m,3H),2.75-3.23(m,1H),3.42-4.06(m,1H),5.13-5.65(m,1H),6.89-6.99(m,1H),7.21-7.33(m,1H),7.54-7.67(m,1H),7.70-7.83(m,1H),8.08-8.21(m,1H),8.39-8.57(m,1H),8.68-8.79(m,1H),8.79-8.93(m,1H),11.12-11.35(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值431.2；實測值432.2；Rt=1.306min。Prepared by General Procedure 1. Yield: 2.9 mg, 1.93% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.75-0.84 (m, 2H), 0.97-1.15 (m, 5H), 1.23-1.38 (m, 1H), 1.51-1.63 (m,1H),1.81-1.93(m,1H),1.99-2.27(m,3H),2.75-3.23(m,1H),3.42-4.06(m,1H),5.13-5.65(m,1H) ,6.89-6.99(m,1H),7.21-7.33(m,1H),7.54-7.67(m,1H),7.70-7.83(m,1H),8.08-8.21(m,1H),8.39-8.57( m, 1H), 8.68-8.79 (m, 1H), 8.79-8.93 (m, 1H), 11.12-11.35 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 431.2; found 432.2; Rt=1.306 min.

實例471. 外消旋-5-{2-[(2R,5S)-2-{4-[(1H-咪唑-1-基)甲基]苯基}-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物238)之合成Example 471. Racemic-5-{2-[(2R,5S)-2-{4-[(1H-imidazol-1-yl)methyl]phenyl}-5-methylpiperidine-1- [Synthesis of]-2-oxoacetamido}pyridine-3-carboxamide (Compound 238)

Figure 110128222-A0202-12-1881-987
Figure 110128222-A0202-12-1881-987

藉由一般程序1製備。產率：26.6mg，17.02%1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.08(m,3H),1.26-1.40(m,1H),1.58-1.68(m,1H),1.81-1.91(m,1H),2.00-2.26(m,2H),2.74-3.24(m,1H),3.43-4.03(m,1H),5.13-5.57(m,3H),7.25-7.28(m,1H),7.29(s,2H),7.30-7.35(m,1H),7.55-7.65(m,1H),7.91-7.98(m,1H),8.08-8.22(m,1H),8.40-8.51(m,1H),8.61-8.66(m,1H),8.71-8.79 (m,1H),8.81-8.92(m,1H),11.12-11.28(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值446.2；實測值447.2；Rt=0.809min。Prepared by General Procedure 1. Yield: 26.6 mg, 17.02% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.08 (m, 3H), 1.26-1.40 (m, 1H), 1.58-1.68 (m, 1H), 1.81-1.91 (m,1H), 2.00-2.26(m,2H), 2.74-3.24(m,1H), 3.43-4.03(m,1H), 5.13-5.57(m,3H), 7.25-7.28(m,1H) ,7.29(s,2H),7.30-7.35(m,1H),7.55-7.65(m,1H),7.91-7.98(m,1H),8.08-8.22(m,1H),8.40-8.51(m, 1H), 8.61-8.66 (m, 1H), 8.71-8.79 (m, 1H), 8.81-8.92 (m, 1H), 11.12-11.28 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 446.2; found 447.2; Rt=0.809 min.

實例472. 外消旋-5-{2-[(2R,5S)-5-甲基-2-{4-[(1H-1,2,4-三唑-1-基)甲基]苯基}哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物252)之合成Example 472. Racemic-5-{2-[(2R,5S)-5-methyl-2-{4-[(1H-1,2,4-triazol-1-yl)methyl]benzene Synthesis of yl}piperidin-1-yl]-2-oxoacetamido}pyridine-3-carboxamido (Compound 252)

Figure 110128222-A0202-12-1882-988
Figure 110128222-A0202-12-1882-988

藉由一般程序1製備。產率：22.2mg，14.17%1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.08(m,3H),1.26-1.40(m,1H),1.58-1.68(m,1H),1.81-1.91(m,1H),2.00-2.26(m,2H),2.74-3.24(m,1H),3.43-4.03(m,1H),5.13-5.57(m,3H),7.25-7.28(m,1H),7.29(s,2H),7.30-7.35(m,1H),7.55-7.65(m,1H),7.91-7.98(m,1H),8.08-8.22(m,1H),8.40-8.51(m,1H),8.61-8.66(m,1H),8.71-8.79(m,1H),8.81-8.92(m,1H),11.12-11.28(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值447.2；實測值448.2；Rt=1.008min。Prepared by General Procedure 1. Yield: 22.2 mg, 14.17% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.08 (m, 3H), 1.26-1.40 (m, 1H), 1.58-1.68 (m, 1H), 1.81-1.91 (m,1H), 2.00-2.26(m,2H), 2.74-3.24(m,1H), 3.43-4.03(m,1H), 5.13-5.57(m,3H), 7.25-7.28(m,1H) ,7.29(s,2H),7.30-7.35(m,1H),7.55-7.65(m,1H),7.91-7.98(m,1H),8.08-8.22(m,1H),8.40-8.51(m, 1H), 8.61-8.66 (m, 1H), 8.71-8.79 (m, 1H), 8.81-8.92 (m, 1H), 11.12-11.28 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 447.2; found 448.2; Rt=1.008 min.

實例473. 外消旋-5-{2-[(2R,5S)-2-(3,4-二氯苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物243)之合成Example 473. Racemic-5-{2-[(2R,5S)-2-(3,4-dichlorophenyl)-5-methylpiperidin-1-yl]-2-side oxyethyl Synthesis of amido}pyridine-3-carboxamide (compound 243)

Figure 110128222-A0202-12-1882-989
Figure 110128222-A0202-12-1882-989

藉由一般程序1製備。產率：13.4mg，8.79%1 H NMR(600MHz, DMSO-d 6 )δ 0.93-1.08(m,3H),1.24-1.42(m,1H),1.56-1.70(m,1H),1.78-1.97(m,1H),2.01-2.28(m,2H),2.76-3.25(m,1H),3.43-4.09(m,1H),5.12-5.58(m,1H),7.27-7.36(m,1H),7.51-7.56(m,1H),7.56-7.62(m,1H),7.62-7.70(m,1H),8.10-8.20(m,1H),8.42-8.52(m,1H),8.71-8.80(m,1H),8.80-8.93(m,1H),11.09-11.34(m,1H)。LCMS(ESI)：[M+2H]+ m/z：計算值435.3；實測值437.1；Rt=1.336min。Prepared by General Procedure 1. Yield: 13.4 mg, 8.79% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.93-1.08 (m, 3H), 1.24-1.42 (m, 1H), 1.56-1.70 (m, 1H), 1.78-1.97 (m,1H), 2.01-2.28(m,2H), 2.76-3.25(m,1H), 3.43-4.09(m,1H), 5.12-5.58(m,1H), 7.27-7.36(m,1H) ,7.51-7.56(m,1H),7.56-7.62(m,1H),7.62-7.70(m,1H),8.10-8.20(m,1H),8.42-8.52(m,1H),8.71-8.80( m, 1H), 8.80-8.93 (m, 1H), 11.09-11.34 (m, 1H). LCMS (ESI): [M+2H] + m/z: calculated 435.3; found 437.1; Rt=1.336 min.

實例474. 外消旋-5-{2-[(2R,5S)-2-(4-氯-3-氟苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物327)之合成Example 474. Racemic-5-{2-[(2R,5S)-2-(4-chloro-3-fluorophenyl)-5-methylpiperidin-1-yl]-2-pendoxyl Synthesis of Acetamido}pyridine-3-carbamoylamine (Compound 327)

Figure 110128222-A0202-12-1883-990
Figure 110128222-A0202-12-1883-990

藉由一般程序1製備。產率：7.0mg，4.78%1 H NMR(600MHz,DMSO-d 6 )δ 1.01(m,3H),1.32(m,1H),1.63(m,1H),1.88(m,1H),2.10(m,2H),2.90(m,1H),3.84(m,1H),5.35(m,1H),7.19(m,1H),7.36(m,1H),7.60(m,2H),8.15(m,1H),8.46(m,1H),8.76(m,1H),8.87(m,1H),11.24(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=1.311min。Prepared by General Procedure 1. Yield: 7.0 mg, 4.78% 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.01 (m, 3H), 1.32 (m, 1H), 1.63 (m, 1H), 1.88 (m, 1H), 2.10 ( m, 2H), 2.90(m, 1H), 3.84(m, 1H), 5.35(m, 1H), 7.19(m, 1H), 7.36(m, 1H), 7.60(m, 2H), 8.15(m , 1H), 8.46 (m, 1H), 8.76 (m, 1H), 8.87 (m, 1H), 11.24 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=1.311 min.

實例475. 外消旋-5-{2-[(2R,5S)-2-(3-氟苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物247)之合成Example 475. Racemic-5-{2-[(2R,5S)-2-(3-fluorophenyl)-5-methylpiperidin-1-yl]-2-oxyacetamido } Synthesis of pyridine-3-carboxamide (compound 247)

Figure 110128222-A0202-12-1883-991
Figure 110128222-A0202-12-1883-991

藉由一般程序1製備。產率：9.8mg，7.28%1 H NMR(600MHz,DMSO-d 6 )δ 0.95-1.08(m,3H),1.29-1.43(m,1H),1.59-1.71(m,1H),1.81-1.95(m,1H),2.00-2.15(m,1H),2.17-2.29(m,1H),2.74-3.25(m,1H),3.46-4.08(m,1H),5.13-5.69(m,1H),7.05-7.22(m,3H),7.37-7.50(m,1H),7.54-7.66(m,1H),8.09-8.22(m,1H),8.41-8.54(m,1H),8.70-8.80(m,1H),8.80-8.93(m,1H),11.29(br s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值384.2；實測值385.2；Rt=1.235min。Prepared by General Procedure 1. Yield: 9.8 mg, 7.28% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.95-1.08 (m, 3H), 1.29-1.43 (m, 1H), 1.59-1.71 (m, 1H), 1.81-1.95 (m,1H), 2.00-2.15(m,1H), 2.17-2.29(m,1H), 2.74-3.25(m,1H), 3.46-4.08(m,1H), 5.13-5.69(m,1H) ,7.05-7.22(m,3H),7.37-7.50(m,1H),7.54-7.66(m,1H),8.09-8.22(m,1H),8.41-8.54(m,1H),8.70-8.80( m, 1H), 8.80-8.93 (m, 1H), 11.29 (br s, 1H). LCMS (ESI): [M+H] + m/z: calculated 384.2; found 385.2; Rt=1.235 min.

實例476. 外消旋-5-{2-[(2R,5S)-2-[3-(二氟甲基)苯基]-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物268)之合成Example 476. Racemic-5-{2-[(2R,5S)-2-[3-(difluoromethyl)phenyl]-5-methylpiperidin-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 268)

Figure 110128222-A0202-12-1884-992
Figure 110128222-A0202-12-1884-992

藉由一般程序1製備。產率：7.6mg，5.21%1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.07(m,3H),1.28-1.39(m,1H),1.60-1.69(m,1H),1.82-1.95(m,1H),2.04-2.17(m,1H),2.18-2.30(m,1H),2.74-3.25(m,1H),3.51-4.10(m,1H),5.18-5.75(m,1H),6.90-7.15(m,1H),7.45-7.67(m,5H),8.09-8.22(m,1H),8.41-8.55(m,1H),8.69-8.81(m,1H),8.81-8.98(m,1H),11.19-11.34(m,1H)。Prepared by General Procedure 1. Yield: 7.6 mg, 5.21% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.07 (m, 3H), 1.28-1.39 (m, 1H), 1.60-1.69 (m, 1H), 1.82-1.95 (m,1H), 2.04-2.17(m,1H), 2.18-2.30(m,1H), 2.74-3.25(m,1H), 3.51-4.10(m,1H), 5.18-5.75(m,1H) ,6.90-7.15(m,1H),7.45-7.67(m,5H),8.09-8.22(m,1H),8.41-8.55(m,1H),8.69-8.81(m,1H),8.81-8.98( m, 1H), 11.19-11.34 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值416.2；實測值417.2；Rt=3.096min。LCMS (ESI): [M+H] + m/z: calculated 416.2; found 417.2; Rt=3.096 min.

實例477. 外消旋-5-{2-[(2R,5S)-2-(3-環丁基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物261)之合成Example 477. Racemic-5-{2-[(2R,5S)-2-(3-cyclobutylphenyl)-5-methylpiperidin-1-yl]-2-oxoacetone Synthesis of Amino}pyridine-3-carboxamide (Compound 261)

Figure 110128222-A0202-12-1885-993
Figure 110128222-A0202-12-1885-993

藉由一般程序1製備。產率：1.8mg，1.22% LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=1.386min。Prepared by General Procedure 1. Yield: 1.8 mg, 1.22% LCMS (ESI): [M+H] + m/z: calcd 420.2; found 421.2; Rt=1.386 min.

實例478. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[3-(三氟甲氧基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物279)之合成Example 478. Racemic-5-{2-[(2R,5S)-5-methyl-2-[3-(trifluoromethoxy)phenyl]piperidin-1-yl]-2-side Synthesis of Oxyacetamido}pyridine-3-carbamoylamine (Compound 279)

Figure 110128222-A0202-12-1885-994
Figure 110128222-A0202-12-1885-994

藉由一般程序1製備。產率：19.6g，12.43%1 H NMR(600MHz,DMSO-d 6 )δ 0.97-1.07(m,3H),1.28-1.42(m,1H),1.58-1.68(m,1H),1.83-1.96(m,1H),2.01-2.16(m,1H),2.16-2.30(m,1H),2.71-3.24(m,1H),3.47-4.07(m,1H),5.19-5.70(m,1H),7.23-7.32(m,2H),7.34-7.44(m,1H),7.50-7.61(m,2H),8.10-8.21(m,1H),8.39-8.53(m,1H),8.70-8.80(m,1H),8.80-8.92(m,1H),11.17-11.38(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值450.2；實測值451.2；Rt=3.477min。Prepared by General Procedure 1. Yield: 19.6 g, 12.43% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.97-1.07 (m, 3H), 1.28-1.42 (m, 1H), 1.58-1.68 (m, 1H), 1.83-1.96 (m,1H), 2.01-2.16(m,1H), 2.16-2.30(m,1H), 2.71-3.24(m,1H), 3.47-4.07(m,1H), 5.19-5.70(m,1H) ,7.23-7.32(m,2H),7.34-7.44(m,1H),7.50-7.61(m,2H),8.10-8.21(m,1H),8.39-8.53(m,1H),8.70-8.80( m, 1H), 8.80-8.92 (m, 1H), 11.17-11.38 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 450.2; found 451.2; Rt=3.477 min.

實例479. 外消旋-5-{2-[(2R,5S)-2-(2,3-二氫-1H-茚-5-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物277)之合成Example 479. Racemic-5-{2-[(2R,5S)-2-(2,3-dihydro-1H-inden-5-yl)-5-methylpiperidin-1-yl]- Synthesis of 2-oxyacetamido}pyridine-3-carboxamido (Compound 277)

Figure 110128222-A0202-12-1886-725
Figure 110128222-A0202-12-1886-725

藉由一般程序1製備。產率：4.8mg，3.73%1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.07(m,3H),1.27-1.38(m,1H),1.62-1.74(m,1H),1.79-1.91(m,1H),1.95-2.12(m,3H),2.15-2.23(m,1H),2.77-2.85(m,4H),3.23-3.27(m,1H),3.46-4.01(m,1H),4.99-5.62(m,1H),7.02-7.10(m,1H),7.14-7.24(m,2H),7.50-7.68(m,1H),8.06-8.22(m,1H),8.38-8.53(m,1H),8.69-8.79(m,1H),8.79-9.01(m,1H),11.02-11.40(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.2；Rt=3.466min。Prepared by General Procedure 1. Yield: 4.8 mg, 3.73% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.07 (m, 3H), 1.27-1.38 (m, 1H), 1.62-1.74 (m, 1H), 1.79-1.91 (m,1H),1.95-2.12(m,3H),2.15-2.23(m,1H),2.77-2.85(m,4H),3.23-3.27(m,1H),3.46-4.01(m,1H) ,4.99-5.62(m,1H),7.02-7.10(m,1H),7.14-7.24(m,2H),7.50-7.68(m,1H),8.06-8.22(m,1H),8.38-8.53( m, 1H), 8.69-8.79 (m, 1H), 8.79-9.01 (m, 1H), 11.02-11.40 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.2; Rt=3.466 min.

實例480. 外消旋-5-{2-[(2R,5S)-2-(1-苯并呋喃-6-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物241)之合成Example 480. Racemic-5-{2-[(2R,5S)-2-(1-benzofuran-6-yl)-5-methylpiperidin-1-yl]-2-pendoxyl Synthesis of Acetamido}pyridine-3-carbamoylamine (Compound 241)

Figure 110128222-A0202-12-1886-726
Figure 110128222-A0202-12-1886-726

藉由一般程序1製備。產率：10.0mg，7.03%1 H NMR(600MHz,DMSO-d 6 )δ 1.01-1.06(m,3H),1.28-1.39(m,1H),1.69-1.77(m,1H),1.83-1.94(m,1H),2.05-2.20(m,1H),2.26-2.34(m,1H),2.81-3.21(m,1H),3.47-4.06(m,1H),5.18-5.75(m,1H),6.90-6.95(m,1H),7.20-7.28(m,1H),7.52-7.56(m,1H),7.56-7.62(m,1H),7.62-7.68(m,1H),7.95-8.00(m,1H),8.09-8.22(m,1H),8.42-8.53(m,1H),8.70-8.80(m,1H),8.82-8.93(m,1H),11.11-11.39(m,1H)。Prepared by General Procedure 1. Yield: 10.0 mg, 7.03% 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.01-1.06 (m, 3H), 1.28-1.39 (m, 1H), 1.69-1.77 (m, 1H), 1.83-1.94 (m,1H), 2.05-2.20(m,1H), 2.26-2.34(m,1H), 2.81-3.21(m,1H), 3.47-4.06(m,1H), 5.18-5.75(m,1H) ,6.90-6.95(m,1H),7.20-7.28(m,1H),7.52-7.56(m,1H),7.56-7.62(m,1H),7.62-7.68(m,1H),7.95-8.00( m, 1H), 8.09-8.22 (m, 1H), 8.42-8.53 (m, 1H), 8.70-8.80 (m, 1H), 8.82-8.93 (m, 1H), 11.11-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.1；Rt=1.248min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.1; Rt=1.248 min.

實例481. 外消旋-5-{2-[(2R,5S)-2-(2,3-二氫-1-苯并呋喃-6-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物405)之合成Example 481. Racemic-5-{2-[(2R,5S)-2-(2,3-dihydro-1-benzofuran-6-yl)-5-methylpiperidin-1-yl Synthesis of ]-2-oxyacetamido}pyridine-3-carboxamide (Compound 405)

Figure 110128222-A0202-12-1887-727
Figure 110128222-A0202-12-1887-727

藉由一般程序1製備。產率：8.8mg，6.0%1 H NMR(500MHz,DMSO)δ 1.00-1.05(m,3H),1.26-1.38(m,1H),1.66-1.78(m,1H),1.84-1.96(m,1H),1.97-2.10(m,1H),2.15-2.25(m,1H),2.82-3.14(m,2H),3.46-4.04(m,1H),4.23-4.59(m,3H),5.05-5.60(m,1H),6.68-6.77(m,1H),6.77-6.88(m,1H),7.17-7.31(m,1H),7.56-7.69(m,1H),8.10-8.26(m,1H),8.43-8.56(m,1H),8.72-8.83(m,1H),8.84-8.96(m,1H),11.08-11.38(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值408.2；實測值409.2；Rt=3.179min。Prepared by General Procedure 1. Yield: 8.8 mg, 6.0% 1 H NMR (500 MHz, DMSO) δ 1.00-1.05 (m, 3H), 1.26-1.38 (m, 1H), 1.66-1.78 (m, 1H), 1.84-1.96 (m, 1H), 1.97-2.10(m, 1H), 2.15-2.25(m, 1H), 2.82-3.14(m, 2H), 3.46-4.04(m, 1H), 4.23-4.59(m, 3H), 5.05- 5.60(m,1H),6.68-6.77(m,1H),6.77-6.88(m,1H),7.17-7.31(m,1H),7.56-7.69(m,1H),8.10-8.26(m,1H) ), 8.43-8.56(m, 1H), 8.72-8.83(m, 1H), 8.84-8.96(m, 1H), 11.08-11.38(m, 1H). LCMS (ESI): [M+H] + m/z: calculated 408.2; found 409.2; Rt=3.179 min.

實例482. 外消旋-5-{2-[(2R,5S)-2-(3-氰基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物239)之合成Example 482. Racemic-5-{2-[(2R,5S)-2-(3-cyanophenyl)-5-methylpiperidin-1-yl]-2-oxyacetamide Synthesis of pyridine-3-carboxamide (Compound 239)

Figure 110128222-A0202-12-1887-728
Figure 110128222-A0202-12-1887-728

藉由一般程序1製備。產率：14.5mg，10.58%1 H NMR(600MHz,DMSO-d 6 )δ 0.83-1.08(m,3H),1.23-1.39(m,1H),1.56-1.70(m,1H),1.82-1.97(m,1H),2.00-2.19(m,1H),2.19-2.35(m,1H),2.73-3.26(m,1H),3.48-4.06(m, 1H),5.12-5.72(m,1H),7.56-7.71(m,3H),7.72-7.81(m,2H),8.09-8.21(m,1H),8.40-8.54(m,1H),8.72-8.80(m,1H),8.80-8.94(m,1H),11.15-11.39(m,1H)。Prepared by General Procedure 1. Yield: 14.5 mg, 10.58% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.83-1.08 (m, 3H), 1.23-1.39 (m, 1H), 1.56-1.70 (m, 1H), 1.82-1.97 (m,1H),2.00-2.19(m,1H),2.19-2.35(m,1H),2.73-3.26(m,1H),3.48-4.06(m,1H),5.12-5.72(m,1H) ,7.56-7.71(m,3H),7.72-7.81(m,2H),8.09-8.21(m,1H),8.40-8.54(m,1H),8.72-8.80(m,1H),8.80-8.94( m, 1H), 11.15-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值391.2；實測值392.2；Rt=1.169min。LCMS (ESI): [M+H] + m/z: calculated 391.2; found 392.2; Rt=1.169 min.

實例483. 外消旋-5-{2-[(2R,5S)-2-(1,3-二氧雜茚-5-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物270)之合成Example 483. Racemic-5-{2-[(2R,5S)-2-(1,3-dioxinden-5-yl)-5-methylpiperidin-1-yl]-2- Synthesis of Pendant Oxyacetamido}Pyridin-3-Carboxamide (Compound 270)

Figure 110128222-A0202-12-1888-729
Figure 110128222-A0202-12-1888-729

藉由一般程序1製備。產率：2.4mg，1.67% LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值411.0；Rt=1.181min。Prepared by General Procedure 1. Yield: 2.4 mg, 1.67% LCMS (ESI): [M+H] + m/z: calcd 410.2; found 411.0; Rt=1.181 min.

實例484. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[3-(三氟甲基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物265)之合成Example 484. Racemic-5-{2-[(2R,5S)-5-methyl-2-[3-(trifluoromethyl)phenyl]piperidin-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 265)

Figure 110128222-A0202-12-1888-730
Figure 110128222-A0202-12-1888-730

藉由一般程序1製備。產率：11.7mg，7.69%1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.08(m,3H),1.28-1.42(m,1H),1.57-1.70(m,1H),1.82-1.96(m,1H),2.03-2.19(m,1H),2.19-2.32(m,1H),2.70-3.24(m,1H),3.50-4.07(m,1H),5.22-5.76(m,1H),7.57-7.72(m,5H),8.08-8.19(m,1H),8.38-8.53(m,1H),8.67-8.78(m,1H),8.78-8.93(m,1H),11.29(br s,1H)LCMS(ESI)：[M+H]+ m/z：計算值434.2；實測值435.2；Rt=3.373min。Prepared by General Procedure 1. Yield: 11.7 mg, 7.69% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.08 (m, 3H), 1.28-1.42 (m, 1H), 1.57-1.70 (m, 1H), 1.82-1.96 (m,1H), 2.03-2.19(m,1H), 2.19-2.32(m,1H), 2.70-3.24(m,1H), 3.50-4.07(m,1H), 5.22-5.76(m,1H) ,7.57-7.72(m,5H),8.08-8.19(m,1H),8.38-8.53(m,1H),8.67-8.78(m,1H),8.78-8.93(m,1H),11.29(br s , 1H) LCMS (ESI): [M+H] + m/z: calculated 434.2; found 435.2; Rt=3.373 min.

實例485. 外消旋-5-{2-[(2R,5S)-2-(3,4-二氫-2H-1-苯并哌喃-6-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物341)之合成Example 485. Racemic-5-{2-[(2R,5S)-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-5-methylpiperidine- Synthesis of 1-yl]-2-oxoacetamido}pyridine-3-carboxamide (compound 341)

Figure 110128222-A0202-12-1889-731
Figure 110128222-A0202-12-1889-731

藉由一般程序1製備。產率：10.2mg，6.90%1 H NMR(600MHz,DMSO-d 6 )δ 1.00(m,3H),1.31(m,1H),1.70(m,1H),1.88(m,3H),2.01(m,1H),2.14(m,1H),2.71(m,2H),3.03(m,1H),3.68(m,1H),4.08(m,2H),5.26(m,1H),6.70(m,1H),6.98(m,2H),7.59(m,1H),8.15(m,1H),8.46(m,1H),8.75(m,1H),8.85(m,1H),11.19(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值422.2；實測值423.2；Rt=3.122min。Prepared by General Procedure 1. Yield: 10.2 mg, 6.90% 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00 (m, 3H), 1.31 (m, 1H), 1.70 (m, 1H), 1.88 (m, 3H), 2.01 ( m, 1H), 2.14(m, 1H), 2.71(m, 2H), 3.03(m, 1H), 3.68(m, 1H), 4.08(m, 2H), 5.26(m, 1H), 6.70(m ,1H),6.98(m,2H),7.59(m,1H),8.15(m,1H),8.46(m,1H),8.75(m,1H),8.85(m,1H),11.19(m, 1H). LCMS (ESI): [M+H] + m/z: calculated 422.2; found 423.2; Rt=3.122 min.

實例486. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[6-(甲胺基)吡啶-3-基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物209)之合成Example 486. Racemic-5-{2-[(2R,5S)-5-methyl-2-[6-(methylamino)pyridin-3-yl]piperidin-1-yl]-2- Synthesis of Pendant Oxyacetamido}Pyridine-3-Carboxamide (Compound 209)

Figure 110128222-A0202-12-1889-732
Figure 110128222-A0202-12-1889-732

藉由一般程序1製備。產率：18.3mg，13.19%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.34(m,1H),1.94(m,4H),2.75(m,3H),3.10(m,1H),3.68(m,1H),5.26(m,1H),6.46(m,2H),7.35(m,1H),7.61(m,1H),7.96(m,1H),8.17(m,1H),8.48(m,1H),8.78(m,1H),8.89(m,1H),11.19(m,1H)LCMS(ESI)： [M+H]+ m/z：計算值396.2；實測值397.2；Rt=0.782min。Prepared by General Procedure 1. Yield: 18.3 mg, 13.19% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.34 (m, 1H), 1.94 (m, 4H), 2.75 (m, 3H) ,3.10(m,1H),3.68(m,1H),5.26(m,1H),6.46(m,2H),7.35(m,1H),7.61(m,1H),7.96(m,1H), 8.17(m,1H), 8.48(m,1H), 8.78(m,1H), 8.89(m,1H), 11.19(m,1H) LCMS(ESI): [M+H] + m/z: Calculated value 396.2; observed value 397.2; Rt=0.782min.

實例487. 外消旋-5-{2-[(2R,5S)-2-(6-胺基吡啶-3-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物224)之合成Example 487. Racemic-5-{2-[(2R,5S)-2-(6-aminopyridin-3-yl)-5-methylpiperidin-1-yl]-2-pendoxyl Synthesis of Acetamido}pyridine-3-carbamoylamine (Compound 224)

Figure 110128222-A0202-12-1890-733
Figure 110128222-A0202-12-1890-733

藉由一般程序1製備。產率：6.7mg，5.01%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.02(m,3H),1.34(m,1H),1.96(m,4H),3.01(m,1H),3.61(m,1H),5.25(m,1H),5.88(s,2H),6.45(m,1H),7.34(m,1H),7.61(m,1H),7.87(s,1H),8.17(m,1H),8.48(m,1H),8.77(m,1H),8.88(m,1H)LCMS(ESI)：[M+H]+ m/z：計算值382.2；實測值383.1；Rt=0.742min。Prepared by General Procedure 1. Yield: 6.7 mg, 5.01% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.02 (m, 3H), 1.34 (m, 1H), 1.96 (m, 4H), 3.01 (m, 1H) ,3.61(m,1H),5.25(m,1H),5.88(s,2H),6.45(m,1H),7.34(m,1H),7.61(m,1H),7.87(s,1H), 8.17(m,1H), 8.48(m,1H), 8.77(m,1H), 8.88(m,1H) LCMS(ESI): [M+H] + m/z: calculated 382.2; found 383.1; Rt=0.742min.

實例488. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[4-(4-甲基-1H-吡唑-1-基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物218)之合成Example 488. Racemic-5-{2-[(2R,5S)-5-methyl-2-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]piperidine- Synthesis of 1-yl]-2-oxoacetamido}pyridine-3-carboxamide (compound 218)

Figure 110128222-A0202-12-1890-734
Figure 110128222-A0202-12-1890-734

藉由一般程序1製備。產率：20.8mg，13.31%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.05(m,3H),1.37(m,1H),1.71(m,1H),1.92(m,1H),2.10(s,4H),2.26(m,1H),3.05(m,1H),3.78(m,1H),5.42(m,1H),7.44(m,2H),7.58(m,2H), 7.79(m,2H),8.17(m,1H),8.26(m,1H),8.50(m,1H),8.78(m,1H),8.90(m,1H),11.29(s,1H)LCMS(ESI)：[M+H]+ m/z：計算值446.2；實測值447.2；Rt=1.234minPrepared by General Procedure 1. Yield: 20.8 mg, 13.31% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.05 (m, 3H), 1.37 (m, 1H), 1.71 (m, 1H), 1.92 (m, 1H) ,2.10(s,4H),2.26(m,1H),3.05(m,1H),3.78(m,1H),5.42(m,1H),7.44(m,2H),7.58(m,2H), 7.79(m, 2H), 8.17(m, 1H), 8.26(m, 1H), 8.50(m, 1H), 8.78(m, 1H), 8.90(m, 1H), 11.29(s, 1H) LCMS( ESI): [M+H] + m/z: Calculated 446.2; Measured 447.2; Rt=1.234min

實例489. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[6-(吡咯啶-1-基)吡啶-3-基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物207)之合成Example 489. Racemic-5-{2-[(2R,5S)-5-methyl-2-[6-(pyrrolidin-1-yl)pyridin-3-yl]piperidin-1-yl] Synthesis of -2-oxyacetamido}pyridine-3-carboxamido (Compound 207)

Figure 110128222-A0202-12-1891-735
Figure 110128222-A0202-12-1891-735

藉由一般程序1製備。產率：10.9mg，7.13%1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.32(m,1H),1.89(m,6H),2.05(m,2H),3.10(m,1H),3.35(s,4H),3.61(m,1H),5.25(m,1H),6.41(m,1H),7.41(m,1H),7.59(m,1H),8.01(m,1H),8.14(m,1H),8.44(m,1H),8.75(m,1H),8.85(m,1H),11.15(m,1H)Prepared by General Procedure 1. Yield: 10.9 mg, 7.13% 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.00 (m, 3H), 1.32 (m, 1H), 1.89 (m, 6H), 2.05 (m, 2H) ,3.10(m,1H),3.35(s,4H),3.61(m,1H),5.25(m,1H),6.41(m,1H),7.41(m,1H),7.59(m,1H), 8.01(m, 1H), 8.14(m, 1H), 8.44(m, 1H), 8.75(m, 1H), 8.85(m, 1H), 11.15(m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=0.866min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=0.866 min.

實例490. 外消旋-5-{2-[(2R,5S)-2-(4-氟-3-甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物222)之合成Example 490. Racemic-5-{2-[(2R,5S)-2-(4-fluoro-3-methoxyphenyl)-5-methylpiperidin-1-yl]-2-side Synthesis of Oxyacetamido}pyridine-3-carbamoylamine (Compound 222)

Figure 110128222-A0202-12-1891-736
Figure 110128222-A0202-12-1891-736

藉由一般程序1製備。產率：2.2mg，1.52%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.34(m,1H),1.71(m,1H),1.92(m,1H),2.16(m,3H),3.71(m,4H),5.34(m,1H),6.90(m,1H),7.05(m,1H),7.21(m,1H),7.63(m,1H), 8.17(m,1H),8.49(m,1H),8.77(m,1H),8.87(m,1H),11.27(s,1H)LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.2；Rt=1.219min。Prepared by General Procedure 1. Yield: 2.2 mg, 1.52% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.34 (m, 1H), 1.71 (m, 1H), 1.92 (m, 1H) ,2.16(m,3H),3.71(m,4H),5.34(m,1H),6.90(m,1H),7.05(m,1H),7.21(m,1H),7.63(m,1H), 8.17(m,1H), 8.49(m,1H), 8.77(m,1H), 8.87(m,1H), 11.27(s,1H) LCMS(ESI): [M+H] + m/z: Calculated Value 414.2; Measured value 415.2; Rt=1.219min.

實例491. 外消旋-5-{2-[(2R,5S)-5-甲基-2-{4-[(嗎啉-4-基)甲基]苯基}哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物213)之合成Example 491. Racemic-5-{2-[(2R,5S)-5-methyl-2-{4-[(morpholin-4-yl)methyl]phenyl}piperidin-1-yl Synthesis of ]-2-oxyacetamido}pyridine-3-carboxamide (Compound 213)

Figure 110128222-A0202-12-1892-737
Figure 110128222-A0202-12-1892-737

藉由一般程序1製備。產率：20.4mg，12.52%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.04(m,3H),1.35(m,1H),1.69(m,1H),1.89(m,1H),2.14(m,2H),2.33(m,4H),2.96(m,1H),3.44(m,3H),3.55(m,4H),5.38(m,1H),7.31(m,4H),7.61(m,1H),8.16(m,1H),8.48(m,1H),8.83(m,2H),11.22(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值465.2；實測值466.2；Rt=0.854min。Prepared by General Procedure 1. Yield: 20.4 mg, 12.52% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.04 (m, 3H), 1.35 (m, 1H), 1.69 (m, 1H), 1.89 (m, 1H) ,2.14(m,2H),2.33(m,4H),2.96(m,1H),3.44(m,3H),3.55(m,4H),5.38(m,1H),7.31(m,4H), 7.61 (m, 1H), 8.16 (m, 1H), 8.48 (m, 1H), 8.83 (m, 2H), 11.22 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 465.2; found 466.2; Rt=0.854 min.

實例492. 外消旋-5-{2-[(2R,5S)-2-(4-氯-3-甲基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物173)之合成Example 492. Racemic-5-{2-[(2R,5S)-2-(4-chloro-3-methylphenyl)-5-methylpiperidin-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 173)

Figure 110128222-A0202-12-1892-738
Figure 110128222-A0202-12-1892-738

藉由一般程序1製備。產率：12.8mg，8.81% LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.2；Rt=1.359min。Prepared by General Procedure 1. Yield: 12.8 mg, 8.81% LCMS (ESI): [M+H] + m/z: calcd 414.2; found 415.2; Rt=1.359 min.

實例493. 外消旋-5-{2-[(2R,5S)-2-[3-(3,5-二甲基-1H-吡唑-1-基)苯基]-5-甲基哌Example 493. Racemic-5-{2-[(2R,5S)-2-[3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]-5-methyl Piper 啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物153)之合成Synthesis of pyridin-1-yl]-2-oxoacetamido}pyridine-3-carboxamido (compound 153)

Figure 110128222-A0202-12-1893-739
Figure 110128222-A0202-12-1893-739

藉由一般程序1製備。產率：15.1mg，9.37%1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.03(dd,3H),1.34(m,1H),1.67(m,1H),1.98(m,2H),2.15(m,3H),2.25(m,4H),2.82(m,1H),3.77(m,1H),6.05(m,2H),7.36(m,3H),7.51(m,1H),7.59(m,1H),8.14(m,1H),8.47(m,1H),8.76(m,1H),8.86(m,1H),11.26(m,1H)。Prepared by General Procedure 1. Yield: 15.1 mg, 9.37% 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.03 (dd, 3H), 1.34 (m, 1H), 1.67 (m, 1H), 1.98 (m, 2H) ,2.15(m,3H),2.25(m,4H),2.82(m,1H),3.77(m,1H),6.05(m,2H),7.36(m,3H),7.51(m,1H), 7.59 (m, 1H), 8.14 (m, 1H), 8.47 (m, 1H), 8.76 (m, 1H), 8.86 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值460.2；實測值461.2；Rt=1.160min。LCMS (ESI): [M+H] + m/z: calculated 460.2; found 461.2; Rt=1.160 min.

實例494. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[3-甲基-4-(氧戊環-3-基氧基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物171)之合成Example 494. Racemic-5-{2-[(2R,5S)-5-methyl-2-[3-methyl-4-(oxolan-3-yloxy)phenyl]piperidine Synthesis of -1-yl]-2-oxoacetamido}pyridine-3-carboxamide (Compound 171)

Figure 110128222-A0202-12-1893-740
Figure 110128222-A0202-12-1893-740

藉由一般程序1製備。產率：21.6mg，12.23%1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.69(m,1H),1.92(m,3H),2.11(m,3H),2.19(m,2H),3.03(m,1H),3.76(m,5H),4.97(m,1H),6.88(m,1H),7.08(m,2H),7.58(m,1H),8.14(m,1H),8.46(m,1H),8.80(m,2H),11.19(m,1H)LCMS(ESI)：[M+H]+ m/z：計算值466.3；實測值467.2；Rt=1.175min。Prepared by General Procedure 1. Yield: 21.6 mg, 12.23% 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.69 (m, 1H), 1.92 (m, 3H) ,2.11(m,3H),2.19(m,2H),3.03(m,1H),3.76(m,5H),4.97(m,1H),6.88(m,1H),7.08(m,2H), 7.58(m,1H), 8.14(m,1H), 8.46(m,1H), 8.80(m,2H), 11.19(m,1H) LCMS(ESI): [M+H] + m/z: Calculated Value 466.3; Measured value 467.2; Rt=1.175min.

實例495. 外消旋-5-{2-[(2R,5S)-5-甲基-2-(2-甲基-2,3-二氫-1-苯并呋喃-5-基)哌Example 495. Racemic-5-{2-[(2R,5S)-5-methyl-2-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)piperidine 啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物151)之合成Synthesis of pyridin-1-yl]-2-oxoacetamido}pyridine-3-carboxamide (compound 151)

Figure 110128222-A0202-12-1894-741
Figure 110128222-A0202-12-1894-741

藉由一般程序1製備。產率：22.4mg，15.15%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.37(m,4H),1.75(m,1H),1.89(m,1H),2.11(m,2H),2.89(m,2H),3.70(m,1H),4.88(m,1H),5.29(m,1H),6.71(dd,1H),7.04(m,1H),7.16(m,1H),7.60(m,1H),8.16(m,1H),8.48(m,1H),8.77(m,1H),8.88(m,1H),11.19(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值422.2；實測值423.2；Rt=1.263min。Prepared by General Procedure 1. Yield: 22.4 mg, 15.15% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.37 (m, 4H), 1.75 (m, 1H), 1.89 (m, 1H) ,2.11(m,2H),2.89(m,2H),3.70(m,1H),4.88(m,1H),5.29(m,1H),6.71(dd,1H),7.04(m,1H), 7.16(m,1H), 7.60(m,1H), 8.16(m,1H), 8.48(m,1H), 8.77(m,1H), 8.88(m,1H), 11.19(m,1H). LCMS (ESI): [M+H] + m/z: calculated 422.2; found 423.2; Rt=1.263 min.

實例496. 外消旋-5-{2-[(2R,5S)-5-甲基-2-(2-甲基喹啉-6-基)哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物167)之合成Example 496. Racemic-5-{2-[(2R,5S)-5-methyl-2-(2-methylquinolin-6-yl)piperidin-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 167)

Figure 110128222-A0202-12-1894-742
Figure 110128222-A0202-12-1894-742

藉由一般程序1製備。產率：18.2mg，12.05%1 H NMR(DMSO-d6,400MHz)：δ(ppm)1.07(m,3H),1.41(m,1H),1.85(m,2H),2.30(m,2H),2.65(m,4H),3.82(m,1H),5.58(m,1H),7.42(m,1H),7.70(m,2H),7.93(m,2H),8.24(m,2H),8.50(m,1H),8.84(m,2H),11.30(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值431.2；實測值432.2；Rt=0.859min。Prepared by General Procedure 1. Yield: 18.2 mg, 12.05% 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.07 (m, 3H), 1.41 (m, 1H), 1.85 (m, 2H), 2.30 (m, 2H) ,2.65(m,4H),3.82(m,1H),5.58(m,1H),7.42(m,1H),7.70(m,2H),7.93(m,2H),8.24(m,2H), 8.50 (m, 1H), 8.84 (m, 2H), 11.30 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 431.2; found 432.2; Rt=0.859 min.

實例497. 外消旋-5-{2-[(2R,5S)-2-(3-氟-4-甲基苯基)-5-甲基哌哌-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物162)之合成Example 497. Racemic-5-{2-[(2R,5S)-2-(3-fluoro-4-methylphenyl)-5-methylpiperi-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 162)

Figure 110128222-A0202-12-1895-743
Figure 110128222-A0202-12-1895-743

藉由一般程序1製備。產率：8.6mg，6.17%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.34(m,1H),1.67(m,1H),1.89(m,1H),2.03(m,1H),2.21(m,4H),3.02(m,1H),3.75(m,1H),5.35(m,1H),7.08(m,2H),7.31(m,1H),7.61(m,1H),8.17(m,1H),8.48(m,1H),8.83(m,2H),11.25(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值398.2；實測值399.2；Rt=1.189min。Prepared by General Procedure 1. Yield: 8.6 mg, 6.17% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.34 (m, 1H), 1.67 (m, 1H), 1.89 (m, 1H) ,2.03(m,1H),2.21(m,4H),3.02(m,1H),3.75(m,1H),5.35(m,1H),7.08(m,2H),7.31(m,1H), 7.61 (m, 1H), 8.17 (m, 1H), 8.48 (m, 1H), 8.83 (m, 2H), 11.25 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 398.2; found 399.2; Rt=1.189 min.

實例498. 外消旋-5-{2-[(2R,5S)-2-(3,4-二甲基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物180)之合成Example 498. Racemic-5-{2-[(2R,5S)-2-(3,4-dimethylphenyl)-5-methylpiperidin-1-yl]-2-pendoxyl Synthesis of Acetamido}pyridine-3-carbamoylamine (Compound 180)

Figure 110128222-A0202-12-1895-744
Figure 110128222-A0202-12-1895-744

藉由一般程序1製備。產率：13.1mg，9.49%1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.01(m,3H),1.31(m,1H),1.66(m,1H),1.86(m,1H),2.03(m,1H),2.18(m,7H),3.08(m,1H),3.71(m,1H),5.31(m,1H),7.07(m,3H),7.58(m,1H),8.14(m,1H),8.46(m,1H),8.80(m,2H),11.20(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.2；Rt=1.274min。Prepared by General Procedure 1. Yield: 13.1 mg, 9.49% 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.01 (m, 3H), 1.31 (m, 1H), 1.66 (m, 1H), 1.86 (m, 1H) ,2.03(m,1H),2.18(m,7H),3.08(m,1H),3.71(m,1H),5.31(m,1H),7.07(m,3H),7.58(m,1H), 8.14 (m, 1H), 8.46 (m, 1H), 8.80 (m, 2H), 11.20 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.2; Rt=1.274 min.

實例499. 外消旋-5-{2-[(2R,5S)-2-(3-氯-4-甲基苯基)-5-甲基哌啶-1-基]-2-側氧Example 499. Racemic-5-{2-[(2R,5S)-2-(3-chloro-4-methylphenyl)-5-methylpiperidin-1-yl]-2-oxo 基乙醯胺基}吡啶-3-甲醯胺(化合物179)之合成Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 179)

Figure 110128222-A0202-12-1896-745
Figure 110128222-A0202-12-1896-745

藉由一般程序1製備。產率：25.4mg，17.49%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.34(m,1H),1.65(m,1H),1.90(m,1H),2.11(m,2H),2.31(m,3H),2.80(m,1H),3.48(m,1H),5.35(m,1H),7.21(m,1H),7.36(m,2H),7.61(d,1H),8.17(m,1H),8.48(m,1H),8.83(m,2H),11.26(s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.4；Rt=1.319min。Prepared by General Procedure 1. Yield: 25.4 mg, 17.49% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.34 (m, 1H), 1.65 (m, 1H), 1.90 (m, 1H) ,2.11(m,2H),2.31(m,3H),2.80(m,1H),3.48(m,1H),5.35(m,1H),7.21(m,1H),7.36(m,2H), 7.61 (d, 1H), 8.17 (m, 1H), 8.48 (m, 1H), 8.83 (m, 2H), 11.26 (s, 1H). LCMS (ESI): [M+H] + m/z: calculated 414.2; found 415.4; Rt=1.319 min.

實例500. 外消旋-5-{2-[(2R,5S)-2-(3,5-二氟苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物416)之合成Example 500. Racemic-5-{2-[(2R,5S)-2-(3,5-difluorophenyl)-5-methylpiperidin-1-yl]-2-side oxyethyl Synthesis of amido}pyridine-3-carboxamide (compound 416)

Figure 110128222-A0202-12-1896-746
Figure 110128222-A0202-12-1896-746

藉由一般程序1製備。產率：3.4mg,2.35%1 H NMR(500MHz,DMSO-d 6 )δ 0.99-1.08(m,3H),1.21-1.37(m,1H),1.60-1.75(m,1H),1.82-1.99(m,1H),2.07-2.22(m,1H),2.79-3.26(m,1H),3.52-4.11(m,1H),5.12-5.68(m,1H),6.95-7.11(m,2H),7.10-7.25(m,1H),7.45-7.65(m,2H),8.08-8.30(m,1H),8.37-8.60(m,1H),8.71-8.83(m,1H),8.83-9.02(m,1H),11.21-11.45(m,1H)。Prepared by General Procedure 1. Yield: 3.4 mg, 2.35% 1 H NMR (500 MHz, DMSO- d 6 ) δ 0.99-1.08 (m, 3H), 1.21-1.37 (m, 1H), 1.60-1.75 (m, 1H), 1.82-1.99 (m,1H), 2.07-2.22(m,1H), 2.79-3.26(m,1H), 3.52-4.11(m,1H), 5.12-5.68(m,1H), 6.95-7.11(m,2H) ,7.10-7.25(m,1H),7.45-7.65(m,2H),8.08-8.30(m,1H),8.37-8.60(m,1H),8.71-8.83(m,1H),8.83-9.02( m, 1H), 11.21-11.45 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值403.0；Rt=1.209min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 403.0; Rt=1.209 min.

實例501. 外消旋-5-{2-[(2R,5S)-2-(3,5-二氯苯基)-5-甲基哌啶-1-基]-2-側氧基乙Example 501. Racemic-5-{2-[(2R,5S)-2-(3,5-dichlorophenyl)-5-methylpiperidin-1-yl]-2-side oxyethyl 醯胺基}吡啶-3-甲醯胺(化合物206)之合成Synthesis of amido}pyridine-3-carboxamide (compound 206)

Figure 110128222-A0202-12-1897-747
Figure 110128222-A0202-12-1897-747

藉由一般程序1製備。產率：2.5mg，1.64%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.35(m,1H),1.65(m,1H),1.91(m,1H),2.15(m,2H),3.52(m,1H),3.87(m,1H),5.37(m,1H),7.36(m,2H),7.58(m,2H),8.17(m,1H),8.51(m,1H),8.83(m,2H),11.31(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=1.377min。Prepared by General Procedure 1. Yield: 2.5 mg, 1.64% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.35 (m, 1H), 1.65 (m, 1H), 1.91 (m, 1H) ,2.15(m,2H),3.52(m,1H),3.87(m,1H),5.37(m,1H),7.36(m,2H),7.58(m,2H),8.17(m,1H), 8.51 (m, 1H), 8.83 (m, 2H), 11.31 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=1.377 min.

實例502. 外消旋-5-{2-[(2R,5S)-2-(3-胺基-4-氯苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物280)之合成Example 502. Racemic-5-{2-[(2R,5S)-2-(3-amino-4-chlorophenyl)-5-methylpiperidin-1-yl]-2-oxygen Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 280)

Figure 110128222-A0202-12-1897-748
Figure 110128222-A0202-12-1897-748

藉由一般程序1製備。產率：4.9mg，3.37%1 H NMR(600MHz,DMSO-d 6 )δ 0.92-1.06(m,3H),1.25-1.37(m,1H),1.64-1.75(m,1H),1.81-1.95(m,1H),1.95-2.12(m,2H),2.81-3.25(m,1H),3.46-4.03(m,1H),5.02-5.29(m,1H),5.29-5.51(m,2H),6.45-6.54(m,1H),6.73-6.83(m,1H),7.11-7.20(m,1H),7.52-7.63(m,1H),8.08-8.21(m,1H),8.43-8.53(m,1H),8.71-8.79(m,1H),8.83-8.93(m,1H),10.73-11.52(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值415.2；實測值416.2；Rt=1.199min。Prepared by General Procedure 1. Yield: 4.9 mg, 3.37% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.92-1.06 (m, 3H), 1.25-1.37 (m, 1H), 1.64-1.75 (m, 1H), 1.81-1.95 (m,1H),1.95-2.12(m,2H),2.81-3.25(m,1H),3.46-4.03(m,1H),5.02-5.29(m,1H),5.29-5.51(m,2H) ,6.45-6.54(m,1H),6.73-6.83(m,1H),7.11-7.20(m,1H),7.52-7.63(m,1H),8.08-8.21(m,1H),8.43-8.53( m, 1H), 8.71-8.79 (m, 1H), 8.83-8.93 (m, 1H), 10.73-11.52 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 415.2; found 416.2; Rt=1.199 min.

實例503. 外消旋-5-{2-[(2R,5S)-2-(4-環丁基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物406)之合成Example 503. Racemic-5-{2-[(2R,5S)-2-(4-cyclobutylphenyl)-5-methylpiperidin-1-yl]-2-oxoacetyl Synthesis of amino}pyridine-3-carboxamide (compound 406)

Figure 110128222-A0202-12-1898-749
Figure 110128222-A0202-12-1898-749

藉由一般程序1製備。產率：27.1mg，15.5%1 H NMR(500MHz,DMSO)δ 1.01-1.06(m,3H),1.28-1.42(m,1H),1.66-1.75(m,1H),1.76-1.90(m,2H),1.91-2.04(m,2H),2.04-2.15(m,3H),2.18-2.34(m,3H),2.80-3.29(m,1H),3.50-4.06(m,1H),5.12-5.65(m,1H),7.22-7.31(m,4H),7.55-7.70(m,1H),8.05-8.28(m,1H),8.45-8.58(m,1H),8.75-8.85(m,1H),8.85-8.97(m,1H),11.09-11.39(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=1.420min。Prepared by General Procedure 1. Yield: 27.1 mg, 15.5% 1 H NMR (500 MHz, DMSO) δ 1.01-1.06 (m, 3H), 1.28-1.42 (m, 1H), 1.66-1.75 (m, 1H), 1.76-1.90 (m, 2H), 1.91-2.04(m, 2H), 2.04-2.15(m, 3H), 2.18-2.34(m, 3H), 2.80-3.29(m, 1H), 3.50-4.06(m, 1H), 5.12- 5.65(m,1H),7.22-7.31(m,4H),7.55-7.70(m,1H),8.05-8.28(m,1H),8.45-8.58(m,1H),8.75-8.85(m,1H ), 8.85-8.97 (m, 1H), 11.09-11.39 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=1.420 min.

實例504. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[4-(三氟甲基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物251)之合成Example 504. Racemic-5-{2-[(2R,5S)-5-methyl-2-[4-(trifluoromethyl)phenyl]piperidin-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 251)

Figure 110128222-A0202-12-1898-750
Figure 110128222-A0202-12-1898-750

藉由一般程序1製備。產率：3.4mg，2.27%1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.07(m,3H),1.27-1.40(m,1H),1.57-1.68(m,1H),1.82-1.96(m,1H),2.05-2.18(m,1H),2.19-2.31(m,1H),2.73-3.25(m,1H),3.46-4.12(m, 1H),5.18-5.80(m,1H),7.50-7.57(m,2H),7.58-7.65(m,1H),7.69-7.79(m,2H),8.07-8.23(m,1H),8.41-8.55(m,1H),8.71-8.80(m,1H),8.81-8.95(m,1H),11.16-11.33(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值434.2；實測值435.0；Rt=1.366min。Prepared by General Procedure 1. Yield: 3.4 mg, 2.27% 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.96-1.07 (m, 3H), 1.27-1.40 (m, 1H), 1.57-1.68 (m, 1H), 1.82-1.96 (m,1H),2.05-2.18(m,1H),2.19-2.31(m,1H),2.73-3.25(m,1H),3.46-4.12(m,1H),5.18-5.80(m,1H) ,7.50-7.57(m,2H),7.58-7.65(m,1H),7.69-7.79(m,2H),8.07-8.23(m,1H),8.41-8.55(m,1H),8.71-8.80( m, 1H), 8.81-8.95 (m, 1H), 11.16-11.33 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 434.2; found 435.0; Rt=1.366 min.

實例505. 外消旋-5-{2-[(2R,5S)-2-(4-甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物228)之合成Example 505. Racemic-5-{2-[(2R,5S)-2-(4-methoxyphenyl)-5-methylpiperidin-1-yl]-2-pendoxetylacetone Synthesis of Amino}pyridine-3-carboxamide (Compound 228)

Figure 110128222-A0202-12-1899-751
Figure 110128222-A0202-12-1899-751

藉由一般程序1製備。產率：2.1mg，1.51%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.35(m,1H),1.80(m,3H),2.02(m,1H),2.19(m,1H),3.64(m,4H),5.34(m,1H),6.95(m,2H),7.26(m,2H),7.61(m,1H),8.16(m,1H),8.48(m,1H),8.77(m,1H),8.89(m,1H),11.26(s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=1.195min。Prepared by General Procedure 1. Yield: 2.1 mg, 1.51% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.35 (m, 1H), 1.80 (m, 3H), 2.02 (m, 1H) ,2.19(m,1H),3.64(m,4H),5.34(m,1H),6.95(m,2H),7.26(m,2H),7.61(m,1H),8.16(m,1H), 8.48 (m, 1H), 8.77 (m, 1H), 8.89 (m, 1H), 11.26 (s, 1H). LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=1.195 min.

實例506. 外消旋-5-{2-[(2R,5S)-2-(3,5-二甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物428)之合成Example 506. Racemic-5-{2-[(2R,5S)-2-(3,5-dimethoxyphenyl)-5-methylpiperidin-1-yl]-2-oxygen Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 428)

Figure 110128222-A0202-12-1899-752
Figure 110128222-A0202-12-1899-752

藉由一般程序1製備。產率：14.7mg，7.2%1 H NMR(500MHz,DMSO-d 6 )δ 0.91-1.10(m,3H),1.28-1.41(m,1H),1.62-1.75(m,1H),1.84-1.97 (m,1H),1.99-2.11(m,1H),2.14-2.24(m,1H),2.83-3.20(m,1H),3.44-3.52(m,0.7H),3.68-3.80(m,6H),3.97-4.07(m,0.3H),5.08-5.61(m,1H),6.33-6.55(m,3H),7.55-7.69(m,1H),8.11-8.23(m,1H),8.42-8.55(m,1H),8.73-8.82(m,1H),8.83-8.93(m,1H),11.18-11.42(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值426.2；實測值427.0；Rt=3.024min。Prepared by General Procedure 1. Yield: 14.7 mg, 7.2% 1 H NMR (500 MHz, DMSO- d 6 ) δ 0.91-1.10 (m, 3H), 1.28-1.41 (m, 1H), 1.62-1.75 (m, 1H), 1.84-1.97 (m,1H),1.99-2.11(m,1H),2.14-2.24(m,1H),2.83-3.20(m,1H),3.44-3.52(m,0.7H),3.68-3.80(m,6H ),3.97-4.07(m,0.3H),5.08-5.61(m,1H),6.33-6.55(m,3H),7.55-7.69(m,1H),8.11-8.23(m,1H),8.42- 8.55 (m, 1H), 8.73-8.82 (m, 1H), 8.83-8.93 (m, 1H), 11.18-11.42 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 426.2; found 427.0; Rt=3.024 min.

實例507. 外消旋-5-{2-[(2R,5S)-2-(2-甲氧基吡啶-4-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物225)之合成Example 507. Racemic-5-{2-[(2R,5S)-2-(2-methoxypyridin-4-yl)-5-methylpiperidin-1-yl]-2-oxo Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 225)

Figure 110128222-A0202-12-1900-753
Figure 110128222-A0202-12-1900-753

藉由一般程序1製備。產率：1.3mg，0.94% LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值398.2；Rt=1.088min。Prepared by General Procedure 1. Yield: 1.3 mg, 0.94% LCMS (ESI): [M+H] + m/z: calcd. 397.2; found 398.2; Rt=1.088 min.

實例508. 外消旋-5-{2-[(2R,5S)-2-(4-胺甲醯基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物220)之合成Example 508. Racemic-5-{2-[(2R,5S)-2-(4-aminocarbamoylphenyl)-5-methylpiperidin-1-yl]-2-side oxyethyl Synthesis of amido}pyridine-3-carboxamide (compound 220)

Figure 110128222-A0202-12-1900-754
Figure 110128222-A0202-12-1900-754

藉由一般程序1製備。產率：16.7mg，11.65%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.04(m,3H),1.38(m,1H),1.66(m,1H),1.89(m,1H),2.17(m,2H),3.02(m,1H),3.79(m,1H),5.43(m,1H),7.40(m,3H),7.61(m,1H),7.89(m,2H),7.97(m,1H),8.17(m,1H),8.49(m,1H),8.78(m,1H),8.89(m,1H),11.27(m,1H)。Prepared by General Procedure 1. Yield: 16.7 mg, 11.65% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.04 (m, 3H), 1.38 (m, 1H), 1.66 (m, 1H), 1.89 (m, 1H) ,2.17(m,2H),3.02(m,1H),3.79(m,1H),5.43(m,1H),7.40(m,3H),7.61(m,1H),7.89(m,2H), 7.97(m,1H), 8.17(m,1H), 8.49(m,1H), 8.78(m,1H), 8.89(m,1H), 11.27(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.2；Rt=0.944min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.2; Rt=0.944 min.

實例509. 外消旋-5-{2-[(2R,5S)-2-(3-甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物214)之合成Example 509. Racemic-5-{2-[(2R,5S)-2-(3-methoxyphenyl)-5-methylpiperidin-1-yl]-2-oxoacetone Synthesis of amino}pyridine-3-carboxamide (compound 214)

Figure 110128222-A0202-12-1901-755
Figure 110128222-A0202-12-1901-755

藉由一般程序1製備。產率：19.1mg,13.76%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.04(m,3H),1.34(m,1H),1.68(m,1H),1.90(m,1H),2.14(m,3H),3.66(m,4H),5.36(m,1H),6.89(m,3H),7.33(m,1H),7.61(m,1H),8.17(m,1H),8.49(m,1H),8.83(m,2H),11.27(s,1H)。LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=1.177min。Prepared by General Procedure 1. Yield: 19.1 mg, 13.76% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.04 (m, 3H), 1.34 (m, 1H), 1.68 (m, 1H), 1.90 (m, 1H) ,2.14(m,3H),3.66(m,4H),5.36(m,1H),6.89(m,3H),7.33(m,1H),7.61(m,1H),8.17(m,1H), 8.49 (m, 1H), 8.83 (m, 2H), 11.27 (s, 1H). LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=1.177 min.

實例510. 外消旋-5-{2-[(2R,5S)-2-(3-氟-4-甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物208)之合成Example 510. Racemic-5-{2-[(2R,5S)-2-(3-fluoro-4-methoxyphenyl)-5-methylpiperidin-1-yl]-2-side Synthesis of Oxyacetamido}pyridine-3-carbamoylamine (Compound 208)

Figure 110128222-A0202-12-1901-756
Figure 110128222-A0202-12-1901-756

藉由一般程序1製備。產率：24.1mg，16.61%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.34(m,1H),1.68(m,1H),1.89(m,1H),2.10(m,2H),2.79(m,1H),3.70(m,4H),5.32(m,1H),7.15(m,3H),7.61(m,1H),8.17(m,1H),8.48(m,1H),8.78(m,1H),8.89(m,1H),11.25(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值414.2；實測值415.2；Rt=1.181min。Prepared by General Procedure 1. Yield: 24.1 mg, 16.61% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.34 (m, 1H), 1.68 (m, 1H), 1.89 (m, 1H) , 2.10(m, 2H), 2.79(m, 1H), 3.70(m, 4H), 5.32(m, 1H), 7.15(m, 3H), 7.61(m, 1H), 8.17(m, 1H), 8.48 (m, 1H), 8.78 (m, 1H), 8.89 (m, 1H), 11.25 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 414.2; found 415.2; Rt=1.181 min.

實例511. 外消旋-5-{2-[(2R,5S)-2-(3,4-二甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物230)之合成Example 511. Racemic-5-{2-[(2R,5S)-2-(3,4-dimethoxyphenyl)-5-methylpiperidin-1-yl]-2-oxygen Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 230)

Figure 110128222-A0202-12-1902-757
Figure 110128222-A0202-12-1902-757

藉由一般程序1製備。產率：12.4mg，8.31%1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.03(m,3H),1.35(m,1H),1.72(m,1H),1.89(m,1H),2.07(m,1H),2.20(m,1H),2.97(m,1H),3.74(m,7H),5.33(m,1H),6.91(m,3H),7.61(m,1H),8.17(m,1H),8.49(m,1H),8.77(m,1H),8.88(m,1H),11.25(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值426.2；實測值427.2；Rt=1.142min。Prepared by General Procedure 1. Yield: 12.4 mg, 8.31% 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 1.03 (m, 3H), 1.35 (m, 1H), 1.72 (m, 1H), 1.89 (m, 1H) ,2.07(m,1H),2.20(m,1H),2.97(m,1H),3.74(m,7H),5.33(m,1H),6.91(m,3H),7.61(m,1H), 8.17 (m, 1H), 8.49 (m, 1H), 8.77 (m, 1H), 8.88 (m, 1H), 11.25 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 426.2; found 427.2; Rt=1.142 min.

實例512. 外消旋-5-{2-[(2R,5S)-2-(3-氯苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物174)之合成Example 512. Racemic-5-{2-[(2R,5S)-2-(3-chlorophenyl)-5-methylpiperidin-1-yl]-2-oxyacetamido } Synthesis of pyridine-3-carboxamide (Compound 174)

Figure 110128222-A0202-12-1902-758
Figure 110128222-A0202-12-1902-758

藉由一般程序1製備。產率：5.7mg，4.06%1 H NMR(DMSO-d6,400MHz)：δ(ppm)1.04(m,3H),1.35(m,1H),1.66(m,1H),1.92(m,1H),2.14(m,2H),3.03(m,1H),3.78(m,1H),5.39(m,1H),7.39(m,4H),7.62(m,1H),8.18(m,1H),8.50(m,1H),8.84(m,2H),11.29(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值400.2；實測值401.2；Rt=1.250min。Prepared by General Procedure 1. Yield: 5.7 mg, 4.06% 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.04 (m, 3H), 1.35 (m, 1H), 1.66 (m, 1H), 1.92 (m, 1H) ,2.14(m,2H),3.03(m,1H),3.78(m,1H),5.39(m,1H),7.39(m,4H),7.62(m,1H),8.18(m,1H), 8.50 (m, 1H), 8.84 (m, 2H), 11.29 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 400.2; found 401.2; Rt=1.250 min.

實例513. 外消旋-5-{2-[(2R,5S)-2-(3-胺甲醯基苯基)-5-甲基哌啶-1-基]-2-側氧Example 513. Racemic-5-{2-[(2R,5S)-2-(3-aminocarbamoylphenyl)-5-methylpiperidin-1-yl]-2-oxygen 基乙醯胺基}吡啶-3-甲醯胺(化合物125)之合成Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 125)

Figure 110128222-A0202-12-1903-759
Figure 110128222-A0202-12-1903-759

藉由一般程序製備。產率：2.9mg，2.02%Prepared by general procedure. Yield: 2.9mg, 2.02%

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.4；Rt=2.455min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.4; Rt=2.455 min.

實例514. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[4-(環氧乙烷-4-基氧基)苯基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物269)之合成Example 514. Racemic-5-{2-[(2R,5S)-5-methyl-2-[4-(oxiran-4-yloxy)phenyl]piperidin-1-yl Synthesis of ]-2-oxyacetamido}pyridine-3-carboxamide (Compound 269)

Figure 110128222-A0202-12-1903-760
Figure 110128222-A0202-12-1903-760

藉由一般程序製備。產率：8.1mg，4.96%Prepared by general procedure. Yield: 8.1 mg, 4.96%

1 H NMR(600MHz,DMSO-d6 )δ 0.98-1.03(m,3H),1.27-1.36(m,1H),1.49-1.57(m,2H),1.65-1.73(m,1H),1.79-1.89(m,1H),1.90-1.97(m,2H),1.98-2.12(m,1H),2.14-2.22(m,1H),2.79-3.21(m,1H),3.40-3.49(m,3H),3.80-3.98(m,2H),4.48-4.59(m,1H),5.02-5.60(m,1H),6.92-7.00(m,2H),7.18-7.28(m,2H),7.55-7.66(m,1H),8.10-8.21(m,1H),8.41-8.53(m,1H),8.67-8.80(m,1H),8.81-8.93(m,1H),11.08-11.35(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.98-1.03(m,3H), 1.27-1.36(m,1H), 1.49-1.57(m,2H), 1.65-1.73(m,1H), 1.79- 1.89(m,1H),1.90-1.97(m,2H),1.98-2.12(m,1H),2.14-2.22(m,1H),2.79-3.21(m,1H),3.40-3.49(m,3H ),3.80-3.98(m,2H),4.48-4.59(m,1H),5.02-5.60(m,1H),6.92-7.00(m,2H),7.18-7.28(m,2H),7.55-7.66 (m,1H),8.10-8.21(m,1H),8.41-8.53(m,1H),8.67-8.80(m,1H),8.81-8.93(m,1H),11.08-11.35(m,1H) .

LCMS(ESI)：[M+H]+ m/z：計算值466.2；實測值467.2；Rt=3.057min。LCMS (ESI): [M+H] + m/z: calculated 466.2; found 467.2; Rt=3.057 min.

實例515. 外消旋-5-{2-[(2R,5S)-2-(5-氟吡啶-3-基)-5-甲基哌啶-1-基]-2-側氧基Example 515. Racemic-5-{2-[(2R,5S)-2-(5-fluoropyridin-3-yl)-5-methylpiperidin-1-yl]-2-pendoxyl 乙醯胺基}吡啶-3-甲醯胺(化合物248)之合成Synthesis of Acetamido}pyridine-3-carbamoylamine (Compound 248)

Figure 110128222-A0202-12-1904-761
Figure 110128222-A0202-12-1904-761

藉由一般程序製備。產率：7.3mg，5.41%Prepared by general procedure. Yield: 7.3 mg, 5.41%

1 H NMR(600MHz,DMSO-d 6 )δ 0.84-1.09(m,3H),1.28-1.40(m,1H),1.61-1.74(m,1H),1.84-1.97(m,1H),2.01-2.18(m,1H),2.18-2.32(m,1H),2.76-3.26(m,1H),3.46-4.08(m,1H),5.25-5.76(m,1H),7.56-7.64(m,1H),7.64-7.73(m,1H),8.15(d,1H),8.42-8.53(m,3H),8.70-8.80(m,1H),8.82-8.93(m,1H),11.20-11.31(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.84-1.09(m,3H), 1.28-1.40(m,1H), 1.61-1.74(m,1H), 1.84-1.97(m,1H), 2.01- 2.18(m,1H),2.18-2.32(m,1H),2.76-3.26(m,1H),3.46-4.08(m,1H),5.25-5.76(m,1H),7.56-7.64(m,1H) ), 7.64-7.73(m, 1H), 8.15(d, 1H), 8.42-8.53(m, 3H), 8.70-8.80(m, 1H), 8.82-8.93(m, 1H), 11.20-11.31(m , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值385.3；實測值386.1；Rt=1.031min。LCMS (ESI): [M+H] + m/z: calculated 385.3; found 386.1; Rt=1.031 min.

實例516. 外消旋-5-{2-[(2R,5S)-5-甲基-2-(喹啉-3-基)哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物257)之合成Example 516. Racemic-5-{2-[(2R,5S)-5-methyl-2-(quinolin-3-yl)piperidin-1-yl]-2-oxoacetamide Synthesis of pyridine-3-carboxamide (Compound 257)

Figure 110128222-A0202-12-1904-762
Figure 110128222-A0202-12-1904-762

藉由一般程序製備。產率：6.6mg，4.52%Prepared by general procedure. Yield: 6.6 mg, 4.52%

1 H NMR(600MHz,DMSO-d 6 )δ 0.82-1.13(m,3H),1.31-1.50(m,1H),1.71-1.81(m,1H),1.85-1.99(m,1H),2.06-2.34(m,1H),2.65-3.23(m,1H),3.32-3.38(m,1H),3.56-4.11(m,1H),5.39-5.97(m,1H),7.47-7.64(m,2H),7.69-7.79(m,1H),7.96-8.03(m,2H),8.07-8.19(m,1H),8.26-8.34(m,1H),8.38-8.55(m,1H),8.64 -8.79(m,1H),8.79-8.88(m,1H),8.88-8.94(m,1H),11.03-11.68(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.82-1.13(m,3H), 1.31-1.50(m,1H), 1.71-1.81(m,1H), 1.85-1.99(m,1H), 2.06- 2.34(m,1H), 2.65-3.23(m,1H), 3.32-3.38(m,1H), 3.56-4.11(m,1H), 5.39-5.97(m,1H), 7.47-7.64(m,2H ),7.69-7.79(m,1H),7.96-8.03(m,2H),8.07-8.19(m,1H),8.26-8.34(m,1H),8.38-8.55(m,1H),8.64-8.79 (m, 1H), 8.79-8.88 (m, 1H), 8.88-8.94 (m, 1H), 11.03-11.68 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值417.2；實測值418.0；Rt=1.045min。LCMS (ESI): [M+H] + m/z: calculated 417.2; found 418.0; Rt=1.045 min.

實例517. 外消旋-5-{2-[(2R,5S)-2-{咪唑并[1,2-a]吡啶-6-基}-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物234)之合成Example 517. Racemic-5-{2-[(2R,5S)-2-{imidazo[1,2-a]pyridin-6-yl}-5-methylpiperidin-1-yl]- Synthesis of 2-oxyacetamido}pyridine-3-carboxamido (Compound 234)

Figure 110128222-A0202-12-1905-763
Figure 110128222-A0202-12-1905-763

藉由一般程序製備。產率：6.7mg，4.71%Prepared by general procedure. Yield: 6.7mg, 4.71%

1 H NMR(600MHz,DMSO-d 6 )δ 0.95-1.15(m,3H),1.30-1.47(m,1H),1.80-2.01(m,2H),2.02-2.24(m,2H),2.83-3.27(m,1H),3.46-4.07(m,1H),5.15-5.76(m,1H),6.86-7.27(m,1H),7.51-7.64(m,3H),7.87-7.96(m,1H),8.08-8.21(m,1H),8.44-8.58(m,2H),8.71-8.79(m,1H),8.81-8.94(m,1H),11.25(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.95-1.15(m,3H), 1.30-1.47(m,1H), 1.80-2.01(m,2H), 2.02-2.24(m,2H), 2.83- 3.27(m,1H),3.46-4.07(m,1H),5.15-5.76(m,1H),6.86-7.27(m,1H),7.51-7.64(m,3H),7.87-7.96(m,1H) ), 8.08-8.21(m, 1H), 8.44-8.58(m, 2H), 8.71-8.79(m, 1H), 8.81-8.94(m, 1H), 11.25(br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值406.2；實測值407.1；Rt=0.800min。LCMS (ESI): [M+H] + m/z: calculated 406.2; found 407.1; Rt=0.800 min.

實例518. 外消旋-5-{2-[(2R,5S)-5-甲基-2-{[1,2,4]三唑并[4,3-a]吡啶-6-基}哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物272)之合成Example 518. Racemic-5-{2-[(2R,5S)-5-methyl-2-{[1,2,4]triazolo[4,3-a]pyridin-6-yl} Synthesis of piperidin-1-yl]-2-oxoacetamido}pyridine-3-carboxamido (compound 272)

Figure 110128222-A0202-12-1905-764
Figure 110128222-A0202-12-1905-764

藉由一般程序製備。產率：5.2mg，3.65%Prepared by general procedure. Yield: 5.2mg, 3.65%

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.07(m,3H),1.31-1.42(m,1H),1.81-1.96 (m,2H),2.05-2.20(m,2H),2.74-3.15(m,1H),3.50-4.07(m,1H),5.17-5.64(m,1H),7.23-7.48(m,1H),7.49-7.62(m,1H),7.74-7.86(m,1H),8.06-8.18(m,1H),8.37-8.49(m,1H),8.52-8.59(m,1H),8.64-8.75(m,1H),8.76-8.92(m,1H),9.15-9.23(m,1H),11.24(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.07(m,3H), 1.31-1.42(m,1H), 1.81-1.96(m,2H), 2.05-2.20(m,2H), 2.74- 3.15(m,1H),3.50-4.07(m,1H),5.17-5.64(m,1H),7.23-7.48(m,1H),7.49-7.62(m,1H),7.74-7.86(m,1H) ),8.06-8.18(m,1H),8.37-8.49(m,1H),8.52-8.59(m,1H),8.64-8.75(m,1H),8.76-8.92(m,1H),9.15-9.23 (m, 1H), 11.24 (br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.2；Rt=2.016min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.2; Rt=2.016 min.

實例519. 外消旋-5-{2-[(2R,5S)-2-(2,3-二氫-1-苯并呋喃-5-基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物282)之合成Example 519. Racemic-5-{2-[(2R,5S)-2-(2,3-dihydro-1-benzofuran-5-yl)-5-methylpiperidin-1-yl Synthesis of ]-2-oxoacetamido}pyridine-3-carboxamide (Compound 282)

Figure 110128222-A0202-12-1906-765
Figure 110128222-A0202-12-1906-765

藉由一般程序製備。產率：7.3mg，5.11%Prepared by general procedure. Yield: 7.3 mg, 5.11%

1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.06(m,3H),1.25-1.37(m,1H),1.67-1.79(m,1H),1.80-1.94(m,1H),1.98-2.11(m,1H),2.12-2.23(m,1H),2.81-3.11(m,1H),3.13-3.24(m,2H),3.42-3.98(m,1H),4.44-4.53(m,2H),4.96-5.66(m,1H),6.65-6.82(m,1H),6.98-7.08(m,1H),7.13-7.24(m,1H),7.53-7.66(m,1H),8.07-8.23(m,1H),8.41-8.54(m,1H),8.71-8.79(m,1H),8.79-8.96(m,1H),11.05-11.31(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.96-1.06(m,3H), 1.25-1.37(m,1H), 1.67-1.79(m,1H), 1.80-1.94(m,1H), 1.98- 2.11(m,1H), 2.12-2.23(m,1H), 2.81-3.11(m,1H), 3.13-3.24(m,2H), 3.42-3.98(m,1H), 4.44-4.53(m,2H) ),4.96-5.66(m,1H),6.65-6.82(m,1H),6.98-7.08(m,1H),7.13-7.24(m,1H),7.53-7.66(m,1H),8.07-8.23 (m, 1H), 8.41-8.54 (m, 1H), 8.71-8.79 (m, 1H), 8.79-8.96 (m, 1H), 11.05-11.31 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值408.2；實測值409.4；Rt=2.925min。LCMS (ESI): [M+H] + m/z: calculated 408.2; found 409.4; Rt=2.925 min.

實例520. 外消旋-5-{2-[(2R,5S)-5-甲基-2-{1-甲基-1H-吡唑并[4,3-b]吡啶-6-基}哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物178)之合成Example 520. Racemic-5-{2-[(2R,5S)-5-methyl-2-{1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl} Synthesis of piperidin-1-yl]-2-oxoacetamido}pyridine-3-carboxamido (compound 178)

Figure 110128222-A0202-12-1907-766
Figure 110128222-A0202-12-1907-766

藉由一般程序製備。產率：14.1mg，9.56%Prepared by general procedure. Yield: 14.1 mg, 9.56%

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.04(m,3H),1.37(m,1H),1.78(m,1H),1.91(m,1H),2.18(m,1H),2.33(m,1H),2.95(m,1H),3.46(m,1H),4.07(m,3H),5.57(m,1H),7.58(m,1H),8.16(m,3H),8.48(m,2H),8.80(m,2H),11.24(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.04(m, 3H), 1.37(m, 1H), 1.78(m, 1H), 1.91(m, 1H), 2.18(m, 1H), 2.33(m, 1H), 2.95(m, 1H), 3.46(m, 1H), 4.07(m, 3H), 5.57(m, 1H), 7.58(m, 1H), 8.16(m, 3H), 8.48 (m, 2H), 8.80 (m, 2H), 11.24 (m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.0；Rt=1.003min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.0; Rt=1.003 min.

實例521. 外消旋-5-{2-[(2R,5S)-5-甲基-2-(8-甲基喹啉-3-基)哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物215)之合成Example 521. Racemic-5-{2-[(2R,5S)-5-methyl-2-(8-methylquinolin-3-yl)piperidin-1-yl]-2-oxygen Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 215)

Figure 110128222-A0202-12-1907-767
Figure 110128222-A0202-12-1907-767

藉由一般程序製備。產率：3.8mg，2.52%Prepared by general procedure. Yield: 3.8mg, 2.52%

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.07(m,3H),1.42(m,1H),1.79(m,1H),1.94(m,1H),2.22(m,1H),2.38(m,2H),2.72(m,3H),3.82(m,1H),5.64(m,1H),7.51(m,1H),7.61(m,2H),7.83(m,1H),8.24(m,2H),8.49(m,1H),8.77(m,1H),8.90(m,2H),11.29(m,1H) 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.07(m, 3H), 1.42(m, 1H), 1.79(m, 1H), 1.94(m, 1H), 2.22(m, 1H), 2.38(m, 2H), 2.72(m, 3H), 3.82(m, 1H), 5.64(m, 1H), 7.51(m, 1H), 7.61(m, 2H), 7.83(m, 1H), 8.24 (m, 2H), 8.49 (m, 1H), 8.77 (m, 1H), 8.90 (m, 2H), 11.29 (m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值431.2；實測值432.2；Rt=1.137min。LCMS (ESI): [M+H] + m/z: calculated 431.2; found 432.2; Rt=1.137 min.

實例522. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[5-(1H-吡唑-1-基)吡啶-3-基]哌啶-1-Example 522. Racemic-5-{2-[(2R,5S)-5-methyl-2-[5-(1H-pyrazol-1-yl)pyridin-3-yl]piperidin-1- 基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物226)之合成[Synthesis of]-2-oxoacetamido}pyridine-3-carboxamido (Compound 226)

Figure 110128222-A0202-12-1908-768
Figure 110128222-A0202-12-1908-768

藉由一般程序製備。產率：20.5mg，13.51%Prepared by general procedure. Yield: 20.5mg, 13.51%

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.06(m,3H),1.38(m,1H),1.72(m,1H),1.96(m,1H),2.22(m,2H),3.40(m,1H),3.75(m,1H),5.53(m,1H),6.62(m,1H),7.61(m,1H),7.83(m,1H),8.17(m,2H),8.50(m,2H),8.64(m,1H),8.78(m,1H),8.88(m,1H),9.03(m,1H),11.29(m,1H) 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.06(m, 3H), 1.38(m, 1H), 1.72(m, 1H), 1.96(m, 1H), 2.22(m, 2H), 3.40(m, 1H), 3.75(m, 1H), 5.53(m, 1H), 6.62(m, 1H), 7.61(m, 1H), 7.83(m, 1H), 8.17(m, 2H), 8.50 (m, 2H), 8.64 (m, 1H), 8.78 (m, 1H), 8.88 (m, 1H), 9.03 (m, 1H), 11.29 (m, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值433.2；實測值434.2；Rt=1.031min。LCMS (ESI): [M+H] + m/z: calculated 433.2; found 434.2; Rt=1.031 min.

實例523. 外消旋-5-{2-[(2R,5S)-5-甲基-2-[2-(三氟甲基)吡啶-4-基]哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物221)之合成Example 523. Racemic-5-{2-[(2R,5S)-5-methyl-2-[2-(trifluoromethyl)pyridin-4-yl]piperidin-1-yl]-2 -Synthesis of Pendant Oxyacetamido}pyridine-3-Carboxamide (Compound 221)

Figure 110128222-A0202-12-1908-769
Figure 110128222-A0202-12-1908-769

藉由一般程序製備。產率：19.2mg，12.60%Prepared by general procedure. Yield: 19.2 mg, 12.60%

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.04(m,3H),1.36(m,1H),1.58(m,1H),1.92(m,1H),2.23(m,2H),2.80(m,1H),3.83(m,1H),5.49(m,1H),7.65(m,2H),7.79(m,1H),8.17(d,1H),8.49(m,1H),8.81(m,3H),11.33(s,1H)。 1 H NMR (DMSO-d6, 500MHz): δ (ppm) 1.04 (m, 3H), 1.36 (m, 1H), 1.58 (m, 1H), 1.92 (m, 1H), 2.23 (m, 2H), 2.80(m, 1H), 3.83(m, 1H), 5.49(m, 1H), 7.65(m, 2H), 7.79(m, 1H), 8.17(d, 1H), 8.49(m, 1H), 8.81 (m, 3H), 11.33 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值435.2；實測值436.2；Rt=1.173min。LCMS (ESI): [M+H] + m/z: calculated 435.2; found 436.2; Rt=1.173 min.

實例524. 外消旋-5-{2-[(2R,5S)-2-[4-(3,5-二甲基-1H-吡唑-1-基)苯基]-5-甲基哌Example 524. Racemic-5-{2-[(2R,5S)-2-[4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]-5-methyl Piper 啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物157)之合成Synthesis of pyridin-1-yl]-2-oxoacetamido}pyridine-3-carboxamide (compound 157)

Figure 110128222-A0202-12-1909-770
Figure 110128222-A0202-12-1909-770

藉由一般程序製備。產率：15.5mg，9.62%Prepared by general procedure. Yield: 15.5mg, 9.62%

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.06(m,3H),1.38(m,1H),1.72(m,1H),2.05(m,2H),2.17(m,3H),2.29(m,4H),2.98(m,1H),3.80(m,1H),5.86(m,2H),7.43(m,1H),7.50(m,3H),7.61(m,1H),8.17(m,1H),8.50(m,1H),8.78(m,1H),8.90(m,1H),11.26(m,1H)。 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.06(m, 3H), 1.38(m, 1H), 1.72(m, 1H), 2.05(m, 2H), 2.17(m, 3H), 2.29(m, 4H), 2.98(m, 1H), 3.80(m, 1H), 5.86(m, 2H), 7.43(m, 1H), 7.50(m, 3H), 7.61(m, 1H), 8.17 (m, 1H), 8.50 (m, 1H), 8.78 (m, 1H), 8.90 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值460.3；實測值461.2；Rt=1.129min。LCMS (ESI): [M+H] + m/z: calculated 460.3; found 461.2; Rt=1.129 min.

實例525. 外消旋-5-{2-[(2R,5S)-5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物403)之合成Example 525. Racemic-5-{2-[(2R,5S)-5-methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl]-2-oxygen Synthesis of Acetylamino}pyridine-3-carbamoylamine (Compound 403)

Figure 110128222-A0202-12-1909-771
Figure 110128222-A0202-12-1909-771

藉由一般程序製備。產率：2.2mg，1.45%Prepared by general procedure. Yield: 2.2mg, 1.45%

LCMS(ESI)：[M+H]+ m/z：計算值420.2；實測值421.2；Rt=1.247min。LCMS (ESI): [M+H] + m/z: calculated 420.2; found 421.2; Rt=1.247 min.

實例526. 外消旋-5-{2-[(2R,5S)-2-[4-(1-羥基環丁基)苯基]-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物259)之合成Example 526. Racemic-5-{2-[(2R,5S)-2-[4-(1-hydroxycyclobutyl)phenyl]-5-methylpiperidin-1-yl]-2- Synthesis of Pendant Oxyacetamido}Pyridine-3-Carboxamide (Compound 259)

Figure 110128222-A0202-12-1910-772
Figure 110128222-A0202-12-1910-772

藉由一般程序製備。產率：11.3mg，7.54%Prepared by general procedure. Yield: 11.3 mg, 7.54%

1 H NMR(600MHz,DMSO-d 6 )δ 0.74-1.07(m,3H),1.28-1.40(m,1H),1.55-1.74(m,2H),1.81-1.94(m,2H),1.97-2.17(m,1H),2.17-2.31(m,3H),2.31-2.37(m,2H),2.77-3.25(m,1H),3.44-4.05(m,1H),5.12-5.68(m,2H),7.24-7.34(m,2H),7.43-7.51(m,2H),7.53-7.65(m,1H),8.08-8.22(m,1H),8.42-8.55(m,1H),8.71-8.80(m,1H),8.81-8.94(m,1H),11.15-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.74-1.07(m,3H), 1.28-1.40(m,1H), 1.55-1.74(m,2H), 1.81-1.94(m,2H), 1.97- 2.17(m,1H), 2.17-2.31(m,3H), 2.31-2.37(m,2H), 2.77-3.25(m,1H), 3.44-4.05(m,1H), 5.12-5.68(m,2H) ),7.24-7.34(m,2H),7.43-7.51(m,2H),7.53-7.65(m,1H),8.08-8.22(m,1H),8.42-8.55(m,1H),8.71-8.80 (m, 1H), 8.81-8.94 (m, 1H), 11.15-11.34 (m, 1H).

LCMS(ESI)：[M+3H]+ m/z：計算值436.2；實測值439.2；Rt=1.201min。LCMS (ESI): [M+3H] + m/z: calculated 436.2; found 439.2; Rt=1.201 min.

LCMS(ESI)：[M+H]+ m/z：計算值416.2；實測值417.4；Rt=3.108min。LCMS (ESI): [M+H] + m/z: calculated 416.2; found 417.4; Rt=3.108 min.

實例527. 外消旋-5-{2-[(2R,5S)-2-(3-氰基-4-甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物237)之合成Example 527. Racemic-5-{2-[(2R,5S)-2-(3-cyano-4-methoxyphenyl)-5-methylpiperidin-1-yl]-2- Synthesis of Pendant Oxyacetamido}Pyridine-3-Carboxamide (Compound 237)

Figure 110128222-A0202-12-1910-773
Figure 110128222-A0202-12-1910-773

藉由一般程序製備。產率：8.5mg，5.76%Prepared by general procedure. Yield: 8.5mg, 5.76%

1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.07(m,3H),1.25-1.38(m,1H),1.59-1.68(m,1H),1.82-1.93(m,1H),2.00-2.11(m,1H),2.16-2.26(m,1H),2.78-3.23(m,1H),3.44-3.49(m,0.6H),3.86-3.92(m,3H),3.95-4.00(m,0.4H),4.98-5.61(m, 1H),7.19-7.31(m,1H),7.56-7.68(m,3H),8.10-8.20(m,1H),8.40-8.52(m,1H),8.70-8.79(m,1H),8.80-8.93(m,1H),11.18-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.96-1.07(m,3H), 1.25-1.38(m,1H), 1.59-1.68(m,1H), 1.82-1.93(m,1H), 2.00- 2.11(m, 1H), 2.16-2.26(m, 1H), 2.78-3.23(m, 1H), 3.44-3.49(m, 0.6H), 3.86-3.92(m, 3H), 3.95-4.00(m, 0.4H), 4.98-5.61(m, 1H), 7.19-7.31(m, 1H), 7.56-7.68(m, 3H), 8.10-8.20(m, 1H), 8.40-8.52(m, 1H), 8.70 -8.79(m, 1H), 8.80-8.93(m, 1H), 11.18-11.34(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值421.2；實測值422.2；Rt=2.961min。LCMS (ESI): [M+H] + m/z: calculated 421.2; found 422.2; Rt=2.961 min.

實例528. 外消旋-5-{2-[(2R,5S)-2-[5-甲氧基-6-(三氟甲基)吡啶-3-基]-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物223)之合成Example 528. Racemic-5-{2-[(2R,5S)-2-[5-methoxy-6-(trifluoromethyl)pyridin-3-yl]-5-methylpiperidine- Synthesis of 1-yl]-2-oxyacetamido}pyridine-3-carboxamide (Compound 223)

Figure 110128222-A0202-12-1911-774
Figure 110128222-A0202-12-1911-774

藉由一般程序製備。產率：15.4mg，9.45%Prepared by general procedure. Yield: 15.4 mg, 9.45%

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.05(m,3H),1.36(m,1H),1.70(m,1H),1.94(m,1H),2.20(m,2H),3.50(m,2H),3.96(m,3H),5.48(m,1H),7.63(m,2H),8.22(m,2H),8.49(m,1H),8.83(m,2H),11.28(m,1H)。 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.05(m, 3H), 1.36(m, 1H), 1.70(m, 1H), 1.94(m, 1H), 2.20(m, 2H), 3.50(m, 2H), 3.96(m, 3H), 5.48(m, 1H), 7.63(m, 2H), 8.22(m, 2H), 8.49(m, 1H), 8.83(m, 2H), 11.28 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值465.2；實測值466.2；Rt=1.193min。LCMS (ESI): [M+H] + m/z: calculated 465.2; found 466.2; Rt=1.193 min.

實例529. 外消旋-5-{2-[(2R,5S)-2-(4-氯-3-甲氧基苯基)-5-甲基哌啶-1-基]-2-側氧基乙醯胺基}吡啶-3-甲醯胺(化合物114)之合成Example 529. Racemic-5-{2-[(2R,5S)-2-(4-chloro-3-methoxyphenyl)-5-methylpiperidin-1-yl]-2-side Synthesis of Oxyacetamido}pyridine-3-carbamoylamine (Compound 114)

Figure 110128222-A0202-12-1911-775
Figure 110128222-A0202-12-1911-775

藉由一般程序製備。產率：16mg，10.7%Prepared by general procedure. Yield: 16mg, 10.7%

1 H NMR(500MHz,CDCl3 )δ 1.11(m,3H),1.39(m,2H),2.00(m,2H),2.22(m,2H),3.46(m,1H),3.90(m,3H),4.43(m,1H),5.95(m,1H),6.84(m,2H),7.34(m,1H), 8.85(m,2H),9.50(m,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.11 (m, 3H), 1.39 (m, 2H), 2.00 (m, 2H), 2.22 (m, 2H), 3.46 (m, 1H), 3.90 (m, 3H) ), 4.43(m, 1H), 5.95(m, 1H), 6.84(m, 2H), 7.34(m, 1H), 8.85(m, 2H), 9.50(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值430.2；實測值431.2；Rt=3.356min。LCMS (ESI): [M+H] + m/z: calculated 430.2; found 431.2; Rt=3.356 min.

實例530. 2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1126)之合成Example 530. 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzene Synthesis of Thiazol-5-yl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 1126)

Figure 110128222-A0202-12-1912-776
Figure 110128222-A0202-12-1912-776

步驟1：2-甲氧基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazole Synthesis of -5-yl]-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide

向2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(489mg，2.04mmol)、2-(1-甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(500mg，1.37mmol，HCl)及HATU(856mg，2.25mmol)於DMF(5mL)中之混合物中添加DIPEA(1.1mL，6.32mmol)。將混合物在20℃下攪拌1小時。藉由製備型HPLC純化(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80×40mm×3μm；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內18%至48% B，保持100% B達2.0min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化混合物，以得到呈白色乾燥粉末之2-甲氧基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(240mg，31.9%產率)。LCMS(ESI)[M+H]+ m/z：計算值551.2；實測值551.3。To 2-[(5-aminocarbamoyl-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (489 mg, 2.04 mmol), 2-(1-methyl-4- piperidinyl)-5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (500 mg, 1.37 mmol, HCl) and HATU (856 mg, 2.25 mmol) in DMF ( To the mixture in 5 mL) was added DIPEA (1.1 mL, 6.32 mmol). The mixture was stirred at 20°C for 1 hour. Purification by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex Gemini-NX 80 x 40 mm x 3 μm; mobile phase A: with 10 mmol NH4HCO3 of H 2 O (v%); mobile phase B: MeCN; gradient: 18% to 48% B in 9.5min, hold 100% B for 2.0min; flow rate: 25mL/min; column temperature: 30°C; wavelength : 220 nm, 254 nm), the mixture was purified to give 2-methoxy-5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4- piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (240 mg, 31.9% yield Rate). LCMS (ESI) [M+H] + m/z: calcd 551.2; found 551.3.

步驟2：2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1126)之合成Step 2: 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzene Synthesis of Thiazol-5-yl]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (Compound 1126)

藉由掌性SFC(儀器：SFC-80Q；管柱：Daicel Chiralpak OD-H 250× 30mm I.D.5μm；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=40/60；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離2-甲氧基-5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(240mg，0.436mmol)，以得到化合物1126。By chiral SFC (instrument: SFC-80Q; column: Daicel Chiralpak OD-H 250×30 mm ID 5 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=40/ 60; flow rate: 80 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; dresser temperature: 25 °C; wavelength: 220 nm) separation of 2-methoxy Base-5-[[2-[(5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1 -Piperidinyl]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (240 mg, 0.436 mmol) to give compound 1126.

化合物1126：2-甲氧基-5-[[2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(160mg，66.7%產率，峰2，保留時間=2.600min，具有反式相對化學之單一已知鏡像異構物，白色乾燥粉末)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.35-8.73(m,2H),7.88-8.01(m,2H),7.39-7.50(m,1H),5.41-5.90(m,1H),3.93-4.19(m,4H),3.77(d,J =13.8Hz,1H),3.43(d,J =14.1Hz,1H),2.96-3.27(m,4H),2.13-2.43(m,10H),1.87-2.07(m,4H),1.46(d,J =12.3Hz,1H),1.14(d,J =7.0Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值551.2，實測值551.2；HPLC：在220nm下為98.13%，在254nm下為99.22%；99.7%ee。Compound 1126: 2-Methoxy-5-[[2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzene thiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (160 mg, 66.7% yield, peak 2, retention time = 2.600 min , a single known enantiomer with trans relative chemistry, white dry powder). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.35-8.73 (m, 2H), 7.88-8.01 (m, 2H), 7.39-7.50 (m, 1H), 5.41-5.90 (m, 1H), 3.93 -4.19(m,4H),3.77(d, J =13.8Hz,1H),3.43(d, J =14.1Hz,1H),2.96-3.27(m,4H),2.13-2.43(m,10H), 1.87-2.07(m, 4H), 1.46(d, J =12.3Hz, 1H), 1.14(d, J =7.0Hz, 3H); LCMS(ESI)[M+H] + m/z: Calculated 551.2 , the observed value is 551.2; HPLC: 98.13% at 220 nm, 99.22% at 254 nm; 99.7% ee.

實例531. 5-[[2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1255)之合成Example 531. 5-[[2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl Synthesis of ]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 1255)

Figure 110128222-A0202-12-1913-777
Figure 110128222-A0202-12-1913-777

步驟1：5-[[2-[(5S)-5-甲啶-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(5S)-5-Methidine-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]- Synthesis of 1-Piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide

將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(50.0mg，0.239mmol)、2-(1-甲基-4-哌啶基)-5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(50mg，0.152 mmol)、HATU(70mg，0.184mmol)及DIPEA(0.08mL，0.459mmol)於DMF(3mL)中之混合物在20℃下攪拌2小時。在減壓下濃縮混合物，以得到粗產物，其藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80 * 40mm * 3μm；流動相A：具有0.05% NH3 -H2 O+10mM NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內26%至56% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm、254nm)進行純化，以得到呈黃色油狀物之5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(40mg，50.6%產率)。LCMS(ESI)[M+H]+ m/z：計算值521.2，實測值521.2。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (50.0 mg, 0.239 mmol), 2-(1-methyl-4-piperidinyl)- 5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (50 mg, 0.152 mmol), HATU (70 mg, 0.184 mmol) and DIPEA (0.08 mL, 0.459 mmol) were added to The mixture in DMF (3 mL) was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to give crude product, which was purified by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex Gemini-NX 80*40mm* 3 μm; mobile phase A: H2O with 0.05% NH3 - H2O + 10 mM NH4HCO3 (v%); mobile phase B: MeCN; gradient: 26% to 56% B in 9.5 min, hold 100% B for 2 min; flow rate: 25 mL/min; column temperature: 30 °C; wavelength: 220 nm, 254 nm) for purification to obtain 5-[[2-[(5S)-5-methasone as a yellow oil Alkyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (40 mg, 50.6% yield). LCMS (ESI) [M+H] + m/z: calcd 521.2, found 521.2.

步驟2：5-[[2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物1255)之合成Step 2: 5-[[2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl Synthesis of ]-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 1255)

藉由SFC(儀器：Berger，Multigr AM-II；管柱：Daicel Chiralcel OD-H 250mm×30mm×5μm；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=50/50；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化5-[[2-[(5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(40mg，0.0768mmol)，以得到5-[[2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(21mg，具有反式相對化學之單一已知鏡像異構物，峰2，保留時間：6.929min，白色固體)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.32-9.17(m,3H),7.84-8.07(m,2H),7.46(br s,1H),5.44-5.89(m,1H),3.77-4.07(m,1H),3.46(br d,J =13.4Hz,2H),3.02-3.21(m,2H),2.18-2.43(m,9H),1.98(br s,4H),1.50(br s,1H),1.15(br d,J =6.6Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值521.2，實測值521.3；HPLC：在220nm下為100%，在254nm下為100%；100%ee，99.5%de。By SFC (instrument: Berger, Multigr AM-II; column: Daicel Chiralcel OD-H 250 mm×30 mm×5 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)= 50/50; flow rate: 80 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; dresser temperature: 25 °C; wavelength: 220 nm) Purification 5- [[2-[(5S)-5-Methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl ]-2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (40 mg, 0.0768 mmol) to give 5-[[2-[(2R,5S)-5-methyl-2- [2-(1-Methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (21 mg, single known enantiomer with trans relative chemistry, peak 2, retention time: 6.929 min, white solid). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.32-9.17 (m, 3H), 7.84-8.07 (m, 2H), 7.46 (br s, 1H), 5.44-5.89 (m, 1H), 3.77- 4.07(m,1H),3.46(br d, J =13.4Hz,2H),3.02-3.21(m,2H),2.18-2.43(m,9H),1.98(br s,4H),1.50(br s ,1H),1.15(br d, J =6.6Hz,3H); LCMS(ESI) [M+H] + m/z: calcd 521.2, found 521.3; HPLC: 100% at 220nm, at 254nm Below is 100%; 100%ee, 99.5%de.

實例532. 2-甲氧基-5-(2-((2R,5S )-5-甲基-2-(3-(4-甲基哌嗪-1-基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1277)之合成Example 532. 2-Methoxy-5-(2-(( 2R,5S )-5-methyl-2-(3-(4-methylpiperazin-1-yl)phenyl)piperidine-1 Synthesis of -yl)-2-oxyacetamido)nicotinamide (compound 1277)

Figure 110128222-A0202-12-1915-778
Figure 110128222-A0202-12-1915-778

將1-甲基-4-[3-[(2R,5S )-5-甲基-2-哌啶基]苯基]哌嗪(115mg，420.61μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(100.60mg，420.61μmol)及TEA(425.61mg，4.21mmol，586.24μL)一起混合於DMF(5mL)中。向其中添加HATU(239.89mg，630.91μmol)且將所得混合物在20℃下攪拌16h，然後提交至反相HPLC(2-10min 50-70% MeOH+NH3 流速30mL/min(裝載泵4mL MeOH)，管柱：sun fire c18)，以得到2-甲氧基-5-[[2-側氧基-2-[(2R,5S )-5-甲基-2-[3-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(64mg，129.40μmol，30.77%產率)。1-Methyl-4-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenyl]piperazine (115 mg, 420.61 μmol), 2-[(5-aminocarboxylate (100.60 mg, 420.61 μmol) and TEA (425.61 mg, 4.21 mmol, 586.24 μL) were mixed together in DMF (5 mL) . To this was added HATU (239.89 mg, 630.91 μmol) and the resulting mixture was stirred at 20 °C for 16 h before submitting to reverse phase HPLC (2-10 min 50-70% MeOH+NH 3 flow rate 30 mL/min (load pump 4 mL MeOH) , column: sun fire c18) to obtain 2-methoxy-5-[[2-oxy-2-[( 2R,5S )-5-methyl-2-[3-(4-methyl) (64 mg, 129.40 μmol, 30.77% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.10(m,3H),1.27-1.41(m,1H),1.60-1.77(m,1H),1.82-1.94(m,1H),1.97-2.15(m,1H),2.15-2.27(m,4H),2.40-2.46(m,4H),2.78-2.83(m,0.3H),3.04-3.16(m,4H),3.23-3.27(m,0.7H),3.40-3.49(m,0.7H),3.91-3.99(m,3H),3.99-4.04(m,0.3H),5.08-5.64(m,1H),6.69-6.78(m,1H),6.78-6.86(m,2H),7.16-7.26(m,1H),7.65-7.79(m,2H),8.38-8.49(m,1H),8.49-8.60(m,1H),10.94-11.12(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.10 (m, 3H), 1.27-1.41 (m, 1H), 1.60-1.77 (m, 1H), 1.82-1.94 (m, 1H), 1.97 -2.15(m, 1H), 2.15-2.27(m, 4H), 2.40-2.46(m, 4H), 2.78-2.83(m, 0.3H), 3.04-3.16(m, 4H), 3.23-3.27(m ,0.7H),3.40-3.49(m,0.7H),3.91-3.99(m,3H),3.99-4.04(m,0.3H),5.08-5.64(m,1H),6.69-6.78(m,1H ),6.78-6.86(m,2H),7.16-7.26(m,1H),7.65-7.79(m,2H),8.38-8.49(m,1H),8.49-8.60(m,1H),10.94-11.12 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=2.246min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=2.246 min.

實例533. 5-(2-((2R,5S )-2-(3-氯-4-(2-(二甲胺基)乙基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1341)之合成Example 533. 5-(2-(( 2R,5S )-2-(3-chloro-4-(2-(dimethylamino)ethyl)phenyl)-5-methylpiperidin-1-yl )-2-oxyacetamido)-2-methoxynicotinamide (compound 1341) synthesis

Figure 110128222-A0202-12-1916-779
Figure 110128222-A0202-12-1916-779

將2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(71.54mg，299.11μmol)及2-[2-氯-4-[外消旋 -(2R,5S )-5-甲基-2-哌啶基]苯基]-N,N -二甲基乙胺(0.07g，249.26μmol)混合於DMF(10mL)中。將反應懸浮液冷卻至20℃且添加HATU(113.73mg，299.11μmol)，隨後添加TEA(75.67mg，747.77μmol，104.22μL)，且在環境溫度下攪拌13h。將反應混合物在真空中蒸發且藉由製備型(30-90% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min)純化0.3g所獲得之粗產物，以得到產物2-甲氧基-5-[[2-側氧基-2-[外消旋 -(2R,5S )-2-[3-氯-4-[2-(二甲胺基)乙基]苯基]-5-甲基-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(0.0179g，35.66μmol，14.31%產率)。2-[(5-Aminocarboxy-6-methoxy-3-pyridinyl)amino]-2-oxoacetic acid (71.54 mg, 299.11 μmol) and 2-[2-chloro-4- [ Rac- ( 2R,5S )-5-methyl-2-piperidinyl]phenyl] -N,N -dimethylethylamine (0.07 g, 249.26 μmol) was mixed in DMF (10 mL). The reaction suspension was cooled to 20°C and HATU (113.73 mg, 299.11 μmol) was added followed by TEA (75.67 mg, 747.77 μmol, 104.22 μL) and stirred at ambient temperature for 13 h. The reaction mixture was evaporated in vacuo and 0.3 g of the obtained crude product was purified by prep (30-90% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min) to give the product 2-methoxy-5-[[2-oxy-2-[ rac- ( 2R,5S )-2-[3-chloro-4-[2-(dimethylamino)ethyl] Phenyl]-5-methyl-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (0.0179 g, 35.66 μmol, 14.31% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(d,3H),1.34(m,1H),1.64(m,1H),1.86(m,1H),2.01(m,1H),2.18(s,6H),2.42(m,2H),2.79(m,3H),3.23(m,1H),3.46(m,1H),3.98(s,3H),5.53(m,1H),7.20(m,1H),7.35(m,1H),7.40(m,1H),7.72(m,2H),8.46(m,1H),8.56(m,1H),11.09(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(d,3H), 1.34(m,1H), 1.64(m,1H), 1.86(m,1H), 2.01(m,1H), 2.18(s, 6H), 2.42(m, 2H), 2.79(m, 3H), 3.23(m, 1H), 3.46(m, 1H), 3.98(s, 3H), 5.53(m, 1H), 7.20 (m, 1H), 7.35 (m, 1H), 7.40 (m, 1H), 7.72 (m, 2H), 8.46 (m, 1H), 8.56 (m, 1H), 11.09 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值502.2；實測值503.2；Rt=2.589min。LCMS (ESI): [M] + m/z: calculated 502.2; found 503.2; Rt=2.589 min.

實例534. 5-(2-((2R,5S )-2-(3-(2-(二甲胺基)乙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1352)之合成Example 534. 5-(2-(( 2R,5S )-2-(3-(2-(dimethylamino)ethoxy)phenyl)-5-methylpiperidin-1-yl)-2 -Synthesis of pendant oxyacetamido)-2-methoxynicotinamide (compound 1352)

Figure 110128222-A0202-12-1916-780
Figure 110128222-A0202-12-1916-780

將N,N -二甲基-2-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]乙胺(200mg，762.23μmol)、2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(182.31mg，762.23μmol)及TEA(385.65mg，3.81mmol，531.20μL)混合於DMF(2mL)中且向其中添加HATU(347.79mg，914.67μmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 40-65% MeOH+NH3 ，30mL/min(裝載泵4mL MeOH+NH3 )管柱：SunFire 100*19mm，5微米)，以獲得2-甲氧基-5-[[2-側氧基-2-[(2R,5S )-2-[3-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(36.4mg，75.28μmol，9.88%產率)及2-甲氧基-5-[[2-側氧基-2-[(2R,5S )-2-[3-[2-(二甲胺基)乙氧基]苯基]-5-甲基-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(124.7mg，257.88μmol，33.83%產率)。 N,N -dimethyl-2-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]ethanamine (200 mg, 762.23 μmol), 2-[(5 -Aminocarboxy-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (182.31 mg, 762.23 μmol) and TEA (385.65 mg, 3.81 mmol, 531.20 μL) were mixed in DMF ( 2 mL) and to this was added HATU (347.79 mg, 914.67 μmol). The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 40-65% MeOH+ NH3 , 30 mL/min (loading pump 4 mL MeOH+ NH3 ) Column: SunFire 100*19 mm, 5 microns) to obtain 2-formaldehyde Oxy-5-[[2-oxy-2-[( 2R,5S )-2-[3-[2-(dimethylamino)ethoxy]phenyl]-5-methyl-1 -Piperidinyl]acetoxy]amino]pyridine-3-carboxamide (36.4 mg, 75.28 μmol, 9.88% yield) and 2-methoxy-5-[[2-pendoxyl-2- [( 2R,5S )-2-[3-[2-(dimethylamino)ethoxy]phenyl]-5-methyl-1-piperidinyl]acetyl]amino]pyridine-3 - Formamide (124.7 mg, 257.88 μmol, 33.83% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.08(m,3H),1.27-1.40(m,1H),1.61-1.71(m,1H),1.83-1.94(m,1H),1.98-2.12(m,1H),2.17-2.21(m,6H),2.55-2.62(m,3H),2.77-3.25(m,1H),3.36-3.49(m,1H),3.91-3.98(m,3H),4.00-4.06(m,2H),5.09-5.65(m,1H),6.80-6.94(m,3H),7.24-7.33(m,1H),7.67-7.81(m,2H),8.38-8.48(m,1H),8.48-8.60(m,1H),10.96-11.14(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.08(m,3H), 1.27-1.40(m,1H), 1.61-1.71(m,1H), 1.83-1.94(m,1H) ,1.98-2.12(m,1H),2.17-2.21(m,6H),2.55-2.62(m,3H),2.77-3.25(m,1H),3.36-3.49(m,1H),3.91-3.98( m,3H),4.00-4.06(m,2H),5.09-5.65(m,1H),6.80-6.94(m,3H),7.24-7.33(m,1H),7.67-7.81(m,2H), 8.38-8.48 (m, 1H), 8.48-8.60 (m, 1H), 10.96-11.14 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值483.2；實測值484.2；Rt=2.191min。LCMS (ESI): [M] + m/z: calculated 483.2; found 484.2; Rt=2.191 min.

實例535. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1260)及2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1278)之合成Example 535. 2-Methoxy-5-[[2-Pendox-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S) -1-Methylpyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (Compound 1260) and 2-methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R)-1 Synthesis of -Methylpyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (Compound 1278)

Figure 110128222-A0202-12-1918-781
Figure 110128222-A0202-12-1918-781

步驟1：2-甲氧基-5-[[2-側氧基-2-[外消旋-(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methoxy-5-[[2-Pendoxyloxy-2-[racemic-(5S)-5-methyl-2-[2-(1-methylpyrrolidine-3- Synthesis of )-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide

Figure 110128222-A0202-12-1918-782
Figure 110128222-A0202-12-1918-782

向2-[(5-胺甲醯基-6-甲氧基-3-吡啶基)胺基]-2-側氧基乙酸(400mg，1.67mmol)、2-(1-甲基吡咯啶-3-基)-5-[外消旋-(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑(500mg，1.58mmol)於DMF(6mL)中之混合物中添加HATU(760mg，2.00mmol)及DIPEA(0.87mL，4.99mmol)。將所得混合物在20℃下攪拌2小時。在減壓下濃縮混合物。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80 * 40mm * 3μm；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在9.5min內28%至58% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈黃色固體之2-甲氧基-5-[[2-側氧基-2-[外消旋-(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(110mg，12.3%產率)。HPLC：在220nm下為89.17%，在254nm下為93.20%。To 2-[(5-aminocarbamoyl-6-methoxy-3-pyridyl)amino]-2-oxoacetic acid (400 mg, 1.67 mmol), 2-(1-methylpyrrolidine- In a mixture of 3-yl)-5-[rac-(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazole (500 mg, 1.58 mmol) in DMF (6 mL) HATU (760 mg, 2.00 mmol) and DIPEA (0.87 mL, 4.99 mmol) were added. The resulting mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Phenomenex Gemini-NX 80*40mm* 3 μm; mobile phase A: with 10 mmol of NH4HCO3 H2O (v%); Mobile Phase B: MeCN; Gradient: 28% to 58% B in 9.5min, hold 100% B for 2min; Flow Rate: 25mL/min; Column Temperature: 30°C; Wavelength: 220nm , 254 nm), the residue was purified to give 2-methoxy-5-[[2-oxy-2-[racemic-(5S)-5-methyl-2-[2- as a yellow solid (1-Methylpyrrolidin-3-yl)-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (110 mg, 12.3 %Yield). HPLC: 89.17% at 220 nm, 93.20% at 254 nm.

步驟2：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合Step 2: 2-Methoxy-5-[[2-Pendoxyloxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S) -1-Methylpyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 物1260)及2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1278)之合成Compound 1260) and 2-methoxy-5-[[2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R )-1-Methylpyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (Compound 1278 ) synthesis

藉由SFC(儀器：Berger，multigr AM-II；管柱：Daicel chiralpak IC 250mm×30mm×5μm；流動相：超臨界CO2 /MeOH-MeCN(0.1% NH3- H2 O，v%)=50/50；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化2-甲氧基-5-[[2-側氧基-2-[外消旋-(5S)-5-甲基-2-[2-(1-甲基吡咯啶-3-基)-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(110mg，0.205mmol)。將級分在減壓下濃縮，然後凍乾隔夜，以得到化合物1260及化合物1278 。By SFC (instrument: Berger, multigr AM-II; column: Daicel chiralpak IC 250mm x 30mm x 5μm; mobile phase: supercritical CO 2 /MeOH-MeCN (0.1% NH 3 -H 2 O, v%) = 50/50; flow rate: 80 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; dresser temperature: 25 °C; wavelength: 220 nm) Purification 2- Methoxy-5-[[2-oxy-2-[rac-(5S)-5-methyl-2-[2-(1-methylpyrrolidin-3-yl)-1, 3-Benzothiazol-5-yl]-1-piperidinyl]acetoxy]amino]pyridine-3-carboxamide (110 mg, 0.205 mmol). The fractions were concentrated under reduced pressure and then lyophilized overnight to give compound 1260 and compound 1278 .

化合物1260 ：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(30.5mg，單一未知鏡像異構物，峰1，保留時間：3.854min，白色固體)。 Compound 1260 : 2-methoxy-5-[[2-side oxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S) -1-Methylpyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (30.5 mg, Single unknown enantiomer, peak 1, retention time: 3.854 min, white solid).

1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.57-8.72(m,1H),8.34-8.54(m,1H),7.87-8.00(m,2H),7.42(br d,J =7.9Hz,1H),5.41-5.87(m,1H),4.00-4.16(m,3H),3.91(br s,1H),3.76(br d,J =13.6Hz,1H),3.43(br d,J =12.9Hz,1H),3.15(br s,1H),2.74-2.94(m,3H),2.43(s,4H),2.19-2.38(m,3H),1.94(br s,2H),1.46(br d,J =11.9Hz,1H),1.14(br d,J =6.6Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值537.2，實測值537.2；HPLC：在220nm下為99.36%，在254nm下為100%；98.6%ee。 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.57-8.72 (m, 1H), 8.34-8.54 (m, 1H), 7.87-8.00 (m, 2H), 7.42 (br d, J =7.9Hz, 1H), 5.41-5.87(m, 1H), 4.00-4.16(m, 3H), 3.91(br s, 1H), 3.76(br d, J =13.6Hz, 1H), 3.43(br d, J =12.9 Hz,1H),3.15(br s,1H),2.74-2.94(m,3H),2.43(s,4H),2.19-2.38(m,3H),1.94(br s,2H),1.46(br d , J =11.9Hz,1H),1.14(br d, J =6.6Hz,3H); LCMS(ESI)[M+H] + m/z: calculated 537.2, found 537.2; HPLC: at 220nm 99.36%, 100% at 254nm; 98.6%ee.

化合物1278 ：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(31.5mg，單一未知鏡像異構物，峰2，保留時間：7.108min，白色固體)。 Compound 1278 : 2-Methoxy-5-[[2-sideoxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R) -1-Methylpyrrolidin-3-yl]-1,3-benzothiazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (31.5 mg, Single unknown enantiomer, peak 2, retention time: 7.108 min, white solid).

1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.58-8.75(m,1H),8.33-8.54(m,1H),7.80-8.08(m,2H),7.34-7.52(m,1H),5.37-5.93(m,1H),3.99-4.17(m,3H),3.90(br s, 1H),3.76(br d,J =14.3Hz,1H),3.43(br d,J =14.1Hz,1H),3.10-3.24(m,1H),2.73-2.95(m,3H),2.43(s,4H),2.17-2.38(m,3H),1.94(br s,2H),1.46(br d,J =12.8Hz,1H),1.14(br d,J =6.3Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值537.2，實測值537.2；HPLC：在220nm下為98.90%，在254nm下為100%；98.7%ee。 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.58-8.75 (m, 1H), 8.33-8.54 (m, 1H), 7.80-8.08 (m, 2H), 7.34-7.52 (m, 1H), 5.37 -5.93(m,1H),3.99-4.17(m,3H),3.90(br s,1H),3.76(br d, J =14.3Hz,1H),3.43(br d, J =14.1Hz,1H) , 3.10-3.24(m, 1H), 2.73-2.95(m, 3H), 2.43(s, 4H), 2.17-2.38(m, 3H), 1.94(br s, 2H), 1.46(br d, J = 12.8Hz, 1H), 1.14 (br d, J =6.3Hz, 3H); LCMS (ESI) [M+H] + m/z: calcd 537.2, found 537.2; HPLC: 98.90% at 220nm, 100% at 254nm; 98.7% ee.

方案E-式5化合物之合成Scheme E - Synthesis of Compounds of Formula 5

式5化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 5 are compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as described herein.

一般程序5General Procedure 5

Figure 110128222-A0202-12-1920-783
Figure 110128222-A0202-12-1920-783

注意，分離步驟為視情況任選的，且在某些情況下用於分離順式/反式非鏡像異構物，且在某些情況下分離不同的鏡像異構物，如詳細程序中所述。在某些情況下，起始哌啶呈限定順式或反式組態，在彼等情況下，掌性分離步驟僅得到所描繪之四種鏡像異構物中之兩者Note that the separation step is optional and in some cases is used to separate cis/trans non-spiroisomers, and in some cases different enantiomers, as described in the detailed procedure described. In some cases, the starting piperidine is in a defined cis or trans configuration, in which case the chiral separation step yields only two of the four enantiomers depicted

一般文庫程序General Library Program

將DIPEA(1.5當量+1.0當量，若使用鹽形式之反應物)添加到吡啶反應物(1.0 當量)於MeCN(0.7mL)中之溶液中。將所得混合物在室溫下攪拌30min，隨後逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(1.0當量)。然後，將混合物再攪拌30min且添加哌啶反應物(1.1當量)。將反應混合物在室溫下攪拌1h，然後在100℃下攪拌16h。此後，使所得混合物冷卻至室溫且添加MeOH(2.0mL)。攪拌懸浮液，直到觀測到澄清溶液且添加SiliaMetS DMT(二巰基三嗪)(50.0mg)。將所獲得之懸浮液在室溫下攪拌30min且過濾出。將濾液在減壓下濃縮且將殘餘物再溶解於DMSO(0.5mL)中。使所得溶液經歷HPLC(裝備有DAD及質量偵測器之Agilent 1260 Infinity系統；Waters SunFire C18 OBD製備型管柱，100A，5mkm，19* 100mm，具有SunFire C18製備型保護柱，100A，10mkm，19* 100mm；MeOH-H2 O為流動相，Run Time 5min)，以得到式5產物。DIPEA (1.5 equiv + 1.0 equiv if reactant in salt form was used) was added to a solution of pyridine reactant (1.0 equiv) in MeCN (0.7 mL). The resulting mixture was stirred at room temperature for 30 min, followed by the dropwise addition of 2,2,2-trifluoroethyl 2-chloro-2-pendoxoacetic acid (1.0 equiv.). Then, the mixture was stirred for an additional 30 min and the piperidine reactant (1.1 equiv) was added. The reaction mixture was stirred at room temperature for 1 h, then at 100 °C for 16 h. After this time, the resulting mixture was cooled to room temperature and MeOH (2.0 mL) was added. The suspension was stirred until a clear solution was observed and SiliaMetS DMT (dimercaptotriazine) (50.0 mg) was added. The obtained suspension was stirred at room temperature for 30 min and filtered off. The filtrate was concentrated under reduced pressure and the residue was redissolved in DMSO (0.5 mL). The resulting solution was subjected to HPLC (Agilent 1260 Infinity system equipped with DAD and mass detector; Waters SunFire C18 OBD preparative column, 100A, 5mkm, 19 * 100mm, with SunFire C18 preparative guard column, 100A, 10mkm, 19 * 100mm; MeOH- H2O as mobile phase, Run Time 5min) to obtain formula 5 product.

實例536. 2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物2)、2-(5-甲基-2-苯基-1-哌啶基)-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物3)、2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物5)Example 536. 2-[(2S,5R)-5-Methyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-pendant oxyacetyl Amine (Compound 2), 2-(5-Methyl-2-phenyl-1-piperidinyl)-N-(5-methyl-3-pyridyl)-2-oxoacetamide (Compound 3), 2-[(2S,5S)-5-methyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-side oxyacetyl Amine (Compound 5)

Figure 110128222-A0202-12-1921-784
Figure 110128222-A0202-12-1921-784

藉由一般文庫程序製備2-(5-甲基-2-苯基哌啶-1-基)-N-(5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物1 )。產率：11.3mg(11.3%)。2-(5-Methyl-2-phenylpiperidin-1-yl)-N-(5-methylpyridin-3-yl)-2-oxyacetamide ( compound ) was prepared by the general library procedure 1 ). Yield: 11.3 mg (11.3%).

1 H NMR(500MHz,DMSO-d6 )δ 1.11(m,3H),1.42(m,1H),1.80(m,1H),1.91(m,1H),2.14(m,1H),2.25(m,1H),2.33(m,3H),2.81(m,0.4H),3.28(m,0.6H),4.11(m,1H),5.48(m,1H),7.24(m,1H),7.34(m,4H),7.95(m,1H),8.07(m,1H),8.56(m,1H),10.88(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.11(m, 3H), 1.42(m, 1H), 1.80(m, 1H), 1.91(m, 1H), 2.14(m, 1H), 2.25(m ,1H),2.33(m,3H),2.81(m,0.4H),3.28(m,0.6H),4.11(m,1H),5.48(m,1H),7.24(m,1H),7.34( m, 4H), 7.95 (m, 1H), 8.07 (m, 1H), 8.56 (m, 1H), 10.88 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值337.2；實測值338.2；Rt=3.157min。LCMS (ESI): [M+H] + m/z: calculated 337.2; found 338.2; Rt=3.157 min.

掌性分離條件：儀器：製備型Agilent HPLC 1200(DAD)；反相及梯度：己烷-IPA-MeOH，70-15-15，12mL/min管柱：CHIRALPAK OJ-H，250* 20mm，5μm；注入體積：600mLChiral separation conditions: Instrument: Preparative Agilent HPLC 1200 (DAD); Reverse Phase and Gradient: Hexane-IPA-MeOH, 70-15-15, 12mL/min Column: CHIRALPAK OJ-H, 250 * 20mm, 5μm ;Injection volume: 600mL

觀測到三種產物：2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(6.35mg，18.82μmol，12.12%產率)(化合物2 ；米色固體)、2-(5-甲基-2-苯基-1-哌啶基)-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(3.54mg，10.49μmol，6.76%產率)(灰色固體)、2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(10.16mg，30.11μmol，19.39%產率)(米色固體)。Three products were observed: 2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-pendoxyl Acetamide (6.35 mg, 18.82 μmol, 12.12% yield) ( compound 2 ; beige solid), 2-(5-methyl-2-phenyl-1-piperidinyl)-N-(5-methyl) -3-Pyridinyl)-2-oxyacetamide (3.54 mg, 10.49 μmol, 6.76% yield) (grey solid), 2-[(2S,5S)-5-methyl-2-phenyl -1-Piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (10.16 mg, 30.11 μmol, 19.39% yield) (beige solid).

2-(5-甲基-2-苯基-1-哌啶基)-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物3)(呈非鏡像異構物之混合物獲得)：2-(5-Methyl-2-phenyl-1-piperidinyl)-N-(5-methyl-3-pyridyl)-2-oxyacetamide (compound 3) (non-mirror image obtained as a mixture of isomers):

1 H NMR(500MHz,CDCl3 )δ 0.87(m,3H),1.30(m,1H),1.79(m,2H),2.04(m,1H),2.36(m,3H),2.53(m,1H),2.66(m,1H),4.64(m,1H),6.23(m,1H),7.30(m,3H),7.40(m,2H),8.06(m,1H),8.26(m,1H),8.51(m,1H),9.27(m,1H)。 1 H NMR (500MHz, CDCl 3 ) δ 0.87 (m, 3H), 1.30 (m, 1H), 1.79 (m, 2H), 2.04 (m, 1H), 2.36 (m, 3H), 2.53 (m, 1H) ), 2.66(m, 1H), 4.64(m, 1H), 6.23(m, 1H), 7.30(m, 3H), 7.40(m, 2H), 8.06(m, 1H), 8.26(m, 1H) , 8.51 (m, 1H), 9.27 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值337.18；實測值339.03；Rt=4.808min。LCMS (ESI): [M+2H] + m/z: calculated 337.18; found 339.03; Rt=4.808 min.

RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6mL/min)=10.295min。RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 10.295 min.

2-[(2S,5S)-5-甲基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物5) (10.16mg，30.11μmol，19.39%產率)： 2-[(2S,5S)-5-methyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (compound 5) (10.16 mg, 30.11 μmol, 19.39% yield):

1 H NMR(500MHz,CDCl3 )δ 0.99(m,3H),1.35(m,1H),1.80(m,1H),2.01(m,1H),2.24(m,1H),2.37(m,3H),2.61(m,1H),3.21(m,1H),4.53(m,1H),6.20(m,1H),7.30(m,3H),7.39(m,2H),8.06(m,1H),8.25(m,1H),8.50(m,1H),9.29(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.99(m,3H), 1.35(m,1H), 1.80(m,1H), 2.01(m,1H), 2.24(m,1H), 2.37(m,3H) ), 2.61(m, 1H), 3.21(m, 1H), 4.53(m, 1H), 6.20(m, 1H), 7.30(m, 3H), 7.39(m, 2H), 8.06(m, 1H) , 8.25 (m, 1H), 8.50 (m, 1H), 9.29 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值337.18；實測值339.03；Rt=4.743min。LCMS (ESI): [M+2H] + m/z: calculated 337.18; found 339.03; Rt=4.743 min.

RT(OJ-H，己烷-IPA-MeOH，70-15-15，0.6mL/min)=28.230min。RT (OJ-H, Hexane-IPA-MeOH, 70-15-15, 0.6 mL/min) = 28.230 min.

2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物2)：2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide (compound 2):

1 H NMR(500MHz,CDCl3 )δ 1.12(d,3H),1.42(m,1H),1.95(m,2H),2.27(m,2H),2.36(m,3H),3.21(m,1H),4.56(m,1H),6.16(m,1H),7.30(m,3H),7.39(m,2H),8.04(m,1H),8.25(m,1H),8.50(m,1H),9.33(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.12(d,3H), 1.42(m,1H), 1.95(m,2H), 2.27(m,2H), 2.36(m,3H), 3.21(m,1H) ), 4.56(m, 1H), 6.16(m, 1H), 7.30(m, 3H), 7.39(m, 2H), 8.04(m, 1H), 8.25(m, 1H), 8.50(m, 1H) , 9.33 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值337.18；實測值339.03；Rt=4.740min。LCMS (ESI): [M+2H] + m/z: calculated 337.18; found 339.03; Rt=4.740 min.

RT(OJ-H，己烷-IPA-MeOH，70RT (OJ-H, hexane-IPA-MeOH, 70

實例537.N -(5-甲基-3-吡啶基)-2-[(2R )-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯胺及N -(5-甲基-3-吡啶基)-2-[(2S )-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯胺(化合物4及化合物6)之掌性分離Example 537. N- (5-Methyl-3-pyridyl)-2-[( 2R )-2-( m-tolyl )-1-piperidinyl]-2-oxyacetamide and N -(5-Methyl-3-pyridyl)-2-[( 2S )-2-( m-tolyl )-1-piperidinyl]-2-oxoacetamide (Compound 4 and Compound 6 ) palmar separation

Figure 110128222-A0202-12-1923-785
Figure 110128222-A0202-12-1923-785

使N -(5-甲基-3-吡啶基)-2-[2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯胺(34.6mg，102.54μmol)(透過一般程序製備)經歷掌性層析(管柱：Chiralpak OJ-H 250 x 30mm，5um；流動相：CO2 -MeOH，60-40；流速：80mL/min；管柱溫度：40℃；波長：225nm)，以獲得N -(5-甲基-3-吡啶基)-2-[(2R )-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯胺(12.42mg，化合物4 )及N-(5-甲基-3-吡啶基)-2-[(2S )-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯胺(化合物6 )。 N- (5-methyl-3-pyridyl)-2-[2-( m-tolyl )-1-piperidinyl]-2-oxyacetamide (34.6 mg, 102.54 μmol) (through General procedure preparation) was subjected to chiral chromatography (column: Chiralpak OJ-H 250 x 30mm, 5um; mobile phase: CO2 -MeOH, 60-40; flow rate: 80 mL/min; column temperature: 40°C; wavelength: 225 nm) to obtain N- (5-methyl-3-pyridyl)-2-[( 2R )-2-( m-tolyl )-1-piperidinyl]-2-oxyacetamide (12.42 mg, compound 4 ) and N-(5-methyl-3-pyridyl)-2-[( 2S )-2-( m-tolyl )-1-piperidinyl]-2-pendantoxy Acetamide ( compound 6 ).

N -(5-甲基-3-吡啶基)-2-[(2R )-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯胺(化合物4) N- (5-Methyl-3-pyridyl)-2-[( 2R )-2-( m-tolyl )-1-piperidinyl]-2-oxoacetamide (Compound 4)

1 H NMR(DMSO+CCl4, 500MHz)：δ(ppm)1.60(m,2H),1.68(m,2H),1.94(m,1H),2.35(m,6H),2.45(m,1H),3.05(m,1H),4.07(m,1H),5.46(m,1H),7.04(m,1H),7.10(m,2H),7.24(m,1H),7.98(m,1H),8.08(m,1H),8.55(m,1H),10.91(m,1H)。 1 H NMR (DMSO+CCl 4 , 500MHz): δ (ppm) 1.60 (m, 2H), 1.68 (m, 2H), 1.94 (m, 1H), 2.35 (m, 6H), 2.45 (m, 1H) ,3.05(m,1H),4.07(m,1H),5.46(m,1H),7.04(m,1H),7.10(m,2H),7.24(m,1H),7.98(m,1H), 8.08 (m, 1H), 8.55 (m, 1H), 10.91 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值337.2；實測值338.0；Rt=4.543min。LCMS (ESI): [M+H] + m/z: calculated 337.2; found 338.0; Rt=4.543 min.

掌性HPLC：Rt=3.864min(管柱：CHIRALPAK OJ-H，150 x 4.6mm，5μm；流動相：CO2 -MeOH，60-40；流速：2.0mL/min)。Chiral HPLC: Rt=3.864 min (column: CHIRALPAK OJ-H, 150 x 4.6 mm, 5 μm; mobile phase: CO2 -MeOH, 60-40; flow rate: 2.0 mL/min).

N -(5-甲基-3-吡啶基)-2-[(2S )-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯胺(化合物6)。 N- (5-Methyl-3-pyridyl)-2-[( 2S )-2-( m-tolyl )-1-piperidinyl]-2-oxoacetamide (compound 6).

1 H NMR(DMSO+CCl4, 500MHz)δ(ppm)1.58(m,2H),1.68(m,2H),1.97(m,1H),2.35(m,6H),2.46(m,1H),3.04(m,1H),4.07(m,1H),5.46(m,1H),7.04(m,1H),7.10(m,2H),7.24(m,1H),8.00(m,1H),8.08(m,1H),8.55(m,1H),10.91(m,1H)。 1 H NMR(DMSO+CCl 4, 500MHz)δ(ppm)1.58(m,2H),1.68(m,2H),1.97(m,1H),2.35(m,6H),2.46(m,1H), 3.04(m, 1H), 4.07(m, 1H), 5.46(m, 1H), 7.04(m, 1H), 7.10(m, 2H), 7.24(m, 1H), 8.00(m, 1H), 8.08 (m, 1H), 8.55 (m, 1H), 10.91 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值337.2；實測值338.0；Rt=4.542min。LCMS (ESI): [M+H] + m/z: calculated 337.2; found 338.0; Rt=4.542 min.

掌性HPLC：Rt=5.894min(管柱：CHIRALPAK OJ-H，150 x 4.6mm，5μm；流動相：CO2 -MeOH，60-40；流速：2.0mL/min)Chiral HPLC: Rt=5.894 min (column: CHIRALPAK OJ-H, 150 x 4.6 mm, 5 μm; mobile phase: CO 2 -MeOH, 60-40; flow rate: 2.0 mL/min)

方案F-式6化合物之合成Scheme F - Synthesis of Compounds of Formula 6

式6化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 6 are compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as described herein.

一般程序6General Procedure 6

Figure 110128222-A0202-12-1924-786
Figure 110128222-A0202-12-1924-786

步驟1：6B之合成Step 1: Synthesis of 6B

在0℃下，向6A (1.0當量)之溶液中分批添加硼氫化鈉(1.0當量)。將所得混合物在室溫下攪拌2h且在真空中移除揮發物。將殘餘物用水(2mL)稀釋且用DCM(3*4mL)萃取。將有機層經Na2 SO4 乾燥且在真空中移除溶劑，以獲得6B。 To a solution of 6A (1.0 equiv) was added sodium borohydride (1.0 equiv) portionwise at 0°C. The resulting mixture was stirred at room temperature for 2 h and the volatiles were removed in vacuo. The residue was diluted with water (2 mL) and extracted with DCM (3*4 mL). The organic layer was dried over Na 2 SO 4 and the solvent was removed in vacuo to obtain 6B.

步驟1A：3.1D之合成Step 1A: Synthesis of 3.1D

向6A (1.0當量)於溶劑(5mL)中之經攪拌之溶液中添加鹼(2.5當量)。將所得懸浮液用氬氣除氣。添加配體(0.05當量)及Pd催化劑(0.05當量)。將反應混合物在70...100℃下攪拌14...36h。反應完成(藉由LCMS監測)之後，使所得混合物冷卻至室溫，透過SiO2 薄層過濾且用溶劑(2mL)洗滌。在真空中移除揮發物且使殘餘物經歷純化，以得到6D 。To a stirred solution of 6A (1.0 equiv) in solvent (5 mL) was added base (2.5 equiv). The resulting suspension was degassed with argon. Ligand (0.05 equiv) and Pd catalyst (0.05 equiv) were added. The reaction mixture was stirred at 70...100°C for 14...36 h. After completion of the reaction (monitored by LCMS), the resulting mixture was cooled to room temperature, filtered through a thin layer of SiO2 and washed with solvent (2 mL). Volatiles were removed in vacuo and the residue was subjected to purification to give 6D .

布赫瓦爾德反應步驟：Buchwald reaction steps:

Figure 110128222-A0202-12-1925-787
Figure 110128222-A0202-12-1925-787

步驟2：6C之合成Step 2: Synthesis of 6C

將6B (1.0當量)溶解於DCM(5mL)中且逐滴添加二碳酸二-第三丁酯(1.02當量)於DCM(2mL)中之溶液(劇烈氣體逸出！)。將所得混合物在25℃下攪拌4h。然後，在減壓下移除揮發物，以得到化合物及使用方法 6B (1.0 equiv) was dissolved in DCM (5 mL) and a solution of di-tert-butyl dicarbonate (1.02 equiv) in DCM (2 mL) was added dropwise (vigorous gas evolution!). The resulting mixture was stirred at 25 °C for 4 h. Then, volatiles are removed under reduced pressure to obtain compounds and methods of use

步驟2A：6F之合成Step 2A: Synthesis of 6F

在0℃下，向6D (1.0當量)之溶液中分批添加硼氫化鈉(1.0當量)。將所得混合物在室溫下攪拌2h且在真空中移除揮發物。將殘餘物用水(2mL)稀釋且用DCM(3*4mL)萃取。將有機層經Na2 SO4 乾燥且在真空中移除溶劑，以獲得6F。 To a solution of 6D (1.0 equiv) at 0°C was added sodium borohydride (1.0 equiv) portionwise. The resulting mixture was stirred at room temperature for 2 h and the volatiles were removed in vacuo. The residue was diluted with water (2 mL) and extracted with DCM (3*4 mL). The organic layer was dried over Na 2 SO 4 and the solvent was removed in vacuo to obtain 6F.

步驟3：6E之合成Step 3: Synthesis of 6E

向6C (1.0當量)於溶劑(5mL)中之經攪拌之溶液中添加鹼(2.5當量)。 將所得懸浮液用氬氣除氣。添加配體(0.05當量)及Pd催化劑(0.05當量)。將反應混合物在70...100℃下攪拌14...36h。反應完成(藉由LCMS監測)之後，使所得混合物冷卻至室溫，透過SiO2 薄層過濾且用溶劑(2mL)洗滌。在真空中移除揮發物且使殘餘物經歷純化，以得到6E 。To a stirred solution of 6C (1.0 equiv) in solvent (5 mL) was added base (2.5 equiv). The resulting suspension was degassed with argon. Ligand (0.05 equiv) and Pd catalyst (0.05 equiv) were added. The reaction mixture was stirred at 70...100°C for 14...36 h. After completion of the reaction (monitored by LCMS), the resulting mixture was cooled to room temperature, filtered through a thin layer of SiO2 and washed with solvent (2 mL). Volatiles were removed in vacuo and the residue was subjected to purification to give 6E .

布赫瓦爾德反應步驟：Buchwald reaction steps:

Figure 110128222-A0202-12-1926-788
Figure 110128222-A0202-12-1926-788

步驟3A：6H之合成Step 3A: Synthesis of 6H

在0℃下，將2-氯-2-側氧基乙酸苯甲酯(1.1當量)於MeCN(2mL)中之溶液逐滴添加到6F (1.0當量)及DIPEA(2.5當量)於MeCN(4mL)中之經攪拌之溶液中。使反應混合物升溫至25℃且攪拌12h。然後，在真空中蒸發揮發物。使殘餘物經歷HPLC純化，以得到6I。 A solution of benzyl 2-chloro-2-oxoacetate (1.1 equiv) in MeCN (2 mL) was added dropwise to 6F (1.0 equiv) and DIPEA (2.5 equiv) in MeCN (4 mL) at 0°C ) in a stirred solution. The reaction mixture was warmed to 25 °C and stirred for 12 h. Then, the volatiles were evaporated in vacuo. The residue was subjected to HPLC purification to give 6I.

步驟4：6F之合成Step 4: Synthesis of 6F

將6E (1.0當量)溶解於溶劑(2...10mL)中且添加酸(50.0當量)。將反應混合物在室溫下攪拌1...4h。在真空中移除溶劑，以獲得6F. 。 6E (1.0 equiv) was dissolved in solvent (2...10 mL) and acid (50.0 equiv) was added. The reaction mixture was stirred at room temperature for 1...4h. The solvent was removed in vacuo to obtain 6F. .

Boc移除步驟：Boc removal steps:

Figure 110128222-A0202-12-1926-789
Figure 110128222-A0202-12-1926-789

步驟4A：6I之合成Step 4A: Synthesis of 6I

將6H(1.0當量)之溶液與MeOH中之氨溶液(20.0當量)混合且在45℃下攪拌12小時。然後，在真空中移除揮發物，以得到6I。 A solution of 6H (1.0 equiv) was mixed with ammonia solution in MeOH (20.0 equiv) and stirred at 45°C for 12 hours. Then, the volatiles were removed in vacuo to give 6I.

步驟5：6G之合成Step 5: Synthesis of 6G

將6F (1.0當量)、草醯胺酸(1.0當量)及TEA(2.5當量+1.0當量/各酸當量，若使用胺鹽)或DIPEA(2.5當量+1.0當量/各酸當量，若使用胺鹽)一起混合於DMF或DMS+SO中。向其中添加HATU(1.5當量)且將所得混合物攪拌隔夜。在真空中濃縮反應混合物且藉由HPLC純化殘餘物，以獲得6G 。 Combine 6F (1.0 equiv), oxalic acid (1.0 equiv) and TEA (2.5 equiv + 1.0 equiv/each acid equiv, if using amine salt) or DIPEA (2.5 equiv + 1.0 equiv/each acid equiv, if using amine salt ) together in DMF or DMS+SO. To this was added HATU (1.5 equiv) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to obtain 6G .

步驟5A：6G 之合成Step 5A: Synthesis of 6G

在Ar氣氛下，將6I (1.0當量)、R3 I(1.0當量)、CuI(0.2當量)、CuI(0.2當量)、N1 ,N2 -二甲基環己-1,2-二胺(0.2當量)及Cs2 CO3 一起混合於二噁烷(6mL)中。將反應混合物在100℃下攪拌48h。然後，使混合物冷卻至室溫且過濾出。使濾液經歷HPLC，以得到6G。Under Ar atmosphere, 6I (1.0 equiv.), R3I (1.0 equiv.), CuI (0.2 equiv.), CuI (0.2 equiv.), N1, N2 -dimethylcyclohexyl- 1,2 -diamine were combined (0.2 equiv) and Cs2CO3 were mixed together in dioxane (6 mL). The reaction mixture was stirred at 100 °C for 48 h. Then, the mixture was cooled to room temperature and filtered off. The filtrate was subjected to HPLC to give 6G.

實例538. 外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1209)、rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1371)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1116)之合成Example 538. Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(4-methyl) Piperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1209), rel-N-(6-amino-5-ethyl-3-pyridyl) )-2-[(2R,5S)-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-side oxyethyl Amide (compound 1371) and rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(4- Synthesis of Methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1116)

步驟1：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1209)之合成Step 1: Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(4-methyl) Synthesis of piperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1209)

Figure 110128222-A0202-12-1927-790
Figure 110128222-A0202-12-1927-790

藉由一般程序方案F步驟5製備Prepared by General Procedure F, Step 5

HPLC條件：45-60% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min甲醇)；YMC Triart C18 100x20mm，5umHPLC conditions: 45-60% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min (loading pump 4 mL/min methanol); YMC Triart C18 100x20mm, 5um

產率：0.4g(33.63%)Yield: 0.4g (33.63%)

1 H NMR(600MHz,dmso)δ 0.98-1.13(m,6H),1.26-1.37(m,1H),1.60-1.74(m,1H),1.78-1.91(m,1H),1.92-2.18(m,2H),2.20(s,3H),2.34-2.39(m,2H),2.40-2.44(m,4H),2.70(d,0.5H),3.07-3.12(m,4H),3.17(d,0.5H),3.37-4.00(m,1H),5.01-5.55(m,1H),5.57-5.67(m,2H),6.88-6.97(m,2H),7.09-7.19(m,2H),7.43-7.52(m,1H),7.98-8.09(m,1H),10.44-10.54(m,1H)。 1 H NMR(600MHz,dmso)δ 0.98-1.13(m,6H),1.26-1.37(m,1H),1.60-1.74(m,1H),1.78-1.91(m,1H),1.92-2.18(m ,2H),2.20(s,3H),2.34-2.39(m,2H),2.40-2.44(m,4H),2.70(d,0.5H),3.07-3.12(m,4H),3.17(d, 0.5H), 3.37-4.00(m, 1H), 5.01-5.55(m, 1H), 5.57-5.67(m, 2H), 6.88-6.97(m, 2H), 7.09-7.19(m, 2H), 7.43 -7.52 (m, 1H), 7.98-8.09 (m, 1H), 10.44-10.54 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值465.2；實測值465.2；Rt=1.937min。LCMS (ESI): [M+H] + m/z: calculated 465.2; found 465.2; Rt=1.937 min.

步驟2：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1371)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1116)之合成Step 2: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(4-methylpiperazine -1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1371) and rel-N-(6-amino-5-ethyl-3-pyridyl)- 2-[(2S,5R)-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 1116)

Figure 110128222-A0202-12-1928-791
Figure 110128222-A0202-12-1928-791

藉由一般程序方案F步驟6製備Prepared by General Procedure F, Step 6

掌性分離條件： Chiralpak AS-H(250*20，5mkm)，己烷-IPA-MeOH，80-10-10，12mL/min，注入體積：200.000μl；管柱溫度：24℃；波長：205nm，264nm)，化合物1371之保留時間=88.90min且化合物1116之保留時間=62.12min Chiral separation conditions: Chiralpak AS-H (250*20, 5mkm), hexane-IPA-MeOH, 80-10-10, 12mL/min, injection volume: 200.000μl; column temperature: 24°C; wavelength: 205nm , 264nm), the retention time of compound 1371=88.90min and the retention time of compound 1116=62.12min

化合物1371：Compound 1371:

產率：140.0mg(35.0%)Yield: 140.0 mg (35.0%)

RT(Chiralpak IA(250*4.6mm，5mkm)，MeOH-IPA，50-50，0.8mL/min)=48.14min。RT (Chiralpak IA (250*4.6mm, 5mkm), MeOH-IPA, 50-50, 0.8mL/min)=48.14min.

1 H NMR(600MHz,dmso)δ 0.99-1.34(m,7H),1.65-2.20(m,8H),2.35-2.42(m,4H),2.70(m,1H),3.05-3.18(m,4H),3.40(d,1H),3.97(d,1H),5.05-5.63(m,3H),6.90-6.93(m,2H),7.11-7.18(m,2H),7.46-7.49(d,1H),8.01-8.05(d,1H),10.49(m,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.34(m,7H),1.65-2.20(m,8H),2.35-2.42(m,4H),2.70(m,1H),3.05-3.18(m,4H) ), 3.40(d, 1H), 3.97(d, 1H), 5.05-5.63(m, 3H), 6.90-6.93(m, 2H), 7.11-7.18(m, 2H), 7.46-7.49(d, 1H ), 8.01-8.05 (d, 1H), 10.49 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值466.2；實測值466.2；Rt=0.830min。LCMS (ESI): [M+2H] + m/z: calculated 466.2; found 466.2; Rt=0.830 min.

化合物1116：Compound 1116:

產率：190.0mg(47.5%)Yield: 190.0 mg (47.5%)

RT(Chiralpak IA(250*4.6mm，5mkm)，MeOH-IPA，50-50，0.8mL/min)=32.53min。RT (Chiralpak IA (250*4.6mm, 5mkm), MeOH-IPA, 50-50, 0.8mL/min)=32.53min.

1 H NMR(600MHz,dmso)δ 0.99-1.34(m,7H),1.67-2.20(m,8H),2.35-2.43(m,4H),2.70(m,1H),3.06-3.19(m,4H),3.40(d,1H),3.97(d,1H),5.04-5.63(m,3H),6.90-6.93(m,2H),7.11-7.19(m,2H),7.46-7.49(d,1H),8.01-8.05(d,1H),10.49(m,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.34(m,7H),1.67-2.20(m,8H),2.35-2.43(m,4H),2.70(m,1H),3.06-3.19(m,4H) ), 3.40(d, 1H), 3.97(d, 1H), 5.04-5.63(m, 3H), 6.90-6.93(m, 2H), 7.11-7.19(m, 2H), 7.46-7.49(d, 1H) ), 8.01-8.05 (d, 1H), 10.49 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值466.2；實測值466.2；Rt=0.826min。LCMS (ESI): [M+2H] + m/z: calculated 466.2; found 466.2; Rt=0.826 min.

實例539. N-[6-胺基-5-(氧呾-3-基)-3-吡啶基]-2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1356)之合成Example 539. N-[6-Amino-5-(oxypyr-3-yl)-3-pyridyl]-2-[(2R,5S)-2-(1,3-benzothiazole-5- Synthesis of )-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 1356)

Figure 110128222-A0202-12-1929-792
Figure 110128222-A0202-12-1929-792

將2-[(2R,5S)-2-(1,3-苯并噻唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(140mg，362μmol)添加到5-碘-3-(氧呾-3-基)吡啶-2-胺(100mg，362μmol)、 Cu(11.5mg，181μmol)、碘化銅(I)(6.90mg，36.2μmol，1.23μL)及碳酸銫(236mg，724μmol)於二噁烷(2.00mL)中之混合物中。使所得混合物在100℃下攪拌18h。透過矽藻土墊過濾所獲得之混合物且在真空中濃縮。使殘餘物經歷HPLC(0.5-6.5min 20-0%水-ACN，+0.1體積% 25%NH3 水溶液，30mL/min，管柱：XBridge，100x19mm，5μm)。使所獲得之材料(44.3mg)經歷掌性HPLC(第1次運行-Chiralcel OJ-H(250*21，5mkm)，己烷-IPA-MeOH，50-25-25，12mL/min，在38.717min下之主峰；第2次運行-Chiralpak IA II(250*21，5mkm)，IPA-MeOH，50-50，10mL/min)，以得到化合物1356(20.7mg，99+ee，在兩次運行後)。2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (140 mg, 362 μmol ) was added to 5-iodo-3-(oxon-3-yl)pyridin-2-amine (100 mg, 362 μmol), Cu (11.5 mg, 181 μmol), copper(I) iodide (6.90 mg, 36.2 μmol, 1.23 μmol) μL) and cesium carbonate (236 mg, 724 μmol) in dioxane (2.00 mL). The resulting mixture was stirred at 100 °C for 18 h. The resulting mixture was filtered through a pad of celite and concentrated in vacuo. The residue was subjected to HPLC (0.5-6.5 min 20-0% water-ACN, +0.1 vol% 25% NH3 in water, 30 mL/min, column: XBridge, 100x19 mm, 5 μm). The material obtained (44.3 mg) was subjected to chiral HPLC (run 1 - Chiralcel OJ-H (250*21, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 12 mL/min at 38.717 Main peak at min; 2nd run - Chiralpak IA II (250*21, 5mkm), IPA-MeOH, 50-50, 10mL/min) to give compound 1356 (20.7mg, 99+ee, in two runs back).

分析型：化合物1356之RT(Chiralcel OJ-H(250*4.6mm，5mkm)，己烷-IPA-MeOH，50-25-25，0,6mL/min)-39.803min。Analytical: RT for compound 1356 (Chiralcel OJ-H (250*4.6 mm, 5 mkm), Hexane-IPA-MeOH, 50-25-25, 0,6 mL/min) - 39.803 min.

1H NMR(600MHz,DMSO-d6 )：δ(ppm)0.92-1.06(m,3H),1.22-1.41(m,2H),1.72-1.92(m,2H),2.08-2.33(m,2H),2.80-2.83(m,1H),3.86-4.56(m,3H),4.87-4.95(m,2H),5.35-5.74(m,3H),7.43-7.76(m,3H),8.02-8.19(m,2H),9.39-9.41(m,1H),10.61-10.67(m,1H)1H NMR (600MHz, DMSO-d 6 ): δ (ppm) 0.92-1.06 (m, 3H), 1.22-1.41 (m, 2H), 1.72-1.92 (m, 2H), 2.08-2.33 (m, 2H) ,2.80-2.83(m,1H),3.86-4.56(m,3H),4.87-4.95(m,2H),5.35-5.74(m,3H),7.43-7.76(m,3H),8.02-8.19( m,2H),9.39-9.41(m,1H),10.61-10.67(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值452.19；實測值452.0；Rt=0.824。LCMS (ESI): [M+H] + m/z: calculated 452.19; found 452.0; Rt=0.824.

1H NMR(600MHz,DMSO-d6 )δ 1.03-1.06(m,3H),1.33-1.41(m,1H),1.71-1.91(m,2H),2.09-2.37(m,2H),3.53-4.24(m,3H),4.47-4.56(m,2H),4.87-4.95(m,2H),5.36-5.73(m,3H),7.43-7.51(m,1H),7.68-7.76(m,1H),8.02-8.19(m,3H),9.39(s,1H),10.61-10.67(d,1H)。1H NMR (600MHz, DMSO-d 6 )δ 1.03-1.06(m,3H), 1.33-1.41(m,1H), 1.71-1.91(m,2H), 2.09-2.37(m,2H), 3.53-4.24 (m,3H),4.47-4.56(m,2H),4.87-4.95(m,2H),5.36-5.73(m,3H),7.43-7.51(m,1H),7.68-7.76(m,1H) , 8.02-8.19(m, 3H), 9.39(s, 1H), 10.61-10.67(d, 1H).

實例540. 外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1105)、rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1193)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1328)之合成Example 540. Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(4-methyl) Piperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1105), rel-N-(6-amino-5-methyl-3-pyridyl) )-2-[(2S,5R)-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-side oxyethyl Amide (Compound 1193) and rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(4- Synthesis of Methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1328)

Figure 110128222-A0202-12-1931-793
Figure 110128222-A0202-12-1931-793

步驟1：1-甲基-4-(4-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯基)哌嗪之合成Step 1: Synthesis of 1-methyl-4-(4-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenyl)piperazine

藉由一般程序6步驟1A製備。Prepared by General Procedure 6, Step 1A.

產率：4.0g(74.33%)Yield: 4.0 g (74.33%)

LCMS(ESI)：[M+H]+ m/z：計算值272.2；實測值272.2；Rt=0.608min。LCMS (ESI): [M+H] + m/z: calculated 272.2; found 272.2; Rt=0.608 min.

步驟2：外消旋-1-甲基-4-[4-[(2S,5R)-5-甲基-2-哌啶基]苯基]哌嗪之合成Step 2: Synthesis of racemic-1-methyl-4-[4-[(2S,5R)-5-methyl-2-piperidinyl]phenyl]piperazine

藉由一般程序6步驟2A製備Prepared by General Procedure 6 Step 2A

產率：3.7g(91.82%)Yield: 3.7g (91.82%)

LCMS(ESI)：[M+H]+ m/z：計算值274.4；實測值374.4；Rt=0.464min。LCMS (ESI): [M+H] + m/z: calculated 274.4; found 374.4; Rt=0.464 min.

步驟3：外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 3: Racemic-N-[3-Methyl-5-[[2-[(2R,5S)-5-methyl-2-[4-(4-methylpiperazin-1-yl) Synthesis of phenyl]-1-piperidinyl]-2-oxoacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

藉由一般程序6步驟5製備Prepared by General Procedure 6 Step 5

HPLC條件： 40-90% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min；管柱：YMC Triart C18 100x20mm，5um HPLC conditions: 40-90% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min; Column: YMC Triart C18 100x20mm, 5um

產率：260.0mg(43.91%)Yield: 260.0 mg (43.91%)

LCMS(ESI)：[M+H]+ m/z：計算值552.4；實測值552.4；Rt=2.770min。LCMS (ESI): [M+H] + m/z: calculated 552.4; found 552.4; Rt=2.770 min.

步驟4：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1105)之合成Step 4: Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(4-methyl) Synthesis of piperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1105)

藉由一般程序6步驟6製備Prepared by General Procedure 6 Step 6

HPLC條件： 30-50% 0-6min H2 O/MeCN/0.1% NH4 OH，流速：30mL/min；管柱：YMC Triart C18 100x20mm，5um HPLC conditions: 30-50% 0-6 min H2O /MeCN/0.1% NH4OH , flow rate: 30 mL/min; column: YMC Triart C18 100x20mm, 5um

產率：154.0mg(72.39%)Yield: 154.0 mg (72.39%)

LCMS(ESI)：[M+H]+ m/z：計算值451.2；實測值451.2；Rt=1.320min。LCMS (ESI): [M+H] + m/z: calculated 451.2; found 451.2; Rt=1.320 min.

步驟5：rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1193)及rel-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(4-甲基哌嗪-1-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1328)之合成Step 5: rel-N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(4-methylpiperazine -1-yl)phenyl]-1-piperidinyl]-2-oxyacetamide (compound 1193) and rel-N-(6-amino-5-methyl-3-pyridyl)- 2-[(2R,5S)-5-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 1328)

藉由一般程序6步驟7製備Prepared by General Procedure 6 Step 7

掌性分離條件：Chiralpak IB(250 * 20mm，10mkm)；流動相：CO2 -MeOH，60-40.流速：80mL/min；管柱溫度：40℃；波長：215nm。化合物1193)=12.65min；保留時間(化合物1328)=16.12minChiral separation conditions: Chiralpak IB (250*20mm, 10mkm); mobile phase: CO2 -MeOH, 60-40. Flow rate: 80mL/min; column temperature: 40°C; wavelength: 215nm. Compound 1193) = 12.65min; retention time (Compound 1328) = 16.12min

化合物1193：Compound 1193:

產率：49.14mg(34.90%)。Yield: 49.14 mg (34.90%).

RT(Chiralpak IA，IPA-MeOH，50-50，1.0mL/min)=26.336min。RT (Chiralpak IA, IPA-MeOH, 50-50, 1.0 mL/min) = 26.336 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.31(m,1H),1.67(m,1H),1.84(m,1H),2.01(m,4H),2.21(m,4H),2.45(m,4H),3.11(m,5H),3.68(dd,1H),5.57(m,3H),6.92(m,2H),7.15(m,2H),7.46(m,1H),7.99(m,1H),10.47(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.31 (m, 1H), 1.67 (m, 1H), 1.84 (m, 1H), 2.01 (m, 4H) ,2.21(m,4H),2.45(m,4H),3.11(m,5H),3.68(dd,1H),5.57(m,3H),6.92(m,2H),7.15(m,2H), 7.46 (m, 1H), 7.99 (m, 1H), 10.47 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值452.2；實測值452.2；Rt=1.619min。LCMS (ESI): [M+2H] + m/z: calculated 452.2; found 452.2; Rt=1.619 min.

化合物1328：Compound 1328:

產率：45.07mg(32.01%)。Yield: 45.07 mg (32.01%).

RT(Chiralpak IA，IPA-MeOH，50-50，1.0mL/min)=34.522min。RT (Chiralpak IA, IPA-MeOH, 50-50, 1.0 mL/min) = 34.522 min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.31(m,1H),1.66(m,1H),1.84(m,1H),2.01(m,4H),2.20(m,4H),2.42(m,5H),3.15(m,4H),3.68(m,1H), 5.57(m,3H),6.92(m,2H),7.15(dd,2H),7.46(m,1H),8.00(m,1H),10.46(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.31 (m, 1H), 1.66 (m, 1H), 1.84 (m, 1H), 2.01 (m, 4H) , 2.20(m, 4H), 2.42(m, 5H), 3.15(m, 4H), 3.68(m, 1H), 5.57(m, 3H), 6.92(m, 2H), 7.15(dd, 2H), 7.46 (m, 1H), 8.00 (m, 1H), 10.46 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值452.2；實測值452.2；Rt=1.619min。LCMS (ESI): [M+2H] + m/z: calculated 452.2; found 452.2; Rt=1.619 min.

實例541. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[4-(4-乙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1360)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-[4-(4-乙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1097)之合成Example 541. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[4-(4-ethylpiperazin-1-yl) Phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1360) and rel-N-(6-amino-5-ethyl-3-pyridyl)- 2-[(2S,5R)-2-[4-(4-Ethylpiperazin-1-yl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 1097)

Figure 110128222-A0202-12-1933-794
Figure 110128222-A0202-12-1933-794

步驟1：1-乙基-4-[4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯基]哌嗪之合成Step 1: Synthesis of 1-ethyl-4-[4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenyl]piperazine

藉由一般程序6步驟1A(方法C)製備Prepared by General Procedure 6 Step 1A (Method C)

產率：0.65g(粗品)Yield: 0.65g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值286.2；實測值286.2；Rt=0.617min。LCMS (ESI): [M+H] + m/z: calculated 286.2; found 286.2; Rt=0.617 min.

步驟2：外消旋-1-乙基-4-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪之合成Step 2: Synthesis of Racemic-1-ethyl-4-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine

藉由一般程序6步驟2A製備Prepared by General Procedure 6 Step 2A

產率：0.39g(95.62%)Yield: 0.39g (95.62%)

LCMS(ESI)：[M+H]+ m/z：計算值288.2；實測值288.2；Rt=0.606min。LCMS (ESI): [M+H] + m/z: calculated 288.2; found 288.2; Rt=0.606 min.

步驟3：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[4-(4-乙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 3: Racemic-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-2-[4-(4-ethylpiperazine-1- Synthesis of phenyl)-phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide

藉由一般程序6步驟5製備Prepared by General Procedure 6 Step 5

HPLC條件： 2-10min 40-100% MeCN/H2 O 30mL/min(裝載泵4mL MeCN管柱；SunFire 100*19mm，5微米 HPLC conditions: 2-10min 40-100% MeCN/ H2O 30mL/min (loading pump 4mL MeCN column; SunFire 100*19mm, 5 microns

產率：0.18g(18.25%)Yield: 0.18g (18.25%)

LCMS(ESI)：[M+H]+ m/z：計算值480.2；實測值480.2；Rt=0.781min。LCMS (ESI): [M+H] + m/z: calculated 480.2; found 480.2; Rt=0.781 min.

步驟4：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[4-(4-乙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1360)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-[4-(4-乙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1097)之合成Step 4: rel-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-2-[4-(4-ethylpiperazin-1-yl) Phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1360) and rel-N-(6-amino-5-ethyl-3-pyridyl)- 2-[(2S,5R)-2-[4-(4-Ethylpiperazin-1-yl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide Synthesis of (Compound 1097)

藉由一般程序方案F步驟6製備Prepared by General Procedure F, Step 6

掌性分離條件：Chiralpak AS-H(250 * 20mm；5m)；流動相：己烷-IPA-MeOH，70-15-15流速：12mL/min；管柱溫度：20℃；波長：205nm，保留時間(異構物A)=11.37min；保留時間(異構物B)=19.30minChiral separation conditions: Chiralpak AS-H (250*20mm; 5m); Mobile phase: Hexane-IPA-MeOH, 70-15-15 Flow rate: 12mL/min; Column temperature: 20°C; Wavelength: 205nm, retention Time (Isomer A)=11.37min; Retention Time (Isomer B)=19.30min

化合物1360：Compound 1360:

產率：42.0mg(23.33%)Yield: 42.0 mg (23.33%)

RT(Chiralpak AS-H(250 * 20mm；5m)，己烷-IPA-MeOH，60-20-20，流速：0.6mL/min)=12.74min。RT (Chiralpak AS-H (250*20mm; 5m), Hexane-IPA-MeOH, 60-20-20, flow rate: 0.6 mL/min) = 12.74 min.

1 H NMR(600MHz,cd3 od)δ 1.11(d,3H),1.14-1.27(m,6H),1.39-1.46(m,1H),1.85-1.99(m,2H),2.08-2.28(m,2H),2.45-2.53(m,4H),2.61-2.67(m,4H),3.00-3.38(m,5H),3.61-4.08(m,1H),5.21-5.71(m,1H),6.93-7.03(m,2H),7.20-7.28(m,2H),7.49-7.66(m,1H),7.94-8.12(m,1H)。 1 H NMR (600MHz, cd 3 od) δ 1.11(d, 3H), 1.14-1.27(m, 6H), 1.39-1.46(m, 1H), 1.85-1.99(m, 2H), 2.08-2.28(m ,2H),2.45-2.53(m,4H),2.61-2.67(m,4H),3.00-3.38(m,5H),3.61-4.08(m,1H),5.21-5.71(m,1H),6.93 -7.03(m, 2H), 7.20-7.28(m, 2H), 7.49-7.66(m, 1H), 7.94-8.12(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值479.4；實測值479.4；Rt=2.042min。LCMS (ESI): [M+H] + m/z: calculated 479.4; found 479.4; Rt=2.042 min.

化合物1097：Compound 1097:

產率：42.0mg(23.33%)Yield: 42.0 mg (23.33%)

RT(Chiralpak AS-H(250 * 20mm；5m)，己烷-IPA-MeOH，60-20-20，流速： 0.6mL/min)=8.94min。RT (Chiralpak AS-H (250*20mm; 5m), Hexane-IPA-MeOH, 60-20-20, flow rate: 0.6mL/min)=8.94min.

1 H NMR(600MHz,dmso)δ 0.99-1.03(m,6H),1.06-1.13(m,3H),1.26-1.36(m,1H),1.62-1.73(m,1H),1.79-1.90(m,1H),1.93-2.10(m,1H),2.12-2.22(m,1H),2.34-2.41(m,4H),2.49-2.53(m,4H),2.67-3.20(m,5H),3.37-4.00(m,1H),5.00-5.55(m,1H),5.57-5.66(m,2H),6.89-6.95(m,2H),7.10-7.19(m,2H),7.44-7.52(m,1H),7.98-8.07(m,1H),10.38-10.53(m,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.03(m,6H),1.06-1.13(m,3H),1.26-1.36(m,1H),1.62-1.73(m,1H),1.79-1.90(m ,1H),1.93-2.10(m,1H),2.12-2.22(m,1H),2.34-2.41(m,4H),2.49-2.53(m,4H),2.67-3.20(m,5H),3.37 -4.00(m, 1H), 5.00-5.55(m, 1H), 5.57-5.66(m, 2H), 6.89-6.95(m, 2H), 7.10-7.19(m, 2H), 7.44-7.52(m, 1H), 7.98-8.07 (m, 1H), 10.38-10.53 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值479.4；實測值479.4；Rt=2.035min。LCMS (ESI): [M+H] + m/z: calculated 479.4; found 479.4; Rt=2.035 min.

實例542. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[4-(4-異丙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1208)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-[4-(4-異丙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1234)之合成Example 542. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[4-(4-isopropylpiperazin-1-yl ) Phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1208) and rel-N-(6-amino-5-ethyl-3-pyridyl) -2-[(2S,5R)-2-[4-(4-isopropylpiperazin-1-yl)phenyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Synthesis of amide (compound 1234)

Figure 110128222-A0202-12-1935-795
Figure 110128222-A0202-12-1935-795

步驟1：外消旋-(2R,5S)-2-[4-(4-異丙基哌嗪-1-基)苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: tertiary butyl rac-(2R,5S)-2-[4-(4-isopropylpiperazin-1-yl)phenyl]-5-methylpiperidine-1-carboxylate synthesis

藉由一般程序方案F步驟3(方法C)製備Prepared by General Procedure F, Step 3 (Method C)

產率：0.7g(粗品)Yield: 0.7g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值402.2；Rt=1.054min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 402.2; Rt=1.054 min.

步驟2：外消旋-1-異丙基-4-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]哌嗪之合成Step 2: Synthesis of racemic-1-isopropyl-4-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperazine

藉由一般程序方案F步驟4(方法A)製備Prepared by General Procedure F, Step 4 (Method A)

產率：0.58g(88.88%，2HCl)Yield: 0.58g (88.88%, 2HCl)

LCMS(ESI)：[M+H]+ m/z：計算值302.2；實測值302.2；Rt=0.671min。LCMS (ESI): [M+H] + m/z: calculated 302.2; found 302.2; Rt=0.671 min.

步驟3：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[4-(4-異丙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 3: Racemic-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-2-[4-(4-isopropylpiperazine-1 Synthesis of -yl)phenyl]-5-methyl-1-piperidinyl]-2-side oxyacetamide

藉由一般程序方案F步驟5製備Prepared by General Procedure F, Step 5

HPLC條件：2-10min 50-100%甲醇/水；流速30mL/min；裝載泵4mL/min甲醇；管柱SunFire 19*100mmHPLC conditions: 2-10min 50-100% methanol/water; flow rate 30mL/min; loading pump 4mL/min methanol; column SunFire 19*100mm

產率：0.178g(18.78%)Yield: 0.178g (18.78%)

LCMS(ESI)：[M+H]+ m/z：計算值493.2；實測值493.2；Rt=0.854min。LCMS (ESI): [M+H] + m/z: calculated 493.2; found 493.2; Rt=0.854 min.

步驟4：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[4-(4-異丙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1208)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-2-[4-(4-異丙基哌嗪-1-基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1234)之合成Step 4: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[4-(4-isopropylpiperazin-1-yl ) Phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1208) and rel-N-(6-amino-5-ethyl-3-pyridyl) -2-[(2S,5R)-2-[4-(4-isopropylpiperazin-1-yl)phenyl]-5-methyl-1-piperidinyl]-2-side oxyethyl Synthesis of amide (compound 1234)

藉由一般程序方案F步驟6製備Prepared by General Procedure F, Step 6

掌性分離條件：Chiralpak AS-H(250*20,5mkm)，己烷-IPA-MeOH，70-15-15，流速12mL/min；保留時間=10.582min且保留時間=16.370min。Chiral separation conditions: Chiralpak AS-H (250*20,5mkm), Hexane-IPA-MeOH, 70-15-15, flow rate 12 mL/min; retention time=10.582 min and retention time=16.370 min.

化合物1208：Compound 1208:

產率：72.8mg(40.90%)Yield: 72.8 mg (40.90%)

RT(Chiralpak AS-H(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=7.584min。RT (Chiralpak AS-H (250*20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=7.584min.

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.99(m,9H),1.09(m,3H),1.30(m,1H),1.68(m,1H),1.85(m,1H),1.91(m,1H),2.12(m,2H),2.38(m,2H),2.55(m,4H),2.69(m,1H),3.09(m,5H),3.68(dd,1H),5.58(m,3H),6.92(m,2H),7.15(m,2H), 7.48(m,1H),8.03(m,1H),10.47(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.99 (m, 9H), 1.09 (m, 3H), 1.30 (m, 1H), 1.68 (m, 1H), 1.85 (m, 1H) ,1.91(m,1H),2.12(m,2H),2.38(m,2H),2.55(m,4H),2.69(m,1H),3.09(m,5H),3.68(dd,1H), 5.58(m, 3H), 6.92(m, 2H), 7.15(m, 2H), 7.48(m, 1H), 8.03(m, 1H), 10.47(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值493.2；實測值493.2；Rt=1.815min。LCMS (ESI): [M+H] + m/z: calculated 493.2; found 493.2; Rt=1.815 min.

化合物1234：Compound 1234:

產率：61.9mg(34.78%)Yield: 61.9 mg (34.78%)

RT(Chiralpak AS-H(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=9.703min。RT (Chiralpak AS-H (250*20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=9.703min.

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.99(m,9H),1.09(m,3H),1.30(m,1H),1.68(m,1H),1.85(m,1H),1.91(m,1H),2.12(m,2H),2.38(m,2H),2.55(m,4H),2.69(m,1H),3.09(m,5H),3.68(dd,1H),5.58(m,3H),6.92(m,2H),7.15(m,2H),7.48(m,1H),8.03(m,1H),10.47(m,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 0.99 (m, 9H), 1.09 (m, 3H), 1.30 (m, 1H), 1.68 (m, 1H), 1.85 (m, 1H) ,1.91(m,1H),2.12(m,2H),2.38(m,2H),2.55(m,4H),2.69(m,1H),3.09(m,5H),3.68(dd,1H), 5.58 (m, 3H), 6.92 (m, 2H), 7.15 (m, 2H), 7.48 (m, 1H), 8.03 (m, 1H), 10.47 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值493.2；實測值493.2；Rt=1.814min。LCMS (ESI): [M+H] + m/z: calculated 493.2; found 493.2; Rt=1.814 min.

實例543. rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2-甲基-2,9-二氮雜螺[5.5]十一烷-9-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1269)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2-甲基-2,9-二氮雜螺[5.5]十一烷-9-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1243)之合成Example 543. rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(2-methyl-2 ,9-diazaspiro[5.5]undecan-9-yl)phenyl]-1-piperidinyl]-2-oxyacetamide (compound 1269) and rel-N-(6-amine yl-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2-methyl-2,9-diazaspiro[5.5]ten Synthesis of monoalk-9-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1243)

Figure 110128222-A0202-12-1937-796
Figure 110128222-A0202-12-1937-796

步驟1：(2S,5R)-5-甲基-2-[4-(2-甲基-2,9-二氮雜螺[[5.5]十一烷-9-基)苯基]哌啶-1-甲酸第三丁酯之合成Step 1: (2S,5R)-5-Methyl-2-[4-(2-methyl-2,9-diazaspiro[[5.5]undecan-9-yl)phenyl]piperidine -Synthesis of tert-butyl 1-carboxylate

藉由一般程序方案F步驟3(方法B)製備Prepared by General Procedure F, Step 3 (Method B)

HPLC條件：60-88% 0-6min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min甲醇)；管柱：YMC Triart C18 100x20mm，5umHPLC conditions: 60-88% 0-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min (load pump 4 mL/min methanol); column: YMC Triart C18 100x20mm, 5um

產率：42.0mg(6.74%)Yield: 42.0 mg (6.74%)

LCMS(ESI)：[M+H]+ m/z：計算值442.4；實測值442.4；Rt=2.592min。LCMS (ESI): [M+H] + m/z: calculated 442.4; found 442.4; Rt=2.592 min.

步驟2：外消旋-2-甲基-9-[4-[(2S,5R)-5-甲基-2-哌啶基]苯基]-2,9-二氮雜螺[5.5]十一烷之合成Step 2: Racemic-2-methyl-9-[4-[(2S,5R)-5-methyl-2-piperidinyl]phenyl]-2,9-diazaspiro[5.5] Synthesis of Undecane

藉由一般程序方案F步驟4(方法A)製備Prepared by General Procedure F, Step 4 (Method A)

產率：43.0mg(99.37%，3HCl)Yield: 43.0 mg (99.37%, 3HCl)

LCMS(ESI)：[M+H]+ m/z：計算值342.4；實測值342.4；Rt=1.466min。LCMS (ESI): [M+H] + m/z: calculated 342.4; found 342.4; Rt=1.466 min.

步驟3：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2-甲基-2,9-二氮雜螺[5.5]十一烷-9-基)苯基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 3: Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(2-methyl) Synthesis of -2,9-diazaspiro[5.5]undecan-9-yl)phenyl]-1-piperidinyl]-2-oxoacetamide

藉由一般程序方案F步驟5製備Prepared by General Procedure F, Step 5

HPLC條件：60-100% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min甲醇)；管柱：YMC Triart C18 100x20mm，5umHPLC conditions: 60-100% 0-5 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min (load pump 4 mL/min methanol); Column: YMC Triart C18 100x20mm, 5um

產率：14.0mg(20.87%)Yield: 14.0 mg (20.87%)

LCMS(ESI)：[M+H]+ m/z：計算值533.2；實測值533.2；Rt=2.228min。LCMS (ESI): [M+H] + m/z: calculated 533.2; found 533.2; Rt=2.228 min.

步驟4：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2-甲基-2,9-二氮雜螺[5.5]十一烷-9-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1269)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2-甲基-2,9-二氮雜螺[5.5]十一烷-9-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1243)之合成Step 4: rel-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(2-methyl-2 ,9-diazaspiro[5.5]undecan-9-yl)phenyl]-1-piperidinyl]-2-oxyacetamide (compound 1269) and rel-N-(6-amine yl-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2-methyl-2,9-diazaspiro[5.5]ten Synthesis of monoalk-9-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1243)

藉由一般程序方案F步驟6製備Prepared by General Procedure F, Step 6

掌性分離條件：Chiralpak IB(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，流速12mL/min；注入體積：200.000μl；管柱溫度：24℃；波長：205nm， 264nm)，保留時間(化合物1269)=16.655min)且保留時間(化合物1243)=21.256minChiral separation conditions: Chiralpak IB (250*20mm, 5mkm), hexane-IPA-MeOH, 50-25-25, flow rate 12mL/min; injection volume: 200.000μl; column temperature: 24°C; wavelength: 205nm, 264nm), retention time (compound 1269)=16.655min) and retention time (compound 1243)=21.256min

化合物1269：Compound 1269:

產率：3.8mg(38.00%)Yield: 3.8 mg (38.00%)

RT(Chiralpak IB(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=16.655min。RT (Chiralpak IB (250*20mm, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=16.655min.

1 H NMR(600MHz,dmso)δ 0.99-1.11(m,6H),1.22-1.31(m,3H),1.52-1.67(m,6H),1.81-2.15(m,8H),2.39-2.40(m,2H),2.69-2.71(m,1H),3.11-3.18(m,6H),3.39-3.98(m,2H),5.04-5.63(m,3H),6.90-6.93(m,2H),7.10-7.16(m,2H),7.46-7.49(d,1H),8.01-8.05(d,1H),10.45-10.49(d,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.11(m,6H),1.22-1.31(m,3H),1.52-1.67(m,6H),1.81-2.15(m,8H),2.39-2.40(m ,2H),2.69-2.71(m,1H),3.11-3.18(m,6H),3.39-3.98(m,2H),5.04-5.63(m,3H),6.90-6.93(m,2H),7.10 -7.16(m, 2H), 7.46-7.49(d, 1H), 8.01-8.05(d, 1H), 10.45-10.49(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值533.2；實測值533.2；Rt=0.752min。LCMS (ESI): [M+H] + m/z: calculated 533.2; found 533.2; Rt=0.752 min.

化合物1243：Compound 1243:

產率：2.8mg(28.00%)Yield: 2.8 mg (28.00%)

RT(Chiralpak IB(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=21.256min。RT (Chiralpak IB (250*20mm, 5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min) = 21.256min.

1 H NMR(600MHz,dmso)δ 0.99-1.22(m,6H),1.22-1.29(m,3H),1.51-1.67(m,6H),1.82-2.16(m,8H),2.40(m,2H),2.69-2.71(m,2H),3.10-3.18(m,5H),3.39-3.98(m,2H),5.04-5.63(m,3H),6.90-6.93(m,2H),7.10-7.16(m,2H),7.46-7.49(d,1H),8.07-8.05(d,1H),10.45-10.49(d,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.22(m,6H),1.22-1.29(m,3H),1.51-1.67(m,6H),1.82-2.16(m,8H),2.40(m,2H) ), 2.69-2.71(m, 2H), 3.10-3.18(m, 5H), 3.39-3.98(m, 2H), 5.04-5.63(m, 3H), 6.90-6.93(m, 2H), 7.10-7.16 (m,2H), 7.46-7.49(d,1H), 8.07-8.05(d,1H), 10.45-10.49(d,1H).

LCMS(ESI)：[M+H]+ m/z：計算值533.2；實測值533.2；Rt=0.758min。LCMS (ESI): [M+H] + m/z: calculated 533.2; found 533.2; Rt=0.758 min.

實例544. N-(6-胺基-5-乙基吡啶-3-基)-2-[(2R,5S)-2-[4-(4-{[乙基(甲基)胺基]甲基}哌啶-1-基)苯基]-5-甲基哌啶-1-基]-2-側氧基乙醯胺(化合物1232)之合成：Example 544. N-(6-Amino-5-ethylpyridin-3-yl)-2-[(2R,5S)-2-[4-(4-{[ethyl(methyl)amino] Synthesis of methyl}piperidin-1-yl)phenyl]-5-methylpiperidin-1-yl]-2-oxyacetamide (compound 1232):

Figure 110128222-A0202-12-1940-797
Figure 110128222-A0202-12-1940-797

產率：13.70mg；26.30%。Yield: 13.70 mg; 26.30%.

1 H NMR(600MHz,dmso)δ 0.94-0.96(m,3H),0.98-1.03(m,3H),1.08-1.18(m,5H),1.23-1.38(m,1H),1.54-1.60(m,1H),1.63-1.72(m,1H),1.73-1.77(m,2H),1.80-1.90(m,1H),1.92-2.06(m,1H),2.11(s,6H),2.14-2.22(m,1H),2.28-2.33(m,2H),2.39-2.41(m,1H),2.60-2.65(m,2H),2.72-3.20(m,1H),3.38-3.43(m,0.7H),3.62-3.66(m,2H),3.93-4.01(m,0.3H),5.02-5.57(m,1H),5.58-5.66(m,2H),6.88-6.93(m,2H),7.09-7.17(m,2H),7.44-7.52(m,1H),7.99-8.07(m,1H),10.39-10.56(m,1H)。 1 H NMR(600MHz,dmso)δ 0.94-0.96(m,3H),0.98-1.03(m,3H),1.08-1.18(m,5H),1.23-1.38(m,1H),1.54-1.60(m ,1H),1.63-1.72(m,1H),1.73-1.77(m,2H),1.80-1.90(m,1H),1.92-2.06(m,1H),2.11(s,6H),2.14-2.22 (m,1H),2.28-2.33(m,2H),2.39-2.41(m,1H),2.60-2.65(m,2H),2.72-3.20(m,1H),3.38-3.43(m,0.7H ),3.62-3.66(m,2H),3.93-4.01(m,0.3H),5.02-5.57(m,1H),5.58-5.66(m,2H),6.88-6.93(m,2H),7.09- 7.17 (m, 2H), 7.44-7.52 (m, 1H), 7.99-8.07 (m, 1H), 10.39-10.56 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值521.4；實測值521.4；Rt=2.050min。LCMS (ESI): [M+H] + m/z: calculated 521.4; found 521.4; Rt=2.050 min.

實例545. N-(6-胺基-5-乙基吡啶-3-基)-2-[(2R,5S)-5-甲基-2-(4-{4-[(吡咯啶-1-基)甲基]哌啶-1-基}苯基)哌啶-1-基]-2-側氧基乙醯胺(化合物1276)之合成Example 545. N-(6-Amino-5-ethylpyridin-3-yl)-2-[(2R,5S)-5-methyl-2-(4-{4-[(pyrrolidine-1 Synthesis of -yl)methyl]piperidin-1-yl}phenyl)piperidin-1-yl]-2-oxoacetamide (compound 1276)

Figure 110128222-A0202-12-1940-798
Figure 110128222-A0202-12-1940-798

產率：22.70mg；21.30%。Yield: 22.70 mg; 21.30%.

1 H NMR(600MHz,dmso)δ 0.97-1.03(m,3H),1.07-1.13(m,3H),1.15-1.22(m,2H),1.27-1.36(m,1H),1.50-1.74(m,7H),1.75-2.22(m,6H),2.24-2.28(m,2H),2.38-2.41(m,5H),2.62-2.73(m,1H),3.13-3.99(m,4H),5.00-5.53(m,1H),5.55-5.65(m,2H),6.88-6.94(m,2H),7.07-7.19(m,2H),7.44-7.52(m,1H),7.99-8.09(m,1H),10.43-10.53(m,1H)。 1 H NMR(600MHz,dmso)δ 0.97-1.03(m,3H),1.07-1.13(m,3H),1.15-1.22(m,2H),1.27-1.36(m,1H),1.50-1.74(m ,7H),1.75-2.22(m,6H),2.24-2.28(m,2H),2.38-2.41(m,5H),2.62-2.73(m,1H),3.13-3.99(m,4H),5.00 -5.53(m,1H),5.55-5.65(m,2H),6.88-6.94(m,2H),7.07-7.19(m,2H),7.44-7.52(m,1H),7.99-8.09(m, 1H), 10.43-10.53 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值534.4；實測值534.4；Rt=1.677min。LCMS (ESI): [M+2H] + m/z: calculated 534.4; found 534.4; Rt=1.677 min.

實例546. 外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1329)、rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1150)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1339)之合成Example 546. Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2-methyl) -5-oxa-2,8-diazaspiro[3.5]non-8-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1329), rel-N -(6-Amino-5-ethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[4-(2-methyl-5-oxa-2, 8-Diazaspiro[3.5]non-8-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1150) and rel-N-(6-amino-5 -Ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2-methyl-5-oxa-2,8-diazaspiro[3.5 ] Non-8-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1339) Synthesis

Figure 110128222-A0202-12-1941-799
Figure 110128222-A0202-12-1941-799

步驟1：外消旋-2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬烷之合成Step 1: Synthesis of racemic-2-methyl-5-oxa-2,8-diazaspiro[3.5]nonane

將LiAlH4 (374.08mg，9.86mmol)懸浮於THF(50mL)中且逐滴添加5-氧雜-2,8-二氮雜螺[3.5]壬烷-2-甲酸第三丁酯(1.5g，6.57mmol)於THF(50mL)中之溶液。完成添加之後，將反應混合物回流1h，然後使其冷卻至室溫。將水(10mL)小心逐滴添加到經預冷卻之反應混合物中。將所得混合物攪拌30min且過濾。將濾餅用THF(3*40mL)沖洗且將濾液在真空中濃縮，以獲得粗品2-甲基 -5-氧雜-2,8-二氮雜螺[3.5]壬烷(1.2g，8.44mmol，128.43%產率)。所獲得之材料不經純化即用於下一步驟中。LiAlH 4 (374.08 mg, 9.86 mmol) was suspended in THF (50 mL) and tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (1.5 g was added dropwise) , 6.57 mmol) in THF (50 mL). After the addition was complete, the reaction mixture was refluxed for 1 h and then allowed to cool to room temperature. Water (10 mL) was carefully added dropwise to the precooled reaction mixture. The resulting mixture was stirred for 30 min and filtered. The filter cake was rinsed with THF (3*40 mL) and the filtrate was concentrated in vacuo to give crude 2-methyl-5-oxa-2,8-diazaspiro[3.5]nonane (1.2 g, 8.44 g mmol, 128.43% yield). The material obtained was used in the next step without purification.

產率：1.2g(粗品)Yield: 1.2g (crude)

1 H NMR(500MHz,CDCl 3 )δ(ppm)1.23(m,1H),2.35(s,3H),2.77-2.97(m,4H),3.41-3.43(m,2H),3.55-3.57(m,2H),4.84(s,2H)。 1 H NMR (500MHz, CDCl 3 ) δ(ppm) 1.23(m, 1H), 2.35(s, 3H), 2.77-2.97(m, 4H), 3.41-3.43(m, 2H), 3.55-3.57(m , 2H), 4.84(s, 2H).

步驟2：外消旋-(2R,5S)-5-甲基-2-[4-(2-甲基-2,6-二氮雜螺[3.5]壬-6-基)苯基]哌啶-1-甲酸第三丁酯之合成Step 2: Racemic-(2R,5S)-5-methyl-2-[4-(2-methyl-2,6-diazaspiro[3.5]non-6-yl)phenyl]piperidine Synthesis of tert-butyl pyridine-1-carboxylate

藉由一般程序方案F步驟3(方法E)製備Prepared by General Procedure F, Step 3 (Method E)

產率：0.1g(48.12%)Yield: 0.1 g (48.12%)

LCMS(ESI)：[M+H]+ m/z：計算值416.4；實測值416.4；Rt=1.064min。LCMS (ESI): [M+H] + m/z: calculated 416.4; found 416.4; Rt=1.064 min.

步驟3：外消旋-2-甲基-8-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]-5-氧雜-2,8-二氮雜螺[3.5]壬烷之合成Step 3: Racemic-2-methyl-8-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]-5-oxa-2,8-diaza Synthesis of heterospiro[3.5]nonane

藉由一般程序方案F步驟4(方法B)製備Prepared by General Scheme F, Step 4 (Method B)

產率：0.12g(粗品)Yield: 0.12g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值316.2；實測值316.2；Rt=0.700min。LCMS (ESI): [M+H] + m/z: calculated 316.2; found 316.2; Rt=0.700 min.

步驟4：外消旋-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1329)之合成Step 4: Racemic-N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2-methyl) Synthesis of -5-oxa-2,8-diazaspiro[3.5]non-8-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1329)

藉由一般程序方案F步驟5製備Prepared by General Procedure F, Step 5

HPLC條件：40-50% 2-10min；水/MeCN；流速30mL/min；裝載泵4mL/minMeCN；管柱SunFire 19*100mm，5umHPLC conditions: 40-50% 2-10min; water/MeCN; flow rate 30mL/min; loading pump 4mL/minMeCN; column SunFire 19*100mm, 5um

產率：28.0mg(14.53%)Yield: 28.0 mg (14.53%)

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.71-0.78(m,1H),0.99-1.13(m,5H),1.29-2.20(m,5H),2.32-2.40(m,4H),2.89-2.90(m,2H),3.03(m,2H),3.13-3.18(m, 3H),3.38-3.42(m,3H),3.64-4.19(m,3H),5.05-5.63(m,3H),6.93-6.97(m,2H),7.15-7.21(m,2H),7.46-7.51(m,1H),7.99-8.16(m,1H),10.47-10.54(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.71-0.78 (m, 1H), 0.99-1.13 (m, 5H), 1.29-2.20 (m, 5H), 2.32-2.40 (m, 4H) ), 2.89-2.90(m, 2H), 3.03(m, 2H), 3.13-3.18(m, 3H), 3.38-3.42(m, 3H), 3.64-4.19(m, 3H), 5.05-5.63(m , 3H), 6.93-6.97(m, 2H), 7.15-7.21(m, 2H), 7.46-7.51(m, 1H), 7.99-8.16(m, 1H), 10.47-10.54(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值507.4；實測值507.4；Rt=2.217min。LCMS (ESI): [M+H] + m/z: calculated 507.4; found 507.4; Rt=2.217 min.

步驟5：rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[4-(2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1150)及rel-N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1339)之合成Step 5: rel-N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[4-(2-methyl-5 -oxa-2,8-diazaspiro[3.5]non-8-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1150) and rel-N-( 6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(2-methyl-5-oxa-2,8- Synthesis of Diazaspiro[3.5]non-8-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1339)

藉由一般程序方案F步驟6製備Prepared by General Procedure F, Step 6

掌性分離條件：Chiracel OD-H(250 * 20mm，5mkm)；流動相：己烷-IPA-MeOH，80-10-10；流速=12mL/min；管柱溫度：24℃；波長：205nm；保留時間(異構物A)=63.71min，保留時間(異構物B)=85.15min。Chiracel OD-H (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 80-10-10; flow rate=12mL/min; column temperature: 24°C; wavelength: 205nm; Retention time (Isomer A)=63.71 min, Retention time (Isomer B)=85.15 min.

化合物1339：Compound 1339:

產率：12.21mg(48.84%)Yield: 12.21 mg (48.84%)

RT(Chiracel OD-H(250 * 20mm,5mkm)；己烷-IPA-MeOH,80-10-10；0.6mL/min)=75.345min。RT (Chiracel OD-H (250*20mm, 5mkm); Hexane-IPA-MeOH, 80-10-10; 0.6mL/min)=75.345min.

1 H NMR(600MHz,dmso)δ 0.97-1.04(m,3H),1.05-1.14(m,3H),1.32(t,1H),1.68(d,1H),1.85(d,1H),2.03(d,1H),2.16(d,1H),2.35(s,3H),2.40(d,3H),2.69-3.06(m,5H),3.19(d,3H),3.38-4.02(m,6H),5.30(d,1H),5.62(d,2H),6.95(dd,2H),7.18(dd,2H),7.44-7.52(m,1H),8.03(d,1H),10.48(d,1H)。 1 H NMR (600MHz, dmso)δ 0.97-1.04(m, 3H), 1.05-1.14(m, 3H), 1.32(t, 1H), 1.68(d, 1H), 1.85(d, 1H), 2.03( d, 1H), 2.16(d, 1H), 2.35(s, 3H), 2.40(d, 3H), 2.69-3.06(m, 5H), 3.19(d, 3H), 3.38-4.02(m, 6H) ,5.30(d,1H),5.62(d,2H),6.95(dd,2H),7.18(dd,2H),7.44-7.52(m,1H),8.03(d,1H),10.48(d,1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值507.2；實測值507.2；Rt=0.886min。LCMS (ESI): [M+H] + m/z: calculated 507.2; found 507.2; Rt=0.886 min.

化合物1150：Compound 1150:

產率：11.18mg(44.72%)Yield: 11.18 mg (44.72%)

RT(Chiracel OD-H(250 * 20mm,5mkm)；己烷-IPA-MeOH,80-10-10；0.6mL/min)=59.883min。RT (Chiracel OD-H (250*20mm, 5mkm); Hexane-IPA-MeOH, 80-10-10; 0.6mL/min)=59.883min.

1 H NMR(600MHz,dmso)δ 0.99-1.13(m,6H),1.27-1.37(m,1H),1.63-1.72(m,1H),1.79-1.90(m,1H),1.92-2.22(m,2H),2.36-2.39(m,4H),2.70-3.07(m,5H),3.13-3.22(m,3H),3.42-3.98(m,5H),5.02-5.57(m,1H),5.58-5.66(m,2H),6.93-6.99(m,2H),7.13-7.23(m,2H),7.44-7.52(m,1H),7.99-8.09(m,1H),10.44-10.53(m,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.13(m,6H),1.27-1.37(m,1H),1.63-1.72(m,1H),1.79-1.90(m,1H),1.92-2.22(m ,2H),2.36-2.39(m,4H),2.70-3.07(m,5H),3.13-3.22(m,3H),3.42-3.98(m,5H),5.02-5.57(m,1H),5.58 -5.66(m, 2H), 6.93-6.99(m, 2H), 7.13-7.23(m, 2H), 7.44-7.52(m, 1H), 7.99-8.09(m, 1H), 10.44-10.53(m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值508.4；實測值508.4；Rt=0.883min。LCMS (ESI): [M+2H] + m/z: calculated 508.4; found 508.4; Rt=0.883 min.

實例547.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(3-(2-(二甲胺基)丙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1290)之合成Example 547. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(3-(2-(dimethylamino)propoxy)benzene yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1290)

Figure 110128222-A0202-12-1944-800
Figure 110128222-A0202-12-1944-800

步驟1：1-(3-溴苯氧基)丙-2-酮之合成Step 1: Synthesis of 1-(3-bromophenoxy)propan-2-one

將3-溴苯酚(6.6g，38.15mmol)及碳酸銫(21.13g，64.85mmol)溶解於DMF(70mL)中且在室溫下攪拌15min。添加1-氯丙-2-酮(5.29g，57.22mmol，4.56mL)且將所得混合物在室溫下攪拌隔夜。3-Bromophenol (6.6 g, 38.15 mmol) and cesium carbonate (21.13 g, 64.85 mmol) were dissolved in DMF (70 mL) and stirred at room temperature for 15 min. 1-Chloropropan-2-one (5.29 g, 57.22 mmol, 4.56 mL) was added and the resulting mixture was stirred at room temperature overnight.

LCMS(ESI)：[M]+ m/z：計算值229.2；實測值230.2；Rt=1.253min。LCMS (ESI): [M] + m/z: calculated 229.2; found 230.2; Rt=1.253 min.

步驟2：1-(3-溴苯氧基)-N,N-二甲基丙-2-胺之合成Step 2: Synthesis of 1-(3-bromophenoxy)-N,N-dimethylpropan-2-amine

將N -甲基甲胺(4.92g，43.65mmol，6.35mL)及乙酸(2.62g，43.65mmol，2.50mL)添加到1-(3-溴苯氧基)丙-2-酮(5g，21.83mmol)於MeOH(50mL)中之溶液中。將所得混合物在20℃下攪拌1h，之後向其中添加氰基硼氫化鈉(2.74g，43.65mmol)。此後，繼續攪拌16h。然後，在減壓下移除溶劑且將殘餘物分 配於10%K2 CO3 水溶液(30ml)與DCM(80ml)之間。將有機層分離，經固體K2 CO3 乾燥且在減壓下濃縮，藉由FCC(Companion comb flash；40g SiO2 ，CHCl3 -MeCN 0~100%，流速=40mL/min，cv=15)純化，以獲得1-(3-溴苯氧基)-N,N -二甲基丙-2-胺(1g，3.87mmol，17.75%產率)。 N -methylmethylamine (4.92 g, 43.65 mmol, 6.35 mL) and acetic acid (2.62 g, 43.65 mmol, 2.50 mL) were added to 1-(3-bromophenoxy)propan-2-one (5 g, 21.83 g mmol) in MeOH (50 mL). The resulting mixture was stirred at 20°C for 1 h before adding sodium cyanoborohydride (2.74 g, 43.65 mmol). Thereafter, stirring was continued for 16 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 10 % aqueous K2CO3 ( 30 ml) and DCM (80 ml). The organic layer was separated, dried over solid K2CO3 and concentrated under reduced pressure by FCC (Companion comb flash; 40 g SiO2 , CHCl3 - MeCN 0~100%, flow rate=40 mL/min, cv=15) Purified to obtain 1-(3-bromophenoxy) -N,N -dimethylpropan-2-amine (1 g, 3.87 mmol, 17.75% yield).

LCMS(ESI)：[M]+ m/z：計算值258.2；實測值259.2；Rt=0.877min。LCMS (ESI): [M] + m/z: calculated 258.2; found 259.2; Rt=0.877 min.

步驟3：N,N-二甲基-1-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)丙-2-胺之合成Step 3: N,N-Dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy Synthesis of yl)propan-2-amine

將1-(3-溴苯氧基)-N,N -二甲基丙-2-胺(872mg，3.38mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(857.76mg，3.38mmol)及乙酸鉀(663.00mg，6.76mmol，422.29μL)於二噁烷(10mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後添加Pd(dppf)Cl2 *DCM(247.16mg，337.78μmol)且將反應混合物在氬氣、90℃下攪拌12h，然後冷卻且過濾。將濾餅用二噁烷(2*50ml)洗滌且丟棄。將濾液在真空中濃縮，以得到呈棕色油狀物之粗品N,N -二甲基-1-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]丙-2-胺，其直接用於該步驟中。1-(3-Bromophenoxy) -N,N -dimethylpropan-2-amine (872 mg, 3.38 mmol), 4,4,5,5-tetramethyl-2-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (857.76 mg, 3.38 mmol) and A mixture of potassium acetate (663.00 mg, 6.76 mmol, 422.29 [mu]L) in dioxane (10 mL) was evacuated and backfilled with argon. This was repeated twice, then Pd(dppf)Cl 2 *DCM (247.16 mg, 337.78 μmol) was added and the reaction mixture was stirred under argon at 90° C. for 12 h, then cooled and filtered. The filter cake was washed with dioxane (2*50ml) and discarded. The filtrate was concentrated in vacuo to give crude N,N -dimethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxane as a brown oil Boron-2-yl)phenoxy]propan-2-amine, which was used directly in this step.

步驟4：(3S)-6-(3-(2-(二甲胺基)丙氧基)苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (3S)-6-(3-(2-(dimethylamino)propoxy)phenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid 3rd Synthesis of Butyl Ester

將N,N -二甲基-1-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]丙-2-胺(1.56g，5.10mmol)、(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.76g，5.10mmol)及碳酸鈉(1.08g，10.21mmol，427.35μL)混合於二噁烷(9mL)及水(3mL)之混合物中且將所得混合物抽真空且用氬氣回填三次。將Pd(dppf)Cl2 *DCM(208.43mg，255.23μmol)添加到先前混合物中且將所得混合物在90℃下加熱隔夜。將反應混合物用水(30ml)稀釋且將所得混合物用EtOAc(2*30ml)萃取。將經合併之有機層用鹽水洗滌(30ml)，經硫酸鈉乾 燥，過濾且在真空中濃縮，以獲得(3S )-6-[3-[2-(二甲胺基)丙氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.63g，4.34mmol，85.11%產率)。 N,N -dimethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy] Propan-2-amine (1.56 g, 5.10 mmol), ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid Tertiary butyl ester (1.76 g, 5.10 mmol) and sodium carbonate (1.08 g, 10.21 mmol, 427.35 μL) were combined in a mixture of dioxane (9 mL) and water (3 mL) and the resulting mixture was evacuated and flushed with argon Backfill three times. Pd(dppf)Cl2*DCM ( 208.43 mg, 255.23 μmol) was added to the previous mixture and the resulting mixture was heated at 90°C overnight. The reaction mixture was diluted with water (30ml) and the resulting mixture was extracted with EtOAc (2*30ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give ( 3S )-6-[3-[2-(dimethylamino)propoxy]benzene yl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.63 g, 4.34 mmol, 85.11% yield).

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=1.313min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=1.313 min.

步驟5：N,N-二甲基-1-(3-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯氧基)丙-2-胺之合成Step 5: N,N-Dimethyl-1-(3-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)phenoxy)propan-2- Synthesis of Amines

將(3S )-6-[3-[2-(二甲胺基)丙氧基]苯基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.63g，4.35mmol)溶解於DCM(6mL)中且向其中添加TFA(6mL)。攪拌所得混合物1h。將反應混合物在真空中濃縮。將K2 CO3 水溶液(12g於140ml水中)添加到殘餘物中且將所得混合物用DCM(2*40ml)萃取。將經合併之有機層經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得N,N -二甲基-1-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]丙-2-胺(1g，3.64mmol，83.73%產率)。( 3S )-6-[3-[2-(dimethylamino)propoxy]phenyl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.63 g, 4.35 mmol) was dissolved in DCM (6 mL) and TFA (6 mL) was added to it. The resulting mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo. Aqueous K2CO3 ( 12g in 140ml water) was added to the residue and the resulting mixture was extracted with DCM ( 2 *40ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain N,N -dimethyl-1-[3-[( 3S )-3-methyl-2,3,4,5 - Tetrahydropyridin-6-yl]phenoxy]propan-2-amine (1 g, 3.64 mmol, 83.73% yield).

LCMS(ESI)：[M]+ m/z：計算值274.2；實測值275.2；Rt=0.590min。LCMS (ESI): [M] + m/z: calculated 274.2; found 275.2; Rt=0.590 min.

步驟6：N,N-二甲基-1-(3-((2R,5S)-5-甲基哌啶-2-基)苯氧基)丙-2-胺之合成Step 6: Synthesis of N,N-dimethyl-1-(3-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)propan-2-amine

將N,N -二甲基-1-[3-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]苯氧基]丙-2-胺(1g，3.64mmol)溶解於MeOH(20mL)中且分批添加硼氫化鈉(413.62mg，10.93mmol，385.12μL)。將所得混合物攪拌隔夜。將水(10ml)添加到反應混合物中且在真空中濃縮所得混合物。將殘餘物用水(30ml)稀釋且將所得混合物用DCM(2*40ml)萃取。將經合併之有機層經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得N,N -二甲基-1-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]丙-2-胺(1.03g，粗品)。 N,N -dimethyl-1-[3-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]phenoxy]propan-2-amine ( 1 g, 3.64 mmol) was dissolved in MeOH (20 mL) and sodium borohydride (413.62 mg, 10.93 mmol, 385.12 μL) was added portionwise. The resulting mixture was stirred overnight. Water (10 ml) was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water (30ml) and the resulting mixture was extracted with DCM (2*40ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain N,N -dimethyl-1-[3-[( 2R,5S )-5-methyl-2-piperidinyl ]phenoxy]propan-2-amine (1.03 g, crude).

LCMS(ESI)：[M]+ m/z：計算值276.2；實測值277.2；Rt=0.672min。LCMS (ESI): [M] + m/z: calculated 276.2; found 277.2; Rt=0.672 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(3-(2-(二甲胺基)丙氧基)苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1290)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(3-(2-(dimethylamino)propoxy)benzene yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1290)

將N,N -二甲基-1-[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]丙-2-胺(328mg，1.19mmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(248.24mg， 1.19mmol)及TEA(600.37mg，5.93mmol，826.95μL)一起混合於DMF(3mL)中且向其中添加HATU(541.43mg，1.42mmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min 30-60% MeOH+NH3 30ml/min(裝載泵4ml MeOH)，管柱：SunFire 100*19mm，5微米)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[2-(二甲胺基)丙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(15.7mg，33.58μmol，2.83%產率)及N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-2-[3-[2-(二甲胺基)丙氧基]苯基]-5-甲基-1-哌啶基]乙醯胺(32.7mg，69.93μmol，5.89%產率)。 N,N -dimethyl-1-[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]propan-2-amine (328 mg, 1.19 mmol), 2- [(6-Amino-5-ethyl-3-pyridinyl)amino]-2-oxoacetic acid (248.24 mg, 1.19 mmol) and TEA (600.37 mg, 5.93 mmol, 826.95 μL) were mixed together in DMF (3 mL) and to this was added HATU (541.43 mg, 1.42 mmol). The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min 30-60% MeOH+ NH3 30 ml/min (loading pump 4 ml MeOH), column: SunFire 100*19 mm, 5 microns) to obtain N- (6-amine) yl-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-2-[3-[2-(dimethylamino)propoxy]phenyl]- 5-Methyl-1-piperidinyl]acetamide (15.7 mg, 33.58 μmol, 2.83% yield) and N- (6-amino-5-ethyl-3-pyridyl)-2-oxo yl-2-[( 2R,5S )-2-[3-[2-(dimethylamino)propoxy]phenyl]-5-methyl-1-piperidinyl]acetamide (32.7 mg , 69.93 μmol, 5.89% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,6H),1.06-1.13(m,3H),1.27-1.38(m,1H),1.58-1.71(m,1H),1.80-1.93(m,1H),1.95-2.18(m,2H),2.19-2.22(m,6H),2.36-2.42(m,2H),2.73-3.26(m,2H),3.44-4.05(m,3H),5.10-5.55(m,1H),5.57-5.67(m,2H),6.77-6.94(m,3H),7.21-7.32(m,1H),7.42-7.54(m,1H),7.97-8.09(m,1H),10.47-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.03(m,6H), 1.06-1.13(m,3H), 1.27-1.38(m,1H), 1.58-1.71(m,1H) ,1.80-1.93(m,1H),1.95-2.18(m,2H),2.19-2.22(m,6H),2.36-2.42(m,2H),2.73-3.26(m,2H),3.44-4.05( m,3H),5.10-5.55(m,1H),5.57-5.67(m,2H),6.77-6.94(m,3H),7.21-7.32(m,1H),7.42-7.54(m,1H), 7.97-8.09 (m, 1H), 10.47-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值467.2；實測值468.2；Rt=2.156min。LCMS (ESI): [M] + m/z: calculated 467.2; found 468.2; Rt=2.156 min.

實例548.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)咪唑并[1,2-a ]吡啶-7-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1274)之合成Example 548. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidine-4 Synthesis of -yl)imidazo[ 1,2-a ]pyridin-7-yl)piperidin-1-yl)-2-oxoacetamide (compound 1274)

Figure 110128222-A0202-12-1947-801
Figure 110128222-A0202-12-1947-801

步驟1：4-(7-溴咪唑并[1,2-a]吡啶-2-基)哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-butyl 4-(7-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

將4-溴吡啶-2-胺(2.83g，16.33mmol)及4-(2-溴乙醯基)哌啶-1-甲酸第 三丁酯(5g，16.33mmol)溶解於EtOH(50mL)中且將其回流16h。然後將其蒸發，以得到4-(7-溴咪唑并[1,2-a ]吡啶-2-基)哌啶-1-甲酸第三丁酯(5.6g，14.73mmol，90.18%產率)。4-Bromopyridin-2-amine (2.83 g, 16.33 mmol) and 3-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (5 g, 16.33 mmol) were dissolved in EtOH (50 mL) And it was refluxed for 16h. It was then evaporated to give tert-butyl 4-(7-bromoimidazo[ 1,2-a ]pyridin-2-yl)piperidine-1-carboxylate (5.6 g, 14.73 mmol, 90.18% yield) .

LCMS(ESI)：[M]+ m/z：計算值380.2；實測值381.2；Rt=0.950min。LCMS (ESI): [M] + m/z: calculated 380.2; found 381.2; Rt=0.950 min.

步驟2：7-溴-2-(哌啶-4-基)咪唑并[1,2-a]吡啶之合成Step 2: Synthesis of 7-bromo-2-(piperidin-4-yl)imidazo[1,2-a]pyridine

將4-(7-溴咪唑并[1,2-a]吡啶-2-基)哌啶-1-甲酸第三丁酯(5.6g，14.73mmol)溶解於MeOH(50mL)中且添加二噁烷/HCl(14.73mmol，6mL)。然後將反應混合物在室溫下攪拌4h且將其過濾。將固體乾燥，以得到7-溴-2-(4-哌啶基)咪唑并[1,2-a ]吡啶(4.9g，13.88mmol，94.24%產率，2HCl)。4-(7-Bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (5.6 g, 14.73 mmol) was dissolved in MeOH (50 mL) and dioxane was added alkane/HCl (14.73 mmol, 6 mL). The reaction mixture was then stirred at room temperature for 4 h and it was filtered. The solid was dried to give 7-bromo-2-(4-piperidinyl)imidazo[ 1,2-a ]pyridine (4.9 g, 13.88 mmol, 94.24% yield, 2HCl).

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=0.339min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=0.339 min.

步驟3：7-溴-2-(1-甲基哌啶-4-基)咪唑并[1,2-a]吡啶之合成Step 3: Synthesis of 7-bromo-2-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine

將用7-8% MeOH穩定之37重量%甲醛水溶液(833.38mg，27.76mmol，769.51μL)及乙酸鈉(2.28g，27.76mmol，1.49mL)添加到7-溴-2-(4-哌啶基)咪唑并[1,2-a ]吡啶(4.9g，13.88mmol，2HCl)於MeOH(77.88mL)中之溶液中。將所得混合物在20℃下攪拌1小時，之後向其中添加氰基硼氫化鈉(1.74g，27.76mmol)。此後，繼續攪拌16h。然後，在減壓下移除溶劑且將殘餘物分配於15%K2 CO3 水溶液(30ml)與DCM(50ml)之間。將有機層分離，經固體Na2 SO4 乾燥且在減壓下濃縮，留下7-溴-2-(1-甲基-4-哌啶基)咪唑并[1,2-a ]吡啶(4g，13.60mmol，97.98%產率)。Aqueous 37 wt% formaldehyde stabilized with 7-8% MeOH (833.38 mg, 27.76 mmol, 769.51 μL) and sodium acetate (2.28 g, 27.76 mmol, 1.49 mL) were added to 7-bromo-2-(4-piperidine) yl)imidazo[ 1,2-a ]pyridine (4.9 g, 13.88 mmol, 2HCl) in MeOH (77.88 mL). The resulting mixture was stirred at 20°C for 1 hour, after which sodium cyanoborohydride (1.74 g, 27.76 mmol) was added. Thereafter, stirring was continued for 16 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 15 % aqueous K2CO3 (30ml) and DCM (50ml). The organic layer was separated, dried over solid Na 2 SO 4 and concentrated under reduced pressure to leave 7-bromo-2-(1-methyl-4-piperidinyl)imidazo[ 1,2-a ]pyridine ( 4 g, 13.60 mmol, 97.98% yield).

LCMS(ESI)：[M]+ m/z：計算值294.2；實測值295.2；Rt=0.256min。LCMS (ESI): [M] + m/z: calculated 294.2; found 295.2; Rt=0.256 min.

步驟4：2-(1-甲基哌啶-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)咪唑并[1,2-a]吡啶之合成Step 4: 2-(1-Methylpiperidin-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)imidazo[1,2-a]pyridine

向7-溴-2-(1-甲基-4-哌啶基)咪唑并[1,2-a ]吡啶(4g，13.60mmol)之溶液中添加乙酸鉀(2.67g，27.19mmol，1.70mL)及雙( 頻哪醇)二硼(3.45g，13.60 mmol)。將反應混合物除氣且一次性添加Pd(dppf)Cl2 *DCM(555.18mg，679.83μmol)。將混合物用Ar進一步除氣且在90℃下加熱16h。在此時間之後，使反應混合物冷卻至室溫，過濾且在真空中移除溶劑，以得到2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)咪唑并[1,2-a ]吡啶(4.6g，13.48mmol，99.14%產率)。To a solution of 7-bromo-2-(1-methyl-4-piperidinyl)imidazo[ 1,2-a ]pyridine (4 g, 13.60 mmol) was added potassium acetate (2.67 g, 27.19 mmol, 1.70 mL) ) and bis( pinacol)diboron (3.45 g, 13.60 mmol). The reaction mixture was degassed and Pd(dppf)Cl2*DCM ( 555.18 mg, 679.83 μmol) was added in one portion. The mixture was further degassed with Ar and heated at 90 °C for 16 h. After this time, the reaction mixture was cooled to room temperature, filtered and the solvent was removed in vacuo to give 2-(1-methyl-4-piperidinyl)-7-(4,4,5,5- Tetramethyl-1,3,2-dioxaborol-2-yl)imidazo[ 1,2-a ]pyridine (4.6 g, 13.48 mmol, 99.14% yield).

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=0.209min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=0.209 min.

步驟5：(S)-3-甲基-6-(2-(1-甲基哌啶-4-基)咪唑并[1,2-a]吡啶-7-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-3-Methyl-6-(2-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridin-7-yl)-3,4-di Synthesis of Hydropyridine-1(2H)-Carboxylic Acid 3-Butyl Ester

將(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(6.98g，20.22mmol)、2-(1-甲基-4-哌啶基)-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)咪唑并[1,2-a ]吡啶(4.6g，13.48mmol)及碳酸鈉(4.29g，40.44mmol，1.69mL)添加到二噁烷(58.95mL)及水(19.65mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(550.40mg，673.98μmol)。將反應混合物在氬氣、70℃下攪拌16h，然後冷卻且過濾。將濾餅用二噁烷(2*20ml)洗滌且丟棄。將濾液在真空中蒸發，以得到呈棕色油狀物之(3S )-3-甲基-6-[2-(1-甲基-4-哌啶基)咪唑并[1,2-a ]吡啶-7-基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5g，12.18mmol，90.35%產率)，其不經純化即用於下一步驟中。( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (6.98 g, 20.22 mmol), 2-(1-Methyl-4-piperidinyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)imidazole To a mixture of dioxane (58.95 mL) and water (19.65 mL) was added [ 1,2-a ]pyridine (4.6 g, 13.48 mmol) and sodium carbonate (4.29 g, 40.44 mmol, 1.69 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM ( 550.40 mg, 673.98 μmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 16 h, then cooled and filtered. The filter cake was washed with dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give ( 3S )-3-methyl-6-[2-(1-methyl-4-piperidinyl)imidazo[ 1,2-a ] as a brown oil Pyridin-7-yl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (5 g, 12.18 mmol, 90.35% yield) was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=0.928min。LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=0.928 min.

步驟6：(S)-7-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-甲基哌啶-4-基)咪唑并[1,2-a]吡啶之合成Step 6: (S)-7-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-methylpiperidin-4-yl)imidazo[1 Synthesis of ,2-a]pyridine

將(3S )-3-甲基-6-[2-(1-甲基-4-哌啶基)咪唑并[1,2-a ]吡啶-7-基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5g，12.18mmol)溶解於MeOH(50mL)中且向其中添加二噁烷/HCl(10.96mmol，5mL)。然後將其在室溫下攪拌2h。將反應混合 物蒸發，以得到2-(1-甲基-4-哌啶基)-7-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]咪唑并[1,2-a ]吡啶(3.8g，9.91mmol，81.39%產率，2HCl)。( 3S )-3-methyl-6-[2-(1-methyl-4-piperidinyl)imidazo[ 1,2-a ]pyridin-7-yl]-3,4-dihydro- 2H -Pyridine-1-carboxylic acid tert-butyl ester (5 g, 12.18 mmol) was dissolved in MeOH (50 mL) and to it was added dioxane/HCl (10.96 mmol, 5 mL). It was then stirred at room temperature for 2 h. The reaction mixture was evaporated to give 2-(1-methyl-4-piperidinyl)-7-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl] Imidazo[ 1,2-a ]pyridine (3.8 g, 9.91 mmol, 81.39% yield, 2HCl).

LCMS(ESI)：[M]+ m/z：計算值310.2；實測值311.2；Rt=0.581min。LCMS (ESI): [M] + m/z: calculated 310.2; found 311.2; Rt=0.581 min.

步驟7：7-((5S)-5-甲基哌啶-2-基)-2-(1-甲基哌啶-4-基)咪唑并[1,2-a]吡啶之合成Step 7: Synthesis of 7-((5S)-5-methylpiperidin-2-yl)-2-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine

在0℃下，向2-(1-甲基-4-哌啶基)-7-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]咪唑并[1,2-a ]吡啶(3.8g，9.91mmol，2HCl)於MeOH(50mL)中之經攪拌之溶液中添加硼氫化鈉(750.03mg，19.82mmol，698.35μL)。將所得反應混合物在25℃下攪拌16h。完成之後，將反應混合物在減壓下濃縮，然後用水20mL及50ml EtOAc萃取。將經合併之有機相用鹽水20mL洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得2-(1-甲基-4-哌啶基)-7-[(2R,5S )-5-甲基-2-哌啶基]咪唑并[1,2-a ]吡啶(2.5g，8.00mmol，80.72%產率)，其不經進一步純化即用於下一步驟中。To 2-(1-methyl-4-piperidinyl)-7-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]imidazole at 0 °C To a stirred solution of [ 1,2-a ]pyridine (3.8 g, 9.91 mmol, 2HCl) in MeOH (50 mL) was added sodium borohydride (750.03 mg, 19.82 mmol, 698.35 μL). The resulting reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure, then extracted with 20 mL of water and 50 mL of EtOAc. The combined organic phases were washed with brine 20 mL, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 2-(1-methyl-4-piperidinyl)-7-[( 2R,5S )- 5-Methyl-2-piperidinyl]imidazo[ 1,2-a ]pyridine (2.5 g, 8.00 mmol, 80.72% yield) was used in the next step without further purification.

LCMS(ESI)：[M]+ m/z：計算值312.2；實測值313.2；Rt=0.255min。LCMS (ESI): [M] + m/z: calculated 312.2; found 313.2; Rt=0.255min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)咪唑并[1,2-a]吡啶-7-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1274)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidine-4 Synthesis of -yl)imidazo[1,2-a]pyridin-7-yl)piperidin-1-yl)-2-oxoacetamide (compound 1274)

將DIPEA(308.90mg，2.39mmol，416.30μL)添加到相應2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(0.2g，956.02μmol)及2-(1-甲基-4-哌啶基)-7-[(2R,5S )-5-甲基-2-哌啶基]咪唑并[1,2-a ]吡啶(298.71mg，956.02μmol)於DMF(19.58mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(399.86mg，1.05mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*1005mkm管柱且以MeCN+FA為溶析液混合物)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[2-(1-甲基-4-哌啶基)咪唑并[1,2-a ]吡啶-7-基]-1-哌啶基]乙醯胺(21.9mg，39.84μmol，4.17%產率，HCOOH)。DIPEA (308.90 mg, 2.39 mmol, 416.30 μL) was added to the corresponding 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (0.2 g, 956.02 μmol ) and 2-(1-methyl-4-piperidinyl)-7-[( 2R,5S )-5-methyl-2-piperidinyl]imidazo[ 1,2-a ]pyridine (298.71 mg , 956.02 μmol) in DMF (19.58 mL). The resulting mixture was stirred for 5 min before HATU (399.86 mg, 1.05 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*1005mkm column with MeCN+FA as eluent mixture) to give N- (6-amino-5-ethyl-3-pyridyl)-2 -Pendant oxy-2-[( 2R,5S )-5-methyl-2-[2-(1-methyl-4-piperidinyl)imidazo[ 1,2-a ]pyridin-7-yl ]-1-Piperidinyl]acetamide (21.9 mg, 39.84 μmol, 4.17% yield, HCOOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.14(m,6H),1.30-1.39(m,1H),1.66 -1.74(m,3H),1.76-2.18(m,7H),2.19-2.27(m,4H),2.35-2.42(m,1H),2.62-2.65(m,1H),2.76-2.91(m,3H),3.93-4.07(m,1H),5.13-5.58(m,1H),5.58-5.67(m,2H),6.71-6.86(m,1H),7.33-7.54(m,2H),7.62-7.69(m,1H),7.99-8.09(m,1H),8.40-8.45(m,1H),10.50-10.64(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.14(m, 6H), 1.30-1.39(m, 1H), 1.66-1.74(m, 3H), 1.76-2.18(m, 7H) ,2.19-2.27(m,4H),2.35-2.42(m,1H),2.62-2.65(m,1H),2.76-2.91(m,3H),3.93-4.07(m,1H),5.13-5.58( m,1H),5.58-5.67(m,2H),6.71-6.86(m,1H),7.33-7.54(m,2H),7.62-7.69(m,1H),7.99-8.09(m,1H), 8.40-8.45 (m, 1H), 10.50-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值503.2；實測值504.2；Rt=1.336min。LCMS (ESI): [M] + m/z: calculated 503.2; found 504.2; Rt=1.336 min.

實例549.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-(((R )-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1178)之合成Example 549. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-(((( R )-1-methyl) Synthesis of pyrrolidin-3-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1178)

Figure 110128222-A0202-12-1951-802
Figure 110128222-A0202-12-1951-802

步驟1：(2R,5S)-2-(3-(((R)-1-((苯甲氧基)羰基)吡咯啶-3-基)甲氧基)苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: (2R,5S)-2-(3-(((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)methoxy)phenyl)-5-methyl Synthesis of tert-butyl piperidine-1-carboxylate

將(2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯(0.9g，3.09mmol)、(3R )-3-(甲基磺醯基氧基甲基)吡咯啶-1-甲酸苯甲酯(1.26g，4.02mmol)及99%無水碳酸鉀(853.78mg，6.18mmol，372.83μL)一起混合於MeCN(19.63mL)中且在81℃下加熱36h。在真空下濃縮反應混合物。將所獲得之殘餘物溶解於EtOAc/H2 O中，分離EtOAc層且將水層用EtOAc萃取兩次。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空下濃縮。藉由FCC(於己烷中之MTBE，0%至100%)純化粗產物。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[[(3R )-1-苯甲氧基羰基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.25g，491.50μmol，15.91%產率)。( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (0.9 g, 3.09 mmol), ( 3R )-3-(methylsulfonyl Benzyloxymethyl)pyrrolidine-1-carboxylate (1.26 g, 4.02 mmol) and 99% anhydrous potassium carbonate (853.78 mg, 6.18 mmol, 372.83 μL) were mixed together in MeCN (19.63 mL) and placed in 81 Heated at ℃ for 36h. The reaction mixture was concentrated under vacuum. The obtained residue was dissolved in EtOAc/ H2O , the EtOAc layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by FCC (MTBE in hexanes, 0% to 100%). ( 2R,5S )-5-methyl-2-[3-[[( 3R )-1-benzyloxycarbonylpyrrolidin-3-yl]methoxy]phenyl was obtained as a pale yellow gum ] tert-butyl piperidine-1-carboxylate (0.25 g, 491.50 μmol, 15.91% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值408.2；實測值409.2；Rt=1.814min。LCMS (ESI): [M-Boc] + m/z: calculated 408.2; found 409.2; Rt=1.814 min.

步驟2：(2R,5S)-5-甲基-2-(3-((R)-吡咯啶-3-基甲氧基)苯基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-5-methyl-2-(3-((R)-pyrrolidin-3-ylmethoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester

在H2 (1atm)、20℃下，將(2R,5S )-5-甲基-2-[3-[[(3R )-1-苯甲氧基羰基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.25g，491.50μmol)於MeOH(10mL)中之溶液經Pd/C(10%)(0.075g，491.50μmol)氫化12h。過濾反應混合物，將濾餅用MeOH洗滌且在減壓下濃縮濾液。所獲得之產物不經進一步純化即用於下一步驟中。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[[(3R )-吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，粗品)。( 2R,5S )-5-methyl-2-[3-[[( 3R )-1-benzyloxycarbonylpyrrolidin-3-yl]methoxy under H 2 (1 atm) at 20°C A solution of tert-butyl]phenyl]piperidine-1-carboxylate (0.25 g, 491.50 μmol) in MeOH (10 mL) was hydrogenated over Pd/C (10%) (0.075 g, 491.50 μmol) for 12 h. The reaction mixture was filtered, the filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The product obtained was used in the next step without further purification. ( 2R,5S )-5-methyl-2-[3-[[( 3R )-pyrrolidin-3-yl]methoxy]phenyl]piperidine-1-carboxylic acid was obtained as a pale yellow gum Tertiary butyl ester (0.21 g, crude).

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=1.241min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=1.241 min.

步驟3：(2R,5S)-5-甲基-2-(3-(((R)-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶-1-甲酸第三丁酯之合成Step 3: (2R,5S)-5-methyl-2-(3-(((R)-1-methylpyrrolidin-3-yl)methoxy)phenyl)piperidine-1-carboxylic acid Synthesis of tributyl ester

將(2R,5S )-5-甲基-2-[3-[[(3R )-吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，560.72μmol)、用7-8% MeOH穩定之37重量%甲醛水溶液(25.25mg，841.09μmol，23.32μL)及乙酸(67.35mg，1.12mmol，64.20μL)溶解於MeOH(5mL)中且攪拌1h，然後在用冰+水冷卻時分批添加氰基硼氫化鈉(105.71mg，1.68mmol)且將反應混合物攪拌12h。蒸發溶劑，將所獲得之殘餘物溶解於Na2 CO3 (水溶液)中且用DCM(3*50ml)萃取，將DCM層經Na2 SO4 乾燥，過濾且在真空上蒸發。所獲得之產物不經進一步純化即用於下一步驟中。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[[(3R )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，540.48μmol，96.39%產率)。( 2R,5S )-5-methyl-2-[3-[[( 3R )-pyrrolidin-3-yl]methoxy]phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.21 g , 560.72 μmol), 37 wt% aqueous formaldehyde stabilized with 7-8% MeOH (25.25 mg, 841.09 μmol, 23.32 μL) and acetic acid (67.35 mg, 1.12 mmol, 64.20 μL) were dissolved in MeOH (5 mL) and stirred for 1 h , then sodium cyanoborohydride (105.71 mg, 1.68 mmol) was added portionwise while cooling with ice+water and the reaction mixture was stirred for 12 h. The solvent was evaporated, the obtained residue was dissolved in Na2CO3 ( aq ) and extracted with DCM (3*50ml), the DCM layer was dried over Na2SO4 , filtered and evaporated in vacuo. The product obtained was used in the next step without further purification. ( 2R,5S )-5-methyl-2-[3-[[( 3R )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine was obtained as a pale yellow gum - 3-Butyl 1-carboxylate (0.21 g, 540.48 μmol, 96.39% yield).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=0.954min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=0.954 min.

步驟4：(2R,5S)-5-甲基-2-(3-(((R)-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶之合成Step 4: Synthesis of (2R,5S)-5-methyl-2-(3-(((R)-1-methylpyrrolidin-3-yl)methoxy)phenyl)piperidine

將(2R,5S )-5-甲基-2-[3-[[(3R )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，540.48μmol)溶解於MeOH(7mL)及二噁烷/HCl(7mL) 之混合物中。將所得澄清溶液在20℃下攪拌4h。在真空下濃縮反應混合物。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[[(3R )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶(0.2g，粗品，2HCl)。( 2R,5S )-5-methyl-2-[3-[[( 3R )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine-1-carboxylic acid tert-butyl The ester (0.21 g, 540.48 μmol) was dissolved in a mixture of MeOH (7 mL) and dioxane/HCl (7 mL). The resulting clear solution was stirred at 20 °C for 4 h. The reaction mixture was concentrated under vacuum. ( 2R,5S )-5-methyl-2-[3-[[( 3R )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine was obtained as a pale yellow gum (0.2 g, crude, 2HCl).

LCMS(ESI)：[M]+ m/z：計算值288.2；實測值289.2；Rt=0.601min。LCMS (ESI): [M] + m/z: calculated 288.2; found 289.2; Rt=0.601 min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-(((R)-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1178)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-((((R)-1-methyl) Synthesis of pyrrolidin-3-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1178)

將(2R,5S )-5-甲基-2-[3-[[(3R )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶(0.2g，553.48μmol，2HCl)、TEA(392.05mg，3.87mmol，540.01μL)及2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(115.79mg，553.48μmol)溶解於DMF(5mL)中且一次性添加HATU(231.50mg，608.83μmol)，將所得混合物在20℃下攪拌3h。將反應混合物提交至HPLC(2-10min 60-85% MeOH+NH3 流速30ml/min(裝載泵4ml MeOH)，管柱：SunFire C18)。獲得呈淡黃色固體之N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-[[(3R )-1-甲基吡咯啶-3-基]甲氧基]苯基]-1-哌啶基]乙醯胺(0.099g，206.42μmol，37.29%產率)。( 2R,5S )-5-methyl-2-[3-[[( 3R )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine (0.2 g, 553.48 μmol, 2HCl), TEA (392.05 mg, 3.87 mmol, 540.01 μL) and 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (115.79 mg, 553.48 μmol ) was dissolved in DMF (5 mL) and HATU (231.50 mg, 608.83 μmol) was added in one portion and the resulting mixture was stirred at 20° C. for 3 h. The reaction mixture was submitted to HPLC (2-10 min 60-85% MeOH+ NH3 flow rate 30 ml/min (loading pump 4 ml MeOH), column: SunFire C18). N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3- was obtained as a pale yellow solid [[( 3R )-1-methylpyrrolidin-3-yl]methoxy]phenyl]-1-piperidinyl]acetamide (0.099 g, 206.42 μmol, 37.29% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.71-1.04(m,3H),1.07-1.16(m,3H),1.24-1.37(m,1H),1.42-1.52(m,1H),1.61-1.73(m,1H),1.80-1.96(m,2H),1.97-2.14(m,1H),2.14-2.20(m,1H),2.21(s,3H),2.29-2.45(m,5H),2.51-2.52(m,2H),2.73-3.24(m,1H),3.42-3.47(m,0.7H),3.78-3.87(m,2H),3.99-4.05(m,0.3H),5.03-5.57(m,1H),5.57-5.69(m,2H),6.77-6.94(m,3H),7.23-7.32(m,1H),7.42-7.55(m,1H),7.98-8.10(m,1H),10.47(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.71-1.04(m,3H), 1.07-1.16(m,3H), 1.24-1.37(m,1H), 1.42-1.52(m,1H) ,1.61-1.73(m,1H),1.80-1.96(m,2H),1.97-2.14(m,1H),2.14-2.20(m,1H),2.21(s,3H),2.29-2.45(m, 5H), 2.51-2.52(m, 2H), 2.73-3.24(m, 1H), 3.42-3.47(m, 0.7H), 3.78-3.87(m, 2H), 3.99-4.05(m, 0.3H), 5.03-5.57(m, 1H), 5.57-5.69(m, 2H), 6.77-6.94(m, 3H), 7.23-7.32(m, 1H), 7.42-7.55(m, 1H), 7.98-8.10(m , 1H), 10.47(br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=0.754min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=0.754 min.

實例550.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-((1-甲基哌啶-4-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1348)之合成Example 550. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-((1-methylpiperidine- Synthesis of 4-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1348)

Figure 110128222-A0202-12-1954-803
Figure 110128222-A0202-12-1954-803

步驟1：(2R,5S)-2-(3-((1-((苯甲氧基)羰基)哌啶-4-基)甲氧基)苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: (2R,5S)-2-(3-((1-((benzyloxy)carbonyl)piperidin-4-yl)methoxy)phenyl)-5-methylpiperidine-1 -Synthesis of tert-butyl formate

Figure 110128222-A0202-12-1954-804
Figure 110128222-A0202-12-1954-804

將(2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯(0.9g，3.09mmol)、4-(甲基磺醯基氧基甲基)哌啶-1-甲酸苯甲酯(1.52g，4.63mmol)及99%無水碳酸鉀(853.75mg，6.18mmol，372.82μL)一起混合於MeCN(20mL)中且在80℃下加熱12h。在真空下濃縮反應混合物。將所獲得之殘餘物溶解於EtOAc/H2 O中，分離EtOAc層且將水層用EtOAc萃取兩次。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由FCC(於己烷中之MTBE，0%至100%)純化粗產物。獲得呈淡黃色膠狀物之(2R,5S )-2-[3-[(1-苯甲氧基羰基-4-哌啶基)甲氧基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(0.75g，1.43mmol，46.46%產率)。( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (0.9 g, 3.09 mmol), 4-(methylsulfonyloxymethyl) benzyl)piperidine-1-carboxylate (1.52 g, 4.63 mmol) and 99% anhydrous potassium carbonate (853.75 mg, 6.18 mmol, 372.82 μL) were mixed together in MeCN (20 mL) and heated at 80 °C for 12 h. The reaction mixture was concentrated under vacuum. The obtained residue was dissolved in EtOAc/ H2O , the EtOAc layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by FCC (MTBE in hexanes, 0% to 100%). ( 2R,5S )-2-[3-[(1-benzyloxycarbonyl-4-piperidinyl)methoxy]phenyl]-5-methylpiperidine- 3-Butyl 1-carboxylate (0.75 g, 1.43 mmol, 46.46% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值422.2；實測值423.2；Rt=1.863min。LCMS (ESI): [M-Boc] + m/z: calculated 422.2; found 423.2; Rt=1.863 min.

步驟2：(2R,5S)-5-甲基-2-(3-(哌啶-4-基甲氧基)苯基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-5-methyl-2-(3-(piperidin-4-ylmethoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester

在H2 (1atm)、20℃下，將(2R,5S )-2-[3-[(1-苯甲氧基羰基-4-哌啶基)甲氧基]苯基]-5-甲基哌啶-1-甲酸第三丁酯(0.75g，1.43mmol)於MeOH(10mL)中之溶液經Pd/C(10%)(0.1g，1.43mmol)氫化12h。過濾反應混合物，將濾餅用MeOH洗滌且在減壓下濃縮濾液。所獲得之產物不經進一步純化即用於下一步驟 中。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-(4-哌啶基甲氧基)苯基]哌啶-1-甲酸第三丁酯(0.61g，粗品)。( 2R,5S )-2-[3-[(1-benzyloxycarbonyl-4-piperidinyl)methoxy]phenyl]-5-methyl under H2 (1 atm) at 20°C A solution of tert-butyl piperidine-1-carboxylate (0.75 g, 1.43 mmol) in MeOH (10 mL) was hydrogenated over Pd/C (10%) (0.1 g, 1.43 mmol) for 12 h. The reaction mixture was filtered, the filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The product obtained was used in the next step without further purification. ( 2R,5S )-5-methyl-2-[3-(4-piperidinylmethoxy)phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.61 g) was obtained as a pale yellow gum ,Crude).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=1.269min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=1.269 min.

步驟3：(2R,5S)-5-甲基-2-(3-((1-甲基哌啶-4-基)甲氧基)苯基)哌啶-1-甲酸第三丁酯之合成Step 3: (2R,5S)-5-methyl-2-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester synthesis

將(2R,5S )-5-甲基-2-[3-(4-哌啶基甲氧基)苯基]哌啶-1-甲酸第三丁酯(0.61g，1.57mmol)、用7-8% MeOH穩定之37重量%甲醛水溶液(70.71mg，2.35mmol，65.29μL)及乙酸(188.56mg，3.14mmol，179.75μL)溶解於MeOH(10mL)中且攪拌1h，然後在用冰+水冷卻時分批添加氰基硼氫化鈉(295.98mg，4.71mmol)且將反應混合物攪拌12h。蒸發溶劑，將所獲得之殘餘物溶解於Na2 CO3 (水溶液)中且用DCM(3*50ml)萃取，將DCM層經Na2 SO4 乾燥，過濾且在真空上蒸發。所獲得之產物不經進一步純化即用於下一步驟中。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[(1-甲基-4-哌啶基)甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.41g，1.02mmol，64.87%產率)。( 2R,5S )-5-methyl-2-[3-(4-piperidinylmethoxy)phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.61 g, 1.57 mmol) was treated with 7 -8% MeOH stabilized 37 wt% aqueous formaldehyde solution (70.71 mg, 2.35 mmol, 65.29 μL) and acetic acid (188.56 mg, 3.14 mmol, 179.75 μL) were dissolved in MeOH (10 mL) and stirred for 1 h, then washed with ice+water Sodium cyanoborohydride (295.98 mg, 4.71 mmol) was added portionwise while cooling and the reaction mixture was stirred for 12 h. The solvent was evaporated, the obtained residue was dissolved in Na2CO3 ( aq ) and extracted with DCM (3*50ml), the DCM layer was dried over Na2SO4 , filtered and evaporated in vacuo. The product obtained was used in the next step without further purification. ( 2R,5S )-5-methyl-2-[3-[(1-methyl-4-piperidinyl)methoxy]phenyl]piperidine-1-carboxylic acid was obtained as a pale yellow gum Tertiary butyl ester (0.41 g, 1.02 mmol, 64.87% yield).

LCMS(ESI)：[M]+ m/z：計算值402.2；實測值403.2；Rt=0.967min。LCMS (ESI): [M] + m/z: calculated 402.2; found 403.2; Rt=0.967 min.

步驟4：1-甲基-4-((3-((2R,5S)-5-甲基哌啶-2-基)苯氧基)甲基)哌啶之合成Step 4: Synthesis of 1-methyl-4-((3-((2R,5S)-5-methylpiperidin-2-yl)phenoxy)methyl)piperidine

將(2R,5S )-5-甲基-2-[3-[(1-甲基-4-哌啶基)甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.41g，1.02mmol)溶解於MeOH(7mL)及二噁烷(HCl)(7mL)之混合物中。將所得澄清溶液在20℃下攪拌4h。將反應混合物在真空中濃縮。獲得呈淡黃色固體之1-甲基-4-[[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]甲基]哌啶(0.3g，799.20μmol，78.47%產率，2HCl)。( 2R,5S )-5-methyl-2-[3-[(1-methyl-4-piperidinyl)methoxy]phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.41 g , 1.02 mmol) was dissolved in a mixture of MeOH (7 mL) and dioxane (HCl) (7 mL). The resulting clear solution was stirred at 20 °C for 4 h. The reaction mixture was concentrated in vacuo. 1-Methyl-4-[[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]methyl]piperidine (0.3 g, 799.20 μmol) was obtained as a pale yellow solid , 78.47% yield, 2HCl).

LCMS(ESI)：[M]+ m/z：計算值302.2；實測值303.2；Rt=0.631min。LCMS (ESI): [M] + m/z: calculated 302.2; found 303.2; Rt=0.631 min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-((1-甲基哌啶-4-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1348)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-((1-methylpiperidine- Synthesis of 4-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1348)

將1-甲基-4-[[3-[(2R,5S )-5-甲基-2-哌啶基]苯氧基]甲基]哌啶(0.3g，799.20μmol，2HCl)、TEA(566.10mg，5.59mmol，779.75μL)及2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(167.19mg，799.20μmol)溶解於DMF(5mL)中且一次性添加HATU(334.27mg，879.12μmol)，將所得混合物在20℃下攪拌3h。將反應混合物提交至HPLC(2-10min 60-80% MeOH+NH3 流速30ml/min(裝載泵4ml MeOH)，管柱：SunFire C18)。獲得呈淡黃色固體之N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-[(1-甲基-4-哌啶基)甲氧基]苯基]-1-哌啶基]乙醯胺(0.153g，309.94μmol，38.78%產率)。1-Methyl-4-[[3-[( 2R,5S )-5-methyl-2-piperidinyl]phenoxy]methyl]piperidine (0.3 g, 799.20 μmol, 2HCl), TEA (566.10 mg, 5.59 mmol, 779.75 μL) and 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (167.19 mg, 799.20 μmol) were dissolved in DMF (5 mL) and HATU (334.27 mg, 879.12 μmol) was added in one portion and the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was submitted to HPLC (2-10 min 60-80% MeOH+ NH3 flow 30 ml/min (loading pump 4 ml MeOH), column: SunFire C18). N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3- was obtained as a pale yellow solid [(1-Methyl-4-piperidinyl)methoxy]phenyl]-1-piperidinyl]acetamide (0.153 g, 309.94 μmol, 38.78% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.76-1.03(m,3H),1.06-1.14(m,3H),1.22-1.37(m,3H),1.62-1.75(m,4H),1.80-1.85(m,2H),1.86-2.11(m,2H),2.12(s,3H),2.14-2.26(m,1H),2.37-2.44(m,2H),2.73-2.80(m,2.3H),3.21-3.25(m,0.7H),3.43-3.48(m,0.7H),3.76-3.84(m,2H),3.99-4.06(m,0.3H),5.08-5.57(m,1H),5.58-5.68(m,2H),6.76-6.91(m,3H),7.22-7.32(m,1H),7.43-7.54(m,1H),7.97-8.12(m,1H),10.21(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.76-1.03(m,3H), 1.06-1.14(m,3H), 1.22-1.37(m,3H), 1.62-1.75(m,4H) ,1.80-1.85(m,2H),1.86-2.11(m,2H),2.12(s,3H),2.14-2.26(m,1H),2.37-2.44(m,2H),2.73-2.80(m, 2.3H), 3.21-3.25(m, 0.7H), 3.43-3.48(m, 0.7H), 3.76-3.84(m, 2H), 3.99-4.06(m, 0.3H), 5.08-5.57(m, 1H) ), 5.58-5.68(m, 2H), 6.76-6.91(m, 3H), 7.22-7.32(m, 1H), 7.43-7.54(m, 1H), 7.97-8.12(m, 1H), 10.21(br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值493.2；實測值494.2；Rt=0.773min。LCMS (ESI): [M] + m/z: calculated 493.2; found 494.2; Rt=0.773 min.

實例551.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(3-(((S )-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1179)之合成Example 551. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(3-(((( S )-1-methyl) Synthesis of pyrrolidin-3-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1179)

Figure 110128222-A0202-12-1956-805
Figure 110128222-A0202-12-1956-805

步驟1：(2R,5S)-2-(3-(((S)-1-((苯甲氧基)羰基)吡咯啶-3-基)甲氧基)苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: (2R,5S)-2-(3-(((S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)methoxy)phenyl)-5-methyl Synthesis of tert-butyl piperidine-1-carboxylate

將(2R,5S )-2-(3-羥基苯基)-5-甲基哌啶-1-甲酸第三丁酯(0.9g，3.09mmol)、(3S )-3-(甲基磺醯基氧基甲基)吡咯啶-1-甲酸苯甲酯(1.26g，4.02mmol)及99%無水碳酸鉀(853.78mg，6.18mmol，372.83μL)一起混合於MeCN(19.92mL)中且在81℃下加熱36h。在真空下濃縮反應混合物。將所獲得之殘餘物溶解於EtOAc/H2 O中，分離EtOAc層且將水層用EtOAc萃取兩次。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由FCC(於己烷中之MTBE，0%至100%)純化粗產物。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[[(3S )-1-苯甲氧基羰基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.25g，491.50μmol，15.91%產率)。( 2R,5S )-2-(3-hydroxyphenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (0.9 g, 3.09 mmol), ( 3S )-3-(methylsulfonyl Benzyloxymethyl)pyrrolidine-1-carboxylate (1.26 g, 4.02 mmol) and 99% anhydrous potassium carbonate (853.78 mg, 6.18 mmol, 372.83 μL) were mixed together in MeCN (19.92 mL) and placed in 81 Heated at ℃ for 36h. The reaction mixture was concentrated under vacuum. The obtained residue was dissolved in EtOAc/ H2O , the EtOAc layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by FCC (MTBE in hexanes, 0% to 100%). ( 2R,5S )-5-methyl-2-[3-[[( 3S )-1-benzyloxycarbonylpyrrolidin-3-yl]methoxy]phenyl was obtained as a pale yellow gum ] tert-butyl piperidine-1-carboxylate (0.25 g, 491.50 μmol, 15.91% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值408.2；實測值409.2；Rt=1.814min。LCMS (ESI): [M-Boc] + m/z: calculated 408.2; found 409.2; Rt=1.814 min.

步驟2：(2R,5S)-5-甲基-2-(3-((S)-吡咯啶-3-基甲氧基)苯基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-5-methyl-2-(3-((S)-pyrrolidin-3-ylmethoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester

在H2 (1atm)、20℃下，將(2R,5S )-5-甲基-2-[3-[[(3S )-1-苯甲氧基羰基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.25g，491.50μmol)於MeOH(10mL)中之溶液經Pd/C(10%)(0.075g，491.50μmol)氫化12h。過濾反應混合物，將濾餅用MeOH洗滌且在減壓下濃縮濾液。所獲得之產物不經進一步純化即用於下一步驟中。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[[(3S )-吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，粗品)。( 2R,5S )-5-methyl-2-[3-[[( 3S )-1-benzyloxycarbonylpyrrolidin-3-yl]methoxy under H 2 (1 atm) at 20°C A solution of tert-butyl]phenyl]piperidine-1-carboxylate (0.25 g, 491.50 μmol) in MeOH (10 mL) was hydrogenated over Pd/C (10%) (0.075 g, 491.50 μmol) for 12 h. The reaction mixture was filtered, the filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The product obtained was used in the next step without further purification. ( 2R,5S )-5-methyl-2-[3-[[( 3S )-pyrrolidin-3-yl]methoxy]phenyl]piperidine-1-carboxylic acid was obtained as a pale yellow gum Tertiary butyl ester (0.21 g, crude).

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=1.249min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=1.249 min.

步驟3：(2R,5S)-5-甲基-2-(3-(((S)-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶-1-甲酸第三丁酯之合成Step 3: (2R,5S)-5-methyl-2-(3-(((S)-1-methylpyrrolidin-3-yl)methoxy)phenyl)piperidine-1-carboxylic acid Synthesis of tributyl ester

將(2R,5S )-5-甲基-2-[3-[[(3S )-吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，560.72μmol)、用7-8% MeOH穩定之37重量%甲醛水溶液(25.25mg，841.09μmol，23.32μL)及乙酸(67.35mg，1.12mmol，64.20μL)溶解於MeOH (5mL)中且攪拌1h，然後在用冰+水冷卻時分批添加氰基硼氫化鈉(105.71mg，1.68mmol)且將反應混合物攪拌12h。蒸發溶劑，將所獲得之殘餘物溶解於Na2 CO3 (水溶液)中且用DCM(3*50ml)萃取，將DCM層經Na2 SO4 乾燥，過濾且在真空上蒸發。所獲得之產物不經進一步純化即用於下一步驟中。獲得呈淡黃色膠狀物之(2R,5S )-5-甲基-2-[3-[[(3S )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，540.48μmol，96.39%產率)。( 2R,5S )-5-methyl-2-[3-[[( 3S )-pyrrolidin-3-yl]methoxy]phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.21 g , 560.72 μmol), 37 wt% aqueous formaldehyde stabilized with 7-8% MeOH (25.25 mg, 841.09 μmol, 23.32 μL) and acetic acid (67.35 mg, 1.12 mmol, 64.20 μL) were dissolved in MeOH (5 mL) and stirred for 1 h , then sodium cyanoborohydride (105.71 mg, 1.68 mmol) was added portionwise while cooling with ice+water and the reaction mixture was stirred for 12 h. The solvent was evaporated, the obtained residue was dissolved in Na2CO3 ( aq ) and extracted with DCM (3*50ml), the DCM layer was dried over Na2SO4 , filtered and evaporated in vacuo. The product obtained was used in the next step without further purification. ( 2R,5S )-5-methyl-2-[3-[[( 3S )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine was obtained as a pale yellow gum - 3-Butyl 1-carboxylate (0.21 g, 540.48 μmol, 96.39% yield).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=0.956min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=0.956 min.

步驟4：(2R,5S)-5-甲基-2-(3-(((S)-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶之合成Step 4: Synthesis of (2R,5S)-5-methyl-2-(3-(((S)-1-methylpyrrolidin-3-yl)methoxy)phenyl)piperidine

將(2R,5S )-5-甲基-2-[3-[[(3S )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶-1-甲酸第三丁酯(0.21g，540.48μmol)溶解於MeOH(7mL)及二噁烷(HCl)(7mL)之混合物中。將所得澄清溶液在20℃下攪拌12h。在真空下濃縮反應混合物。獲得呈淡黃色固體之(2R,5S )-5-甲基-2-[3-[[(3S )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶(0.18g，498.13μmol，92.16%產率，2HCl)。( 2R,5S )-5-methyl-2-[3-[[( 3S )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine-1-carboxylic acid tert-butyl The ester (0.21 g, 540.48 μmol) was dissolved in a mixture of MeOH (7 mL) and dioxane (HCl) (7 mL). The resulting clear solution was stirred at 20 °C for 12 h. The reaction mixture was concentrated under vacuum. ( 2R,5S )-5-methyl-2-[3-[[( 3S )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine (0.18) was obtained as a pale yellow solid g, 498.13 μmol, 92.16% yield, 2HCl).

LCMS(ESI)：[M]+ m/z：計算值288.2；實測值289.2；Rt=0.604min。LCMS (ESI): [M] + m/z: calculated 288.2; found 289.2; Rt=0.604 min.

步驟5：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3-(((S)-1-甲基吡咯啶-3-基)甲氧基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物1179)之合成Step 5: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3-(((S)-1-methyl) Synthesis of pyrrolidin-3-yl)methoxy)phenyl)piperidin-1-yl)-2-oxoacetamide (compound 1179)

將(2R,5S )-5-甲基-2-[3-[[(3S )-1-甲基吡咯啶-3-基]甲氧基]苯基]哌啶(0.18g，498.13μmol，2HCl)、TEA(352.84mg，3.49mmol，486.01μL)及2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(104.21mg，498.13μmol)溶解於DMF(5mL)中且一次性添加HATU(208.35mg，547.95μmol)，將所得混合物在20℃下攪拌3h。將反應混合物提交至HPLC(2-10min 60-85% MeOH+NH3 流速30ml/min(裝載泵4ml MeOH)，管柱：SunFire C18)。獲得呈淡黃色固體之N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[3-[[(3S )-1-甲基吡咯啶-3-基]甲氧基]苯基]-1-哌啶基]乙醯胺(0.078g，162.63μmol，32.65%產率)。( 2R,5S )-5-methyl-2-[3-[[( 3S )-1-methylpyrrolidin-3-yl]methoxy]phenyl]piperidine (0.18 g, 498.13 μmol, 2HCl), TEA (352.84 mg, 3.49 mmol, 486.01 μL) and 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (104.21 mg, 498.13 μmol ) was dissolved in DMF (5 mL) and HATU (208.35 mg, 547.95 μmol) was added in one portion and the resulting mixture was stirred at 20° C. for 3 h. The reaction mixture was submitted to HPLC (2-10 min 60-85% MeOH+ NH3 flow rate 30 ml/min (loading pump 4 ml MeOH), column: SunFire C18). N- (6-amino-5-ethyl-3-pyridyl)-2-oxy-2-[( 2R,5S )-5-methyl-2-[3- was obtained as a pale yellow solid [[( 3S )-1-methylpyrrolidin-3-yl]methoxy]phenyl]-1-piperidinyl]acetamide (0.078 g, 162.63 μmol, 32.65% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.75-1.02(m,3H),1.07-1.15(m,3H),1.26-1.38(m,1H),1.42-1.55(m,1H),1.58-1.73(m,1H),1.80-1.95(m,2H),1.98-2.11(m,1H),2.11-2.20(m,1H),2.21(s,3H),2.29-2.43(m,5H),2.50-2.52(m,2H),2.72-2.77(m,0.3H),3.20-3.26(m,0.7H),3.42-3.50(m,0.7H),3.76-3.86(m,2H),3.97-4.05(m,0.3H),5.07-5.59(m,1H),5.59-5.69(m,2H),6.75-6.95(m,3H),7.23-7.34(m,1H),7.41-7.55(m,1H),7.96-8.13(m,1H),10.45(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.75-1.02(m,3H), 1.07-1.15(m,3H), 1.26-1.38(m,1H), 1.42-1.55(m,1H) ,1.58-1.73(m,1H),1.80-1.95(m,2H),1.98-2.11(m,1H),2.11-2.20(m,1H),2.21(s,3H),2.29-2.43(m, 5H), 2.50-2.52(m, 2H), 2.72-2.77(m, 0.3H), 3.20-3.26(m, 0.7H), 3.42-3.50(m, 0.7H), 3.76-3.86(m, 2H) ,3.97-4.05(m,0.3H),5.07-5.59(m,1H),5.59-5.69(m,2H),6.75-6.95(m,3H),7.23-7.34(m,1H),7.41-7.55 (m, 1H), 7.96-8.13 (m, 1H), 10.45 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=2.217min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=2.217 min.

方案G-式7化合物之合成Scheme G - Synthesis of Compounds of Formula 7

式7化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 7 are compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as described herein.

一般程序7General Procedure 7

Figure 110128222-A0202-12-1959-806
Figure 110128222-A0202-12-1959-806

步驟1：7B之合成Step 1: Synthesis of 7B

將7A (1.0當量)溶解於DCM(280mL)中且逐滴添加二碳酸二-第三丁 酯(1.02當量)於DCM(20mL)中之溶液(劇烈氣體逸出！)。將所得混合物在20℃下攪拌4h。然後，在減壓下移除揮發物，得到粗產物，其藉由FCC(CHCl3 -MeCN，100%-0%至0%-100%)進行純化，以得到(2R,5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(7B )。 7A (1.0 equiv) was dissolved in DCM (280 mL) and a solution of di-tert-butyl dicarbonate (1.02 equiv) in DCM (20 mL) was added dropwise (vigorous gas evolution!). The resulting mixture was stirred at 20 °C for 4 h. Then, the volatiles were removed under reduced pressure to give the crude product, which was purified by FCC ( CHCl3 -MeCN, 100%-0% to 0%-100%) to give (2R,5S)-2- (4-Bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester ( 7B ).

步驟2：7C之合成Step 2: Synthesis of 7C

向(2R,5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(7B ；1.0當量)及相應胺(1.0當量)於溶劑(5mL)中之經攪拌之溶液中添加鹼(2.5當量)。將所得懸浮液用氬氣除氣。添加配體(0.05當量)及Pd催化劑(0.05當量)。將反應混合物在65...100℃下攪拌15...48h。反應完成(藉由LCMS監測)之後，使所得混合物冷卻至室溫，透過SiO2 薄層過濾且用溶劑(2mL)洗滌。在真空中移除揮發物且使殘餘物經歷純化，以得到7C 。To (2R,5S)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester ( 7B ; 1.0 equiv) and the corresponding amine (1.0 equiv) in solvent (5 mL) To the stirred solution was added base (2.5 equiv.). The resulting suspension was degassed with argon. Ligand (0.05 equiv) and Pd catalyst (0.05 equiv) were added. The reaction mixture was stirred at 65...100°C for 15...48h. After completion of the reaction (monitored by LCMS), the resulting mixture was cooled to room temperature, filtered through a thin layer of SiO2 and washed with solvent (2 mL). Volatiles were removed in vacuo and the residue was subjected to purification to give 7C .

布赫瓦爾德反應步驟：Buchwald reaction steps:

Figure 110128222-A0202-12-1960-807
Figure 110128222-A0202-12-1960-807

步驟3：7D之合成Step 3: Synthesis of 7D

將7C 溶解於溶劑(2...10mL)中且添加酸(50.0當量)。將反應混合物在 室溫下攪拌1...4h。在真空中移除溶劑，以獲得7D 。 7C was dissolved in solvent (2...10 mL) and acid (50.0 equiv) was added. The reaction mixture was stirred at room temperature for 1...4h. The solvent was removed in vacuo to obtain 7D .

Boc移除步驟：Boc removal steps:

Figure 110128222-A0202-12-1961-808
Figure 110128222-A0202-12-1961-808

步驟4：7之合成Step 4: Synthesis of 7

將7D (1.0當量)、草醯胺酸(1.0當量)及TEA(2.5當量+1.0當量/各酸當量，若使用胺鹽)一起混合於DMF中。向其中添加HATU(1.5當量)且將所得混合物攪拌隔夜。在真空中濃縮反應混合物且藉由HPLC純化殘餘物，以獲得7 。 7D (1.0 equiv), oxalic acid (1.0 equiv) and TEA (2.5 equiv + 1.0 equiv per acid equiv, if using amine salt) were mixed together in DMF. To this was added HATU (1.5 equiv) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to obtain 7 .

步驟4A：7E之合成Step 4A: Synthesis of 7E

將7D (1.0當量)及TEA(1.2當量)溶解於THF中且冷卻至0℃，隨後逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(1.1當量)且將反應混合物在0℃下攪拌2h。該混合物(7E )不經進一步純化即用於下一步驟中。 7D (1.0 equiv) and TEA (1.2 equiv) were dissolved in THF and cooled to 0°C, followed by dropwise addition of 2,2,2-trifluoroethyl 2-chloro-2-pendoxoacetic acid (1.1 equiv) And the reaction mixture was stirred at 0 °C for 2 h. This mixture ( 7E ) was used in the next step without further purification.

步驟4B：7E之合成Step 4B: Synthesis of 7E

透過7E (1.0當量)於THF(50mL)中之溶液，將氨(50.0當量)在20℃下鼓泡10min。將混合物攪拌2h，在真空中蒸發且用MTBE-MeCN研磨。過濾沉澱且乾燥，以得到7F。 Ammonia (50.0 equiv) was bubbled through a solution of 7E (1.0 equiv) in THF (50 mL) at 20 °C for 10 min. The mixture was stirred for 2 h, evaporated in vacuo and triturated with MTBE-MeCN. The precipitate was filtered and dried to give 7F.

步驟4C：7之合成Step 4C: Synthesis of 7

在Ar氣氛下，將7F (1.0當量)、R3 I(1.0當量)、CuI(0.2當量)、CuI(0.2當量)、N1 ,N2 -二甲基環己-1,2-二胺(0.2當量)及Cs2 CO3 一起混合於二噁烷(6mL)中。將反應混合物在100℃下攪拌48h。然後，使混合物冷卻至室溫且過濾出。使濾液經歷HPLC，以得到7。 Under Ar atmosphere, 7F (1.0 equiv.), R3I (1.0 equiv.), CuI (0.2 equiv.), CuI (0.2 equiv.), N1, N2 -dimethylcyclohexyl- 1,2 -diamine were combined (0.2 equiv) and Cs2CO3 were mixed together in dioxane (6 mL). The reaction mixture was stirred at 100 °C for 48 h. Then, the mixture was cooled to room temperature and filtered off. The filtrate was subjected to HPLC to give 7.

實例552. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(9-甲基-2,9-二氮雜螺[5.5]十一烷-2-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1401)之合成Example 552. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(9-methyl-2,9 - Synthesis of Diazaspiro[5.5]undecan-2-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1401)

Figure 110128222-A0202-12-1962-809
Figure 110128222-A0202-12-1962-809

步驟1：(5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (5S)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

藉由一般程序7製備。Prepared by General Procedure 7.

產率：14g(87.34%)Yield: 14g (87.34%)

LCMS(ESI)：[M-Boc]+ m/z：計算值254.0；實測值254.0；Rt=1.539min。LCMS (ESI): [M-Boc] + m/z: calculated 254.0; found 254.0; Rt=1.539 min.

步驟2：(2R,5S)-5-甲基-2-[4-(9-甲基-2,9-二氮雜螺[5.5]十一烷-2-基)苯基]哌啶-1-甲酸第三丁酯之合成Step 2: (2R,5S)-5-Methyl-2-[4-(9-methyl-2,9-diazaspiro[5.5]undecan-2-yl)phenyl]piperidine- Synthesis of 3-butyl 1-formate

藉由一般程序7製備Prepared by General Procedure 7

產率：105.0mg(粗品)Yield: 105.0 mg (crude)

LCMS(ESI)：[M+H]+ m/z：計算值442.4；實測值442.4；Rt=1.159min。LCMS (ESI): [M+H] + m/z: calculated 442.4; found 442.4; Rt=1.159 min.

步驟3：9-甲基-2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]-2,9-二氮雜螺[5.5]十一烷之合成Step 3: 9-methyl-2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]-2,9-diazaspiro[5.5]undecane synthesis

藉由一般程序方案7製備Prepared by General Procedure Scheme 7

產率：96.0mg(粗品)Yield: 96.0 mg (crude)

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值342.2；Rt=0.754min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 342.2; Rt=0.754 min.

步驟4：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-(9-甲基-2,9-二氮雜螺[5.5]十一烷-2-基)苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1401)之合成Step 4: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-(9-methyl-2,9 - Synthesis of Diazaspiro[5.5]undecan-2-yl)phenyl]-1-piperidinyl]-2-oxoacetamide (Compound 1401)

藉由一般程序方案G步驟4製備Prepared by General Procedure G, Step 4

產率：10.5mg(7.01%)。Yield: 10.5 mg (7.01%).

HPLC條件： 2-10min 40-65%水-MeOH-0.1% NH4 OH；30mL/min；裝載泵MeOH-0.1% NH4 OH 4mL/min；管柱SunFire 19*100mm，5mkm HPLC conditions: 2-10 min 40-65% water-MeOH-0.1% NH4OH ; 30 mL/min; loading pump MeOH-0.1% NH4OH 4 mL/min; column SunFire 19*100mm, 5mkm

1 H NMR(600MHz,dmso)δ 0.88-1.03(m,3H),1.04-1.15(m,4H),1.26-1.35(m,1H),1.36-1.44(m,4H),1.48-1.54(m,2H),1.59-1.64(m,2H),1.64-1.76(m,1H),1.77-1.91(m,1H),1.92-2.10(m,1H),2.11-2.19(m,4H),2.20-2.26(m,2H),2.26-2.33(m,2H),2.39-2.42(m,1H),2.70-2.74(m,0.4H),2.89-2.94(m,2H),3.01-3.08(m,2H),3.16-3.22(m,0.6H),3.50-3.98(m,1H),5.02-5.59(m,1H),5.59-5.69(m,2H),6.85-6.93(m,2H),7.08-7.21(m,2H),7.40-7.55(m,1H),7.97-8.10(m,1H),10.42-10.51(m,1H)。 1 H NMR(600MHz,dmso)δ 0.88-1.03(m,3H),1.04-1.15(m,4H),1.26-1.35(m,1H),1.36-1.44(m,4H),1.48-1.54(m ,2H),1.59-1.64(m,2H),1.64-1.76(m,1H),1.77-1.91(m,1H),1.92-2.10(m,1H),2.11-2.19(m,4H),2.20 -2.26(m, 2H), 2.26-2.33(m, 2H), 2.39-2.42(m, 1H), 2.70-2.74(m, 0.4H), 2.89-2.94(m, 2H), 3.01-3.08(m ,2H),3.16-3.22(m,0.6H),3.50-3.98(m,1H),5.02-5.59(m,1H),5.59-5.69(m,2H),6.85-6.93(m,2H), 7.08-7.21 (m, 2H), 7.40-7.55 (m, 1H), 7.97-8.10 (m, 1H), 10.42-10.51 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值533.4；實測值533.4；Rt=1.961min。LCMS (ESI): [M+H] + m/z: calculated 533.4; found 533.4; Rt=1.961 min.

實例553. rel-2-[(2R,5S)-2-[4-[(4aR,8aS)-1-甲基-2,3,4,4a,5,7,8,8a-八氫-1,6-萘啶-6-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1111)及rel-2-[(2R,5S)-2-[4-[(4aS,8aR)-1-甲基-2,3,4,4a,5,7,8,8a-八氫-1,6-萘啶-6-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1132)之合成Example 553. rel-2-[(2R,5S)-2-[4-[(4aR,8aS)-1-methyl-2,3,4,4a,5,7,8,8a-octahydro- 1,6-Naphthyridin-6-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxygen Ethylacetamide (Compound 1111) and rel-2-[(2R,5S)-2-[4-[(4aS,8aR)-1-methyl-2,3,4,4a,5,7,8 ,8a-Octahydro-1,6-naphthyridin-6-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl )-2-oxyacetamide (Compound 1132) Synthesis

Figure 110128222-A0202-12-1964-810
Figure 110128222-A0202-12-1964-810

步驟1：(5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成藉由一般程序方案G步驟1製備產率：14g(87.34%)Step 1: Synthesis of (5S)-3-butyl 2-(4-bromophenyl)-5-methylpiperidine-1-carboxylate Prepared by General Procedure Scheme G, Step 1 Yield: 14 g (87.34%)

LCMS(ESI)：[M-Boc]+ m/z：計算值254.0；實測值254.0；Rt=1.539min。LCMS (ESI): [M-Boc] + m/z: calculated 254.0; found 254.0; Rt=1.539 min.

步驟2：(2R,5S)-2-[4-[(4aS,8aR)-1-甲基-2,3,4,4a,5,7,8,8a-八氫-1,6-萘啶-6-基]苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: (2R,5S)-2-[4-[(4aS,8aR)-1-methyl-2,3,4,4a,5,7,8,8a-octahydro-1,6-naphthalene Synthesis of pyridin-6-yl]phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

藉由一般程序方案G步驟2(方法B)製備Prepared by General Procedure G, Step 2 (Method B)

產率：0.8g(粗品)Yield: 0.8g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值428.4；實測值428.4；Rt=1.268min。LCMS (ESI): [M+H] + m/z: calculated 428.4; found 428.4; Rt=1.268 min.

步驟3：(4aS,8aR)-1-甲基-6-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]-2,3,4,4a,5,7,8,8a-八氫-1,6-萘啶之合成Step 3: (4aS,8aR)-1-Methyl-6-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]-2,3,4,4a,5 Synthesis of ,7,8,8a-octahydro-1,6-naphthyridine

藉由一般程序方案G步驟3(方法A)製備Prepared by General Procedure G, Step 3 (Method A)

產率：0.7g(85.64%)Yield: 0.7g (85.64%)

LCMS(ESI)：[M+H]+ m/z：計算值328.4；實測值328.4；Rt=0.666min。LCMS (ESI): [M+H] + m/z: calculated 328.4; found 328.4; Rt=0.666 min.

步驟4：2-[(2R,5S)-2-[4-[(4aS,8aR)-1-甲基-2,3,4,4a,5,7,8,8a-八氫-1,6-萘啶-6-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺之合成 藉由一般程序7步驟4製備 Step 4: 2-[(2R,5S)-2-[4-[(4aS,8aR)-1-methyl-2,3,4,4a,5,7,8,8a-octahydro-1, 6-Naphthyridin-6-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-side oxyethyl Synthesis of amides Prepared by General Procedure 7, Step 4

產率：340.0mg(40.91%)Yield: 340.0 mg (40.91%)

HPLC條件：40-40-90% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min甲醇)；YMC Triart C18 100x 20mm，5umHPLC conditions: 40-40-90% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 mL/min (loading pump 4 mL/min methanol); YMC Triart C18 100x 20mm, 5um

LCMS(ESI)：[M+H]+ m/z：計算值519.2；實測值519.2；Rt=2.452min。LCMS (ESI): [M+H] + m/z: calculated 519.2; found 519.2; Rt=2.452 min.

步驟5：rel-2-[(2R,5S)-2-[4-[(4aR,8aS)-1-甲基-2,3,4,4a,5,7,8,8a-八氫-1,6-萘啶-6-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1111)及rel-2-[(2R,5S)-2-[4-[(4aS,8aR)-1-甲基-2,3,4,4a,5,7,8,8a-八氫-1,6-萘啶-6-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1132)之合成Step 5: rel-2-[(2R,5S)-2-[4-[(4aR,8aS)-1-methyl-2,3,4,4a,5,7,8,8a-octahydro- 1,6-Naphthyridin-6-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-oxygen Ethylacetamide (Compound 1111) and rel-2-[(2R,5S)-2-[4-[(4aS,8aR)-1-methyl-2,3,4,4a,5,7,8 ,8a-Octahydro-1,6-naphthyridin-6-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl )-2-oxyacetamide (Compound 1132) Synthesis

藉由一般程序7步驟5製備Prepared by General Procedure 7 Step 5

化合物1132： 產率：103mg(60.59%)。 Compound 1132: Yield: 103 mg (60.59%).

化合物1111： 產率：94mg(55.29%)。 Compound 1111: Yield: 94 mg (55.29%).

掌性分離條件：管柱：Chiralpak IB(250*20mm，5mkm)流動相：己烷-IPA-MeOH，50-25-25流速：12mL/min；m=0.25g，注入37，6.75mg/注入，V=11.11，15.4h.Chiral separation conditions: Column: Chiralpak IB (250*20mm, 5mkm) Mobile phase: Hexane-IPA-MeOH, 50-25-25 Flow rate: 12mL/min; m=0.25g, injection 37, 6.75mg/injection , V=11.11, 15.4h.

化合物1111：Compound 1111:

RT(Chiralpak IB(250 * 4.6,5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=16.35min。RT (Chiralpak IB (250*4.6,5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=16.35min.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.04(m,3H),1.07-1.14(m,3H),1.27-1.35(m,1H),1.40-1.73(m,7H),1.80-2.33(m,10H),2.37-2.42(m,2H),2.64-3.24(m,5H),3.38-4.00(m,1H),5.02-5.54(m,1H),5.58-5.66(m,2H),6.87-6.94(m,2H),7.07-7.18(m,2H),7.44-7.52(m,1H),8.00-8.09(m,1H),10.40-10.55(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.04(m,3H), 1.07-1.14(m,3H), 1.27-1.35(m,1H), 1.40-1.73(m,7H) ,1.80-2.33(m,10H),2.37-2.42(m,2H),2.64-3.24(m,5H),3.38-4.00(m,1H),5.02-5.54(m,1H),5.58-5.66( m, 2H), 6.87-6.94 (m, 2H), 7.07-7.18 (m, 2H), 7.44-7.52 (m, 1H), 8.00-8.09 (m, 1H), 10.40-10.55 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值518.0；實測值518.0；Rt=2.214min。LCMS (ESI): [M] + m/z: calculated 518.0; found 518.0; Rt=2.214 min.

化合物1132：Compound 1132:

RT(Chiralpak IB(250 * 4.6,5mkm)，己烷-IPA-MeOH，50-25-25，0.6mL/min)=19.69min。RT (Chiralpak IB (250*4.6,5mkm), Hexane-IPA-MeOH, 50-25-25, 0.6mL/min)=19.69min.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.03(m,3H),1.07-1.13(m,3H),1.27-1.73(m,8H),1.80-2.26(m,9H),2.37-2.43(m,2H),2.61-3.26(m,6H),3.37-4.00(m,1H),5.01-5.54(m,1H),5.57-5.66(m,2H),6.87-6.94(m,2H),7.06-7.17(m,2H),7.44-7.52(m,1H),7.99-8.09(m,1H),10.40-10.53(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.03(m,3H), 1.07-1.13(m,3H), 1.27-1.73(m,8H), 1.80-2.26(m,9H) ,2.37-2.43(m,2H),2.61-3.26(m,6H),3.37-4.00(m,1H),5.01-5.54(m,1H),5.57-5.66(m,2H),6.87-6.94( m, 2H), 7.06-7.17 (m, 2H), 7.44-7.52 (m, 1H), 7.99-8.09 (m, 1H), 10.40-10.53 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值519.4；實測值519.4；Rt=2.216min。LCMS (ESI): [M+H] + m/z: calculated 519.4; found 519.4; Rt=2.216 min.

rel-2-[(2R,5S)-2-[4-[(4aR,8aS)-7-甲基-1,3,4,4a,5,6,8,8a-八氫-2,7-萘啶-2-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1204)及rel-2-[(2R,5S)-2-[4-[(4aS,8aR)-7-甲基-1,3,4,4a,5,6,8,8a-八氫-2,7-萘啶-2-基]苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基乙醯胺(化合物1144)之合成rel-2-[(2R,5S)-2-[4-[(4aR,8aS)-7-methyl-1,3,4,4a,5,6,8,8a-octahydro-2,7 -Naphthyridin-2-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2-pendoxetylacetone Amine (Compound 1204) and rel-2-[(2R,5S)-2-[4-[(4aS,8aR)-7-methyl-1,3,4,4a,5,6,8,8a- Octahydro-2,7-naphthyridin-2-yl]phenyl]-5-methyl-1-piperidinyl]-N-(6-amino-5-ethyl-3-pyridyl)-2 - Synthesis of Pendant Oxyacetamide (Compound 1144)

Figure 110128222-A0202-12-1967-811
Figure 110128222-A0202-12-1967-811

藉由一般程序方案G步驟5製備。Prepared by General Procedure G, Step 5.

化合物1204： 產率：49.0mg(46.65%)。 Compound 1204: Yield: 49.0 mg (46.65%).

化合物1144： 產率：39.0mg(37.15%)。 Compound 1144: Yield: 39.0 mg (37.15%).

HPLC條件： 15-15-65% 0-1-6min H2 O/MeCN/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min乙腈)；管柱：XBridge BEH C18 5um 130A HPLC conditions: 15-15-65% 0-1-6 min H2O /MeCN/0.1% NH4OH , flow rate: 30 mL/min (load pump 4 mL/min acetonitrile); column: XBridge BEH C18 5um 130A

掌性分離條件： 管柱：ChiralART YMC(250 * 20mm，5mkm)；流動相：IPA-MeOH，50-50.流速：12mL/min；管柱溫度：24℃；波長：205nm Chiral separation conditions: Column: ChiralART YMC (250*20mm, 5mkm); Mobile phase: IPA-MeOH, 50-50. Flow rate: 12mL/min; Column temperature: 24°C; Wavelength: 205nm

化合物1204：Compound 1204:

1H NMR(600MHz,dmso)δ 0.94-1.05(m,3H),1.06-1.13(m,3H),1.26-1.36(m,1H),1.37-1.78(m,7H),1.80-1.91(m,2H),1.93-2.10(m,5H),2.12-2.21(m,2H),2.32-2.42(m,3H),2.70-3.26(m,5H),3.36-4.00(m,1H),4.99-5.54(m,1H),5.54-5.65(m,2H),6.86-6.94(m,2H),7.07-7.17(m,2H),7.43-7.53(m,1H),7.97-8.10(m,1H),10.47(s,1H)。1H NMR(600MHz,dmso)δ 0.94-1.05(m,3H),1.06-1.13(m,3H),1.26-1.36(m,1H),1.37-1.78(m,7H),1.80-1.91(m, 2H), 1.93-2.10(m, 5H), 2.12-2.21(m, 2H), 2.32-2.42(m, 3H), 2.70-3.26(m, 5H), 3.36-4.00(m, 1H), 4.99- 5.54(m,1H),5.54-5.65(m,2H),6.86-6.94(m,2H),7.07-7.17(m,2H),7.43-7.53(m,1H),7.97-8.10(m,1H ), 10.47(s, 1H).

RT(Chiralpak IA(250 * 4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=26.19min。RT (Chiralpak IA (250*4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=26.19min.

LCMS(ESI)：[M+H]+ m/z：計算值519.2；實測值519.2；Rt=1.704min。LCMS (ESI): [M+H] + m/z: calculated 519.2; found 519.2; Rt=1.704 min.

化合物1144：Compound 1144:

1H NMR(600MHz,dmso)δ 0.97-1.03(m,3H),1.07-1.13(m,3H),1.27-1.35(m, 1H),1.40-1.75(m,7H),1.81-1.97(m,3H),2.02-2.22(m,7H),2.33-2.42(m,2H),2.69-3.25(m,5H),3.38-3.99(m,1H),5.00-5.54(m,1H),5.56-5.65(m,2H),6.85-6.92(m,2H),7.06-7.18(m,2H),7.42-7.54(m,1H),7.98-8.09(m,1H),10.39-10.55(m,1H)。1H NMR(600MHz,dmso)δ 0.97-1.03(m,3H),1.07-1.13(m,3H),1.27-1.35(m, 1H), 1.40-1.75(m, 7H), 1.81-1.97(m, 3H), 2.02-2.22(m, 7H), 2.33-2.42(m, 2H), 2.69-3.25(m, 5H), 3.38- 3.99(m,1H),5.00-5.54(m,1H),5.56-5.65(m,2H),6.85-6.92(m,2H),7.06-7.18(m,2H),7.42-7.54(m,1H ), 7.98-8.09 (m, 1H), 10.39-10.55 (m, 1H).

RT(Chiralpak IA(250 * 4.6，5mkm)，IPA-MeOH，50-50，0.6mL/min)=20.31min。RT (Chiralpak IA (250*4.6, 5mkm), IPA-MeOH, 50-50, 0.6mL/min)=20.31min.

LCMS(ESI)：[M+H]+ m/z：計算值519.2；實測值519.2；Rt=1.703min。LCMS (ESI): [M+H] + m/z: calculated 519.2; found 519.2; Rt=1.703 min.

實例554. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-[(1-甲基-4-哌啶基)胺基]苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1112)之合成Example 554. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-[(1-methyl-4- Synthesis of piperidinyl)amino]phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1112)

Figure 110128222-A0202-12-1968-908
Figure 110128222-A0202-12-1968-908

步驟2：(2R,5S)-5-甲基-2-[4-[(1-甲基-4-哌啶基)胺基]苯基]哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-5-methyl-2-[4-[(1-methyl-4-piperidinyl)amino]phenyl]piperidine-1-carboxylic acid tert-butyl ester

藉由一般程序方案G步驟2製備。產率：94.0mg(9.55%)Prepared by General Procedure G, Step 2. Yield: 94.0 mg (9.55%)

LCMS(ESI)：[M+H]+ m/z：計算值388.2；實測值388.2；Rt=1.075min。LCMS (ESI): [M+H] + m/z: calculated 388.2; found 388.2; Rt=1.075 min.

步驟3：1-甲基-N-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]哌啶-4-胺之合成Step 3: Synthesis of 1-methyl-N-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]piperidin-4-amine

藉由一般程序方案G步驟3(方法B)製備。產率：150.0mg(粗品)Prepared by General Procedure G, Step 3 (Method B). Yield: 150.0 mg (crude)

LCMS(ESI)：[M+H]+ m/z：計算值288.2；實測值288.2；Rt=0.583min。LCMS (ESI): [M+H] + m/z: calculated 288.2; found 288.2; Rt=0.583 min.

步驟4：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[4-[(1-甲基-4-哌啶基)胺基]苯基]-1-哌啶基]-2-側氧基乙醯胺(化合物1112)之合成Step 4: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[4-[(1-methyl-4- Synthesis of piperidinyl)amino]phenyl]-1-piperidinyl]-2-oxoacetamide (compound 1112)

藉由一般程序方案G步驟4製備。產率：42.5mg(35.56%)Prepared by General Procedure G, Step 4. Yield: 42.5 mg (35.56%)

HPLC條件： 2-10min 30-45%水-MeOH-0.1% NH4 OH；30mL/min；裝載泵MeOH-0.1% NH4 OH；4mL/min；管柱SunFire 19*100mm，5mkm HPLC conditions: 2-10 min 30-45% water-MeOH-0.1% NH4OH ; 30 mL/min; loading pump MeOH-0.1% NH4OH; 4 mL/min; column SunFire 19*100mm, 5mkm

1 H NMR(dmso,600MHz)：δ(ppm)0.71-0.78(m,1H),0.98-1.13(m,5H),1.27-1.36(m,3H),1.59-1.99(m,7H),2.14(s,3H),2.35-2.41(m,2H),2.68-2.70(m,2H),3.12-3.19(m,1H),3.36-4.14(m,3H),5.37-5.62(m,4H),6.54-6.57(m,2H),6.96-7.03(m,2H),7.46-7.51(m,1H),7.99-8.07(m,1H),10.27(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.71-0.78 (m, 1H), 0.98-1.13 (m, 5H), 1.27-1.36 (m, 3H), 1.59-1.99 (m, 7H), 2.14 (s,3H), 2.35-2.41(m,2H), 2.68-2.70(m,2H), 3.12-3.19(m,1H), 3.36-4.14(m,3H), 5.37-5.62(m,4H) , 6.54-6.57(m, 2H), 6.96-7.03(m, 2H), 7.46-7.51(m, 1H), 7.99-8.07(m, 1H), 10.27(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值479.2；實測值479.2；Rt=0.841min。LCMS (ESI): [M+H] + m/z: calculated 479.2; found 479.2; Rt=0.841 min.

方案H-式8化合物之合成Scheme H - Synthesis of Compounds of Formula 8

式8化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 8 are compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as described herein.

一般程序8General Procedure 8

Figure 110128222-A0202-12-1969-813
Figure 110128222-A0202-12-1969-813

步驟1A：8-C之合成Step 1A: Synthesis of 8-C

將磷酸(4當量)及五氧化二磷(4當量)混合在一起。將反應懸浮液在室溫下攪拌10min，然後在Ar下添加8a-A(1當量)，隨後添加8a-B(1.2當量)。將溶液在110℃下攪拌18h，然後將其用水研磨，鹼化(NaOH，10%水溶液)至pH=10，用DCM萃取兩次，乾燥且在真空中蒸發，以得到8-C。Phosphoric acid (4 equiv) and phosphorus pentoxide (4 equiv) were mixed together. The reaction suspension was stirred at room temperature for 10 min, then 8a-A (1 equiv) was added under Ar, followed by 8a-B (1.2 equiv). The solution was stirred at 110 °C for 18 h, then it was triturated with water, basified (NaOH, 10% aq.) to pH=10, extracted twice with DCM, dried and evaporated in vacuo to give 8-C.

步驟1B：8-C之合成Step 1B: Synthesis of 8-C

向8b-A(1當量)於DMSO中之經攪拌之溶液中添加8b-B(1當量)。將所得混合物在100℃下攪拌14h。將反應混合物倒入到冷水中且用MTBE萃取兩次。將經合併之有機層用水及鹽水洗滌，經Na2 SO4 乾燥。在真空中蒸發MTBE，以得到8-C。To a stirred solution of 8b-A (1 equiv) in DMSO was added 8b-B (1 equiv). The resulting mixture was stirred at 100 °C for 14 h. The reaction mixture was poured into cold water and extracted twice with MTBE. The combined organic layers were washed with water and brine, dried over Na2SO4 . MTBE was evaporated in vacuo to give 8-C.

步驟1C：8-C之合成Step 1C: Synthesis of 8-C

向8c-A(1當量)於1,2-二氯乙烷中之經攪拌之溶液中添加8c-B(2當量)且使其在25℃下攪拌2h，添加(三乙醯氧基)硼氫化鈉(2當量)。將反應混合物在25℃下攪拌16h。完成之後，將反應混合物蒸發，用水萃取且藉由K2 CO3 中和至pH=10。將水相用CHCl3 萃取兩次。將經合併之有機相經Na2 SO4 乾燥且在減壓下蒸發，以得到8-C。(將TEA(1.5當量/各酸當量，若使用胺鹽)添加到相應胺之溶液中)To a stirred solution of 8c-A (1 equiv) in 1,2-dichloroethane was added 8c-B (2 equiv) and allowed to stir at 25°C for 2 h, (triacetoxy) was added Sodium borohydride (2 equiv.). The reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was evaporated, extracted with water and neutralized to pH = 10 by K2CO3. The aqueous phase was extracted twice with CHCl3 . The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give 8-C. (TEA (1.5 equiv/equivalent of each acid, if amine salt is used) is added to the solution of the corresponding amine)

步驟2：8-D之合成Step 2: Synthesis of 8-D

將8-C(1當量)、B2 Pin2 (1.1當量)及KOAc(2當量)混合於二噁烷中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(0.05當量)。將反應混合物在氬氣、90℃下攪拌14h，然後冷卻且過濾。將濾餅用二噁烷洗滌兩次。蒸發溶劑，以得到8-D。8-C (1 equiv), B2Pin2 (1.1 equiv) and KOAc ( 2 equiv) were mixed in dioxane. The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM (0.05 equiv ) was added under argon. The reaction mixture was stirred under argon at 90 °C for 14 h, then cooled and filtered. The filter cake was washed twice with dioxane. The solvent was evaporated to give 8-D.

步驟3：8-F之合成Step 3: Synthesis of 8-F

將8-D(1當量)、(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡 啶-1-甲酸第三丁酯(1.2當量)、碳酸鈉(3當量)一起混合於二噁烷-水混合物(3：1)中。將所得混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後添加Pd(dppf)Cl2 *DCM(819.86mg，1.00mmol)且將反應混合物在氬氣、90℃下攪拌隔夜，然後冷卻，且在真空中濃縮。將殘餘物用MTBE稀釋且攪拌0.5h。在大部分殘餘物已溶解之後，添加無水硫酸鈉，且過濾所得混合物。將濾餅另外用MTBE(5*50ml)洗滌且丟棄。將濾液在真空中濃縮，以得到8-F。8-D (1 equiv), ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.2 equiv), sodium carbonate (3 equiv) were mixed together in a dioxane-water mixture (3:1). The resulting mixture was evacuated and backfilled with argon. This was repeated twice, then Pd(dppf)Cl2*DCM ( 819.86 mg, 1.00 mmol) was added and the reaction mixture was stirred under argon at 90°C overnight, then cooled and concentrated in vacuo. The residue was diluted with MTBE and stirred for 0.5 h. After most of the residue had dissolved, anhydrous sodium sulfate was added, and the resulting mixture was filtered. The filter cake was additionally washed with MTBE (5*50ml) and discarded. The filtrate was concentrated in vacuo to give 8-F.

步驟4：8-G之合成Step 4: Synthesis of 8-G

將8-F(1當量)於TFA(15當量)中之溶液在室溫下攪拌1h，然後在真空中濃縮。將冷水添加到殘餘物中，且將所得混合物用DCM萃取兩次。丟棄DCM層，且將水層鹼化至pH 11。將所得混合物用DCM萃取兩次。將經合併之有機萃取物經硫酸鈉乾燥，且在真空中濃縮，以得到8-G。A solution of 8-F (1 equiv) in TFA (15 equiv) was stirred at room temperature for 1 h, then concentrated in vacuo. Cold water was added to the residue, and the resulting mixture was extracted twice with DCM. The DCM layer was discarded, and the aqueous layer was basified to pH 11. The resulting mixture was extracted twice with DCM. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 8-G.

步驟5：8-H之合成Step 5: Synthesis of 8-H

將8-G(1當量)溶解於MeOH中且將所得溶液在冰浴中冷卻至0℃。將硼氫化鈉(2當量)分批添加到先前溶液中。在添加完成之後，使反應混合物升溫至室溫且攪拌隔夜。將水添加到反應混合物且將所得混合物在真空中濃縮。將殘餘物用水稀釋且將所得混合物用DCM萃取兩次，經Na2 SO4 乾燥，過濾且蒸發，以獲得8-H。8-G (1 equiv) was dissolved in MeOH and the resulting solution was cooled to 0 °C in an ice bath. Sodium borohydride (2 equiv) was added portionwise to the previous solution. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water and the resulting mixture was extracted twice with DCM, dried over Na2SO4 , filtered and evaporated to obtain 8-H.

步驟6A：式8之合成Step 6A: Synthesis of Formula 8

將8-H(1當量)、草醯胺酸(1當量)及TEA(2.5當量+1.0當量/各酸當量，若使用胺鹽)一起混合於DMF中。向其中添加HATU(1.5當量)且將所得混合物攪拌隔夜。將反應混合物在真空中濃縮且藉由HPLC純化殘餘物，以獲得式8。8-H (1 equiv), oxalic acid (1 equiv) and TEA (2.5 equiv + 1.0 equiv per acid equiv, if using amine salt) were mixed together in DMF. To this was added HATU (1.5 equiv) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to obtain formula 8.

步驟6B：式8之合成Step 6B: Synthesis of Formula 8

將DIPEA(2.5當量+1.0當量/各酸當量，若使用胺鹽)添加到相應胺或其鹽(8-H)(1當量)及草醯胺酸(1當量)於DMF中之溶液中。將所得混合物攪拌5 min，隨後添加HATU(1.1當量)於DME中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之濾液經歷HPLC(Waters SunFire C18 19*100 5mkm管柱且以H2 O-MeOH為流動相)，以得到純產物(式8)。DIPEA (2.5 equiv + 1.0 equiv per acid equiv, if an amine salt is used) was added to a solution of the corresponding amine or its salt (8-H) (1 equiv) and oxalic acid (1 equiv) in DMF. The resulting mixture was stirred for 5 min, then a solution of HATU (1.1 equiv) in DME was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained filtrate was subjected to HPLC (Waters SunFire C18 19*100 5mkm column with H2O -MeOH as mobile phase) to give pure product (Formula 8).

實例555.N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基-1H -咪唑-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1280)之合成Example 555. N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methyl- 1H -imidazole Synthesis of -4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1280)

Figure 110128222-A0202-12-1972-909
Figure 110128222-A0202-12-1972-909

步驟1：2-(5-溴苯并[d]噻唑-2-基)-2,2-二氟-N,N-二甲基乙胺之合成Step 1: Synthesis of 2-(5-Bromobenzo[d]thiazol-2-yl)-2,2-difluoro-N,N-dimethylethylamine

藉由一般程序方案H步驟1A製備。產率：8.3g粗品。Prepared by General Procedure H, Step 1A. Yield: 8.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值321.2；實測值322.2；Rt=1.068min。LCMS (ESI): [M] + m/z: calculated 321.2; found 322.2; Rt=1.068 min.

步驟2：2,2-二氟-N,N-二甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 2: 2,2-Difluoro-N,N-dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of -2-yl)benzo[d]thiazol-2-yl)ethanamine

將2-(5-溴-1,3-苯并噻唑-2-基)-2,2-二氟-N,N -二甲基乙胺(8.3g，25.84mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(7.87g，31.01mmol)及乙酸鉀(5.07g，51.68mmol，3.23mL)一起混合於二噁烷(100mL)中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下，添加XPhos(2.46g，5.17mmol)及參(二苯亞甲基丙酮)二鈀(0)(1.18g，1.29mmol)。將所得混合物在100℃下攪拌16h。然後，將其在減壓下濃縮且藉由梯度管柱層析(SiO2 ，CHCl3 /MTBE)純化殘餘物，得到2,2-二氟-N,N -二甲基 -2-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]乙胺(8.8g，23.90mmol，92.47%產率)。2-(5-Bromo-1,3-benzothiazol-2-yl)-2,2-difluoro- N,N -dimethylethylamine (8.3 g, 25.84 mmol), 4,4,5 ,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxo Bororolane (7.87 g, 31.01 mmol) and potassium acetate (5.07 g, 51.68 mmol, 3.23 mL) were mixed together in dioxane (100 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, under argon flow, XPhos (2.46 g, 5.17 mmol) and gins(dibenzylideneacetone)dipalladium(0) (1.18 g, 1.29 mmol) were added. The resulting mixture was stirred at 100 °C for 16 h. Then, it was concentrated under reduced pressure and the residue was purified by gradient column chromatography ( SiO2 , CHCl3 /MTBE) to give 2,2-difluoro- N,N -dimethyl-2-[5 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazol-2-yl]ethanamine (8.8 g, 23.90 mmol, 92.47% yield).

LCMS(ESI)：[M]+ m/z：計算值368.2；實測值369.2；Rt=1.076min。LCMS (ESI): [M] + m/z: calculated 368.2; found 369.2; Rt=1.076 min.

步驟3：(S)-6-(2-(2-(二甲胺基)-1,1-二氟乙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(2-(dimethylamino)-1,1-difluoroethyl)benzo[d]thiazol-5-yl)-3-methyl-3, Synthesis of 4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟3製備。產率：2.22g(88.77%)。Prepared by General Procedure H, Step 3. Yield: 2.22 g (88.77%).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=1.299min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=1.299 min.

步驟4：(S)-2,2-二氟-N,N-二甲基-2-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 4: (S)-2,2-Difluoro-N,N-dimethyl-2-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzene Synthesis of [d]thiazol-2-yl)ethanamine

藉由一般程序方案H步驟4製備。產率：1.14g(66.59%)。Prepared by General Procedure H, Step 4. Yield: 1.14 g (66.59%).

LCMS(ESI)：[M]+ m/z：計算值337.2；實測值338.2；Rt=0.586min。LCMS (ESI): [M] + m/z: calculated 337.2; found 338.2; Rt=0.586 min.

步驟5：2,2-二氟-N,N-二甲基-2-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 5: 2,2-Difluoro-N,N-dimethyl-2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole-2- Synthesis of ethyl) ethylamine

藉由一般程序方案H步驟5製備。產率：1.04g(90.69%)。Prepared by General Procedure H, Step 5. Yield: 1.04 g (90.69%).

LCMS(ESI)：[M]+ m/z：計算值339.2；實測值340.2；Rt=0.771min。LCMS (ESI): [M] + m/z: calculated 339.2; found 340.2; Rt=0.771 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-1H-咪唑-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1280)之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-1H-imidazole) Synthesis of -4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1280)

藉由一般程序方案H步驟6A製備。產率：133mg(56.72%)。Prepared by General Procedure H, Step 6A. Yield: 133 mg (56.72%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-5min 40-100%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 40-100% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.07(t,3H),1.11-1.14(m,3H),1.32-1.41(m,1H),1.67-1.71(m,2H),1.86-1.90(m,1H),2.06-2.13(m,1H),2.17-2.23(m,6H),2.34-2.41(m,3H),2.78-2.81(m,1H),3.49-4.07(m,2H),5.32-5.72(m,3H),7.43-7.60(m,2H),7.99-8.11(m,2H),8.22-8.26(m,1H),10.54-10.59(m, 1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.07(t,3H), 1.11-1.14(m,3H), 1.32-1.41(m,1H), 1.67-1.71(m,2H) ,1.86-1.90(m,1H),2.06-2.13(m,1H),2.17-2.23(m,6H),2.34-2.41(m,3H),2.78-2.81(m,1H),3.49-4.07( m, 2H), 5.32-5.72 (m, 3H), 7.43-7.60 (m, 2H), 7.99-8.11 (m, 2H), 8.22-8.26 (m, 1H), 10.54-10.59 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值530.2；實測值531.2；Rt=2.162min。LCMS (ESI): [M] + m/z: calculated 530.2; found 531.2; Rt=2.162 min.

實例556.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-((乙基(異丙基 )胺基)甲基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1380)之合成Example 556. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-((ethyl( isopropyl )amino)methyl ) Synthesis of benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1380)

Figure 110128222-A0202-12-1974-815
Figure 110128222-A0202-12-1974-815

步驟1：N-((5-溴苯并[d]噻唑-2-基)甲基)-N-乙基丙-2-胺之合成Step 1: Synthesis of N-((5-bromobenzo[d]thiazol-2-yl)methyl)-N-ethylpropan-2-amine

藉由一般程序方案H步驟1C製備。產率：1.2g(92.74%)。Prepared by General Procedure H, Step 1C. Yield: 1.2 g (92.74%).

LCMS(ESI)：[M]+ m/z：計算值313.2；實測值314.2；Rt=1.016min。LCMS (ESI): [M] + m/z: calculated 313.2; found 314.2; Rt=1.016 min.

步驟2：N-乙基-N-((5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)甲基)丙-2-胺之合成Step 2: N-ethyl-N-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d Synthesis of ]thiazol-2-yl)methyl)propan-2-amine

藉由一般程序方案H步驟2製備。產率：1.3g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 1.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值360.2；實測值361.2；Rt=1.192min。LCMS (ESI): [M] + m/z: calculated 360.2; found 361.2; Rt=1.192 min.

步驟3：(S)-6-(2-((乙基(異丙基)胺基)甲基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-((Ethyl(isopropyl)amino)methyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydro Synthesis of tert-butyl pyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：0.65g(41.94%)。Prepared by General Procedure H, Step 3. Yield: 0.65 g (41.94%).

CC條件： 藉由矽膠使用CHCl3 /EtOAc作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using CHCl3 /EtOAc as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.340min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.340 min.

步驟4：(S)-N-乙基-N-((5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)甲基)丙-2-胺之合成Step 4: (S)-N-ethyl-N-((5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl ) methyl) propan-2-amine synthesis

使(3S )-6-[2-[[乙基(異丙基 )胺基]甲基]-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(650.00mg，1.51mmol)於MeOH(10mL)及二噁烷/HCl(5mL)中之經攪拌之溶液在25℃下攪拌16h。完成之後，將反應混合物蒸發，將粗產物用水(20mL)萃取且藉由NaHCO3 中和至pH=8。將水相用CHCl3 (2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物N -乙基-N -[[5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑-2-基]甲基]丙-2-胺(0.49g，1.49mmol，98.29%產率)。make ( 3S )-6-[2-[[ethyl( isopropyl )amino]methyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro - A stirred solution of tert-butyl 2H -pyridine-1-carboxylate (650.00 mg, 1.51 mmol) in MeOH (10 mL) and dioxane/HCl (5 mL) was stirred at 25 °C for 16 h. After completion, the reaction mixture was evaporated, the crude product was extracted with water (20 mL) and neutralized to pH=8 by NaHCO3 . The aqueous phase was extracted with CHCl3 (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Isolation of the desired product N -ethyl- N -[[5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole-2 -yl]methyl]propan-2-amine (0.49 g, 1.49 mmol, 98.29% yield).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.483min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.483 min.

步驟5：N-乙基-N-(((5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)甲基)丙-2-胺之合成Step 5: N-Ethyl-N-(((5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)methyl)propan-2 -Synthesis of amines

藉由一般程序方案H步驟5製備。產率：0.49g(99.39%)。Prepared by General Procedure H, Step 5. Yield: 0.49 g (99.39%).

LCMS(ESI)：[M]+ m/z：計算值331.2；實測值332.2；Rt=0.777min。LCMS (ESI): [M] + m/z: calculated 331.2; found 332.2; Rt=0.777 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-((乙基(異丙基)胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1380)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-((ethyl(isopropyl)amino)methyl ) Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1380)

藉由一般程序方案H步驟6B製備。產率：48mg(30.44%)。Prepared by General Procedure H, Step 6B. Yield: 48 mg (30.44%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 60-80%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 60-80% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.06(m,10H),1.11-1.13(t,3H),1.32-1.39(m,1H),1.69-1.71(m,2H),1.85-1.89(m,1H),2.06-2.20(m,2H),2.27-2.41(m,3H),2.56-2.79(m,3H),2.98-3.02(m,1H),3.47-4.05(m,3H),5.27-5.69(m,3H),7.31-7.51(m,2H),7.80-7.83(d,1H),7.99-8.07(m,2H),10.55(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.06(m, 10H), 1.11-1.13(t, 3H), 1.32-1.39(m, 1H), 1.69-1.71(m, 2H) ,1.85-1.89(m,1H),2.06-2.20(m,2H),2.27-2.41(m,3H),2.56-2.79(m,3H),2.98-3.02(m,1H),3.47-4.05( m, 3H), 5.27-5.69 (m, 3H), 7.31-7.51 (m, 2H), 7.80-7.83 (d, 1H), 7.99-8.07 (m, 2H), 10.55 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=1.999min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=1.999 min.

實例557.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(吡啶-3-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1200)之合成Example 557. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(pyridin-3-yl)benzo Synthesis of [ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1200)

Figure 110128222-A0202-12-1976-816
Figure 110128222-A0202-12-1976-816

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(吡啶-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1200)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(pyridin-3-yl)benzo Synthesis of [d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1200)

藉由一般程序方案H步驟6B製備。產率：18.9mg(12.37%)。Prepared by General Procedure H, Step 6B. Yield: 18.9 mg (12.37%).

HPLC條件： 管柱：SunFire C18 100*19mm，5微米；2-10min 50-75% MeOH+NH3 ，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-10 min 50-75% MeOH+ NH3 , flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03-1.06(t,3H),1.12-1.14(m,3H),1.34-1.42(m,1H),1.70-1.75(m,1H),1.88-1.96(m,1H),2.11-2.29(m,1H),2.30-2.35(m,1H),2.40-2.48(m,1H),2.81-2.8(m,1H),3.50-4.08(m,2H),5.33-5.73(m,3H),7.36-7.62(m,3H),8.00-8.08(m,2H),8.21-8.22(m,1H),8.43-8.46(m,1H),8.74-8.75(d,1H),9.25-9.27(m,1H),10.57(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03-1.06(t,3H), 1.12-1.14(m,3H), 1.34-1.42(m,1H), 1.70-1.75(m,1H) ,1.88-1.96(m,1H),2.11-2.29(m,1H),2.30-2.35(m,1H),2.40-2.48(m,1H),2.81-2.8(m,1H),3.50-4.08( m,2H),5.33-5.73(m,3H),7.36-7.62(m,3H),8.00-8.08(m,2H),8.21-8.22(m,1H),8.43-8.46(m,1H), 8.74-8.75 (d, 1H), 9.25-9.27 (m, 1H), 10.57 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值500.2；實測值501.2；Rt=2.793min。LCMS (ESI): [M] + m/z: calculated 500.2; found 501.2; Rt=2.793 min.

實例558.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-((異丙基(甲基)胺基)甲基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1303)之合成Example 558. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-((isopropyl(methyl)amino)methyl ) Synthesis of benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1303)

Figure 110128222-A0202-12-1977-817
Figure 110128222-A0202-12-1977-817

步驟1：N-((5-溴苯并[d]噻唑-2-基)甲基)-N-甲基丙-2-胺之合成Step 1: Synthesis of N-((5-bromobenzo[d]thiazol-2-yl)methyl)-N-methylpropan-2-amine

藉由一般程序方案H步驟1C製備。產率：1.2g(97.09%)。Prepared by General Procedure H, Step 1C. Yield: 1.2 g (97.09%).

LCMS(ESI)：[M]+ m/z：計算值299.2；實測值300.2；Rt=0.789min。LCMS (ESI): [M] + m/z: calculated 299.2; found 300.2; Rt=0.789 min.

步驟2：N-甲基-N-((5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)甲基)丙-2-胺之合成Step 2: N-methyl-N-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d Synthesis of ]thiazol-2-yl)methyl)propan-2-amine

藉由一般程序方案H步驟2製備。產率：1.3g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 1.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值346.2；實測值347.2；Rt=0.917min。LCMS (ESI): [M] + m/z: calculated 346.2; found 347.2; Rt=0.917 min.

步驟3：(S)-6-(2-((異丙基(甲基)胺基)甲基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-((isopropyl(methyl)amino)methyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydro Synthesis of tert-butyl pyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：0.6g(38.46%)。Prepared by General Procedure H, Step 3. Yield: 0.6 g (38.46%).

CC條件： 藉由矽膠使用CHCl3 /EtOAc作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using CHCl3 /EtOAc as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.292min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.292 min.

步驟4：(S)-N-甲基-N-((5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[[d]噻唑-2-基)甲基)丙-2-胺之合成Step 4: (S)-N-methyl-N-((5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[[d]thiazole-2- Synthesis of base)methyl)propan-2-amine

使(3S )-6-[2-[[異丙基(甲基)胺基]甲基]-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(600.00mg，1.44mmol)於MeOH(10mL)及二噁烷/HCl(5mL)中之經攪拌之溶液在25℃下攪拌16h。完成之後，將反應混合物蒸發，將粗產物用水(20mL)萃取且藉由NaHCO3 中和至pH=8。將水相用CHCl3 (2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物N -甲基-N -[[5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑-2-基]甲基]丙-2-胺(0.45g，1.43mmol，98.80%產率)。make ( 3S )-6-[2-[[isopropyl(methyl)amino]methyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro - A stirred solution of tert-butyl 2H -pyridine-1-carboxylate (600.00 mg, 1.44 mmol) in MeOH (10 mL) and dioxane/HCl (5 mL) was stirred at 25 °C for 16 h. After completion, the reaction mixture was evaporated, the crude product was extracted with water (20 mL) and neutralized to pH=8 by NaHCO3 . The aqueous phase was extracted with CHCl3 (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Isolation of the desired product N -methyl- N -[[5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole-2 -yl]methyl]propan-2-amine (0.45 g, 1.43 mmol, 98.80% yield).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.395min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.395 min.

步驟5：N-甲基-N-((5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)甲基)丙-2-胺之合成Step 5: N-Methyl-N-((5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)methyl)propan-2- Synthesis of Amines

藉由一般程序方案H步驟5製備。產率：0.45g(99.37%)。Prepared by General Procedure H, Step 5. Yield: 0.45 g (99.37%).

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.744min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.744 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-((異丙基(甲基)胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1303)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-((isopropyl(methyl)amino)methyl ) Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1303)

藉由一般程序方案H步驟6B製備。產率：62mg(38.70%)。Prepared by General Procedure H, Step 6B. Yield: 62 mg (38.70%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 50-80%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 50-80% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03-1.14(m,12H),1.32-1.40(m,1H),1.67-1.71(m,1H),1.85-1.89(m,1H),2.08(m,1H),2.18-2.26(m,4H),2.34-2.41(m,2H),2.77-2.95(m,2H),3.47-4.05(m,3H),5.28-5.69(m,3H),7.32-7.51(m,2H),7.82-7.86(d,1H),7.99-8.07(m,2H),10.52-10.57(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03-1.14(m,12H), 1.32-1.40(m,1H), 1.67-1.71(m,1H), 1.85-1.89(m,1H) ,2.08(m,1H),2.18-2.26(m,4H),2.34-2.41(m,2H),2.77-2.95(m,2H),3.47-4.05(m,3H),5.28-5.69(m, 3H), 7.32-7.51 (m, 2H), 7.82-7.86 (d, 1H), 7.99-8.07 (m, 2H), 10.52-10.57 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=1.915min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=1.915 min.

實例559.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(N-嗎啉基甲基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1092)之合成Example 559. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(N-morpholinylmethyl) Synthesis of Benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1092)

Figure 110128222-A0202-12-1979-818
Figure 110128222-A0202-12-1979-818

步驟1：4-((5-氯苯并[d]噻唑-2-基)甲基)嗎啉之合成Step 1: Synthesis of 4-((5-Chlorobenzo[d]thiazol-2-yl)methyl)morpholine

向5-氯-2-(氯甲基)-1,3-苯并噻唑(5g，22.92mmol)及嗎啉(2.00g，22.92mmol，2.01mL)於MeCN(50mL)中之溶液中添加碳酸鉀(6.34g，45.85mmol，2.77mL)。然後將反應混合物在70℃下攪拌24h，然後在真空中蒸發。將殘餘物用水(50mL)稀釋且用DCM(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到4-[(5-氯-1,3-苯并噻唑-2-基)甲基]嗎啉(6g，22.32mmol，97.38%產率)。To a solution of 5-chloro-2-(chloromethyl)-1,3-benzothiazole (5 g, 22.92 mmol) and morpholine (2.00 g, 22.92 mmol, 2.01 mL) in MeCN (50 mL) was added carbonic acid Potassium (6.34 g, 45.85 mmol, 2.77 mL). The reaction mixture was then stirred at 70 °C for 24 h, then evaporated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 4-[(5-chloro-1,3-benzothiazol-2-yl)methyl]morpholine (6 g, 22.32 mmol, 97.38% yield).

LCMS(ESI)：[M]+ m/z：計算值268.2；實測值269.2；Rt=0.918min。LCMS (ESI): [M] + m/z: calculated 268.2; found 269.2; Rt=0.918 min.

步驟2：4-((5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)甲基)嗎啉之合成Step 2: 4-((5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d]thiazole-2- Synthesis of yl)methyl)morpholine

將乙酸鉀(4.38g，44.65mmol，2.79mL)添加到4-[(5-氯-1,3-苯并噻唑-2-基)甲基]嗎啉(6g，22.32mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(6.24g，24.56mmol)於二噁烷(100mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加參(二苯亞甲基丙酮)二鈀(0)(1.02g，1.12mmol)及XPhos(2.13g，4.46mmol)。在90℃、惰性氣氛下將所得混合物攪拌18h。然後，將其冷卻，用EtOAc(100mL)稀釋且過濾出。將濾液在減壓下濃縮且藉由矽膠急驟層析使用0至100% CHCl3 -MeCN 梯度溶析來純化殘餘物，以得到4-[[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]甲基]嗎啉(8g，22.21mmol，99.46%產率)。Potassium acetate (4.38 g, 44.65 mmol, 2.79 mL) was added to 4-[(5-chloro-1,3-benzothiazol-2-yl)methyl]morpholine (6 g, 22.32 mmol) and 4,4 ,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2- A solution of dioxaborolane (6.24 g, 24.56 mmol) in dioxane (100 mL). The reaction flask was evacuated and refilled with argon 3 times. Paras(dibenzylideneacetone)dipalladium(0) (1.02 g, 1.12 mmol) and XPhos (2.13 g, 4.46 mmol) were then added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 18 h. It was then cooled, diluted with EtOAc (100 mL) and filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% CHCl3 -MeCN gradient to give 4-[[5-(4,4,5,5-tetramethyl yl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazol-2-yl]methyl]morpholine (8 g, 22.21 mmol, 99.46% yield) .

LCMS(ESI)：[M]+ m/z：計算值360.2；實測值361.2；Rt=1.128min。LCMS (ESI): [M] + m/z: calculated 360.2; found 361.2; Rt=1.128 min.

步驟3：(S)-3-甲基-6-(2-(N-嗎啉基甲基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(N-morpholinylmethyl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H) -Synthesis of tert-butyl formate

藉由一般程序8製備。產率：12g粗品。Prepared by General Procedure 8. Yield: 12 g crude.

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.299min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.299 min.

步驟4：(S)-4-((5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)甲基)嗎啉之合成Step 4: (S)-4-((5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)methyl)? Synthesis of morpholino

藉由一般程序方案8製備。產率：5g粗品。Prepared by general procedure Scheme 8. Yield: 5 g crude.

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.774min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.774 min.

步驟5：4-((5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)甲基)嗎啉之合成Step 5: Synthesis of 4-((5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)methyl)morpholine

藉由一般程序方案H步驟5製備。產率：4g粗品。Prepared by General Procedure H, Step 5. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值331.2；實測值332.2；Rt=0.798min。LCMS (ESI): [M] + m/z: calculated 331.2; found 332.2; Rt=0.798 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(N-嗎啉基甲基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1092)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(N-morpholinylmethyl) Synthesis of Benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1092)

藉由一般程序方案8製備。產率：90mg(31.20%)。Prepared by general procedure Scheme 8. Yield: 90 mg (31.20%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 35-35-60%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 35-35-60% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.06(t,3H),1.11-1.13(m,3H),1.32-1.39(m,2H),1.69-1.89(m,3H),2.05-2.20(m,2H),2.27-2.41(m,3H),2.52-2.54(m,2H),2.77-2.79(m,1H),3.47-3.61(m,4H),3.91-4.05(m,2H),5.28-5.69(m,3H),7.35-7.51(m,2H),7.86-8.07(m,3H),10.55(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.06(t,3H), 1.11-1.13(m,3H), 1.32-1.39(m,2H), 1.69-1.89(m,3H) ,2.05-2.20(m,2H),2.27-2.41(m,3H),2.52-2.54(m,2H),2.77-2.79(m,1H),3.47-3.61(m,4H),3.91-4.05( m, 2H), 5.28-5.69 (m, 3H), 7.35-7.51 (m, 2H), 7.86-8.07 (m, 3H), 10.55 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=2.102min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=2.102 min.

實例560.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(羥基甲基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1152)之合成Example 560. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(hydroxymethyl)benzo[ d ]thiazole-5- Synthesis of )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1152)

Figure 110128222-A0202-12-1981-819
Figure 110128222-A0202-12-1981-819

步驟1：N-((5-溴苯并[d]噻唑-2-基)甲基)-N-異丙基丙-2-胺之合成Step 1: Synthesis of N-((5-bromobenzo[d]thiazol-2-yl)methyl)-N-isopropylpropan-2-amine

藉由一般程序方案H步驟1C製備。產率：0.8g(59.18%)。Prepared by General Procedure H, Step 1C. Yield: 0.8 g (59.18%).

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=1.122min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=1.122 min.

步驟2：N-異丙基-N-((5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)甲基)丙-2-胺之合成Step 2: N-isopropyl-N-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[ d] Synthesis of thiazol-2-yl)methyl)propan-2-amine

藉由一般程序方案H步驟2製備。產率：1.1g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 1.1 g crude.

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=1.196min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=1.196 min.

步驟3：(S)-6-(2-(羥基甲基)苯并[d]噻丙-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(Hydroxymethyl)benzo[d]thipropan-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid Synthesis of tributyl ester

將N -異丙基-N -[[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]甲基]丙-2-胺(1.1g，2.94mmol)及(3S )-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.12g，3.23mmol)混合於二噁烷(30mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加於水(10mL)中之碳酸鈉(934.33mg，8.82mmol，369.01μL)及Pd(dppf)Cl2 *DCM(119.98mg，146.92μmol)。將反應混合物在氬氣、90℃下攪拌12h。然後將反應混合物冷卻且在真空中蒸發，倒入到水(100ml)中且用EtOAc(3x20ml)萃取。將經合併之有機萃取物用水(2*10ml)洗滌，經硫酸鈉乾燥且在 真空中蒸發，以得到粗產物，其藉由管柱層析以體系CHCl3 /MeOH(1：1)進行純化，以得到兩種級分：(3S )-6-[2-[(二異丙基胺基)甲基]-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0.95g，2.14mmol，72.87%產率)及(3S )-6-[2-(羥基甲基)-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0.1g，277.42μmol，9.44%產率)。 N - isopropyl-N -[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3- Benzothiazol-2-yl]methyl]propan-2-amine (1.1 g, 2.94 mmol) and ( 3S )-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4 -Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.12 g, 3.23 mmol) was mixed in dioxane (30 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (934.33 mg, 8.82 mmol, 369.01 μL) and Pd(dppf)Cl in water ( 10 mL) were added under argon *DCM (119.98 mg, 146.92 μmol). The reaction mixture was stirred under argon at 90 °C for 12 h. The reaction mixture was then cooled and evaporated in vacuo, poured into water (100ml) and extracted with EtOAc (3x20ml). The combined organic extracts were washed with water (2*10ml), dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by column chromatography with the system CHCl3 /MeOH (1:1) , to obtain two fractions: ( 3S )-6-[2-[(diisopropylamino)methyl]-1,3-benzothiazol-5-yl]-3-methyl-3, 4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (0.95 g, 2.14 mmol, 72.87% yield) and ( 3S )-6-[2-(hydroxymethyl)-1,3-benzoyl Thiazol-5-yl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (0.1 g, 277.42 μmol, 9.44% yield).

LCMS(ESI)：[M]+ m/z：計算值360.2；實測值361.2；Rt=1.423min。LCMS (ESI): [M] + m/z: calculated 360.2; found 361.2; Rt=1.423 min.

步驟4：(S)-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)甲醇之合成Step 4: Synthesis of (S)-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)methanol

將(3S)-6-[2-(羥基甲基)-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0,1g，277.42μmol)溶解於二噁烷/HCl(50mL)中且將所得反應混合物在25℃下攪拌12h。然後將溶劑蒸發至乾，藉由水(20ml)稀釋殘餘物，且藉由DCM(3*20mL)洗滌所得水相。然後將NaHCO3 添加到鹼性反應物中且將此水相藉由DCM(3*30mL)進行萃取，經Na2 SO4 乾燥且在減壓下蒸發，以得到純的[5-[(3S )-3-甲基-1,2,3,4-四氫吡啶-6-基]-1,3-苯并噻唑-2-基]甲醇(0.04g，153.64μmol，55.38%產率)。(3S)-6-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid third Butyl ester (0,1 g, 277.42 μmol) was dissolved in dioxane/HCl (50 mL) and the resulting reaction mixture was stirred at 25 °C for 12 h. The solvent was then evaporated to dryness, the residue was diluted with water (20 ml) and the resulting aqueous phase was washed with DCM (3*20 mL). NaHCO 3 was then added to the basic reaction and the aqueous phase was extracted by DCM (3*30 mL), dried over Na 2 SO 4 and evaporated under reduced pressure to give pure [5-[( 3S )-3-methyl-1,2,3,4-tetrahydropyridin-6-yl]-1,3-benzothiazol-2-yl]methanol (0.04 g, 153.64 μmol, 55.38% yield).

LCMS(ESI)：[M]+ m/z：計算值260.2；實測值261.2；Rt=0.514min。LCMS (ESI): [M] + m/z: calculated 260.2; found 261.2; Rt=0.514 min.

步驟5：(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)甲醇之合成Step 5: Synthesis of (5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)methanol

藉由一般程序方案H步驟5製備。產率：40mg粗品。Prepared by General Procedure H, Step 5. Yield: 40 mg crude.

LCMS(ESI)：[M]+ m/z：計算值262.2；實測值263.2；Rt=0.813min。LCMS (ESI): [M] + m/z: calculated 262.2; found 263.2; Rt=0.813 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(羥基甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1152)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(hydroxymethyl)benzo[d]thiazole-5- Synthesis of )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1152)

藉由一般程序方案H步驟6B製備。產率：28.8mg(41.65%)。Prepared by General Procedure H, Step 6B. Yield: 28.8 mg (41.65%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 25-75%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 25-75% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

然後藉由掌性層析純化產物N-(6-胺基-5-乙基-3-吡啶 基)-2-[(2R,5S)-2-[2-(羥基甲基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.0288g，63.50μmol，41.65%產率)，以得到作為第2批的更純的產物N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[2-(羥基甲基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(13.81mg，30.45μmol，19.97%產率)-化合物1152 。The product N-(6-amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-2-[2-(hydroxymethyl)-1 was then purified by chiral chromatography, 3-Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (0.0288 g, 63.50 μmol, 41.65% yield) was obtained as batch 2 The purer product of N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[2-(hydroxymethyl)-1,3-benzo Thiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (13.81 mg, 30.45 μmol, 19.97% yield) - Compound 1152 .

掌性層析之條件：Conditions for chiral chromatography:

Chirailcel OD-H(250*20mm，5mkm)，己烷-IPA-MeOH，80-10-10，10ml/min。Chirailcel OD-H (250*20mm, 5mkm), Hexane-IPA-MeOH, 80-10-10, 10ml/min.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.75-1.05(m,3H),1.06-1.14(m,3H),1.28-1.44(m,1H),1.67-1.75(m,1H),1.82-1.94(m,1H),2.03-2.22(m,1H),2.25-2.37(m,2H),2.39-2.44(m,1H),2.75-3.28(m,1H),3.47-F1(m,1H),4.82-4.87(m,2H),5.26-5.61(m,1H),5.61-5.75(m,2H),6.29(br s,1H),7.32-7.43(m,1H),7.43-7.55(m,1H),7.83-7.90(m,1H),7.97-8.12(m,2H),10.55(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.75-1.05(m,3H), 1.06-1.14(m,3H), 1.28-1.44(m,1H), 1.67-1.75(m,1H) ,1.82-1.94(m,1H),2.03-2.22(m,1H),2.25-2.37(m,2H),2.39-2.44(m,1H),2.75-3.28(m,1H),3.47-F1( m,1H),4.82-4.87(m,2H),5.26-5.61(m,1H),5.61-5.75(m,2H),6.29(br s,1H),7.32-7.43(m,1H),7.43 -7.55(m, 1H), 7.83-7.90(m, 1H), 7.97-8.12(m, 2H), 10.55(br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=2.154min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=2.154 min.

實例561. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(四氫呋喃-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1145)之合成Example 561. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(tetrahydrofuran-3-yl)benzo Synthesis of [d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1145)

Figure 110128222-A0202-12-1983-820
Figure 110128222-A0202-12-1983-820

藉由一般程序方案H步驟6A製備。產率：200mg(50.45%)。Prepared by General Procedure H, Step 6A. Yield: 200 mg (50.45%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-1-6min 40-40-75%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-1-6min 40-40-75% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH) .

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.36(m,1H),1.70(m,1H),1.87(m,1H),1.99(m,3H),2.25(m,2H),2.42(m,2H),2.96(dd,1H),3.64(m,2H),4.03(m,4H),5.63(m,3H),7.41(m,2H),7.91(m,1H),8.04(m,2H),10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.36(m, 1H), 1.70(m, 1H), 1.87(m, 1H), 1.99(m, 3H), 2.25(m, 2H), 2.42(m, 2H), 2.96(dd, 1H), 3.64(m, 2H), 4.03(m, 4H), 5.63(m, 3H), 7.41(m, 2H), 7.91 (m, 1H), 8.04 (m, 2H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值479.2；實測值480.2；Rt=1.254min。LCMS (ESI): [M] + m/z: calculated 479.2; found 480.2; Rt=1.254 min.

實例562. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-1H-咪唑-2-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1186)之合成Example 562. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-1H-imidazole Synthesis of -2-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1186)

Figure 110128222-A0202-12-1984-821
Figure 110128222-A0202-12-1984-821

藉由一般程序方案H步驟6A製備。產率：199mg(50.80%)。Prepared by General Procedure H, Step 6A. Yield: 199 mg (50.80%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 20-20-45%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03-1.05(m,3H),1.34-1.40(m,1H),1.73(m,1H),1.87-2.19(m,5H),2.30-2.33(m,1H),3.40-3.52(m,2H),4.05-4.33(m,4H),5.58-5.71(m,2H),7.13(s,1H),7.41-7.50(m,3H),7.92-8.13(m,3H),10.53-10.58(m,1H)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 20-20-45% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN ). 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.03-1.05 (m, 3H), 1.34-1.40 (m, 1H), 1.73 (m, 1H), 1.87-2.19 (m, 5H), 2.30 -2.33(m,1H),3.40-3.52(m,2H),4.05-4.33(m,4H),5.58-5.71(m,2H),7.13(s,1H),7.41-7.50(m,3H) , 7.92-8.13 (m, 3H), 10.53-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值489.2；實測值490.2；Rt=2.879min。LCMS (ESI): [M] + m/z: calculated 489.2; found 490.2; Rt=2.879min.

實例563. 2-((2R,5S )-2-(2-(1-乙醯基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物1093)之合成Example 563. 2-(( 2R,5S )-2-(2-(1-Acetylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1 Synthesis of -yl)-N-(6-amino - 5-methylpyridin-3-yl)-2-oxoacetamide (compound 1093)

Figure 110128222-A0202-12-1985-822
Figure 110128222-A0202-12-1985-822

步驟1：1-(4-(5-氯苯并[d]噻唑-2-基)哌啶-1-基)乙酮之合成Step 1: Synthesis of 1-(4-(5-Chlorobenzo[d]thiazol-2-yl)piperidin-1-yl)ethanone

在0℃下，將乙醯氯(931.68mg，11.87mmol，722.23uL)逐滴添加到5-氯-2-(4-哌啶基)-1,3-苯并噻唑(2.5g，9.89mmol)及TEA(1.50g，14.84mmol，2.07mL)於DCM(75mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌2h，然後用水(25ml)洗滌。將有機層分離，經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色固體之1-[4-(5-氯-1,3-苯并噻唑-2-基)-1-哌啶基]乙酮(2.8g，9.50mmol，96.03%產率)。Acetyl chloride (931.68 mg, 11.87 mmol, 722.23 uL) was added dropwise to 5-chloro-2-(4-piperidinyl)-1,3-benzothiazole (2.5 g, 9.89 mmol) at 0 °C ) and TEA (1.50 g, 14.84 mmol, 2.07 mL) in a stirred solution of DCM (75 mL). The resulting mixture was stirred at 0 °C for 2 h, then washed with water (25 ml). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give 1-[4-(5-chloro-1,3-benzothiazol-2-yl)-1-piperidinyl as a pale yellow solid ] Ethanone (2.8 g, 9.50 mmol, 96.03% yield).

LCMS(ESI)：[M]+ m/z：計算值294.2；實測值295.2；Rt=1.357min。LCMS (ESI): [M] + m/z: calculated 294.2; found 295.2; Rt=1.357 min.

步驟2：1-(4-(5-(4.4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)哌啶-1-基)乙酮之合成Step 2: 1-(4-(5-(4.4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d]thiazol-2- Synthesis of yl)piperidin-1-yl)ethanone

將1-[4-(5-氯-1,3-苯并噻唑-2-基)-1-哌啶基]乙酮(2.3g，7.80mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.18g，8.58mmol)及乙酸鉀(1.53g，15.60mmol，975.39uL)於二噁烷(100mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(357.22mg，390.10umol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(743.87mg，1.56mmol)，且將反應混合物在95℃下攪拌18h。將反應混合物冷卻且在真空中濃縮。藉由矽膠管柱層析 使用氯仿/乙酸乙酯梯度(0-100%乙酸乙酯)純化殘餘物，以得到呈淡黃色固體之1-[4-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]-1-哌啶基]乙酮(2.3g，5.95mmol，76.31%產率)。1-[4-(5-Chloro-1,3-benzothiazol-2-yl)-1-piperidinyl]ethanone (2.3 g, 7.80 mmol), 4,4,5,5-tetramethyl yl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A mixture of alkane (2.18 g, 8.58 mmol) and potassium acetate (1.53 g, 15.60 mmol, 975.39 uL) in dioxane (100 mL) was evacuated and backfilled with argon. This operation was repeated twice, followed by the addition of bis(1,5-diphenylpent-1,4-dien-3-one)dipalladium ( 357.22 mg, 390.10 umol) and dicyclohexyl[2 ',4',6'-Sham(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (743.87 mg, 1.56 mmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography using a chloroform/ethyl acetate gradient (0-100% ethyl acetate) to give 1-[4-[5-(4,4,5,5 as a pale yellow solid -Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazol-2-yl]-1-piperidinyl]ethanone (2.3g, 5.95 mmol, 76.31% yield).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.347min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.347 min.

步驟3：(S)-6-(2-(1-乙醯基哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1-Acetylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine- Synthesis of 1(2H)-tert-butyl formate

藉由一般程序方案8製備。產率：2.2g(81.10%)。Prepared by general procedure Scheme 8. Yield: 2.2 g (81.10%).

CC條件： 藉由矽膠使用CHCl3 /EtOAc作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using CHCl3 /EtOAc as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值455.2；實測值456.2；Rt=1.546min。LCMS (ESI): [M] + m/z: calculated 455.2; found 456.2; Rt=1.546 min.

步驟4：(S)-1-(4-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)哌啶-1-基)乙酮之合成Step 4: (S)-1-(4-(5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)piperidine Synthesis of -1-yl)ethanone

藉由一般程序8製備。產率：1.2g(69.91%)。Prepared by General Procedure 8. Yield: 1.2 g (69.91%).

LCMS(ESI)：[M]+ m/z：計算值355.2；實測值356.2；Rt=0.730min。LCMS (ESI): [M] + m/z: calculated 355.2; found 356.2; Rt=0.730 min.

步驟5：1-(4-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)哌啶-1-基)乙酮之合成Step 5: Compound of 1-(4-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)piperidin-1-yl)ethanone synthesis

藉由一般程序方案H步驟5製備。產率：0.7g(58%)。Prepared by General Procedure H, Step 5. Yield: 0.7 g (58%).

LCMS(ESI)：[M]+ m/z：計算值357.2；實測值358.2；Rt=0.750min。LCMS (ESI): [M] + m/z: calculated 357.2; found 358.2; Rt=0.750 min.

步驟6：2-((2R,5S)-2-(2-(1-乙醯基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物1093)之合成Step 6: 2-((2R,5S)-2-(2-(1-Acetylpiperidin-4-yl)benzo[d]thiazol-5-yl)-5-methylpiperidine-1 Synthesis of -yl)-N-(6-amino-5-methylpyridin-3-yl)-2-oxoacetamide (compound 1093)

藉由一般程序8製備。產率：48mg(8.02%)。Prepared by General Procedure 8. Yield: 48 mg (8.02%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 30-30-50%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 30-30-50% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN ).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.35(m,1H),1.59(m,1H),1.73(m,2H),1.87(m,1H),2.03(m,6H),2.11(m,3H),2.31(m,1H),2.76(m,1H), 3.19(m,2H),3.40(m,2H),3.68(dd,1H),4.22(dd,1H),5.56(m,3H),7.43(m,2H),7.88(m,1H),8.00(m,1H),8.09(m,1H),10.56(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.35(m, 1H), 1.59(m, 1H), 1.73(m, 2H), 1.87(m, 1H), 2.03(m, 6H), 2.11(m, 3H), 2.31(m, 1H), 2.76(m, 1H), 3.19(m, 2H), 3.40(m, 2H), 3.68(dd, 1H), 4.22 (dd, 1H), 5.56 (m, 3H), 7.43 (m, 2H), 7.88 (m, 1H), 8.00 (m, 1H), 8.09 (m, 1H), 10.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值534.2；實測值535.2；Rt=2.699min。LCMS (ESI): [M] + m/z: calculated 534.2; found 535.2; Rt=2.699 min.

實例564. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-1H-咪唑-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1214)之合成Example 564. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-1H-imidazole Synthesis of -4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1214)

Figure 110128222-A0202-12-1987-823
Figure 110128222-A0202-12-1987-823

藉由一般程序方案H步驟6A製備。產率：267mg(57.10%)。Prepared by General Procedure H, Step 6A. Yield: 267 mg (57.10%).

HPLC條件：管柱：Chromatorex C18 100*19mm，5微米；0-5min 20-70%水-MeOH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: Chromatorex C18 100*19 mm, 5 microns; 0-5 min 20-70% water-MeOH, flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.05(m,3H),1.69-2.37(m,8H),2.79-2.81(m,1H),3.47-4.06(m,4H),5.27-5.70(m,3H),7.31-7.55(m,2H),7.78-8.06(m,5H),10.52-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.05(m,3H), 1.69-2.37(m,8H), 2.79-2.81(m,1H), 3.47-4.06(m,4H) , 5.27-5.70(m, 3H), 7.31-7.55(m, 2H), 7.78-8.06(m, 5H), 10.52-10.62(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值489.2；實測值490.2；Rt=2.455min。LCMS (ESI): [M] + m/z: calculated 489.2; found 490.2; Rt=2.455min.

實例565.N -(6-胺基-5-環丙基吡啶-3-基)-2-(2-(2-(2-甲氧基乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1176及化合物1332)之合成Example 565. N- (6-amino-5-cyclopropylpyridin-3-yl)-2-(2-(2-(2-methoxyethyl)benzo[ d ]thiazol-5-yl) )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1176 and Compound 1332) Synthesis

Figure 110128222-A0202-12-1988-824
Figure 110128222-A0202-12-1988-824

步驟1：外消旋-(3-環丙基-5-(2-((2R,5S)-2-(2-(2-甲氧基乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Racemic-(3-cyclopropyl-5-(2-((2R,5S)-2-(2-(2-methoxyethyl)benzo[d]thiazol-5-yl) Synthesis of 3-butyl )-5-methylpiperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamate

藉由一般程序方案H步驟6A製備。產率：0.7g粗品。Prepared by General Procedure H, Step 6A. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值534.2；實測值535.2；Rt=2.624min。LCMS (ESI): [M] + m/z: calculated 534.2; found 535.2; Rt=2.624 min.

步驟2：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-(2-甲氧基乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-(2-methoxyethyl)benzo[d]thiazol-5-yl) Synthesis of -5-methylpiperidin-1-yl)-2-oxoacetamide

將N -[3-環丙基-5-[[2-[(2R,5S )-2-[2-(2-甲氧基乙基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.7g，1.18mmol)於二噁烷(6mL)及水(3mL)中之溶液在65℃下攪拌64h且在真空中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：XBridge BEH C18 5um 130A；以45-45-80% 0-1-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min為流動相)，以得到N -(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S )-2-[2-(2-甲氧基乙基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(158mg，320.08umol，27.15%產率)。 N- [3-Cyclopropyl-5-[[2-[( 2R,5S )-2-[2-(2-methoxyethyl)-1,3-benzothiazol-5-yl] - 3-butyl 5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.7 g, 1.18 mmol) in dioxane (6 mL) ) and water (3 mL) were stirred at 65 °C for 64 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: XBridge BEH C18 5um 130A; mobile phase with 45-45-80% 0-1-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30 ml/min) , to give N- (6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2R,5S )-2-[2-(2-methoxyethyl)-1,3 - Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (158 mg, 320.08 umol, 27.15% yield).

LCMS(ESI)：[M]+ m/z：計算值493.2；實測值494.2；Rt=2.452min。LCMS (ESI): [M] + m/z: calculated 493.2; found 494.2; Rt=2.452 min.

步驟3：掌性分離(化合物1176及化合物1332)Step 3: Chiral separation (compound 1176 and compound 1332)

對外消旋N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-(2-甲氧基乙基)苯并[d ] 噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(158mg，320.08μmol)進行掌性分離(管柱：Chiralpak IC-III(250*20，5mkm)，IPA-MeOH，50-50，10ml/min)，以獲得N -(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S )-2-[2-(2-甲氧基乙基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(60mg，121.55umol，75.95%產率)(RT=24.22)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R )-2-[2-(2-甲氧基乙基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(57mg，115.47umol，72.15%產率)(RT=38.03)。Racemic N- (6-amino-5-methylpyridin-3-yl)-2-(2-(2-(2-methoxyethyl)benzo[ d ]thiazol-5-yl) Chiral separation (column: Chiralpak IC-III (250*20, 5mkm), IPA-MeOH , 50-50, 10ml/min) to obtain N- (6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2R,5S )-2-[2-(2-methyl) Oxyethyl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (60 mg, 121.55 umol, 75.95% yield) (RT=24.22) and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2S,5R )-2-[2-(2-methoxyethyl)- 1,3-Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (57 mg, 115.47 umol, 72.15% yield) (RT=38.03).

化合物1176於分析條件下(管柱：IC，以IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為18.91min且化合物1332之保留時間為29.26min。The retention time of compound 1176 under analytical conditions (column: IC, with IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 18.91 min and that of compound 1332 was 29.26 min.

化合物1176：Compound 1176:

保留時間：18.91minRetention time: 18.91min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.36-0.53(m,2H),0.82-0.91(m,2H),0.99-1.07(m,3H),1.30-1.42(m,1H),1.57-1.75(m,2H),1.82-1.91(m,1H),2.06-2.23(m,1H),2.26-2.36(m,1H),2.75-3.26(m,1H),3.27(s,3H),3.31-3.34(m,2H),3.44-3.52(m,0.6H),3.72-3.79(m,2H),4.02-4.07(m,0.4H),5.25-5.70(m,1H),5.70-5.82(m,2H),7.24-7.46(m,2H),7.83-7.90(m,1H),7.96-8.10(m,2H),10.46-10.66(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.36-0.53(m, 2H), 0.82-0.91(m, 2H), 0.99-1.07(m, 3H), 1.30-1.42(m, 1H) ,1.57-1.75(m,2H),1.82-1.91(m,1H),2.06-2.23(m,1H),2.26-2.36(m,1H),2.75-3.26(m,1H),3.27(s, 3H), 3.31-3.34(m, 2H), 3.44-3.52(m, 0.6H), 3.72-3.79(m, 2H), 4.02-4.07(m, 0.4H), 5.25-5.70(m, 1H), 5.70-5.82(m, 2H), 7.24-7.46(m, 2H), 7.83-7.90(m, 1H), 7.96-8.10(m, 2H), 10.46-10.66(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值493.2；實測值494.2；Rt=2.609minLCMS(ESI): [M] + m/z: Calculated 493.2; Measured 494.2; Rt=2.609min

化合物1332：Compound 1332:

保留時間：29.26minRetention time: 29.26min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.38-0.52(m,2H),0.81-0.91(m,2H),1.00-1.07(m,3H),1.31-1.42(m,1H),1.59-1.75(m,2H),1.79-1.95(m,1H),2.06-2.22(m,1H),2.26-2.35(m,1H),2.76-3.26(m,1H),3.27(s,3H),3.31-3.34(m,2H),3.44-3.53(m,0.6H),3.71-3.80(m,2H),4.02-4.06(m,0.4H),5.25-5.70(m,1H), 5.70-5.84(m,2H),7.27-7.43(m,2H),7.82-7.92(m,1H),7.96-8.10(m,2H),10.46-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.38-0.52(m, 2H), 0.81-0.91(m, 2H), 1.00-1.07(m, 3H), 1.31-1.42(m, 1H) ,1.59-1.75(m,2H),1.79-1.95(m,1H),2.06-2.22(m,1H),2.26-2.35(m,1H),2.76-3.26(m,1H),3.27(s, 3H), 3.31-3.34(m, 2H), 3.44-3.53(m, 0.6H), 3.71-3.80(m, 2H), 4.02-4.06(m, 0.4H), 5.25-5.70(m, 1H), 5.70-5.84(m, 2H), 7.27-7.43(m, 2H), 7.82-7.92(m, 1H), 7.96-8.10(m, 2H), 10.46-10.57(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值493.2；實測值494.2；Rt=2.605min。LCMS (ESI): [M] + m/z: calculated 493.2; found 494.2; Rt=2.605 min.

實例566. 2-((2R,5S)-2-(2-((二甲胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基-N-(5-側氧基-5,6,7,8-四氫-1,6-萘啶-3-基)乙醯胺(化合物1354)之合成Example 566. 2-((2R,5S)-2-(2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl) - Synthesis of 2-oxo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetamide (compound 1354)

Figure 110128222-A0202-12-1990-825
Figure 110128222-A0202-12-1990-825

步驟1：(3-環丙基-5-(2-((2R,5S)-2-(2-((二甲胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Cyclopropyl-5-(2-((2R,5S)-2-(2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-5 -Synthesis of tert-butyl methylpiperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamate

藉由一般程序方案H步驟6A製備。產率：268mg粗品。Prepared by General Procedure H, Step 6A. Yield: 268 mg crude.

HPLC條件：管柱：SunFire C18 100*19mm，5微米；2-10min 50-80% MeOH+NH3 ；(裝載泵4ml/min MeOH+NH3 )。HPLC conditions: Column: SunFire C18 100*19mm, 5 microns; 2-10 min 50-80% MeOH+ NH3 ; (loading pump 4 ml/min MeOH+ NH3 ).

LCMS(ESI)：[M]+ m/z：計算值592.2；實測值593.2；Rt=1.029min。LCMS (ESI): [M] + m/z: calculated 592.2; found 593.2; Rt=1.029 min.

步驟2：2-((2R,5S)-2-(2-((二甲胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基-N-(5-側氧基-5,6,7,8-四氫-1,6-萘啶-3-基)乙醯胺(化合物1354)之合成Step 2: 2-((2R,5S)-2-(2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl) - Synthesis of 2-oxo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetamide (compound 1354)

將N -[3-環丙基-5-[[2-[(2R,5S )-2-[2-[(二甲胺基)甲基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(73mg，87.44umol)溶解於水(1mL)及二噁烷(1mL)之混合物中且在100℃下在攪拌下加熱12h。將粗產物溶解於DMSO中且使其經歷HPLC(SYSTEM 2-10min 30-55% MeCN+NH3 流速30ml/min(裝載泵4ml/min)，管柱Sun Fire C18 100*19mm)。獲得N -(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S )-2-[2-[(二甲胺基)甲基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(19.8mg，40.19umol，45.97%產率)。 N- [3-Cyclopropyl-5-[[2-[( 2R,5S )-2-[2-[(dimethylamino)methyl]-1,3-benzothiazol-5-yl ]-5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (73 mg, 87.44 umol) was dissolved in water (1 mL) and dioxane (1 mL) and heated at 100 °C with stirring for 12 h. The crude product was dissolved in DMSO and subjected to HPLC (SYSTEM 2-10min 30-55% MeCN+ NH3 flow rate 30ml/min (loading pump 4ml/min), column Sun Fire C18 100*19mm). Obtained N- (6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2R,5S )-2-[2-[(dimethylamino)methyl]-1,3- Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (19.8 mg, 40.19 umol, 45.97% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.38-0.51(m,2H),0.82-0.91(m,2H),0.98-1.06(m,3H),1.28-1.41(m,1H),1.58-1.73(m,2H),1.81-1.93(m,1H),2.04-2.20(m,1H),2.25-2.32(m,7H),2.75-3.26(m,1H),3.45-4.09(m,3H),5.26-5.70(m,1H),5.72-5.82(m,2H),7.26-7.46(m,2H),7.82-7.90(m,1H),7.96-8.08(m,2H),10.43-10.60(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.38-0.51(m, 2H), 0.82-0.91(m, 2H), 0.98-1.06(m, 3H), 1.28-1.41(m, 1H) ,1.58-1.73(m,2H),1.81-1.93(m,1H),2.04-2.20(m,1H),2.25-2.32(m,7H),2.75-3.26(m,1H),3.45-4.09( m,3H),5.26-5.70(m,1H),5.72-5.82(m,2H),7.26-7.46(m,2H),7.82-7.90(m,1H),7.96-8.08(m,2H), 10.43-10.60 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值492.2；實測值493.2；Rt=1.651min。LCMS (ESI): [M] + m/z: calculated 492.2; found 493.2; Rt=1.651 min.

實例567. 外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-1H-吡唑-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1104)之合成Example 567. Racemic-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl) Synthesis of -1H-pyrazol-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1104)

Figure 110128222-A0202-12-1991-826
Figure 110128222-A0202-12-1991-826

藉由一般程序8步驟6A製備。產率：88.4mg(20.15%)。Prepared by General Procedure 8, Step 6A. Yield: 88.4 mg (20.15%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-5min 30-70%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 30-70% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

化合物1104：Compound 1104:

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.38(m,1H),1.72(m,1H),1.86(m,1H),2.00(m,3H),2.26(m,2H),3.92(m,5H),5.64(m,3H),7.40(m,2H),7.95(m,4H),8.48(m,1H),10.58(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.38(m, 1H), 1.72(m, 1H), 1.86(m, 1H), 2.00(m, 3H), 2.26(m, 2H), 3.92(m, 5H), 5.64(m, 3H), 7.40(m, 2H), 7.95(m, 4H), 8.48(m, 1H), 10.58(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值489.2；實測值490.2；Rt=2.469min。LCMS (ESI): [M] + m/z: calculated 489.2; found 490.2; Rt=2.469 min.

實例568. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-2-(2-(1-環丙基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1181)之合成Example 568. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-cyclopropylpiperidin-4-yl)benzene Synthesis of [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1181)

Figure 110128222-A0202-12-1992-827
Figure 110128222-A0202-12-1992-827

藉由一般程序方案H步驟6A製備。產率：53mg(12.63%)。Prepared by General Procedure H, Step 6A. Yield: 53 mg (12.63%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-5min 50-100%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 50-100% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.30(m,2H),0.41(m,2H),1.03(m,3H),1.35(m,1H),1.62(m,1H),1.70(m,3H),1.87(m,1H),2.05(m,5H),2.32(m,3H),2.89(m,3H),3.09(m,1H),3.75(dd,1H),5.63(m,3H),7.34(d,1H),7.41(m,1H),7.50(s,1H),7.98(m,3H),10.55(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.30(m, 2H), 0.41(m, 2H), 1.03(m, 3H), 1.35(m, 1H), 1.62(m, 1H), 1.70(m,3H),1.87(m,1H),2.05(m,5H),2.32(m,3H),2.89(m,3H),3.09(m,1H),3.75(dd,1H),5.63 (m, 3H), 7.34 (d, 1H), 7.41 (m, 1H), 7.50 (s, 1H), 7.98 (m, 3H), 10.55 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值532.2；實測值533.2；Rt=2.114min。LCMS (ESI): [M] + m/z: calculated 532.2; found 533.2; Rt=2.114 min.

實例569.N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(4-甲基哌嗪-1-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1158)之合成Example 569. N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(4-methylpiperazine-1 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1158)

步驟1：(S)-6-(苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of (S)-6-(benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1992-828
Figure 110128222-A0202-12-1992-828

藉由一般程序方案H步驟3製備。產率：3g(45.56%)。Prepared by General Procedure H, Step 3. Yield: 3 g (45.56%).

CC條件： 藉由矽膠使用己烷/MTBE作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=1.635min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=1.635 min.

步驟2：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 2: Synthesis of (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-1993-829
Figure 110128222-A0202-12-1993-829

藉由一般程序方案H步驟4製備。產率：2g(95.77%)。Prepared by General Procedure H, Step 4. Yield: 2 g (95.77%).

LCMS(ESI)：[M]+ m/z：計算值229.2；實測值230.2；Rt=0.783min。LCMS (ESI): [M] + m/z: calculated 229.2; found 230.2; Rt=0.783 min.

步驟3：5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-1993-830
Figure 110128222-A0202-12-1993-830

藉由一般程序方案H步驟5製備。產率：2g(99.13%)。Prepared by General Procedure H, Step 5. Yield: 2 g (99.13%).

LCMS(ESI)：[M]+ m/z：計算值231.2；實測值232.2；Rt=0.795min。LCMS (ESI): [M] + m/z: calculated 231.2; found 232.2; Rt=0.795 min.

步驟4：(2R,5S)-2-(苯并[d]噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of (2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1993-831
Figure 110128222-A0202-12-1993-831

在25℃下，將二碳酸二-第三丁酯(493.15mg，2.26mmol，518.56μL)一次性添加到5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑(0.5g，2.15mmol)於DCM(15mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌1h，然後在真空中濃縮，以得到呈棕色膠狀物之(2R,5S )-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(800mg，粗品)，其在靜置時結晶，以得到棕色固體。Di-tert-butyl dicarbonate (493.15 mg, 2.26 mmol, 518.56 μL) was added in one portion to 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1 at 25 °C , 3-benzothiazole (0.5 g, 2.15 mmol) in a stirred solution of DCM (15 mL). The resulting mixture was stirred at 25 °C for 1 h, then concentrated in vacuo to give ( 2R,5S )-2-(1,3-benzothiazol-5-yl)-5-methyl as a brown gum 3-Butyl piperidine-1-carboxylate (800 mg, crude), which crystallized on standing to give a brown solid.

LCMS(ESI)：[M]+ m/z：計算值332.2；實測值333.2；Rt=3.995min。LCMS (ESI): [M] + m/z: calculated 332.2; found 333.2; Rt=3.995 min.

步驟5：(2R,5S)-2-(2-溴苯并[d]噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of (2R,5S)-2-(2-bromobenzo[d]thiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-1994-832
Figure 110128222-A0202-12-1994-832

在25℃下，將第三丁醇鈉(563.68mg，5.87mmol)一次性添加到(2R,5S )-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(650mg，1.96mmol)及四溴化碳(778.05mg，2.35mmol，227.50μL)於DMF(10mL)中之經攪拌之溶液中(輕微放熱反應！)。將所得混合物在25℃下攪拌12h，然後用水(15ml)稀釋且用MTBE(3*15ml)萃取。將經合併之有機萃取物用水(2*5ml)洗滌，經硫酸鈉乾燥且在真空中濃縮，以得到呈棕色固體之(2R,5S )-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(750mg，1.82mmol，93.25%產率)，其直接用於下一步驟中。Sodium tert-butoxide (563.68 mg, 5.87 mmol) was added in one portion to ( 2R,5S )-2-(1,3-benzothiazol-5-yl)-5-methylpiperidine at 25°C - A stirred solution of tert-butyl 1-carboxylate (650 mg, 1.96 mmol) and carbon tetrabromide (778.05 mg, 2.35 mmol, 227.50 μL) in DMF (10 mL) (slightly exothermic reaction!). The resulting mixture was stirred at 25°C for 12h, then diluted with water (15ml) and extracted with MTBE (3*15ml). The combined organic extracts were washed with water (2*5ml), dried over sodium sulfate and concentrated in vacuo to give ( 2R,5S )-2-(2-bromo-1,3-benzol) as a brown solid Thiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (750 mg, 1.82 mmol, 93.25% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值411.2；實測值412.2；Rt=4.734min。LCMS (ESI): [M] + m/z: calculated 411.2; found 412.2; Rt=4.734 min.

步驟6：(2R,5S)-5-甲基-2-(2-(4-甲基哌嗪-1-基)苯并[d]噻唑-5-基)哌啶-1-甲酸第三丁酯之合成Step 6: (2R,5S)-5-methyl-2-(2-(4-methylpiperazin-1-yl)benzo[d]thiazol-5-yl)piperidine-1-carboxylic acid 3rd Synthesis of Butyl Ester

Figure 110128222-A0202-12-1994-833
Figure 110128222-A0202-12-1994-833

在25℃下，將1-甲基哌嗪(852.22mg，8.51mmol，943.77μL)一次性添加到(2R,5S )-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(700mg， 1.70mmol)於MeCN(20mL)中之溶液中。將所得混合物在70℃下攪拌8h，然後冷卻且在真空中濃縮。將殘餘物用10%氫氧化鈉水溶液鹼化至pH 11且用DCM(2*25ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈棕色固體之(2R,5S )-5-甲基-2-[2-(4-甲基哌嗪-1-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(750mg，粗品)，其直接用於下一步驟中。1-Methylpiperazine (852.22 mg, 8.51 mmol, 943.77 μL) was added in one portion to ( 2R,5S )-2-(2-bromo-1,3-benzothiazol-5-yl at 25 °C )-3-butyl 5-methylpiperidine-1-carboxylate (700 mg, 1.70 mmol) in MeCN (20 mL). The resulting mixture was stirred at 70 °C for 8 h, then cooled and concentrated in vacuo. The residue was basified to pH 11 with 10% aqueous sodium hydroxide solution and extracted with DCM (2*25ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give ( 2R,5S )-5-methyl-2-[2-(4-methylpiperazin-1-yl as a brown solid )-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (750 mg, crude), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值430.2；實測值431.2；Rt=3.638min。LCMS (ESI): [M] + m/z: calculated 430.2; found 431.2; Rt=3.638 min.

步驟7：2-(4-甲基哌嗪-1-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 7: Synthesis of 2-(4-Methylpiperazin-1-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-1995-834
Figure 110128222-A0202-12-1995-834

將於二噁烷中之4.0M氯化氫溶液(31.50g，120.09mmol，39.38mL，13.9%純度)一次性添加到(2R,5S )-5-甲基-2-[2-(4-甲基哌嗪-1-基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(775.25mg，1.80mmol)於MeOH(25.01mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌1h，然後在真空中蒸發至乾，以得到呈棕色固體之粗品2-(4-甲基哌嗪-1-基)-5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑(900mg，粗品，3HCl)，其直接用於下一步驟中。A 4.0M solution of hydrogen chloride in dioxane (31.50 g, 120.09 mmol, 39.38 mL, 13.9% purity) was added in one portion to ( 2R,5S )-5-methyl-2-[2-(4-methyl) Piperazin-1-yl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester (775.25 mg, 1.80 mmol) in a stirred solution of MeOH (25.01 mL) . The resulting mixture was stirred at 25°C for 1 h, then evaporated to dryness in vacuo to give crude 2-(4-methylpiperazin-1-yl)-5-[( 2R,5S )-5 as a brown solid -Methyl-2-piperidinyl]-1,3-benzothiazole (900 mg, crude, 3HCl), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值330.2；實測值331.2；Rt=0.544min。LCMS (ESI): [M] + m/z: calculated 330.2; found 331.2; Rt=0.544 min.

步驟8：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(4-甲基哌嗪-1-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1158)之合成Step 8: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(4-methylpiperazine-1 Synthesis of -yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1158)

Figure 110128222-A0202-12-1996-835
Figure 110128222-A0202-12-1996-835

藉由一般程序方案H步驟6A製備。產率：83mg(18.01%)。Prepared by General Procedure H, Step 6A. Yield: 83 mg (18.01%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 30-30-65%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5 min 30-30-65% water-MeCN+0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.34(m,1H),1.71(m,1H),1.86(m,1H),2.03(m,3H),2.13(m,1H),2.21(s,4H),2.42(t,4H),3.01(dd,1H),3.52(m,5H),5.60(m,3H),7.04(dd,1H),7.43(m,2H),7.75(m,1H),8.01(m,1H),10.52(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(m, 3H), 1.34(m, 1H), 1.71(m, 1H), 1.86(m, 1H), 2.03(m, 3H), 2.13(m, 1H), 2.21(s, 4H), 2.42(t, 4H), 3.01(dd, 1H), 3.52(m, 5H), 5.60(m, 3H), 7.04(dd, 1H), 7.43 (m, 2H), 7.75 (m, 1H), 8.01 (m, 1H), 10.52 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值507.2；實測值508.2；Rt=1.998min。LCMS (ESI): [M] + m/z: calculated 507.2; found 508.2; Rt=1.998 min.

實例570.N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(氧呾-3-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1266)之合成Example 570. N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(oxypyridin-3-yl)benzene Synthesis of [ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1266)

Figure 110128222-A0202-12-1996-836
Figure 110128222-A0202-12-1996-836

步驟1：5-溴-2-(氧呾-3-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(oxon-3-yl)benzo[d]thiazole

藉由一般程序方案H步驟1B製備。產率：2.7g粗品。Prepared by General Procedure H, Step IB. Yield: 2.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值270.2；實測值271.2；Rt=1.154min。LCMS (ESI): [M] + m/z: calculated 270.2; found 271.2; Rt=1.154 min.

步驟2：2-(氧呾-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻Step 2: 2-(Oxylan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo [d] thiophene 唑之合成Synthesis of azoles

藉由一般程序方案H步驟2製備。產率：1.6g(50.47%)。Prepared by General Procedure Scheme H, Step 2. Yield: 1.6 g (50.47%).

CC條件： 藉由矽膠使用環己烷/MTBE作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using cyclohexane/MTBE as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=1.507min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=1.507 min.

步驟3：(S)-3-甲基-6-(2-(氧呾-3-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(oxypyr-3-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)- Synthesis of tert-butyl formate

藉由一般程序方案H步驟3製備。產率：1.2g(61.55%)。Prepared by General Procedure H, Step 3. Yield: 1.2 g (61.55%).

CC條件： 藉由矽膠使用己烷/MTBE作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.534min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.534 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(氧呾-3-基)苯并[d]噻唑之合成Step 4: Synthesis of (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(oxon-3-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.33g(89.07%)。Prepared by General Procedure H, Step 4. Yield: 0.33 g (89.07%).

LCMS(ESI)：[M]+ m/z：計算值286.2；實測值287.2；Rt=0.853min。LCMS (ESI): [M] + m/z: calculated 286.2; found 287.2; Rt=0.853 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(氧呾-3-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(oxon-3-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.21g(63.19%)。Prepared by General Procedure H, Step 5. Yield: 0.21 g (63.19%).

LCMS(ESI)：[M]+ m/z：計算值288.2；實測值289.2；Rt=0.904min。LCMS (ESI): [M] + m/z: calculated 288.2; found 289.2; Rt=0.904 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(氧呾-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1266)之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(oxypyridin-3-yl)benzene Synthesis of [d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1266)

藉由一般程序方案H步驟6A製備。產率：101mg(29.79%)。Prepared by General Procedure H, Step 6A. Yield: 101 mg (29.79%).

HPLC條件：管柱：Chromatorex C18 100*19mm，5微米；0-1-6min 25-25-50%水-MeCN，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: Chromatorex C18 100*19 mm, 5 microns; 0-1-6 min 25-25-50% water-MeCN, flow rate: 30 ml/min; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.36(m,1H),1.71(m,1H),1.87(m,1H),2.00(m,3H),2.14(m,1H),2.31(m,1H),2.79(m,1H),3.76(dd,1H),4.75(m,1H),4.83(m,2H),5.00(m,2H),5.64(m,3H),7.43(m,2H),7.98(m,2H),8.10(m,1H),10.56(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.36(m, 1H), 1.71(m, 1H), 1.87(m, 1H), 2.00(m, 3H), 2.14(m, 1H), 2.31(m, 1H), 2.79(m, 1H), 3.76(dd, 1H), 4.75(m, 1H), 4.83(m, 2H), 5.00(m, 2H), 5.64 (m, 3H), 7.43 (m, 2H), 7.98 (m, 2H), 8.10 (m, 1H), 10.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值465.2；實測值466.2；Rt=2.604min。LCMS (ESI): [M] + m/z: calculated 465.2; found 466.2; Rt=2.604 min.

實例571. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(2-N-嗎啉基乙基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1387)之合成Example 571. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(2-N-morpholinoethyl) Synthesis of yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1387)

Figure 110128222-A0202-12-1998-837
Figure 110128222-A0202-12-1998-837

藉由一般程序方案H步驟6A製備。產率：211mg(42.27%)。Prepared by General Procedure H, Step 6A. Yield: 211 mg (42.27%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-5min 35-35-70%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 35-35-70% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.34(m,1H),1.70(m,1H),1.87(m,1H),2.00(m,3H),2.13(m,1H),2.30(m,2H),2.46(m,4H),2.75(t,2H),3.25(t,2H),3.55(m,5H),5.63(m,3H),7.40(m,2H),7.95(m,3H),10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(m, 3H), 1.34(m, 1H), 1.70(m, 1H), 1.87(m, 1H), 2.00(m, 3H), 2.13(m, 1H), 2.30(m, 2H), 2.46(m, 4H), 2.75(t, 2H), 3.25(t, 2H), 3.55(m, 5H), 5.63(m, 3H), 7.40 (m, 2H), 7.95 (m, 3H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=2.140min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=2.140 min.

實例572. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-2-(2-(1-(2-氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1114)之合成Example 572. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-(2-fluoroethyl)piperidine-4 Synthesis of -yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1114)

Figure 110128222-A0202-12-1998-838
Figure 110128222-A0202-12-1998-838

藉由一般程序方案H步驟6A製備。產率：109mg(33.25%)。Prepared by General Procedure H, Step 6A. Yield: 109 mg (33.25%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 30-30-45%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 30-30-45% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.35(m,1H),1.70(m,1H),1.81(m,4H),2.00(m,3H),2.08(m,2H),2.20(t,2H),2.31(m,1H),2.64(m,2H),3.02(m,4H),3.75(dd,1H),4.49(t,1H),4.57(t,1H),5.63(m,3H),7.40(m,2H),7.98(m,3H),10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.35(m, 1H), 1.70(m, 1H), 1.81(m, 4H), 2.00(m, 3H), 2.08(m, 2H), 2.20(t, 2H), 2.31(m, 1H), 2.64(m, 2H), 3.02(m, 4H), 3.75(dd, 1H), 4.49(t, 1H), 4.57 (t, 1H), 5.63 (m, 3H), 7.40 (m, 2H), 7.98 (m, 3H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值538.2；實測值539.2；Rt=2.191min。LCMS (ESI): [M] + m/z: calculated 538.2; found 539.2; Rt=2.191 min.

實例573. N-(6-胺基-5-環丙基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1331及化合物1218)之合成Example 573. N-(6-Amino-5-cyclopropylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazole- Synthesis of 5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1331 and Compound 1218)

Figure 110128222-A0202-12-1999-839
Figure 110128222-A0202-12-1999-839

步驟1：外消旋-(3-環丙基-5-(2-((2R,5S)-2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成 Step 1: Racemic-(3-Cyclopropyl-5-(2-((2R,5S)-2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazole- Synthesis of 5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester

藉由一般程序方案H步驟6A製備。產率：223g(33.29%)。Prepared by General Procedure H, Step 6A. Yield: 223 g (33.29%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-2-5min 50-50-85%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-2-5min 50-50-85% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN ).

LCMS(ESI)：[M]+ m/z：計算值606.2；實測值607.2；Rt=2.835min。LCMS (ESI): [M] + m/z: calculated 606.2; found 607.2; Rt=2.835 min.

步驟2：N-(6-胺基-5-環丙基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-Step 2: N-(6-Amino-5-cyclopropylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazole- 5- 基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Synthesis of ethyl)-5-methylpiperidin-1-yl)-2-oxoacetamide

將N -[3-環丙基-5-[[2-[(2R,5S )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(223mg，367.52umol)於二噁烷(2mL)及水(1mL)中之溶液在65℃下攪拌48h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以35-65% 0-5min H2 O/MeCN/0.1% NH4 OH，流速：30ml/min，流速：30ml/min)純化殘餘物，以得到N -(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(84mg，165.79umol，45.11%產率)。 N- [3-Cyclopropyl-5-[[2-[( 2R,5S )-2-[2-[2-(dimethylamino)ethyl]-1,3-benzothiazole-5 -yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (223mg, 367.52umol) in dioxane A solution in (2 mL) and water (1 mL) was stirred at 65 °C for 48 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: YMC Triart C18 100x20mm, 5um; with 35-65% 0-5min H2O /MeCN/0.1% NH4OH , flow rate: 30ml/min, flow rate: 30ml/min) to give N- (6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2R,5S )-2-[2-[2-(dimethylamino)ethyl] -1,3-Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (84 mg, 165.79 umol, 45.11% yield).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=1.869min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=1.869 min.

步驟3：掌性分離(化合物1331及化合物1218)Step 3: Chiral separation (compound 1331 and compound 1218)

Figure 110128222-A0202-12-2000-840
Figure 110128222-A0202-12-2000-840

對外消旋N -(6-胺基-5-環丙基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(84mg，165.79μmol)進行掌性分離(管柱：Chiralpak AS-H(250*20，5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min，然後第一管柱之另一個管柱：Chiralcel OJ-H(250*30，5mkm)，己烷-IPA-MeOH，70-15-15，12ml/min)，以獲得N -(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(31mg，61.18umol，73.81%產率)(RT=27.27)及N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2S,5R )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌 啶基]-2-側氧基乙醯胺(27mg，53.29umol，64.29%產率)(RT=15.45)。Racemic N- (6-amino-5-cyclopropylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazole- 5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamide (84 mg, 165.79 μmol) for chiral separation (column: Chiralpak AS-H (250*20, 5mkm) , Hexane-IPA-MeOH, 70-15-15, 12ml/min, then another column of the first column: Chiralcel OJ-H (250*30, 5mkm), Hexane-IPA-MeOH, 70- 15-15, 12ml/min) to obtain N- (6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2R,5S )-2-[2-[2-(di Methylamino)ethyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (31 mg, 61.18 umol, 73.81% yield rate) (RT=27.27) and N-(6-amino-5-cyclopropyl-3-pyridyl)-2-[( 2S,5R )-2-[2-[2-(dimethylamino) )ethyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (27 mg, 53.29 umol, 64.29% yield) ( RT=15.45).

化合物1331於分析條件下(管柱：AS-H，以己烷-IPA-MeOH，70-15-15，0.6ml/min為流動相)之保留時間為21.46min且化合物1218之保留時間為13.49min。The retention time of compound 1331 under analytical conditions (column: AS-H, hexane-IPA-MeOH, 70-15-15, 0.6 ml/min as mobile phase) was 21.46 min and the retention time of compound 1218 was 13.49 min.

化合物1331：Compound 1331:

保留時間：21.46minRetention time: 21.46min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.36-0.49(m,2H),0.82-0.90(m,2H),0.99-1.06(m,3H),1.31-1.43(m,1H),1.60-1.72(m,2H),1.81-1.90(m,1H),2.03-2.17(m,1H),2.21(s,6H),2.27-2.34(m,1H),2.66-2.72(m,2H),2.76-3.20(m,1H),3.21-3.26(m,2H),3.34-4.08(m,1H),5.25-5.70(m,1H),5.71-5.83(m,2H),7.27-7.35(m,1H),7.36-7.41(m,1H),7.80-7.89(m,1H),7.98-8.02(m,1H),8.03-8.08(m,1H),10.45-10.64(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.36-0.49(m, 2H), 0.82-0.90(m, 2H), 0.99-1.06(m, 3H), 1.31-1.43(m, 1H) ,1.60-1.72(m,2H),1.81-1.90(m,1H),2.03-2.17(m,1H),2.21(s,6H),2.27-2.34(m,1H),2.66-2.72(m, 2H), 2.76-3.20(m, 1H), 3.21-3.26(m, 2H), 3.34-4.08(m, 1H), 5.25-5.70(m, 1H), 5.71-5.83(m, 2H), 7.27- 7.35(m, 1H), 7.36-7.41(m, 1H), 7.80-7.89(m, 1H), 7.98-8.02(m, 1H), 8.03-8.08(m, 1H), 10.45-10.64(m, 1H) ).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=1.812min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=1.812 min.

化合物1218：Compound 1218:

保留時間：13.49minRetention time: 13.49min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.38-0.49(m,2H),0.80-0.92(m,2H),0.98-1.06(m,3H),1.29-1.40(m,1H),1.60-1.75(m,2H),1.79-1.91(m,1H),2.03-2.17(m,1H),2.20(s,6H),2.26-2.34(m,1H),2.66-2.74(m,2H),2.74-3.19(m,1H),3.19-3.23(m,2H),3.37-4.08(m,1H),5.26-5.70(m,1H),5.70-5.82(m,2H),7.22-7.36(m,1H),7.36-7.42(m,1H),7.81-7.89(m,1H),7.96-8.14(m,2H),10.45-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.38-0.49(m, 2H), 0.80-0.92(m, 2H), 0.98-1.06(m, 3H), 1.29-1.40(m, 1H) ,1.60-1.75(m,2H),1.79-1.91(m,1H),2.03-2.17(m,1H),2.20(s,6H),2.26-2.34(m,1H),2.66-2.74(m, 2H), 2.74-3.19(m, 1H), 3.19-3.23(m, 2H), 3.37-4.08(m, 1H), 5.26-5.70(m, 1H), 5.70-5.82(m, 2H), 7.22- 7.36(m,1H), 7.36-7.42(m,1H), 7.81-7.89(m,1H), 7.96-8.14(m,2H), 10.45-10.57(m,1H).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=1.806min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=1.806 min.

實例574. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(2-(吡咯啶-1-基)乙基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1296)之合成Example 574. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(2-(pyrrolidine-1- Synthesis of yl)ethyl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1296)

Figure 110128222-A0202-12-2002-841
Figure 110128222-A0202-12-2002-841

藉由一般程序方案H步驟6A製備。產率：100mg(40.02%)。Prepared by General Procedure H, Step 6A. Yield: 100 mg (40.02%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 30-55%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 30-55% water-MeCN + 0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.07(m,3H),1.29-1.41(m,1H),1.64-1.75(m,5H),1.79-1.93(m,1H),1.95-2.04(m,3H),2.07-2.22(m,1H),2.25-2.36(m,1H),2.50-2.53(m,4H),2.75-2.80(m,0.3H),2.81-2.90(m,2H),3.20-3.28(m,2.7H),3.43-4.07(m,1H),5.22-5.59(m,1H),5.59-5.73(m,2H),7.31-7.41(m,1H),7.42-7.53(m,1H),7.79-7.91(m,1H),7.94-8.07(m,2H),10.45-10.67(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.07(m,3H), 1.29-1.41(m,1H), 1.64-1.75(m,5H), 1.79-1.93(m,1H) ,1.95-2.04(m,3H),2.07-2.22(m,1H),2.25-2.36(m,1H),2.50-2.53(m,4H),2.75-2.80(m,0.3H),2.81-2.90 (m,2H),3.20-3.28(m,2.7H),3.43-4.07(m,1H),5.22-5.59(m,1H),5.59-5.73(m,2H),7.31-7.41(m,1H) ), 7.42-7.53 (m, 1H), 7.79-7.91 (m, 1H), 7.94-8.07 (m, 2H), 10.45-10.67 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=2.173min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=2.173 min.

實例575. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-2-(2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1377)之合成Example 575. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-(2,2-difluoroethyl)piperidine) Synthesis of pyridin-4-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1377)

Figure 110128222-A0202-12-2002-842
Figure 110128222-A0202-12-2002-842

步驟1：5-氯-2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-(2,2-difluoroethyl)piperidin-4-yl)benzo[d]thiazole

將5-氯-2-(4-哌啶基)-1,3-苯并噻唑(3.6g，11.05mmol，2HCl)、三氟甲磺酸2,2-二氟乙酯(2.84g，13.26mmol)及TEA(5.59g，55.27mmol，7.70mL)於MeCN(100mL)中之混合物在60℃下攪拌72h，然後冷卻且在真空中濃縮。將殘餘物用水(50ml)稀釋且用10%氫氧化鈉水溶液鹼化至pH 11。將所得混合物用MTBE(250ml)萃取。將有機層用水(50ml)洗滌，經硫酸鈉乾燥且在真空中濃縮，以得到呈棕色固體之粗品5-氯-2-[1-(2,2-二氟乙基)-4-哌啶基]-1,3-苯并噻唑(3g，9.47mmol，85.67%產率)，其直接用於下一步驟中。5-Chloro-2-(4-piperidinyl)-1,3-benzothiazole (3.6 g, 11.05 mmol, 2HCl), 2,2-difluoroethyl trifluoromethanesulfonate (2.84 g, 13.26 g mmol) and TEA (5.59 g, 55.27 mmol, 7.70 mL) in MeCN (100 mL) was stirred at 60 °C for 72 h, then cooled and concentrated in vacuo. The residue was diluted with water (50 ml) and basified to pH 11 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with MTBE (250 ml). The organic layer was washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo to give crude 5-chloro-2-[1-(2,2-difluoroethyl)-4-piperidine as a brown solid yl]-1,3-benzothiazole (3 g, 9.47 mmol, 85.67% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值316.2；實測值317.2；Rt=2.015min。LCMS (ESI): [M] + m/z: calculated 316.2; found 317.2; Rt=2.015 min.

步驟2：2-(1-(2,2-二氟乙基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-(2,2-Difluoroethyl)piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)benzo[d]thiazole

將5-氯-2-[1-(2,2-二氟乙基)-4-哌啶基]-1,3-苯并噻唑(3g，9.47mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.65g，10.42mmol)及乙酸鉀(1.86g，18.94mmol，1.18mL)於二噁烷(100mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(433.58mg，473.49umol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(902.89mg，1.89mmol)，且將反應混合物在95℃下攪拌18h。將反應混合物冷卻且在真空中濃縮。藉由矽膠管柱層析使用己烷/乙酸乙酯梯度(0-100%乙酸乙酯)來純化殘餘物，以得到呈米色固體之2-[1-(2,2-二氟乙基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(1.5g，3.67mmol，38.79%產率)。5-Chloro-2-[1-(2,2-difluoroethyl)-4-piperidinyl]-1,3-benzothiazole (3 g, 9.47 mmol), 4,4,5,5- Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A mixture of cyclopentane (2.65 g, 10.42 mmol) and potassium acetate (1.86 g, 18.94 mmol, 1.18 mL) in dioxane (100 mL) was evacuated and backfilled with argon. This operation was repeated twice, then ginseng (1,5-diphenylpent-1,4-dien-3-one)dipalladium (433.58 mg, 473.49 umol) and dicyclohexyl[2 ',4',6'-para(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (902.89 mg, 1.89 mmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane/ethyl acetate gradient (0-100% ethyl acetate) to give 2-[1-(2,2-difluoroethyl) as a beige solid -4-Piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (1.5 g, 3.67 mmol, 38.79% yield).

LCMS(ESI)：[M]+ m/z：計算值408.2；實測值409.2；Rt=0.989min。LCMS (ESI): [M] + m/z: calculated 408.2; found 409.2; Rt=0.989 min.

步驟3：(S)-6-(2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1-(2,2-Difluoroethyl)piperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3 Synthesis of 3-butyl ,4-dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：0.9g(51.29%)。Prepared by General Procedure H, Step 3. Yield: 0.9 g (51.29%).

CC條件： 藉由矽膠使用己烷/MTBE作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值477.2；實測值478.2；Rt=1.120min。LCMS (ESI): [M] + m/z: calculated 477.2; found 478.2; Rt=1.120 min.

步驟4：(S)-2-(1-(2,2-二氟乙基)哌啶-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1-(2,2-Difluoroethyl)piperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridine- Synthesis of 2-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.67g(9F9%)。Prepared by General Procedure H, Step 4. Yield: 0.67 g (9F 9%).

LCMS(ESI)：[M]+ m/z：計算值377.2；實測值378.2；Rt=0.707min。LCMS (ESI): [M] + m/z: calculated 377.2; found 378.2; Rt=0.707 min.

步驟5：2-(1-(2,2-二氟乙基)哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: 2-(1-(2,2-Difluoroethyl)piperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d ]Synthesis of thiazole

藉由一般程序方案H步驟5製備。產率：0.55g(81.65%)。Prepared by General Procedure H, Step 5. Yield: 0.55 g (81.65%).

LCMS(ESI)：[M]+ m/z：計算值379.2；實測值380.2；Rt=0.744min。LCMS (ESI): [M] + m/z: calculated 379.2; found 380.2; Rt=0.744 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-2-(2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1377)之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-(2,2-difluoroethyl)piperidine) Synthesis of pyridin-4-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1377)

藉由一般程序方案H步驟6A製備。產率：109mg(29.72%)。Prepared by General Procedure H, Step 6A. Yield: 109 mg (29.72%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 30-30-50%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 30-30-50% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN ).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.99-1.06(m,3H),1.26-1.41(m,1H),1.63-1.94(m,5H),1.96-2.04(m,3H),2.05-2.11(m,3H),2.13-2.29(m,1H),2.33-2.37(m,2H),2.72-2.78(m,2H),2.96-3.00(m,2H),3.07-3.14(m,1H),3.35-4.10(m,1H),5.26-5.62(m,1H),5.62-5.72(m,2H),6.14(tt,1H),7.34-7.53(m,2H),7.85-7.93(m,1H),7.95-8.08(m,2H),10.50-10.58(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.99-1.06(m,3H), 1.26-1.41(m,1H), 1.63-1.94(m,5H), 1.96-2.04(m,3H) ,2.05-2.11(m,3H),2.13-2.29(m,1H),2.33-2.37(m,2H),2.72-2.78(m,2H),2.96-3.00(m,2H),3.07-3.14( m,1H),3.35-4.10(m,1H),5.26-5.62(m,1H),5.62-5.72(m,2H),6.14(tt,1H),7.34-7.53(m,2H),7.85- 7.93 (m, 1H), 7.95-8.08 (m, 2H), 10.50-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值556.2；實測值557.2；Rt=2.426min。LCMS (ESI): [M] + m/z: calculated 556.2; found 557.2; Rt=2.426 min.

實例576. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-2-(2-(1-乙基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1335)之合成Example 576. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-ethylpiperidin-4-yl)benzo Synthesis of [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1335)

Figure 110128222-A0202-12-2005-843
Figure 110128222-A0202-12-2005-843

步驟1：5-氯-2-(哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(piperidin-4-yl)benzo[d]thiazole

在攪拌之情況下，將五氧化二磷(V)(50g，352.25mmol)分批添加到磷酸(60g，612.27mmol，35.29mL)中。將所得混合物在80-90℃下攪拌，直到形成澄清溶液，然後在氬氣下一次性添加哌啶-4-甲酸(15g，116.14mmol)及2-胺基-4-氯苯硫酚(18.54g，116.14mmol)且將所得混合物在氬氣、160℃下攪拌15h，然後冷卻且用水(500ml)稀釋。過濾所得沉澱，將其轉移至燒杯且用10%氫氧化鈉水溶液鹼化至pH 11。將所得混合物用DCM(2*250ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥，然後將於二噁烷中之4.0M氯化氫溶液(157.50g，600.44mmol，150mL，13.9%純度)緩慢添加到該產物之無水二氯甲烷溶液中。過濾所得沉澱，用DCM(3*50ml)洗滌且在真空中乾燥，以得到呈綠色固體之5-氯-2-(4-哌啶基)-1,3-苯并噻唑(22g，67.55mmol，58.16%產率，2HCl)，其直接用於下一步驟中。Phosphorus (V) pentoxide (50 g, 352.25 mmol) was added portionwise to phosphoric acid (60 g, 612.27 mmol, 35.29 mL) with stirring. The resulting mixture was stirred at 80-90 °C until a clear solution formed, then piperidine-4-carboxylic acid (15 g, 116.14 mmol) and 2-amino-4-chlorothiophenol (18.54 g) were added in one portion under argon g, 116.14 mmol) and the resulting mixture was stirred under argon at 160 °C for 15 h, then cooled and diluted with water (500 ml). The resulting precipitate was filtered, transferred to a beaker and basified to pH 11 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with DCM (2*250ml). The combined organic extracts were dried over sodium sulfate, then a 4.0M solution of hydrogen chloride in dioxane (157.50 g, 600.44 mmol, 150 mL, 13.9% purity) was slowly added to a solution of the product in dry dichloromethane. The resulting precipitate was filtered, washed with DCM (3*50 ml) and dried in vacuo to give 5-chloro-2-(4-piperidinyl)-1,3-benzothiazole (22 g, 67.55 mmol) as a green solid , 58.16% yield, 2HCl), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值252.2；實測值253.2；Rt=0.963min。LCMS (ESI): [M] + m/z: calculated 252.2; found 253.2; Rt=0.963 min.

步驟1：5-氯-2-(1-乙基哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-ethylpiperidin-4-yl)benzo[d]thiazole

在25℃下，將乙醛(973.88mg，22.11mmol，790.23uL)一次性添加到5-氯-2-(4-哌啶基)-1,3-苯并噻唑(4g，12.28mmol，2HCl)及無水乙酸鈉(2.52g，30.70mmol，1.65mL)於MeOH(100mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌2h，然後在25℃下一次性添加氰基硼氫化鈉(1.54g，24.56mmol)。將反應混合物在25℃下攪拌12h，LCMS僅顯示存在起始材料。添加更多乙醛(1.08 g，24.56mmol)，且將反應混合物在25℃下攪拌24h，然後在真空中濃縮。將殘餘物用水(40ml)稀釋且用10%氫氧化鈉水溶液鹼化至pH 10-11。將所得混合物用MTBE(2*150ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥，且在真空中濃縮，以得到呈淡黃色固體之5-氯-2-(1-乙基-4-哌啶基)-1,3-苯并噻唑(2.4g，8.55mmol，69.59%產率)，其直接用於下一步驟中。Acetaldehyde (973.88 mg, 22.11 mmol, 790.23 uL) was added in one portion to 5-chloro-2-(4-piperidinyl)-1,3-benzothiazole (4 g, 12.28 mmol, 2HCl) at 25 °C ) and anhydrous sodium acetate (2.52 g, 30.70 mmol, 1.65 mL) in a stirred mixture of MeOH (100 mL). The resulting mixture was stirred at 25 °C for 2 h, then sodium cyanoborohydride (1.54 g, 24.56 mmol) was added in one portion at 25 °C. The reaction mixture was stirred at 25°C for 12h, LCMS only showed the presence of starting material. Add more acetaldehyde (1.08 g, 24.56 mmol), and the reaction mixture was stirred at 25 °C for 24 h, then concentrated in vacuo. The residue was diluted with water (40 ml) and basified to pH 10-11 with 10% aqueous sodium hydroxide solution. The resulting mixture was extracted with MTBE (2*150ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 5-chloro-2-(1-ethyl-4-piperidinyl)-1,3-benzo as a pale yellow solid Thiazole (2.4 g, 8.55 mmol, 69.59% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=2.381min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=2.381 min.

步驟2：2-(1-乙基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Ethylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)benzo[d]thiazole

將5-氯-2-(1-乙基-4-哌啶基)-1,3-苯并噻唑(2.4g，8.55mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.39g，9.40mmol)及乙酸鉀(1.68g，17.09mmol，1.07mL)於二噁烷(100mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(391.31mg，427.33umol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(814.86mg，1.71mmol)，且將反應混合物在95℃下攪拌18h。將反應混合物冷卻且在真空中濃縮。藉由矽膠管柱層析使用MTBE/MeOH梯度(0-100% MeOH)純化殘餘物，以得到呈淡棕色固體之2-(1-乙基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(1.2g，3.22mmol，37.71%產率)。5-Chloro-2-(1-ethyl-4-piperidinyl)-1,3-benzothiazole (2.4 g, 8.55 mmol), 4,4,5,5-tetramethyl-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (2.39 g, 9.40 mmol) and potassium acetate (1.68 g, 17.09 mmol, 1.07 mL) in dioxane (100 mL) was evacuated and backfilled with argon. This operation was repeated twice, followed by the addition of bis(1,5-diphenylpent-1,4-dien-3-one)dipalladium ( 391.31 mg, 427.33 umol) and dicyclohexyl[2 ',4',6'-para(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (814.86 mg, 1.71 mmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography using an MTBE/MeOH gradient (0-100% MeOH) to give 2-(1-ethyl-4-piperidinyl)-5-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (1.2 g, 3.22 mmol, 37.71% yield).

LCMS(ESI)：[M]+ m/z：計算值372.2；實測值373.2；Rt=1.181min。LCMS (ESI): [M] + m/z: calculated 372.2; found 373.2; Rt=1.181 min.

步驟3：(S)-6-(2-(1-乙基哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1-Ethylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：1.4g粗品。Prepared by General Procedure H, Step 3. Yield: 1.4 g crude.

LCMS(ESI)：[M]+ m/z：計算值441.2；實測值442.2；Rt=2.481min。LCMS (ESI): [M] + m/z: calculated 441.2; found 442.2; Rt=2.481 min.

步驟4：(S)-2-(1-乙基哌啶-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之Step 4: (S)-2-(1-Ethylpiperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d ] thiazole 合成synthesis

藉由一般程序方案H步驟4製備。產率：250mg粗品。Prepared by General Procedure H, Step 4. Yield: 250 mg crude.

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=0.567min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=0.567 min.

步驟5：2-(1-乙基哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 2-(1-Ethylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：130mg(51.69%)。Prepared by General Procedure H, Step 5. Yield: 130 mg (51.69%).

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=0.610min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=0.610 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-2-(2-(1-乙基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1335)之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-ethylpiperidin-4-yl)benzo Synthesis of [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1335)

藉由一般程序方案H步驟6A製備。產率：13mg(6.60%)。Prepared by General Procedure H, Step 6A. Yield: 13 mg (6.60%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-5min 30-80%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 30-80% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,5H),1.32-1.39(m,2H),1.69-2.09(m,10H),2.28-2.37(m,3H),2.77-3.10(m,5H),3.46-3.48(m,1H),4.03-4.05(m,1H),5.27-5.69(m,3H),7.34-7.50(m,2H),7.86-8.06(m,3H),10.52-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m, 5H), 1.32-1.39(m, 2H), 1.69-2.09(m, 10H), 2.28-2.37(m, 3H) ,2.77-3.10(m,5H),3.46-3.48(m,1H),4.03-4.05(m,1H),5.27-5.69(m,3H),7.34-7.50(m,2H),7.86-8.06( m, 3H), 10.52-10.57 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=1.879min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=1.879 min.

實例577.N -(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-(氧呾-3-基)哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1268)之合成Example 577. N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-(oxo-3- Synthesis of yl)piperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1268)

步驟1：5-氯-2-(1-(氧呾-3-基)哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-Chloro-2-(1-(Oxy-3-yl)piperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2007-844
Figure 110128222-A0202-12-2007-844

在25℃下，將氧呾-3-酮(1.33g，18.42mmol，1.19mL)一次性添加到5-氯-2-(4-哌啶基)-1,3-苯并噻唑(4g，12.28mmol，2HCl)及無水乙酸鈉(2.52g， 30.70mmol，1.65mL)於MeOH(100mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌2h，然後一次性添加氰基硼氫化鈉(1.54g，24.56mmol)。將反應混合物在25℃下攪拌15h，然後在真空中濃縮至乾。將殘餘物用水(40ml)稀釋且用10%氫氧化鈉水溶液鹼化至pH 10-11。將所得混合物用DCM(2*75ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈綠色固體之5-氯-2-[1-(氧呾-3-基)-4-哌啶基]-1,3-苯并噻唑(3.5g，11.33mmol，92.28%產率)，其直接用於下一步驟中。At 25°C, oxon-3-one (1.33 g, 18.42 mmol, 1.19 mL) was added in one portion to 5-chloro-2-(4-piperidinyl)-1,3-benzothiazole (4 g, 12.28mmol, 2HCl) and anhydrous sodium acetate (2.52g, 30.70 mmol, 1.65 mL) in a stirred mixture of MeOH (100 mL). The resulting mixture was stirred at 25 °C for 2 h, then sodium cyanoborohydride (1.54 g, 24.56 mmol) was added in one portion. The reaction mixture was stirred at 25 °C for 15 h, then concentrated to dryness in vacuo. The residue was diluted with water (40 ml) and basified to pH 10-11 with 10% aqueous sodium hydroxide solution. The resulting mixture was extracted with DCM (2*75ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 5-chloro-2-[1-(oxypyr-3-yl)-4-piperidinyl]-1 as a green solid, 3-benzothiazole (3.5 g, 11.33 mmol, 92.28% yield) was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值308.2；實測值309.2；Rt=1.776min。LCMS (ESI): [M] + m/z: calculated 308.2; found 309.2; Rt=1.776 min.

步驟2：2-(1-(氧呾-3-基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-(Oxy-3-yl)piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of cyclopentan-2-yl)benzo[d]thiazole

將5-氯-2-[1-(氧呾-3-基)-4-哌啶基]-1,3-苯并噻唑(3.5g，11.33mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.17g，12.47mmol)及乙酸鉀(2.22g，22.67mmol，1.42mL)於二噁烷(100mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(518.90mg，566.66umol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(1.08g，2.27mmol)，且將反應混合物在95℃下攪拌36h。將反應混合物冷卻且在真空中濃縮。藉由矽膠管柱層析使用氯仿/MeCN梯度(0-100% MeCN)純化殘餘物，以得到呈綠色固體之2-[1-(氧呾-3-基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(2.6g，6.49mmol，57.30%產率)。5-Chloro-2-[1-(oxygen-3-yl)-4-piperidinyl]-1,3-benzothiazole (3.5 g, 11.33 mmol), 4,4,5,5-tetra Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane A mixture of pentane (3.17 g, 12.47 mmol) and potassium acetate (2.22 g, 22.67 mmol, 1.42 mL) in dioxane (100 mL) was evacuated and backfilled with argon. This operation was repeated twice, followed by the addition of bis(1,5-diphenylpent-1,4-dien-3-one)dipalladium ( 518.90 mg, 566.66 umol) and dicyclohexyl[2 ',4',6'-para(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (1.08 g, 2.27 mmol), and the reaction mixture was heated at 95 °C Stir for 36h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography using a chloroform/MeCN gradient (0-100% MeCN) to give 2-[1-(oxon-3-yl)-4-piperidinyl]- as a green solid 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazole (2.6 g, 6.49 mmol, 57.30 %Yield).

LCMS(ESI)：[M]+ m/z：計算值400.2；實測值401.2；Rt=1.113min。LCMS (ESI): [M] + m/z: calculated 400.2; found 401.2; Rt=1.113 min.

步驟3：(S)-3-甲基-6-(2-(1-(氧呾-3-基)哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(1-(oxypyr-3-yl)piperidin-4-yl)benzo[d]thiazol-5-yl)-3,4 -Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：2.7g(88.52%)。Prepared by General Procedure H, Step 3. Yield: 2.7 g (88.52%).

CC條件： 藉由矽膠使用CHCl3 /MeCN梯度(0-100% MeCN)作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using a CHCl3 /MeCN gradient (0-100% MeCN) as the eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值469.2；實測值470.2；Rt=1.233min。LCMS (ESI): [M] + m/z: calculated 469.2; found 470.2; Rt=1.233 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-(氧呾-3-基)哌啶-4-基)苯并[d]噻唑之合成Step 4: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-(oxo-3-yl)piperidin-4- Synthesis of yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：900mg粗品。Prepared by General Procedure H, Step 4. Yield: 900 mg crude.

LCMS(ESI)：[M]+ m/z：計算值369.2；實測值370.2；Rt=0.484min。LCMS (ESI): [M] + m/z: calculated 369.2; found 370.2; Rt=0.484 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1-(氧呾-3-基)哌啶-4-基)苯并[d]噻唑唑之合成Step 5: 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-(oxypyr-3-yl)piperidin-4-yl)benzo[d]thiazole Synthesis of azoles

藉由一般程序方案H步驟5製備。產率：650mg(71.83%)。Prepared by General Procedure H, Step 5. Yield: 650 mg (71.83%).

LCMS(ESI)：[M]+ m/z：計算值371.2；實測值372.2；Rt=0.625min。LCMS (ESI): [M] + m/z: calculated 371.2; found 372.2; Rt=0.625 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-(氧呾-3-基)哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1268)之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-(oxo-3- Synthesis of yl)piperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1268)

藉由一般程序方案H步驟6A製備。產率：117mg(31.69%)。Prepared by General Procedure H, Step 6A. Yield: 117 mg (31.69%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 20-20-45%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 20-20-45% water-MeCN+0.1% NH4OH ; (loading pump 4ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.04(m,3H),1.32-1.39(m,1H),1.66-1.70(m,3H),1.79-2.31(m,8H),2.76-2.78(m,3H),3.10-3.14(m,1H),3.40-3.48(m,2H),4.040(m,1H),4.42-4.54(dt,4H),5.27(m,1H),5.58-5.69(m,3H),7.34-7.50(m,2H),7.86-8.07(m,3H),10.52-10.57(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.04(m,3H), 1.32-1.39(m,1H), 1.66-1.70(m,3H), 1.79-2.31(m,8H) ,2.76-2.78(m,3H),3.10-3.14(m,1H),3.40-3.48(m,2H),4.040(m,1H),4.42-4.54(dt,4H),5.27(m,1H) , 5.58-5.69(m, 3H), 7.34-7.50(m, 2H), 7.86-8.07(m, 3H), 10.52-10.57(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=2.201min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=2.201 min.

實例578. N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-2-側氧基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1333)之合成Example 578. N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-2-side Synthesis of oxypiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1333)

Figure 110128222-A0202-12-2010-845
Figure 110128222-A0202-12-2010-845

藉由一般程序方案H步驟6A製備。產率：63.4mg(11.95%)。Prepared by General Procedure H, Step 6A. Yield: 63.4 mg (11.95%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 40-40-65%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 40-40-65% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.04(m,3H),1.31-1.39(m,1H),1.69-1.71(m,1H),1.84-2.31(m,9H),2.60-2.82(m,5H),3.39-4.05(m,4H),5.27-5.69(m,3H),7.36-7.50(m,2H),7.88-8.09(m,3H),10.52-10.56(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.04(m,3H), 1.31-1.39(m,1H), 1.69-1.71(m,1H), 1.84-2.31(m,9H) ,2.60-2.82(m,5H),3.39-4.05(m,4H),5.27-5.69(m,3H),7.36-7.50(m,2H),7.88-8.09(m,3H),10.52-10.56( m, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=2.359min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=2.359 min.

實例579.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-(氧呾-3-基)哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1224)之合成Example 579. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-(oxo-3- Synthesis of yl)piperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1224)

Figure 110128222-A0202-12-2010-846
Figure 110128222-A0202-12-2010-846

藉由一般程序方案H步驟6A製備。產率：96mg(42.26%)。Prepared by General Procedure H, Step 6A. Yield: 96 mg (42.26%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 20-45%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 20-45% water-MeCN + 0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.14(m,6H),1.32-1.39(m,1H),1.69-1.97(m,6H),2.09-2.11(m,3H),2.28-2.40(m,3H),2.76-2.77(m,2H),3.12(m,1H),3.40-4.06(m,3H),4.42-4.54(m,4H),5.28-5.69(m,3H),7.34-7.51(m,2H), 7.86-8.07(m,3H),10.52-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.02-1.14 (m, 6H), 1.32-1.39 (m, 1H), 1.69-1.97 (m, 6H), 2.09-2.11 (m, 3H) ,2.28-2.40(m,3H),2.76-2.77(m,2H),3.12(m,1H),3.40-4.06(m,3H),4.42-4.54(m,4H),5.28-5.69(m, 3H), 7.34-7.51 (m, 2H), 7.86-8.07 (m, 3H), 10.52-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值562.2；實測值563.2；Rt=1.926min。LCMS (ESI): [M] + m/z: calculated 562.2; found 563.2; Rt=1.926 min.

實例580. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-2-側氧基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1110、化合物1256及化合物1136)之合成Example 580. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-2-side Synthesis of Oxypiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1110, Compound 1256 and Compound 1136)

Figure 110128222-A0202-12-2011-847
Figure 110128222-A0202-12-2011-847

步驟1：4-(5-氯苯并[d]噻唑-2-基)-1-甲基哌啶-2-酮之合成Step 1: Synthesis of 4-(5-Chlorobenzo[d]thiazol-2-yl)-1-methylpiperidin-2-one

Figure 110128222-A0202-12-2011-848
Figure 110128222-A0202-12-2011-848

藉由一般程序方案H步驟1A製備。產率：3.1g(35.25%)。Prepared by General Procedure H, Step 1A. Yield: 3.1 g (35.25%).

CC條件： 藉由矽膠使用CHCl3 /MTBE(梯度10-100% MTBE)作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using CHCl3 /MTBE (gradient 10-100% MTBE) as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=1.118min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=1.118 min.

步驟2：1-甲基-4-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)哌啶-2-酮之合成Step 2: 1-Methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d] Synthesis of Thiazol-2-yl)piperidin-2-one

Figure 110128222-A0202-12-2011-849
Figure 110128222-A0202-12-2011-849

將參 (二苯亞甲基丙酮)二鈀(0)(303.31mg，331.23umol)及XPhos(631.61mg，1.32mmol)添加到4-(5-氯-1,3-苯并噻唑-2-基)-1-甲基哌啶-2-酮(3.1g，11.04mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.64g，14.35mmol)於二噁烷(100mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加乙酸鉀(2.17g，22.08mmol，1.38mL)。在惰性氣氛下將所得混合物在100℃下攪拌12h，然後冷卻且在真空中蒸發，倒入到水(200ml)中且用DCM(2x100ml)萃取，經硫酸鈉乾燥且在真空中蒸發，留下5g粗產物，5g粗產物藉由矽膠管柱層析使用CHCl3 /MeCN梯度(10-100% MeCN)進行純化，以得到1-甲基-4-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]哌啶-2-酮(3g，8.06mmol，72.99%產率)。Ps(dibenzylideneacetone)dipalladium(0) ( 303.31 mg, 331.23 umol) and XPhos (631.61 mg, 1.32 mmol) were added to 4-(5-chloro-1,3-benzothiazole-2- yl)-1-methylpiperidin-2-one (3.1 g, 11.04 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, A solution of 3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (3.64 g, 14.35 mmol) in dioxane (100 mL) . The reaction flask was evacuated and refilled with argon 3 times. Then potassium acetate (2.17 g, 22.08 mmol, 1.38 mL) was added under a stream of argon. The resulting mixture was stirred at 100°C for 12h under an inert atmosphere, then cooled and evaporated in vacuo, poured into water (200ml) and extracted with DCM (2x100ml), dried over sodium sulfate and evaporated in vacuo to leave 5g crude product, 5g crude product was purified by silica gel column chromatography using CHCl3 /MeCN gradient (10-100% MeCN) to give 1-methyl-4-[5-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazol-2-yl]piperidin-2-one (3g, 8.06mmol, 72.99 %Yield).

LCMS(ESI)：[M]+ m/z：計算值372.2；實測值373.2；Rt=1.299min。LCMS (ESI): [M] + m/z: calculated 372.2; found 373.2; Rt=1.299 min.

步驟3：(3S)-3-甲基-6-(2-(1-甲基-2-側氧基哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (3S)-3-Methyl-6-(2-(1-methyl-2-oxypiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4 -Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

Figure 110128222-A0202-12-2012-850
Figure 110128222-A0202-12-2012-850

藉由一般程序方案H步驟3製備。產率：3g粗品。Prepared by General Procedure H, Step 3. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值441.2；實測值442.2；Rt=4.017min。LCMS (ESI): [M] + m/z: calculated 441.2; found 442.2; Rt=4.017 min.

步驟4：1-甲基-4-(5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)哌啶-2-酮之合成Step 4: 1-Methyl-4-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl) Synthesis of piperidin-2-one

Figure 110128222-A0202-12-2013-851
Figure 110128222-A0202-12-2013-851

藉由一般程序8步驟4製備。產率：1.1g粗品。Prepared by General Procedure 8, Step 4. Yield: 1.1 g crude.

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=0.860min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=0.860 min.

步驟5：1-甲基-4-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)哌啶-2-酮之合成Step 5: Synthesis of 1-methyl-4-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)piperidin-2-one

Figure 110128222-A0202-12-2013-852
Figure 110128222-A0202-12-2013-852

藉由一般程序8步驟5製備。產率：0.7g粗品。Prepared by General Procedure 8, Step 5. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=0.706min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=0.706 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-2-側氧基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-2-side Synthesis of oxypiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-side oxyacetamide

藉由一般程序方案H步驟6A製備。產率：48mg(15.42%)。Prepared by General Procedure H, Step 6A. Yield: 48 mg (15.42%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 30-30-75%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20 mm, 5 microns; 0-1-6 min 30-30-75% water-MeOH+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

化合物1110：Compound 1110:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.13(m,6H),1.32-1.39(m,1H),1.69-1.90(m,2H),2.08-2.19(m,2H),2.31-2.40(m,3H),2.59-2.82(m,5H),3.40-4.06 (m,4H),5.27-5.69(m,3H),7.36-7.51(m,2H),7.88-8.16(m,3H),10.53-10.59(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.13(m, 6H), 1.32-1.39(m, 1H), 1.69-1.90(m, 2H), 2.08-2.19(m, 2H) ,2.31-2.40(m,3H),2.59-2.82(m,5H),3.40-4.06(m,4H),5.27-5.69(m,3H),7.36-7.51(m,2H),7.88-8.16( m, 3H), 10.53-10.59 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值534.2；實測值535.2；Rt=2.632min。LCMS (ESI): [M] + m/z: calculated 534.2; found 535.2; Rt=2.632 min.

步驟7：掌性分離(化合物1256及化合物1136)Step 7: Chiral separation (compound 1256 and compound 1136)

對外消旋N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(1-甲基-2-側氧基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.068g，127.18μmol)進行掌性分離(管柱：Chiralpak OJ-H(250-20mm-5m)；流動相：己烷-IPA-MeOH，70-15-15流速：15mL/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(1-甲基-2-側氧基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.02603g，48.68μmol，38.28%產率)及N-(6-胺基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[2-(三氟甲基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(0.05775g，124.60umol，50.22%產率)。Racemic N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(1-methyl-2-side oxy-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (0.068 g, 127.18 μmol) was chiral ( Column: Chiralpak OJ-H (250-20mm-5m); Mobile phase: Hexane-IPA-MeOH, 70-15-15 Flow rate: 15mL/min) to obtain N- (6-amino-5-ethyl) yl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(1-methyl-2-oxy-4-piperidinyl)-1,3- Benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (0.02603 g, 48.68 μmol, 38.28% yield) and N-(6-amino-3-pyridyl) -2-[( 2S,5R )-5-methyl-2-[2-(trifluoromethyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-side Oxyacetamide (0.05775 g, 124.60 umol, 50.22% yield).

化合物1256於分析條件下(管柱：OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為31.50min且化合物1136之保留時間為38.37min。The retention time of compound 1256 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 31.50 min and the retention time of compound 1136 was 38.37 min .

化合物1256：Compound 1256:

保留時間：31.50minRetention time: 31.50min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.14(m,6H),1.32-1.40(m,1H),1.65-1.74(m,1H),1.84-1.92(m,1H),2.05-2.18(m,2H),2.28-2.43(m,5H),2.58-2.81(m,3H),2.82(s,3H),3.36-3.44(m,1H),3.46-4.07(m,2H),5.25-5.73(m,3H),7.34-7.53(m,2H),7.87-7.95(m,1H),7.96-8.12(m,2H),10.50-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.01-1.14 (m, 6H), 1.32-1.40 (m, 1H), 1.65-1.74 (m, 1H), 1.84-1.92 (m, 1H) ,2.05-2.18(m,2H),2.28-2.43(m,5H),2.58-2.81(m,3H),2.82(s,3H),3.36-3.44(m,1H),3.46-4.07(m, 2H), 5.25-5.73 (m, 3H), 7.34-7.53 (m, 2H), 7.87-7.95 (m, 1H), 7.96-8.12 (m, 2H), 10.50-10.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值534.2；實測值535.2；Rt=2.624min。LCMS (ESI): [M] + m/z: calculated 534.2; found 535.2; Rt=2.624 min.

化合物1136：Compound 1136:

保留時間：38.37minRetention time: 38.37min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm) 1 H NMR (600MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值534.2；實測值535.2；Rt=2.627min。LCMS (ESI): [M] + m/z: calculated 534.2; found 535.2; Rt=2.627 min.

實例581.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1-(2-氟乙基)哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1174)之合成Example 581. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1-(2-fluoroethyl)piperidine-4 Synthesis of -yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1174)

步驟1：5-氯-2-(1-(2-氟乙基)哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-(2-fluoroethyl)piperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2015-853
Figure 110128222-A0202-12-2015-853

將5-氯-2-(4-哌啶基)-1,3-苯并噻唑(5g，15.35mmol，2HCl)、甲磺酸2-氟乙酯(2.29g，16.12mmol)及TEA(6.21g，61.41mmol，8.56mL)於MeCN(100mL)中之混合物在50℃下攪拌24h。等分試樣之LCMS顯示61%轉化。將甲磺酸2-氟乙酯(2.18g，15.35mmol)及TEA(4.66g，46.06mmol，6.42mL)添加到反應混合物且將其在60℃下攪拌72h，然後冷卻且在真空中濃縮。將殘餘物用水(50ml)稀釋且用10%氫氧化鈉水溶液鹼化至pH 11。將所得混合物用MTBE(250ml)萃取。將有機層用水(50ml)洗滌，經硫酸鈉乾燥且在真空中濃縮，以得到呈棕色固體之5-氯-2-[1-(2-氟乙基)-4-哌啶基]-1,3-苯并噻唑(3.3g，11.04mmol，71.94%產率)。Combine 5-chloro-2-(4-piperidinyl)-1,3-benzothiazole (5 g, 15.35 mmol, 2HCl), 2-fluoroethyl methanesulfonate (2.29 g, 16.12 mmol) and TEA (6.21 mmol) g, 61.41 mmol, 8.56 mL) in MeCN (100 mL) was stirred at 50 °C for 24 h. LCMS of an aliquot showed 61% conversion. 2-Fluoroethyl methanesulfonate (2.18 g, 15.35 mmol) and TEA (4.66 g, 46.06 mmol, 6.42 mL) were added to the reaction mixture and it was stirred at 60 °C for 72 h, then cooled and concentrated in vacuo. The residue was diluted with water (50 ml) and basified to pH 11 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with MTBE (250 ml). The organic layer was washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo to give 5-chloro-2-[1-(2-fluoroethyl)-4-piperidinyl]-1 as a brown solid , 3-benzothiazole (3.3 g, 11.04 mmol, 71.94% yield).

LCMS(ESI)：[M]LCMS (ESI): [M] ++ m/z：計算值298.2；實測值299.2；Rt=1.812min。m/z: Calculated value 298.2; Measured value 299.2; Rt=1.812min.

步驟2：2-(1-(2-氟乙基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-(2-Fluoroethyl)piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborocycle Synthesis of Pentan-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2016-854
Figure 110128222-A0202-12-2016-854

將5-氯-2-[1-(2-氟乙基)-4-哌啶基]-1,3-苯并噻唑(3.3g，11.04mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.08g，12.15mmol)及乙酸鉀(2.17g，22.09mmol，1.38mL)於二噁烷(100mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(505.66mg，552.20umol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(1.05g，2.21mmol)，且將反應混合物在95℃下攪拌18h。將反應混合物冷卻且在真空中濃縮。藉由矽膠管柱層析使用MeCN/MeOH梯度(0-100% MeOH)純化殘餘物，以得到呈淡黃色固體之2-[1-(2-氟乙基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(2.8g，7.17mmol，64.95%產率)。5-Chloro-2-[1-(2-fluoroethyl)-4-piperidinyl]-1,3-benzothiazole (3.3 g, 11.04 mmol), 4,4,5,5-tetramethyl yl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A mixture of alkane (3.08 g, 12.15 mmol) and potassium acetate (2.17 g, 22.09 mmol, 1.38 mL) in dioxane (100 mL) was evacuated and backfilled with argon. This operation was repeated twice, followed by the addition of bis(1,5-diphenylpent-1,4-dien-3-one)dipalladium ( 505.66 mg, 552.20 umol) and dicyclohexyl[2 ',4',6'-para(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (1.05 g, 2.21 mmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography using a MeCN/MeOH gradient (0-100% MeOH) to give 2-[1-(2-fluoroethyl)-4-piperidinyl]- as a pale yellow solid 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (2.8 g, 7.17 mmol, 64.95 %Yield).

LCMS(ESI)：[M]+ m/z：計算值390.2；實測值391.2；Rt=1.011min。LCMS (ESI): [M] + m/z: calculated 390.2; found 391.2; Rt=1.011 min.

步驟3：(S)-6-(2-(1-(2-氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1-(2-Fluoroethyl)piperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4- Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

Figure 110128222-A0202-12-2017-855
Figure 110128222-A0202-12-2017-855

藉由一般程序方案H步驟3製備。產率：2g(60.66%)。Prepared by General Procedure H, Step 3. Yield: 2 g (60.66%).

CC條件： 藉由矽膠使用CHCl3 /MeCN作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using CHCl3 /MeCN as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值459.2；實測值460.2；Rt=1.248min。LCMS (ESI): [M] + m/z: calculated 459.2; found 460.2; Rt=1.248 min.

步驟4：(S)-2-(1-(2-氟乙基)哌啶-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1-(2-Fluoroethyl)piperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl ) Synthesis of Benzo[d]thiazole

Figure 110128222-A0202-12-2017-856
Figure 110128222-A0202-12-2017-856

藉由一般程序方案H步驟4製備。產率：760mg(48.58%)。Prepared by General Procedure H, Step 4. Yield: 760 mg (48.58%).

LCMS(ESI)：[M]+ m/z：計算值359.2；實測值360.2；Rt=0.574min。LCMS (ESI): [M] + m/z: calculated 359.2; found 360.2; Rt=0.574 min.

步驟5：2-(1-(2-氟乙基)哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Compound of 2-(1-(2-fluoroethyl)piperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole synthesis

Figure 110128222-A0202-12-2018-857
Figure 110128222-A0202-12-2018-857

藉由一般程序方案H步驟5製備。產率：620mg(81.12%)。Prepared by General Procedure H, Step 5. Yield: 620 mg (81.12%).

LCMS(ESI)：[M]+ m/z：計算值361.2；實測值362.2；Rt=0.724min。LCMS (ESI): [M] + m/z: calculated 361.2; found 362.2; Rt=0.724 min.

N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(1-(2-氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1174)之合成N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-(2-fluoroethyl)piperidin-4-yl) Synthesis of Benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1174)

Figure 110128222-A0202-12-2018-858
Figure 110128222-A0202-12-2018-858

藉由一般程序方案H步驟6A製備。產率：70.6mg(30.79%)。Prepared by General Procedure H, Step 6A. Yield: 70.6 mg (30.79%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 50-50-60%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20 mm, 5 microns; 0-1-5 min 50-50-60% water-MeOH+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.13(m,6H),1.32-1.39(m,1H),1.69-1.89(m,4H),2.07-2.22(m,5H),2.28-2.41(m,3H),2.60-2.67(m,2H),2.77-2.97(m,3H),3.07-3.11(m,1H),3.46-4.05(m,1H),4.48-4.58(dt,2 H),5.27-5.69(m,3H),7.34-7.51(m,2H),7.86-7.90(d,1H),7.99-8.07(m,2H),10.53-10.58(d,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.13(m, 6H), 1.32-1.39(m, 1H), 1.69-1.89(m, 4H), 2.07-2.22(m, 5H) ,2.28-2.41(m,3H),2.60-2.67(m,2H),2.77-2.97(m,3H),3.07-3.11(m,1H),3.46-4.05(m,1H),4.48-4.58( dt,2H), 5.27-5.69(m,3H), 7.34-7.51(m,2H), 7.86-7.90(d,1H), 7.99-8.07(m,2H), 10.53-10.58(d,1H) .

LCMS(ESI)：[M]+ m/z：計算值552.2；實測值553.2；Rt=2.212min。LCMS (ESI): [M] + m/z: calculated 552.2; found 553.2; Rt=2.212 min.

實例582.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1304)之合成Example 582. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1-(2,2-difluoroethyl)piperidine Synthesis of pyridin-4-yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1304)

步驟1：5-氯-2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-(2,2-difluoroethyl)piperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2019-859
Figure 110128222-A0202-12-2019-859

將5-氯-2-(4-哌啶基)-1,3-苯并噻唑(3.6g，11.05mmol，2HCl)、三氟甲磺酸2,2-二氟乙酯(2.84g，13.26mmol)及TEA(5.59g，55.27mmol，7.70mL)於MeCN(100mL)中之混合物在60℃下攪拌72h，然後冷卻且在真空中濃縮。將殘餘物用水(50ml)稀釋且用10%氫氧化鈉水溶液鹼化至pH 11。將所得混合物用MTBE(250ml)萃取。將有機層用水(50ml)洗滌，經硫酸鈉乾燥且在真空中濃縮，以得到呈棕色固體之粗品5-氯-2-[1-(2,2-二氟乙基)-4-哌啶基]-1,3-苯并噻唑(3g，9.47mmol，85.67%產率)，其直接用於下一步驟中。5-Chloro-2-(4-piperidinyl)-1,3-benzothiazole (3.6 g, 11.05 mmol, 2HCl), 2,2-difluoroethyl trifluoromethanesulfonate (2.84 g, 13.26 g mmol) and TEA (5.59 g, 55.27 mmol, 7.70 mL) in MeCN (100 mL) was stirred at 60 °C for 72 h, then cooled and concentrated in vacuo. The residue was diluted with water (50 ml) and basified to pH 11 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with MTBE (250 ml). The organic layer was washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo to give crude 5-chloro-2-[1-(2,2-difluoroethyl)-4-piperidine as a brown solid yl]-1,3-benzothiazole (3 g, 9.47 mmol, 85.67% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值316.2；實測值317.2；Rt=2.015min。LCMS (ESI): [M] + m/z: calculated 316.2; found 317.2; Rt=2.015 min.

步驟2：2-(1-(2,2-二氟乙基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-(2,2-Difluoroethyl)piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2020-860
Figure 110128222-A0202-12-2020-860

將5-氯-2-[1-(2,2-二氟乙基)-4-哌啶基]-1,3-苯并噻唑(3g，9.47mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.65g，10.42mmol)及乙酸鉀(1.86g，18.94mmol，1.18mL)於二噁烷(100mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(433.58mg，473.49umol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(902.89mg，1.89mmol)，且將反應混合物在95℃下攪拌18h。將反應混合物冷卻且在真空中濃縮。藉由矽膠管柱層析使用己烷/乙酸乙酯梯度(0-100%乙酸乙酯)來純化殘餘物，以得到呈米色固體之2-[1-(2,2-二氟乙基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(1.5g，3.67mmol，38.79%產率)。5-Chloro-2-[1-(2,2-difluoroethyl)-4-piperidinyl]-1,3-benzothiazole (3 g, 9.47 mmol), 4,4,5,5- Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane A mixture of cyclopentane (2.65 g, 10.42 mmol) and potassium acetate (1.86 g, 18.94 mmol, 1.18 mL) in dioxane (100 mL) was evacuated and backfilled with argon. This operation was repeated twice, then ginseng (1,5-diphenylpent-1,4-dien-3-one)dipalladium (433.58 mg, 473.49 umol) and dicyclohexyl[2 ',4',6'-para(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (902.89 mg, 1.89 mmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane/ethyl acetate gradient (0-100% ethyl acetate) to give 2-[1-(2,2-difluoroethyl) as a beige solid -4-Piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (1.5 g, 3.67 mmol, 38.79% yield).

LCMS(ESI)：[M]+ m/z：計算值408.2；實測值409.2；Rt=0.989min。LCMS (ESI): [M] + m/z: calculated 408.2; found 409.2; Rt=0.989 min.

步驟3：(S)-6-(2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1-(2,2-Difluoroethyl)piperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3 Synthesis of 3-butyl ,4-dihydropyridine-1(2H)-carboxylate

Figure 110128222-A0202-12-2021-861
Figure 110128222-A0202-12-2021-861

藉由一般程序方案H步驟3製備。產率：0.9g(51.29%)。Prepared by General Procedure H, Step 3. Yield: 0.9 g (51.29%).

CC條件： 藉由矽膠使用己烷/MTBE作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值477.2；實測值478.2；Rt=1.120min。LCMS (ESI): [M] + m/z: calculated 477.2; found 478.2; Rt=1.120 min.

步驟4：(S)-2-(1-(2,2-二氟乙基)哌啶-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1-(2,2-Difluoroethyl)piperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridine- Synthesis of 2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2021-862
Figure 110128222-A0202-12-2021-862

藉由一般程序方案H步驟4製備。產率：0.67g(94.19%)。Prepared by General Procedure H, Step 4. Yield: 0.67 g (94.19%).

LCMS(ESI)：[M]+ m/z：計算值377.2；實測值378.2；Rt=0.707min。LCMS (ESI): [M] + m/z: calculated 377.2; found 378.2; Rt=0.707 min.

步驟5：2-(1-(2,2-二氟乙基)哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: 2-(1-(2,2-Difluoroethyl)piperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d ]Synthesis of thiazole

Figure 110128222-A0202-12-2022-863
Figure 110128222-A0202-12-2022-863

藉由一般程序方案H步驟5製備。產率：0.55g(81.65%)。Prepared by General Procedure H, Step 5. Yield: 0.55 g (81.65%).

LCMS(ESI)：[M]+ m/z：計算值379.2；實測值380.2；Rt=0.744min。LCMS (ESI): [M] + m/z: calculated 379.2; found 380.2; Rt=0.744 min.

步驟6：N-(6-胺基-5-乙基唑啶-3-基)-2-((2R,5S)-2-(2-(1-(2,2-二氟乙基)哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1304)之合成Step 6: N-(6-Amino-5-ethylazolidin-3-yl)-2-((2R,5S)-2-(2-(1-(2,2-difluoroethyl) Synthesis of piperidin-4-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1304)

Figure 110128222-A0202-12-2022-864
Figure 110128222-A0202-12-2022-864

藉由一般程序方案H步驟6A製備。產率：26mg(11.53%)。Prepared by General Procedure H, Step 6A. Yield: 26 mg (11.53%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 30-55%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5 min 30-55% water-MeCN+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.13(m,6H),1.32-1.39(m,1H),1.69-1.90(m,4H),2.06-2.18(m,3H),2.28-2.40(m,4H),2.72-2.78(m,3H),2.97-3.10(m,3H),3.47-4.05(m,2H),5.28-5.69(m,3H),6.04-6.23(m,1H),7.34-7.51(m,2H),7.86-8.07(m,3H),10.53-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.13(m, 6H), 1.32-1.39(m, 1H), 1.69-1.90(m, 4H), 2.06-2.18(m, 3H) ,2.28-2.40(m,4H),2.72-2.78(m,3H),2.97-3.10(m,3H),3.47-4.05(m,2H),5.28-5.69(m,3H),6.04-6.23( m, 1H), 7.34-7.51 (m, 2H), 7.86-8.07 (m, 3H), 10.53-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值570.2；實測值571.2；Rt=2.104min。LCMS (ESI): [M] + m/z: calculated 570.2; found 571.2; Rt=2.104 min.

實例583.外消旋-N,N -二甲基-2-(5-((2R,5S )-5-甲基哌啶-2-基)苯并[d ]噻唑-2-Example 583. Racemic-N,N -dimethyl-2-(5-(( 2R,5S )-5-methylpiperidin-2-yl)benzo[ d ]thiazol-2- 基)乙胺之合成Synthesis of ethyl) ethylamine

步驟1：2-(5-溴苯并[d]噻唑-2-基)-N,N-二甲基乙胺之合成Step 1: Synthesis of 2-(5-bromobenzo[d]thiazol-2-yl)-N,N-dimethylethylamine

Figure 110128222-A0202-12-2023-865
Figure 110128222-A0202-12-2023-865

藉由一般程序方案J步驟1A製備。產率：1g(11.18%)。Prepared by General Procedure J, Step 1A. Yield: 1 g (11.18%).

CC條件： 藉由矽膠使用CHCl3 /MeOH作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using CHCl3 /MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值285.2；實測值286.2；Rt=0.824min。LCMS (ESI): [M] + m/z: calculated 285.2; found 286.2; Rt=0.824 min.

步驟2：N,N-二甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 2: N,N-Dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo Synthesis of [d]thiazol-2-yl)ethanamine

Figure 110128222-A0202-12-2023-866
Figure 110128222-A0202-12-2023-866

藉由一般程序方案J步驟2製備。產率：1.1g粗品Prepared by General Procedure J, Step 2. Yield: 1.1 g crude

LCMS(ESI)：[M]+ m/z：計算值332.2；實測值333.2；Rt=1.004min。LCMS (ESI): [M] + m/z: calculated 332.2; found 333.2; Rt=1.004 min.

步驟3：6-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: 6-(2-(2-(Dimethylamino)ethyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)- Synthesis of tert-butyl formate

Figure 110128222-A0202-12-2024-867
Figure 110128222-A0202-12-2024-867

藉由一般程序方案J步驟3製備。產率：1.5g粗品。Prepared by General Procedure J, Step 3. Yield: 1.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值401.2；實測值402.2；Rt=1.064min。LCMS (ESI): [M] + m/z: calculated 401.2; found 402.2; Rt=1.064 min.

步驟4：N,N-二甲基-2-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 4: N,N-Dimethyl-2-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)ethyl Synthesis of Amines

Figure 110128222-A0202-12-2024-868
Figure 110128222-A0202-12-2024-868

藉由一般程序方案J步驟4製備。產率：1.3g粗品。Prepared by General Procedure J, Step 4. Yield: 1.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值301.2；實測值302.2；Rt=0.641min。LCMS (ESI): [M] + m/z: calculated 301.2; found 302.2; Rt=0.641 min.

步驟5：外消旋-N,N-二甲基-2-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 5: Racemic-N,N-Dimethyl-2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)ethyl Synthesis of Amines

Figure 110128222-A0202-12-2024-869
Figure 110128222-A0202-12-2024-869

藉由一般程序方案H步驟5製備。產率：1.2g粗品。Prepared by General Procedure H, Step 5. Yield: 1.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值303.2；實測值304.2；Rt=0.486min。LCMS (ESI): [M] + m/z: calculated 303.2; found 304.2; Rt=0.486 min.

實例584.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(2-(吡咯啶-1-基)乙基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1095)之合成Example 584. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(2-(pyrrolidine-1- Synthesis of yl)ethyl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1095)

Figure 110128222-A0202-12-2025-870
Figure 110128222-A0202-12-2025-870

藉由一般程序8製備。產率：33mg(21.42%)。Prepared by General Procedure 8. Yield: 33 mg (21.42%).

HPLC條件：管柱：YMC Triart C18 100*19mm，5微米；0-1-5min 30-30-65%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*19mm, 5 microns; 0-1-5 min 30-30-65% water-MeCN+0.1% NH4OH ; (loading pump 4 ml/min MeCN).

化合物1095：Compound 1095:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.14(m,6H),1.32-1.40(m,2H),1.68(m,5H),1.85-1.90(m,2H),2.06-2.37(m,5H),2.76-2.86(m,3H),3.24(m,2H),3.47-4.05(m,2H),5.28-5.69(m,3H),7.32-7.51(m,2H),7.84-7.88(d,1H),8.00-8.07(m,2H),10.51-10.56(d,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.02-1.14 (m, 6H), 1.32-1.40 (m, 2H), 1.68 (m, 5H), 1.85-1.90 (m, 2H), 2.06 -2.37(m,5H),2.76-2.86(m,3H),3.24(m,2H),3.47-4.05(m,2H),5.28-5.69(m,3H),7.32-7.51(m,2H) , 7.84-7.88(d, 1H), 8.00-8.07(m, 2H), 10.51-10.56(d, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=1.944min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=1.944 min.

實例585. 2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-N -(6-甲基-5-(氧呾-3-基)吡啶-3-基)-2-側氧基乙醯胺(化合物1309)之合成Example 585. 2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1- Synthesis of N- (6-methyl-5-(oxo-3-yl)pyridin-3-yl)-2-oxoacetamide (Compound 1309)

Figure 110128222-A0202-12-2025-871
Figure 110128222-A0202-12-2025-871

藉由一般程序方案H步驟6B製備。產率：9mg(5.31%)。Prepared by General Procedure H, Step 6B. Yield: 9 mg (5.31%).

HPLC條件：管柱：SunFire C18 100*19mm，5微米；2-10min 50-100% MeOH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: SunFire C18 100*19mm, 5 microns; 2-10 min 50-100% MeOH; (loading pump 4 ml/min MeOH).

藉由掌性HPLC(管柱：Chiralcel OD-H(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)純化2-[(2R,5S )-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-N -[6-甲基-5-(氧呾-3-基)-3-吡啶基]-2-側氧基乙醯胺，以獲得2-[(2R,5S )-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-N -[6-甲基-5-(氧呾-3-基)-3-吡啶基]-2-側氧基乙醯胺(0.009g，16.43μmol，5.31%產率)。2-[( 2R,5S )-5- was purified by chiral HPLC (column: Chiralcel OD-H (250*20mm, 5mkm), Hexane-IPA-MeOH, 50-25-25, 12ml/min) Methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1 - piperidinyl]-N-[6-methyl-5 -(Oxy-3-yl)-3-pyridinyl]-2-oxoacetamide to give 2-[( 2R,5S )-5-methyl-2-[2-(1-methyl) yl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-N-[6-methyl-5-( oxypyr -3-yl)-3- Pyridinyl]-2-pendant oxyacetamide (0.009 g, 16.43 μmol, 5.31% yield).

化合物1309於分析條件下(管柱：OD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)17.78min。Compound 1309 was subjected to analytical conditions (column: OD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) for 17.78 min.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.08(m,3H),1.27-1.42(m,1H),1.66-1.77(m,1H),1.77-2.00(m,3H),2.08-2.21(m,3H),2.22-2.28(m,3H),2.28-2.36(m,3H),2.45-2.46(m,3H),2.82-3.09(m,3H),3.09-3.22(m,1H),3.54-4.07(m,1H),4.36-4.50(m,1H),4.52-4.67(m,2H),4.86-4.99(m,2H),5.27-5.75(m,1H),7.34-7.46(m,1H),7.85-7.97(m,1H),7.98-8.12(m,2H),8.52-8.67(m,1H),10.84-11.29(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.08(m,3H), 1.27-1.42(m,1H), 1.66-1.77(m,1H), 1.77-2.00(m,3H) ,2.08-2.21(m,3H),2.22-2.28(m,3H),2.28-2.36(m,3H),2.45-2.46(m,3H),2.82-3.09(m,3H),3.09-3.22( m,1H),3.54-4.07(m,1H),4.36-4.50(m,1H),4.52-4.67(m,2H),4.86-4.99(m,2H),5.27-5.75(m,1H), 7.34-7.46(m,1H), 7.85-7.97(m,1H), 7.98-8.12(m,2H), 8.52-8.67(m,1H), 10.84-11.29(m,1H).

LCMS(ESI)：[M]+ m/z：計算值547.2；實測值548.2；Rt=2.313min。LCMS (ESI): [M] + m/z: calculated 547.2; found 548.2; Rt=2.313 min.

實例586.N -(5,6-二甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1137)之合成Example 586. N- (5,6-Lutidine-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidin-4-yl ) Synthesis of benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1137)

Figure 110128222-A0202-12-2026-872
Figure 110128222-A0202-12-2026-872

藉由一般程序方案H步驟6A製備。產率：47mg(27.84%)。Prepared by General Procedure H, Step 6A. Yield: 47 mg (27.84%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-1-6min 10-10-60%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-1-6 min 10-10-60% water-MeCN+0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.07(m,3H),1.29-1.42(m,1H),1.64-1.75(m,1H),1.76-1.92(m,3H),1.99-2.13(m,5H),2.17-2.25(m,6H),2.31-2.39(m,4H),2.50-2.51(m,1H),2.80-2.85(m,2H),3.00-3.10(m,1H),3.43-4.06(m,1H),5.22-5.76(m,1H),7.32-7.44(m,1H),7.72-7.85(m,1H),7.85-7.94(m,1H),8.02-8.09(m,1H),8.39-8.55(m,1H),10.79-11.14(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.07(m,3H), 1.29-1.42(m,1H), 1.64-1.75(m,1H), 1.76-1.92(m,3H) ,1.99-2.13(m,5H),2.17-2.25(m,6H),2.31-2.39(m,4H),2.50-2.51(m,1H),2.80-2.85(m,2H),3.00-3.10( m,1H),3.43-4.06(m,1H),5.22-5.76(m,1H),7.32-7.44(m,1H),7.72-7.85(m,1H),7.85-7.94(m,1H), 8.02-8.09 (m, 1H), 8.39-8.55 (m, 1H), 10.79-11.14 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值505.2；實測值506.2；Rt=1.873min。LCMS (ESI): [M] + m/z: calculated 505.2; found 506.2; Rt=1.873 min.

實例587.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基-1H -吡唑-5-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1389)之合成Example 587. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methyl- 1H -pyridin Synthesis of oxazol-5-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1389)

步驟1：5-氯-2-(1-甲基-1H-吡唑-5-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-methyl-1H-pyrazol-5-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2027-873
Figure 110128222-A0202-12-2027-873

藉由一般程序方案H步驟1A製備。產率：8g(96.96%)。Prepared by General Procedure H, Step 1A. Yield: 8 g (96.96%).

LCMS(ESI)：[M]+ m/z：計算值249.2；實測值250.2；Rt=1.539min。LCMS (ESI): [M] + m/z: calculated 249.2; found 250.2; Rt=1.539 min.

步驟2：2-(1-甲基-1H-吡唑-5-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Methyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of -2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2027-874
Figure 110128222-A0202-12-2027-874

將乙酸鉀(6.29g，64.07mmol，4.01mL)添加到5-氯-2-(2-甲基吡唑-3-基)-1,3-苯并噻唑(8.00g，32.04mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(8.95g，35.24mmol)於二噁烷(100mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加參(二苯亞甲基丙酮)二鈀(0)(1.47g，1.60mmol)及X-Phos(3.05g，6.41mmol)。在90℃、惰性氣氛下將所得混合物攪拌18h。然後，將其冷卻，用EtOAc(200mL)稀釋且過濾出。將濾液在減壓下濃縮且藉由矽膠急驟層析使用0至100%氯仿-MTBE梯度溶析來純化殘餘物，以得到2-(2-甲基吡唑-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(6.7g，19.63mmol，61.29%產率)。Potassium acetate (6.29 g, 64.07 mmol, 4.01 mL) was added to 5-chloro-2-(2-methylpyrazol-3-yl)-1,3-benzothiazole (8.00 g, 32.04 mmol) and 4 ,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3, A solution of 2-dioxaborolane (8.95 g, 35.24 mmol) in dioxane (100 mL). The reaction flask was evacuated and refilled with argon 3 times. Paras(dibenzylideneacetone)dipalladium(0) (1.47 g, 1.60 mmol) and X-Phos (3.05 g, 6.41 mmol) were then added under argon flow. The resulting mixture was stirred at 90 °C under an inert atmosphere for 18 h. It was then cooled, diluted with EtOAc (200 mL) and filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% chloroform-MTBE gradient to give 2-(2-methylpyrazol-3-yl)-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (6.7 g, 19.63 mmol, 61.29% yield ).

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=1.600min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=1.600 min.

步驟3：(S)-3-甲基-6-(2-(1-甲基-1H-吡唑-5-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(1-methyl-1H-pyrazol-5-yl)benzo[d]thiazol-5-yl)-3,4-dihydro Synthesis of tert-butyl pyridine-1(2H)-carboxylate

Figure 110128222-A0202-12-2028-875
Figure 110128222-A0202-12-2028-875

藉由一般程序方案H步驟3製備。產率：12g粗品。Prepared by General Procedure H, Step 3. Yield: 12 g crude.

LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=1.654min。LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=1.654 min.

步驟4：(S)-2-(1-甲基-1H-吡唑-5-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1-Methyl-1H-pyrazol-5-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzene Synthesis of [d]thiazoles

Figure 110128222-A0202-12-2029-876
Figure 110128222-A0202-12-2029-876

藉由一般程序方案H步驟4製備。產率：8g粗品。Prepared by General Procedure H, Step 4. Yield: 8 g crude.

LCMS(ESI)：[M]+ m/z：計算值310.2；實測值311.2；Rt=0.983min。LCMS (ESI): [M] + m/z: calculated 310.2; found 311.2; Rt=0.983 min.

步驟5：2-(1-甲基-1H-吡唑-5-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 2-(1-Methyl-1H-pyrazol-5-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2029-877
Figure 110128222-A0202-12-2029-877

藉由一般程序方案H步驟5製備。產率：8g(99.35%)。Prepared by General Procedure H, Step 5. Yield: 8 g (99.35%).

LCMS(ESI)：[M]+ m/z：計算值312.2；實測值313.2；Rt=0.967min。LCMS (ESI): [M] + m/z: calculated 312.2; found 313.2; Rt=0.967 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-1H-吡唑-5-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1389)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-1H-pyridin Synthesis of oxazol-5-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1389)

Figure 110128222-A0202-12-2029-878
Figure 110128222-A0202-12-2029-878

藉由一般程序方案H步驟6A製備。產率：28mg(4.34%)。Prepared by General Procedure H, Step 6A. Yield: 28 mg (4.34%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 10-10-65%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 10-10-65% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.04-1.19(m,6H),1.29-1.50(m,1H),1.67-1.81(m,1H),1.84-2.00(m,1H),2.07-2.28(m,1H),2.34-2.47(m,3H),2.82-3.26(m,1H),3.51-4.15(m,1H),4.30(s,3H),5.31-5.61(m,1H),5.60-5.79(m,2H),6.96-7.03(m,1H),7.43-7.50(m,1H),7.50-7.56(m,1H),7.57-7.65(m,1H),7.98-8.11(m,2H),8.13-8.24(m,1H),10.49-10.66(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.04-1.19(m, 6H), 1.29-1.50(m, 1H), 1.67-1.81(m, 1H), 1.84-2.00(m, 1H) ,2.07-2.28(m,1H),2.34-2.47(m,3H),2.82-3.26(m,1H),3.51-4.15(m,1H),4.30(s,3H),5.31-5.61(m, 1H), 5.60-5.79(m, 2H), 6.96-7.03(m, 1H), 7.43-7.50(m, 1H), 7.50-7.56(m, 1H), 7.57-7.65(m, 1H), 7.98- 8.11 (m, 2H), 8.13-8.24 (m, 1H), 10.49-10.66 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值503.2；實測值504.2；Rt=2.867min。LCMS (ESI): [M] + m/z: calculated 503.2; found 504.2; Rt=2.867 min.

實例588. N-(5-氯-6-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1102)之合成Example 588. N-(5-Chloro-6-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidine-4- Synthesis of yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1102)

Figure 110128222-A0202-12-2030-879
Figure 110128222-A0202-12-2030-879

藉由一般程序方案H步驟6A製備。產率：113mg(39.32%)。Prepared by General Procedure H, Step 6A. Yield: 113 mg (39.32%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 60-90%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6 min 60-90% water-MeOH+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.07(m,3H),1.30-1.40(m,1H),1.69-1.92(m,4H),2.00-2.13(m,5H),2.18(s,3H),2.28-2.35(m,1H),2.50(s,3H),2.80-3.09(m,4H),3.48-4.04(m,1H),5.28-5.73(m,1H),7.32-7.42(m,1H),7.86-7.92(m,1H),8.00-8.25(m,2H),8.52-8.69(m,1H),11.14-11.34(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.07(m,3H), 1.30-1.40(m,1H), 1.69-1.92(m,4H), 2.00-2.13(m,5H) ,2.18(s,3H),2.28-2.35(m,1H),2.50(s,3H),2.80-3.09(m,4H),3.48-4.04(m,1H),5.28-5.73(m,1H) , 7.32-7.42(m, 1H), 7.86-7.92(m, 1H), 8.00-8.25(m, 2H), 8.52-8.69(m, 1H), 11.14-11.34(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值526.2；實測值527.2；Rt=3.173min。LCMS (ESI): [M] + m/z: calculated 526.2; found 527.2; Rt=3.173 min.

實例589. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(2-N-嗎啉基乙基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1248)之合成Example 589. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(2-N-morpholinoethyl) Synthesis of yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1248)

Figure 110128222-A0202-12-2031-880
Figure 110128222-A0202-12-2031-880

步驟1：4-(2-(5-氯苯并[d]噻唑-2-基)乙基)嗎啉之合成Step 1: Synthesis of 4-(2-(5-Chlorobenzo[d]thiazol-2-yl)ethyl)morpholine

藉由一般程序方案H步驟1A製備。產率：3.5g(39.52%)。Prepared by General Procedure H, Step 1A. Yield: 3.5 g (39.52%).

CC條件： 藉由矽膠使用CHCl3 /MeCN作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using CHCl3 /MeCN as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值282.2；實測值283.2；Rt=0.916min。LCMS (ESI): [M] + m/z: calculated 282.2; found 283.2; Rt=0.916 min.

步驟2：4-(2-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)乙基)嗎啉之合成Step 2: 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d]thiazole- Synthesis of 2-yl)ethyl)morpholine

將乙酸鉀(2.43g，24.75mmol，1.55mL)添加到4-[2-(5-氯-1,3-苯并噻唑-2-基)乙基]嗎啉(3.5g，12.38mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.46g，13.61mmol)於二噁烷(40mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加參(二苯亞甲基丙酮)二鈀(0)(566.68mg，618.84umol)及XPhos(1.18g，2.48mmol)。在惰性氣氛下將所得混合物在90℃下攪拌18h。然後，將其冷卻，用EtOAc(200mL)稀釋且用Na2 CO3 (50mL，飽和水溶液)洗滌。將有機層經Na2 SO4 乾燥，在減壓下濃縮且藉由矽膠急驟層析使用0至100%氯仿-MeCN梯度溶析來純化殘餘物，以得到產物4-[2-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]乙基]嗎啉(2.1g，5.61mmol，45.33%產率)。Potassium acetate (2.43 g, 24.75 mmol, 1.55 mL) was added to 4-[2-(5-chloro-1,3-benzothiazol-2-yl)ethyl]morpholine (3.5 g, 12.38 mmol) and 4,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3 , 2-dioxaborolane (3.46 g, 13.61 mmol) in dioxane (40 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, paras(dibenzylideneacetone)dipalladium(0) (566.68 mg, 618.84 umol) and XPhos (1.18 g, 2.48 mmol) were added under argon flow. The resulting mixture was stirred at 90 °C for 18 h under an inert atmosphere. It was then cooled, diluted with EtOAc ( 200 mL) and washed with Na2CO3 (50 mL, saturated aqueous solution). The organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% chloroform-MeCN gradient to give the product 4-[2-[5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazol-2-yl]ethyl]morpholine ( 2.1 g, 5.61 mmol, 45.33% yield).

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=0.889min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=0.889 min.

步驟3：(S)-3-甲基-6-(2-(2-N-嗎啉基乙基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(2-N-morpholinoethyl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1( Synthesis of 2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：3.5g粗品。Prepared by General Procedure H, Step 3. Yield: 3.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值443.2；實測值444.2；Rt=1.080min。LCMS (ESI): [M] + m/z: calculated 443.2; found 444.2; Rt=1.080 min.

步驟4：(S)-4-(2-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)乙基)嗎啉之合成Step 4: (S)-4-(2-(5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl)ethyl ) Synthesis of Morpholine

藉由一般程序方案H步驟4製備。產率：3.5g粗品。Prepared by General Procedure H, Step 4. Yield: 3.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=0.501min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=0.501 min.

步驟5：4-(2-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)乙基)嗎啉之合成Step 5: Synthesis of 4-(2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)ethyl)morpholine

藉由一般程序方案H步驟5製備。產率：2g粗品。Prepared by General Procedure H, Step 5. Yield: 2 g crude.

LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=0.551min。LCMS (ESI): [M] + m/z: calculated 345.2; found 346.2; Rt=0.551 min.

Figure 110128222-A0202-12-2032-881
Figure 110128222-A0202-12-2032-881

藉由一般程序方案H步驟6A製備。產率：92mg(39.48%)。Prepared by General Procedure H, Step 6A. Yield: 92 mg (39.48%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 15-65%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5 min 15-65% water-MeCN + 0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.14(m,6H),1.32-1.41(m,1H),1.65-1.73(m,1H),1.82-1.91(m,1H),2.05-2.46(m,8H),2.73-2.76(m,2H),3.24-3.27(m,2H),3.45-4.06(m,6H),5.28-5.71(m,3H),7.30-7.42(m,1H),7.43-7.54(m,1H),7.82-7.90(m,1H),7.97-8.09(m,2H),10.46-10.64(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.14(m, 6H), 1.32-1.41(m, 1H), 1.65-1.73(m, 1H), 1.82-1.91(m, 1H) ,2.05-2.46(m,8H),2.73-2.76(m,2H),3.24-3.27(m,2H),3.45-4.06(m,6H),5.28-5.71(m,3H),7.30-7.42( m, 1H), 7.43-7.54 (m, 1H), 7.82-7.90 (m, 1H), 7.97-8.09 (m, 2H), 10.46-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值536.2；實測值537.2；Rt=2.116min。LCMS (ESI): [M] + m/z: calculated 536.2; found 537.2; Rt=2.116 min.

實例590. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(4-甲基哌嗪-1-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1244)之合成Example 590. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(4-methylpiperazine-1 Synthesis of -yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1244)

Figure 110128222-A0202-12-2033-882
Figure 110128222-A0202-12-2033-882

藉由一般程序方案H步驟6A製備。產率：42.6mg(17.96%)。Prepared by General Procedure H, Step 6A. Yield: 42.6 mg (17.96%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 10-10-60%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6 min 10-10-60% water-MeCN+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.05(m,3H),1.06-1.13(m,3H),1.29-1.40(m,1H),1.65-1.74(m,1H),1.81-1.91(m,1H),2.01-2.15(m,1H),2.21(s,3H),2.23-2.31(m,1H),2.33-2.40(m,2H),2.41-2.43(m,4H),2.73-3.27(m,1H),3.46-4.01(m,5H),5.18-5.66(m,3H),7.00-7.09(m,1H),7.36-7.52(m,2H),7.72-7.78(m,1H),7.99-8.08(m,1H),10.48-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.05(m,3H), 1.06-1.13(m,3H), 1.29-1.40(m,1H), 1.65-1.74(m,1H) ,1.81-1.91(m,1H),2.01-2.15(m,1H),2.21(s,3H),2.23-2.31(m,1H),2.33-2.40(m,2H),2.41-2.43(m, 4H), 2.73-3.27(m, 1H), 3.46-4.01(m, 5H), 5.18-5.66(m, 3H), 7.00-7.09(m, 1H), 7.36-7.52(m, 2H), 7.72- 7.78 (m, 1H), 7.99-8.08 (m, 1H), 10.48-10.60 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值521.2；實測值522.2；Rt=2.333min。LCMS (ESI): [M] + m/z: calculated 521.2; found 522.2; Rt=2.333 min.

實例591.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(2-甲基-2-氮雜螺[3.3]庚-6-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1283)之合成Example 591. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(2-methyl-2-nitrogen Synthesis of heterospiro[3.3]hept-6-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1283)

Figure 110128222-A0202-12-2033-883
Figure 110128222-A0202-12-2033-883

藉由一般程序方案H步驟6A製備。產率：83mg(26.61%)。Prepared by General Procedure H, Step 6A. Yield: 83 mg (26.61%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 20-20-60%水 -MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 20-20-60% water-MeCN+0.1% NH4OH ; (loading pump 4ml/min MeCN).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.00-1.14(m,6H),1.31-1.41(m,1H),1.65-1.74(m,1H),1.82-1.91(m,1H),2.00-2.25(m,5H),2.27-2.35(m,2H),2.39-2.43(m,2H),2.55-2.60(m,2H),3.04(s,2H),3.20(s,2H),3.38-4.06(m,3H),5.26-5.70(m,3H),7.31-7.41(m,1H),7.42-7.54(m,1H),7.83-7.91(m,1H),7.96-8.10(m,2H),10.44-10.71(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.00-1.14(m,6H), 1.31-1.41(m,1H), 1.65-1.74(m,1H), 1.82-1.91(m,1H) ,2.00-2.25(m,5H),2.27-2.35(m,2H),2.39-2.43(m,2H),2.55-2.60(m,2H),3.04(s,2H),3.20(s,2H) ,3.38-4.06(m,3H),5.26-5.70(m,3H),7.31-7.41(m,1H),7.42-7.54(m,1H),7.83-7.91(m,1H),7.96-8.10( m, 2H), 10.44-10.71 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值532.2；實測值533.2；Rt=2.002min。LCMS (ESI): [M] + m/z: calculated 532.2; found 533.2; Rt=2.002 min.

實例592.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-((二甲胺基)甲基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1325)之合成Example 592. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-((dimethylamino)methyl)benzo[ d ] Synthesis of thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1325)

Figure 110128222-A0202-12-2034-884
Figure 110128222-A0202-12-2034-884

藉由一般程序方案H步驟6A製備。產率：54.9mg(17.20%)。Prepared by General Procedure H, Step 6A. Yield: 54.9 mg (17.20%).

HPLC條件：管柱：SunFire C18 100*19mm，5微米；2-10min 10-50% MeCN+FA；(裝載泵4ml/min MeCN)。HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-10 min 10-50% MeCN+FA; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.14(m,6H),1.31-1.41(m,1H),1.65-1.74(m,1H),1.83-1.93(m,1H),2.05-2.22(m,1H),2.25-2.36(m,8H),2.39-2.42(m,1H),2.77-3.27(m,1H),3.47-4.05(m,3H),5.24-5.62(m,1H),5.62-5.72(m,2H),7.32-7.55(m,2H),7.82-7.92(m,1H),7.97-8.12(m,2H),10.49-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.14(m, 6H), 1.31-1.41(m, 1H), 1.65-1.74(m, 1H), 1.83-1.93(m, 1H) ,2.05-2.22(m,1H),2.25-2.36(m,8H),2.39-2.42(m,1H),2.77-3.27(m,1H),3.47-4.05(m,3H),5.24-5.62( m, 1H), 5.62-5.72 (m, 2H), 7.32-7.55 (m, 2H), 7.82-7.92 (m, 1H), 7.97-8.12 (m, 2H), 10.49-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值480.2；實測值481.2；Rt=1.782min。LCMS (ESI): [M] + m/z: calculated 480.2; found 481.2; Rt=1.782 min.

實例593. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基吖呾-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1151)之合成Example 593. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylazidine-3 Synthesis of -yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1151)

Figure 110128222-A0202-12-2035-885
Figure 110128222-A0202-12-2035-885

步驟1：3-(5-氯苯并[d]噻唑-2-基)吖呾-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-(5-chlorobenzo[d]thiazol-2-yl)acridine-1-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟1B製備。產率：1.5g(14.74%)。Prepared by General Procedure H, Step IB. Yield: 1.5 g (14.74%).

CC條件： 藉由矽膠使用己烷/MTBE作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值324.2；實測值325.2；Rt=1.591min。LCMS (ESI): [M] + m/z: calculated 324.2; found 325.2; Rt=1.591 min.

步驟2：2-(吖呾-3-基)-5-氯苯并[d]噻唑之合成Step 2: Synthesis of 2-(acridine-3-yl)-5-chlorobenzo[d]thiazole

將3-(5-氯-1,3-苯并噻唑-2-基)吖呾-1-甲酸第三丁酯(2g，6.16mmol)用於二噁烷中之4.0M氯化氫溶液(10.67g，292.55mmol，13.33mL)處理。將所得混合物在25℃下攪拌12h。過濾沉澱且另外用MTBE處理。然後在真空中乾燥，以得到2-(吖呾-3-基)-5-氯-1,3-苯并噻唑(2g，粗品，HCl)。3-(5-Chloro-1,3-benzothiazol-2-yl)acridine-1-carboxylic acid tert-butyl ester (2 g, 6.16 mmol) was used in a 4.0 M solution of hydrogen chloride in dioxane (10.67 g , 292.55 mmol, 13.33 mL) treatment. The resulting mixture was stirred at 25 °C for 12 h. The precipitate was filtered and treated additionally with MTBE. It was then dried in vacuo to give 2-(acridine-3-yl)-5-chloro-1,3-benzothiazole (2 g, crude, HCl).

LCMS(ESI)：[M]+ m/z：計算值224.2；實測值225.2；Rt=0.570min。LCMS (ESI): [M] + m/z: calculated 224.2; found 225.2; Rt=0.570 min.

步驟3：5-氯-2-(1-甲基吖呾-3-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-chloro-2-(1-methylacridin-3-yl)benzo[d]thiazole

向2-(吖呾-3-基)-5-氯-1,3-苯并噻唑(3g，11.49mmol，HCl)於MeOH(24.06mL)中之經攪拌之溶液中添加用7-8% MeOH穩定之37重量%甲醛水溶液(1.40g，17.23mmol，1.29mL，37%純度)及無水乙酸鈉(2.36g，28.72mmol，1.54mL)。將所得混合物在25℃下攪拌2h。然後分批添加氰基硼氫化鈉(1.44g，22.97mmol)。將所得混合物在25℃下攪拌12h。蒸發甲醇。將殘餘物用水(50ml)稀釋且用DCM(3*25ml)萃取。將經合併之有機層經Na2 SO4 乾燥。在真空中蒸發DCM，以得到5-氯-2-(1-甲基吖呾-3-基)-1,3-苯并噻唑(2.3g，9.63mmol，83.87% 產率)。To a stirred solution of 2-(acridine-3-yl)-5-chloro-1,3-benzothiazole (3 g, 11.49 mmol, HCl) in MeOH (24.06 mL) was added 7-8% MeOH stabilized 37 wt% aqueous formaldehyde solution (1.40 g, 17.23 mmol, 1.29 mL, 37% pure) and anhydrous sodium acetate (2.36 g, 28.72 mmol, 1.54 mL). The resulting mixture was stirred at 25 °C for 2 h. Then sodium cyanoborohydride (1.44 g, 22.97 mmol) was added portionwise. The resulting mixture was stirred at 25 °C for 12 h. Methanol was evaporated. The residue was diluted with water (50ml) and extracted with DCM (3*25ml). The combined organic layers were dried over Na2SO4 . The DCM was evaporated in vacuo to give 5-chloro-2-(1-methylazrazin-3-yl)-1,3-benzothiazole (2.3 g, 9.63 mmol, 83.87% yield).

LCMS(ESI)：[M]+ m/z：計算值238.2；實測值239.2；Rt=1.608min。LCMS (ESI): [M] + m/z: calculated 238.2; found 239.2; Rt=1.608 min.

步驟4：2-(1-甲基吖呾-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 4: 2-(1-Methylacridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)benzo[d]thiazole

將5-氯-2-(1-甲基吖呾-3-基)-1,3-苯并噻唑(2.3g，9.63mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.69g，10.60mmol)及乙酸鉀(1.89g，19.27mmol，1.20mL)混合於二噁烷(40mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加參 (二苯亞甲基丙酮)二鈀(0)(441.11mg，481.70μmol)。將反應混合物在氬氣、90℃下攪拌14h，然後冷卻且在減壓下濃縮。藉由管柱層析純化殘餘物，以得到2-(1-甲基吖呾-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(0.6g，1.82mmol，18.86%產率)。5-Chloro-2-(1-methylazidine-3-yl)-1,3-benzothiazole (2.3 g, 9.63 mmol), 4,4,5,5-tetramethyl-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (2.69 g, 10.60 mmol) and potassium acetate (1.89 g, 19.27 mmol, 1.20 mL) were mixed in dioxane (40 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times, followed by the addition of para(dibenzylideneacetone)dipalladium(0) ( 441.11 mg, 481.70 μmol) under argon. The reaction mixture was stirred under argon at 90 °C for 14 h, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-(1-methylazrazin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Bororol-2-yl)-1,3-benzothiazole (0.6 g, 1.82 mmol, 18.86% yield).

LCMS(ESI)：[M]+ m/z：計算值330.2；實測值331.2；Rt=0.942min。LCMS (ESI): [M] + m/z: calculated 330.2; found 331.2; Rt=0.942 min.

步驟5：(S)-3-甲基-6-(2-(1-甲基吖呾-3-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-3-Methyl-6-(2-(1-methylazrazin-3-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：0.8g粗品Prepared by General Procedure H, Step 3. Yield: 0.8 g crude

LCMS(ESI)：[M]+ m/z：計算值399.2；實測值400.2；Rt=1.232min。LCMS (ESI): [M] + m/z: calculated 399.2; found 400.2; Rt=1.232 min.

步驟6：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-甲基吖呾-3-基)苯并[d]噻唑之合成Step 6: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-methylacridin-3-yl)benzo[d ]Synthesis of thiazole

藉由一般程序方案H步驟4製備。產率：0.5g(83.4%)。Prepared by General Procedure H, Step 4. Yield: 0.5 g (83.4%).

LCMS(ESI)：[M]+ m/z：計算值299.2；實測值300.2；Rt=0.497min。LCMS (ESI): [M] + m/z: calculated 299.2; found 300.2; Rt=0.497 min.

步驟7：2-(1-甲基吖呾-3-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 7: Synthesis of 2-(1-Methylacridin-3-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.35g粗品。Prepared by General Procedure H, Step 5. Yield: 0.35 g crude.

LCMS(ESI)：[M]+ m/z：計算值301.2；實測值302.2；Rt=0.556min。LCMS (ESI): [M] + m/z: calculated 301.2; found 302.2; Rt=0.556 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基吖呾-3-基)苯并d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1151 )之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylazidine-3 Synthesis of -yl)benzo-d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide ( compound 1151 )

藉由一般程序方案H步驟6A製備。產率：29mg(12.68%)。Prepared by General Procedure H, Step 6A. Yield: 29 mg (12.68%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 10-10-50%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 10-10-50% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN )

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.15(m,6H),1.30-1.41(m,1H),1.64-1.75(m,1H),1.81-1.91(m,1H),2.05-2.21(m,1H),2.22-2.32(m,4H),2.32-2.36(m,1H),2.39-2.42(m,1H),2.76-3.27(m,1H),3.32-3.36(m,2H),3.46-4.09(m,4H),5.24-5.72(m,3H),7.33-7.55(m,2H),7.84-7.92(m,1H),7.96-8.11(m,2H),10.50-10.65(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.15(m,6H), 1.30-1.41(m,1H), 1.64-1.75(m,1H), 1.81-1.91(m,1H) ,2.05-2.21(m,1H),2.22-2.32(m,4H),2.32-2.36(m,1H),2.39-2.42(m,1H),2.76-3.27(m,1H),3.32-3.36( m,2H),3.46-4.09(m,4H),5.24-5.72(m,3H),7.33-7.55(m,2H),7.84-7.92(m,1H),7.96-8.11(m,2H), 10.50-10.65 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值492.2；實測值493.2；Rt=2.240min。LCMS (ESI): [M] + m/z: calculated 492.2; found 493.2; Rt=2.240 min.

實例594. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(四氫-2H-哌喃-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1231)之合成Example 594. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(tetrahydro-2H-pyran- Synthesis of 4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1231)

Figure 110128222-A0202-12-2037-886
Figure 110128222-A0202-12-2037-886

步驟1：5-氯-2-(四氫-2H-哌喃-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2037-887
Figure 110128222-A0202-12-2037-887

藉由一般程序方案H步驟1A製備。產率：1.3g(81.78%)。Prepared by General Procedure H, Step 1A. Yield: 1.3 g (81.78%).

LCMS(ESI)：[M]+ m/z：計算值253.2；實測值254.2；Rt=1.258min。LCMS (ESI): [M] + m/z: calculated 253.2; found 254.2; Rt=1.258 min.

步驟2：2-(四氫-21H-哌喃-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(Tetrahydro-21H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 Synthesis of -yl)benzo[d]thiazole

Figure 110128222-A0202-12-2038-888
Figure 110128222-A0202-12-2038-888

將5-氯-2-四氫哌喃-4-基-1,3-苯并噻唑(1.3g，5.12mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.30g，5.12mmol)、參 (二苯亞甲基丙酮)二鈀(0)(703.71mg，768.48μmol)及二環己基-[2-(2,4,6-三異丙基苯基)苯基]磷烷(293.08mg，614.78μmol)混合於二噁烷(40mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次。添加乙酸鉀(1.01g，10.25mmol，640.51μL)且將反應混合物在氬氣、100℃下攪拌12h。然後將反應混合物冷卻且透過薄矽膠墊過濾。將濾餅用二噁烷(2*10ml)洗滌且丟棄。所獲得之粗品2-四氫哌喃-4-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(1.72g，4.98mmol，97.24%產率)不經純化即用於下一步驟中。5-Chloro-2-tetrahydropyran-4-yl-1,3-benzothiazole (1.3 g, 5.12 mmol), 4,4,5,5-tetramethyl-2-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.30 g, 5.12 mmol), See (dibenzylideneacetone)dipalladium(0) (703.71mg, 768.48μmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (293.08 mg, 614.78 μmol) in dioxane (40 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times. Potassium acetate (1.01 g, 10.25 mmol, 640.51 μL) was added and the reaction mixture was stirred under argon at 100 °C for 12 h. The reaction mixture was then cooled and filtered through a thin pad of silica gel. The filter cake was washed with dioxane (2*10ml) and discarded. The obtained crude 2-tetrahydropyran-4-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)- 1,3-benzothiazole (1.72 g, 4.98 mmol, 97.24% yield) was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=1.607min。LCMS (ESI): [M] + m/z: calculated 345.2; found 346.2; Rt=1.607 min.

步驟3：(S)-3-甲基-6-(2-(四氫-2H-哌喃-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine- Synthesis of 1(2H)-tert-butyl formate

Figure 110128222-A0202-12-2039-889
Figure 110128222-A0202-12-2039-889

藉由一般程序方案H步驟3製備。產率：1.14g粗品。Prepared by General Procedure H, Step 3. Yield: 1.14 g crude.

LCMS(ESI)：[M]+ m/z：計算值414.2；實測值415.2；Rt=1.540min。LCMS (ESI): [M] + m/z: calculated 414.2; found 415.2; Rt=1.540 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(四氫-2H-哌喃-4-基)苯并[d]噻唑之合成Step 4: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)benzo[ d] Synthesis of thiazole

Figure 110128222-A0202-12-2039-890
Figure 110128222-A0202-12-2039-890

將(3S )-3-甲基-6-(2-四氫哌喃-4-基-1,3-苯并噻唑-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.14g，2.75mmol)溶解於二噁烷/HCl(10mL)中且將反應混合物在25℃下攪拌12h。完成之後，在減壓下蒸發溶劑，將殘餘物溶解於10mL水中，藉由DCM(3*20mL)洗滌水溶液。將NaHCO3 添加到鹼性反應物中且藉由DCM(3*30mL)萃取此溶液。將此有機相經Na2 SO4 乾燥且在減壓下蒸發，以得到粗品5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]-2-四氫哌喃-4-基-1,3-苯并噻唑(0.07g，222.62μmol，8.11%產率)，其用於下一步驟中。( 3S )-3-methyl-6-(2-tetrahydropyran-4-yl-1,3-benzothiazol-5-yl)-3,4-dihydro- 2H -pyridine-1- 3-Butyl formate (1.14 g, 2.75 mmol) was dissolved in dioxane/HCl (10 mL) and the reaction mixture was stirred at 25 °C for 12 h. After completion, the solvent was evaporated under reduced pressure, the residue was dissolved in 10 mL of water, and the aqueous solution was washed with DCM (3*20 mL). NaHCO3 was added to the basic reaction and this solution was extracted with DCM (3*30 mL). This organic phase was dried over Na2SO4 and evaporated under reduced pressure to give crude 5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-2 - Tetrahydropyran-4-yl-1,3-benzothiazole (0.07 g, 222.62 μmol, 8.11% yield), which was used in the next step.

LCMS(ESI)：[M]+ m/z：計算值314.2；實測值315.2；Rt=0.969min。LCMS (ESI): [M] + m/z: calculated 314.2; found 315.2; Rt=0.969 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(四氯-2H-哌喃-4-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(tetrachloro-2H-pyran-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2040-891
Figure 110128222-A0202-12-2040-891

藉由一般程序方案H步驟5製備。產率：50mg(67.81%)。Prepared by General Procedure H, Step 5. Yield: 50 mg (67.81%).

LCMS(ESI)：[M]+ m/z：計算值316.2；實測值317.2；Rt=0.895min。LCMS (ESI): [M] + m/z: calculated 316.2; found 317.2; Rt=0.895 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(四氫-2H-哌喃-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1231)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(tetrahydro-2H-pyran- Synthesis of 4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1231)

藉由一般程序方案H步驟6B製備。產率：20.95mg(7.26%)。Prepared by General Procedure H, Step 6B. Yield: 20.95 mg (7.26%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 50-50-65%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 50-50-65% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.05(m,3H),1.06-1.15(m,3H),1.29-1.41(m,1H),1.66-1.75(m,1H),1.79-1.91(m,3H),1.96-2.12(m,3H),2.17-2.36(m,2H),2.39-2.42(m,1H),2.76-3.22(m,1H),3.36-3.42(m,1H),3.46-4.06(m,5H),5.26-5.71(m,3H),7.34-7.53(m,2H),7.86-7.93(m,1H),7.97-8.09(m,2H),10.55(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.05(m,3H), 1.06-1.15(m,3H), 1.29-1.41(m,1H), 1.66-1.75(m,1H) ,1.79-1.91(m,3H),1.96-2.12(m,3H),2.17-2.36(m,2H),2.39-2.42(m,1H),2.76-3.22(m,1H),3.36-3.42( m,1H),3.46-4.06(m,5H),5.26-5.71(m,3H),7.34-7.53(m,2H),7.86-7.93(m,1H),7.97-8.09(m,2H), 10.55(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值507.2；實測值508.2；Rt=2.996min。LCMS (ESI): [M] + m/z: calculated 507.2; found 508.2; Rt=2.996 min.

實例595.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1,2,2-三甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1125)之合成Example 595. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1,2,2-trimethyl) Synthesis of ylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1125)

步驟1：5-氯-2-(2,2-二甲基哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(2,2-dimethylpiperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2041-892
Figure 110128222-A0202-12-2041-892

藉由一般程序方案H步驟1A製備。產率：6.8g(77.52%)。Prepared by General Procedure H, Step 1A. Yield: 6.8 g (77.52%).

CC條件： 藉由矽膠使用MTBE/MeOH作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using MTBE/MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=0.859min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=0.859 min.

步驟2：5-氯-2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-chloro-2-(1,2,2-trimethylpiperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2041-893
Figure 110128222-A0202-12-2041-893

將用7-8% MeOH穩定之37重量%甲醛水溶液(577.47mg，19.23mmol，533.21μL)及乙酸(1.15g，19.23mmol，1.10mL)添加到5-氯-2-(2,2-二甲基-4-哌啶基)-1,3-苯并噻唑(2.7g，9.61mmol)於MeOH(60mL)中之溶液中。將所得混合物在20℃下攪拌1h，之後向其中添加氰基硼氫化鈉(1.21g，19.23mmol)。此後，繼續攪拌16h。然後，在減壓下移除溶劑且將殘餘物分配於10%K2 CO3 水溶液(20ml)與DCM(40ml)之間。將有機層分離，經固體K2CO3乾燥且在減壓下濃縮，留下5-氯-2-(1,2,2-三甲基-4-哌啶基)-1,3-苯并噻唑(2.7g，9.16mmol，95.24%產率)。Aqueous 37 wt% formaldehyde stabilized with 7-8% MeOH (577.47 mg, 19.23 mmol, 533.21 μL) and acetic acid (1.15 g, 19.23 mmol, 1.10 mL) were added to 5-chloro-2-(2,2-di). Methyl-4-piperidinyl)-1,3-benzothiazole (2.7 g, 9.61 mmol) in MeOH (60 mL). The resulting mixture was stirred at 20°C for 1 h before adding sodium cyanoborohydride (1.21 g, 19.23 mmol). Thereafter, stirring was continued for 16 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 10 % aqueous K2CO3 (20ml) and DCM (40ml). The organic layer was separated, dried over solid K2CO3 and concentrated under reduced pressure to leave 5-chloro-2-(1,2,2-trimethyl-4-piperidinyl)-1,3-benzothiazole ( 2.7 g, 9.16 mmol, 95.24% yield).

LCMS(ESI)：[M]+ m/z：計算值294.2；實測值295.2；Rt=1.019min。LCMS (ESI): [M] + m/z: calculated 294.2; found 295.2; Rt=1.019 min.

步驟3：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 3: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-2-(1,2,2-trimethyl Synthesis of piperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2042-894
Figure 110128222-A0202-12-2042-894

將5-氯-2-(1,2,2-三甲基-4-哌啶基)-1,3-苯并噻唑(2.7g，9.16mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.67g，10.53mmol)及乙酸鉀(1.80g，18.31mmol，1.14mL)一起混合於二噁烷(50mL)中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下，添加XPhos(873.10mg，1.83mmol)及參 (二苯亞甲基丙酮)二鈀(0)(419.28mg，457.87μmol)。將所得混合物在100℃下攪拌16h。然後，將其在減壓下濃縮且藉由梯度管柱層析(SiO2 ，MTBE/MeOH)純化殘餘物，得到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-(1,2,2-三甲基-4-哌啶基)-1,3-苯并噻唑(1.96g，5.07mmol，55.40%產率)。5-Chloro-2-(1,2,2-trimethyl-4-piperidinyl)-1,3-benzothiazole (2.7 g, 9.16 mmol), 4,4,5,5-tetramethyl yl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane Alkane (2.67 g, 10.53 mmol) and potassium acetate (1.80 g, 18.31 mmol, 1.14 mL) were mixed together in dioxane (50 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, under argon flow, XPhos (873.10 mg, 1.83 mmol) and gins (dibenzylideneacetone)dipalladium(0) (419.28 mg, 457.87 μmol) were added. The resulting mixture was stirred at 100 °C for 16 h. It was then concentrated under reduced pressure and the residue was purified by gradient column chromatography ( SiO2 , MTBE/MeOH) to give 5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborol-2-yl)-2-(1,2,2-trimethyl-4-piperidinyl)-1,3-benzothiazole (1.96 g, 5.07 mmol, 55.40 %Yield).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.101min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.101 min.

步驟4：(3S)-3-甲基-6-(2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (3S)-3-Methyl-6-(2-(1,2,2-trimethylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4- Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

Figure 110128222-A0202-12-2042-895
Figure 110128222-A0202-12-2042-895

藉由一般程序方案H步驟3製備。產率：2.5g粗品。Prepared by General Procedure H, Step 3. Yield: 2.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值455.2；實測值456.2；Rt=1.357min。LCMS (ESI): [M] + m/z: calculated 455.2; found 456.2; Rt=1.357 min.

步驟5：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 5: 5-((S)-5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1,2,2-trimethylpiperidin-4-yl ) Synthesis of Benzo[d]thiazole

Figure 110128222-A0202-12-2043-896
Figure 110128222-A0202-12-2043-896

藉由一般程序方案H步驟4製備。產率：1.6g粗品。Prepared by General Procedure H, Step 4. Yield: 1.6 g crude.

LCMS(ESI)：[M]+ m/z：計算值355.2；實測值356.2；Rt=0.716min。LCMS (ESI): [M] + m/z: calculated 355.2; found 356.2; Rt=0.716 min.

步驟6：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 6: Compound of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1,2,2-trimethylpiperidin-4-yl)benzo[d]thiazole synthesis

Figure 110128222-A0202-12-2043-897
Figure 110128222-A0202-12-2043-897

藉由一般程序方案H步驟5製備。產率：1.2g(74.58%)。Prepared by General Procedure H, Step 5. Yield: 1.2 g (74.58%).

LCMS(ESI)：[M]+ m/z：計算值357.2；實測值358.2；Rt=0.715min。LCMS (ESI): [M] + m/z: calculated 357.2; found 358.2; Rt=0.715min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1125)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1,2,2-trimethyl) Synthesis of ylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1125)

Figure 110128222-A0202-12-2044-898
Figure 110128222-A0202-12-2044-898

藉由一般程序方案H步驟6A製備。產率：94mg(24.65%)。Prepared by General Procedure H, Step 6A. Yield: 94 mg (24.65%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 50-50-90%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 50-50-90% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.88-1.00(m,4H),1.00-1.08(m,4H),1.09-1.14(m,5H),1.29-1.42(m,1H),1.62(t,1H),1.67-1.76(m,2H),1.82-1.90(m,2H),1.99-2.13(m,2H),2.15(s,3H),2.17-2.36(m,2H),2.39-2.42(m,1H),2.54-2.63(m,2H),2.74-3.27(m,1H),3.46-4.07(m,1H),5.23-5.71(m,3H),7.31-7.42(m,1H),7.42-7.52(m,1H),7.83-7.89(m,1H),7.95-8.11(m,2H),10.43-10.66(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.88-1.00(m, 4H), 1.00-1.08(m, 4H), 1.09-1.14(m, 5H), 1.29-1.42(m, 1H) ,1.62(t,1H),1.67-1.76(m,2H),1.82-1.90(m,2H),1.99-2.13(m,2H),2.15(s,3H),2.17-2.36(m,2H) ,2.39-2.42(m,1H),2.54-2.63(m,2H),2.74-3.27(m,1H),3.46-4.07(m,1H),5.23-5.71(m,3H),7.31-7.42( m, 1H), 7.42-7.52 (m, 1H), 7.83-7.89 (m, 1H), 7.95-8.11 (m, 2H), 10.43-10.66 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=2.034min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=2.034 min.

實例596.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1-乙基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1252)之合成Example 596. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1-ethylpiperidin-4-yl)benzo Synthesis of [ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1252)

Figure 110128222-A0202-12-2044-899
Figure 110128222-A0202-12-2044-899

藉由一般程序方案H步驟6A製備。產率：93mg(49.79%)。Prepared by General Procedure H, Step 6A. Yield: 93 mg (49.79%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 45-90%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 45-90% water-MeOH + 0.1% NH4OH ; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.13(m,9H),1.31-1.41(m,1H),1.66-1.80(m,3H),1.82-1.92(m,1H),2.00-2.10(m,5H),2.31-2.36(m,3H),2.41(q,1H),2.74-3.28(m,5H),3.43-4.09(m,1H),5.21-5.72(m,3H),7.31-7.43(m,1H),7.43-7.56(m,1H),7.82-7.95(m,1H),7.98-8.10(m,2H),10.50-10.64(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.13(m, 9H), 1.31-1.41(m, 1H), 1.66-1.80(m, 3H), 1.82-1.92(m, 1H) ,2.00-2.10(m,5H),2.31-2.36(m,3H),2.41(q,1H),2.74-3.28(m,5H),3.43-4.09(m,1H),5.21-5.72(m, 3H), 7.31-7.43 (m, 1H), 7.43-7.56 (m, 1H), 7.82-7.95 (m, 1H), 7.98-8.10 (m, 2H), 10.50-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值534.2；實測值535.2；Rt=1.967min。LCMS (ESI): [M] + m/z: calculated 534.2; found 535.2; Rt=1.967 min.

實例597.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1,2,2,6,6-五甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1340)之合成Example 597. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1,2,2,6, Synthesis of 6-pentamethylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1340)

Figure 110128222-A0202-12-2045-900
Figure 110128222-A0202-12-2045-900

藉由一般程序方案H步驟6A製備。產率：83mg(28.75%)。Prepared by General Procedure H, Step 6A. Yield: 83 mg (28.75%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 50-50-90%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 50-50-90% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.10(m,11H),1.11-1.15(m,8H),1.28-1.40(m,1H),1.60-1.75(m,3H),1.81-1.92(m,1H),1.92-1.97(m,2H),2.05-2.19(m,1H),2.21(s,3H),2.28-2.35(m,1H),2.39-2.43(m,1H),2.76-3.28(m,1H),3.46-4.07(m,2H),5.23-5.73(m,3H),7.32-7.43(m,1H),7.43-7.53(m,1H),7.85-7.93(m,1H),7.98-8.09(m,2H),10.51-10.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.10(m,11H), 1.11-1.15(m,8H), 1.28-1.40(m,1H), 1.60-1.75(m,3H) ,1.81-1.92(m,1H),1.92-1.97(m,2H),2.05-2.19(m,1H),2.21(s,3H),2.28-2.35(m,1H),2.39-2.43(m, 1H), 2.76-3.28(m, 1H), 3.46-4.07(m, 2H), 5.23-5.73(m, 3H), 7.32-7.43(m, 1H), 7.43-7.53(m, 1H), 7.85- 7.93 (m, 1H), 7.98-8.09 (m, 2H), 10.51-10.63 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值576.2；實測值577.2；Rt=2.156min。LCMS (ESI): [M] + m/z: calculated 576.2; found 577.2; Rt=2.156 min.

實例598.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(4-甲基嗎啉-2-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1275)之合成Example 598. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(4-methylmorpholine-2 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1275)

Figure 110128222-A0202-12-2046-901
Figure 110128222-A0202-12-2046-901

步驟1：2-(5-氯苯并[d]噻唑-2-基)-4-甲基嗎啉之合成Step 1: Synthesis of 2-(5-Chlorobenzo[d]thiazol-2-yl)-4-methylmorpholine

藉由一般程序方案H步驟1A製備。產率：11.5g粗品。Prepared by General Procedure H, Step 1A. Yield: 11.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值268.2；實測值269.2；Rt=0.966min。LCMS (ESI): [M] + m/z: calculated 268.2; found 269.2; Rt=0.966 min.

步驟2：4-甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)嗎啉之合成Step 2: 4-Methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d] Synthesis of Thiazol-2-yl)morpholine

將2-(5-氯-1,3-苯并噻唑-2-基)-4-甲基嗎啉(11.5g，42.79mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(11.95g，47.07mmol)及乙酸鉀(8.40g，85.58mmol，5.35mL)混合於二噁烷(150mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加參 (二苯亞甲基丙酮)二鈀(0)(1.57g，1.71mmol)及XPhos(3.26g，6.85mmol)。將反應混合物在氬氣、95℃下攪拌18h，然後冷卻，過濾且在減壓下濃縮。藉由梯度層析(MTBE-MeOH)純化殘餘物，以得到4-甲基-2-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]嗎啉(11g，30.53mmol，71.36%產率)。2-(5-Chloro-1,3-benzothiazol-2-yl)-4-methylmorpholine (11.5 g, 42.79 mmol), 4,4,5,5-tetramethyl-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (11.95g, 47.07 mmol) and potassium acetate (8.40 g, 85.58 mmol, 5.35 mL) were mixed in dioxane (150 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times, followed by the addition of bis(dibenzylideneacetone)dipalladium(0) (1.57 g, 1.71 mmol) and XPhos (3.26 g under argon) , 6.85 mmol). The reaction mixture was stirred under argon at 95 °C for 18 h, then cooled, filtered and concentrated under reduced pressure. The residue was purified by gradient chromatography (MTBE-MeOH) to give 4-methyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Cyclopentan-2-yl)-1,3-benzothiazol-2-yl]morpholine (11 g, 30.53 mmol, 71.36% yield).

LCMS(ESI)：[M]+ m/z：計算值360.2；實測值361.2；Rt=1.012min。LCMS (ESI): [M] + m/z: calculated 360.2; found 361.2; Rt=1.012 min.

步驟3：(3S)-3-甲基-6-(2-(4-甲基嗎啉-2-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (3S)-3-Methyl-6-(2-(4-methylmorpholin-2-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：3g粗品。Prepared by General Procedure H, Step 3. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.232min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.232 min.

步驟4：4-甲基-2-(5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)嗎啉之合成Step 4: 4-Methyl-2-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl) Synthesis of Morpholine

藉由一般程序方案H步驟4製備。產率：1.3g粗品。Prepared by General Procedure H, Step 4. Yield: 1.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.673min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.673 min.

步驟5：4-甲基-2-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)嗎啉之合成Step 5: Synthesis of 4-methyl-2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)morpholine

藉由一般程序方案H步驟5製備。產率：0.9g粗品。Prepared by General Procedure H, Step 5. Yield: 0.9 g crude.

LCMS(ESI)：[M]+ m/z：計算值331.2；實測值332.2；Rt=0.695min。LCMS (ESI): [M] + m/z: calculated 331.2; found 332.2; Rt=0.695 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(4-甲基嗎啉-2-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1275)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(4-methylmorpholine-2 Synthesis of -yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1275)

藉由一般程序方案H步驟6A製備。產率：35mg(8.88%)。Prepared by General Procedure H, Step 6A. Yield: 35 mg (8.88%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-1-6min 10-10-60%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-1-6min 10-10-60% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH) .

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.06-1.16(m,3H),1.66-1.76(m,1H),1.81-1.89(m,1H),2.01-2.22(m,4H),2.24(s,3H),2.27-2.35(m,2H),2.38-2.42(m,2H),2.67-2.78(m,1H),3.15-3.27(m,1H),3.43-3.52(m,0.6H),3.75-3.82(m,1H),3.94-4.10(m,1.4H),4.86-4.96(m,1H),5.27-5.62(m,1H),5.64-5.73(m,2H),7.36-7.44(m,1H),7.45-7.54(m,1H),7.87-7.95(m,1H),7.96-8.08(m,1H),8.08-8.16(m,1H),10.46-10.62(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.06-1.16(m,3H), 1.66-1.76(m,1H), 1.81-1.89(m,1H) ,2.01-2.22(m,4H),2.24(s,3H),2.27-2.35(m,2H),2.38-2.42(m,2H),2.67-2.78(m,1H),3.15-3.27(m, 1H), 3.43-3.52(m, 0.6H), 3.75-3.82(m, 1H), 3.94-4.10(m, 1.4H), 4.86-4.96(m, 1H), 5.27-5.62(m, 1H), 5.64-5.73(m, 2H), 7.36-7.44(m, 1H), 7.45-7.54(m, 1H), 7.87-7.95(m, 1H), 7.96-8.08(m, 1H), 8.08-8.16(m , 1H), 10.46-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=1.536min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=1.536 min.

實例599.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(4-甲基嗎啉-2-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1134及化合物1203)之合成Example 599. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(4-methylmorpholine-2 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1134 and Compound 1203)

Figure 110128222-A0202-12-2048-902
Figure 110128222-A0202-12-2048-902

對外消旋N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[2-(4-甲基嗎啉-2-基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(74mg，141.58μmol)進行掌性分離(管柱：Chiralpak IC 50*20，5-III流動相：IPA-MeOH，50-50流速：10mL/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[2-[(2S )-4-甲基嗎啉-2-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(16mg，30.61μmol，43.24%產率)(RT=30.24min)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[2-[(2R )-4-甲基嗎啉-2-基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(19mg，36.35μmol，51.35%產率)(RT=41.35min)。Racemic N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[2-(4-methylmorpholine-2 Chiral separation (column: Chiralpak IC 50* 20,5-III mobile phase: IPA-MeOH, 50-50 flow rate: 10 mL/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-pendoxyl-2 -[( 2R,5S )-5-methyl-2-[2-[( 2S )-4-methylmorpholin-2-yl]-1,3-benzothiazol-5-yl]-1- Piperidinyl]acetamide (16 mg, 30.61 μmol, 43.24% yield) (RT=30.24 min) and N-(6-amino-5-ethyl-3-pyridyl)-2-pendoxo- 2-[( 2R,5S )-5-methyl-2-[2-[( 2R )-4-methylmorpholin-2-yl]-1,3-benzothiazol-5-yl]-1 -Piperidinyl]acetamide (19 mg, 36.35 μmol, 51.35% yield) (RT=41.35 min).

化合物1134於分析條件下(管柱：IC，以IPA-MeOH，50-50，0.6mL/min為流動相)之保留時間為22.27min且化合物1202之保留時間為29.82min。The retention time of compound 1134 under analytical conditions (column: IC, with IPA-MeOH, 50-50, 0.6 mL/min as mobile phase) was 22.27 min and that of compound 1202 was 29.82 min.

化合物1134：保留時間：22.27minCompound 1134: retention time: 22.27min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.14(m,6H),1.30-1.42(m,1H),1.64-1.74(m,1H),1.78-2.05(m,2H),2.06-2.23(m,2H),2.23-2.39(m,7H),2.39-2.43(m,2H),2.73-2.88(m,1H),3.34-3.52(m,1H),3.75-3.88(m,1H),4.02-4.12(m,1H),4.93-5.29(m,1H),5.69-5.82(m,2H),7.38-7.46(m,1H),7.46-7.55(m,1H),7.86-7.95(m,1H),7.99-8.09(m,1H),8.09-8.15(m,1H),10.47-10.70(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.01-1.14 (m, 6H), 1.30-1.42 (m, 1H), 1.64-1.74 (m, 1H), 1.78-2.05 (m, 2H) ,2.06-2.23(m,2H),2.23-2.39(m,7H),2.39-2.43(m,2H),2.73-2.88(m,1H),3.34-3.52(m,1H),3.75-3.88( m,1H),4.02-4.12(m,1H),4.93-5.29(m,1H),5.69-5.82(m,2H),7.38-7.46(m,1H),7.46-7.55(m,1H), 7.86-7.95(m,1H), 7.99-8.09(m,1H), 8.09-8.15(m,1H), 10.47-10.70(m,1H).

LCMS(ESI)：[M+1]+ m/z：計算值522.2；實測值523.2；Rt=1.949min。LCMS (ESI): [M+1] + m/z: calculated 522.2; found 523.2; Rt=1.949 min.

化合物1202：保留時間：29.82minCompound 1202: retention time: 29.82min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.14(m,6H),1.30-1.42(m,1H),1.64-1.74(m,1H),1.78-2.05(m,2H),2.06-2.23(m,2H),2.23-2.39(m,7H),2.39-2.43 (m,2H),2.73-2.88(m,1H),3.34-3.52(m,1H),3.75-3.88(m,1H),4.02-4.12(m,1H),4.93-5.29(m,1H),5.69-5.82(m,2H),7.38-7.46(m,1H),7.46-7.55(m,1H),7.86-7.95(m,1H),7.99-8.09(m,1H),8.09-8.15(m,1H),10.47-10.70(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.01-1.14 (m, 6H), 1.30-1.42 (m, 1H), 1.64-1.74 (m, 1H), 1.78-2.05 (m, 2H) ,2.06-2.23(m,2H),2.23-2.39(m,7H),2.39-2.43(m,2H),2.73-2.88(m,1H),3.34-3.52(m,1H),3.75-3.88( m,1H),4.02-4.12(m,1H),4.93-5.29(m,1H),5.69-5.82(m,2H),7.38-7.46(m,1H),7.46-7.55(m,1H), 7.86-7.95(m,1H), 7.99-8.09(m,1H), 8.09-8.15(m,1H), 10.47-10.70(m,1H).

LCMS(ESI)：[M+1]+ m/z：計算值522.2；實測值523.2；Rt=1.951min。LCMS (ESI): [M+1] + m/z: calculated 522.2; found 523.2; Rt=1.951 min.

實例600.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(3-(二甲胺基)丙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1262)之合成Example 600. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(3-(dimethylamino)propyl)benzo Synthesis of [ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1262)

Figure 110128222-A0202-12-2049-903
Figure 110128222-A0202-12-2049-903

步驟1：3-(5-氯苯并[d]噻唑-2-基)-N,N-二甲基丙-1-胺之合成Step 1: Synthesis of 3-(5-Chlorobenzo[d]thiazol-2-yl)-N,N-dimethylpropan-1-amine

使2-胺基-4-氯苯硫酚(1g，6.26mmol)及4-(二甲胺基)丁酸(1.3g，7.76mmol，HCl)於PPA(5mL)之經攪拌之溶液在120℃下攪拌16h。完成之後，將反應混合物用水(100mL)萃取且藉由NaOH中和至pH=8。將水相用EtOAc(2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物3-(5-氯-1,3-苯并噻唑-2-基)-N,N -二甲基丙-1-胺(1.2g，4.71mmol，75.19%產率)。A stirred solution of 2-amino-4-chlorothiophenol (1 g, 6.26 mmol) and 4-(dimethylamino)butyric acid (1.3 g, 7.76 mmol, HCl) in PPA (5 mL) was added at 120 Stir at ℃ for 16h. After completion, the reaction mixture was extracted with water (100 mL) and neutralized to pH=8 by NaOH. The aqueous phase was extracted with EtOAc (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The desired product, 3-(5-chloro-1,3-benzothiazol-2-yl) -N,N -dimethylpropan-1-amine (1.2 g, 4.71 mmol, 75.19% yield) was isolated.

LCMS(ESI)：[M]+ m/z：計算值254.2；實測值255.2；Rt=0.909min。LCMS (ESI): [M] + m/z: calculated 254.2; found 255.2; Rt=0.909 min.

步驟2：N,N-二甲基-3-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)丙-1-胺之合成Step 2: N,N-Dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo Synthesis of [d]thiazol-2-yl)propan-1-amine

向3-(5-氯-1,3-苯并噻唑-2-基)-N,N -二甲基丙-1-胺(0.6g，2.35mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜 硼雜環戊烷(0.6g，2.36mmol)於二噁烷(10mL)中之經攪拌之溶液中添加Pd2 dba3 (0.4g，436.82μmol)及XPhos(0.4g，839.10μmol)。將所得懸浮液在50℃下用氬氣除氣0.5h。添加乙酸鉀(0.5g，5.09mmol，318.47μL)。將反應混合物在100℃下攪拌16h。完成之後，將反應混合物在減壓下濃縮，用水(20mL)萃取，將水相用CHCl3 (2*20mL)萃取。將有機相用10% HCl(2*40ml)萃取。將水相藉由NaHCO3 中和至pH=8，用CHCl3 (2*20mL)萃取。將有機相經Na2 SO4 乾燥且在真空中蒸發。分離所要產物N,N -二甲基-3-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]丙-1-胺(0.8g，2.31mmol，98.10%產率)。To 3-(5-chloro-1,3-benzothiazol-2-yl) -N,N -dimethylpropan-1-amine (0.6 g, 2.35 mmol) and 4,4,5,5-tetrakis Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane To a stirred solution of pentane (0.6 g, 2.36 mmol) in dioxane (10 mL) was added Pd2dba3 ( 0.4 g, 436.82 [mu]mol) and XPhos (0.4 g, 839.10 [mu]mol). The resulting suspension was degassed with argon at 50 °C for 0.5 h. Potassium acetate (0.5 g, 5.09 mmol, 318.47 μL) was added. The reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure, extracted with water (20 mL), and the aqueous phase was extracted with CHCl3 (2*20 mL). The organic phase was extracted with 10% HCl (2*40ml). The aqueous phase was neutralized to pH=8 by NaHCO3 , extracted with CHCl3 (2*20 mL). The organic phase was dried over Na2SO4 and evaporated in vacuo. Isolation of the desired product N,N -dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1 , 3-benzothiazol-2-yl]propan-1-amine (0.8 g, 2.31 mmol, 98.10% yield).

LCMS(ESI)：[M]+ m/z：計算值346.2；實測值347.2；Rt=0.940min。LCMS (ESI): [M] + m/z: calculated 346.2; found 347.2; Rt=0.940 min.

步驟3：(S)-6-(2-(3-(二甲胺基)丙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(3-(Dimethylamino)propyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：0.4g粗品。Prepared by General Procedure H, Step 3. Yield: 0.4 g crude.

CC條件： 藉由矽膠使用EtOAc/MeOH作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using EtOAc/MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.033min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.033 min.

步驟4：(S)-N,N-二甲基-3-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)丙-1-胺之合成Step 4: (S)-N,N-Dimethyl-3-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 Synthesis of -yl)propan-1-amine

使(3S )-6-[2-[3-(二甲胺基)丙基]-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(400.00mg，962.49μmol)於MeOH(10mL)及二噁烷/HCl(10mL)中之經攪拌之溶液在25℃下攪拌16h。完成之後，將反應混合物蒸發，將粗產物用水(20mL)萃取且藉由NaHCO3 中和至pH=8。將水相用CHCl3 (2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物N,N -二甲基-3-[5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑-2-基]丙-1-胺(0.3g，950.95μmol，98.80%產率)。Make ( 3S )-6-[2-[3-(dimethylamino)propyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro- 2H- A stirred solution of tert-butyl pyridine-1-carboxylate (400.00 mg, 962.49 μmol) in MeOH (10 mL) and dioxane/HCl (10 mL) was stirred at 25 °C for 16 h. After completion, the reaction mixture was evaporated, the crude product was extracted with water (20 mL) and neutralized to pH=8 by NaHCO3 . The aqueous phase was extracted with CHCl3 (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Isolation of the desired product N,N -dimethyl-3-[5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole -2-yl]propan-1-amine (0.3 g, 950.95 μmol, 98.80% yield).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.671min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.671 min.

步驟5：N,N-二甲基-3-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)丙-1-胺之合成Step 5: N,N-Dimethyl-3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-1-amine synthesis

藉由一般程序方案H步驟5製備。產率：0.3g粗品。Prepared by General Procedure H, Step 5. Yield: 0.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.754min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.754 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(3-(二甲胺基)丙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1262)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(3-(dimethylamino)propyl)benzo Synthesis of [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1262)

藉由一般程序方案H步驟6B製備。產率：27mg(5.62%)。Prepared by General Procedure H, Step 6B. Yield: 27 mg (5.62%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 30-30-80%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 30-30-80% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.17(m,6H),1.28-1.42(m,1H),1.66-1.76(m,1H),1.83-1.95(m,3H),2.06-2.19(m,7H),2.21-2.33(m,3H),2.33-2.45(m,2H),2.77-3.27(m,3H),3.45-4.07(m,1H),5.23-5.72(m,3H),7.33-7.42(m,1H),7.42-7.54(m,1H),7.82-7.93(m,1H),7.96-8.11(m,2H),10.49-10.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.17(m,6H), 1.28-1.42(m,1H), 1.66-1.76(m,1H), 1.83-1.95(m,3H) ,2.06-2.19(m,7H),2.21-2.33(m,3H),2.33-2.45(m,2H),2.77-3.27(m,3H),3.45-4.07(m,1H),5.23-5.72( m, 3H), 7.33-7.42 (m, 1H), 7.42-7.54 (m, 1H), 7.82-7.93 (m, 1H), 7.96-8.11 (m, 2H), 10.49-10.63 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=2.054min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=2.054 min.

實例601.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-3-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1388)之合成Example 601. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidine-3 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1388)

Figure 110128222-A0202-12-2051-904
Figure 110128222-A0202-12-2051-904

藉由一般程序方案H步驟6A製備。產率：32mg(6.75%)。Prepared by General Procedure H, Step 6A. Yield: 32 mg (6.75%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 45-45-80%水 -MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 45-45-80% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.14(m,6H),1.29-1.40(m,1H),1.55-1.65(m,2H),1.67-1.76(m,2H),1.83-1.92(m,1H),2.00-2.19(m,3H),2.22(s,3H),2.23-2.33(m,2H),2.34-2.44(m,2H),2.61-3.07(m,4H),3.44-4.07(m,1H),5.24-5.73(m,3H),7.33-7.54(m,2H),7.84-7.92(m,1H),7.97-8.18(m,2H),10.49-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.01-1.14 (m, 6H), 1.29-1.40 (m, 1H), 1.55-1.65 (m, 2H), 1.67-1.76 (m, 2H) ,1.83-1.92(m,1H),2.00-2.19(m,3H),2.22(s,3H),2.23-2.33(m,2H),2.34-2.44(m,2H),2.61-3.07(m, 4H), 3.44-4.07(m, 1H), 5.24-5.73(m, 3H), 7.33-7.54(m, 2H), 7.84-7.92(m, 1H), 7.97-8.18(m, 2H), 10.49- 10.60 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=2.114min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=2.114 min.

實例602.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-((2R,4r,6S )-1,2,6-三甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1261)之合成Example 602. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(( 2R,4r,6S )- Synthesis of 1,2,6-trimethylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1261)

Figure 110128222-A0202-12-2052-905
Figure 110128222-A0202-12-2052-905

步驟1：5-氯-2-((2R,4r,6S)-2,6-二甲基哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)benzo[d]thiazole

藉由一般程序方案H步驟1A製備。產率：5.5g(91.96%)。Prepared by General Procedure H, Step 1A. Yield: 5.5 g (91.96%).

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=1.025min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=1.025 min.

步驟2：5-氯-2-((2R,4r,6S)-1,2,6-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-chloro-2-((2R,4r,6S)-1,2,6-trimethylpiperidin-4-yl)benzo[d]thiazole

將用7-8% MeOH穩定之37重量%甲醛水溶液(1.18g，39.17mmol，1.09mL)及乙酸(2.35g，39.17mmol，2.24mL)添加到5-氯-2-[(2R,6S )-2,6-二甲基-4-哌啶基]-1,3-苯并噻唑(5.5g，19.59mmol)於MeOH(80mL)中之溶液中。將所得混合物在20℃下攪拌1h，之後向其中添加氰基硼氫化鈉(2.46g，39.17mmol)。 此後，繼續攪拌16h。然後，在減壓下移除溶劑且將殘餘物分配於10%K2 CO3 水溶液(40ml)與DCM(60ml)之間。將有機層分離，經固體K2 CO3 乾燥且在減壓下濃縮，留下5-氯-2-[(2R,6S )-1,2,6-三甲基-4-哌啶基]-1,3-苯并噻唑(5.8g，粗品)。Aqueous 37 wt% formaldehyde stabilized with 7-8% MeOH (1.18 g, 39.17 mmol, 1.09 mL) and acetic acid (2.35 g, 39.17 mmol, 2.24 mL) were added to 5-chloro-2-[( 2R,6S ) -2,6-Dimethyl-4-piperidinyl]-1,3-benzothiazole (5.5 g, 19.59 mmol) in MeOH (80 mL). The resulting mixture was stirred at 20°C for 1 h before adding sodium cyanoborohydride (2.46 g, 39.17 mmol). Thereafter, stirring was continued for 16 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 10 % aqueous K2CO3 (40ml) and DCM (60ml). The organic layer was separated, dried over solid K2CO3 and concentrated under reduced pressure to leave 5 -chloro- 2 -[( 2R,6S )-1,2,6-trimethyl-4-piperidinyl] -1,3-benzothiazole (5.8 g, crude).

LCMS(ESI)：[M]+ m/z：計算值294.2；實測值295.2；Rt=1.020min。LCMS (ESI): [M] + m/z: calculated 294.2; found 295.2; Rt=1.020 min.

步驟3：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-((2R,4r,6S)-1,2,6-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 3: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-2-((2R,4r,6S)-1 Synthesis of ,2,6-trimethylpiperidin-4-yl)benzo[d]thiazole

將5-氯-2-[(2R,6S )-1,2,6-三甲基-4-哌啶基]-1,3-苯并噻唑(5.8g，19.67mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(5.74g，22.62mmol)及乙酸鉀(3.86g，39.34mmol，2.46mL)一起混合於二噁烷(80mL)中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下，添加XPhos(1.88g，3.93mmol)及參 (二苯亞甲基丙酮)二鈀(0)(900.68mg，983.58μmol)。將所得混合物在100℃下攪拌16h。然後，將其在減壓下濃縮且藉由梯度管柱層析(SiO2 ，MTBE/MeOH)純化殘餘物，得到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-[(2R,6S )-1,2,6-三甲基-4-哌啶基]-1,3-苯并噻唑(4.95g，12.81mmol，65.13%產率)。5-Chloro-2-[( 2R,6S )-1,2,6-trimethyl-4-piperidinyl]-1,3-benzothiazole (5.8 g, 19.67 mmol), 4,4, 5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-di Oxaborolane (5.74 g, 22.62 mmol) and potassium acetate (3.86 g, 39.34 mmol, 2.46 mL) were mixed together in dioxane (80 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, under an argon flow, XPhos (1.88 g, 3.93 mmol) and gins (dibenzylideneacetone)dipalladium(0) (900.68 mg, 983.58 μmol) were added. The resulting mixture was stirred at 100 °C for 16 h. It was then concentrated under reduced pressure and the residue was purified by gradient column chromatography ( SiO2 , MTBE/MeOH) to give 5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborol-2-yl)-2-[( 2R,6S )-1,2,6-trimethyl-4-piperidinyl]-1,3-benzothiazole (4.95 g, 12.81 mmol, 65.13% yield).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=1.060min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=1.060 min.

步驟4：(S)-3-甲基-6-(2-((2R,4r,6S)-1,2,6-三甲基哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (S)-3-Methyl-6-(2-((2R,4r,6S)-1,2,6-trimethylpiperidin-4-yl)benzo[d]thiazole-5 -Synthesis of tert-butyl)-3,4-dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：3.7g粗品。Prepared by General Procedure H, Step 3. Yield: 3.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值455.2；實測值456.2；Rt=3.417min。LCMS (ESI): [M] + m/z: calculated 455.2; found 456.2; Rt=3.417 min.

步驟5：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-((2R,4r,6S)-1,2,6-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 5: 5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-((2R,4r,6S)-1,2,6-tris Synthesis of Methylpiperidin-4-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：1.27g粗品。Prepared by General Procedure H, Step 4. Yield: 1.27 g crude.

LCMS(ESI)：[M]+ m/z：計算值355.2；實測值356.2；Rt=0.696min。LCMS (ESI): [M] + m/z: calculated 355.2; found 356.2; Rt=0.696 min.

步驟6：5-((2R,5S)-5-甲基哌啶-2-基)-2-((2R,4r,6S)-1,2,6-三甲基哌啶-4-基)苯并[d]噻唑之合成Step 6: 5-((2R,5S)-5-methylpiperidin-2-yl)-2-((2R,4r,6S)-1,2,6-trimethylpiperidin-4-yl ) Synthesis of Benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.93g(72.82%)。Prepared by General Procedure H, Step 5. Yield: 0.93 g (72.82%).

LCMS(ESI)：[M]+ m/z：計算值357.2；實測值358.2；Rt=0.762min。LCMS (ESI): [M] + m/z: calculated 357.2; found 358.2; Rt=0.762 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-((2R,4r,6S)-1,2,6-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1261)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-((2R,4r,6S)- Synthesis of 1,2,6-Trimethylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1261)

藉由一般程序方案H步驟6A製備。產率：42mg(12.77%)。Prepared by General Procedure H, Step 6A. Yield: 42 mg (12.77%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 50-50-90%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 50-50-90% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

藉由掌性HPLC(管柱：Chiralpak IC-III(250 * 20mm，5mkm)；流動相：IPA-MeOH，50-50；流速：12mL/min)純化N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-((2R,4r,6S )-1,2,6-三甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺，以獲得N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-((2R,4r,6S )-1,2,6-三甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(42mg，78.55μmol，12.77%產率)。Purification of N- (6-amino-5-ethyl) by chiral HPLC (column: Chiralpak IC-III (250*20mm, 5mkm); mobile phase: IPA-MeOH, 50-50; flow rate: 12 mL/min) pyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(( 2R,4r,6S )-1,2,6-trimethylpiperidine-4- yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamide to obtain N- (6-amino-5-ethylpyridin-3-yl) -2-(( 2R,5S )-5-methyl-2-(2-(( 2R,4r,6S )-1,2,6-trimethylpiperidin-4-yl)benzo[ d ] Thiazol-5-yl)piperidin-1-yl)-2-oxyacetamide (42 mg, 78.55 μmol, 12.77% yield).

化合物1261於分析條件下(管柱；IC，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為31.03min。The retention time of compound 1261 under analytical conditions (column; IC, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 31.03 min.

保留時間：31.03minRetention time: 31.03min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(t,3H),1.05-1.14(m,9H),1.29-1.40(m,1H),1.52(q,2H),1.65-1.74(m,1H),1.82-1.91(m,1H),2.00-2.12(m,3H),2.17(s,3H),2.18-2.21(m,2H),2.27-2.43(m,3H),2.75-3.28(m,2H),3.44-4.07(m,1H),5.26-5.75(m,3H),7.31-7.54(m,2H),7.84-7.93(m,1H),7.97-8.11(m,2H),10.48-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ(ppm) 1.03(t, 3H), 1.05-1.14(m, 9H), 1.29-1.40(m, 1H), 1.52(q, 2H), 1.65-1.74 (m,1H),1.82-1.91(m,1H),2.00-2.12(m,3H),2.17(s,3H),2.18-2.21(m,2H),2.27-2.43(m,3H),2.75 -3.28(m, 2H), 3.44-4.07(m, 1H), 5.26-5.75(m, 3H), 7.31-7.54(m, 2H), 7.84-7.93(m, 1H), 7.97-8.11(m, 2H), 10.48-10.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=2.176min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=2.176 min.

實例603.N -(5-乙基-6-甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1100)之合成Example 603. N- (5-ethyl-6-methylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidine-4 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1100)

Figure 110128222-A0202-12-2055-906
Figure 110128222-A0202-12-2055-906

藉由一般程序方案H步驟6A製備。產率：51mg(16.17%)。Prepared by General Procedure H, Step 6A. Yield: 51 mg (16.17%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-6min 50-85%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-6 min 50-85% water-MeOH + 0.1% NH4OH ; (loading pump 4 ml/min MeOH).

化合物1100：Compound 1100:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.08(m,3H),1.08-1.19(m,3H),1.30-1.41(m,1H),1.64-1.88(m,4H),1.90-2.10(m,5H),2.18(s,3H),2.26-2.35(m,1H),2.36-2.42(m,3H),2.52-2.62(m,3H),2.81-2.85(m,2H),3.00-3.10(m,1H),3.44-4.08(m,1H),5.25-5.82(m,1H),7.32-7.43(m,1H),7.76-7.91(m,2H),8.01-8.10(m,1H),8.43-8.59(m,1H),10.91-11.08(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.08(m,3H), 1.08-1.19(m,3H), 1.30-1.41(m,1H), 1.64-1.88(m,4H) ,1.90-2.10(m,5H),2.18(s,3H),2.26-2.35(m,1H),2.36-2.42(m,3H),2.52-2.62(m,3H),2.81-2.85(m, 2H), 3.00-3.10(m, 1H), 3.44-4.08(m, 1H), 5.25-5.82(m, 1H), 7.32-7.43(m, 1H), 7.76-7.91(m, 2H), 8.01- 8.10 (m, 1H), 8.43-8.59 (m, 1H), 10.91-11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值519.2；實測值520.2；Rt=2.263min。LCMS (ESI): [M] + m/z: calculated 519.2; found 520.2; Rt=2.263 min.

實例604.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(3-((二甲胺基)甲基)氧呾-3-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1165)之合成Example 604. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(3-((dimethylamino)methyl)oxy Synthesis of pyridin-3-yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1165)

Figure 110128222-A0202-12-2056-907
Figure 110128222-A0202-12-2056-907

步驟1：2-(3-(疊氮基甲基)氧呾-3-基)-5-氯苯并[d]噻唑之合成Step 1: Synthesis of 2-(3-(azidomethyl)oxon-3-yl)-5-chlorobenzo[d]thiazole

藉由一般程序方案H步驟1B製備。產率：11g粗品Prepared by General Procedure H, Step IB. Yield: 11 g crude

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=3.578min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=3.578 min.

步驟2：(3-(5-氯苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 2: Synthesis of (3-(5-Chlorobenzo[d]thiazol-2-yl)oxon-3-yl)methanamine

將2-[3-(疊氮基甲基)氧呾-3-基]-5-氯-1,3-苯并噻唑(11g，39.18mmol)(大約50mL)之粗品MTBE溶液用甲醇(100mL)稀釋且添加氯化銨(12.58g，235.10mmol，8.22mL)。在攪拌之情況下，在25℃下，將鋅粉(7.69g，117.55mmol)分批添加到以上混合物中。將反應混合物在25℃下攪拌12h，然後過濾。將濾餅用MeOH(2*25mL)洗滌且丟棄。將經合併之濾液在真空中濃縮。將殘餘物用MTBE(100mL)稀釋且用5%硫酸氫鈉水溶液(100mL)萃取。然後將所得硫酸氫胺水溶液用10%氫氧化鈉水溶液鹼化至pH 11且用DCM(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色膠狀物之粗品[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]甲胺(1.2g，4.71mmol，12.02%產率)，其直接用於下一步驟中。A crude MTBE solution of 2-[3-(azidomethyl)oxon-3-yl]-5-chloro-1,3-benzothiazole (11 g, 39.18 mmol) (approximately 50 mL) was dissolved in methanol (100 mL). ) was diluted and ammonium chloride (12.58 g, 235.10 mmol, 8.22 mL) was added. Zinc powder (7.69 g, 117.55 mmol) was added portionwise to the above mixture at 25°C with stirring. The reaction mixture was stirred at 25 °C for 12 h, then filtered. The filter cake was washed with MeOH (2*25 mL) and discarded. The combined filtrates were concentrated in vacuo. The residue was diluted with MTBE (100 mL) and extracted with 5% aqueous sodium bisulfate (100 mL). The resulting aqueous ammonium bisulfate solution was then basified to pH 11 with 10% aqueous sodium hydroxide solution and extracted with DCM (2*50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude [3-(5-chloro-1,3-benzothiazol-2-yl)oxyquinone- as a pale yellow gum 3-yl]methanamine (1.2 g, 4.71 mmol, 12.02% yield) was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值254.2；實測值255.2；Rt=1.985min。LCMS (ESI): [M] + m/z: calculated 254.2; found 255.2; Rt=1.985 min.

步驟3：1-(3-(5-氯苯并[d]噻唑-2-基)氧呾-3-基)-N,N-二甲基甲胺之合成Step 3: Synthesis of 1-(3-(5-chlorobenzo[d]thiazol-2-yl)oxypyr-3-yl)-N,N-dimethylmethanamine

在25℃下，將用7-8% MeOH穩定之37重量%甲醛水溶液(946.16mg，11.66mmol，873.64μL，37%純度)及乙酸(518.63mg，8.64mmol，494.41μL)添加到[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]甲胺(1.1g，4.32mmol)於MeOH(30.49 mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌1h，然後在25℃下一次性添加氰基硼氫化鈉(542.73mg，8.64mmol)(發泡！)。將反應混合物在25℃下攪拌12h，然後在真空中濃縮。將殘餘物用10%氫氧化鈉水溶液(20mL)稀釋且用DCM(2*20mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色膠狀物之粗品1-[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]-N,N -二甲基甲胺(1.3g，粗品)，其直接用於下一步驟中。At 25°C, 37 wt% aqueous formaldehyde stabilized with 7-8% MeOH (946.16 mg, 11.66 mmol, 873.64 μL, 37% pure) and acetic acid (518.63 mg, 8.64 mmol, 494.41 μL) were added to [3- In a stirred solution of (5-chloro-1,3-benzothiazol-2-yl)oxypyran-3-yl]methanamine (1.1 g, 4.32 mmol) in MeOH (30.49 mL). The resulting mixture was stirred at 25°C for 1 h, then sodium cyanoborohydride (542.73 mg, 8.64 mmol) was added in one portion at 25°C (foaming!). The reaction mixture was stirred at 25 °C for 12 h, then concentrated in vacuo. The residue was diluted with 10% aqueous sodium hydroxide solution (20 mL) and extracted with DCM (2*20 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 1-[3-(5-chloro-1,3-benzothiazol-2-yl)oxyl as a pale yellow gum Zyr-3-yl] -N,N -dimethylmethylamine (1.3 g, crude), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值282.2；實測值283.2；Rt=1.530min。LCMS (ESI): [M] + m/z: calculated 282.2; found 283.2; Rt=1.530 min.

步驟4：N,N-二甲基-1-(3-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 4: N,N-Dimethyl-1-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl ) Synthesis of benzo[d]thiazol-2-yl)oxo-3-yl)methanamine

將1-[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]-N,N -二甲基甲胺(1.4g，4.95mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.38g，5.45mmol)及乙酸鉀(971.72mg，9.90mmol，618.93μL)於二噁烷(35mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(226.67mg，247.53μmol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(472.02mg，990.14μmol)，且將反應混合物在95℃下攪拌18h。冷卻反應混合物且過濾。將濾餅用二噁烷(2*10mL)洗滌且丟棄。將經合併之濾液在真空中濃縮。將殘餘物用DCM(30mL)稀釋且用硫酸氫鈉(1.19g，9.90mmol)於水(20mL)中之溶液萃取(重複兩次)。將經合併之水層用10%氫氧化鈉水溶液鹼化至pH 10且用DCM(3*25mL)反萃取。兩種DCM萃取物之蒸發未顯示所要產物。其看起來像硼酸酯在水性介質中水解且呈硼酸留在水相中。經合併之水層(大約100mL)含有N,N -二甲基-1-[3-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]氧呾-3-基]甲胺(1.85g，4.94mmol，100.00%產率)(理論量之產物，最可能呈硼酸形式)，其直接用於下一步驟中。1-[3-(5-Chloro-1,3-benzothiazol-2-yl)oxypyr-3-yl] -N,N -dimethylmethanamine (1.4 g, 4.95 mmol), 4, 4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2 - A mixture of dioxaborolane (1.38 g, 5.45 mmol) and potassium acetate (971.72 mg, 9.90 mmol, 618.93 μL) in dioxane (35 mL) was evacuated and backfilled with argon. This operation was repeated twice, followed by addition of ginseng (1,5-diphenylpent-1,4-dien-3-one)dipalladium (226.67 mg, 247.53 μmol) and dicyclohexyl[2 under argon ',4',6'-para(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (472.02 mg, 990.14 μmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and filtered. The filter cake was washed with dioxane (2*10 mL) and discarded. The combined filtrates were concentrated in vacuo. The residue was diluted with DCM (30 mL) and extracted with a solution of sodium bisulfate (1.19 g, 9.90 mmol) in water (20 mL) (repeated twice). The combined aqueous layers were basified to pH 10 with 10% aqueous sodium hydroxide and back extracted with DCM (3*25 mL). Evaporation of the two DCM extracts did not reveal the desired product. It appears that the borate ester is hydrolyzed in the aqueous medium and remains in the aqueous phase as boric acid. The combined aqueous layers (approximately 100 mL) contained N,N -dimethyl-1-[3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Cyclopentan-2-yl)-1,3-benzothiazol-2-yl]oxon-3-yl]methanamine (1.85 g, 4.94 mmol, 100.00% yield) (theoretical product, most likely as boronic acid), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=2.586min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=2.586 min.

步驟5：(S)-6-(2-(3-((二甲胺基)甲基)氧呾-3-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-6-(2-(3-((dimethylamino)methyl)oxypyr-3-yl)benzo[d]thiazol-5-yl)-3-methyl-3 Synthesis of 3-butyl ,4-dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：1.3g粗品。Prepared by General Procedure H, Step 3. Yield: 1.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值443.2；實測值444.2；Rt=1.279min。LCMS (ESI): [M] + m/z: calculated 443.2; found 444.2; Rt=1.279 min.

步驟6：(S)-N,N-二甲基-1-(3-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 6: (S)-N,N-Dimethyl-1-(3-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d] Synthesis of Thiazol-2-yl)oxo-3-yl)methanamine

Figure 110128222-A0202-12-2058-616
Figure 110128222-A0202-12-2058-616

藉由一般程序方案H步驟4製備。產率：450mg粗品。Prepared by General Procedure H, Step 4. Yield: 450 mg crude.

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=0.624min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=0.624 min.

步驟7：N,N-二甲基-1-(3-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 7: N,N-Dimethyl-1-(3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)oxygen Synthesis of -3-yl)methylamine

藉由一般程序方案H步驟5製備。產率：330mg(72.91%)。Prepared by General Procedure H, Step 5. Yield: 330 mg (72.91%).

LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=0.574min。LCMS (ESI): [M] + m/z: calculated 345.2; found 346.2; Rt=0.574 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(3-((二甲胺基)甲基)氧呾-3-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1165)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(3-((dimethylamino)methyl)oxy Synthesis of pyridin-3-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1165)

藉由一般程序方案H步驟6A製備。產率：47mg(23.27%)。Prepared by General Procedure H, Step 6A. Yield: 47 mg (23.27%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 30-30-60%水-MeCN+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 30-30-60% water-MeCN+0.1% NH 4 OH, flow rate: 30 mL/min; (loading pump 4 mL/min MeCN ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.14(m,6H),1.31-1.43(m,1H),1.67 -1.77(m,1H),1.85-1.93(m,1H),2.04-2.31(m,8H),2.33-2.43(m,2H),2.78-3.26(m,3H),3.47-4.09(m,1H),4.74(d,2H),4.95(d,2H),5.28-5.74(m,3H),7.36-7.44(m,1H),7.45-7.54(m,1H),7.92-8.10(m,3H),10.37(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.14(m, 6H), 1.31-1.43(m, 1H), 1.67-1.77(m, 1H), 1.85-1.93(m, 1H) ,2.04-2.31(m,8H),2.33-2.43(m,2H),2.78-3.26(m,3H),3.47-4.09(m,1H),4.74(d,2H),4.95(d,2H) , 5.28-5.74(m, 3H), 7.36-7.44(m, 1H), 7.45-7.54(m, 1H), 7.92-8.10(m, 3H), 10.37(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值536.2；實測值537.2；Rt=1.983min。LCMS (ESI): [M] + m/z: calculated 536.2; found 537.2; Rt=1.983 min.

實例605. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4S,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基-1-哌啶基]乙醯胺(化合物1139)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4R,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基-1-哌啶基]乙醯胺(化合物1172)之合成Example 605. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,4S,5R)-2-[3-[2 -(Dimethylamino)ethoxy]phenyl]-4-methoxy-5-methyl-1-piperidinyl]acetamide (Compound 1139) and N-(6-amino-5- Ethyl-3-pyridyl)-2-oxo-2-[rac-(2R,4R,5R)-2-[3-[2-(dimethylamino)ethoxy]phenyl ]-4-Methoxy-5-methyl-1-piperidinyl]acetamide (Compound 1172)

Figure 110128222-A0202-12-2059-617
Figure 110128222-A0202-12-2059-617

步驟1：外消旋-(6R,9R)-9-(3-溴苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷之合成Step 1: Synthesis of racemic-(6R,9R)-9-(3-bromophenyl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane

將3-溴苯甲醛(2.80g，15.15mmol，1.77mL)及2-(2-甲基-1,3-二氧環 戊烷-2-基)丙-1-胺(2.2g，15.15mmol)溶解於甲苯(35mL)中且添加對甲苯磺酸單水合物(8.65g，45.45mmol，6.97mL)。將所得混合物以迪安-斯塔克分離器回流隔夜。將反應混合物冷卻且用K2 CO3 水溶液(10g於60mL水中)鹼化。將所得混合物用EtOAc(2*75mL)萃取且將經合併之有機層用鹽水(50mL)洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮。將殘餘物溶解於CHCl3 (75mL)中且將所得溶液用NaHSO4 水溶液(2.5g於25mL中，兩次)萃取。將經合併之水層用CHCl3 (2*45mL)洗滌且用K2 CO3 水溶液(10g於30mL水中)鹼化。將所得混合物用CHCl3(2*50mL)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得外消旋-(6R,9R)-9-(3-溴苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(2.5g，8.01mmol，52.85%產率)。Combine 3-bromobenzaldehyde (2.80 g, 15.15 mmol, 1.77 mL) and 2-(2-methyl-1,3-dioxolan-2-yl)propan-1-amine (2.2 g, 15.15 mmol) ) was dissolved in toluene (35 mL) and p-toluenesulfonic acid monohydrate (8.65 g, 45.45 mmol, 6.97 mL) was added. The resulting mixture was refluxed with a Dean-Stark separator overnight. The reaction mixture was cooled and basified with aqueous K2CO3 ( 10 g in 60 mL water). The resulting mixture was extracted with EtOAc (2*75 mL) and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in CHCl3 (75 mL) and the resulting solution was extracted with aqueous NaHSO4 (2.5 g in 25 mL, twice). The combined aqueous layers were washed with CHCl3 ( 2 *45 mL) and basified with aqueous K2CO3 ( 10 g in 30 mL water). The resulting mixture was extracted with CHCl3 (2*50 mL) and the combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo to obtain rac-(6R,9R)-9-(3-bromo Phenyl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane (2.5 g, 8.01 mmol, 52.85% yield).

LCMS(ESI)：[M+H]+ m/z：計算值312.0；實測值312.0；Rt=0.804min。LCMS (ESI): [M+H] + m/z: calculated 312.0; found 312.0; Rt=0.804 min.

步驟2：外消旋-(2R,5R)-2-(3-溴苯基)-5-甲基哌啶-4-酮之合成Step 2: Synthesis of racemic-(2R,5R)-2-(3-bromophenyl)-5-methylpiperidin-4-one

將外消旋-(6R,9R)-9-(3-溴苯基)-6-甲基-1,4-二氧雜-8-氮雜螺[4.5]癸烷(2.5g，8.01mmol)溶解於6N HCl(40mL)中且將所得混合物在80℃下加熱隔夜。將反應混合物冷卻，轉移至分液漏斗且用EtOAc(2*40mL)洗滌。將水層用K2 CO3 中和。將所得混合物用EtOAc(2*50mL)萃取且將經合併之有機層經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得外消旋-(2R,5R)-2-(3-溴苯基)-5-甲基哌啶-4-酮(1.56g，5.83mmol，72.84%產率)。rac-(6R,9R)-9-(3-bromophenyl)-6-methyl-1,4-dioxa-8-azaspiro[4.5]decane (2.5 g, 8.01 mmol ) was dissolved in 6N HCl (40 mL) and the resulting mixture was heated at 80 °C overnight. The reaction mixture was cooled, transferred to a separatory funnel and washed with EtOAc (2*40 mL). The aqueous layer was neutralized with K2CO3 . The resulting mixture was extracted with EtOAc (2*50 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain rac-(2R,5R)-2-(3-bromophenyl) )-5-methylpiperidin-4-one (1.56 g, 5.83 mmol, 72.84% yield).

LCMS(ESI)：[M+H]+ m/z：計算值268.0；實測值268.0；Rt=0.668min。LCMS (ESI): [M+H] + m/z: calculated 268.0; found 268.0; Rt=0.668 min.

步驟3：外消旋-(2R,5R)-2-(3-溴苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of racemic-(2R,5R)-2-(3-bromophenyl)-5-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester

將外消旋-(2R,5R)-2-(3-溴苯基)-5-甲基哌啶-4-酮(1.56g，5.83mmol)及三乙胺(885.30mg，8.75mmol，1.22mL)溶解於DCM(20mL)中且逐滴添加二碳酸二-第三丁酯(1.46g，6.71mmol，1.54mL)於DCM(5mL)中之溶液。將所得 混合物攪拌隔夜。在真空中濃縮反應混合物且將殘餘物再溶解於DCM(50mL)中。將所得溶液用NaHSO4 溶液(45mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。藉由管柱層析(梯度，於己烷中之EtOAc，0至50%)純化殘餘物，以獲得外消旋-(2R,5R)-2-(3-溴苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯(377mg，1.02mmol，17.55%產率)及外消旋-(2R,5R)-2-(3-溴苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯(1.14g，3.09mmol，52.98%產率)。Mix rac-(2R,5R)-2-(3-bromophenyl)-5-methylpiperidin-4-one (1.56 g, 5.83 mmol) and triethylamine (885.30 mg, 8.75 mmol, 1.22 g mL) was dissolved in DCM (20 mL) and a solution of di-tert-butyl dicarbonate (1.46 g, 6.71 mmol, 1.54 mL) in DCM (5 mL) was added dropwise. The resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was redissolved in DCM (50 mL). The resulting solution was washed with NaHSO4 solution (45 mL), dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (gradient, EtOAc in hexanes, 0 to 50%) to obtain rac-(2R,5R)-2-(3-bromophenyl)-5-methan tert-butyl-4-oxypiperidine-1-carboxylate (377 mg, 1.02 mmol, 17.55% yield) and rac-(2R,5R)-2-(3-bromophenyl)-5 - Methyl-4-pendoxopiperidine-1-carboxylic acid tert-butyl ester (1.14 g, 3.09 mmol, 52.98% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.16(d,3H),1.45(s,9H),2.45(m,1H),2.84-2.92(m,2H),3.64(m,1H),3.77(m,1H),5.48(m,1H),7.14-7.18(m,2H),7.36(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.16(d,3H), 1.45(s,9H), 2.45(m,1H), 2.84-2.92(m,2H), 3.64(m,1H) ), 3.77(m, 1H), 5.48(m, 1H), 7.14-7.18(m, 2H), 7.36(s, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值314.2；實測值314.2；Rt=1.536min。LCMS (ESI): [M-tBu] + m/z: calculated 314.2; found 314.2; Rt=1.536 min.

步驟4：外消旋-(2R,5R)-2-(3-溴苯基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 4: Synthesis of racemic-(2R,5R)-2-(3-bromophenyl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將外消旋-(2R,5R)-2-(3-溴苯基)-5-甲基-4-側氧基哌啶-1-甲酸第三丁酯(1.14g，3.09mmol)溶解於MeOH(15mL)中且將所得溶液在冰浴中冷卻至0℃。將硼氫化鈉(175.36mg，4.64mmol，163.28μL)添加到先前溶液中且使所得混合物升溫至室溫且攪拌隔夜。添加水(10mL)且將所得混合物在真空中濃縮。將所得混合物用DCM(2*35mL)萃取且將經合併之有機層用水(10mL)洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得外消旋-(2R,5R)-2-(3-溴苯基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯(1.15g，粗品)。Racemic-(2R,5R)-2-(3-bromophenyl)-5-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester (1.14 g, 3.09 mmol) was dissolved in MeOH (15 mL) and the resulting solution was cooled to 0 °C in an ice bath. Sodium borohydride (175.36 mg, 4.64 mmol, 163.28 μL) was added to the previous solution and the resulting mixture was allowed to warm to room temperature and stirred overnight. Water (10 mL) was added and the resulting mixture was concentrated in vacuo. The resulting mixture was extracted with DCM (2*35 mL) and the combined organic layers were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain rac-(2R,5R)-2- (3-Bromophenyl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.15 g, crude).

LCMS(ESI)：[M-Boc]+ m/z：計算值272.0；實測值272.0；Rt=1.416min。LCMS (ESI): [M-Boc] + m/z: calculated 272.0; found 272.0; Rt=1.416 min.

步驟5：外消旋-(2R,5R)-2-(3-溴苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of racemic-(2R,5R)-2-(3-bromophenyl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將外消旋-(2R,5R)-2-(3-溴苯基)-4-羥基-5-甲基哌啶-1-甲酸第三丁酯(1.15g，3.09mmol)溶解於DMF(10mL)中且分批添加於礦物油中之氰化鈉(油分散物)60%分散物(355.45mg，9.28mmol，60%純度)。將所得混合物攪拌1h且一 次性添加碘甲烷(1.32g，9.28mmol，577.51μL)。將所得混合物攪拌隔夜。將反應混合物倒入到水(50mL)中且將所得混合物用MTBE(2*50mL)萃取。將經合併之有機層用水(3*50mL)、鹽水(50mL)洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮，以獲得外消旋-(2R,5R)-2-(3-溴苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(1.26g，粗品)。Racemic-(2R,5R)-2-(3-bromophenyl)-4-hydroxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.15 g, 3.09 mmol) was dissolved in DMF ( 10 mL) and portionwise added sodium cyanide (oil dispersion) 60% dispersion (355.45 mg, 9.28 mmol, 60% purity) in mineral oil. The resulting mixture was stirred for 1 h and a Iodomethane (1.32 g, 9.28 mmol, 577.51 [mu]L) was added in one portion. The resulting mixture was stirred overnight. The reaction mixture was poured into water (50 mL) and the resulting mixture was extracted with MTBE (2*50 mL). The combined organic layers were washed with water (3*50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain rac-(2R,5R)-2-(3-bromobenzene (1.26 g, crude).

LCMS(ESI)：[M-tBu]+ m/z：計算值328.2；實測值328.2；Rt=1.667min。LCMS (ESI): [M-tBu] + m/z: calculated 328.2; found 328.2; Rt=1.667 min.

步驟6：外消旋-(2R,5R)-4-甲氧基-5-甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁酯之合成 將外消旋-(2R,5R)-2-(3-溴苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(1.26g，3.27mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(871.42mg，3.43mmol)混合於二噁烷(16mL)中且向其中添加乙酸鉀(801.88mg，8.17mmol，510.75μL)。將所得混合物抽真空且用氬氣回填三次，且添加Pd(dppf)Cl2 -CH2 Cl2 (133.45mg，163.41μmol)。將所得混合物在100℃下加熱隔夜。在真空中濃縮反應混合物且將水(35mL)添加到殘餘物中。將所得混合物用MTBE(2*50mL)萃取且將經合併之有機層用水(25mL)、鹽水(25mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得外消旋-(2R,5R)-4-甲氧基-5-甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁酯(1.79g，粗品)。 Step 6: Racemic-(2R,5R)-4-methoxy-5-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxo Synthesis of tert-butyl borolan-2-yl)phenyl]piperidine-1-carboxylate Oxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.26 g, 3.27 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl) (871.42 mg, 3.43 mmol) was mixed with dioxane (16 mL) ) and thereto was added potassium acetate (801.88 mg, 8.17 mmol, 510.75 μL). The resulting mixture was evacuated and backfilled with argon three times, and Pd(dppf)Cl2- CH2Cl2 ( 133.45 mg , 163.41 μmol) was added. The resulting mixture was heated at 100°C overnight. The reaction mixture was concentrated in vacuo and water (35 mL) was added to the residue. The resulting mixture was extracted with MTBE (2*50 mL) and the combined organic layers were washed with water (25 mL), brine (25 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain rac-( 2R,5R)-4-methoxy-5-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.79 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值377.2；實測值377.2；Rt=4.523min。LCMS (ESI): [M+H] + m/z: calculated 377.2; found 377.2; Rt=4.523 min.

步驟7：外消旋-(2R,5R)-2-(3-羥基苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 7: Synthesis of racemic-(2R,5R)-2-(3-hydroxyphenyl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將外消旋-(2R,5R)-4-甲氧基-5-甲基-2-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]哌啶-1-甲酸第三丁酯(1.79g，4.14mmol)溶解於THF(16mL)中且向其中小心添加35%過氧化氫(603.56mg，6.21mmol，548.69μL，35% 純度)。添加完成之後，將所得混合物攪拌1h且添加氫氧化鈉珠粒水溶液(264.96mg，6.62mmol，124.39μL)。添加完成之後，將所得混合物攪拌1h。將反應混合物用檸檬酸酸化且將所得混合物轉移至分液漏斗。將有機層分離且將水層用MTBE(2*50mL)萃取。將經合併之有機層用亞硫酸鈉水溶液洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得外消旋-(2R,5R)-2-(3-羥基苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(1.51g，粗品)，其不經純化即用於下一步驟中。Racemic-(2R,5R)-4-methoxy-5-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Heterocyclopentan-2-yl)phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.79 g, 4.14 mmol) was dissolved in THF (16 mL) and to it was carefully added 35% hydrogen peroxide (603.56 mg, 6.21 mmol, 548.69 μL, 35% purity). After the addition was complete, the resulting mixture was stirred for 1 h and aqueous sodium hydroxide beads (264.96 mg, 6.62 mmol, 124.39 μL) were added. After the addition was complete, the resulting mixture was stirred for 1 h. The reaction mixture was acidified with citric acid and the resulting mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with MTBE (2*50 mL). The combined organic layers were washed with aqueous sodium sulfite, dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain rac-(2R,5R)-2-(3-hydroxyphenyl)-4-methan Oxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.51 g, crude) was used in the next step without purification.

LCMS(ESI)：[M-Boc]+ m/z：計算值222.2；實測值222.2；Rt=1.362min。LCMS (ESI): [M-Boc] + m/z: calculated 222.2; found 222.2; Rt=1.362 min.

步驟8：外消旋-(2R,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯之合成Step 8: Racemic-(2R,5R)-2-[3-[2-(dimethylamino)ethoxy]phenyl]-4-methoxy-5-methylpiperidine-1- Synthesis of tert-butyl formate

將外消旋-(2R,5R)-2-(3-羥基苯基)-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(1.51g，4.71mmol)、2-溴-N,N-二甲基乙胺(5.49g，23.55mmol，HBr)及碳酸銫(7.67g，23.55mmol)一起混合於DMF(15mL)中且將所得混合物在60℃下加熱隔夜。將反應混合物倒入到水(50mL)中且將所得混合物用EtOAc(3*50mL)萃取。將經合併之有機層用水(3*50mL)、鹽水(50mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮。將殘餘物(1.109g)再溶解於DMF(15mL)中且向其中添加第三丁醇鉀(2.38g，21.20mmol)，隨後添加2-溴-N,N-二甲基乙胺；HBr(2.19g，9.42mmol)。將所得混合物在90℃下加熱隔夜。藉由等分試樣之LCMS，留下5%起始材料。將1.1g 2-溴-N,N-二甲基乙胺(HBr)及1.2g第三丁醇鉀添加到反應混合物中且將所得混合物在90℃下加熱隔夜。將反應混合物倒入到水(50mL)中且將所得混合物用MTBE(3*50mL)萃取。將經合併之有機層用水(3*50mL)、鹽水(50mL)洗滌，經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得外消旋-(2R,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(1.05g，2.67mmol，56.79%產率)。Racemic-(2R,5R)-2-(3-hydroxyphenyl)-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.51 g, 4.71 mmol), 2 -Bromo-N,N-dimethylethylamine (5.49 g, 23.55 mmol, HBr) and cesium carbonate (7.67 g, 23.55 mmol) were mixed together in DMF (15 mL) and the resulting mixture was heated at 60 °C overnight. The reaction mixture was poured into water (50 mL) and the resulting mixture was extracted with EtOAc (3*50 mL). The combined organic layers were washed with water (3*50 mL), brine (50 mL), dried over Na2SO4 , filtered and concentrated in vacuo. The residue (1.109 g) was redissolved in DMF (15 mL) and potassium tert-butoxide (2.38 g, 21.20 mmol) was added followed by 2-bromo-N,N-dimethylethylamine; HBr ( 2.19 g, 9.42 mmol). The resulting mixture was heated at 90°C overnight. By LCMS of an aliquot, 5% of the starting material was left. 1.1 g of 2-bromo-N,N-dimethylethylamine (HBr) and 1.2 g of potassium tert-butoxide were added to the reaction mixture and the resulting mixture was heated at 90°C overnight. The reaction mixture was poured into water (50 mL) and the resulting mixture was extracted with MTBE (3*50 mL). The combined organic layers were washed with water (3*50 mL), brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain rac-(2R,5R)-2-[3- [2-(Dimethylamino)ethoxy]phenyl]-4-methoxy-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.05 g, 2.67 mmol, 56.79% yield).

LCMS(ESI)：[M+H]+ m/z：計算值393.2；實測值393.2；Rt=1.015min。LCMS (ESI): [M+H] + m/z: calculated 393.2; found 393.2; Rt=1.015 min.

步驟9：N,N-二甲基-2-[3-[外消旋-(2R,5R)-4-甲氧基-5-甲基-2-哌啶基]苯氧基]乙胺之合成Step 9: N,N-Dimethyl-2-[3-[rac-(2R,5R)-4-methoxy-5-methyl-2-piperidinyl]phenoxy]ethanamine synthesis

將外消旋-(2R,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基哌啶-1-甲酸第三丁酯(1.05g，2.67mmol)溶解於DCM(4mL)中且添加TFA(4mL)。攪拌所得混合物1h。將反應混合物倒入到K2 CO3 水溶液(10g於45mL水中)且將所得混合物用DCM(2*45mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得N,N-二甲基-2-[3-[外消旋-(2R,5R)-4-甲氧基-5-甲基-2-哌啶基]苯氧基]乙胺(851mg，粗品)。Racemic-(2R,5R)-2-[3-[2-(dimethylamino)ethoxy]phenyl]-4-methoxy-5-methylpiperidine-1-carboxylic acid Tributyl ester (1.05 g, 2.67 mmol) was dissolved in DCM (4 mL) and TFA (4 mL) was added. The resulting mixture was stirred for 1 h. The reaction mixture was poured into aqueous K2CO3 ( 10 g in 45 mL water) and the resulting mixture was extracted with DCM (2*45 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain N,N-dimethyl-2-[3-[rac-(2R,5R)-4-methoxy yl-5-methyl-2-piperidinyl]phenoxy]ethanamine (851 mg, crude).

LCMS(ESI)：[M+H]+ m/z：計算值293.2；實測值293.2；Rt=0.474min。LCMS (ESI): [M+H] + m/z: calculated 293.2; found 293.2; Rt=0.474 min.

步驟10：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4S,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基-1-哌啶基]乙醯胺(化合物1139)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4R,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基-1-哌啶基]乙醯胺(化合物1172)之合成Step 10: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,4S,5R)-2-[3-[2 -(Dimethylamino)ethoxy]phenyl]-4-methoxy-5-methyl-1-piperidinyl]acetamide (Compound 1139) and N-(6-amino-5- Ethyl-3-pyridyl)-2-oxo-2-[rac-(2R,4R,5R)-2-[3-[2-(dimethylamino)ethoxy]phenyl ]-4-Methoxy-5-methyl-1-piperidinyl]acetamide (Compound 1172)

將N,N-二甲基-2-[3-[外消旋-(2R,5R)-4-甲氧基-5-甲基-2-哌啶基]苯氧基]乙胺(334mg，1.14mmol)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(238.95mg，1.14mmol)及三乙胺(577.90mg，5.71mmol，796.01μL)一起混合於DMF(3mL)中且向其中添加HATU(521.16mg，1.37mmol)。將所得混合物攪拌隔夜。將反應混合物提交至HPLC且純化(2-10min；0-25%水/MeOH+NH3 30mL/min；裝載泵4mL/min MeOH+NH3 ；管柱SunFire 19*100mm，5um)，以獲得N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4S,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基-1-哌啶基]乙醯胺(101.7mg，210.30μmol，18.41%產率)及N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,4R,5R)-2-[3-[2-(二甲胺基)乙氧基]苯基]-4-甲氧基-5-甲基-1-哌啶基]乙醯胺(54mg，111.66μmol，9.78%產率)。N,N-Dimethyl-2-[3-[rac-(2R,5R)-4-methoxy-5-methyl-2-piperidinyl]phenoxy]ethanamine (334 mg , 1.14 mmol), 2-[(6-amino-5-ethyl-3-pyridinyl)amino]-2-oxoacetic acid (238.95 mg, 1.14 mmol) and triethylamine (577.90 mg, 5.71 mmol) mmol, 796.01 μL) were mixed together in DMF (3 mL) and to this was added HATU (521.16 mg, 1.37 mmol). The resulting mixture was stirred overnight. The reaction mixture was submitted to HPLC and purified (2-10 min; 0-25% water/MeOH+ NH3 30 mL/min; loading pump 4 mL/min MeOH+ NH3 ; column SunFire 19*100 mm, 5um) to obtain N -(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,4S,5R)-2-[3-[2-(dimethyl Amino)ethoxy]phenyl]-4-methoxy-5-methyl-1-piperidinyl]acetamide (101.7 mg, 210.30 μmol, 18.41% yield) and N-(6-amine yl-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,4R,5R)-2-[3-[2-(dimethylamino)ethoxy yl]phenyl]-4-methoxy-5-methyl-1-piperidinyl]acetamide (54 mg, 111.66 μmol, 9.78% yield).

化合物1139： 產率：101.7mg(18.41%)nLCMS(ESI)：[M+H]+ m/z：計算值485.2；實測值485.2；Rt=1.806min。 Compound 1139: Yield: 101.7 mg (18.41%) nLCMS (ESI): [M+H] + m/z: calcd. 485.2; found 485.2; Rt=1.806 min.

化合物1172： 產率：54.0mg(9.78%)LCMS(ESI)：[M+H]+ m/z：計算值485.2；實測值485.2；Rt=1.813min。 Compound 1172: Yield: 54.0 mg (9.78%) LCMS (ESI): [M+H] + m/z: calcd. 485.2; found 485.2; Rt=1.813 min.

實例606.N -(5,6-二甲基吡啶-3-基)-2-((2R ,5S )-5-甲基-2-(2-(1-甲基吖呾-3-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1123)之合成Example 606. N- (5,6-Lutidine-3-yl)-2-(( 2R , 5S )-5-methyl-2-(2-(1-methylazidine-3 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1123)

Figure 110128222-A0202-12-2065-618
Figure 110128222-A0202-12-2065-618

藉由一般程序方案H步驟6A製備。產率：47.5mg(13.63%)。Prepared by General Procedure H, Step 6A. Yield: 47.5 mg (13.63%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 30-80%水-MeOH+0.1% NH4 OH；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 30-80% water-MeOH + 0.1% NH4OH ; (loading pump 4 mL/min MeOH).

1 H NMR(500MHz,dmso)δ 1.01-1.06(m,3H),1.30-1.41(m,1H),1.66-1.76(m,1H),1.81-1.92(m,1H),2.04-2.14(m,1H),2.15-2.32(m,8H),2.34-2.39(m,3H),2.78-3.06(m,1H),3.44-4.06(m,5H),5.24-5.76(m,1H),7.34-7.45(m,1H),7.72-7.85(m,1H),7.87-7.94(m,1H),8.02-8.10(m,1H),8.40-8.54(m,1H),10.81-11.10(m,1H)。 1 H NMR(500MHz,dmso)δ 1.01-1.06(m,3H),1.30-1.41(m,1H),1.66-1.76(m,1H),1.81-1.92(m,1H),2.04-2.14(m ,1H),2.15-2.32(m,8H),2.34-2.39(m,3H),2.78-3.06(m,1H),3.44-4.06(m,5H),5.24-5.76(m,1H),7.34 -7.45(m,1H),7.72-7.85(m,1H),7.87-7.94(m,1H),8.02-8.10(m,1H),8.40-8.54(m,1H),10.81-11.10(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值477.2；實測值478.2；Rt=2.209min。LCMS (ESI): [M] + m/z: calculated 477.2; found 478.2; Rt=2.209 min.

實例607. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1183、化合物1397及化合物1129)之合成Example 607. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1,2,2-trimethyl) Synthesis of ylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1183, Compound 1397 and Compound 1129)

Figure 110128222-A0202-12-2066-619
Figure 110128222-A0202-12-2066-619

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1,2,2-trimethyl) Synthesis of ylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide

藉由一般程序方案H步驟6A製備。產率：94mg(24.65%)。Prepared by General Procedure H, Step 6A. Yield: 94 mg (24.65%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 50-50-90%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 50-50-90% water-MeOH+0.1% NH4OH , flow rate: 30mL/min; (loading pump 4mL/min MeOH ).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=1.860min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=1.860 min.

步驟2：掌性分離(化合物1183、化合物1397及化合物1129)Step 2: Chiral separation (Compound 1183, Compound 1397 and Compound 1129)

對外消旋N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(0.079g，147.74μmol)進行掌性分離(管柱：Chiralpak IA(250 x 20mm，5mkm)；流動相：己烷-IPA-MeOH，40-30-30流速：12mL/min)，以獲得N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(rel-(S)-1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(0.0364g，68.07μmol，92.15%產率)(RT=45.37)及N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(rel-(R)-1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(0.0389g，72.75μmol，98.48%產率)(RT=34.77)。Racemic N-(6-amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1,2,2-trimethyl) chiral separation (column: Chiralpak IA (250 x 20 mm, 5 mkm); mobile phase: hexane-IPA-MeOH, 40-30-30 flow rate: 12 mL/min) to obtain N-(6-amino-5-ethylpyridine-3- yl)-2-((2R,5S)-5-methyl-2-(2-(rel-(S)-1,2,2-trimethylpiperidin-4-yl)benzo[d] Thiazol-5-yl)piperidin-1-yl)-2-oxyacetamide (0.0364 g, 68.07 μmol, 92.15% yield) (RT=45.37) and N-(6-amino-5- Ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(rel-(R)-1,2,2-trimethylpiperidin-4-yl )benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamide (0.0389 g, 72.75 μmol, 98.48% yield) (RT=34.77).

化合物1183於分析條件下(管柱：IA，以己烷-IPA-MeOH，40-30-30，0.6mL/min為流動相)之保留時間為46.41min且化合物1129之保留時間為35.14min。The retention time of compound 1183 under analytical conditions (column: IA, with hexane-IPA-MeOH, 40-30-30, 0.6 mL/min as mobile phase) was 46.41 min and that of compound 1129 was 35.14 min.

藉由掌性HPLC(管柱：Chiralcel OD-H(250*20mm，5mkm)；流動相：己烷-IPA-MeOH 70-15-15；流速：12mL/min)進一步純化30mg化合物1183， 得到N -(6-胺基-5-乙基吡啶-3-基)-2-((2R, 5S )-2-(2-((S )-2,2-二甲基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(19mg，35.53μmol，48.10%產率)(RT=17.56)。30 mg of compound 1183 was further purified by chiral HPLC (column: Chiralcel OD-H (250*20 mm, 5 mkm); mobile phase: hexane-IPA-MeOH 70-15-15; flow rate: 12 mL/min) to give N -(6-Amino-5-ethylpyridin-3-yl)-2-(( 2R, 5S)-2-(2-((S ) -2,2-dimethylpiperidine-4 -yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamide (19 mg, 35.53 μmol, 48.10% yield) (RT=17.56 ).

化合物1397於分析條件下(管柱：OD-H，以己烷-IPA-MeOH，60-20-20，0.6mL/min為流動相)之保留時間為13.69min。The retention time of compound 1397 under analytical conditions (column: OD-H, hexane-IPA-MeOH, 60-20-20, 0.6 mL/min as mobile phase) was 13.69 min.

化合物1183： 1 H NMR(500MHz,dmso)δ 0.98-1.05(m,6H),1.06-1.16(m,6H),1.30-1.41(m,1H),1.62-1.77(m,3H),1.82-1.94(m,2H),1.99-2.11(m,2H),2.20(s,3H),2.25-2.35(m,2H),2.38-2.43(m,2H),2.56-2.71(m,2H),2.75-3.20(m,1H),3.45-4.07(m,1H),5.25-5.60(m,1H),5.62-5.74(m,2H),7.31-7.42(m,1H),7.42-7.56(m,1H),7.83-7.92(m,1H),7.95-8.12(m,2H),10.51-10.63(m,1H)。 Compound 1183: 1 H NMR (500 MHz, dmso) δ 0.98-1.05 (m, 6H), 1.06-1.16 (m, 6H), 1.30-1.41 (m, 1H), 1.62-1.77 (m, 3H), 1.82- 1.94(m,2H),1.99-2.11(m,2H),2.20(s,3H),2.25-2.35(m,2H),2.38-2.43(m,2H),2.56-2.71(m,2H), 2.75-3.20(m, 1H), 3.45-4.07(m, 1H), 5.25-5.60(m, 1H), 5.62-5.74(m, 2H), 7.31-7.42(m, 1H), 7.42-7.56(m , 1H), 7.83-7.92 (m, 1H), 7.95-8.12 (m, 2H), 10.51-10.63 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值548.2；實測值549.2；Rt=0.755min。LCMS (ESI): [M+1] + m/z: calculated 548.2; found 549.2; Rt=0.755min.

化合物1397： 1 H NMR(500MHz,dmso)δ 0.98-1.05(m,6H),1.06-1.16(m,6H),1.30-1.41(m,1H),1.62-1.77(m,3H),1.82-1.94(m,2H),1.99-2.11(m,2H),2.20(s,3H),2.25-2.35(m,2H),2.38-2.43(m,2H),2.56-2.71(m,2H),2.75-3.20(m,1H),3.45-4.07(m,1H),5.25-5.60(m,1H),5.62-5.74(m,2H),7.31-7.42(m,1H),7.42-7.56(m,1H),7.83-7.92(m,1H),7.95-8.12(m,2H),10.51-10.63(m,1H)。 Compound 1397: 1 H NMR (500 MHz, dmso) δ 0.98-1.05 (m, 6H), 1.06-1.16 (m, 6H), 1.30-1.41 (m, 1H), 1.62-1.77 (m, 3H), 1.82- 1.94(m,2H),1.99-2.11(m,2H),2.20(s,3H),2.25-2.35(m,2H),2.38-2.43(m,2H),2.56-2.71(m,2H), 2.75-3.20(m, 1H), 3.45-4.07(m, 1H), 5.25-5.60(m, 1H), 5.62-5.74(m, 2H), 7.31-7.42(m, 1H), 7.42-7.56(m , 1H), 7.83-7.92 (m, 1H), 7.95-8.12 (m, 2H), 10.51-10.63 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=2.426min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=2.426 min.

化合物1129： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.00(m,3H),1.02-1.09(m,4H),1.09-1.15(m,5H),1.29-1.42(m,1H),1.60-1.78(m,3H),1.83-1.93(m,2H),1.99-2.16(m,2H),2.16(s,3H),2.21-2.37(m,2H),2.39-2.43(m,1H),2.52-2.58(m,2H),2.60-2.67(m,1H),2.77-3.24(m,1H),3.48-4.07(m,1H),5.19-5.62(m,1H),5.61-5.72(m,2H),7.31-7.43(m,1H),7.42-7.57(m,1H),7.84-7.92(m,1H),7.97-8.11(m,2H),10.48-10.66(m,1H)。 Compound 1129: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.97-1.00 (m, 3H), 1.02-1.09 (m, 4H), 1.09-1.15 (m, 5H), 1.29-1.42 (m) ,1H),1.60-1.78(m,3H),1.83-1.93(m,2H),1.99-2.16(m,2H),2.16(s,3H),2.21-2.37(m,2H),2.39-2.43 (m,1H), 2.52-2.58(m,2H), 2.60-2.67(m,1H), 2.77-3.24(m,1H), 3.48-4.07(m,1H), 5.19-5.62(m,1H) ,5.61-5.72(m,2H),7.31-7.43(m,1H),7.42-7.57(m,1H),7.84-7.92(m,1H),7.97-8.11(m,2H),10.48-10.66( m, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=2.257min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=2.257 min.

實例608.N -(5,6-二甲基吡啶-3-基)-2-((2R ,5S )-5-甲基-2-(2-(1,2,2-三甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1215及化合物1113)之合成Example 608. N- (5,6-Lutidine-3-yl)-2-(( 2R , 5S )-5-methyl-2-(2-(1,2,2-trimethyl) Synthesis of ylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamide (compound 1215 and compound 1113)

Figure 110128222-A0202-12-2068-620
Figure 110128222-A0202-12-2068-620

步驟1：N-(5,6-二甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1,2,2-三甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(5,6-Lutidine-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1,2,2-trimethylpiperidine) Synthesis of pyridin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide

藉由一般程序方案H步驟6A製備。產率：81mg(36.18%)。Prepared by General Procedure H, Step 6A. Yield: 81 mg (36.18%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-6min 60-75%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeCN)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-6 min 60-75% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeCN).

LCMS(ESI)：[M]+ m/z：計算值533.2；實測值534.2；Rt=1.881min。LCMS (ESI): [M] + m/z: calculated 533.2; found 534.2; Rt=1.881 min.

步驟2：掌性分離(化合物1215及化合物1113)Step 2: Chiral separation (compound 1215 and compound 1113)

對外消旋N -(5,6-二甲基-3-吡啶基)-2-側氧基-2-[外消旋 -(2R,5S )-5-甲基-2-[2-(1,2,2-三甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(0.081g，151.76μmol)進行掌性分離(管柱：Chiralpak IA-III(250-20mm-5m)；流動相：IPA-MeOH，50-50流速：12mL/min)，以獲得N -(5,6-二甲基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[2-[(4R )-1,2,2-三甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(0.031g，58.08μmol，38.27%產率)及N-(5,6-二甲基-3-吡啶基)-2-側氧基-2-[(2R,5S )-5-甲基-2-[2-[(4S )-1,2,2-三甲基-4-哌啶基]-1,3-苯并噻唑-5-基]-1-哌啶基]乙醯胺(0.05775g，124.60umol，50.22%產率)。Racemic N- (5,6-dimethyl-3-pyridyl)-2-oxy-2-[ racemic- ( 2R,5S )-5-methyl-2-[2-( 1,2,2-Trimethyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]acetamide (0.081 g, 151.76 μmol) for chiral separation (column: Chiralpak IA-III (250-20mm-5m); mobile phase: IPA-MeOH, 50-50 flow rate: 12 mL/min) to obtain N- (5,6-dimethyl-3-pyridyl )-2-oxy-2-[( 2R,5S )-5-methyl-2-[2-[( 4R )-1,2,2-trimethyl-4-piperidinyl]-1 ,3-benzothiazol-5-yl]-1-piperidinyl]acetamide (0.031 g, 58.08 μmol, 38.27% yield) and N-(5,6-dimethyl-3-pyridyl) -2-oxy-2-[( 2R,5S )-5-methyl-2-[2-[( 4S )-1,2,2-trimethyl-4-piperidinyl]-1, 3-Benzothiazol-5-yl]-1-piperidinyl]acetamide (0.05775 g, 124.60 umol, 50.22% yield).

化合物1215 於分析條件下(管柱：IA，以IPA-MeOH，50-50，0.6mL/min為流動相)之保留時間為61.75min且化合物1113之保留時間為27.05min。The retention time of compound 1215 under analytical conditions (column: IA, with IPA-MeOH, 50-50, 0.6 mL/min as mobile phase) was 61.75 min and the retention time of compound 1113 was 27.05 min.

化合物1215： 保留時間：61.75min Compound 1215: retention time: 61.75min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(s,3H),1.00-1.06(m,3H),1.10(s,3H),1.30-1.41(m,1H),1.59-1.65(m,1H),1.66-1.77(m,2H),1.83-1.92(m,2H),1.98-2.13(m,2H),2.15(s,3H),2.16-2.25(m,3H),2.28-2.38(m,4H),2.52-2.62(m,3H),2.80-3.26(m,1H),3.44-4.05(m,1H),5.23-5.74(m,1H),7.32-7.44(m,1H),7.71-7.84(m,1H),7.85-7.92(m,1H),8.00-8.08(m,1H),8.39-8.53(m,1H),10.72-11.13(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98(s, 3H), 1.00-1.06(m, 3H), 1.10(s, 3H), 1.30-1.41(m, 1H), 1.59-1.65 (m,1H),1.66-1.77(m,2H),1.83-1.92(m,2H),1.98-2.13(m,2H),2.15(s,3H),2.16-2.25(m,3H),2.28 -2.38(m, 4H), 2.52-2.62(m, 3H), 2.80-3.26(m, 1H), 3.44-4.05(m, 1H), 5.23-5.74(m, 1H), 7.32-7.44(m, 1H), 7.71-7.84 (m, 1H), 7.85-7.92 (m, 1H), 8.00-8.08 (m, 1H), 8.39-8.53 (m, 1H), 10.72-11.13 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值533.2；實測值534.2；Rt=2.106min。LCMS (ESI): [M] + m/z: calculated 533.2; found 534.2; Rt=2.106 min.

化合物1113： 保留時間：27.05min Compound 1113: retention time: 27.05min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(s,3H),1.00-1.07(m,3H),1.11(s,3H),1.30-1.41(m,1H),1.58-1.65(m,1H),1.65-1.76(m,2H),1.81-1.93(m,2H),1.98-2.13(m,2H),2.14-2.19(m,4H),2.24(s,2H),2.29-2.38(m,4H),2.52-2.62(m,3H),2.81-3.27(m,1H),3.43-4.05(m,1H),5.23-5.73(m,1H),7.33-7.43(m,1H),7.72-7.84(m,1H),7.86-7.92(m,1H),8.01-8.08(m,1H),8.39-8.55(m,1H),10.69-11.19(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98(s, 3H), 1.00-1.07(m, 3H), 1.11(s, 3H), 1.30-1.41(m, 1H), 1.58-1.65 (m,1H),1.65-1.76(m,2H),1.81-1.93(m,2H),1.98-2.13(m,2H),2.14-2.19(m,4H),2.24(s,2H),2.29 -2.38(m, 4H), 2.52-2.62(m, 3H), 2.81-3.27(m, 1H), 3.43-4.05(m, 1H), 5.23-5.73(m, 1H), 7.33-7.43(m, 1H), 7.72-7.84 (m, 1H), 7.86-7.92 (m, 1H), 8.01-8.08 (m, 1H), 8.39-8.55 (m, 1H), 10.69-11.19 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值533.2；實測值534.2；Rt=2.108min。LCMS (ESI): [M] + m/z: calculated 533.2; found 534.2; Rt=2.108 min.

實例609.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-((R )-2-(二甲胺基)丙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1198)之合成Example 609. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-((( R )-2-(dimethylamino)propane) Synthesis of yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1198)

Figure 110128222-A0202-12-2069-621
Figure 110128222-A0202-12-2069-621

步驟1：(R)-1-(5-氯苯并[d]噻唑-2-基)-N,N-二甲基丙-2-胺之合成Step 1: Synthesis of (R)-1-(5-chlorobenzo[d]thiazol-2-yl)-N,N-dimethylpropan-2-amine

使(3R)-3-(二甲胺基)丁酸(1g，7.62mmol)及2-胺基-4-氯苯硫酚(1g，6.26mmol)於PPA(5mL)之經攪拌之溶液在120℃下攪拌24h。完成之後，將反應混合物用水(50mL)萃取且藉由NaOH中和至pH=8。將水相用EtOAc(2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠管柱層析使用MeOH/EtOAc(1：5，v：v)作為溶析液(Rt=0.2)純化粗產物，以得到(2R )-1-(5-氯-1,3-苯并噻唑-2-基)-N,N -二甲基丙-2-胺(0.7g，2.75mmol，43.86%產率)。分離所要產物(2R )-1-(5-氯-1,3-苯并噻唑-2-基)-N,N -二甲基丙-2-胺(0.7g，2.75mmol，43.86%產率)。A stirred solution of (3R)-3-(dimethylamino)butyric acid (1 g, 7.62 mmol) and 2-amino-4-chlorothiophenol (1 g, 6.26 mmol) in PPA (5 mL) was added to Stir at 120°C for 24h. After completion, the reaction mixture was extracted with water (50 mL) and neutralized to pH=8 by NaOH. The aqueous phase was extracted with EtOAc (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using MeOH/EtOAc (1:5, v:v) as eluent (Rt=0.2) to give ( 2R )-1-(5-chloro-1,3- Benzothiazol-2-yl) -N,N -dimethylpropan-2-amine (0.7 g, 2.75 mmol, 43.86% yield). The desired product ( 2R )-1-(5-chloro-1,3-benzothiazol-2-yl) -N,N -dimethylpropan-2-amine (0.7 g, 2.75 mmol, 43.86% yield) was isolated ).

LCMS(ESI)：[M]+ m/z：計算值254.2；實測值255.2；Rt=0.934min。LCMS (ESI): [M] + m/z: calculated 254.2; found 255.2; Rt=0.934 min.

步驟2：(R)-N,N-二甲基-1-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 2: (R)-N,N-Dimethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)benzo[d]thiazol-2-yl)propan-2-amine

向(2R )-1-(5-氯-1,3-苯并噻唑-2-基)-N,N -二甲基丙-2-胺(0.7g，2.75mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(0.7g，2.76mmol)於二噁烷(30mL)中之經攪拌之溶液中添加Pd2 (dba)3 (0.5g，546.03μmol)及XPhos(0.5g，1.05mmol)。將所得懸浮液在50℃下用氬氣除氣0.5h。添加乙酸鉀(0.55g，5.60mmol，350.32μL)。將反應混合物在100℃下攪拌16h。完成之後，將反應混合物在減壓下濃縮，用水(50mL)萃取，將水相用CHCl3 (2*50mL)萃取。將有機相用10% HCl(2*50mL)萃取。將水相藉由NaHCO3 中和至pH=8，用CHCl3 (2*50mL)萃取。將有機相經Na2 SO4 乾燥且在真空中蒸發。分離所要產物(2R )-N,N -二甲基-1-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]丙-2-胺(0.4g，1.16mmol，42.04%產率)。To ( 2R )-1-(5-chloro-1,3-benzothiazol-2-yl) -N,N -dimethylpropan-2-amine (0.7 g, 2.75 mmol) and 4,4,5 ,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxo To a stirred solution of borolane (0.7 g, 2.76 mmol) in dioxane (30 mL) was added Pd2(dba )3 ( 0.5 g, 546.03 μmol) and XPhos (0.5 g, 1.05 mmol) . The resulting suspension was degassed with argon at 50 °C for 0.5 h. Potassium acetate (0.55 g, 5.60 mmol, 350.32 μL) was added. The reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure, extracted with water (50 mL), and the aqueous phase was extracted with CHCl3 (2*50 mL). The organic phase was extracted with 10% HCl (2*50 mL). The aqueous phase was neutralized to pH=8 by NaHCO3 , extracted with CHCl3 (2*50 mL). The organic phase was dried over Na2SO4 and evaporated in vacuo. Isolation of the desired product ( 2R ) -N,N -dimethyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-1,3-benzothiazol-2-yl]propan-2-amine (0.4 g, 1.16 mmol, 42.04% yield).

LCMS(ESI)：[M]+ m/z：計算值346.2；實測值347.2；Rt=1.182min。LCMS (ESI): [M] + m/z: calculated 346.2; found 347.2; Rt=1.182 min.

步驟3：(S)-6-(2-((R)-2-(二甲胺基)丙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-((R)-2-(dimethylamino)propyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-di Synthesis of Hydropyridine-1(2H)-Carboxylic Acid 3-Butyl Ester

藉由一般程序方案H步驟3製備。產率：0.48g粗品。Prepared by General Procedure H, Step 3. Yield: 0.48 g crude.

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.151min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.151 min.

步驟4：(R)-N,N-二甲基-1-(5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 4: (R)-N,N-Dimethyl-1-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d Synthesis of ]thiazol-2-yl)propan-2-amine

使外消旋 -(3S )-3-甲基-6-[2-[外消旋 -(2R )-2-(二甲胺基)丙基]-1,3-苯并噻唑-5-基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0.48g，1.15mmol)於MeOH(10mL)及二噁烷/HCl(5mL)中之經攪拌之溶液在25℃下攪拌16h。完成之後，將反應混合物蒸發，將粗產物用水(20mL)萃取且藉由NaHCO3 中和至pH=8。將水相用CHCl3 (2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物外消旋 -(2R )-N,N -二甲基-1-[5-[外消旋 -(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑-2-基]丙-2-胺(0.36g，1.14mmol，98.80%產率)。make rac- ( 3S )-3-methyl-6-[2-[ rac- ( 2R )-2-(dimethylamino)propyl]-1,3-benzothiazole-5- A stirred solution of tert-butyl]-3,4-dihydro- 2H -pyridine-1-carboxylate (0.48 g, 1.15 mmol) in MeOH (10 mL) and dioxane/HCl (5 mL) in Stir at 25°C for 16h. After completion, the reaction mixture was evaporated, the crude product was extracted with water (20 mL) and neutralized to pH=8 by NaHCO3 . The aqueous phase was extracted with CHCl3 (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Isolation of the desired product rac- ( 2R ) -N,N -dimethyl-1-[5-[ rac- ( 3S )-3-methyl-2,3,4,5-tetrahydropyridine- 6-yl]-1,3-benzothiazol-2-yl]propan-2-amine (0.36 g, 1.14 mmol, 98.80% yield).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.478min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.478 min.

步驟5：(R)-N,N-二甲基-1-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 5: (R)-N,N-Dimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propane -2-Amine Synthesis

藉由一般程序方案H步驟5製備。產率：0.36g粗品。Prepared by General Procedure H, Step 5. Yield: 0.36 g crude.

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.697min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.697 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-((R)-2-(二甲胺基)丙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1198)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-((R)-2-(dimethylamino)propane Synthesis of yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1198)

藉由一般程序方案H步驟6B製備。產率：24mg(8.32%)。Prepared by General Procedure H, Step 6B. Yield: 24 mg (8.32%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 35-60%水-MeCN+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 35-60% water-MeCN+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.09(m,6H),1.30-1.42(m,1H),1.66-1.75(m,1H),1.83-1.93(m,1H),2.05-2.34(m,8H),2.81-3.27(m,4H),3.48-4.09(m,4H),5.27-5.74(m,1H),7.28-7.42(m,1H),7.65-7.77(m,2H),7.83-7.90(m, 1H),7.99-8.05(m,1H),8.39-8.60(m,2H),10.99-11.15(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.09(m, 6H), 1.30-1.42(m, 1H), 1.66-1.75(m, 1H), 1.83-1.93(m, 1H) ,2.05-2.34(m,8H),2.81-3.27(m,4H),3.48-4.09(m,4H),5.27-5.74(m,1H),7.28-7.42(m,1H),7.65-7.77( m, 2H), 7.83-7.90 (m, 1H), 7.99-8.05 (m, 1H), 8.39-8.60 (m, 2H), 10.99-11.15 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=1.854min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=1.854 min.

實例610. 5-(2-((2R,5S )-2-(2-((R )-2-(二甲胺基)丙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1317)之合成Example 610. 5-(2-(( 2R,5S )-2-(2-(( R )-2-(dimethylamino)propyl)benzo[ d ]thiazol-5-yl)-5- Synthesis of methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1317)

Figure 110128222-A0202-12-2072-622
Figure 110128222-A0202-12-2072-622

步驟6：5-(2-((2R,5S)-2-(2-((R)-2-(二甲胺基)丙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1317)之合成Step 6: 5-(2-((2R,5S)-2-(2-((R)-2-(dimethylamino)propyl)benzo[d]thiazol-5-yl)-5- Synthesis of methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1317)

藉由一般程序方案H步驟6B製備。產率：22mg(6.60%)。Prepared by General Procedure H, Step 6B. Yield: 22 mg (6.60%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 40-80%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 40-80% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

藉由掌性HPLC自順式雜質純化產物(管柱：Chiralpak IC(250，20mm，5mkm)；流動相：IPA-MeOH，50-50；流速：10mL/min)(RT=54.03min)。The product was purified from the cis impurity by chiral HPLC (column: Chiralpak IC (250, 20 mm, 5 mkm); mobile phase: IPA-MeOH, 50-50; flow rate: 10 mL/min) (RT=54.03 min).

化合物1317 ：保留時間：39.98min Compound 1317 : retention time: 39.98min

LCMS(ESI)：[M]+ m/z：計算值538.2；實測值539.2；Rt=2.215min。LCMS (ESI): [M] + m/z: calculated 538.2; found 539.2; Rt=2.215 min.

實例611.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1,4-二甲基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1171)之合成Example 611. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1,4-dimethylpiperidin-4-yl) ) Synthesis of benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1171)

Figure 110128222-A0202-12-2073-623
Figure 110128222-A0202-12-2073-623

步驟1：5-氯-2-(1,4-二甲基哌啶-4-基)苯并[d]噻唑胺之合成Step 1: Synthesis of 5-chloro-2-(1,4-dimethylpiperidin-4-yl)benzo[d]thiazolamine

藉由一般程序方案H步驟1A製備。產率：3g(41.38%)。Prepared by General Procedure H, Step 1A. Yield: 3 g (41.38%).

CC條件： 藉由矽膠使用MeCN/MeOH(梯度10-100% MeOH)作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using MeCN/MeOH (gradient 10-100% MeOH) as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=1.529min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=1.529 min.

步驟2：2-(1,4-二甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1,4-Dimethylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of -2-yl)benzo[d]thiazole

將參(二苯亞甲基丙酮)二鈀(0)(652.18mg，712.21μmol)及XPhos(1.36g，2.85mmol)添加到5-氯-2-(1,4-二甲基-4-哌啶基)-1,3-苯并噻唑(4g，14.24mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(4.70g，18.52mmol)於二噁烷(60.00mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加乙酸鉀(2.80g，28.49mmol，1.78mL)。在惰性氣氛下，將所得混合物在100℃下攪拌15h，然後冷卻且在真空中蒸發，倒入到水(120mL)中且用DCM(2x50mL)萃取，經硫酸鈉乾燥且在真空中蒸發，以得到2-(1,4-二甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(0.9g，2.42mmol，16.97%產率)。Palladium (0) (652.18 mg, 712.21 μmol) and XPhos (1.36 g, 2.85 mmol) were added to 5-chloro-2-(1,4-dimethyl-4- piperidinyl)-1,3-benzothiazole (4 g, 14.24 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3, A solution of 2-dioxaborol-2-yl)-1,3,2-dioxaborolane (4.70 g, 18.52 mmol) in dioxane (60.00 mL). The reaction flask was evacuated and refilled with argon 3 times. Then potassium acetate (2.80 g, 28.49 mmol, 1.78 mL) was added under a stream of argon. The resulting mixture was stirred at 100 °C for 15 h under an inert atmosphere, then cooled and evaporated in vacuo, poured into water (120 mL) and extracted with DCM (2 x 50 mL), dried over sodium sulfate and evaporated in vacuo to give yields 2-(1,4-dimethyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1,3-benzothiazole (0.9 g, 2.42 mmol, 16.97% yield).

LCMS(ESI)：[M]+ m/z：計算值372.2；實測值373.2；Rt=3.119min。LCMS (ESI): [M] + m/z: calculated 372.2; found 373.2; Rt=3.119 min.

步驟3：(S)-6-(2-(1,4-二甲基哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1,4-Dimethylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydro Synthesis of tert-butyl pyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：1.3g粗品。Prepared by General Procedure H, Step 3. Yield: 1.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值441.2；實測值442.2；Rt=1.289min。LCMS (ESI): [M] + m/z: calculated 441.2; found 442.2; Rt=1.289 min.

步驟4：(S)-2-(1,4-二甲基哌啶-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1,4-Dimethylpiperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzene Synthesis of [d]thiazoles

藉由一般程序方案H步驟4製備。產率：0.7g粗品。Prepared by General Procedure H, Step 4. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=0.724min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=0.724 min.

步驟5：2-(1,4-二甲基哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 2-(1,4-Dimethylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.55g粗品。Prepared by General Procedure H, Step 5. Yield: 0.55 g crude.

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=1.772min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=1.772 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(1,4-二甲基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1171)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(1,4-dimethylpiperidin-4-yl) ) Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1171)

藉由一般程序方案H步驟6A製備。產率：31.4mg(13.45%)。Prepared by General Procedure H, Step 6A. Yield: 31.4 mg (13.45%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-6min 35-70%水-MeCN+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-6 min 35-70% water-MeCN+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,dmso)δ 0.98-1.06(m,3H),1.06-1.15(m,3H),1.31-1.40(m,4H),1.67-1.75(m,1H),1.78-1.93(m,3H),2.01-2.11(m,1H),2.12-2.17(m,3H),2.17-2.32(m,5H),2.32-2.38(m,2H),2.38-2.44(m,2H),2.77-3.26(m,1H),3.43-4.11(m,1H),5.26-5.61(m,1H),5.62-5.75(m,2H),7.35-7.43(m,1H),7.43-7.53(m,1H),7.85-7.93(m,1H),7.98-8.11(m,2H),10.49-10.68(m,1H)。 1 H NMR(600MHz,dmso)δ 0.98-1.06(m,3H),1.06-1.15(m,3H),1.31-1.40(m,4H),1.67-1.75(m,1H),1.78-1.93(m ,3H),2.01-2.11(m,1H),2.12-2.17(m,3H),2.17-2.32(m,5H),2.32-2.38(m,2H),2.38-2.44(m,2H),2.77 -3.26(m, 1H), 3.43-4.11(m, 1H), 5.26-5.61(m, 1H), 5.62-5.75(m, 2H), 7.35-7.43(m, 1H), 7.43-7.53(m, 1H), 7.85-7.93 (m, 1H), 7.98-8.11 (m, 2H), 10.49-10.68 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值534.2；實測值535.2；Rt=2.430min。LCMS (ESI): [M] + m/z: calculated 534.2; found 535.2; Rt=2.430 min.

實例612.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(四氫呋喃-3-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1242)之合成Example 612. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(tetrahydrofuran-3-yl)benzo Synthesis of [ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1242)

Figure 110128222-A0202-12-2075-624
Figure 110128222-A0202-12-2075-624

步驟1：四氫呋喃-3-羰基氯之合成Step 1: Synthesis of tetrahydrofuran-3-carbonyl chloride

向四氫呋喃-3-甲酸(3g，25.84mmol)於DCM(100mL)中之經攪拌之溶液中添加DMF(1.89mg，25.84umol，2.00uL)，隨後添加草醯氯(9.84g，77.51mmol，6.74mL)。將所得混合物在25℃下攪拌3h。在真空中蒸發DCM，以得到四氫呋喃-3-羰基氯(3.2g，23.78mmol，92.04%產率)，其直接用於下一步驟中。To a stirred solution of tetrahydrofuran-3-carboxylic acid (3 g, 25.84 mmol) in DCM (100 mL) was added DMF (1.89 mg, 25.84 umol, 2.00 uL) followed by oxalic chloride (9.84 g, 77.51 mmol, 6.74 g) mL). The resulting mixture was stirred at 25 °C for 3 h. The DCM was evaporated in vacuo to give tetrahydrofuran-3-carbonyl chloride (3.2 g, 23.78 mmol, 92.04% yield) which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)2.22(m,1H),2.31(m,1H),3.54(m,1H),3.82(m,1H),3.95(m,2H),4.09(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 2.22(m, 1H), 2.31(m, 1H), 3.54(m, 1H), 3.82(m, 1H), 3.95(m, 2H), 4.09( m, 1H).

步驟2：5-溴-2-(四氫呋喃-3-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-bromo-2-(tetrahydrofuran-3-yl)benzo[d]thiazole

向四氫呋喃-3-羰基氯(3.16g，23.52mmol)於NMP(15mL)中之經攪拌之溶液中添加2-胺基-4-溴苯硫酚(4g，19.60mmol)。將所得混合物在100℃下攪拌14h。反應混合物之LCMS分析顯示完全轉化。將反應混合物倒入到水中且用MTBE(3*50ml)萃取。將經合併之有機層用水及鹽水洗滌，經Na2 SO4 乾燥。在真空中蒸發MTBE，以得到粗品5-溴-2-四氫呋喃-3-基-1,3-苯并噻唑(4.5g，15.84mmol，80.80%產率)，其不經純化即用於下一步驟中。To a stirred solution of tetrahydrofuran-3-carbonyl chloride (3.16 g, 23.52 mmol) in NMP (15 mL) was added 2-amino-4-bromothiophenol (4 g, 19.60 mmol). The resulting mixture was stirred at 100 °C for 14 h. LCMS analysis of the reaction mixture showed complete conversion. The reaction mixture was poured into water and extracted with MTBE (3*50ml). The combined organic layers were washed with water and brine, dried over Na2SO4 . MTBE was evaporated in vacuo to give crude 5-bromo-2-tetrahydrofuran-3-yl-1,3-benzothiazole (4.5 g, 15.84 mmol, 80.80% yield) which was used in the next step without purification in steps.

LCMS(ESI)：[M]+ m/z：計算值284.2；實測值285.2；Rt=1.408min。LCMS (ESI): [M] + m/z: calculated 284.2; found 285.2; Rt=1.408 min.

步驟3：2-(四氫呋喃-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 3: 2-(Tetrahydrofuran-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[ d] Synthesis of thiazole

藉由一般程序方案H步驟2製備。產率：4.8g(91.51%)。Prepared by General Procedure Scheme H, Step 2. Yield: 4.8 g (91.51%).

LCMS(ESI)：[M]+ m/z：計算值331.2；實測值332.2；Rt=1.566min。LCMS (ESI): [M] + m/z: calculated 331.2; found 332.2; Rt=1.566 min.

步驟4：(3S)-3-甲基-6-(2-(四氫呋喃-3-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (3S)-3-Methyl-6-(2-(tetrahydrofuran-3-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid Synthesis of tertiary butyl ester

藉由一般程序方案H步驟3製備。產率：0.5g(8.61%)。Prepared by General Procedure H, Step 3. Yield: 0.5 g (8.61%).

CC條件： 藉由矽膠使用己烷/MTBE作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值400.2；實測值401.2；Rt=1.562min。LCMS (ESI): [M] + m/z: calculated 400.2; found 401.2; Rt=1.562 min.

步驟5：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(四氫呋喃-3-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(tetrahydrofuran-3-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：350mg(93.33%)。Prepared by General Procedure H, Step 4. Yield: 350 mg (93.33%).

LCMS(ESI)：[M]+ m/z：計算值300.2；實測值301.2；Rt=0.774min。LCMS (ESI): [M] + m/z: calculated 300.2; found 301.2; Rt=0.774 min.

步驟6：5-((2R,5S)-5-甲基哌啶-2-基)-2-(四氫呋喃-3-基)苯并[d]噻唑之合成Step 6: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(tetrahydrofuran-3-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.25g(70.95%)。Prepared by General Procedure H, Step 5. Yield: 0.25 g (70.95%).

LCMS(ESI)：[M]+ m/z：計算值302.2；實測值303.2；Rt=0.787min。LCMS (ESI): [M] + m/z: calculated 302.2; found 303.2; Rt=0.787 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(四氫呋喃-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1242)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(tetrahydrofuran-3-yl)benzo Synthesis of [d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1242)

藉由一般程序方案H步驟6A製備。產率：127mg(38.91%)。Prepared by General Procedure H, Step 6A. Yield: 127 mg (38.91%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-5min 50-100%水-MeOH+0.1% NH4 OH；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5 min 50-100% water-MeOH + 0.1% NH4OH ; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,dmso)δ 1.00-1.05(m,3H),1.06-1.15(m,3H),1.30-1.41(m,1H),1.65-1.75(m,1H),1.81-1.93(m,1H),2.04-2.18(m,1H),2.20-2.32(m,2H),2.32-2.36(m,1H),2.39-2.44(m,2H),2.76-3.27(m,1H),3.34-3.51(m,1H),3.80-3.85(m,1H),3.90-3.98(m,3H),4.07-4.13(m,1H),5.26-5.61(m,1H),5.61-5.75(m,2H),7.33-7.43(m,1H),7.43-7.55(m,1H),7.84-7.92(m,1H),7.97-8.09(m,2H),10.49-10.71(m,1H)。 1 H NMR(600MHz,dmso)δ 1.00-1.05(m,3H),1.06-1.15(m,3H),1.30-1.41(m,1H),1.65-1.75(m,1H),1.81-1.93(m ,1H),2.04-2.18(m,1H),2.20-2.32(m,2H),2.32-2.36(m,1H),2.39-2.44(m,2H),2.76-3.27(m,1H),3.34 -3.51(m, 1H), 3.80-3.85(m, 1H), 3.90-3.98(m, 3H), 4.07-4.13(m, 1H), 5.26-5.61(m, 1H), 5.61-5.75(m, 2H), 7.33-7.43 (m, 1H), 7.43-7.55 (m, 1H), 7.84-7.92 (m, 1H), 7.97-8.09 (m, 2H), 10.49-10.71 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值493.2；實測值494.2；Rt=2.640min。LCMS (ESI): [M] + m/z: calculated 493.2; found 494.2; Rt=2.640 min.

實例613.N -(5,6-二甲基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1,2,2,6,6-五甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1315)之合成Example 613. N- (5,6-Lutidine-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1,2,2,6,6- Synthesis of Pentamethylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1315)

步驟1：5-氯-2-(2,2,6,6-四甲基哌啶-4-基)苯并[d]噻唑(化合物1315)之合成Step 1: Synthesis of 5-chloro-2-(2,2,6,6-tetramethylpiperidin-4-yl)benzo[d]thiazole (compound 1315)

Figure 110128222-A0202-12-2077-625
Figure 110128222-A0202-12-2077-625

藉由一般程序方案H步驟1A製備。產率：3.75g(40.80%)。Prepared by General Procedure H, Step 1A. Yield: 3.75 g (40.80%).

CC條件： 藉由矽膠使用MTBE/MeOH作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using MTBE/MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值308.2；實測值309.2；Rt=1.063min。LCMS (ESI): [M] + m/z: calculated 308.2; found 309.2; Rt=1.063 min.

步驟2：5-氯-2-(1,2,2,6,6-五甲基哌啶-4-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-chloro-2-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2077-626
Figure 110128222-A0202-12-2077-626

將甲苯磺酸甲酯(2.35g，12.64mmol，1.91mL)及碳酸鉀(3.18g，22.99mmol，1.39mL)添加到5-氯-2-(2,2,6,6-四甲基-4-哌啶基)-1,3-苯并噻唑(3.55g，11.49mmol)於MeCN(50mL)中之溶液中。將所得混合物在80℃下攪拌48h。然後，在減壓下移除溶劑。將殘餘物懸浮於MTBE(60ml)中，過濾且在真空中濃縮，留下5-氯-2-(1,2,2,6,6-五甲基-4-哌啶基)-1,3-苯并噻唑(3.89g，粗品)。Methyl tosylate (2.35 g, 12.64 mmol, 1.91 mL) and potassium carbonate (3.18 g, 22.99 mmol, 1.39 mL) were added to 5-chloro-2-(2,2,6,6-tetramethyl- 4-Piperidinyl)-1,3-benzothiazole (3.55 g, 11.49 mmol) in MeCN (50 mL). The resulting mixture was stirred at 80 °C for 48 h. Then, the solvent was removed under reduced pressure. The residue was suspended in MTBE (60 ml), filtered and concentrated in vacuo to leave 5-chloro-2-(1,2,2,6,6-pentamethyl-4-piperidinyl)-1, 3-benzothiazole (3.89 g, crude).

LCMS(ESI)：[M]+ m/z：計算值322.2；實測值323.2；Rt=1.071min。LCMS (ESI): [M] + m/z: calculated 322.2; found 323.2; Rt=1.071 min.

步驟3：2-(1,2,2,6,6-五甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 3: 2-(1,2,2,6,6-Pentamethylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Synthesis of Bororol-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2078-627
Figure 110128222-A0202-12-2078-627

將5-氯-2-(1,2,2,6,6-五甲基-4-哌啶基)-1,3-苯并噻唑(3.89g，12.05mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.52g，13.85mmol)及乙酸鉀(2.36g，24.09mmol，1.51mL)一起混合於二噁烷(60mL)中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下，添加XPhos(1.15g，2.41mmol)及參(二苯亞甲基丙酮)二鈀(0)(551.60mg，602.36μmol)。將所得混合物在100℃下攪拌16h。然後，將其在減壓下濃縮且藉由梯度管柱層析(SiO2 ，MTBE/MeOH)純化殘餘物，得到2-(1,2,2,6,6-五甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(3g，7.24mmol，60.09%產率)。5-Chloro-2-(1,2,2,6,6-pentamethyl-4-piperidinyl)-1,3-benzothiazole (3.89 g, 12.05 mmol), 4,4,5, 5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxa Borolane (3.52 g, 13.85 mmol) and potassium acetate (2.36 g, 24.09 mmol, 1.51 mL) were mixed together in dioxane (60 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, under argon flow, XPhos (1.15 g, 2.41 mmol) and gins(dibenzylideneacetone)dipalladium(0) (551.60 mg, 602.36 μmol) were added. The resulting mixture was stirred at 100 °C for 16 h. It was then concentrated under reduced pressure and the residue was purified by gradient column chromatography (SiO 2 , MTBE/MeOH) to give 2-(1,2,2,6,6-pentamethyl-4-piperidine) pyridinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (3 g, 7.24 mmol, 60.09% yield).

LCMS(ESI)：[M]+ m/z：計算值414.2；實測值415.2；Rt=1.144min。LCMS (ESI): [M] + m/z: calculated 414.2; found 415.2; Rt=1.144 min.

步驟4：(S)-3-甲基-6-(2-(1,2,2,6,6-五甲基哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (S)-3-Methyl-6-(2-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzo[d]thiazol-5-yl)- Synthesis of 3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Figure 110128222-A0202-12-2078-628
Figure 110128222-A0202-12-2078-628

藉由一般程序方案H步驟3製備。產率：3.6g粗品。Prepared by General Procedure H, Step 3. Yield: 3.6 g crude.

LCMS(ESI)：[M]+ m/z：計算值483.2；實測值484.2；Rt=1.398min。LCMS (ESI): [M] + m/z: calculated 483.2; found 484.2; Rt=1.398 min.

步驟5：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1,2,2,6,6-五甲基哌啶-4-基)苯并Step 5: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1,2,2,6,6-pentamethylpiperidine -4-yl)benzo [d]噻唑之合成Synthesis of [d]thiazole

Figure 110128222-A0202-12-2079-629
Figure 110128222-A0202-12-2079-629

藉由一般程序方案H步驟4製備。產率：1.2g粗品。Prepared by General Procedure H, Step 4. Yield: 1.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值383.2；實測值384.2；Rt=0.753min。LCMS (ESI): [M] + m/z: calculated 383.2; found 384.2; Rt=0.753 min.

步驟6：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1,2,2,6,6-五甲基哌啶-4-基)苯并[d]噻唑之合成Step 6: 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzo[ d] Synthesis of thiazole

Figure 110128222-A0202-12-2079-630
Figure 110128222-A0202-12-2079-630

藉由一般程序方案H步驟5製備。產率：0.92g粗品。Prepared by General Procedure H, Step 5. Yield: 0.92 g crude.

LCMS(ESI)：[M]+ m/z：計算值385.2；實測值386.2；Rt=0.796min。LCMS (ESI): [M] + m/z: calculated 385.2; found 386.2; Rt=0.796 min.

N-(5,6-二甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1,2,2,6,6-五甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1315)之合成N-(5,6-Lutidine-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1,2,2,6,6-pentamethyl) Synthesis of piperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1315)

Figure 110128222-A0202-12-2079-631
Figure 110128222-A0202-12-2079-631

藉由一般程序方案H步驟6A製備。產率：33.7mg(14.30%)。Prepared by General Procedure H, Step 6A. Yield: 33.7 mg (14.30%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 70-70-85%水-MeOH+0.1% NH4 OH；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6 min 70-70-85% water-MeOH+0.1% NH4OH ; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.06(m,3H),1.06-1.09(m,6H),1.10-1.14(m,6H),1.31-1.41(m,1H),1.59-1.76(m,3H),1.82-1.98(m,3H),2.07-2.19(m,2H),2.21(s,3H),2.24(s,2H),2.28-2.38(m,4H),2.80-3.28(m,1H),3.43-4.05(m,2H),5.24-5.73(m,1H),7.34-7.44(m,1H),7.71-7.85(m,1H),7.85-7.92(m,1H),8.02-8.09(m,1H),8.37-8.54(m,1H),10.90-11.03(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.06(m,3H), 1.06-1.09(m,6H), 1.10-1.14(m,6H), 1.31-1.41(m,1H) ,1.59-1.76(m,3H),1.82-1.98(m,3H),2.07-2.19(m,2H),2.21(s,3H),2.24(s,2H),2.28-2.38(m,4H) ,2.80-3.28(m,1H),3.43-4.05(m,2H),5.24-5.73(m,1H),7.34-7.44(m,1H),7.71-7.85(m,1H),7.85-7.92( m, 1H), 8.02-8.09 (m, 1H), 8.37-8.54 (m, 1H), 10.90-11.03 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值561.2；實測值562.2；Rt=2.465min。LCMS (ESI): [M] + m/z: calculated 561.2; found 562.2; Rt=2.465 min.

實例614.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-((3-(二甲胺基)氧呾-3-基)甲基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1399)之合成Example 614. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-((3-(dimethylamino)oxygen-3 Synthesis of -yl)methyl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1399)

Figure 110128222-A0202-12-2080-632
Figure 110128222-A0202-12-2080-632

步驟1：((5-氯苯并[d]噻唑-2-基)甲基)三苯基鏻之合成Step 1: Synthesis of ((5-chlorobenzo[d]thiazol-2-yl)methyl)triphenylphosphonium

將三苯基磷烷(4.01g，15.29mmol)添加到5-氯-2-(氯甲基)-1,3-苯并噻唑(2.9g，13.30mmol)於MeCN(50mL)中之溶液中。將所得混合物在80℃下攪拌24h。然後，在減壓下移除溶劑。將殘餘物用冷MTBE(60mL)研磨。過濾所沉澱之棕色固體且乾燥，得到(5-氯-1,3-苯并噻唑-2-基)甲基三苯基鏻(5.16g，10.74mmol，80.78%產率，Cl- )。Triphenylphosphine (4.01 g, 15.29 mmol) was added to a solution of 5-chloro-2-(chloromethyl)-1,3-benzothiazole (2.9 g, 13.30 mmol) in MeCN (50 mL) . The resulting mixture was stirred at 80 °C for 24 h. Then, the solvent was removed under reduced pressure. The residue was triturated with cold MTBE (60 mL). The precipitated brown solid was filtered and dried to give (5-chloro-1,3-benzothiazol-2-yl)methyltriphenylphosphonium (5.16 g, 10.74 mmol, 80.78% yield, Cl − ).

LCMS(ESI)：[M]+ m/z：計算值480.2；實測值481.2；Rt=1.358min。LCMS (ESI): [M] + m/z: calculated 480.2; found 481.2; Rt=1.358 min.

步驟2：3-((5-氯苯并[d]噻唑-2-基)甲基)-N,N-二甲基氧呾-3-胺之合成Step 2: Synthesis of 3-((5-Chlorobenzo[d]thiazol-2-yl)methyl)-N,N-dimethyloxypyridine-3-amine

將第三丁醇鉀(991.15mg，8.83mmol)添加到(5-氯-1,3-苯并噻唑-2-基)甲基三苯基鏻(4.16g，8.66mmol，Cl-)於THF(80mL)中之懸浮液中。在20℃下攪拌2.5h之後，向其中添加氧呾-3-酮(686.44mg，9.53mmol，610.71μL)且將所得混合物再攪拌2.5h。然後，添加於THF中之17%二甲胺溶液(9.19g，34.64mmol，17%純度)且將所得混合物在50℃下攪拌18h。此後，在減壓下移除溶劑且將固體殘餘物用5% NaHSO4 水溶液(2x60mL)徹底萃取。過濾出不溶性三苯基膦氧化物且將濾液用DCM(20mL)洗滌。分離水層且將其用固體K2 CO3 鹼化至pH

Figure 110128222-A0202-12-2081-546
10-11。將所得混濁溶液用DCM(3x30mL)萃取。將經合併之有機層經固體K2 CO3 乾燥且在減壓下濃縮，得到3-[(5-氯-1,3-苯并噻唑-2-基)甲基]-N,N -二甲基-氧呾-3-胺(2.6g，粗品)。Potassium tert-butoxide (991.15 mg, 8.83 mmol) was added to (5-chloro-1,3-benzothiazol-2-yl)methyltriphenylphosphonium (4.16 g, 8.66 mmol, Cl-) in THF (80 mL). After stirring at 20 °C for 2.5 h, oxon-3-one (686.44 mg, 9.53 mmol, 610.71 μL) was added and the resulting mixture was stirred for an additional 2.5 h. Then, a 17% solution of dimethylamine in THF (9.19 g, 34.64 mmol, 17% purity) was added and the resulting mixture was stirred at 50 °C for 18 h. After this time, the solvent was removed under reduced pressure and the solid residue was extracted thoroughly with 5% aqueous NaHSO 4 (2×60 mL). The insoluble triphenylphosphine oxide was filtered off and the filtrate was washed with DCM (20 mL). The aqueous layer was separated and basified to pH with solid K2CO3
Figure 110128222-A0202-12-2081-546
10-11. The resulting cloudy solution was extracted with DCM (3x30 mL). The combined organic layers were dried over solid K2CO3 and concentrated under reduced pressure to give 3 -[(5-chloro-1,3-benzothiazol-2-yl)methyl] -N,N -di Methyl-oxan-3-amine (2.6 g, crude).

LCMS(ESI)：[M]+ m/z：計算值282.2；實測值283.2；Rt=0.962min。LCMS (ESI): [M] + m/z: calculated 282.2; found 283.2; Rt=0.962 min.

步驟3：N,N-二甲基-3-((5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)甲基)氧呾-3-胺之合成Step 3: N,N-Dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene Synthesis of [d]thiazol-2-yl)methyl)oxo-3-amine

將3-[(5-氯-1,3-苯并噻唑-2-基)甲基]-N,N -二甲基-氧呾-3-胺(2.6g，9.19mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.80g，11.03mmol)及乙酸鉀(1.80g，18.39mmol，1.15mL)一起混合於二噁烷(50mL)中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加參(二苯亞甲基丙酮)二鈀(0)(420.96mg，459.71μmol)及XPhos(876.60mg，1.84mmol)。將所得混合物在100℃下攪拌18h。然後，將其在減壓下濃縮且將殘餘物用MTBE(2x30mL)萃取。將所得MTBE溶液用硫酸氫鈉(3.31g，27.58mmol)於水(50mL)中之溶液萃取。分離水層且透過紙過濾器過濾，以移除混濁。所得澄清溶液按原樣用於下一步驟中。3-[(5-Chloro-1,3-benzothiazol-2-yl)methyl] -N,N -dimethyl-oxan-3-amine (2.6 g, 9.19 mmol), 4,4 ,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2- Dioxaborolane (2.80 g, 11.03 mmol) and potassium acetate (1.80 g, 18.39 mmol, 1.15 mL) were mixed together in dioxane (50 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, under an argon flow, paras(dibenzylideneacetone)dipalladium(0) (420.96 mg, 459.71 μmol) and XPhos (876.60 mg, 1.84 mmol) were added. The resulting mixture was stirred at 100 °C for 18 h. It was then concentrated under reduced pressure and the residue was extracted with MTBE (2x30 mL). The resulting MTBE solution was extracted with a solution of sodium bisulfate (3.31 g, 27.58 mmol) in water (50 mL). The aqueous layer was separated and filtered through a paper filter to remove turbidity. The resulting clear solution was used as is in the next step.

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=1.172min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=1.172 min.

步驟4：(S)-6-(2-((3-(二甲胺基)氧呾-3-基)甲基)苯并[d]噻唑-5-基)-3-甲基-3,4-二Step 4: (S)-6-(2-((3-(Dimethylamino)oxypyran-3-yl)methyl)benzo[d]thiazol-5-yl)-3-methyl-3 ,4-two 氫吡啶-1(2H)-甲酸第三丁酯之合成Synthesis of Hydropyridine-1(2H)-Carboxylic Acid 3-Butyl Ester

藉由一般程序方案H步驟3製備。產率：3.73g粗品。Prepared by General Procedure H, Step 3. Yield: 3.73 g crude.

LCMS(ESI)：[M]+ m/z：計算值443.2；實測值444.2；Rt=1.264min。LCMS (ESI): [M] + m/z: calculated 443.2; found 444.2; Rt=1.264 min.

步驟5：(S)-N,N-二甲基-3-((5-(5-甲基-3，4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)甲基)氧呾-3-胺之合成Step 5: (S)-N,N-Dimethyl-3-((5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole- Synthesis of 2-yl)methyl)oxo-3-amine

藉由一般程序方案H步驟4製備。產率：0.7g粗品。Prepared by General Procedure H, Step 4. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=0.636min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=0.636 min.

步驟6：N,N-二甲基-3-((5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)甲基)氧呾-3-胺之合成Step 6: N,N-Dimethyl-3-((5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)methyl)oxy Synthesis of pyrimidine-3-amine

藉由一般程序方案H步驟5製備。產率：0.57g粗品。Prepared by General Procedure H, Step 5. Yield: 0.57 g crude.

LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=0.575min。LCMS (ESI): [M] + m/z: calculated 345.2; found 346.2; Rt=0.575 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-((3-(二甲胺基)氧呾-3-基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1399)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-((3-(dimethylamino)oxygen-3 Synthesis of -yl)methyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1399)

藉由一般程序方案H步驟6A製備。產率：53.9mg(30.44%)。Prepared by General Procedure H, Step 6A. Yield: 53.9 mg (30.44%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 10-10-45%水-MeCN+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeCN)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 10-10-45% water-MeCN+0.1% NH4OH , flow rate: 30mL/min; (loading pump 4mL/min MeCN ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.05(m,3H),1.06-1.16(m,3H),1.30-1.41(m,1H),1.66-1.76(m,1H),1.83-1.92(m,1H),2.04-2.35(m,9H),2.39-2.43(m,1H),2.74-3.28(m,1H),3.42-4.11(m,3H),4.40-4.50(m,2H),4.50-4.60(m,2H),5.24-5.72(m,3H),7.32-7.55(m,2H),7.84-7.93(m,1H),7.97-8.11(m,2H),10.48-10.65(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.05(m,3H), 1.06-1.16(m,3H), 1.30-1.41(m,1H), 1.66-1.76(m,1H) ,1.83-1.92(m,1H),2.04-2.35(m,9H),2.39-2.43(m,1H),2.74-3.28(m,1H),3.42-4.11(m,3H),4.40-4.50( m,2H),4.50-4.60(m,2H),5.24-5.72(m,3H),7.32-7.55(m,2H),7.84-7.93(m,1H),7.97-8.11(m,2H), 10.48-10.65 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值536.2；實測值537.2；Rt=2.147min。LCMS (ESI): [M] + m/z: calculated 536.2; found 537.2; Rt=2.147 min.

實例615.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(4-甲基嗎啉-3-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1245)之合成Example 615. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(4-methylmorpholine-3 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1245)

Figure 110128222-A0202-12-2083-633
Figure 110128222-A0202-12-2083-633

步驟1：3-(5-氯苯并[d]噻唑-2-基)嗎啉-4-甲酸第三丁酯之合成Step 1: Synthesis of 3-(5-chlorobenzo[d]thiazol-2-yl)morpholine-4-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟1B製備。產率：2.2g(14.14%)。Prepared by General Procedure H, Step IB. Yield: 2.2 g (14.14%).

CC條件： 藉由矽膠使用己烷/MTBE(梯度10-100% MTBE)作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE (gradient 10-100% MTBE) as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值354.2；實測值355.2；Rt=1.582min。LCMS (ESI): [M] + m/z: calculated 354.2; found 355.2; Rt=1.582 min.

步驟2：3-(5-氯苯并[d]噻唑-2-基)嗎啉之合成Step 2: Synthesis of 3-(5-Chlorobenzo[d]thiazol-2-yl)morpholine

將於二噁烷中之4.0M氯化氫溶液(800.00mg，21.94mmol，1mL)添加到3-(5-氯-1,3-苯并噻唑-2-基)嗎啉-4-甲酸第三丁酯(0.2g，563.62μmol)於MeOH(10mL)中之溶液中。將反應混合物在20℃下攪拌7h，然後蒸發且添加到MTBE(10mL)中，過濾出所得沉澱，用MTBE(10mL)洗滌且乾燥，以得到3-(5-氯-1,3-苯并噻唑-2-基)嗎啉(0.1g，343.41μmol，60.93%產率，HCl)。A 4.0M solution of hydrogen chloride in dioxane (800.00 mg, 21.94 mmol, 1 mL) was added to 3-(5-chloro-1,3-benzothiazol-2-yl)morpholine-4-carboxylic acid tert-butyl A solution of ester (0.2 g, 563.62 [mu]mol) in MeOH (10 mL). The reaction mixture was stirred at 20 °C for 7 h, then evaporated and added to MTBE (10 mL), the resulting precipitate was filtered off, washed with MTBE (10 mL) and dried to give 3-(5-chloro-1,3-benzoxy Thiazol-2-yl)morpholine (0.1 g, 343.41 μmol, 60.93% yield, HCl).

LCMS(ESI)：[M]+ m/z：計算值254.2；實測值255.2；Rt=0.746min。LCMS (ESI): [M] + m/z: calculated 254.2; found 255.2; Rt=0.746 min.

步驟3：3-(5-氯苯并[d]噻唑-2-基)-4-甲基嗎啉之合成Step 3: Synthesis of 3-(5-Chlorobenzo[d]thiazol-2-yl)-4-methylmorpholine

將3-(5-氯-1,3-苯并噻唑-2-基)嗎啉(1.3g，4.46mmol，HCl)溶解於MeOH(29.00mL)中且添加無水乙酸鈉(439.47mg，5.36mmol，287.61μL)、用7-8% MeOH穩定之37重量%甲醛水溶液(268.13mg，8.93mmol，247.58μL)，向其中添加AcOH(536.19mg，8.93mmol，511.14μL)且將反應混合物在室溫下攪拌1h。然後分批添加氰基硼氫化鈉(561.08mg，8.93mmol)。將所得混合物在0 ℃下攪拌7h，然後在真空中蒸發。將殘餘物用100mL NaOH(10%)稀釋且用DCM(2*30mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到4-氟-4-(羥基甲基)哌啶-1-甲酸第三丁酯(5.6g，24.01mmol，83.10%產率)。3-(5-Chloro-1,3-benzothiazol-2-yl)morpholine (1.3 g, 4.46 mmol, HCl) was dissolved in MeOH (29.00 mL) and anhydrous sodium acetate (439.47 mg, 5.36 mmol) was added , 287.61 μL), 37 wt% aqueous formaldehyde stabilized with 7-8% MeOH (268.13 mg, 8.93 mmol, 247.58 μL), to which AcOH (536.19 mg, 8.93 mmol, 511.14 μL) was added and the reaction mixture was allowed to cool at room temperature under stirring for 1 h. Then sodium cyanoborohydride (561.08 mg, 8.93 mmol) was added portionwise. Put the resulting mixture at 0 Stirred at °C for 7 h, then evaporated in vacuo. The residue was diluted with 100 mL NaOH (10%) and extracted with DCM (2*30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (5.6 g, 24.01 mmol, 83.10% yield). Rate).

LCMS(ESI)：[M]+ m/z：計算值268.2；實測值269.2；Rt=2.096min。LCMS (ESI): [M] + m/z: calculated 268.2; found 269.2; Rt=2.096 min.

步驟4：4-甲基-3-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)嗎啉之合成Step 4: 4-Methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d] Synthesis of Thiazol-2-yl)morpholine

將參(二苯亞甲基丙酮)二鈀(0)(238.50mg，260.45μmol)及XPhos(496.65mg，1.04mmol)添加到3-(5-氯-1,3-苯并噻唑-2-基)-4-甲基嗎啉(1.4g，5.21mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.72g，6.77mmol)於二噁烷(29.35mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加乙酸鉀(1.53g，15.63mmol，976.85μL)。在惰性氣氛下將所得混合物在100℃下攪拌12h，然後冷卻且在真空中蒸發，倒入到水(200mL)中且用DCM(2x30mL)萃取，經硫酸鈉乾燥且在真空中蒸發，留下1.8g粗產物，1.8g粗產物藉由矽膠管柱層析使用己烷/MTBE梯度(10-100% MTBE)進行純化，得到4-甲基-3-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]嗎啉(1.1g，3.05mmol，58.61%產率)。To 3-(5-chloro-1,3-benzothiazole-2-) gins(dibenzylideneacetone)dipalladium(0) (238.50 mg, 260.45 μmol) and XPhos (496.65 mg, 1.04 mmol) were added yl)-4-methylmorpholine (1.4 g, 5.21 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)-1,3,2-dioxaborolane (1.72 g, 6.77 mmol) in dioxane (29.35 mL). The reaction flask was evacuated and refilled with argon 3 times. Then potassium acetate (1.53 g, 15.63 mmol, 976.85 μL) was added under a stream of argon. The resulting mixture was stirred at 100 °C for 12 h under an inert atmosphere, then cooled and evaporated in vacuo, poured into water (200 mL) and extracted with DCM (2 x 30 mL), dried over sodium sulfate and evaporated in vacuo to leave 1.8 g crude product, 1.8 g crude product was purified by silica gel column chromatography using a hexane/MTBE gradient (10-100% MTBE) to give 4-methyl-3-[5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazol-2-yl]morpholine (1.1 g, 3.05 mmol, 58.61% yield Rate).

LCMS(ESI)：[M]+ m/z：計算值360.2；實測值361.2；Rt=2.608min。LCMS (ESI): [M] + m/z: calculated 360.2; found 361.2; Rt=2.608 min.

步驟5：(3S)-3-甲基-6-(2-(4-甲基嗎啉-3-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (3S)-3-Methyl-6-(2-(4-methylmorpholin-3-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：1.4g粗品。Prepared by General Procedure H, Step 3. Yield: 1.4 g crude.

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=3.782min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=3.782 min.

步驟6：4-甲基-3-(5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)嗎啉之合成Step 6: 4-Methyl-3-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl) Synthesis of Morpholine

藉由一般程序方案H步驟4製備。產率：0.7g粗品。Prepared by General Procedure H, Step 4. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.635min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.635 min.

步驟7：4-甲基-3-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)嗎啉之合成Step 7: Synthesis of 4-methyl-3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)morpholine

藉由一般程序方案H步驟5製備。產率：0.6g(85.19%)。Prepared by General Procedure H, Step 5. Yield: 0.6 g (85.19%).

LCMS(ESI)：[M]+ m/z：計算值331.2；實測值332.2；Rt=0.828min。LCMS (ESI): [M] + m/z: calculated 331.2; found 332.2; Rt=0.828 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(4-甲基嗎啉-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1245)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(4-methylmorpholine-3 Synthesis of -yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1245)

藉由一般程序方案H步驟6A製備。產率：57.4mg(18.20%)。Prepared by General Procedure H, Step 6A. Yield: 57.4 mg (18.20%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-6min 40-90%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeCN)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-6 min 40-90% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeCN).

1 H NMR(600MHz,dmso)δ 1.00-1.05(m,3H),1.05-1.14(m,3H),1.30-1.40(m,1H),1.65-1.74(m,1H),1.82-1.93(m,1H),2.07-2.21(m,4H),2.25-2.36(m,2H),2.40-2.43(m,1H),2.76-3.27(m,2H),3.38-4.08(m,7H),5.26-5.71(m,3H),7.37-7.44(m,1H),7.44-7.54(m,1H),7.88-7.94(m,1H),7.97-8.12(m,2H),10.42-10.65(m,1H)。 1 H NMR(600MHz,dmso)δ 1.00-1.05(m,3H),1.05-1.14(m,3H),1.30-1.40(m,1H),1.65-1.74(m,1H),1.82-1.93(m ,1H),2.07-2.21(m,4H),2.25-2.36(m,2H),2.40-2.43(m,1H),2.76-3.27(m,2H),3.38-4.08(m,7H),5.26 -5.71(m, 3H), 7.37-7.44(m, 1H), 7.44-7.54(m, 1H), 7.88-7.94(m, 1H), 7.97-8.12(m, 2H), 10.42-10.65(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=2.532min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=2.532 min.

實例616.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(2-(二甲胺基)丙-2-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1250)之合成Example 616. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(2-(dimethylamino)propan-2-yl) ) Synthesis of benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1250)

Figure 110128222-A0202-12-2085-634
Figure 110128222-A0202-12-2085-634

步驟1：N-((5-溴苯并[d]噻唑-2-基)甲基)-N-乙基乙胺之合成Step 1: Synthesis of N-((5-bromobenzo[d]thiazol-2-yl)methyl)-N-ethylethylamine

藉由一般程序方案H步驟1C製備。產率：4.1g粗品。Prepared by General Procedure H, Step 1C. Yield: 4.1 g crude.

LCMS(ESI)：[M]+ m/z：計算值299.2；實測值300.2；Rt=0.785min。LCMS (ESI): [M] + m/z: calculated 299.2; found 300.2; Rt=0.785min.

步驟2：N-乙基-N-((5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)甲基)乙胺之合成Step 2: N-ethyl-N-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[d Synthesis of ]thiazol-2-yl)methyl)ethylamine

藉由一般程序方案H步驟2製備。產率：4.2g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 4.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值346.2；實測值347.2；Rt=1.030min。LCMS (ESI): [M] + m/z: calculated 346.2; found 347.2; Rt=1.030 min.

步驟3：(S)-6-(2-((二乙胺基)甲基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-((Diethylamino)methyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H )-Synthesis of tert-butyl formate

藉由一般程序方案H步驟3製備。產率：1.2g(36.07%)。Prepared by General Procedure H, Step 3. Yield: 1.2 g (36.07%).

CC條件： 藉由矽膠使用MTBE/MeOH作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using MTBE/MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.264min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.264 min.

步驟4：(S)-N-乙基-N-((5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)甲基)乙胺之合成Step 4: (S)-N-ethyl-N-((5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazol-2-yl ) methyl) ethylamine synthesis

藉由一般程序方案H步驟4製備。產率：0.67g粗品。Prepared by General Procedure H, Step 4. Yield: 0.67 g crude.

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.225min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.225 min.

步驟5：N-乙基-N-((5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)甲基)乙胺之合成Step 5: Synthesis of N-ethyl-N-((5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)methyl)ethanamine

藉由一般程序方案H步驟5製備。產率：0.62g(91.95%)。Prepared by General Procedure H, Step 5. Yield: 0.62 g (91.95%).

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.697min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.697 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(2-(二甲胺基)丙-2-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1250)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(2-(dimethylamino)propan-2-yl) ) Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1250)

藉由一般程序方案H步驟6A製備。產率：20.8mg(11.91%)。Prepared by General Procedure H, Step 6A. Yield: 20.8 mg (11.91%).

HPLC條件： 管柱：SunFire C18 100*19mm，5微米；2-10min 40-55%水-MeCN+FA，流速：30mL/min；(裝載泵4mL/min MeCN)。 HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-10 min 40-55% water-MeCN+FA, flow rate: 30 mL/min; (loading pump 4 mL/min MeCN).

1 H NMR(600MHz,dmso)δ 0.99-1.05(m,9H),1.05-1.14(m,3H),1.30-1.41(m,1H),1.66-1.75(m,1H),1.82-1.92(m,1H),2.05-2.23(m,1H),2.27-2.35(m,1H),2.40(q,1H),2.57-2.63(m,5H),2.75-3.00(m,1H),3.45-4.07(m,3H),5.23-5.73(m,3H),7.30-7.41(m,1H),7.42-7.55(m,1H),7.81-7.87(m,1H),7.98-8.05(m,1H),8.06-8.21(m,1H),10.49-10.59(m,1H)。 1 H NMR(600MHz, dmso)δ 0.99-1.05(m, 9H), 1.05-1.14(m, 3H), 1.30-1.41(m, 1H), 1.66-1.75(m, 1H), 1.82-1.92(m ,1H),2.05-2.23(m,1H),2.27-2.35(m,1H),2.40(q,1H),2.57-2.63(m,5H),2.75-3.00(m,1H),3.45-4.07 (m,3H),5.23-5.73(m,3H),7.30-7.41(m,1H),7.42-7.55(m,1H),7.81-7.87(m,1H),7.98-8.05(m,1H) , 8.06-8.21 (m, 1H), 10.49-10.59 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=2.151min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=2.151 min.

實例617. 2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-N -(6-甲基-5-(三氟甲基)吡啶-3-基)-2-側氧基乙醯胺(化合物1300)之合成Example 617. 2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1- yl)-N-(6 - methyl-5-(trifluoromethyl)pyridin-3-yl)-2-oxyacetamide (compound 1300)

Figure 110128222-A0202-12-2087-635
Figure 110128222-A0202-12-2087-635

藉由一般程序方案H步驟6A製備。產率：58mg(20.85%)。Prepared by General Procedure H, Step 6A. Yield: 58 mg (20.85%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 40-90%水-MeOH+0.1% NH4 OH；(裝載泵4mL/min MeCN)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 40-90% water-MeOH+0.1% NH4OH ; (loading pump 4 mL/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.07(m,3H),1.31-1.40(m,1H),1.68-1.76(m,1H),1.77-1.84(m,2H),1.84-1.95(m,1H),1.98-2.11(m,5H),2.18(s,3H),2.29-2.34(m,1H),2.54-2.60(m,3H),2.78-3.12(m,4H),3.51-4.04(m,1H),5.28-5.75(m,1H),7.32-7.42(m,1H),7.88(s,1H),8.00-8.11(m,1H),8.31-8.51(m,1H),8.82-8.98(m,1H),11.24-11.49(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.07(m,3H), 1.31-1.40(m,1H), 1.68-1.76(m,1H), 1.77-1.84(m,2H) ,1.84-1.95(m,1H),1.98-2.11(m,5H),2.18(s,3H),2.29-2.34(m,1H),2.54-2.60(m,3H),2.78-3.12(m, 4H), 3.51-4.04(m, 1H), 5.28-5.75(m, 1H), 7.32-7.42(m, 1H), 7.88(s, 1H), 8.00-8.11(m, 1H), 8.31-8.51( m, 1H), 8.82-8.98 (m, 1H), 11.24-11.49 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值559.2；實測值560.2；Rt=3.137min。LCMS (ESI): [M] + m/z: calculated 559.2; found 560.2; Rt=3.137 min.

實例618. 5-(2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶Example 618. 5-(2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidine -1-基)-2-側氧基乙醯胺基)-2-(三氟甲氧基)菸鹼醯胺(化合物1337)之合成Synthesis of -1-yl)-2-oxyacetamido)-2-(trifluoromethoxy)nicotinamide (compound 1337)

Figure 110128222-A0202-12-2088-636
Figure 110128222-A0202-12-2088-636

藉由一般程序方案H步驟6A製備。產率：78mg(31.65%)。Prepared by General Procedure H, Step 6A. Yield: 78 mg (31.65%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 30-80%水-MeOH+0.1% NH4 OH；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 30-80% water-MeOH + 0.1% NH4OH ; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.09(m,3H),1.31-1.43(m,1H),1.66-1.75(m,1H),1.75-1.93(m,3H),1.93-2.16(m,5H),2.18(s,3H),2.28-2.37(m,1H),2.78-2.87(m,2.3H),2.98-3.08(m,1H),3.31-3.37(m,0.7H),3.45-4.12(m,1H),5.15-5.76(m,1H),7.30-7.43(m,1H),7.71-7.83(m,1H),7.85-7.91(m,1H),7.91-8.02(m,1H),8.02-8.10(m,1H),8.27-8.41(m,1H),8.50-8.68(m,1H),11.16-11.59(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.09(m,3H), 1.31-1.43(m,1H), 1.66-1.75(m,1H), 1.75-1.93(m,3H) ,1.93-2.16(m,5H),2.18(s,3H),2.28-2.37(m,1H),2.78-2.87(m,2.3H),2.98-3.08(m,1H),3.31-3.37(m ,0.7H),3.45-4.12(m,1H),5.15-5.76(m,1H),7.30-7.43(m,1H),7.71-7.83(m,1H),7.85-7.91(m,1H), 7.91-8.02(m,1H), 8.02-8.10(m,1H), 8.27-8.41(m,1H), 8.50-8.68(m,1H), 11.16-11.59(m,1H).

LCMS(ESI)：[M+1]+ m/z：計算值604.2；實測值605.2；Rt=2.888min。LCMS (ESI): [M+1] + m/z: calculated 604.2; found 605.2; Rt=2.888 min.

實例619. 2-甲基-5-(2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1326)之合成Example 619. 2-Methyl-5-(2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[ d ]thiazole-5 Synthesis of -yl)piperidin-1-yl)-2-oxoacetamido)nicotinamide (compound 1326)

Figure 110128222-A0202-12-2088-637
Figure 110128222-A0202-12-2088-637

藉由一般程序方案H步驟6A製備。產率：103mg(47.27%)。Prepared by General Procedure H, Step 6A. Yield: 103 mg (47.27%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-5min 15-50%水-MeCN+0.1%NH4 OH；(裝載泵4mL/min MeCN)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5 min 15-50% water-MeCN + 0.1% NH4OH ; (loading pump 4 mL/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.09(m,3H),1.30-1.43(m,1H),1.65-1.74(m,1H),1.75-1.95(m,3H),1.98-2.12(m,5H),2.18(s,3H),2.28-2.35(m,1H),2.43-2.47(m,3H),2.81-2.86(m,2H),3.02-3.11(m,1H),3.32-3.38(m,1H),3.45-4.09(m,1H),5.22-5.73(m,1H),7.32-7.44(m,1H),7.48-7.60(m,1H),7.82-7.89(m,1H),7.89-7.94(m,1H),7.96-8.10(m,2H),8.57-8.79(m,1H),10.80(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.09(m,3H), 1.30-1.43(m,1H), 1.65-1.74(m,1H), 1.75-1.95(m,3H) ,1.98-2.12(m,5H),2.18(s,3H),2.28-2.35(m,1H),2.43-2.47(m,3H),2.81-2.86(m,2H),3.02-3.11(m, 1H), 3.32-3.38(m, 1H), 3.45-4.09(m, 1H), 5.22-5.73(m, 1H), 7.32-7.44(m, 1H), 7.48-7.60(m, 1H), 7.82- 7.89 (m, 1H), 7.89-7.94 (m, 1H), 7.96-8.10 (m, 2H), 8.57-8.79 (m, 1H), 10.80 (br s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值534.2；實測值535.2；Rt=2.375min。LCMS (ESI): [M+1] + m/z: calculated 534.2; found 535.2; Rt=2.375 min.

實例620. 2-甲氧基-5-(2-((2R,5S )-5-甲基-2-(2-(1,2,2,6,6-五甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1108)之合成Example 620. 2-Methoxy-5-(2-(( 2R,5S )-5-methyl-2-(2-(1,2,2,6,6-pentamethylpiperidine-4- Synthesis of yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 1108)

Figure 110128222-A0202-12-2089-638
Figure 110128222-A0202-12-2089-638

藉由一般程序8步驟6A製備。產率：64.1mg(27.16%)。Prepared by General Procedure 8, Step 6A. Yield: 64.1 mg (27.16%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 65-65-80%水-MeOH+0.1% NH4 OH；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6 min 65-65-80% water-MeOH+0.1% NH4OH ; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.06(m,3H),1.06-1.09(m,6H),1.10-1.15(m,6H),1.32-1.41(m,1H),1.59-1.67(m,2H),1.67-1.75(m,1H),1.81-1.98(m,3H),2.04-2.19(m,1H),2.19-2.23(m,3H),2.27-2.37(m,1H),2.80-3.28(m,1H),3.44-3.55(m,1.7H),3.90-3.97(m,3H),4.01-4.05(m,0.3H),5.22-5.76(m,1H),7.33-7.44(m,1H),7.64-7.78(m,2H),7.86-7.92(m,1H),8.03-8.09(m,1H),8.33-8.63(m,2H),10.90-11.19(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.06(m,3H), 1.06-1.09(m,6H), 1.10-1.15(m,6H), 1.32-1.41(m,1H) ,1.59-1.67(m,2H),1.67-1.75(m,1H),1.81-1.98(m,3H),2.04-2.19(m,1H),2.19-2.23(m,3H),2.27-2.37( m, 1H), 2.80-3.28(m, 1H), 3.44-3.55(m, 1.7H), 3.90-3.97(m, 3H), 4.01-4.05(m, 0.3H), 5.22-5.76(m, 1H) ),7.33-7.44(m,1H),7.64-7.78(m,2H),7.86-7.92(m,1H),8.03-8.09(m,1H),8.33-8.63(m,2H),10.90-11.19 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值606.2；實測值607.2；Rt=2.453min。LCMS (ESI): [M] + m/z: calculated 606.2; found 607.2; Rt=2.453 min.

實例621.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1,4-二甲基-5-側氧基哌嗪-2-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1231)之合成Example 621. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1,4-dimethyl-5-pendoxyl) Synthesis of piperazin-2-yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1231)

Figure 110128222-A0202-12-2090-639
Figure 110128222-A0202-12-2090-639

步驟1：5-(5-氯苯并[d]噻唑-2-基)-1-甲基哌嗪-2-酮之合成Step 1: Synthesis of 5-(5-Chlorobenzo[d]thiazol-2-yl)-1-methylpiperazin-2-one

藉由一般程序方案H步驟1A製備。產率：9.5g粗品。Prepared by General Procedure H, Step 1A. Yield: 9.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值281.2；實測值282.2；Rt=0.885min。LCMS (ESI): [M] + m/z: calculated 281.2; found 282.2; Rt=0.885min.

步驟2：5-(5-氯苯并[d]噻唑-2-基)-1,4-二甲基哌嗪-2-酮之合成Step 2: Synthesis of 5-(5-Chlorobenzo[d]thiazol-2-yl)-1,4-dimethylpiperazin-2-one

將5-(5-氯-1,3-苯并噻唑-2-基)-1-甲基哌嗪-2-酮(8.5g，30.17mmol)、甲醛(3.43g，42.23mmol，3.16mL)及乙酸(3.62g，60.33mmol，3.45mL)於MeOH(170mL)中之混合物在室溫下攪拌2h。向混合物中一次性添加氰基硼氫化鈉(3.79g，60.33mmol)。將混合物在20℃下攪拌18h，然後在真空中濃縮。將殘餘物鹼化至pH=9(K2 CO3 10%水溶液)且用DCM(2*90mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到5-(5-氯-1,3-苯并噻唑-2-基)-1,4-二甲基哌嗪-2-酮(9g，粗品)。Combine 5-(5-chloro-1,3-benzothiazol-2-yl)-1-methylpiperazin-2-one (8.5 g, 30.17 mmol), formaldehyde (3.43 g, 42.23 mmol, 3.16 mL) and a mixture of acetic acid (3.62 g, 60.33 mmol, 3.45 mL) in MeOH (170 mL) was stirred at room temperature for 2 h. To the mixture was added sodium cyanoborohydride (3.79 g, 60.33 mmol) in one portion. The mixture was stirred at 20 °C for 18 h, then concentrated in vacuo. The residue was basified to pH= 9 (K2CO3 10 % in water) and extracted with DCM (2*90 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-chloro-1,3-benzothiazol-2-yl)-1,4-dimethylpiperazine-2 - Ketone (9 g, crude).

LCMS(ESI)：[M]+ m/z：計算值295.2；實測值296.2；Rt=1.098min。LCMS (ESI): [M] + m/z: calculated 295.2; found 296.2; Rt=1.098 min.

步驟3：1,4-二甲基-5-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻Step 3: 1,4-Dimethyl-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo [d] thiophene 唑-2-基)哌嗪-2-酮之合成Synthesis of oxazol-2-yl)piperazin-2-one

將乙酸鉀(6.17g，62.88mmol，3.93mL)添加到5-(5-氯-1,3-苯并噻唑-2-基)-1,4-二甲基哌嗪-2-酮(9.3g，31.44mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(8.78g，34.59mmol)於二噁烷(48.09mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加參(二苯亞甲基丙酮)二鈀(0)(1.44g，1.57mmol)及XPhos(3.00g，6.29mmol)。在惰性氣氛下將所得混合物在90℃下攪拌18h。然後，將其冷卻，用EtOAc(200mL)稀釋且用Na2 CO3 (50mL，飽和水溶液)洗滌。將有機層經Na2 SO4 乾燥，在減壓下濃縮且藉由矽膠急驟層析使用0至100% CHCl3 -MeCN梯度溶析來純化殘餘物，以得到產物1,4-二甲基-5-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]哌嗪-2-酮(8.8g，22.72mmol，72.27%產率)。Potassium acetate (6.17 g, 62.88 mmol, 3.93 mL) was added to 5-(5-chloro-1,3-benzothiazol-2-yl)-1,4-dimethylpiperazin-2-one (9.3 g, 31.44 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-1,3,2-dioxaborolane (8.78 g, 34.59 mmol) in dioxane (48.09 mL). The reaction flask was evacuated and refilled with argon 3 times. Paras(dibenzylideneacetone)dipalladium(0) (1.44 g, 1.57 mmol) and XPhos (3.00 g, 6.29 mmol) were then added under argon flow. The resulting mixture was stirred at 90 °C for 18 h under an inert atmosphere. It was then cooled, diluted with EtOAc ( 200 mL) and washed with Na2CO3 (50 mL, saturated aqueous solution). The organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a 0 to 100% CHCl 3 -MeCN gradient to give the product 1,4-dimethyl- 5-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazol-2-yl] Piperazin-2-one (8.8 g, 22.72 mmol, 72.27% yield).

LCMS(ESI)：[M]+ m/z：計算值387.2；實測值388.2；Rt=1.213min。LCMS (ESI): [M] + m/z: calculated 387.2; found 388.2; Rt=1.213 min.

步驟4：(3S)-6-(2-(1,4-二甲基-5-側氧基哌嗪-2-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (3S)-6-(2-(1,4-Dimethyl-5-oxypiperazin-2-yl)benzo[d]thiazol-5-yl)-3-methyl- Synthesis of 3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟3製備。產率：17g粗品。Prepared by General Procedure H, Step 3. Yield: 17 g crude.

LCMS(ESI)：[M]+ m/z：計算值456.2；實測值457.2；Rt=1.371min。LCMS (ESI): [M] + m/z: calculated 456.2; found 457.2; Rt=1.371 min.

步驟5：1,4-二甲基-5-(5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)哌嗪-2-酮之合成Step 5: 1,4-Dimethyl-5-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 Synthesis of -yl)piperazin-2-one

藉由一般程序方案H步驟4製備。產率：7g粗品。Prepared by General Procedure H, Step 4. Yield: 7 g crude.

LCMS(ESI)：[M]+ m/z：計算值356.2；實測值357.2；Rt=0.646min。LCMS (ESI): [M] + m/z: calculated 356.2; found 357.2; Rt=0.646 min.

步驟6：1,4-二甲基-5-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)哌嗪-2-酮之合成Step 6: 1,4-Dimethyl-5-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)piperazine-2- Synthesis of Ketones

藉由一般程序方案H步驟5製備。產率：4g粗品。Prepared by General Procedure H, Step 5. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=0.746min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=0.746 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(1,4-二甲基-5-側氧基哌嗪-2-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1231)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(1,4-dimethyl-5-pendoxyl) Synthesis of piperazin-2-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1231)

藉由一般程序方案H步驟6A製備。產率：81mg(26.41%)。Prepared by General Procedure H, Step 6A. Yield: 81 mg (26.41%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 30-80%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 30-80% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,dmso)δ 1.02-1.06(m,3H),1.06-1.16(m,3H),1.30-1.43(m,1H),1.65-1.74(m,1H),1.81-1.91(m,1H),2.07-2.20(m,1H),2.27-2.32(m,4H),2.32-2.36(m,1H),2.37-2.44(m,2H),2.78-2.82(m,0.3H),2.86-2.88(m,3H),3.19-3.28(m,1.7H),3.44-3.53(m,0.7H),3.71-3.78(m,2H),4.03-4.07(m,0.3H),4.32-4.46(m,1H),5.24-5.61(m,1H),5.62-5.73(m,2H),7.40-7.55(m,2H),7.89-7.96(m,1H),7.98-8.07(m,1H),8.10-8.17(m,1H),10.49-10.62(m,1H)。 1 H NMR(600MHz,dmso)δ 1.02-1.06(m,3H),1.06-1.16(m,3H),1.30-1.43(m,1H),1.65-1.74(m,1H),1.81-1.91(m ,1H),2.07-2.20(m,1H),2.27-2.32(m,4H),2.32-2.36(m,1H),2.37-2.44(m,2H),2.78-2.82(m,0.3H), 2.86-2.88(m, 3H), 3.19-3.28(m, 1.7H), 3.44-3.53(m, 0.7H), 3.71-3.78(m, 2H), 4.03-4.07(m, 0.3H), 4.32- 4.46(m,1H),5.24-5.61(m,1H),5.62-5.73(m,2H),7.40-7.55(m,2H),7.89-7.96(m,1H),7.98-8.07(m,1H) ), 8.10-8.17 (m, 1H), 10.49-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值549.2；實測值550.2；Rt=2.332min。LCMS (ESI): [M] + m/z: calculated 549.2; found 550.2; Rt=2.332 min.

實例622.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(2-(甲基(氧呾-3-基)胺基)乙基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1195)之合成Example 622. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(2-(methyl(oxygen Synthesis of -3-yl)amino)ethyl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1195)

Figure 110128222-A0202-12-2092-640
Figure 110128222-A0202-12-2092-640

步驟1：5-溴-2-(2-氯乙基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(2-chloroethyl)benzo[d]thiazole

在15min時段內，向2-胺基-4-溴苯硫酚(1g，4.90mmol，170.94uL)於甲苯(15mL)中之溶液中逐滴添加3-氯丙醯氯(684.34mg，5.39mmol，514.54 μL)，在此期間形成灰白色沉澱。將反應混合物在室溫下攪拌13h。然後，將其用水研磨，中和(NaHCO3 ，5%水溶液)至pH7，用DCM(2x50mL)萃取，乾燥且在真空中蒸發，以得到產物5-溴-2-(2-氯乙基)-1,3-苯并噻唑(1.3g，4.70mmol，95.93%產率)。To a solution of 2-amino-4-bromothiophenol (1 g, 4.90 mmol, 170.94 uL) in toluene (15 mL) was added 3-chloropropane chloride (684.34 mg, 5.39 mmol) dropwise over a 15 min period , 514.54 μL), during which an off-white precipitate formed. The reaction mixture was stirred at room temperature for 13 h. It was then triturated with water, neutralized ( NaHCO3 , 5% aq.) to pH 7, extracted with DCM (2x50 mL), dried and evaporated in vacuo to give the product 5-bromo-2-(2-chloroethyl) -1,3-benzothiazole (1.3 g, 4.70 mmol, 95.93% yield).

LCMS(ESI)：[M]+ m/z：計算值276.2；實測值377.2；Rt=1.505min。LCMS (ESI): [M] + m/z: calculated 276.2; found 377.2; Rt=1.505 min.

步驟2：N-(2-(5-溴苯并[d]噻唑-2-基)乙基)-N-甲基氧呾-3-胺之合成Step 2: Synthesis of N-(2-(5-bromobenzo[d]thiazol-2-yl)ethyl)-N-methyloxan-3-amine

向5-溴-2-(2-氯乙基)-1,3-苯并噻唑(4.9g，17.72mmol)及N -甲基氧呾-3-胺(2.58g，19.49mmol)於MeCN(60mL)中之溶液中添加碳酸鉀顆粒(6.12g，44.29mmol，2.67mL)。然後將反應混合物在40℃下攪拌5天，然後在真空中蒸發。將殘餘物用水(50mL)稀釋且用DCM(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到N -[2-(5-溴-1,3-苯并噻唑-2-基)乙基]-N -甲基-氧呾-3-胺(6g，粗品)。To 5-bromo-2-(2-chloroethyl)-1,3-benzothiazole (4.9 g, 17.72 mmol) and N -methyloxan-3-amine (2.58 g, 19.49 mmol) in MeCN ( To the solution in 60 mL) was added potassium carbonate particles (6.12 g, 44.29 mmol, 2.67 mL). The reaction mixture was then stirred at 40°C for 5 days and then evaporated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give N- [2-(5-bromo-1,3-benzothiazol-2-yl)ethyl] -N -methyl- Oxan-3-amine (6 g, crude).

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.781min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.781 min.

步驟3：N-甲基-N-(2-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)乙基)氧呾-3-胺之合成Step 3: N-methyl-N-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzone) Synthesis of [d]thiazol-2-yl)ethyl)oxo-3-amine

藉由一般程序方案H步驟2製備。產率：16g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 16 g crude.

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=1.006min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=1.006 min.

步驟4：(S)-3-甲基-6-(2-(2-(甲基(氧呾-3-基)胺基)乙基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (S)-3-Methyl-6-(2-(2-(methyl(oxypyr-3-yl)amino)ethyl)benzo[d]thiazol-5-yl)-3 Synthesis of 3-butyl ,4-dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：22g粗品。Prepared by General Procedure H, Step 3. Yield: 22 g crude.

LCMS(ESI)：[M]+ m/z：計算值443.2；實測值444.2；Rt=1.083min。LCMS (ESI): [M] + m/z: calculated 443.2; found 444.2; Rt=1.083 min.

步驟5：(S)-N-甲基-N-(2-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)乙基)氧呾-3-胺之合成Step 5: (S)-N-methyl-N-(2-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 Synthesis of -yl)ethyl)oxo-3-amine

藉由一般程序方案H步驟4製備。產率：5.5g粗品。Prepared by General Procedure H, Step 4. Yield: 5.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=0.640min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=0.640 min.

步驟6：N-甲基-N-(2-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)乙基)氧呾-3-胺之合成Step 6: N-Methyl-N-(2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)ethyl)oxygen -Synthesis of 3-amine

藉由一般程序方案H步驟5製備。產率：4g粗品。Prepared by General Procedure H, Step 5. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=0.707min。LCMS (ESI): [M] + m/z: calculated 345.2; found 346.2; Rt=0.707 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(2-(甲基(氧呾-3-基)胺基)乙基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1195)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(2-(methyl(oxygen Synthesis of -3-yl)amino)ethyl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1195)

藉由一般程序方案H步驟6A製備。產率：5.7mg(1.83%)。Prepared by General Procedure H, Step 6A. Yield: 5.7 mg (1.83%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-6min 35-80%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-6 min 35-80% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

1 H 1H NMR(600MHz,dmso)δ 1.02-1.06(m,3H),1.06-1.15(m,3H),1.31-1.41(m,1H),1.66-1.75(m,1H),1.83-1.93(m,1H),2.14(s,3H),2.15-2.36(m,2H),2.37-2.43(m,2H),2.65-2.69(m,2H),2.76-3.08(m,1H),3.20-3.24(m,2H),3.46-3.50(m,0.7H),3.57-3.61(m,1H),4.02-4.07(m,0.3H),4.40(t,2H),4.50(t,2H),5.26-5.61(m,1H),5.61-5.73(m,2H),7.33-7.42(m,1H),7.42-7.54(m,1H),7.83-7.92(m,1H),7.97-8.09(m,2H),9.33(br s,1H)。 1 H 1H NMR (600MHz, dmso) δ 1.02-1.06 (m, 3H), 1.06-1.15 (m, 3H), 1.31-1.41 (m, 1H), 1.66-1.75 (m, 1H), 1.83-1.93 ( m, 1H), 2.14(s, 3H), 2.15-2.36(m, 2H), 2.37-2.43(m, 2H), 2.65-2.69(m, 2H), 2.76-3.08(m, 1H), 3.20- 3.24(m, 2H), 3.46-3.50(m, 0.7H), 3.57-3.61(m, 1H), 4.02-4.07(m, 0.3H), 4.40(t, 2H), 4.50(t, 2H), 5.26-5.61(m, 1H), 5.61-5.73(m, 2H), 7.33-7.42(m, 1H), 7.42-7.54(m, 1H), 7.83-7.92(m, 1H), 7.97-8.09(m , 2H), 9.33 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值536.2；實測值537.2；Rt=2.164min。LCMS (ESI): [M] + m/z: calculated 536.2; found 537.2; Rt=2.164 min.

實例623.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基-1H -咪唑-2-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1192)之合成Example 623. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methyl- 1H -imidazole Synthesis of -2-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1192)

步驟1：5-氯-2-(1-甲基-1H-咪唑-2-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-methyl-1H-imidazol-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2094-641
Figure 110128222-A0202-12-2094-641

藉由一般程序方案H步驟1B製備。產率：13g(95.54%)。Prepared by General Procedure H, Step IB. Yield: 13 g (95.54%).

LCMS(ESI)：[M]+ m/z：計算值249.2；實測值250.2；Rt=3.165min。LCMS (ESI): [M] + m/z: calculated 249.2; found 250.2; Rt=3.165 min.

步驟2：2-(1-甲基-1H-咪唑-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Methyl-1H-imidazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Synthesis of 2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2095-642
Figure 110128222-A0202-12-2095-642

將5-氯-2-(1-甲基咪唑-2-基)-1,3-苯并噻唑(5g，20.02mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(5.59g，22.02mmol)及乙酸鉀(3.93g，40.05mmol，2.50mL)於二噁烷(100mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(916.75mg，1.00mmol)及二環己基[2',4',6' -參(丙-2-基)-[1,1' -聯苯基]-2-基]磷烷(1.91g，4.00mmol)，且將反應混合物在95℃下攪拌18h。將反應混合物冷卻且在真空中濃縮。藉由矽膠管柱層析使用己烷/MTBE梯度(0-100% MTBE)純化殘餘物，以得到呈紫色固體之2-(1-甲基咪唑-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(7g，粗品)。5-Chloro-2-(1-methylimidazol-2-yl)-1,3-benzothiazole (5 g, 20.02 mmol), 4,4,5,5-tetramethyl-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (5.59 g, 22.02 mmol ) and potassium acetate (3.93 g, 40.05 mmol, 2.50 mL) in dioxane (100 mL) was evacuated and backfilled with argon. This operation was repeated twice, followed by addition of ginseng (1,5-diphenylpent-1,4-dien-3-one)dipalladium (916.75 mg, 1.00 mmol) and dicyclohexyl[ 2 under argon ',4', 6'-para(propan-2-yl)-[ 1,1' -biphenyl]-2-yl]phosphine (1.91 g, 4.00 mmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) to give 2-(1-methylimidazol-2-yl)-5-(4,4 as a purple solid ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (7 g, crude).

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=1.567min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=1.567 min.

步驟3：(S)-3-甲基-6-(2-(1-甲基-1H-咪唑-2-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(1-methyl-1H-imidazol-2-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine -1(2H)-Synthesis of tert-butyl formate

Figure 110128222-A0202-12-2096-643
Figure 110128222-A0202-12-2096-643

藉由一般程序方案H步驟3製備。產率：1.6g(53.20%)。Prepared by General Procedure H, Step 3. Yield: 1.6 g (53.20%).

CC條件： 藉由矽膠使用己烷/MTBE(梯度0-100% MTBE)作為溶析液混合物純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/MTBE (gradient 0-100% MTBE) as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值410.2；實測值411.2；Rt=1.510min。LCMS (ESI): [M] + m/z: calculated 410.2; found 411.2; Rt=1.510 min.

步驟4：(S)-2-(1-甲基-1H-咪唑-2-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1-Methyl-1H-imidazol-2-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo Synthesis of [d]thiazole

Figure 110128222-A0202-12-2096-644
Figure 110128222-A0202-12-2096-644

藉由一般程序方案H步驟4製備。產率：1.1g(90.92%)。Prepared by General Procedure H, Step 4. Yield: 1.1 g (90.92%).

LCMS(ESI)：[M]+ m/z：計算值310.2；實測值311.2；Rt=0.916min。LCMS (ESI): [M] + m/z: calculated 310.2; found 311.2; Rt=0.916 min.

步驟5：2-(1-甲基-1H-咪唑-2-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 2-(1-Methyl-1H-imidazol-2-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2096-645
Figure 110128222-A0202-12-2096-645

藉由一般程序方案H步驟5製備。產率：0.9g(81.29%)。Prepared by General Procedure H, Step 5. Yield: 0.9 g (81.29%).

LCMS(ESI)：[M]+ m/z：計算值312.2；實測值313.2；Rt=0.806min。LCMS (ESI): [M] + m/z: calculated 312.2; found 313.2; Rt=0.806 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基-1H-咪唑-2-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1192)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl-1H-imidazole) Synthesis of -2-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1192)

Figure 110128222-A0202-12-2097-646
Figure 110128222-A0202-12-2097-646

藉由一般程序方案H步驟6A製備。產率：93mg(38.46%)。Prepared by General Procedure H, Step 6A. Yield: 93 mg (38.46%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-1-6min 10-10-60%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-1-6 min 10-10-60% water-MeCN+0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03-1.14(m,6H),1.34-1.41(m,1H),1.73(m,1H),1.87-2.20(m,3H),2.30-2.41(m,2H),2.81-2.83(m,1H),3.33-3.52(m,1H),4.16(s,3H),5.30-5.72(m,3H),7.13(s,1H),7.41-7.52(m,3H),7.92-8.13(m,3H),10.54-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.03-1.14 (m, 6H), 1.34-1.41 (m, 1H), 1.73 (m, 1H), 1.87-2.20 (m, 3H), 2.30 -2.41(m, 2H), 2.81-2.83(m, 1H), 3.33-3.52(m, 1H), 4.16(s, 3H), 5.30-5.72(m, 3H), 7.13(s, 1H), 7.41 -7.52(m, 3H), 7.92-8.13(m, 3H), 10.54-10.60(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值503.2；實測值504.2；Rt=2.408min。LCMS (ESI): [M] + m/z: calculated 503.2; found 504.2; Rt=2.408 min.

實例624.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1-(二甲胺基)丙-2-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1324)之合成Example 624. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1-(dimethylamino)propan-2-yl ) Synthesis of benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1324)

Figure 110128222-A0202-12-2098-647
Figure 110128222-A0202-12-2098-647

步驟1：2-(5-氯苯并[d]噻唑-2-基)-N,N-二甲基丙-1-胺之合成Step 1: Synthesis of 2-(5-Chlorobenzo[d]thiazol-2-yl)-N,N-dimethylpropan-1-amine

使2-胺基-4-氯苯硫酚(1.5g，9.40mmol)及2-胺基-4-氯苯硫酚(1.5g，9.40mmol)於PPA(10mL)中之經攪拌之溶液在140℃下攪拌16h。完成之後，將反應混合物用水(200mL)萃取且藉由NaOH中和至pH=8。將水相用EtOAc(2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物2-(5-氯-1,3-苯并噻唑-2-基)-N,N -二甲基丙-1-胺(1.5g，5.89mmol，62.66%產率)。A stirred solution of 2-amino-4-chlorothiophenol (1.5 g, 9.40 mmol) and 2-amino-4-chlorothiophenol (1.5 g, 9.40 mmol) in PPA (10 mL) was added to Stir at 140°C for 16h. After completion, the reaction mixture was extracted with water (200 mL) and neutralized to pH=8 by NaOH. The aqueous phase was extracted with EtOAc (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The desired product, 2-(5-chloro-1,3-benzothiazol-2-yl) -N,N -dimethylpropan-1-amine (1.5 g, 5.89 mmol, 62.66% yield) was isolated.

LCMS(ESI)：[M]+ m/z：計算值254.2；實測值255.2；Rt=0.672min。LCMS (ESI): [M] + m/z: calculated 254.2; found 255.2; Rt=0.672 min.

步驟2：N,N-二甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)丙-1-胺之合成Step 2: N,N-Dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo Synthesis of [d]thiazol-2-yl)propan-1-amine

向2-(5-氯-1,3-苯并噻唑-2-基)-N,N -二甲基丙-1-胺(1.5g，5.89mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.50g，5.89mmol)於二噁烷(30mL)中之經攪拌之溶液中添加Pd2 (dba)3 (1.08g，1.18mmol)及XPhos(1.12g，2.35mmol)。將所得懸浮液在50℃下用氬氣除氣0.5h。添加乙酸鉀(1.2g，12.23mmol，764.33μL)。將反應混合物在100℃下攪拌16h。完成之後，將反應混合物在減壓下濃縮，用水(50mL)萃取，將水相用CHCl3 (2*50mL)萃取。將有機相用10% HCl(2*50mL)萃取。將水相藉由NaHCO3 中和至pH=8，用CHCl3 (2*50mL)萃取。將有機相經Na2 SO4 乾燥且在真空中蒸發。分離所要產物N,N -二甲基-2-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼 雜環戊烷-2-基)-1,3-苯并噻唑-2-基]丙-1-胺(1.4g，4.04mmol，68.67%產率)。To 2-(5-chloro-1,3-benzothiazol-2-yl) -N,N -dimethylpropan-1-amine (1.5 g, 5.89 mmol) and 4,4,5,5-tetrakis Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane To a stirred solution of pentane (1.50 g, 5.89 mmol) in dioxane (30 mL) was added Pd2(dba )3 ( 1.08 g, 1.18 mmol) and XPhos (1.12 g, 2.35 mmol). The resulting suspension was degassed with argon at 50 °C for 0.5 h. Potassium acetate (1.2 g, 12.23 mmol, 764.33 μL) was added. The reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure, extracted with water (50 mL), and the aqueous phase was extracted with CHCl3 (2*50 mL). The organic phase was extracted with 10% HCl (2*50 mL). The aqueous phase was neutralized to pH=8 by NaHCO3 , extracted with CHCl3 (2*50 mL). The organic phase was dried over Na2SO4 and evaporated in vacuo. Isolation of the desired product N,N -dimethyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1 , 3-benzothiazol-2-yl]propan-1-amine (1.4 g, 4.04 mmol, 68.67% yield).

LCMS(ESI)：[M]+ m/z：計算值346.2；實測值347.2；Rt=1.121min。LCMS (ESI): [M] + m/z: calculated 346.2; found 347.2; Rt=1.121 min.

步驟3：(3S)-6-(2-(1-(二甲胺基)丙-2-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (3S)-6-(2-(1-(Dimethylamino)prop-2-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydro Synthesis of tert-butyl pyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：0.7g粗品。Prepared by General Procedure H, Step 3. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.238min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.238 min.

步驟4：N,N-二甲基-2-(5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)丙-1-胺之合成Step 4: N,N-Dimethyl-2-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 Synthesis of -yl)propan-1-amine

使(3S)-6-[2-[2-(二甲胺基)-1-甲基-乙基]-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(700.00mg，1.68mmol)於MeOH(10mL)及二噁烷/HCl(10mL)中之經攪拌之溶液在25℃下攪拌16h。完成之後，將反應混合物蒸發，將粗產物用水(20mL)萃取且藉由NaHCO3 中和至pH=8。將水相用CHCl3 (2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物N,N -二甲基-2-[5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑-2-基]丙-1-胺(0.5g，1.58mmol，94.10%產率)。make (3S)-6-[2-[2-(dimethylamino)-1-methyl-ethyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4 A stirred solution of -dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (700.00 mg, 1.68 mmol) in MeOH (10 mL) and dioxane/HCl (10 mL) was stirred at 25 °C for 16 h. After completion, the reaction mixture was evaporated, the crude product was extracted with water (20 mL) and neutralized to pH=8 by NaHCO3 . The aqueous phase was extracted with CHCl3 (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Isolation of the desired product N,N -dimethyl-2-[5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole -2-yl]propan-1-amine (0.5 g, 1.58 mmol, 94.10% yield).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.666min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.666 min.

步驟5：N,N-二甲基-2-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)丙-1-胺之合成Step 5: N,N-Dimethyl-2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-1-amine synthesis

藉由一般程序方案H步驟5製備。產率：0.5g粗品。Prepared by General Procedure H, Step 5. Yield: 0.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.471min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.471 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(1-(二甲胺基)丙-2-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1324)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-(dimethylamino)propan-2-yl) ) Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1324)

藉由一般程序方案H步驟6B製備。產率：17mg(10.61%)。Prepared by General Procedure H, Step 6B. Yield: 17 mg (10.61%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 40-90%水 -MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 40-90% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ (ppm)0.98-1.05(m,3H),1.06-1.16(m,3H),1.30-1.44(m,4H),1.66-1.77(m,1H),1.79-1.96(m,1H),2.04-2.11(m,1H),2.15-2.23(m,6H),2.26-2.36(m,1H),2.38-2.47(m,3H),2.61-2.67(m,1H),2.78-3.25(m,1H),3.42-4.09(m,2H),5.24-5.60(m,1H),5.60-5.73(m,2H),7.32-7.42(m,1H),7.43-7.54(m,1H),7.82-7.92(m,1H),7.96-8.11(m,2H),10.32-10.69(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 0.98-1.05 (m, 3H), 1.06-1.16 (m, 3H), 1.30-1.44 (m, 4H), 1.66-1.77 (m, 1H) ,1.79-1.96(m,1H),2.04-2.11(m,1H),2.15-2.23(m,6H),2.26-2.36(m,1H),2.38-2.47(m,3H),2.61-2.67( m,1H),2.78-3.25(m,1H),3.42-4.09(m,2H),5.24-5.60(m,1H),5.60-5.73(m,2H),7.32-7.42(m,1H), 7.43-7.54 (m, 1H), 7.82-7.92 (m, 1H), 7.96-8.11 (m, 2H), 10.32-10.69 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=1.563min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=1.563 min.

實例625.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-(3,3,3-三氟丙基)哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1124)之合成Example 625. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-(3,3,3 Synthesis of -trifluoropropyl)piperidin-4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1124)

Figure 110128222-A0202-12-2100-648
Figure 110128222-A0202-12-2100-648

步驟1：5-氯-2-(1-(3,3,3-三氟丙基)哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)benzo[d]thiazole

將碳酸鉀(3.83g，27.69mmol，1.67mL)添加到5-氯-2-(4-哌啶基)-1,3-苯并噻唑(3.5g，13.85mmol)及甲磺酸3,3,3-三氟丙酯(3.73g，19.39mmol)於MeCN(80mL)中之溶液中。將所得混合物在80℃下攪拌72h。然後，將其在減壓下濃縮且將殘餘物分配於水(30mL)與MTBE(50mL)之間。將有機層分離，經Na2 SO4 乾燥且在真空中蒸發，得到5-氯-2-[1-(3,3,3-三氟丙基)-4-哌啶基]-1,3-苯并噻唑(5.5g，粗品)。Potassium carbonate (3.83 g, 27.69 mmol, 1.67 mL) was added to 5-chloro-2-(4-piperidinyl)-1,3-benzothiazole (3.5 g, 13.85 mmol) and 3,3 methanesulfonic acid , 3-trifluoropropyl ester (3.73 g, 19.39 mmol) in MeCN (80 mL). The resulting mixture was stirred at 80 °C for 72 h. It was then concentrated under reduced pressure and the residue was partitioned between water (30 mL) and MTBE (50 mL). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to give 5 -chloro-2-[1-(3,3,3-trifluoropropyl)-4-piperidinyl]-1,3 - benzothiazole (5.5 g, crude).

LCMS(ESI)：[M]+ m/z：計算值348.2；實測值349.2；Rt=1.055min。LCMS (ESI): [M] + m/z: calculated 348.2; found 349.2; Rt=1.055 min.

步驟2：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-(1-(3,3,3-三氟丙基)哌Step 2: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-2-(1-(3,3,3- trifluoropropyl)piperidine 啶-4-基)苯并[d]噻唑之合成Synthesis of pyridin-4-yl)benzo[d]thiazole

將5-氯-2-[1-(3,3,3-三氟丙基)-4-哌啶基]-1,3-苯并噻唑(6.33g，18.13mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(5.53g，21.76mmol)及乙酸鉀(3.56g，36.27mmol，2.27mL)一起混合於二噁烷(100mL)中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加參 (二苯亞甲基丙酮)二鈀(0)(830.24mg，906.66μmol)及XPhos(1.73g，3.63mmol)。將所得混合物在100℃下攪拌16h。然後，將其在減壓下濃縮且藉由梯度管柱層析(SiO2 ，CHCl3 /MeCN)純化殘餘物，得到5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-[1-(3,3,3-三氟丙基)-4-哌啶基]-1,3-苯并噻唑(1.7g，3.86mmol，21.29%產率)。5-Chloro-2-[1-(3,3,3-trifluoropropyl)-4-piperidinyl]-1,3-benzothiazole (6.33 g, 18.13 mmol), 4,4,5 ,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxo Bororolane (5.53 g, 21.76 mmol) and potassium acetate (3.56 g, 36.27 mmol, 2.27 mL) were mixed together in dioxane (100 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, under an argon flow, paras(dibenzylideneacetone)dipalladium(0) ( 830.24 mg, 906.66 μmol) and XPhos (1.73 g, 3.63 mmol) were added. The resulting mixture was stirred at 100 °C for 16 h. Then, it was concentrated under reduced pressure and the residue was purified by gradient column chromatography (SiO 2 , CHCl 3 /MeCN) to give 5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborol-2-yl)-2-[1-(3,3,3-trifluoropropyl)-4-piperidinyl]-1,3-benzothiazole (1.7 g, 3.86 mmol, 21.29% yield).

LCMS(ESI)：[M]+ m/z：計算值440.2；實測值441.2；Rt=1.192min。LCMS (ESI): [M] + m/z: calculated 440.2; found 441.2; Rt=1.192 min.

步驟3：(S)-3-甲基-6-(2-(1-(3,3,3-三氟丙基)哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)benzo[d]thiazol-5-yl) Synthesis of -3,4-dihydropyridine-1(2H)-carboxylate tert-butyl ester

藉由一般程序方案H步驟3製備。產率：1.97g粗品。Prepared by General Procedure H, Step 3. Yield: 1.97 g crude.

LCMS(ESI)：[M]+ m/z：計算值509.2；實測值510.2；Rt=1.225min。LCMS (ESI): [M] + m/z: calculated 509.2; found 510.2; Rt=1.225 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-(3,3,3-三氟丙基)哌啶-4-基)苯并[d]噻唑之合成Step 4: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-(3,3,3-trifluoropropyl)piperidine Synthesis of pyridin-4-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：1.16g粗品。Prepared by General Procedure H, Step 4. Yield: 1.16 g crude.

LCMS(ESI)：[M]+ m/z：計算值409.2；實測值410.2；Rt=0.746min。LCMS (ESI): [M] + m/z: calculated 409.2; found 410.2; Rt=0.746 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1-(3,3,3-三氟丙基)哌啶-4-基)苯并[d]噻唑之合成Step 5: 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)benzo Synthesis of [d]thiazole

藉由一般程序方案H步驟5製備。產率：830mg粗品。Prepared by General Procedure H, Step 5. Yield: 830 mg crude.

LCMS(ESI)：[M]+ m/z：計算值411.2；實測值422.2；Rt=0.640min。LCMS (ESI): [M] + m/z: calculated 411.2; found 422.2; Rt=0.640 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-(3,3,3-三氟丙基)Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-(3,3,3 -trifluoropropyl) 哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1124)之合成Synthesis of piperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1124)

藉由一般程序方案H步驟6A製備。產率：41mg(26.66%)。Prepared by General Procedure H, Step 6A. Yield: 41 mg (26.66%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-6min 50-90%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-6 min 50-90% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.68-1.04(m,3H),1.05-1.16(m,3H),1.28-1.41(m,1H),1.65-1.73(m,1H),1.75-1.82(m,2H),1.83-1.94(m,1H),2.03-2.17(m,5H),2.24-2.36(m,2H),2.38-2.47(m,3H),2.53-2.56(m,2H),2.91-2.99(m,2H),3.06-3.15(m,1H),3.22-3.28(m,1H),3.35-4.09(m,1H),5.24-5.60(m,1H),5.61-5.74(m,2H),7.31-7.43(m,1H),7.43-7.55(m,1H),7.85-7.92(m,1H),7.96-8.11(m,2H),10.39-10.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.68-1.04(m,3H), 1.05-1.16(m,3H), 1.28-1.41(m,1H), 1.65-1.73(m,1H) ,1.75-1.82(m,2H),1.83-1.94(m,1H),2.03-2.17(m,5H),2.24-2.36(m,2H),2.38-2.47(m,3H),2.53-2.56( m, 2H), 2.91-2.99(m, 2H), 3.06-3.15(m, 1H), 3.22-3.28(m, 1H), 3.35-4.09(m, 1H), 5.24-5.60(m, 1H), 5.61-5.74(m, 2H), 7.31-7.43(m, 1H), 7.43-7.55(m, 1H), 7.85-7.92(m, 1H), 7.96-8.11(m, 2H), 10.39-10.63(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值602.2；實測值603.2；Rt=2.347min。LCMS (ESI): [M] + m/z: calculated 602.2; found 603.2; Rt=2.347 min.

實例626. 2-甲氧基-5-(2-((2R,5S )-5-甲基-2-(2-(2-甲基-2-氮雜螺[3.3 ]庚-6-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1236)之合成Example 626. 2-Methoxy-5-(2-(( 2R,5S )-5-methyl-2-(2-(2-methyl-2-azaspiro[ 3.3 ]hept-6-yl ) Synthesis of benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 1236)

Figure 110128222-A0202-12-2102-649
Figure 110128222-A0202-12-2102-649

步驟1：2-(第三丁氧基羰基)-2-氮雜螺[3.3]庚烷-6-甲酸之合成Step 1: Synthesis of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid

將二碳酸二-第三丁酯(7.88g，36.12mmol，8.29mL)逐滴添加到2-氮雜螺[3.3 ]庚烷-6-甲酸(6.11g，34.40mmol，HCl)於DCM(102.40mL)及TEA(8.70g，85.99mmol，11.99mL)中之懸浮液中。將所得反應混合物在20℃下攪拌16h。然後，添加10%NaHSO4 水溶液(80mL)且繼續攪拌5min。此後，將有機層分離， 經Na2 SO4 乾燥且在減壓下濃縮，留下2-第三丁氧基 羰基-2-氮雜螺[3.3 ]庚烷-6-甲酸(8.8g，粗品)。Di-tert-butyl dicarbonate (7.88 g, 36.12 mmol, 8.29 mL) was added dropwise to 2-azaspiro[ 3.3 ]heptane-6-carboxylic acid (6.11 g, 34.40 mmol, HCl) in DCM (102.40 mL) and a suspension in TEA (8.70 g, 85.99 mmol, 11.99 mL). The resulting reaction mixture was stirred at 20 °C for 16 h. Then, 10% aqueous NaHSO 4 (80 mL) was added and stirring was continued for 5 min. After this time, the organic layer was separated, dried over Na 2 SO 4 and concentrated under reduced pressure to leave 2 -tert- butoxycarbonyl-2-azaspiro[ 3.3 ]heptane-6-carboxylic acid (8.8 g, crude ).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.41(s,9H),1.51(m,1H),2.43(m,4H),3.00(m,1H),3.90(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.41 (s, 9H), 1.51 (m, 1H), 2.43 (m, 4H), 3.00 (m, 1H), 3.90 (m, 4H).

步驟2：6-(5-溴苯并[d]噻唑-2-基)-2-氮雜螺[3.3]庚烷-2-甲酸第三丁酯之合成Step 2: Synthesis of 6-(5-bromobenzo[d]thiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

將三苯基膦(516.35mg，1.97mmol)一次性添加到2-第三丁氧基 羰基-2-氮雜螺[3.3 ]庚烷-6-甲酸(190mg，787.46μmol)、2-胺基-4-溴苯硫酚(160.71mg，787.46μmol)、四氯化碳(795.00mg，5.17mmol，0.5mL)及TEA(398.41mg，3.94mmol，548.78μL)之溶液中。由於放熱反應，所得反應混合物暫時升溫至大約50-60℃。此後，將其在20℃下攪拌18h。然後，在減壓下移除揮發物且將殘餘物用MTBE(100mL)研磨。過濾出所得淺色沉澱。將濾液在減壓下濃縮且藉由梯度管柱層析(SiO2 ，己烷/EtOAc)純化殘餘物，得到6-(5-溴-1,3-苯并噻唑-2-基)-2-氮雜螺[3.3 ]庚烷-2-甲酸第三丁酯(4.6g，11.24mmol，31.53%產率)。Triphenylphosphine (516.35 mg, 1.97 mmol) was added in one portion to 2 -tert- butoxycarbonyl-2-azaspiro[ 3.3 ]heptane-6-carboxylic acid (190 mg, 787.46 μmol), 2-amino -4-Bromothiophenol (160.71 mg, 787.46 μmol), carbon tetrachloride (795.00 mg, 5.17 mmol, 0.5 mL) and TEA (398.41 mg, 3.94 mmol, 548.78 μL). The resulting reaction mixture was briefly warmed to about 50-60°C due to the exothermic reaction. After this time, it was stirred at 20 °C for 18 h. Then, the volatiles were removed under reduced pressure and the residue was triturated with MTBE (100 mL). The resulting pale precipitate was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by gradient column chromatography ( SiO2 , hexane/EtOAc) to give 6-(5-bromo-1,3-benzothiazol-2-yl)-2 - Azaspiro[ 3.3 ]heptane-2-carboxylic acid tert-butyl ester (4.6 g, 11.24 mmol, 31.53% yield).

LCMS(ESI)：[M]+ m/z：計算值409.2；實測值410.2；Rt=1.581min。LCMS (ESI): [M] + m/z: calculated 409.2; found 410.2; Rt=1.581 min.

步驟3：5-溴-2-(2-氮雜螺[3.3]庚-6-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-bromo-2-(2-azaspiro[3.3]hept-6-yl)benzo[d]thiazole

將三氟乙酸(12.81g，112.38mmol，8.66mL)添加到6-(5-溴-1,3-苯并噻唑-2-基)-2-氮雜螺[3.3 ]庚烷-2-甲酸第三丁酯(4.6g，11.24mmol)於DCM(60mL)中之溶液中。將所得混合物在20℃下攪拌5h。然後，將其在減壓下濃縮，留下2-(2-氮雜螺[3.3 ]庚-6-基)-5-溴-1,3-苯并噻唑(5g，粗品，TFA)。Trifluoroacetic acid (12.81 g, 112.38 mmol, 8.66 mL) was added to 6-(5-bromo-1,3-benzothiazol-2-yl)-2-azaspiro[ 3.3 ]heptane-2-carboxylic acid A solution of tert-butyl ester (4.6 g, 11.24 mmol) in DCM (60 mL). The resulting mixture was stirred at 20 °C for 5 h. It was then concentrated under reduced pressure to leave 2-(2-azaspiro[ 3.3 ]heptan-6-yl)-5-bromo-1,3-benzothiazole (5 g, crude, TFA).

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=0.830min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=0.830 min.

步驟4：5-溴-2-(2-甲基-2-氮雜螺[3.3]庚-6-基)苯并[d]噻唑之合成Step 4: Synthesis of 5-bromo-2-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzo[d]thiazole

將用7-8% MeOH穩定之37重量%甲醛水溶液(711.21mg，23.68mmol，656.70μL)及乙酸鈉(1.94g，23.68mmol，1.27mL)添加到2-(2-氮雜螺[3.3 ]庚-6-基)-5-溴-1,3-苯并噻唑(5g，11.84mmol，TFA)於MeOH(60mL)中之溶液中。 將所得混合物在20℃下攪拌1h，之後向其中添加氰基硼氫化鈉(1.49g，23.68mmol)。此後，繼續攪拌16h。然後，在減壓下移除溶劑且將殘餘物分配於15%K2 CO3 水溶液(30mL)與DCM(50mL)之間。將有機層分離，經固體K2 CO3 乾燥且在減壓下濃縮，留下5-溴-2-(2-甲基-2-氮雜螺[3.3 ]庚-6-基)-1,3-苯并噻唑(3.8g，11.76mmol，99.27%產率)。Aqueous 37 wt% formaldehyde stabilized with 7-8% MeOH (711.21 mg, 23.68 mmol, 656.70 μL) and sodium acetate (1.94 g, 23.68 mmol, 1.27 mL) were added to 2-(2-azaspiro[ 3.3 ] Hept-6-yl)-5-bromo-1,3-benzothiazole (5 g, 11.84 mmol, TFA) in MeOH (60 mL). The resulting mixture was stirred at 20°C for 1 h before adding sodium cyanoborohydride (1.49 g, 23.68 mmol). Thereafter, stirring was continued for 16 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 15 % aqueous K2CO3 ( 30 mL) and DCM (50 mL). The organic layer was separated, dried over solid K2CO3 and concentrated under reduced pressure to leave 5 -bromo-2-( 2 -methyl-2-azaspiro[ 3.3 ]hept-6-yl)-1, 3-benzothiazole (3.8 g, 11.76 mmol, 99.27% yield).

LCMS(ESI)：[M]+ m/z：計算值323.2；實測值324.2；Rt=1.079min。LCMS (ESI): [M] + m/z: calculated 323.2; found 324.2; Rt=1.079 min.

步驟5：2-(2-甲基-2-氮雜螺[3.3]庚-6-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 5: 2-(2-Methyl-2-azaspiro[3.3]hept-6-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟2製備。產率：1.5g(34.46%)。Prepared by General Procedure Scheme H, Step 2. Yield: 1.5 g (34.46%).

CC條件： 藉由矽膠使用MTBE/MeOH作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using MTBE/MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值370.2；實測值371.2；Rt=2.997min。LCMS (ESI): [M] + m/z: calculated 370.2; found 371.2; Rt=2.997 min.

步驟6：(S)-3-甲基-6-(2-(2-甲基-2-氮雜螺[3.3]庚-6-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 6: (S)-3-Methyl-6-(2-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzo[d]thiazol-5-yl)-3 Synthesis of 3-butyl ,4-dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：1.2g粗品。Prepared by General Procedure H, Step 3. Yield: 1.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值439.2；實測值440.2；Rt=1.166min。LCMS (ESI): [M] + m/z: calculated 439.2; found 440.2; Rt=1.166 min.

步驟7：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(2-甲基-2-氮雜螺[3.3]庚-6-基)苯并[d]噻唑之合成Step 7: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(2-methyl-2-azaspiro[3.3]heptane- Synthesis of 6-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：700mg粗品。Prepared by General Procedure H, Step 4. Yield: 700 mg crude.

LCMS(ESI)：[M]+ m/z：計算值339.2；實測值340.2；Rt=0.774min。LCMS (ESI): [M] + m/z: calculated 339.2; found 340.2; Rt=0.774 min.

步驟8：2-(2-甲基-2-氮雜螺[3.3]庚-6-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 8: 2-(2-Methyl-2-azaspiro[3.3]hept-6-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d ]Synthesis of thiazole

藉由一般程序方案H步驟5製備。產率：600mg(72.91%)。Prepared by General Procedure H, Step 5. Yield: 600 mg (72.91%).

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=0.770min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=0.770 min.

步驟9：2-甲氧基-5-(2-((2R,5S)-5-甲基-2-(2-(2-甲基-2-氮雜螺[3.3]庚-6-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1236)之合成Step 9: 2-Methoxy-5-(2-((2R,5S)-5-methyl-2-(2-(2-methyl-2-azaspiro[3.3]hept-6-yl ) Synthesis of benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 1236)

藉由一般程序方案H步驟6A製備。產率：42mg(16.99%)。Prepared by General Procedure H, Step 6A. Yield: 42 mg (16.99%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 40-85%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 40-85% water-MeOH+0.1% NH4OH , flow rate: 30 mL/min; (loading pump 4 mL/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.09(m,3H),1.32-1.42(m,1H),1.66-1.76(m,1H),1.83-1.93(m,1H),2.05-2.24(m,4H),2.27-2.35(m,1H),2.40-2.46(m,2H),2.56-2.84(m,3H),3.05(s,2H),3.21(s,2H),3.46-4.08(m,5H),5.25-5.73(m,1H),7.31-7.42(m,1H),7.61-7.78(m,2H),7.83-7.91(m,1H),7.98-8.07(m,1H),8.40-8.63(m,2H),10.98-11.16(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.09(m,3H), 1.32-1.42(m,1H), 1.66-1.76(m,1H), 1.83-1.93(m,1H) ,2.05-2.24(m,4H),2.27-2.35(m,1H),2.40-2.46(m,2H),2.56-2.84(m,3H),3.05(s,2H),3.21(s,2H) ,3.46-4.08(m,5H),5.25-5.73(m,1H),7.31-7.42(m,1H),7.61-7.78(m,2H),7.83-7.91(m,1H),7.98-8.07( m, 1H), 8.40-8.63 (m, 2H), 10.98-11.16 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值562.2；實測值563.2；Rt=2.487min。LCMS (ESI): [M] + m/z: calculated 562.2; found 563.2; Rt=2.487 min.

實例627.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1316及化合物1188)之合成Example 627. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1-(dimethylamino)ethyl)benzo Synthesis of [ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1316 and compound 1188)

Figure 110128222-A0202-12-2105-650
Figure 110128222-A0202-12-2105-650

步驟1：1-(5-溴苯并[d]噻唑-2-基)-N,N-二甲基乙胺之合成Step 1: Synthesis of 1-(5-bromobenzo[d]thiazol-2-yl)-N,N-dimethylethylamine

藉由一般程序方案H步驟1A製備。產率：2.5g(89.45%)。Prepared by General Procedure H, Step 1A. Yield: 2.5 g (89.45%).

LCMS(ESI)：[M]+ m/z：計算值285.2；實測值286.2；Rt=0.759min。LCMS (ESI): [M] + m/z: calculated 285.2; found 286.2; Rt=0.759 min.

步驟2：N,N-二甲基-1-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]Step 2: N,N-Dimethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzone [d] 噻唑-2-基)乙胺之合成Synthesis of Thiazol-2-yl)ethylamine

藉由一般程序方案H步驟2製備。產率：2.9g(99.57%)。Prepared by General Procedure Scheme H, Step 2. Yield: 2.9 g (99.57%).

LCMS(ESI)：[M]+ m/z：計算值332.2；實測值333.2；Rt=1.123min。LCMS (ESI): [M] + m/z: calculated 332.2; found 333.2; Rt=1.123 min.

步驟3：(3S)-6-(2-(1-(二甲胺基)乙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (3S)-6-(2-(1-(Dimethylamino)ethyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：4g粗品。Prepared by General Procedure H, Step 3. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值401.2；實測值402.2；Rt=1.198min。LCMS (ESI): [M] + m/z: calculated 401.2; found 402.2; Rt=1.198 min.

步驟4：N,N-二甲基-1-(5-((S)-5-甲基3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 4: N,N-Dimethyl-1-(5-((S)-5-methyl 3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2- Synthesis of ethyl) ethylamine

藉由一般程序方案H步驟4製備。產率：4g粗品。Prepared by General Procedure H, Step 4. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值301.2；實測值302.2；Rt=0.560min。LCMS (ESI): [M] + m/z: calculated 301.2; found 302.2; Rt=0.560 min.

步驟5：N,N-二甲基-1-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)乙胺之合成Step 5: Synthesis of N,N-dimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)ethanamine

藉由一般程序方案H步驟5製備。產率：4g粗品。Prepared by General Procedure H, Step 5. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值303.2；實測值304.2；Rt=0.509min。LCMS (ESI): [M] + m/z: calculated 303.2; found 304.2; Rt=0.509 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(1-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-(dimethylamino)ethyl)benzo Synthesis of [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide

藉由一般程序方案H步驟6A製備。產率：81mg(29.67%)。Prepared by General Procedure H, Step 6A. Yield: 81 mg (29.67%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-1-6min 15-15-65%水-MeCN+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-1-6min 15-15-65% water-MeCN+0.1% NH4OH , flow rate: 30mL/min; (loading pump 4mL/min MeOH) .

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=2.099min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=2.099 min.

步驟7：掌性分離(化合物1316及化合物1188)Step 7: Chiral separation (compound 1316 and compound 1188)

對外消旋N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[2-[1-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(81mg，163.75umol)進行掌性分離(管柱：Chiralpak AD-H III(250*20mm，5mkm)；己烷-IPA-MeOH， 50-25-25.流速：10mL/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[2-[(1R )-1-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(22.3mg，45.08μmol，55.06%產率)(RT=75.09min)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[2-[(1S )-1-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(25mg，50.54μmol，61.73%產率)(RT=91.19min)。Racemic N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-[2-[1-(dimethylamino)ethyl]-1 ,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (81 mg, 163.75 umol) for chiral separation (column: Chiralpak AD-H III (250*20mm, 5mkm); Hexane-IPA-MeOH, 50-25-25. Flow rate: 10 mL/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)- 2-[( 2R,5S )-2-[2-[( 1R )-1-(dimethylamino)ethyl]-1,3-benzothiazol-5-yl]-5-methyl-1 -Piperidinyl]-2-oxyacetamide (22.3 mg, 45.08 μmol, 55.06% yield) (RT=75.09 min) and N-(6-amino-5-ethyl-3-pyridyl) )-2-[( 2R,5S )-2-[2-[( 1S )-1-(dimethylamino)ethyl]-1,3-benzothiazol-5-yl]-5-methyl -1-Piperidinyl]-2-oxyacetamide (25 mg, 50.54 μmol, 61.73% yield) (RT=91.19 min).

化合物1316於分析條件下(管柱：AD-H，以己烷-IPA-MeOH，50-25-25，0.6mL/min為流動相)之保留時間為58.24min且化合物1188之保留時間為72.96min。The retention time of compound 1316 under analytical conditions (column: AD-H, with hexane-IPA-MeOH, 50-25-25, 0.6 mL/min as mobile phase) was 58.24 min and the retention time of compound 1188 was 72.96 min.

化合物1316：保留時間：58.24minCompound 1316: retention time: 58.24min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.14(m,6H),1.31-1.38(m,1H),1.39-1.42(m,3H),1.66-1.75(m,1H),1.83-1.92(m,1H),2.04-2.21(m,1H),2.27(s,6H),2.29-2.35(m,1H),2.38-2.42(m,1H),2.76-3.29(m,2H),3.47-4.06(m,2H),5.25-5.72(m,3H),7.32-7.43(m,1H),7.43-7.53(m,1H),7.84-7.91(m,1H),7.97-8.11(m,2H),10.50-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.14(m, 6H), 1.31-1.38(m, 1H), 1.39-1.42(m, 3H), 1.66-1.75(m, 1H) ,1.83-1.92(m,1H),2.04-2.21(m,1H),2.27(s,6H),2.29-2.35(m,1H),2.38-2.42(m,1H),2.76-3.29(m, 2H), 3.47-4.06(m, 2H), 5.25-5.72(m, 3H), 7.32-7.43(m, 1H), 7.43-7.53(m, 1H), 7.84-7.91(m, 1H), 7.97- 8.11 (m, 2H), 10.50-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=2.102min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=2.102 min.

化合物1188：保留時間：72.96minCompound 1188: retention time: 72.96min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.15(m,6H),1.31-1.38(m,1H),1.39-1.44(m,3H),1.67-1.74(m,1H),1.82-1.92(m,1H),2.06-2.22(m,1H),2.24-2.36(m,8H),2.39-2.42(m,1H),2.76-3.25(m,1H),3.46-4.08(m,2H),5.24-5.72(m,3H),7.33-7.42(m,1H),7.43-7.53(m,1H),7.84-7.91(m,1H),7.97-8.09(m,2H),10.49-10.61(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.02-1.15 (m, 6H), 1.31-1.38 (m, 1H), 1.39-1.44 (m, 3H), 1.67-1.74 (m, 1H) ,1.82-1.92(m,1H),2.06-2.22(m,1H),2.24-2.36(m,8H),2.39-2.42(m,1H),2.76-3.25(m,1H),3.46-4.08( m,2H),5.24-5.72(m,3H),7.33-7.42(m,1H),7.43-7.53(m,1H),7.84-7.91(m,1H),7.97-8.09(m,2H), 10.49-10.61 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=2.109min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=2.109 min.

實例628.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(2-(二甲胺基)丙基)苯并Example 628. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(2-(dimethylamino)propyl)benzo [d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1345)之合成Synthesis of [ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1345)

Figure 110128222-A0202-12-2108-651
Figure 110128222-A0202-12-2108-651

步驟1：3-(二甲胺基)丁酸之合成Step 1: Synthesis of 3-(dimethylamino)butyric acid

使3-(二甲胺基)丁酸乙酯(0.5g，3.14mmol)於HCl(15%)(5mL)中之經攪拌之溶液在90℃下攪拌2h。完成之後，將反應混合物在減壓下濃縮。分離所要產物3-(二甲胺基)丁酸(0.4g，2.39mmol，75.99%產率，HCl)。A stirred solution of ethyl 3-(dimethylamino)butyrate (0.5 g, 3.14 mmol) in HCl (15%) (5 mL) was stirred at 90 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The desired product, 3-(dimethylamino)butyric acid (0.4 g, 2.39 mmol, 75.99% yield, HCl) was isolated.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.25(d,3H),2.64(s,6H),2.97(m,1H),3.56(m,1H),4.77(m,2H),10.91(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.25(d, 3H), 2.64(s, 6H), 2.97(m, 1H), 3.56(m, 1H), 4.77(m, 2H), 10.91( m, 1H).

步驟2：1-(5-溴苯并[d]噻唑-2-基)-N,N-二甲基丙-2-胺之合成Step 2: Synthesis of 1-(5-bromobenzo[d]thiazol-2-yl)-N,N-dimethylpropan-2-amine

使3-(二甲胺基)丁酸(0.4g，2.39mmol，HCl)及2-胺基-4-溴苯硫酚(0.5g，2.45mmol)於PPA(5mL)中之經攪拌之溶液在140℃下攪拌16h。完成之後，將反應混合物用水(50mL)萃取且藉由NaOH中和至pH=8。將水相用EtOAc(2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物1-(5-溴-1,3-苯并噻唑-2-基)-N,N -二甲基丙-2-胺(0.6g，2.01mmol，84.03%產率)。A stirred solution of 3-(dimethylamino)butyric acid (0.4 g, 2.39 mmol, HCl) and 2-amino-4-bromothiophenol (0.5 g, 2.45 mmol) in PPA (5 mL) Stir at 140°C for 16h. After completion, the reaction mixture was extracted with water (50 mL) and neutralized to pH=8 by NaOH. The aqueous phase was extracted with EtOAc (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The desired product, 1-(5-bromo-1,3-benzothiazol-2-yl) -N,N -dimethylpropan-2-amine (0.6 g, 2.01 mmol, 84.03% yield) was isolated.

LCMS(ESI)：[M]+ m/z：計算值299.2；實測值300.2；Rt=0.938min。LCMS (ESI): [M] + m/z: calculated 299.2; found 300.2; Rt=0.938 min.

步驟3：N,N-二甲基-1-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 3: N,N-Dimethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo Synthesis of [d]thiazol-2-yl)propan-2-amine

藉由一般程序方案H步驟2製備。產率：0.3g(56.64%)。Prepared by General Procedure Scheme H, Step 2. Yield: 0.3 g (56.64%).

CC條件： 藉由矽膠使用EtOAc/MeOH作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using EtOAc/MeOH as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值264.2；實測值265.2；Rt=0.536min。LCMS (ESI): [M] + m/z: calculated 264.2; found 265.2; Rt=0.536 min.

步驟4：(3S)-6-(2-(2-(二甲胺基)丙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (3S)-6-(2-(2-(Dimethylamino)propyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：0.3g(63.56%)。Prepared by General Procedure H, Step 3. Yield: 0.3 g (63.56%).

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=0.992min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=0.992 min.

步驟5：N,N-二甲基-1-(5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 5: N,N-Dimethyl-1-(5-((S)-5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 Synthesis of -yl)propan-2-amine

將(3S )-6-[2-[2-(二甲胺基)丙基]-1,3-苯并噻唑-5-基]-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(0.3g，721.86μmol)於MeOH(15mL)及二噁烷/HCl(5mL)中之經攪拌之溶液在25℃下攪拌4h。完成之後，將反應混合物蒸發，將粗產物用水(20mL)萃取且藉由NaHCO3 中和至pH=8。將水相用CHCl3 (2*20mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。分離所要產物N,N -二甲基-1-[5-[(3S )-3-甲基-2,3,4,5-四氫吡啶-6-基]-1,3-苯并噻唑-2-基]丙-2-胺(0.22g，697.36μmol，96.61%產率)。( 3S )-6-[2-[2-(dimethylamino)propyl]-1,3-benzothiazol-5-yl]-3-methyl-3,4-dihydro- 2H- A stirred solution of tert-butyl pyridine-1-carboxylate (0.3 g, 721.86 μmol) in MeOH (15 mL) and dioxane/HCl (5 mL) was stirred at 25 °C for 4 h. After completion, the reaction mixture was evaporated, the crude product was extracted with water (20 mL) and neutralized to pH=8 by NaHCO3 . The aqueous phase was extracted with CHCl3 (2*20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. Isolation of the desired product N,N -dimethyl-1-[5-[( 3S )-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]-1,3-benzothiazole -2-yl]propan-2-amine (0.22 g, 697.36 μmol, 96.61% yield).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.655min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.655 min.

步驟6：N,N-二甲基-1-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 6: N,N-Dimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-2-amine synthesis

藉由一般程序方案H步驟5製備。產率：0.22g粗品。Prepared by General Procedure H, Step 5. Yield: 0.22 g crude.

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.445min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.445 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(2-(二甲胺基)丙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1345)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(2-(dimethylamino)propyl)benzo Synthesis of [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1345)

藉由一般程序方案H步驟6B製備。產率：38mg(10.78%)。Prepared by General Procedure H, Step 6B. Yield: 38 mg (10.78%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-1-6min 35-50%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-1-6 min 35-50% water-MeCN+0.1% NH4OH , flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.14(m,9H),1.29-1.41(m,1H),1.64-1.75(m,1H),1.81-1.93(m,1H),2.02-2.19(m,1H),2.21(s,6H),2.28-2.34(m,1H),2.39-2.43(m,1H),2.76-3.27(m,5H),3.46-4.07(m,1H),5.24-5.71(m,3H),7.30-7.40(m,1H),7.42-7.52(m,1H),7.81-7.89(m,1H),7.97-8.08(m,2H),10.41(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.14(m,9H), 1.29-1.41(m,1H), 1.64-1.75(m,1H), 1.81-1.93(m,1H) ,2.02-2.19(m,1H),2.21(s,6H),2.28-2.34(m,1H),2.39-2.43(m,1H),2.76-3.27(m,5H),3.46-4.07(m, 1H), 5.24-5.71(m, 3H), 7.30-7.40(m, 1H), 7.42-7.52(m, 1H), 7.81-7.89(m, 1H), 7.97-8.08(m, 2H), 10.41( s, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=2.166min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=2.166 min.

實例629. 5-(2-((2R,5S )-2-(2-(1-環丙基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1219)之合成Example 629. 5-(2-(( 2R,5S )-2-(2-(1-cyclopropylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)-5-methylpiperin Synthesis of pyridin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1219)

步驟1：5-氯-2-(1-環丙基哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(1-cyclopropylpiperidin-4-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2110-652
Figure 110128222-A0202-12-2110-652

藉由一般程序方案H步驟1A製備。產率：8g(90.63%)。Prepared by General Procedure H, Step 1A. Yield: 8 g (90.63%).

LCMS(ESI)：[M]+ m/z：計算值292.2；實測值293.2；Rt=0.848min。LCMS (ESI): [M] + m/z: calculated 292.2; found 293.2; Rt=0.848 min.

步驟2：2-(1-環丙基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Cyclopropylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 Synthesis of -yl)benzo[d]thiazole

Figure 110128222-A0202-12-2110-653
Figure 110128222-A0202-12-2110-653

將5-氯-2-(1-環丙基-4-哌啶基)-1,3-苯并噻唑(4g，13.66mmol)、 4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.82g，15.03mmol)及乙酸鉀(2.68g，27.32mmol，1.71mL)混合於二噁烷(70mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加參(二苯亞甲基丙酮)二鈀(0)(625.43mg，683.00umol)。將反應混合物在氬氣、90℃下攪拌14h，然後冷卻且在減壓下濃縮。藉由管柱層析純化殘餘物，以得到2-(1-環丙基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(2.4g，6.24mmol，45.71%產率)。5-Chloro-2-(1-cyclopropyl-4-piperidinyl)-1,3-benzothiazole (4 g, 13.66 mmol), 4,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3 , 2-Dioxaborolane (3.82 g, 15.03 mmol) and potassium acetate (2.68 g, 27.32 mmol, 1.71 mL) were mixed in dioxane (70 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times, before adding para(dibenzylideneacetone)dipalladium(0) (625.43 mg, 683.00 umol) under argon. The reaction mixture was stirred under argon at 90 °C for 14 h, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-(1-cyclopropyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborol-2-yl)-1,3-benzothiazole (2.4 g, 6.24 mmol, 45.71% yield).

LCMS(ESI)：[M]+ m/z：計算值384.2；實測值385.2；Rt=1.026min。LCMS (ESI): [M] + m/z: calculated 384.2; found 385.2; Rt=1.026 min.

步驟3：(S)-6-(2-(1-環丙基哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1-Cyclopropylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine- Synthesis of 1(2H)-tert-butyl formate

Figure 110128222-A0202-12-2111-654
Figure 110128222-A0202-12-2111-654

藉由一般程序方案H步驟3製備。產率：0.6g(29.90%)。Prepared by General Procedure H, Step 3. Yield: 0.6 g (29.90%).

CC條件： 藉由矽膠使用己烷/EtOAc作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/EtOAc as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.372min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.372 min.

步驟4：(S)-2-(1-環丙基哌啶-4-基)-5-(5-甲基-3,4,5,6-丙氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1-Cyclopropylpiperidin-4-yl)-5-(5-methyl-3,4,5,6-prophydropyridin-2-yl)benzo[ d] Synthesis of thiazole

Figure 110128222-A0202-12-2112-655
Figure 110128222-A0202-12-2112-655

藉由一般程序方案H步驟4製備。產率：0.3g粗品。Prepared by General Procedure H, Step 4. Yield: 0.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值353.2；實測值354.2；Rt=0.719min。LCMS (ESI): [M] + m/z: calculated 353.2; found 354.2; Rt=0.719 min.

步驟5：2-(1-環丙基哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 2-(1-Cyclopropylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2112-656
Figure 110128222-A0202-12-2112-656

藉由一般程序方案H步驟5製備。產率：0.28g粗品。Prepared by General Procedure H, Step 5. Yield: 0.28 g crude.

LCMS(ESI)：[M]+ m/z：計算值355.2；實測值356.2；Rt=0.751min。LCMS (ESI): [M] + m/z: calculated 355.2; found 356.2; Rt=0.751 min.

步驟6：5-(2-((2R,5S)-2-(2-(1-環丙基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1219)之合成Step 6: 5-(2-((2R,5S)-2-(2-(1-cyclopropylpiperidin-4-yl)benzo[d]thiazol-5-yl)-5-methylpiperin Synthesis of pyridin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1219)

Figure 110128222-A0202-12-2112-657
Figure 110128222-A0202-12-2112-657

藉由一般程序方案H步驟6A製備。產率：30mg(13.21%)。Prepared by General Procedure H, Step 6A. Yield: 30 mg (13.21%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-55min 40-90%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-55 min 40-90% water-MeOH + 0.1% NH4OH ; (loading pump 4 ml/min MeOH).

藉由掌性HPLC(管柱：Chiralpak IB(250*30mm，5mkm)，流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min)純化5-[[2-[(2R,5S )-2-[2-(1-環丙基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺，以獲得5-[[2-[(2R,5S )-2-[2-(1-環丙基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-甲氧基吡啶-3-甲醯胺(30mg，52.02μmol，13.21%產率)。Purification of 5-[[2-[( 2R,5S )-2-[2-(1-cyclopropyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-2-methoxypyridine-3-carboxamide to give 5-[[2-[( 2R,5S )-2-[2-(1-cyclopropane yl-4-piperidinyl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-methyl Oxypyridine-3-carboxamide (30 mg, 52.02 μmol, 13.21% yield).

化合物1219於分析條件下(管柱：IB，以己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為15.85min。The retention time of compound 1219 under analytical conditions (column: IB, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 15.85 min.

化合物1219：保留時間：15.85minCompound 1219: retention time: 15.85min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.26-0.32(m,2H),0.38-0.44(m,2H),1.00-1.07(m,3H),1.30-1.42(m,1H),1.58-1.64(m,1H),1.66-1.75(m,3H),1.82-1.93(m,1H),2.02-2.22(m,3H),2.27-2.35(m,3H),2.81-3.28(m,4H),3.47-4.06(m,4H),5.26-5.73(m,1H),7.33-7.43(m,1H),7.66-7.77(m,2H),7.85-7.90(m,1H),8.01-8.09(m,1H),8.38-8.60(m,2H),10.92-11.19(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.26-0.32(m, 2H), 0.38-0.44(m, 2H), 1.00-1.07(m, 3H), 1.30-1.42(m, 1H) ,1.58-1.64(m,1H),1.66-1.75(m,3H),1.82-1.93(m,1H),2.02-2.22(m,3H),2.27-2.35(m,3H),2.81-3.28( m, 4H), 3.47-4.06(m, 4H), 5.26-5.73(m, 1H), 7.33-7.43(m, 1H), 7.66-7.77(m, 2H), 7.85-7.90(m, 1H), 8.01-8.09 (m, 1H), 8.38-8.60 (m, 2H), 10.92-11.19 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值576.2；實測值577.2；Rt=2.630min。LCMS (ESI): [M] + m/z: calculated 576.2; found 577.2; Rt=2.630 min.

實例630.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(吡啶-2-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1238)之合成Example 630. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(pyridin-2-yl)benzo Synthesis of [ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1238)

Figure 110128222-A0202-12-2114-658
Figure 110128222-A0202-12-2114-658

步驟1：5-氯-2-(吡啶-2-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(pyridin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟1A製備。產率：1.3g(28.04%)。Prepared by General Procedure H, Step 1A. Yield: 1.3 g (28.04%).

LCMS(ESI)：[M]+ m/z：計算值246.2；實測值247.2；Rt=1.228min。LCMS (ESI): [M] + m/z: calculated 246.2; found 247.2; Rt=1.228 min.

步驟2：2-(吡啶-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(Pyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[ d] Synthesis of thiazole

將5-氯-2-(2-吡啶基)-1,3-苯并噻唑(1.2g，4.86mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.36g，5.35mmol)及乙酸鉀(954.69mg，9.73mmol，608.08μL)混合於二噁烷(19.82mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加參 (二苯亞甲基丙酮)二鈀(0)(222.70mg，243.20μmol)。將反應混合物在氬氣、90℃下攪拌14h，然後冷卻且在減壓下濃縮。藉由管柱層析(SiO2 ，CHCl3 -MeCN 0~100%，流速=70mL/min，cv=8.8)純化殘餘物，以得到2-(2-吡啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(0.45g，1.33mmol，27.35%產率)。5-Chloro-2-(2-pyridyl)-1,3-benzothiazole (1.2 g, 4.86 mmol), 4,4,5,5-tetramethyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (1.36 g, 5.35 mmol) and potassium acetate (954.69 mg, 9.73 mmol, 608.08 μL) in dioxane (19.82 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times, followed by the addition of para(dibenzylideneacetone)dipalladium(0) ( 222.70 mg, 243.20 μmol) under argon. The reaction mixture was stirred under argon at 90 °C for 14 h, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography ( SiO2 , CHCl3 -MeCN 0~100%, flow rate=70 mL/min, cv=8.8) to give 2-(2-pyridyl)-5-(4,4 , 5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (0.45 g, 1.33 mmol, 27.35% yield).

LCMS(ESI)：[M]+ m/z：計算值338.2；實測值339.2；Rt=1.596min。LCMS (ESI): [M] + m/z: calculated 338.2; found 339.2; Rt=1.596 min.

步驟3：(S)-3-甲基-6-(2-(吡啶-2-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(pyridin-2-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid Synthesis of tertiary butyl ester

藉由一般程序方案H步驟3製備。產率：0.47g粗品。Prepared by General Procedure H, Step 3. Yield: 0.47 g crude.

LCMS(ESI)：[M]+ m/z：計算值407.2；實測值408.2；Rt=1.660min。LCMS (ESI): [M] + m/z: calculated 407.2; found 408.2; Rt=1.660 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(吡啶-2-基)苯并[d]噻唑之合成Step 4: Synthesis of (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(pyridin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.35g(98.72%)。Prepared by General Procedure H, Step 4. Yield: 0.35 g (98.72%).

LCMS(ESI)：[M]+ m/z：計算值307.2；實測值308.2；Rt=0.836min。LCMS (ESI): [M] + m/z: calculated 307.2; found 308.2; Rt=0.836 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(吡啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(pyridin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.35g粗品。Prepared by General Procedure H, Step 5. Yield: 0.35 g crude.

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=0.986min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=0.986 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基2-(2-(吡啶-2-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1238)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl 2-(2-(pyridin-2-yl)benzo[ d] Synthesis of thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1238)

藉由一般程序方案H步驟6B製備。產率：17.5mg(7.49%)。Prepared by General Procedure H, Step 6B. Yield: 17.5 mg (7.49%).

HPLC條件： 管柱：SunFire C18 100*19mm，5微米；2-10min 0-100% MeCN+FA，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-10 min 0-100% MeCN+FA, flow rate: 30 ml/min; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03-1.15(m,6H),1.31-1.44(m,1H),1.70-1.77(m,1H),1.86-1.96(m,1H),2.09-2.26(m,1H),2.30-2.35(m,1H),2.38-2.44(m,2H),2.81-3.22(m,1H),3.48-4.10(m,1H),5.30-5.77(m,3H),7.43-7.48(m,1H),7.48-7.55(m,1H),7.55-7.61(m,1H),7.98-8.09(m,3H),8.13-8.21(m,1H),8.28-8.35(m,1H),8.70-8.76(m,1H),10.52-10.64(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03-1.15(m, 6H), 1.31-1.44(m, 1H), 1.70-1.77(m, 1H), 1.86-1.96(m, 1H) ,2.09-2.26(m,1H),2.30-2.35(m,1H),2.38-2.44(m,2H),2.81-3.22(m,1H),3.48-4.10(m,1H),5.30-5.77( m,3H),7.43-7.48(m,1H),7.48-7.55(m,1H),7.55-7.61(m,1H),7.98-8.09(m,3H),8.13-8.21(m,1H), 8.28-8.35 (m, 1H), 8.70-8.76 (m, 1H), 10.52-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值500.2；實測值501.2；Rt=2.553min。LCMS (ESI): [M] + m/z: calculated 500.2; found 501.2; Rt=2.553 min.

實例631.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(3-(二甲胺基)環丁基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1101)之合成Example 631. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(3-(dimethylamino)cyclobutyl)benzene Synthesis of [ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1101)

Figure 110128222-A0202-12-2116-659
Figure 110128222-A0202-12-2116-659

步驟1：(3-(5-溴苯并[d]噻唑-2-基)環丁基)胺甲酸第三丁酯之合成 藉由一般程序8步驟1B製備。產率：5g(53.24%)。 Step 1: Synthesis of tert-butyl (3-(5-bromobenzo[d]thiazol-2-yl)cyclobutyl)carbamate Prepared by General Procedure 8, Step 1B. Yield: 5 g (53.24%).

LCMS(ESI)：[M]+ m/z：計算值383.2；實測值384.2；Rt=1.402min。LCMS (ESI): [M] + m/z: calculated 383.2; found 384.2; Rt=1.402 min.

步驟2：3-(5-溴苯并[d]噻唑-2-基)環丁胺之合成Step 2: Synthesis of 3-(5-Bromobenzo[d]thiazol-2-yl)cyclobutanamine

將N -[3-(5-溴-1,3-苯并噻唑-2-基)環丁基]胺甲酸第三丁 酯(5g，13.04mmol)用於二噁烷中之4.0M氯化氫溶液(24.00g，658.26mmol，30mL)處理。將所得混合物在25℃下攪拌14h。過濾沉澱且另外用MTBE處理。然後在真空中乾燥，以得到3-(5-溴-1,3-苯并噻唑-2-基)環丁胺(4g，12.51mmol，95.93%產率，HCl)。3-butyl N- [3-(5-bromo-1,3-benzothiazol-2-yl)cyclobutyl] carbamate (5 g, 13.04 mmol) in 4.0 M hydrogen chloride in dioxane (24.00 g, 658.26 mmol, 30 mL) to treat. The resulting mixture was stirred at 25 °C for 14 h. The precipitate was filtered and treated additionally with MTBE. It was then dried in vacuo to give 3-(5-bromo-1,3-benzothiazol-2-yl)cyclobutanamine (4 g, 12.51 mmol, 95.93% yield, HCl).

LCMS(ESI)：[M]+ m/z：計算值284.2；實測值285.2；Rt=0.931min。LCMS (ESI): [M] + m/z: calculated 284.2; found 285.2; Rt=0.931 min.

步驟3：3-(5-溴苯并[d]噻唑-2-基)-N,N-二甲基環丁胺之合成Step 3: Synthesis of 3-(5-Bromobenzo[d]thiazol-2-yl)-N,N-dimethylcyclobutanamine

向3-(5-溴-1,3-苯并噻唑-2-基)環丁胺(4g，12.51mmol，HCl)於MeOH(71.00mL)中之經攪拌之溶液中添加用7-8% MeOH穩定之37重量%甲醛水溶液(2.54g，31.28mmol，2.34mL，37%純度)且添加無水乙酸鈉(2.57g，31.28mmol，1.68mL)。將所得混合物在25℃下攪拌2h。然後分批添加氰基硼氫化鈉(1.57g，25.03mmol)。將所得混合物在25℃下攪拌12h。蒸發MeOH。將殘餘物用水(100ml)稀釋且用DCM(3*50ml)萃取。將經合併之有機層經Na2 SO4 乾燥。在真空中蒸發DCM，以得到3-(5-溴-1,3-苯并噻唑-2-基)-N,N -二甲基-環丁胺(3.9g，粗品)。To a stirred solution of 3-(5-bromo-1,3-benzothiazol-2-yl)cyclobutanamine (4 g, 12.51 mmol, HCl) in MeOH (71.00 mL) was added 7-8% MeOH stabilized 37 wt% aqueous formaldehyde solution (2.54 g, 31.28 mmol, 2.34 mL, 37% pure) and anhydrous sodium acetate (2.57 g, 31.28 mmol, 1.68 mL) was added. The resulting mixture was stirred at 25 °C for 2 h. Then sodium cyanoborohydride (1.57 g, 25.03 mmol) was added portionwise. The resulting mixture was stirred at 25 °C for 12 h. MeOH was evaporated. The residue was diluted with water (100ml) and extracted with DCM (3*50ml). The combined organic layers were dried over Na2SO4 . The DCM was evaporated in vacuo to give 3-(5-bromo-1,3-benzothiazol-2-yl) -N,N -dimethyl-cyclobutanamine (3.9 g, crude).

LCMS(ESI)：[M]+ m/z：計算值311.2；實測值312.2；Rt=0.829min。LCMS (ESI): [M] + m/z: calculated 311.2; found 312.2; Rt=0.829 min.

步驟4：N,N-二甲基-3-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)環丁胺之合成Step 4: N,N-Dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo Synthesis of [d]thiazol-2-yl)cyclobutanamine

藉由一般程序方案H步驟2製備。產率：4g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=1.029min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=1.029 min.

藉由一般程序方案H步驟3製備。產率：7g粗品。Prepared by General Procedure H, Step 3. Yield: 7 g crude.

LCMS(ESI)：[M]+ m/z：計算值427.2；實測值428.2；Rt=1.057min。LCMS (ESI): [M] + m/z: calculated 427.2; found 428.2; Rt=1.057 min.

步驟6：(S)-N,N-二甲基-3-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)環丁胺之合成Step 6: (S)-N,N-Dimethyl-3-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 -Synthesis of cyclobutylamine

藉由一般程序方案H步驟4製備。產率：3g粗品。Prepared by General Procedure H, Step 4. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.635min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.635 min.

步驟7：N,N-二甲基-3-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)環丁胺之合成Step 7: Synthesis of N,N-dimethyl-3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)cyclobutanamine

藉由一般程序方案H步驟5製備。產率：80mg(2.65%)。Prepared by General Procedure H, Step 5. Yield: 80 mg (2.65%).

HPLC條件： 管柱：Chromatorex C18 100*19mm，5微米；0-1-6min 45-45-85%水-MeOH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: Chromatorex C18 100*19 mm, 5 microns; 0-1-6 min 45-45-85% water-MeOH, flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=1.324min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=1.324 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(3-(二甲胺基)環丁基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1101)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(3-(dimethylamino)cyclobutyl)benzene Synthesis of [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1101)

藉由一般程序8步驟6A製備。產率：5mg(1.61%)。Prepared by General Procedure 8, Step 6A. Yield: 5 mg (1.61%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 60-60-70%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 60-60-70% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.14(m,6H),1.32-1.39(m,1H),1.65-1.75(m,1H),1.81-1.93(m,1H),2.04(s,6H),2.09-2.14(m,2H),2.26-2.36(m, 2H),2.39-2.42(m,2H),2.54-2.56(m,2H),2.65-2.71(m,1H),2.77-2.97(m,1H),3.45-4.07(m,2H),5.24-5.71(m,3H),7.32-7.41(m,1H),7.42-7.53(m,1H),7.85-7.91(m,1H),7.98-8.09(m,2H),10.56(s,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.02-1.14 (m, 6H), 1.32-1.39 (m, 1H), 1.65-1.75 (m, 1H), 1.81-1.93 (m, 1H) ,2.04(s,6H),2.09-2.14(m,2H),2.26-2.36(m,2H),2.39-2.42(m,2H),2.54-2.56(m,2H),2.65-2.71(m, 1H), 2.77-2.97(m, 1H), 3.45-4.07(m, 2H), 5.24-5.71(m, 3H), 7.32-7.41(m, 1H), 7.42-7.53(m, 1H), 7.85- 7.91 (m, 1H), 7.98-8.09 (m, 2H), 10.56 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=2.206min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=2.206 min.

實例632.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基吡咯啶-2-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1282)之合成Example 632. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methylpyrrolidine-2 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1282)

Figure 110128222-A0202-12-2118-660
Figure 110128222-A0202-12-2118-660

步驟1：5-溴-2-(1-甲基吡咯啶-2-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(1-methylpyrrolidin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟1A製備。產率：2.8g(97.34%)。Prepared by General Procedure H, Step 1A. Yield: 2.8 g (97.34%).

LCMS(ESI)：[M]+ m/z：計算值297.2；實測值298.2；Rt=0.958min。LCMS (ESI): [M] + m/z: calculated 297.2; found 298.2; Rt=0.958 min.

步驟2：2-(1-甲基吡咯啶-2-基)-5-(4,4,5,5-四甲基1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Methylpyrrolidin-2-yl)-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborol-2-yl ) Synthesis of Benzo[d]thiazole

藉由一般程序方案H步驟2製備。產率：3.2g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 3.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=1.005min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=1.005 min.

步驟3：(3S)-3-甲基-6-(2-(1-甲基吡咯啶-2-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (3S)-3-Methyl-6-(2-(1-methylpyrrolidin-2-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：5g粗品。Prepared by General Procedure H, Step 3. Yield: 5 g crude.

LCMS(ESI)：[M]+ m/z：計算值413.2；實測值414.2；Rt=1.143min。LCMS (ESI): [M] + m/z: calculated 413.2; found 414.2; Rt=1.143 min.

步驟4：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-甲基吡咯啶-2-基)苯并[d]噻唑Step 4: 5-((S)-5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-methylpyrrolidin-2-yl)benzo[d ]thiazole 之合成synthesis

藉由一般程序方案H步驟4製備。產率：1.2g(31.67%)。Prepared by General Procedure H, Step 4. Yield: 1.2 g (31.67%).

LCMS(ESI)：[M]+ m/z：計算值313.2；實測值314.2；Rt=0.624min。LCMS (ESI): [M] + m/z: calculated 313.2; found 314.2; Rt=0.624 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1-甲基吡咯啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-methylpyrrolidin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.85g(70.38%)。Prepared by General Procedure H, Step 5. Yield: 0.85 g (70.38%).

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.664min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.664 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基吡咯啶-2-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1282)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylpyrrolidine-2 Synthesis of -yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1282)

藉由一般程序方案H步驟6A製備。產率：140mg(34.87%)。Prepared by General Procedure H, Step 6A. Yield: 140 mg (34.87%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 40-90%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 40-90% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

對此物質進行掌性分離(管柱：Chiral ART Cellulose-SC(250*20mm，5mkm)；流動相：己烷-IPA-MeOH，70-15-15.流速：12mL/min)。This material was subjected to chiral separation (column: Chiral ART Cellulose-SC (250*20mm, 5mkm); mobile phase: Hexane-IPA-MeOH, 70-15-15. Flow rate: 12 mL/min).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.02-1.06(m,3H),1.06-1.16(m,3H),1.29-1.44(m,1H),1.67-1.91(m,5H),2.08-2.25(m,1H),2.26-2.35(m,2H),2.37(s,3H),2.38-2.40(m,1H),2.40-2.46(m,2H),2.77-3.30(m,2H),3.32-4.12(m,2H),5.24-5.62(m,1H),5.62-5.78(m,2H),7.29-7.43(m,1H),7.43-7.56(m,1H),7.82-7.89(m,1H),7.98-8.11(m,2H),10.56(s,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.02-1.06(m,3H), 1.06-1.16(m,3H), 1.29-1.44(m,1H), 1.67-1.91(m,5H) ,2.08-2.25(m,1H),2.26-2.35(m,2H),2.37(s,3H),2.38-2.40(m,1H),2.40-2.46(m,2H),2.77-3.30(m, 2H), 3.32-4.12(m, 2H), 5.24-5.62(m, 1H), 5.62-5.78(m, 2H), 7.29-7.43(m, 1H), 7.43-7.56(m, 1H), 7.82- 7.89 (m, 1H), 7.98-8.11 (m, 2H), 10.56 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=1.629min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=1.629 min.

實例633.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(1-環丙基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1330)之合成Example 633. N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(1-cyclopropylpiperidin-4-yl)benzene Synthesis of [ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1330)

Figure 110128222-A0202-12-2120-661
Figure 110128222-A0202-12-2120-661

藉由一般程序方案H步驟6A製備。產率：30mg(8.31%)。Prepared by General Procedure H, Step 6A. Yield: 30 mg (8.31%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-1-6min 60-60-80%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-1-6 min 60-60-80% water-MeOH+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

藉由掌性HPLC(管柱：Chiralpak IC-III(250*20mm，5mkm)；流動相：IPA-MeOH，50-50；流速：12mL/min)純化N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[2-(1-環丙基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[2-(1-環丙基-4-哌啶基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(22mg，40.24μmol，3.58%產率)。Purification of N- (6-amino-5-ethyl) by chiral HPLC (column: Chiralpak IC-III (250*20 mm, 5 mkm); mobile phase: IPA-MeOH, 50-50; flow rate: 12 mL/min) yl-3-pyridyl)-2-[( 2R,5S )-2-[2-(1-cyclopropyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-5 -Methyl-1-piperidinyl]-2-oxyacetamide to give N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )- 2-[2-(1-Cyclopropyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-side oxyethyl Amide (22 mg, 40.24 μmol, 3.58% yield).

化合物1330於分析條件下(管柱：IC，IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為30.27min。The retention time of compound 1330 under analytical conditions (column: IC, IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 30.27 min.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.30-0.41(m,4H),1.02-1.13(m,6H),1.31-1.39(m,1H),1.62-1.71(m,3H),1.84-1.89(m,2H),2.05-2.07(m,3H)2.30-2.41(m,4H),2.77-2.79(m,1H),2.99-3.10(m,3H),3.47-4.05(m,2H),5.27-5.69(m,3H),7.33-7.51(m,2H),7.85-7.89(d,1H),7.99-8.06(m,2H),10.52-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.30-0.41(m, 4H), 1.02-1.13(m, 6H), 1.31-1.39(m, 1H), 1.62-1.71(m, 3H) ,1.84-1.89(m,2H),2.05-2.07(m,3H)2.30-2.41(m,4H),2.77-2.79(m,1H),2.99-3.10(m,3H),3.47-4.05(m , 2H), 5.27-5.69(m, 3H), 7.33-7.51(m, 2H), 7.85-7.89(d, 1H), 7.99-8.06(m, 2H), 10.52-10.58(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值546.2；實測值547.2；Rt=1.974min。LCMS (ESI): [M] + m/z: calculated 546.2; found 547.2; Rt=1.974 min.

實例634.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(吡啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1194)之合成Example 634. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(pyridin-4-yl)benzo Synthesis of [ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1194)

Figure 110128222-A0202-12-2121-662
Figure 110128222-A0202-12-2121-662

步驟1：5-氯-2-(吡啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-chloro-2-(pyridin-4-yl)benzo[d]thiazole

藉由一般程序方案H步驟1A製備。產率：0.25g(5.39%)。Prepared by General Procedure H, Step 1A. Yield: 0.25 g (5.39%).

CC條件： 藉由矽膠使用己烷/IPA作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using hexane/IPA as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值246.2；實測值247.2；Rt=1.182min。LCMS (ESI): [M] + m/z: calculated 246.2; found 247.2; Rt=1.182 min.

步驟2：2-(吡啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(Pyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo[ d] Synthesis of thiazole

將5-氯-2-(4-吡啶基)-1,3-苯并噻唑(0.3g，1.22mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(339.66mg，1.34mmol)及乙酸鉀(238.67mg，2.43mmol，152.02μL)混合於二噁烷(20.27mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加參(二苯亞甲基丙酮)二鈀(0)(55.67mg，60.80μmol)。將反應混合物在氬氣、90℃下攪拌14h，然後冷卻且在減壓下濃縮。藉由管柱層析(管柱：SunFire 100*19mm，5微米；2-10min 50-100% MeCN 30ml/min(裝載泵4ml MecN))純化殘餘物，以得到[2-(4-吡啶基)-1,3-苯并噻唑-5-基]硼酸(0.06g，234.29μmol，19.27%產率)。5-Chloro-2-(4-pyridyl)-1,3-benzothiazole (0.3 g, 1.22 mmol), 4,4,5,5-tetramethyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (339.66 mg, 1.34 mmol) and potassium acetate (238.67 mg, 2.43 mmol, 152.02 μL) in dioxane (20.27 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times, followed by the addition of para(dibenzylideneacetone)dipalladium(0) (55.67 mg, 60.80 μmol) under argon. The reaction mixture was stirred under argon at 90 °C for 14 h, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography (column: SunFire 100*19 mm, 5 microns; 2-10 min 50-100% MeCN 30 ml/min (loading pump 4 ml MecN)) to give [2-(4-pyridyl) )-1,3-benzothiazol-5-yl]boronic acid (0.06 g, 234.29 μmol, 19.27% yield).

LCMS(ESI)：[M]+ m/z：計算值338.2；實測值339.2；Rt=1.341min。LCMS (ESI): [M] + m/z: calculated 338.2; found 339.2; Rt=1.341 min.

步驟3：(S)-3-甲基-6-(2-(吡啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-3-Methyl-6-(2-(pyridin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid Synthesis of tertiary butyl ester

藉由一般程序方案H步驟3製備。產率：96mg粗品。Prepared by General Procedure H, Step 3. Yield: 96 mg crude.

LCMS(ESI)：[M]+ m/z：計算值407.2；實測值408.2；Rt=1.323min。LCMS (ESI): [M] + m/z: calculated 407.2; found 408.2; Rt=1.323 min.

步驟4：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(吡啶-4-基)苯并[d]噻唑之合成Step 4: Synthesis of (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(pyridin-4-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：75mg粗品。Prepared by General Procedure H, Step 4. Yield: 75 mg crude.

LCMS(ESI)：[M]+ m/z：計算值307.2；實測值308.2；Rt=0.755min。LCMS (ESI): [M] + m/z: calculated 307.2; found 308.2; Rt=0.755 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(吡啶-4-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(pyridin-4-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：69mg粗品。Prepared by General Procedure H, Step 5. Yield: 69 mg crude.

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=0.770min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=0.770 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(吡啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1194)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(pyridin-4-yl)benzo Synthesis of [d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1194)

藉由一般程序方案H步驟6B製備。產率：10mg(15.28%)。Prepared by General Procedure H, Step 6B. Yield: 10 mg (15.28%).

HPLC條件： 管柱：SunFire C18 100*19mm，5微米；2-10min 50-75% MeOH+NH3 ，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-10 min 50-75% MeOH+ NH3 , flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03-1.05(t,3H),1.12-1.14(m,3H),1.34-1.42(m,2H),1.72-1.74(m,2H),1.87-1.92(m,2H),2.32-2.37(m,1H),2.40-2.42(m,1H),3.50-4.08(m,1H),5.33-5.73(m,3H),7.43-7.56(m,2H),8.03-8.08(m,4H),8.24(m,1H),8.78-8.79(m,2H),10.51(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03-1.05(t,3H), 1.12-1.14(m,3H), 1.34-1.42(m,2H), 1.72-1.74(m,2H) ,1.87-1.92(m,2H),2.32-2.37(m,1H),2.40-2.42(m,1H),3.50-4.08(m,1H),5.33-5.73(m,3H),7.43-7.56( m, 2H), 8.03-8.08 (m, 4H), 8.24 (m, 1H), 8.78-8.79 (m, 2H), 10.51 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值500.2；實測值501.2；Rt=2.663min。LCMS (ESI): [M] + m/z: calculated 500.2; found 501.2; Rt=2.663 min.

實例635. 5-(2-((2R,5S )-2-(2-(1-乙基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1164)之合成Example 635. 5-(2-(( 2R,5S )-2-(2-(1-ethylpiperidin-4-yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidine Synthesis of -1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1164)

Figure 110128222-A0202-12-2123-663
Figure 110128222-A0202-12-2123-663

藉由一般程序方案H步驟6A製備。產率：65mg(39.54%)。Prepared by General Procedure H, Step 6A. Yield: 65 mg (39.54%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 40-40-80%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6 min 40-40-80% water-MeOH+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.03(m,6H),1.32-1.40(m,1H),1.71-1.90(m,4H),2.01-2.19(m,6H),2.29-2.37(m,3H),2.83-2.94(m,2H),3.06-3.11(m,1H),3.49-4.05(m,4H),5.29-5.70(m,1H),7.35-7.42(dd,1H),7.68-7.75(m,2H),7.87-7.89(m,1H),8.03-8.07(m,1H),8.41-8.58(m,2H),11.02-11.10(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.03(m,6H), 1.32-1.40(m,1H), 1.71-1.90(m,4H), 2.01-2.19(m,6H) ,2.29-2.37(m,3H),2.83-2.94(m,2H),3.06-3.11(m,1H),3.49-4.05(m,4H),5.29-5.70(m,1H),7.35-7.42( dd,1H), 7.68-7.75(m,2H), 7.87-7.89(m,1H), 8.03-8.07(m,1H), 8.41-8.58(m,2H), 11.02-11.10(m,1H).

LCMS(ESI)：[M]+ m/z：計算值564.2；實測值565.2；Rt=2.643min。LCMS (ESI): [M] + m/z: calculated 564.2; found 565.2; Rt=2.643 min.

實例636. 5-(2-((2R,5S )-2-(2-((二甲胺基)甲基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1162)之合成Example 636. 5-(2-(( 2R,5S )-2-(2-((dimethylamino)methyl)benzo[ d ]thiazol-5-yl)-5-methylpiperidine-1 Synthesis of -yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1162)

Figure 110128222-A0202-12-2123-664
Figure 110128222-A0202-12-2123-664

步驟1：1-(5-溴苯并[d]噻唑-2-基)-N,N-二甲基甲胺之合成Step 1: Synthesis of 1-(5-bromobenzo[d]thiazol-2-yl)-N,N-dimethylmethanamine

藉由一般程序方案H步驟1C製備。產率：3.7g(82.58%)。Prepared by General Procedure H, Step 1C. Yield: 3.7 g (82.58%).

LCMS(ESI)：[M]+ m/z：計算值271.2；實測值272.2；Rt=0.801min。LCMS (ESI): [M] + m/z: calculated 271.2; found 272.2; Rt=0.801 min.

步驟2：N,N-二甲基-1-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)甲胺之合成Step 2: N,N-Dimethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzone Synthesis of [d]thiazol-2-yl)methanamine

藉由一般程序方案H步驟2製備。產率：12.91g(70.07%)。Prepared by General Procedure Scheme H, Step 2. Yield: 12.91 g (70.07%).

CC條件： 藉由矽膠使用DCM/MeCN(梯度)作為溶析液混合物來純化粗產物。 CC conditions: The crude product was purified by silica gel using DCM/MeCN (gradient) as eluent mixture.

LCMS(ESI)：[M]+ m/z：計算值318.2；實測值319.2；Rt=0.758min。LCMS (ESI): [M] + m/z: calculated 318.2; found 319.2; Rt=0.758 min.

步驟3：(S)-6-(2-((二甲胺基)甲基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H )-Synthesis of tert-butyl formate

藉由一般程序方案H步驟3製備。產率：3.5g粗品。Prepared by General Procedure H, Step 3. Yield: 3.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值387.2；實測值388.2；Rt=1.192min。LCMS (ESI): [M] + m/z: calculated 387.2; found 388.2; Rt=1.192 min.

步驟4：(S)-N,N-二甲基-1-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)甲胺之合成Step 4: (S)-N,N-Dimethyl-1-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 Synthesis of -yl)methylamine

藉由一般程序方案H步驟4製備。產率：3.04g粗品。Prepared by General Procedure H, Step 4. Yield: 3.04 g crude.

LCMS(ESI)：[M]+ m/z：計算值287.2；實測值288.2；Rt=0.602min。LCMS (ESI): [M] + m/z: calculated 287.2; found 288.2; Rt=0.602 min.

步驟5：N,N-二甲基-1-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)甲胺之合成Step 5: Synthesis of N,N-dimethyl-1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)methanamine

藉由一般程序方案H步驟5製備。產率：2.5g粗品。Prepared by General Procedure H, Step 5. Yield: 2.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值289.2；實測值290.2；Rt=0.686min。LCMS (ESI): [M] + m/z: calculated 289.2; found 290.2; Rt=0.686 min.

步驟6：5-(2-((2R,5S)-2-(2-((二甲胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1162)之合成Step 6: 5-(2-((2R,5S)-2-(2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-5-methylpiperidine-1 Synthesis of -yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1162)

藉由一般程序方案H步驟6B製備。產率：68.4mg(38.77%)。Prepared by General Procedure H, Step 6B. Yield: 68.4 mg (38.77%).

HPLC條件： 管柱：SunFire C18 100*19mm，5微米；2-10min 25-30%水-MeOH+NH3 ；(裝載泵4ml/min MeOH+NH3 )。 HPLC conditions: Column: SunFire C18 100*19mm, 5 microns; 2-10 min 25-30% water-MeOH+ NH3 ; (loading pump 4 ml/min MeOH+ NH3 ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.06(m,3H),1.33-1.40(m,1H),1.71 -1.73(m,1H),1.86-1.91(m,1H),2.06-2.21(m,2H),2.30(s,6H),3.49-3.51(m,1H),3.85-4.05(m,5H),5.29-5.73(m,2H),7.36-7.42(m,1H),7.68-7.74(m,2H),7.87-7.88(m,1H),8.03-8.07(m,1H),8.40-8.58(m,2H),11.04(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.06(m,3H), 1.33-1.40(m,1H), 1.71-1.73(m,1H), 1.86-1.91(m,1H) ,2.06-2.21(m,2H),2.30(s,6H),3.49-3.51(m,1H),3.85-4.05(m,5H),5.29-5.73(m,2H),7.36-7.42(m, 1H), 7.68-7.74(m, 2H), 7.87-7.88(m, 1H), 8.03-8.07(m, 1H), 8.40-8.58(m, 2H), 11.04(br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值510.2；實測值511.2；Rt=2.168min。LCMS (ESI): [M] + m/z: calculated 510.2; found 511.2; Rt=2.168 min.

實例637. 2-甲氧基-5-(2-((2R,5S )-5-甲基-2-(2-(2-(吡咯啶-1-基)乙基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1288)之合成Example 637. 2-Methoxy-5-(2-(( 2R,5S )-5-methyl-2-(2-(2-(pyrrolidin-1-yl)ethyl)benzo[ d ] Synthesis of thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 1288)

Figure 110128222-A0202-12-2125-665
Figure 110128222-A0202-12-2125-665

藉由一般程序方案H步驟6A製備。產率：26.7mg(23.85%)。Prepared by General Procedure H, Step 6A. Yield: 26.7 mg (23.85%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 50-50-80%水-MeOH+0.1% NH4 OH；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6 min 50-50-80% water-MeOH+0.1% NH4OH ; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.16(m,4H),1.32-1.39(m,2H),1.68(m,4H),1.85-1.91(m,2H),2.08-2.37(m,2H),2.84-2.86(m,2H),3.23-3.26(m,3H),3.49-3.73(m,2H),3.86-4.20(m,4H),4.48-4.95(m,1H),5.30-5.79(m,2H),7.24-7.54(m,1H),7.69-7.88(m,2H),8.00-8.05(m,1H),8.31-8.68(m,1H),11.02-11.11(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.16(m, 4H), 1.32-1.39(m, 2H), 1.68(m, 4H), 1.85-1.91(m, 2H), 2.08 -2.37(m, 2H), 2.84-2.86(m, 2H), 3.23-3.26(m, 3H), 3.49-3.73(m, 2H), 3.86-4.20(m, 4H), 4.48-4.95(m, 1H), 5.30-5.79(m, 2H), 7.24-7.54(m, 1H), 7.69-7.88(m, 2H), 8.00-8.05(m, 1H), 8.31-8.68(m, 1H), 11.02- 11.11 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值550.2；實測值551.2；Rt=2.099min。LCMS (ESI): [M] + m/z: calculated 550.2; found 551.2; Rt=2.099 min.

實例638.N -(咪唑并[1,2-a ]吡啶-7-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1301)之合成Example 638. N- (imidazo[ 1,2-a ]pyridin-7-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidine-4 Synthesis of -yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1301)

Figure 110128222-A0202-12-2125-666
Figure 110128222-A0202-12-2125-666

藉由一般程序方案H步驟6A製備。產率：86mg(47.56%)。Prepared by General Procedure H, Step 6A. Yield: 86 mg (47.56%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 15-65%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5 min 15-65% water-MeCN + 0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.07(m,3H),1.30-1.41(m,1H),1.64-1.74(m,1H),1.77-1.93(m,3H),1.99-2.14(m,5H),2.18(s,3H),2.29-2.36(m,1H),2.49-2.51(m,3H),2.80-2.86(m,2H),3.01-3.09(m,1H),3.31-3.33(m,1H),3.36-4.07(m,1H),5.27-5.82(m,1H),7.06-7.31(m,1H),7.34-7.44(m,1H),7.86-7.91(m,1H),8.01-8.09(m,1H),8.19-8.35(m,1H),8.69-8.83(m,1H),11.13-11.40(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.07(m,3H), 1.30-1.41(m,1H), 1.64-1.74(m,1H), 1.77-1.93(m,3H) ,1.99-2.14(m,5H),2.18(s,3H),2.29-2.36(m,1H),2.49-2.51(m,3H),2.80-2.86(m,2H),3.01-3.09(m, 1H), 3.31-3.33(m, 1H), 3.36-4.07(m, 1H), 5.27-5.82(m, 1H), 7.06-7.31(m, 1H), 7.34-7.44(m, 1H), 7.86- 7.91(m,1H), 8.01-8.09(m,1H), 8.19-8.35(m,1H), 8.69-8.83(m,1H), 11.13-11.40(m,1H).

LCMS(ESI)：[M]+ m/z：計算值541.2；實測值542.2；Rt=2.872min。LCMS (ESI): [M] + m/z: calculated 541.2; found 542.2; Rt=2.872 min.

實例639.外消旋 -2-(2-甲氧基乙基)-5-((2R,5S )-5-甲基哌啶-2-基)苯并[d ]噻唑之合成Example 639. Synthesis of racemic -2-(2-methoxyethyl)-5-(( 2R,5S )-5-methylpiperidin-2-yl)benzo[ d ]thiazole

步驟1：5-溴-2-(2-甲氧基乙基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(2-methoxyethyl)benzo[d]thiazole

Figure 110128222-A0202-12-2126-667
Figure 110128222-A0202-12-2126-667

將2-胺基-4-溴苯硫酚(5.5g，26.95mmol，170.94uL)、3-甲氧基丙腈(3.44g，40.42mmol，3.67mL)、乙酸銅(II)(489.49mg，2.69mmol)、TEA(2.73g，26.95mmol，3.76mL)溶解於EtOH(100mL)中。將混合物在70℃(油浴溫度)下攪拌13h。在反應完成(藉由LCMS監測)之後，將混合物冷卻至室溫且用Na2 CO3 水溶液萃取，且將粗產物用EtOAc萃取。將有機萃取物在真空中濃縮，且藉由矽膠管柱層析使用己烷/EtOAc作為溶析液來純化所得殘餘物，以得到5-溴-2-(2-甲氧基乙基)-1,3-苯并噻唑(2.75g，10.10mmol，37.49%產率)。2-Amino-4-bromothiophenol (5.5 g, 26.95 mmol, 170.94 uL), 3-methoxypropionitrile (3.44 g, 40.42 mmol, 3.67 mL), copper(II) acetate (489.49 mg, 2.69 mmol), TEA (2.73 g, 26.95 mmol, 3.76 mL) were dissolved in EtOH (100 mL). The mixture was stirred at 70 °C (oil bath temperature) for 13 h. After completion of the reaction (monitored by LCMS ) , the mixture was cooled to room temperature and extracted with aqueous Na2CO3 , and the crude product was extracted with EtOAc. The organic extracts were concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using hexane/EtOAc as eluent to give 5-bromo-2-(2-methoxyethyl)- 1,3-benzothiazole (2.75 g, 10.10 mmol, 37.49% yield).

LCMS(ESI)：[M]+ m/z：計算值272.2；實測值273.2；Rt=1.369min。LCMS (ESI): [M] + m/z: calculated 272.2; found 273.2; Rt=1.369 min.

步驟2：2-(2-甲氧基乙基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(2-Methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene Synthesis of [d]thiazoles

Figure 110128222-A0202-12-2127-668
Figure 110128222-A0202-12-2127-668

藉由一般程序方案J步驟2製備。產率：3.2g粗品。Prepared by General Procedure J, Step 2. Yield: 3.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值319.2；實測值320.2；Rt=1.562min。LCMS (ESI): [M] + m/z: calculated 319.2; found 320.2; Rt=1.562 min.

步驟3：6-(2-(2-甲氧基乙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: 6-(2-(2-Methoxyethyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid 3rd Synthesis of Butyl Ester

Figure 110128222-A0202-12-2127-669
Figure 110128222-A0202-12-2127-669

藉由一般程序方案J步驟3製備。產率：3.2g粗品。Prepared by General Procedure J, Step 3. Yield: 3.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=1.577min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=1.577 min.

步驟4：2-(2-甲氧基乙基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: Synthesis of 2-(2-Methoxyethyl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2128-670
Figure 110128222-A0202-12-2128-670

藉由一般程序方案J步驟4製備。產率：3.2g粗品。Prepared by General Procedure J, Step 4. Yield: 3.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值288.2；實測值289.2；Rt=0.764min。LCMS (ESI): [M] + m/z: calculated 288.2; found 289.2; Rt=0.764 min.

步驟5：外消旋-2-(2-甲氧基乙基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of racemic-2-(2-methoxyethyl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2128-671
Figure 110128222-A0202-12-2128-671

藉由一般程序方案H步驟5製備。產率：3g粗品。Prepared by General Procedure H, Step 5. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值290.2；實測值291.2；Rt=0.877min。LCMS (ESI): [M] + m/z: calculated 290.2; found 291.2; Rt=0.877 min.

實例640. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(3-(二甲胺基)雙環[1.1.1]戊-1-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1404)之合成Example 640. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(3-(dimethylamino)bicyclo[1.1.1 ]Pent-1-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamide (compound 1404) synthesis

Figure 110128222-A0202-12-2129-672
Figure 110128222-A0202-12-2129-672

步驟1：(2R,5S)-2-(苯并[d]噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在室溫下向5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑(3g，7.80mmol)及碳酸氫鈉(1.97g，23.41mmol，910.82μL)於DCM(22.89mL)中之溶液中分批添加二碳酸二-第三丁酯(1.70g，7.80mmol，1.79mL)。當停止氣體逸出時，用10%NaHCO3 水溶液及鹽水洗滌，經Na2 SO4 乾燥且蒸發至乾，以得到呈黃色固體之(2R,5S )-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(2.3g，6.92mmol，88.67%產率)。To 5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzothiazole (3 g, 7.80 mmol) and sodium bicarbonate (1.97 g, 23.41 mmol, To a solution of 910.82 μL) in DCM (22.89 mL) was added di-tert-butyl dicarbonate (1.70 g, 7.80 mmol, 1.79 mL) portionwise. When gas evolution ceased, washed with 10% aqueous NaHCO 3 and brine, dried over Na 2 SO 4 and evaporated to dryness to give ( 2R,5S )-2-(1,3-benzothiazole as a yellow solid -5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2.3 g, 6.92 mmol, 88.67% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.04(d,3H),1.34(m,1H),1.44(s,9H),1.79(m,2H),2.11(m,2H),3.03(m,1H),3.75(m,1H),5.46(m,1H),7.33(d,1H),7.88(d,1H),8.01(s,1H),8.90(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.04(d, 3H), 1.34(m, 1H), 1.44(s, 9H), 1.79(m, 2H), 2.11(m, 2H), 3.03( m, 1H), 3.75 (m, 1H), 5.46 (m, 1H), 7.33 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.90 (s, 1H).

步驟2：(2R,5S)-2-(3-胺基-4-巰基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (2R,5S)-2-(3-amino-4-mercaptophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在Ar氣氛、室溫下，向(2R,5S )-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(3.1g，9.32mmol)於EtOH(50mL)中之溶液中添加單水合肼(4.67g，93.24mmol，4.55mL)。然後將反應混合物在回流下攪拌隔夜。注意：冷凝器頂部用橡膠隔片加蓋且透過針連接具有氬氣之氣球以平衡壓力。藉由LCMS監測反應進展。注意：在LCMS上可發現產物為硫化物或二硫化物，因為硫化物可在LCMS過程期間氧化為二硫化物。然後將所得混合物冷卻，蒸發且分配於水 與EtOAc之間。將有機相用鹽水洗滌，經Na2 SO4 乾燥，且在真空中濃縮，以得到呈棕色油狀物之(2R,5S )-2-(3-胺基-4-氫硫基苯基)-5-甲基哌啶-1-甲酸第三丁酯(3g，9.30mmol，99.77%產率)。To ( 2R,5S )-2-(1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (3.1 g, 9.32 g) under Ar atmosphere at room temperature mmol) in EtOH (50 mL) was added hydrazine monohydrate (4.67 g, 93.24 mmol, 4.55 mL). The reaction mixture was then stirred at reflux overnight. Note: The top of the condenser was capped with a rubber septum and a balloon with argon was attached through the needle to equalize the pressure. The progress of the reaction was monitored by LCMS. Note: The product can be found on LCMS as sulfide or disulfide, since sulfide can be oxidized to disulfide during the LCMS process. The resulting mixture was then cooled, evaporated and partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4 , and concentrated in vacuo to give ( 2R,5S )-2-(3-amino-4-hydrothiophenyl) as a brown oil - 3-butyl 5-methylpiperidine-1-carboxylate (3 g, 9.30 mmol, 99.77% yield).

LCMS(ESI)：[M]+ m/z：計算值322.2；實測值323.2；Rt=4.134min。LCMS (ESI): [M] + m/z: calculated 322.2; found 323.2; Rt=4.134 min.

步驟3：(2R,5S)-2-(2-(3-(甲氧基羰基)雙環[1.1.1]戊-1-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 3: (2R,5S)-2-(2-(3-(methoxycarbonyl)bicyclo[1.1.1]pent-1-yl)benzo[d]thiazol-5-yl)-5-methan Synthesis of tert-butyl piperidine-1-carboxylate

藉由一般程序方案H步驟1B製備。產率：2.5g粗品。Prepared by General Procedure H, Step IB. Yield: 2.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值456.2；實測值457.2；Rt=4.909min。LCMS (ESI): [M] + m/z: calculated 456.2; found 457.2; Rt=4.909 min.

步驟4：3-(5-((2R,5S)-1-(第三丁氧基羰基)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)雙環[1.1.1]戊烷-1-甲酸之合成Step 4: 3-(5-((2R,5S)-1-(tert-butoxycarbonyl)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)bicyclo[ 1.1.1] Synthesis of pentane-1-carboxylic acid

向(2R,5S )-2-[2-(3-甲氧基羰基-1-雙環[1.1.1 ]戊基)-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(2.5g，5.48mmol)於MeOH(50mL)中之溶液中添加氫氧化鈉珠粒(437.99mg，10.95mmol，205.63μL)且使所得混合物在室溫下攪拌18h。然後，將所得混合物蒸發至乾，溶解於水中，酸化至pH=1且用EtOAc萃取兩次，將有機物用鹽水洗滌，經Na2 SO4 乾燥且蒸發。獲得呈米色固體之3-[5-[(2R,5S )-1-第三丁氧基 羰基-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]雙環[1.1.1 ]戊烷-1-甲酸(1.9g，4.29mmol，78.41%產率)。To ( 2R,5S )-2-[2-(3-methoxycarbonyl-1-bicyclo[ 1.1.1 ]pentyl)-1,3-benzothiazol-5-yl]-5-methylpiper To a solution of tert-butyl pyridine-1-carboxylate (2.5 g, 5.48 mmol) in MeOH (50 mL) was added sodium hydroxide beads (437.99 mg, 10.95 mmol, 205.63 μL) and the resulting mixture was allowed to stir at room temperature 18h. The resulting mixture was then evaporated to dryness, dissolved in water, acidified to pH=1 and extracted twice with EtOAc, the organics were washed with brine, dried over Na2SO4 and evaporated. 3-[5-[( 2R,5S )-1 -tert -butoxycarbonyl-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl] was obtained as a beige solid Bicyclo[ 1.1.1 ]pentane-1-carboxylic acid (1.9 g, 4.29 mmol, 78.41% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.97(d,3H),1.29(m,1H),1.38(s,9H),1.40(m,2H),1.52(m,1H),1.80(m,1H),2.07(m,2H),2.43(m,4H),2.99(m,1H),3.63(m,1H),5.30(m,1H),7.28(d,1H),7.79(s,1H),8.03(d,1H),12.57(bds,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.97(d, 3H), 1.29(m, 1H), 1.38(s, 9H), 1.40(m, 2H), 1.52(m, 1H), 1.80(m, 1H), 2.07(m, 2H), 2.43(m, 4H), 2.99(m, 1H), 3.63(m, 1H), 5.30(m, 1H), 7.28(d, 1H), 7.79 (s, 1H), 8.03 (d, 1H), 12.57 (bds, 1H).

步驟5：(2R,5S)-2-(2-(3-(((苯甲氧基)羰基)胺基)雙環[1.1.1]戊-1-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: (2R,5S)-2-(2-(3-(((benzyloxy)carbonyl)amino)bicyclo[1.1.1]pent-1-yl)benzo[d]thiazole-5 -Synthesis of tert-butyl)-5-methylpiperidine-1-carboxylate

向3-[5-[(2R,5S )-1-第三丁氧基 羰基-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]雙環[1.1.1 ]戊烷-1-甲酸(1.7g，3.84mmol)、TEA(427.56mg，4.23mmol，588.93 μL)於甲苯(50mL)中之溶液中添加疊氮磷酸二苯酯(1.06g，3.84mmol，830.40μL)及苯甲醇(498.47mg，4.61mmol，477.00μL)且將所得混合物在90℃下攪拌隔夜。將反應混合物蒸發，溶解於K2 CO3 水溶液/DCM混合物中，將水用DCM反萃取，將經合併之有機物用鹽水洗滌，乾燥且蒸發，以得到呈深黃色膠狀物之(2R,5S )-2-[2-[3-(苯甲氧基羰基胺基)-1-雙環[1.1.1 ]戊基]-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(2g，粗品)。To 3-[5-[( 2R,5S )-1 -tert -butoxycarbonyl-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]bicyclo[ 1.1. 1 ] To a solution of pentane-1-carboxylic acid (1.7 g, 3.84 mmol), TEA (427.56 mg, 4.23 mmol, 588.93 μL) in toluene (50 mL) was added diphenylphosphonium azide (1.06 g, 3.84 mmol, 830.40 μL) and benzyl alcohol (498.47 mg, 4.61 mmol, 477.00 μL) and the resulting mixture was stirred at 90 °C overnight. The reaction mixture was evaporated, dissolved in aq K2CO3/DCM mixture, water was back extracted with DCM, the combined organics were washed with brine, dried and evaporated to give ( 2R,5S as a dark yellow gum) )-2-[2-[3-(benzyloxycarbonylamino)-1-bicyclo[ 1.1.1 ]pentyl]-1,3-benzothiazol-5-yl]-5-methylpiperidine 3-butyl pyridine-1-carboxylate (2 g, crude).

LCMS(ESI)：[M]+ m/z：計算值547.2；實測值548.2；Rt=4.770min。LCMS (ESI): [M] + m/z: calculated 547.2; found 548.2; Rt=4.770 min.

步驟6：(2R,5S)-2-(2-(3-(二甲胺基)雙環[1.1.1]戊-1-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 6: (2R,5S)-2-(2-(3-(dimethylamino)bicyclo[1.1.1]pent-1-yl)benzo[d]thiazol-5-yl)-5-methyl Synthesis of tert-butyl piperidine-1-carboxylate

在三頸圓底燒瓶中，向(2R,5S )-2-[2-[3-(苯甲氧基羰基胺基)-1-雙環[1.1.1 ]戊基]-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(2g，3.65mmol)及用7-8% MeOH穩定之37重量%甲醛水溶液(328.93mg，10.95mmol，303.72μL)於MeOH(50mL)中之溶液中添加乾燥的487型鈀(10%於碳上)(38.86mg，365.16μmol)。將反應燒瓶抽真空且用氫氣(368.04mg，182.58mmol)回填且使混合物攪拌72h。透過薄矽膠墊過濾，隨後濃縮且在真空下乾燥，得到殘餘物，其藉由CC(Interchim；80g SiO2 ，氯仿/MeCN，其中MeCN為0~100%，進一步為MeCN/MeOH，其中MeOH為0~20%，流速=60mL/min，Rv=29-33CV)進行純化，以得到呈黃色油狀物之(2R,5S )-2-[2-[3-(二甲胺基)-1-雙環[1.1.1 ]戊基]-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(0.34g，769.88μmol，21.08%產率)。In a three-neck round bottom flask, add ( 2R,5S )-2-[2-[3-(benzyloxycarbonylamino)-1-bicyclo[ 1.1.1 ]pentyl]-1,3-benzene Thiazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2 g, 3.65 mmol) and 37 wt% aqueous formaldehyde stabilized with 7-8% MeOH (328.93 mg, 10.95 mmol, 303.72 wt %) [mu]L) in MeOH (50 mL) was added dry palladium type 487 (10% on carbon) (38.86 mg, 365.16 [mu]mol). The reaction flask was evacuated and backfilled with hydrogen (368.04 mg, 182.58 mmol) and the mixture was stirred for 72 h. Filtration through a thin pad of silica gel followed by concentration and drying in vacuo gave a residue which was purified by CC (Interchim; 80 g SiO2 , chloroform/MeCN with MeCN 0-100%, further MeCN/MeOH with MeOH 0~20%, flow rate=60mL/min, Rv=29-33CV) for purification to obtain ( 2R,5S )-2-[2-[3-(dimethylamino)-1 as a yellow oil - Bicyclo[ 1.1.1 ]pentyl]-1,3-benzothiazol-5-yl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (0.34 g, 769.88 μmol, 21.08% yield) .

LCMS(ESI)：[M]+ m/z：計算值441.2；實測值442.2；Rt=1.568min。LCMS (ESI): [M] + m/z: calculated 441.2; found 442.2; Rt=1.568 min.

步驟7：N,N-二甲基-3-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)雙環[1.1.1]戊-1-胺之合成Step 7: N,N-Dimethyl-3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)bicyclo[1.1.1 Synthesis of ]pentan-1-amine

在21℃下，向(2R,5S )-2-[2-[3-(二甲胺基)-1-雙環[1.1.1 ]戊基]-1,3-苯并噻唑-5-基]-5-甲基哌啶-1-甲酸第三丁酯(100mg，113.22μmol)於DCM(5mL)中之 溶液中添加於二噁烷中之4.0M氯化氫溶液(20.64mg，566.09μmol，25.80μL)。使所得混合物攪拌6h。將所得混合物蒸發至乾且不經進一步純化即用於下一步驟中。To ( 2R,5S )-2-[2-[3-(dimethylamino)-1-bicyclo[ 1.1.1 ]pentyl]-1,3-benzothiazol-5-yl at 21°C ]- tert-butyl 5-methylpiperidine-1-carboxylate (100 mg, 113.22 μmol) in DCM (5 mL) was added to a 4.0 M solution of hydrogen chloride in dioxane (20.64 mg, 566.09 μmol, 25.80 μL). The resulting mixture was stirred for 6 h. The resulting mixture was evaporated to dryness and used in the next step without further purification.

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=1.225min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=1.225 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(3-(二甲胺基)雙環[1.1.1]戊-1-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1404)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(3-(dimethylamino)bicyclo[1.1.1 ]Pent-1-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxyacetamide (compound 1404) synthesis

藉由一般程序方案H步驟6A製備。產率：14.4mg(24.62%)。Prepared by General Procedure H, Step 6A. Yield: 14.4 mg (24.62%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0.5-6.5min 30-55%水-MeCN+NH3 ，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0.5-6.5 min 30-55% water-MeCN+ NH3 , flow rate: 30 ml/min; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.05(m,3H),1.05-1.15(m,3H),1.27-1.40(m,1H),1.62-1.75(m,1H),1.81-1.92(m,1H),2.02-2.13(m,1H),2.15(s,6H),2.17(s,6H),2.27-2.34(m,1H),2.39-2.45(m,2H),2.77-3.14(m,1H),3.48-4.06(m,1H),5.27-5.61(m,1H),5.62-5.73(m,2H),7.32-7.43(m,1H),7.42-7.55(m,1H),7.86-7.96(m,1H),7.97-8.13(m,2H),10.53(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.05(m,3H), 1.05-1.15(m,3H), 1.27-1.40(m,1H), 1.62-1.75(m,1H) ,1.81-1.92(m,1H),2.02-2.13(m,1H),2.15(s,6H),2.17(s,6H),2.27-2.34(m,1H),2.39-2.45(m,2H) ,2.77-3.14(m,1H),3.48-4.06(m,1H),5.27-5.61(m,1H),5.62-5.73(m,2H),7.32-7.43(m,1H),7.42-7.55( m, 1H), 7.86-7.96 (m, 1H), 7.97-8.13 (m, 2H), 10.53 (br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值532.2；實測值533.2；Rt=2.240min。LCMS (ESI): [M] + m/z: calculated 532.2; found 533.2; Rt=2.240 min.

實例641. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(1-((二甲胺基)甲基)環丙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1347)之合成Example 641. N-(6-amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-((dimethylamino)methyl)cycle Synthesis of propyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1347)

Figure 110128222-A0202-12-2132-673
Figure 110128222-A0202-12-2132-673

步驟1：((1-(5-溴苯并[d]噻唑-2-基)環丙基)甲基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl ((1-(5-bromobenzo[d]thiazol-2-yl)cyclopropyl)methyl)carbamate

藉由一般程序方案H步驟1B製備。產率：5.2g(92.29%)Prepared by General Procedure H, Step IB. Yield: 5.2g (92.29%)

LCMS(ESI)：[M]+ m/z：計算值383.2；實測值384.2；Rt=1.648min。LCMS (ESI): [M] + m/z: calculated 383.2; found 384.2; Rt=1.648 min.

步驟2：(1-(5-溴苯并[d]噻唑-2-基)環丙基)甲胺之合成Step 2: Synthesis of (1-(5-bromobenzo[d]thiazol-2-yl)cyclopropyl)methanamine

在25℃下，將TFA(22.20g，194.70mmol，15mL)一次性添加到N -[[1-(5-溴-1,3-苯并噻唑-2-基)環丙基]甲基]胺甲酸第三丁 酯(2.7g，7.04mmol)於DCM(30mL)中之經攪拌之溶液中。將所得溶液在25℃下攪拌0.5h，然後在真空中濃縮。將殘餘物用冰冷的水(50ml)稀釋且用10%氫氧化鈉水溶液鹼化至pH 11。將所得混合物用DCM(2*50ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈紅色膠狀物之粗品[1-(5-溴-1,3-苯并噻唑-2-基)環丙基]甲胺(1.9g，6.71mmol，95.25%產率)，其直接用於下一步驟中。TFA (22.20 g, 194.70 mmol, 15 mL) was added in one portion to N -[[1-(5-bromo-1,3-benzothiazol-2-yl)cyclopropyl]methyl] at 25 °C A stirred solution of tert -butyl carbamate (2.7 g, 7.04 mmol) in DCM (30 mL). The resulting solution was stirred at 25 °C for 0.5 h, then concentrated in vacuo. The residue was diluted with ice cold water (50 ml) and basified to pH 11 with 10% aqueous sodium hydroxide solution. The resulting mixture was extracted with DCM (2*50ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude [1-(5-bromo-1,3-benzothiazol-2-yl)cyclopropyl] as a red gum Methylamine (1.9 g, 6.71 mmol, 95.25% yield) was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值383.2；實測值384.2；Rt=0.862min。LCMS (ESI): [M] + m/z: calculated 383.2; found 384.2; Rt=0.862 min.

步驟3：1-(1-(5-溴苯并[d]噻唑-2-基)環丙基)-N,N-二甲基甲胺之合成Step 3: Synthesis of 1-(1-(5-Bromobenzo[d]thiazol-2-yl)cyclopropyl)-N,N-dimethylmethanamine

在25℃下，將用7-8% MeOH穩定之37重量%甲醛水溶液(1.6g，19.71mmol，1.48mL，37%純度)及乙酸(805.79mg，13.42mmol，768.15μL)添加到[1-(5-溴-1,3-苯并噻唑-2-基)環丙基]甲胺(1.9g，6.71mmol)於MeOH(60mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌1h，然後在25℃下一次性添加氰基硼氫化鈉(843.23mg，13.42mmol)(發泡！)。將反應混合物在25℃下攪拌18h，然後在真空中濃縮。將殘餘物用10%氫氧化鈉水溶液(40ml)稀釋且用DCM(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈淡棕色膠狀物之粗品1-[1-(5-溴-1,3-苯并噻唑-2-基)環丙基]-N,N -二甲基甲胺(1.9g，6.10mmol，90.99%產率)，其直接用於下一步驟中。Aqueous 37 wt% formaldehyde stabilized with 7-8% MeOH (1.6 g, 19.71 mmol, 1.48 mL, 37% purity) and acetic acid (805.79 mg, 13.42 mmol, 768.15 μL) were added to [1- at 25 °C In a stirred solution of (5-bromo-1,3-benzothiazol-2-yl)cyclopropyl]methanamine (1.9 g, 6.71 mmol) in MeOH (60 mL). The resulting mixture was stirred at 25°C for 1 h, then sodium cyanoborohydride (843.23 mg, 13.42 mmol) was added in one portion at 25°C (foaming!). The reaction mixture was stirred at 25 °C for 18 h, then concentrated in vacuo. The residue was diluted with 10% aqueous sodium hydroxide solution (40ml) and extracted with DCM (2*30ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the crude 1-[1-(5-bromo-1,3-benzothiazol-2-yl) ring as a light brown gum Propyl] -N,N -dimethylmethylamine (1.9 g, 6.10 mmol, 90.99% yield), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值311.2；實測值312.2；Rt=2.196min。LCMS (ESI): [M] + m/z: calculated 311.2; found 312.2; Rt=2.196 min.

步驟4：N,N-二甲基1-(1-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)環丙基)甲胺之合成Step 4: N,N-Dimethyl 1-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) Synthesis of Benzo[d]thiazol-2-yl)cyclopropyl)methanamine

藉由一般程序方案H步驟2製備。產率：2.19g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 2.19 g crude.

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=3.096min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=3.096 min.

步驟5：(S)-6-(2-(1-((二甲胺基)甲基)環丙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-6-(2-(1-((dimethylamino)methyl)cyclopropyl)benzo[d]thiazol-5-yl)-3-methyl-3,4- Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：3.9g粗品。Prepared by General Procedure H, Step 3. Yield: 3.9 g crude.

LCMS(ESI)：[M]+ m/z：計算值427.2；實測值428.2；Rt=1.315min。LCMS (ESI): [M] + m/z: calculated 427.2; found 428.2; Rt=1.315 min.

步驟6：(S)-N,N-二甲基-1-(1-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)環丙基)甲胺之合成Step 6: (S)-N,N-Dimethyl-1-(1-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d] Synthesis of Thiazol-2-yl)cyclopropyl)methanamine

藉由一般程序方案H步驟4製備。產率：0.85g粗品。Prepared by General Procedure H, Step 4. Yield: 0.85 g crude.

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.616min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.616 min.

步驟7：N,N-二甲基-1-(1-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)環丙基)甲胺之合成Step 7: N,N-Dimethyl-1-(1-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)cyclopropane Synthesis of methyl) methylamine

藉由一般程序方案H步驟5製備。產率：0.67g(78.34%)。Prepared by General Procedure H, Step 5. Yield: 0.67 g (78.34%).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.685min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.685 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(1-((二甲胺基)甲基)環丙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1347)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(1-((dimethylamino)methyl)ring Synthesis of propyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1347)

藉由一般程序方案H步驟6A製備。產率：62mg(35.67%)。Prepared by General Procedure H, Step 6A. Yield: 62 mg (35.67%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 50-100%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 50-100% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.09(m,8H)，1.39(m,3H),1.69(m,1H),1.86(m,1H),2.12(m,1H),2.25(s,6H),2.36(m,2H),2.62(m,3H),2.76(m,1H),3.85(m,1H),5.64(m,3H),7.31(m,1H),7.47(m,1H),7.76(m,1H),7.99(m,2H),10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ(ppm) 1.09(m, 8H), 1.39(m, 3H), 1.69(m, 1H), 1.86(m, 1H), 2.12(m, 1H), 2.25(s, 6H), 2.36(m, 2H), 2.62(m, 3H), 2.76(m, 1H), 3.85(m, 1H), 5.64(m, 3H), 7.31(m, 1H), 7.47 (m, 1H), 7.76 (m, 1H), 7.99 (m, 2H), 10.54 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=1.924min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=1.924 min.

實例642. N-(6-胺基-5-乙基吡啶-3-基)-2-(2-甲基-6-(2-(1-甲基哌啶-4-基)苯并Example 642. N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-methyl-6-(2-(1-methylpiperidin-4-yl)benzone) [b]噻吩-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1395及化合物1173)之合成Synthesis of [b]Thien-5-yl)piperidin-1-yl)-2-oxyacetamide (Compound 1395 and Compound 1173)

Figure 110128222-A0202-12-2135-674
Figure 110128222-A0202-12-2135-674

步驟1：5-溴-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

向磷酸(7.82g，79.80mmol，4.60mL)中添加五氧化二磷(V)(9.20g，64.82mmol，4.00mL)，將所得混合物在80℃下攪拌0.25h。然後添加1-甲基哌啶-4-甲酸(2.02g，11.27mmol，HCl)及2-胺基-4-溴苯硫酚(2.3g，11.27mmol)且將所得混合物在160℃下攪拌13h。將混合物冷卻，用冰冷水(150ml)稀釋。將溶液之pH用NaOH調節至10且用DCM(3*40ml)萃取。將經合併之有機層經Na2 SO4 乾燥且在真空中蒸發，以得到5-溴-2-(1-甲基-4-哌啶基)-1,3-苯并噻唑(3.5g，11.25mmol，99.78%產率)。To phosphoric acid (7.82 g, 79.80 mmol, 4.60 mL) was added phosphorous (V) pentoxide (9.20 g, 64.82 mmol, 4.00 mL) and the resulting mixture was stirred at 80 °C for 0.25 h. Then 1-methylpiperidine-4-carboxylic acid (2.02 g, 11.27 mmol, HCl) and 2-amino-4-bromothiophenol (2.3 g, 11.27 mmol) were added and the resulting mixture was stirred at 160 °C for 13 h . The mixture was cooled and diluted with ice cold water (150ml). The pH of the solution was adjusted to 10 with NaOH and extracted with DCM (3*40ml). The combined organic layers were dried over Na 2 SO 4 and evaporated in vacuo to give 5-bromo-2-(1-methyl-4-piperidinyl)-1,3-benzothiazole (3.5 g, 11.25 mmol, 99.78% yield).

LCMS(ESI)：[M]+ m/z：計算值311.2；實測值312.2；Rt=0.774min。LCMS (ESI): [M] + m/z: calculated 311.2; found 312.2; Rt=0.774 min.

步驟2：2-(1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)benzo[d]thiazole

將5-溴-2-(1-甲基-4-哌啶基)-1,3-苯并噻唑(3.5g，11.25mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.86g，11.25mmol)及乙酸鉀(2.21g，22.49mmol，1.41mL)混合於二噁烷(70mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(459.17mg，562.27μmol)。將反應混合物在氬氣、90℃下攪拌13h，然後冷卻且過濾。將濾餅用二噁烷(2*20ml)洗滌且丟棄。將所獲 得之2-(1-甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(3.9g，10.88mmol，96.79%產率)溶液直接用於下一步驟中。5-Bromo-2-(1-methyl-4-piperidinyl)-1,3-benzothiazole (3.5 g, 11.25 mmol), 4,4,5,5-tetramethyl-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (2.86 g, 11.25 mmol) and potassium acetate (2.21 g, 22.49 mmol, 1.41 mL) were mixed in dioxane (70 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM ( 459.17 mg, 562.27 μmol) was added under argon. The reaction mixture was stirred under argon at 90 °C for 13 h, then cooled and filtered. The filter cake was washed with dioxane (2*20ml) and discarded. The obtained 2-(1-methyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1,3-benzothiazole (3.9 g, 10.88 mmol, 96.79% yield) solution was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=0.962min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=0.962 min.

步驟3：2-甲基-6-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: 2-Methyl-6-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)- Synthesis of tert-butyl formate

將碳酸鈉(2.31g，21.77mmol，911.25μL)添加到2-(1-甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(3.9g，10.88mmol)及2-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(3.76g，10.88mmol)於二噁烷(80mL)及H2 O(10mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2 *DCM(444.44mg，544.23μmol)。在惰性氣氛下將所得混合物在90℃下攪拌14h。將反應溶液傾析且在減壓下濃縮。將殘餘物用MTBE(250ml)稀釋。將所得混濁溶液自油狀殘餘物傾析。在真空中蒸發MTBE，以得到2-甲基-6-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5g，粗品)。Sodium carbonate (2.31 g, 21.77 mmol, 911.25 μL) was added to 2-(1-methyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborol-2-yl)-1,3-benzothiazole (3.9 g, 10.88 mmol) and 2-methyl-6-(trifluoromethylsulfonyloxy)-3 , 4-Dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (3.76 g, 10.88 mmol) in dioxane (80 mL) and H2O (10 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, Pd(dppf)Cl 2 *DCM (444.44 mg, 544.23 μmol) was added under argon flow. The resulting mixture was stirred at 90 °C for 14 h under an inert atmosphere. The reaction solution was decanted and concentrated under reduced pressure. The residue was diluted with MTBE (250ml). The resulting cloudy solution was decanted from the oily residue. MTBE was evaporated in vacuo to give 2-methyl-6-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-3,4-dihydro - 2H -Pyridine-1-carboxylic acid tert-butyl ester (5 g, crude).

LCMS(ESI)：[M]+ m/z：計算值427.2；實測值428.2；Rt=1.226min。LCMS (ESI): [M] + m/z: calculated 427.2; found 428.2; Rt=1.226 min.

步驟4：5-(6-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 4: Synthesis of 5-(6-methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

將2-甲基-6-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(5g，11.69mmol)用TFA(13.33g，116.93mmol，9.01mL)稀釋。將所得混合物在25℃下攪拌1h。在真空中蒸發TFA。將殘餘物用水(150ml)稀釋。將所得混濁溶液自油狀殘餘物傾析，然後用NaHCO3 鹼化。將產物用DCM(3*50ml)萃取。將經合併之有機層經Na2 SO4 乾燥。在真空中蒸發DCM，以得到2-(1-甲基-4-哌啶基)-5-(2-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(3g，9.16mmol，78.34%產率)。2-Methyl-6-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl]-3,4-dihydro- 2H -pyridine-1- 3-Butyl formate (5 g, 11.69 mmol) was diluted with TFA (13.33 g, 116.93 mmol, 9.01 mL). The resulting mixture was stirred at 25°C for 1 h. TFA was evaporated in vacuo. The residue was diluted with water (150ml). The resulting cloudy solution was decanted from the oily residue, then basified with NaHCO3 . The product was extracted with DCM (3*50ml). The combined organic layers were dried over Na2SO4 . The DCM was evaporated in vacuo to give 2-(1-methyl-4-piperidinyl)-5-(2-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1, 3-benzothiazole (3 g, 9.16 mmol, 78.34% yield).

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.658min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.658 min.

步驟5：5-(6-甲基哌啶-2-基)-2-(1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-(6-Methylpiperidin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

向2-(1-甲基-4-哌啶基)-5-(2-甲基-2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(3g，9.16mmol)於MeOH(15mL)中之經攪拌之溶液中分批添加硼氫化鈉(346.55mg，9.16mmol，322.67μL)。將反應混合物在25℃下攪拌1h。在真空中蒸發MeOH。將殘餘物用水(50ml)稀釋且用DCM(3*30ml)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥。蒸發DCM，以得到2-(1-甲基-4-哌啶基)-5-(6-甲基-2-哌啶基)-1,3-苯并噻唑(2.3g，6.98mmol，76.20%產率)。To 2-(1-methyl-4-piperidinyl)-5-(2-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole (3 g , 9.16 mmol) in MeOH (15 mL) was added portionwise sodium borohydride (346.55 mg, 9.16 mmol, 322.67 [mu]L). The reaction mixture was stirred at 25 °C for 1 h. MeOH was evaporated in vacuo. The residue was diluted with water (50ml) and extracted with DCM (3*30ml). The combined organic layers were washed with brine, dried over Na2SO4 . The DCM was evaporated to give 2-(1-methyl-4-piperidinyl)-5-(6-methyl-2-piperidinyl)-1,3-benzothiazole (2.3 g, 6.98 mmol, 76.20 g %Yield).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.682min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.682 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-(2-甲基-6-(2-(1-甲基哌啶-4-基)苯并[b]噻吩-5-基)哌啶-1-基)-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-methyl-6-(2-(1-methylpiperidin-4-yl)benzo[ b] Synthesis of thiophen-5-yl)piperidin-1-yl)-2-oxoacetamide

向1-甲基-4-[5-(6-甲基-2-哌啶基)苯并噻吩-2-基]哌啶(500.00mg，747.32μmol，2HCl)、2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(187.61mg，896.78μmol)及TEA(378.11mg，3.74mmol，520.81μL)於DMF(3mL)中之溶液中分批添加HATU(312.57mg，822.05μmol)。將混合物在25℃下攪拌1.5h。將反應混合物提交至HPLC(SYSTEM 40-70% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)目標質量521管柱：YMC Triart C18 100x20mm，5um)，以得到N -(6-胺基-5-乙基-3-吡啶基)-2-[2-甲基-6-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]-1-哌啶基]-2-側氧基乙醯胺(94mg，180.87μmol，24.20%產率)。To 1-methyl-4-[5-(6-methyl-2-piperidinyl)benzothiophen-2-yl]piperidine (500.00 mg, 747.32 μmol, 2HCl), 2-[(6-amine yl-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (187.61 mg, 896.78 μmol) and TEA (378.11 mg, 3.74 mmol, 520.81 μL) in DMF (3 mL) HATU (312.57 mg, 822.05 μmol) was added in portions. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was submitted to HPLC (SYSTEM 40-70% 0-5min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min (loading pump 4ml/min MeOH) target mass 521 Column: YMC Triart C18 100x20mm , 5um) to give N- (6-amino-5-ethyl-3-pyridyl)-2-[2-methyl-6-[2-(1-methyl-4-piperidinyl) Benzothiophen-5-yl]-1-piperidinyl]-2-oxoacetamide (94 mg, 180.87 μmol, 24.20% yield).

LCMS(ESI)：[M]+ m/z：計算值519.2；實測值520.2；Rt=1.816min。LCMS (ESI): [M] + m/z: calculated 519.2; found 520.2; Rt=1.816 min.

步驟7：掌性分離(化合物1173及化合物1395)Step 7: Chiral separation (compound 1173 and compound 1395)

對外消旋N -(6-胺基-5-乙基-3-吡啶基)-2-[2-甲基-6-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]-1-哌啶基]-2-側氧基乙醯胺(94mg，180.87μmol)進行掌性分離(管柱：Chiralpak IA-II(250*20mm，5mkm)；流動相：IPA-MeOH，50-50；流 速：10mL/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,6S )-2-甲基-6-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]-1-哌啶基]-2-側氧基乙醯胺(19mg，36.56μmol，80.85%產率)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,6R )-2-甲基-6-[2-(1-甲基-4-哌啶基)苯并噻吩-5-基]-1-哌啶基]-2-側氧基乙醯胺(10mg，19.24μmol，42.55%產率)。Racemic N- (6-amino-5-ethyl-3-pyridyl)-2-[2-methyl-6-[2-(1-methyl-4-piperidinyl)benzothiophene chiral separation (column: Chiralpak IA-II (250*20mm, 5mkm); mobile phase: IPA-MeOH, 50-50; flow rate: 10 mL/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,6S )-2-methyl- 6-[2-(1-Methyl-4-piperidinyl)benzothiophen-5-yl]-1-piperidinyl]-2-oxyacetamide (19 mg, 36.56 μmol, 80.85% yield rate) and N-(6-amino-5-ethyl-3-pyridyl)-2-[( 2S,6R )-2-methyl-6-[2-(1-methyl-4-piperidine) Peridyl)benzothiophen-5-yl]-1-piperidinyl]-2-oxyacetamide (10 mg, 19.24 μmol, 42.55% yield).

化合物1173於分析條件下(管柱：OD-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為10.09min且化合物1395之保留時間為11.36min。The retention time of compound 1173 under analytical conditions (column: OD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 10.09 min and the retention time of compound 1395 was 11.36 min .

化合物1173：Compound 1173:

保留時間：10.09minRetention time: 10.09min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.68-0.81(m,3H),1.07-1.16(m,3H),1.44-1.57(m,1H),1.58-1.67(m,1H),1.71-1.91(m,5H),2.04-2.18(m,4H),2.23(s,3H),2.35-2.44(m,2H),2.62-2.70(m,1H),2.83-2.97(m,2H),3.03-3.12(m,1H),4.06-4.84(m,1H),5.14-5.63(m,1H),5.63-5.92(m,2H),7.39-7.55(m,2H),7.95-8.09(m,3H),10.58(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.68-0.81(m,3H), 1.07-1.16(m,3H), 1.44-1.57(m,1H), 1.58-1.67(m,1H) ,1.71-1.91(m,5H),2.04-2.18(m,4H),2.23(s,3H),2.35-2.44(m,2H),2.62-2.70(m,1H),2.83-2.97(m, 2H), 3.03-3.12(m, 1H), 4.06-4.84(m, 1H), 5.14-5.63(m, 1H), 5.63-5.92(m, 2H), 7.39-7.55(m, 2H), 7.95- 8.09 (m, 3H), 10.58 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=1.706min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=1.706 min.

化合物1395：Compound 1395:

保留時間：11.36minRetention time: 11.36min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.14(m,3H),1.34-1.40(m,3H),1.40-1.50(m,1H),1.50-1.59(m,1H),1.62-1.77(m,2H),1.77-1.87(m,2H),2.02-2.12(m,3H),2.12-2.36(m,7H),2.39-2.43(m,1H),2.82-3.13(m,3H),4.12-4.41(m,1H),5.31-5.40(m,1H),5.47-5.71(m,2H),7.07-7.53(m,2H),7.73-7.78(m,0.5H),7.84(s,1H),7.93-8.02(m,1H),8.05-8.11(m,0.5H),10.10-10.52(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.14(m,3H), 1.34-1.40(m,3H), 1.40-1.50(m,1H), 1.50-1.59(m,1H) ,1.62-1.77(m,2H),1.77-1.87(m,2H),2.02-2.12(m,3H),2.12-2.36(m,7H),2.39-2.43(m,1H),2.82-3.13( m,3H),4.12-4.41(m,1H),5.31-5.40(m,1H),5.47-5.71(m,2H),7.07-7.53(m,2H),7.73-7.78(m,0.5H) , 7.84(s, 1H), 7.93-8.02(m, 1H), 8.05-8.11(m, 0.5H), 10.10-10.52(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=1.645min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=1.645 min.

實例643. 2-((2R,5S)-2-(2-(1-氮雜雙環[2.2.1]庚-4-基)苯并[d]噻唑-5-基)-5-甲基Example 643. 2-((2R,5S)-2-(2-(1-azabicyclo[2.2.1]heptan-4-yl)benzo[d]thiazol-5-yl)-5-methyl 哌啶-1-基)-N-(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺(化合物1298)之合成Synthesis of piperidin-1-yl)-N-(6-amino-5-ethylpyridin-3-yl)-2-oxoacetamide (compound 1298)

Figure 110128222-A0202-12-2139-675
Figure 110128222-A0202-12-2139-675

步驟1：2-(1-氮雜雙環[2.2.1]庚-4-基)-5-溴苯并[d]噻唑之合成Step 1: Synthesis of 2-(1-azabicyclo[2.2.1]hept-4-yl)-5-bromobenzo[d]thiazole

藉由一般程序方案H步驟1A製備。產率：3.5g(92.4%)。Prepared by General Procedure H, Step 1A. Yield: 3.5 g (92.4%).

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=0.961min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=0.961 min.

步驟2：2-(1-氮雜雙環[2.2.1]庚-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Azabicyclo[2.2.1]hept-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborocycle Synthesis of Pentan-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟2製備。產率：4g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 4 g crude.

LCMS(ESI)：[M]+ m/z：計算值356.2；實測值357.2；Rt=1.025min。LCMS (ESI): [M] + m/z: calculated 356.2; found 357.2; Rt=1.025 min.

步驟3：(S)-6-(2-(1-氮雜雙環[2.2.1]庚-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(1-azabicyclo[2.2.1]hept-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4- Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：8g粗品。Prepared by General Procedure H, Step 3. Yield: 8 g crude.

LCMS(ESI)：[M]+ m/z：計算值425.2；實測值426.2；Rt=1.254min。LCMS (ESI): [M] + m/z: calculated 425.2; found 426.2; Rt=1.254 min.

步驟4：(S)-2-(1-氮雜雙環[2.2.1]庚-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: (S)-2-(1-azabicyclo[2.2.1]heptan-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl ) Synthesis of Benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：6g粗品。Prepared by General Procedure H, Step 4. Yield: 6 g crude.

LCMS(ESI)：[M]+ m/z：計算值325.2；實測值326.2；Rt=0.683min。LCMS (ESI): [M] + m/z: calculated 325.2; found 326.2; Rt=0.683 min.

步驟5：2-(1-氮雜雙環[2.2.1]庚-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Compound of 2-(1-azabicyclo[2.2.1]heptan-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole synthesis

藉由一般程序方案H步驟5製備。產率：2g粗品。Prepared by General Procedure H, Step 5. Yield: 2 g crude.

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.709min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.709 min.

步驟6：2-((2R,5S)-2-(2-(1-氮雜雙環[2.2.1]庚-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-乙基吡啶-3-基)-2-側氧基乙醯胺(化合物1298)之合成Step 6: 2-((2R,5S)-2-(2-(1-azabicyclo[2.2.1]heptan-4-yl)benzo[d]thiazol-5-yl)-5-methyl Synthesis of piperidin-1-yl)-N-(6-amino-5-ethylpyridin-3-yl)-2-oxoacetamide (compound 1298)

藉由一般程序方案H步驟6A製備。產率：71mg(37.36%)。Prepared by General Procedure H, Step 6A. Yield: 71 mg (37.36%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 50-80%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 50-80% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

藉由掌性HPLC(Chiralpak IA-III(250*20，5mkm)，IPA-MeOH，50-50，10ml/min)移除順式雜質。The cis impurity was removed by chiral HPLC (Chiralpak IA-III (250*20, 5mkm), IPA-MeOH, 50-50, 10ml/min).

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.02(m,3H),1.08(m,3H),1.35(m,1H),1.72(m,3H),1.86(m,1H),2.11(m,3H),2.33(m,2H),2.40(m,1H),2.66(m,5H),3.00(m,2H),3.86(m,1H),5.64(m,3H),7.41(m,2H),7.89(m,1H),8.04(m,2H),10.51(s,1H) 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.02(m, 3H), 1.08(m, 3H), 1.35(m, 1H), 1.72(m, 3H), 1.86(m, 1H), 2.11(m, 3H), 2.33(m, 2H), 2.40(m, 1H), 2.66(m, 5H), 3.00(m, 2H), 3.86(m, 1H), 5.64(m, 3H), 7.41 (m, 2H), 7.89 (m, 1H), 8.04 (m, 2H), 10.51 (s, 1H)

LCMS(ESI)：[M+1]+ m/z：計算值518.2；實測值519.2；Rt=2.109min。LCMS (ESI): [M+1] + m/z: calculated 518.2; found 519.2; Rt=2.109 min.

實例644. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-((1R,5S,6s)-3-甲基-3-氮雜雙環[3.1.0]己-6-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1366)之合成Example 644. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-((1R,5S,6s)- 3-Methyl-3-azabicyclo[3.1.0]hex-6-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamide (compound 1366) synthesis

Figure 110128222-A0202-12-2140-676
Figure 110128222-A0202-12-2140-676

步驟1：(1R,5S,6s)-6-(5-溴苯并[d]噻唑-2-基)雙環[3.1.0]己烷-3-甲酸第三丁酯之合成Step 1: Synthesis of (1R,5S,6s)-6-(5-bromobenzo[d]thiazol-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟1B製備。產率：1.5g粗品。Prepared by General Procedure H, Step IB. Yield: 1.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值395.2；實測值396.2；Rt=1.692min。LCMS (ESI): [M] + m/z: calculated 395.2; found 396.2; Rt=1.692 min.

步驟2：2-((1R,5S,6s)-3-氮雜雙環[3.1.0]己-6-基)-5-溴苯并[d]噻唑之合成Step 2: Synthesis of 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-5-bromobenzo[d]thiazole

分別在25℃下向( 1 R, 5 S )-6-(5-溴-1,3-苯并噻唑-2-基)-3-氮雜雙環[3.1.0]己烷-3-甲酸第三丁酯(2.3g，5.82mmol)於DCM(10mL)中之經攪拌之溶液中添加二噁烷/HCl(6.9mL)。將所得反應混合物在25℃下攪拌12h。完成之後，將反應混合物在減壓下濃縮。然後將產物之鹽酸鹽溶解於20ml水中，添加10% Na2 CO3 (20ml)，用DCM(20ml兩次)萃取。將有機層經Na2 SO4 乾燥且蒸發。分離呈黃色狀態之所要產物5-溴-2-[( 1 R, 5 S )-3-氮雜雙環[3.1.0 ]己-6-基]-1,3-苯并噻唑(1.9g，粗品)。to ( 1 R, 5 S )-6-(5-bromo-1,3-benzothiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid at 25 °C, respectively To a stirred solution of tert-butyl ester (2.3 g, 5.82 mmol) in DCM (10 mL) was added dioxane/HCl (6.9 mL). The resulting reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The hydrochloride salt of the product was then dissolved in 20ml of water, 10 % Na2CO3 (20ml) was added and extracted with DCM (20ml twice). The organic layer was dried over Na2SO4 and evaporated. The desired product, 5 -bromo- 2 -[( 1R, 5S )-3-azabicyclo[ 3.1.0 ]hex-6-yl]-1,3-benzothiazole (1.9 g, Crude).

LCMS(ESI)：[M]+ m/z：計算值295.2；實測值296.2；Rt=0.820min。LCMS (ESI): [M] + m/z: calculated 295.2; found 296.2; Rt=0.820 min.

步驟3：5-溴-2-((1R,5S,6s)-3-甲基-3-氮雜雙環[3.1.0]己-6-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-bromo-2-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)benzo[d]thiazole

向5-溴-2-[( 1 R, 5 S )-3-氮雜雙環[3.1.0 ]己-6-基]-1,3-苯并噻唑(1.9g，6.44mmol)於MeOH(100mL)中之經攪拌之溶液中添加37%甲醛水溶液(289.89mg，9.65mmol，267.67μL)及乙酸(773.03mg，12.87mmol，736.92μL)，30分鐘之後，在25℃下分別添加氰基硼氫化鈉(606.71mg，9.65mmol)。將所得反應混合物在25℃下攪拌14h。完成之後，將反應混合物在減壓下濃縮，然後用DCM/水(100ml/50ml)萃取。將有機相經Na2 SO4 乾燥，蒸發，以獲得呈黃色狀態之粗產物。分離呈黃色狀態之所要產物5-溴-2-[( 1 R, 5 S )-3-甲基-3-氮雜雙環[3.1.0 ]己-6-基]-1,3-苯并噻唑(1.7g，5.50mmol，85.42%產率)。To 5 -bromo- 2 -[(1R , 5S )-3-azabicyclo[ 3.1.0 ]hex-6-yl]-1,3-benzothiazole (1.9 g, 6.44 mmol) in MeOH ( 100 mL) was added with 37% aqueous formaldehyde solution (289.89 mg, 9.65 mmol, 267.67 μL) and acetic acid (773.03 mg, 12.87 mmol, 736.92 μL), and after 30 minutes, cyanoboron was added at 25° C. Sodium hydride (606.71 mg, 9.65 mmol). The resulting reaction mixture was stirred at 25 °C for 14 h. After completion, the reaction mixture was concentrated under reduced pressure, then extracted with DCM/water (100ml/50ml). The organic phase was dried over Na2SO4 and evaporated to obtain the crude product in yellow state. The desired product, 5 -bromo-2-[( 1R , 5S )-3-methyl-3-azabicyclo[ 3.1.0 ]hex-6-yl]-1,3-benzoyl, was isolated as a yellow state Thiazole (1.7 g, 5.50 mmol, 85.42% yield).

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=0.951min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=0.951 min.

步驟4：2-((1R,5S,6s)-3-甲基-3-氮雜雙環[3.1.0]己-6-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 4: 2-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)-5-(4,4,5,5-tetramethyl Synthesis of -1,3,2-dioxaborol-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟2製備。產率：1.6g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 1.6 g crude.

LCMS(ESI)：[M]+ m/z：計算值356.2；實測值357.2；Rt=1.081min。LCMS (ESI): [M] + m/z: calculated 356.2; found 357.2; Rt=1.081 min.

步驟5：(S)-3-甲基-6-(2-((1R,5S,6s)-3-甲基-3-氮雜雙環[3.1.0]己-6-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-3-Methyl-6-(2-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)benzo[ d] Synthesis of Thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟3製備。產率：1.7g粗品。Prepared by General Procedure H, Step 3. Yield: 1.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值425.2；實測值426.2；Rt=1.191min。LCMS (ESI): [M] + m/z: calculated 425.2; found 426.2; Rt=1.191 min.

步驟6：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-((1R,5S,6s)-3-甲基-3-氮雜雙環[3.1.0]己-6-基)苯并[d]噻唑之合成Step 6: 5-((S)-5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-((1R,5S,6s)-3-methyl-3- Synthesis of azabicyclo[3.1.0]hex-6-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.434g粗品。Prepared by General Procedure H, Step 4. Yield: 0.434 g crude.

LCMS(ESI)：[M]+ m/z：計算值325.2；實測值326.2；Rt=0.633min。LCMS (ESI): [M] + m/z: calculated 325.2; found 326.2; Rt=0.633 min.

步驟7：2-((1R,5S,6r)-3-甲基-3-氮雜雙環[3.1.0]己-6-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 7: 2-((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)-5-((2R,5S)-5-methylpiperidine Synthesis of pyridin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.187g(42.82%)。Prepared by General Procedure H, Step 5. Yield: 0.187 g (42.82%).

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.707min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.707 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-((1R,5S,6s)-3-甲基-3-氮雜雙環[3.1.0]己-6-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1366)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-((1R,5S,6s)- 3-Methyl-3-azabicyclo[3.1.0]hex-6-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxyacetamide (compound 1366) synthesis

藉由一般程序方案H步驟6B製備。產率：49mg(28.65%)。Prepared by General Procedure H, Step 6B. Yield: 49 mg (28.65%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 40-90%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 40-90% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.05(m,3H),1.05-1.16(m,3H),1.27-1.39(m,1H),1.64-1.73(m,1H),1.81-1.91(m,1H),2.02-2.12(m,1H),2.12-2.16(m,2H),2.26(s,3H),2.33-2.37(m,3H),2.37-2.44(m,2H),2.70(s,1H),2.73-2.79(m,0.3H),3.06-3.10(m,2H),3.24-3.27(m,0.7H),3.38-3.52(m,0.7H),4.01-4.06(m,0.3H),5.24-5.60(m,1H),5.60-5.71(m,2H),7.25-7.38(m,1H),7.41-7.58(m, 1H),7.72-7.85(m,1H),7.92-8.12(m,2H),10.48-10.65(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.05(m,3H), 1.05-1.16(m,3H), 1.27-1.39(m,1H), 1.64-1.73(m,1H) ,1.81-1.91(m,1H),2.02-2.12(m,1H),2.12-2.16(m,2H),2.26(s,3H),2.33-2.37(m,3H),2.37-2.44(m, 2H), 2.70(s, 1H), 2.73-2.79(m, 0.3H), 3.06-3.10(m, 2H), 3.24-3.27(m, 0.7H), 3.38-3.52(m, 0.7H), 4.01 -4.06(m, 0.3H), 5.24-5.60(m, 1H), 5.60-5.71(m, 2H), 7.25-7.38(m, 1H), 7.41-7.58(m, 1H), 7.72-7.85(m , 1H), 7.92-8.12 (m, 2H), 10.48-10.65 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值518.2；實測值519.2；Rt=2.146min。LCMS (ESI): [M] + m/z: calculated 518.2; found 519.2; Rt=2.146 min.

實例645. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(4-甲氧基-1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1118)之合成Example 645. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(4-methoxy-1-methylpiperidine- Synthesis of 4-yl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1118)

Figure 110128222-A0202-12-2143-677
Figure 110128222-A0202-12-2143-677

步驟1：4-(5-氯苯并[d]噻唑-2-基)-4-甲氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 4-(5-chlorobenzo[d]thiazol-2-yl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester

在0℃下，向4-(5-氯-1,3-苯并噻唑-2-基)-4-羥基哌啶-1-甲酸第三丁酯(7g，18.98mmol)於THF(79.82mL)中之經攪拌之溶液中分批添加於礦物油中之氫化鈉(油分散物)60%分散物(872.54mg，20.87mmol，55%純度)。將所得混合物在0℃下攪拌40min。逐滴添加碘甲烷(3.10g，21.82mmol，1.36mL)且將所得混合物在25℃下攪拌12h。將反應混合物倒入到水(150ml)中且將產物用MTBE(3*50ml)萃取。將經合併之有機層用水(2*30ml)洗滌，經Na2 SO4 乾燥。在真空中蒸發溶劑，以得到4-(5-氯-1,3-苯并噻唑-2-基)-4-甲氧基哌啶-1-甲酸第三丁酯(7g，18.28mmol，96.34%產率)。To 4-(5-chloro-1,3-benzothiazol-2-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (7 g, 18.98 mmol) in THF (79.82 mL) at 0 °C Sodium hydride (oil dispersion) 60% dispersion (872.54 mg, 20.87 mmol, 55% purity) in mineral oil was added portionwise to a stirred solution in . The resulting mixture was stirred at 0 °C for 40 min. Iodomethane (3.10 g, 21.82 mmol, 1.36 mL) was added dropwise and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (150ml) and the product was extracted with MTBE (3*50ml). The combined organic layers were washed with water (2*30ml), dried over Na2SO4 . The solvent was evaporated in vacuo to give tert-butyl 4-(5-chloro-1,3-benzothiazol-2-yl)-4-methoxypiperidine-1-carboxylate (7 g, 18.28 mmol, 96.34 g %Yield).

LCMS(ESI)：[M-t -Bu]+ m/z：計算值326.2；實測值327.2；Rt=1.608min。LCMS (ESI): [M- t -Bu] + m/z: calculated 326.2; found 327.2; Rt=1.608 min.

步驟2：5-氯-2-(4-甲氧基哌啶-4-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-chloro-2-(4-methoxypiperidin-4-yl)benzo[d]thiazole

向4-(5-氯-1,3-苯并噻唑-2-基)-4-甲氧基哌啶-1-甲酸第三丁酯(7g，18.28mmol)於DCM(50mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(40.00g，1.10mol，50mL)。將所得混合物在25℃下攪拌14h。在真空中蒸 發溶劑。將殘餘物用MTBE(50ml)稀釋。將固體過濾，用MTBE洗滌，然後在真空中乾燥，以得到5-氯-2-(4-甲氧基-4-哌啶基)-1,3-苯并噻唑(3.3g，10.34mmol，56.54%產率，HCl)。To 3-butyl 4-(5-chloro-1,3-benzothiazol-2-yl)-4-methoxypiperidine-1-carboxylate (7 g, 18.28 mmol) in DCM (50 mL) To the stirred solution was added a 4.0 M solution of hydrogen chloride in dioxane (40.00 g, 1.10 mol, 50 mL). The resulting mixture was stirred at 25 °C for 14 h. steam in vacuum Solvent. The residue was diluted with MTBE (50 ml). The solid was filtered, washed with MTBE, and dried in vacuo to give 5-chloro-2-(4-methoxy-4-piperidinyl)-1,3-benzothiazole (3.3 g, 10.34 mmol, 56.54% yield, HCl).

LCMS(ESI)：[M]+ m/z：計算值282.2；實測值283.2；Rt=1.003min。LCMS (ESI): [M] + m/z: calculated 282.2; found 283.2; Rt=1.003 min.

步驟3：5-氯-2-(4-甲氧基-1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-chloro-2-(4-methoxy-1-methylpiperidin-4-yl)benzo[d]thiazole

向5-氯-2-(4-甲氧基-4-哌啶基)-1,3-苯并噻唑(3g，9.40mmol，HCl)於MeOH(100mL)中之經攪拌之溶液中添加用7-8% MeOH穩定之37重量%甲醛水溶液(1.14g，14.10mmol，1.06mL，37%純度)及無水乙酸鈉(1.54g，18.79mmol，1.01mL)。將所得混合物在25℃下攪拌2h。然後分批添加氰基硼氫化鈉(708.61mg，11.28mmol)。將所得混合物在25℃下攪拌12h。蒸發甲醇。將殘餘物用水(70ml)稀釋且用DCM(3*30ml)萃取。將經合併之有機層用K2 CO3 溶液洗滌且經Na2 SO4 乾燥。在真空中蒸發DCM，以得到5-氯-2-(4-甲氧基-1-甲基-4-哌啶基)-1,3-苯并噻唑(2.1g，7.08mmol，75.29%產率)。To a stirred solution of 5-chloro-2-(4-methoxy-4-piperidinyl)-1,3-benzothiazole (3 g, 9.40 mmol, HCl) in MeOH (100 mL) was added 7-8% MeOH stabilized 37 wt% formaldehyde in water (1.14 g, 14.10 mmol, 1.06 mL, 37% pure) and anhydrous sodium acetate (1.54 g, 18.79 mmol, 1.01 mL). The resulting mixture was stirred at 25 °C for 2 h. Then sodium cyanoborohydride (708.61 mg, 11.28 mmol) was added portionwise. The resulting mixture was stirred at 25 °C for 12 h. Methanol was evaporated. The residue was diluted with water (70ml) and extracted with DCM (3*30ml). The combined organic layers were washed with K2CO3 solution and dried over Na2SO4 . The DCM was evaporated in vacuo to give 5-chloro-2-(4-methoxy-1-methyl-4-piperidinyl)-1,3-benzothiazole (2.1 g, 7.08 mmol, 75.29% yield) Rate).

LCMS(ESI)：[M]+ m/z：計算值296.2；實測值297.2；Rt=2.139min。LCMS (ESI): [M] + m/z: calculated 296.2; found 297.2; Rt=2.139 min.

步驟4：2-(4-甲氧基-1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 4: 2-(4-Methoxy-1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroza Synthesis of cyclopentan-2-yl)benzo[d]thiazole

將5-氯-2-(4-甲氧基-1-甲基-4-哌啶基)-1,3-苯并噻唑(2.1g，7.08mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.98g，7.78mmol)及乙酸鉀(1.39g，14.15mmol，884.52μL)混合於二噁烷(30mL)中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加參(二苯亞甲基丙酮)二鈀(0)(323.94mg，353.76μmol)及X-Phos(337.29mg，707.51μmol)。將反應混合物在氬氣、90℃下攪拌14h。冷卻反應混合物且過濾。將濾餅用二噁烷(2*10ml)洗滌且丟棄。將經合併之濾液在真空中濃縮。將殘餘物用MTBE(50ml)稀釋且用NaHSO4 水溶液(20ml)萃取 (重複3次)。將經合併之水層用10%氫氧化鈉水溶液鹼化至pH 10，以得到2-(4-甲氧基-1-甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(2.6g，6.70mmol，94.63%產率)之水溶液，其直接用於下一步驟中。5-Chloro-2-(4-methoxy-1-methyl-4-piperidinyl)-1,3-benzothiazole (2.1 g, 7.08 mmol), 4,4,5,5-tetrakis Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane Pentane (1.98 g, 7.78 mmol) and potassium acetate (1.39 g, 14.15 mmol, 884.52 μL) were mixed in dioxane (30 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times, followed by the addition of bis(dibenzylideneacetone)dipalladium(0) (323.94 mg, 353.76 μmol) and X-Phos ( 337.29 mg, 707.51 μmol). The reaction mixture was stirred under argon at 90 °C for 14 h. The reaction mixture was cooled and filtered. The filter cake was washed with dioxane (2*10ml) and discarded. The combined filtrates were concentrated in vacuo. The residue was diluted with MTBE (50 ml) and extracted with aqueous NaHSO 4 (20 ml) (repeated 3 times). The combined aqueous layers were basified to pH 10 with 10% aqueous sodium hydroxide to give 2-(4-methoxy-1-methyl-4-piperidinyl)-5-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (2.6 g, 6.70 mmol, 94.63% yield) in water, which used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=1.067min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=1.067 min.

步驟5：(S)-6-(2-(4-甲氧基-1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-6-(2-(4-Methoxy-1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4 -Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：1.9g粗品。Prepared by General Procedure H, Step 3. Yield: 1.9 g crude.

LCMS(ESI)：[M]+ m/z：計算值457.2；實測值458.2；Rt=1.403min。LCMS (ESI): [M] + m/z: calculated 457.2; found 458.2; Rt=1.403 min.

步驟6：(S)-2-(4-甲氧基-1-甲基哌啶-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 6: (S)-2-(4-Methoxy-1-methylpiperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridine-2- Synthesis of yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.76g粗品。Prepared by General Procedure H, Step 4. Yield: 0.76 g crude.

LCMS(ESI)：[M]+ m/z：計算值357.2；實測值358.2；Rt=0.719min。LCMS (ESI): [M] + m/z: calculated 357.2; found 358.2; Rt=0.719 min.

步驟7：2-(4-甲氧基-1-甲基哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 7: 2-(4-Methoxy-1-methylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole synthesis

藉由一般程序方案H步驟5製備。產率：0.5g粗品。Prepared by General Procedure H, Step 5. Yield: 0.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值359.2；實測值360.2；Rt=0.754min。LCMS (ESI): [M] + m/z: calculated 359.2; found 360.2; Rt=0.754 min.

步驟8：N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(4-甲氧基-1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1118)之合成Step 8: N- (6-Amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(4-methoxy-1-methylpiperidine- Synthesis of 4-yl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1118)

藉由一般程序方案H步驟6A製備。產率：56mg(24.37%)。Prepared by General Procedure H, Step 6A. Yield: 56 mg (24.37%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-5min 45-75%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 45-75% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

化合物1118：Compound 1118:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.05(m,3H),1.06-1.14(m,3H),1.31 -1.39(m,1H),1.68-1.73(m,1H),1.84-1.92(m,1H),2.03-2.09(m,3H),2.11-2.16(m,2H),2.18(s,3H),2.25-2.32(m,3H),2.38-2.43(m,2H),2.55-2.59(m,2H),2.77-3.06(m,1H),3.11(s,3H),3.46-4.08(m,1H),5.28-5.73(m,3H),7.37-7.45(m,1H),7.45-7.56(m,1H),7.89-7.96(m,1H),7.98-8.14(m,2H),10.52-10.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.05(m,3H), 1.06-1.14(m,3H), 1.31-1.39(m,1H), 1.68-1.73(m,1H) ,1.84-1.92(m,1H),2.03-2.09(m,3H),2.11-2.16(m,2H),2.18(s,3H),2.25-2.32(m,3H),2.38-2.43(m, 2H), 2.55-2.59(m, 2H), 2.77-3.06(m, 1H), 3.11(s, 3H), 3.46-4.08(m, 1H), 5.28-5.73(m, 3H), 7.37-7.45( m, 1H), 7.45-7.56 (m, 1H), 7.89-7.96 (m, 1H), 7.98-8.14 (m, 2H), 10.52-10.63 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值550.2；實測值551.2；Rt=1.726min。LCMS (ESI): [M] + m/z: calculated 550.2; found 551.2; Rt=1.726 min.

實例646. 5-(2-((2R,5S)-2-(2-(1-((二甲胺基)甲基)環丙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1109)之合成Example 646. 5-(2-((2R,5S)-2-(2-(1-((dimethylamino)methyl)cyclopropyl)benzo[d]thiazol-5-yl)-5 Synthesis of -methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1109)

Figure 110128222-A0202-12-2146-678
Figure 110128222-A0202-12-2146-678

藉由一般程序8步驟6A製備。產率：197mg(21.43%)。Prepared by General Procedure 8, Step 6A. Yield: 197 mg (21.43%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 50-80%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20 mm, 5 microns; 0-1-6 min 50-80% water-MeOH+0.1% NH4OH , flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

然後將其另外使用製備型掌性HPLC(管柱：Chiralcel OD-H(250*20mm，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：12ml/min)進行純化，以得到呈白色固體之化合物1109 2-甲氧基-5-[[2-側氧基-2-[(2R,5S )-2-[2-[1-[(二甲胺基)甲基]環丙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(197mg，357.75μmol，21.43%產率)(RT=16.790min)。It was then additionally purified using preparative chiral HPLC (column: Chiralcel OD-H (250*20mm, 5mkm); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 12ml/min) , to give compound 1109 as a white solid [methyl]cyclopropyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]acetyl]amino]pyridine-3-carbamide (197 mg, 357.75 μmol , 21.43% yield) (RT=16.790 min).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.08(m,5H),1.31-1.41(m,1H),1.41-1.47(m,2H),1.67-1.76(m,1H),1.84-1.96(m,1H),2.01-2.36(m,8H),2.58-2.65 (m,2H),2.78-3.24(m,1H),3.47-4.04(m,4H),5.19-5.71(m,1H),7.25-7.38(m,1H),7.65-8.03(m,4H),8.38-8.59(m,2H),10.96-11.15(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.08(m, 5H), 1.31-1.41(m, 1H), 1.41-1.47(m, 2H), 1.67-1.76(m, 1H) ,1.84-1.96(m,1H),2.01-2.36(m,8H),2.58-2.65(m,2H),2.78-3.24(m,1H),3.47-4.04(m,4H),5.19-5.71( m, 1H), 7.25-7.38 (m, 1H), 7.65-8.03 (m, 4H), 8.38-8.59 (m, 2H), 10.96-11.15 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值550.2；實測值551.2；Rt=2.439min。LCMS (ESI): [M] + m/z: calculated 550.2; found 551.2; Rt=2.439 min.

實例647. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(4-氟-1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1160)之合成Example 647. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(4-fluoro-1-methylpiperidine-4- Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1160)

Figure 110128222-A0202-12-2147-679
Figure 110128222-A0202-12-2147-679

步驟1：4-(5-氯苯并[d]噻唑-2-基)-4-氟哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 4-(5-chlorobenzo[d]thiazol-2-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟1B製備。產率：0.8g粗品。Prepared by General Procedure H, Step IB. Yield: 0.8 g crude.

LCMS(ESI)：[M-t -Bu]+ m/z：計算值314.2；實測值315.2；Rt=1.721min。LCMS (ESI): [M- t -Bu] + m/z: calculated 314.2; found 315.2; Rt=1.721 min.

步驟2：5-氯-2-(4-氟哌啶-4-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-chloro-2-(4-fluoropiperidin-4-yl)benzo[d]thiazole

將於二噁烷中之4.0M氯化氫溶液(1.60g，43.88mmol，2mL)添加到4-(5-氯-1,3-苯并噻唑-2-基)-4-氟-哌啶-1-甲酸第三丁酯(0.8g，2.16mmol)於MeOH(20mL)中之溶液中。將反應混合物在0℃下攪拌6h，然後蒸發且添加到MTBE(40ml)中，將所得沉澱過濾，用MTBE(30ml)洗滌且乾燥，以得到5-氯-2-(4-氟-4-哌啶基)-1,3-苯并噻唑(0.5g，1.63mmol，75.45%產率，HCl)。A 4.0M solution of hydrogen chloride in dioxane (1.60 g, 43.88 mmol, 2 mL) was added to 4-(5-chloro-1,3-benzothiazol-2-yl)-4-fluoro-piperidine-1 - A solution of tert-butyl formate (0.8 g, 2.16 mmol) in MeOH (20 mL). The reaction mixture was stirred at 0°C for 6h, then evaporated and added to MTBE (40ml), the resulting precipitate was filtered, washed with MTBE (30ml) and dried to give 5-chloro-2-(4-fluoro-4- piperidinyl)-1,3-benzothiazole (0.5 g, 1.63 mmol, 75.45% yield, HCl).

LCMS(ESI)：[M]+ m/z：計算值270.2；實測值271.2；Rt=1.483min。LCMS (ESI): [M] + m/z: calculated 270.2; found 271.2; Rt=1.483 min.

步驟3：5-氯-2-(4-氟-1-甲基哌啶-4-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-chloro-2-(4-fluoro-1-methylpiperidin-4-yl)benzo[d]thiazole

將用7-8% MeOH穩定之37重量%甲醛水溶液(146.62mg，4.88mmol，135.39μL)及乙酸(293.20mg，4.88mmol，279.50μL)添加到5-氯-2-(4-氟 -4-哌啶基)-1,3-苯并噻唑(0.5g，1.63mmol，HCl)及無水乙酸鈉(146.86mg，1.79mmol，96.12μL)於MeOH(21.02mL)中之溶液中。將所得混合物在0℃下攪拌1h，之後向其中添加氰基硼氫化鈉(204.55mg，3.26mmol)。此後，繼續攪拌6h。然後，在減壓下移除溶劑且將殘餘物分配於10%K2 CO3 水溶液(20ml)與DCM(40ml)之間。將有機層分離，經固體K2 CO3 乾燥且在減壓下濃縮，留下5-氯-2-(4-氟-1-甲基-4-哌啶基)-1,3-苯并噻唑(0.5g，粗品)。Aqueous 37 wt% formaldehyde stabilized with 7-8% MeOH (146.62 mg, 4.88 mmol, 135.39 μL) and acetic acid (293.20 mg, 4.88 mmol, 279.50 μL) were added to 5-chloro-2-(4-fluoro-4 -Piperidinyl)-1,3-benzothiazole (0.5 g, 1.63 mmol, HCl) and anhydrous sodium acetate (146.86 mg, 1.79 mmol, 96.12 μL) in MeOH (21.02 mL). The resulting mixture was stirred at 0 °C for 1 h before adding sodium cyanoborohydride (204.55 mg, 3.26 mmol). Thereafter, stirring was continued for 6 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 10 % aqueous K2CO3 (20ml) and DCM (40ml). The organic layer was separated, dried over solid K2CO3 and concentrated under reduced pressure to leave 5 -chloro-2-(4-fluoro-1-methyl-4-piperidinyl)-1,3-benzo Thiazole (0.5 g, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)2.12(m,2H),2.45(s,3H),2.52(m,4H),2.75(m,2H),7.54(d,1H),8.14(s,1H),8.19(d,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 2.12(m, 2H), 2.45(s, 3H), 2.52(m, 4H), 2.75(m, 2H), 7.54(d, 1H), 8.14(s, 1H), 8.19(d, 1H).

步驟4：2-(4-氟-1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 4: 2-(4-Fluoro-1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of Alk-2-yl)benzo[d]thiazoles

將參(二苯亞甲基丙酮)二鈀(0)(80.39mg，87.79μmol)及X-Phos(167.40mg，351.15μmol)添加到5-氯-2-(4-氟-1-甲基-4-哌啶基)-1,3-苯并噻唑(0.5g，1.76mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(579.60mg，2.28mmol)於二噁烷(20mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後在氬氣流下添加乙酸鉀(172.31mg，1.76mmol，109.75μL)。在惰性氣氛下將所得混合物在90℃下攪拌15h，然後冷卻且在真空中蒸發，倒入到水(200ml)中且用DCM(2x30ml)萃取，經硫酸鈉乾燥且在真空中蒸發，留下0.6g粗產物，0.6g殘餘物藉由矽膠管柱層析使用MeCN梯度(10-100% MeCN)進行純化，以得到2-(4-氟-1-甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(0.16g，425.20μmol，24.22%產率)。Palladium (0) (80.39 mg, 87.79 μmol) and X-Phos (167.40 mg, 351.15 μmol) were added to 5-chloro-2-(4-fluoro-1-methyl) -4-Piperidinyl)-1,3-benzothiazole (0.5 g, 1.76 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (579.60 mg, 2.28 mmol) in dioxane (20 mL) in solution. The reaction flask was evacuated and refilled with argon 3 times. Potassium acetate (172.31 mg, 1.76 mmol, 109.75 μL) was then added under a stream of argon. The resulting mixture was stirred at 90°C for 15h under an inert atmosphere, then cooled and evaporated in vacuo, poured into water (200ml) and extracted with DCM (2x30ml), dried over sodium sulfate and evaporated in vacuo to leave 0.6g crude product, 0.6g residue was purified by silica gel column chromatography using MeCN gradient (10-100% MeCN) to give 2-(4-fluoro-1-methyl-4-piperidinyl)- 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-benzothiazole (0.16 g, 425.20 μmol, 24.22 %Yield).

LCMS(ESI)：[M]+ m/z：計算值376.2；實測值377.2；Rt=1.181min。LCMS (ESI): [M] + m/z: calculated 376.2; found 377.2; Rt=1.181 min.

步驟5：(S)-6-(2-(4-氟-1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-6-(2-(4-Fluoro-1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-di Synthesis of Hydropyridine-1(2H)-Carboxylic Acid 3-Butyl Ester

藉由一般程序方案H步驟3製備。產率：0.3g粗品。Prepared by General Procedure H, Step 3. Yield: 0.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值445.2；實測值446.2；Rt=3.023min。LCMS (ESI): [M] + m/z: calculated 445.2; found 446.2; Rt=3.023 min.

步驟6：(S)-2-(4-氟-1-甲基哌啶-4-基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 6: (S)-2-(4-Fluoro-1-methylpiperidin-4-yl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl) Synthesis of Benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.2g粗品。Prepared by General Procedure H, Step 4. Yield: 0.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=1.379min。LCMS (ESI): [M] + m/z: calculated 345.2; found 346.2; Rt=1.379 min.

步驟7：2-(4-氟-1-甲基哌啶-4-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 7: Synthesis of 2-(4-Fluoro-1-methylpiperidin-4-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.12g粗品。Prepared by General Procedure H, Step 5. Yield: 0.12 g crude.

LCMS(ESI)：[M]+ m/z：計算值347.2；實測值348.2；Rt=1.802min。LCMS (ESI): [M] + m/z: calculated 347.2; found 348.2; Rt=1.802 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(4-氟-1-甲基哌啶-4-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1160)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(4-fluoro-1-methylpiperidine-4- Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1160)

藉由一般程序方案H步驟6A製備。產率：6.4mg(2.74%)。Prepared by General Procedure H, Step 6A. Yield: 6.4 mg (2.74%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 60-60-85%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 60-60-85% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.06(m,6H),1.30-1.41(m,1H),1.64-1.73(m,1H),1.83-1.92(m,1H),2.10-2.20(m,3H),2.22-2.36(m,8H),2.38-2.42(m,2H),2.70-2.93(m,3H),3.45-4.08(m,1H),5.26-5.74(m,3H),7.40-7.45(m,1H),7.49-7.53(m,1H),7.94-8.07(m,2H),8.13-8.19(m,1H),10.49-10.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.02-1.06 (m, 6H), 1.30-1.41 (m, 1H), 1.64-1.73 (m, 1H), 1.83-1.92 (m, 1H) ,2.10-2.20(m,3H),2.22-2.36(m,8H),2.38-2.42(m,2H),2.70-2.93(m,3H),3.45-4.08(m,1H),5.26-5.74( m, 3H), 7.40-7.45 (m, 1H), 7.49-7.53 (m, 1H), 7.94-8.07 (m, 2H), 8.13-8.19 (m, 1H), 10.49-10.63 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值538.2；實測值539.2；Rt=2.357min。LCMS (ESI): [M] + m/z: calculated 538.2; found 539.2; Rt=2.357 min.

實例648. 5-(2-((2R,5S)-2-(2-(3-((二甲胺基)甲基)氧呾-3-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1155)之合成Example 648. 5-(2-((2R,5S)-2-(2-(3-((dimethylamino)methyl)oxon-3-yl)benzo[d]thiazol-5-yl )-5-methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide (compound 1155) synthesis

Figure 110128222-A0202-12-2150-680
Figure 110128222-A0202-12-2150-680

步驟1：2-(3-(疊氮基甲基)氧呾-3-基)-5-氯苯并[d]噻唑之合成Step 1: Synthesis of 2-(3-(azidomethyl)oxon-3-yl)-5-chlorobenzo[d]thiazole

藉由一般程序方案H步驟1B製備。產率：11g粗品。Prepared by General Procedure H, Step IB. Yield: 11 g crude.

LCMS(ESI)：[M]+ m/z：計算值280.2；實測值281.2；Rt=3.578min。LCMS (ESI): [M] + m/z: calculated 280.2; found 281.2; Rt=3.578 min.

步驟2：(3-(5-氯苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 2: Synthesis of (3-(5-Chlorobenzo[d]thiazol-2-yl)oxon-3-yl)methanamine

將2-[3-(疊氮基甲基)氧呾-3-基]-5-氯-1,3-苯并噻唑(11g，39.18mmol)(大約50ml)之粗MTBE溶液用MeOH(100mL)稀釋且添加氯化銨(12.58g，235.10mmol，8.22mL)。在攪拌之情況下，在25℃下，將鋅粉(7.69g，117.55mmol)分批添加到以上混合物中。將反應混合物在25℃下攪拌12h，然後過濾。將濾餅用MeOH(2*25ml)洗滌且丟棄。將經合併之濾液在真空中濃縮。將殘餘物用MTBE(100ml)稀釋且用5%硫酸氫鈉水溶液(100ml)萃取。然後將所得硫酸氫胺水溶液用10%氫氧化鈉水溶液鹼化至pH 11且用DCM(2*50ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色膠狀物之粗品[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]甲胺(1.2g，4.71mmol，12.02%產率)，其直接用於下一步驟中。A crude MTBE solution of 2-[3-(azidomethyl)oxon-3-yl]-5-chloro-1,3-benzothiazole (11 g, 39.18 mmol) (approximately 50 mL) was dissolved in MeOH (100 mL). ) was diluted and ammonium chloride (12.58 g, 235.10 mmol, 8.22 mL) was added. Zinc powder (7.69 g, 117.55 mmol) was added portionwise to the above mixture at 25°C with stirring. The reaction mixture was stirred at 25 °C for 12 h, then filtered. The filter cake was washed with MeOH (2*25ml) and discarded. The combined filtrates were concentrated in vacuo. The residue was diluted with MTBE (100 ml) and extracted with 5% aqueous sodium bisulfate (100 ml). The resulting aqueous ammonium hydrogen sulfate solution was then basified to pH 11 with 10% aqueous sodium hydroxide solution and extracted with DCM (2*50 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude [3-(5-chloro-1,3-benzothiazol-2-yl)oxyquinone- as a pale yellow gum 3-yl]methanamine (1.2 g, 4.71 mmol, 12.02% yield) was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值254.2；實測值255.2；Rt=1.985min。LCMS (ESI): [M] + m/z: calculated 254.2; found 255.2; Rt=1.985 min.

步驟3：1-(3-(5-氯苯并[d]噻唑-2-基)氧呾-3-基)-N,N-二甲基甲胺之合成Step 3: Synthesis of 1-(3-(5-chlorobenzo[d]thiazol-2-yl)oxypyr-3-yl)-N,N-dimethylmethanamine

在25℃下，將用7-8% MeOH穩定之37重量%甲醛水溶液(946.16mg，11.66mmol，873.64μL，37%純度)及乙酸(518.63mg，8.64mmol，494.41μL)添 加到[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]甲胺(1.1g，4.32mmol)於MeOH(30.49mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌1h，然後在25℃下一次性添加氰基硼氫化鈉(542.73mg，8.64mmol)(發泡！)。將反應混合物在25℃下攪拌12h，然後在真空中濃縮。將殘餘物用10%氫氧化鈉水溶液(20ml)稀釋且用DCM(2*20ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到呈淡黃色膠狀物之粗品1-[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]-N,N -二甲基甲胺(1.3g，粗品)，其直接用於下一步驟中。At 25°C, 37 wt% aqueous formaldehyde stabilized with 7-8% MeOH (946.16 mg, 11.66 mmol, 873.64 μL, 37% pure) and acetic acid (518.63 mg, 8.64 mmol, 494.41 μL) were added to [3- In a stirred solution of (5-chloro-1,3-benzothiazol-2-yl)oxypyran-3-yl]methanamine (1.1 g, 4.32 mmol) in MeOH (30.49 mL). The resulting mixture was stirred at 25°C for 1 h, then sodium cyanoborohydride (542.73 mg, 8.64 mmol) was added in one portion at 25°C (foaming!). The reaction mixture was stirred at 25 °C for 12 h, then concentrated in vacuo. The residue was diluted with 10% aqueous sodium hydroxide solution (20ml) and extracted with DCM (2*20ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 1-[3-(5-chloro-1,3-benzothiazol-2-yl)oxyl as a pale yellow gum Zyr-3-yl] -N,N -dimethylmethylamine (1.3 g, crude), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值282.2；實測值283.2；Rt=1.530min。LCMS (ESI): [M] + m/z: calculated 282.2; found 283.2; Rt=1.530 min.

步驟4：N,N-二甲基-1-(3-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 4: N,N-Dimethyl-1-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl ) Synthesis of benzo[d]thiazol-2-yl)oxo-3-yl)methanamine

將1-[3-(5-氯-1,3-苯并噻唑-2-基)氧呾-3-基]-N,N -二甲基甲胺(1.4g，4.95mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.38g，5.45mmol)及乙酸鉀(971.72mg，9.90mmol，618.93μL)於二噁烷(35mL)中之混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後在氬氣下添加參 (1,5-二苯基戊-1,4-二烯-3-酮)二鈀(226.67mg，247.53μmol)及二環己基[2',4',6'-參(丙-2-基)-[1,1'-聯苯基]-2-基]磷烷(472.02mg，990.14μmol)，且將反應混合物在95℃下攪拌18h。冷卻反應混合物且過濾。將濾餅用二噁烷(2*10ml)洗滌且丟棄。將經合併之濾液在真空中濃縮。將殘餘物用DCM(30ml)稀釋且用硫酸氫鈉(1.19g，9.90mmol)於水(20ml)中之溶液萃取(重複兩次)。將經合併之水層用10%氫氧化鈉水溶液鹼化至pH 10且用DCM(3*25ml)反萃取。兩種DCM萃取物之蒸發未顯示所要產物。其看起來像硼酸酯在水性介質中水解且呈硼酸留在水相中。經合併之水層(大約100ml)含有N,N -二甲基-1-[3-[5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑-2-基]氧呾-3-基]甲胺(1.85g，4.94mmol，100.00%產率)(理論量之產物，最可能呈硼酸形 式)，其直接用於下一步驟中。1-[3-(5-Chloro-1,3-benzothiazol-2-yl)oxypyr-3-yl] -N,N -dimethylmethanamine (1.4 g, 4.95 mmol), 4, 4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2 - A mixture of dioxaborolane (1.38 g, 5.45 mmol) and potassium acetate (971.72 mg, 9.90 mmol, 618.93 μL) in dioxane (35 mL) was evacuated and backfilled with argon. This operation was repeated twice, followed by addition of ginseng (1,5-diphenylpent-1,4-dien-3-one)dipalladium (226.67 mg, 247.53 μmol) and dicyclohexyl[2 under argon ',4',6'-para(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (472.02 mg, 990.14 μmol), and the reaction mixture was heated at 95 °C Stir for 18h. The reaction mixture was cooled and filtered. The filter cake was washed with dioxane (2*10ml) and discarded. The combined filtrates were concentrated in vacuo. The residue was diluted with DCM (30 ml) and extracted with a solution of sodium bisulfate (1.19 g, 9.90 mmol) in water (20 ml) (repeated twice). The combined aqueous layers were basified to pH 10 with 10% aqueous sodium hydroxide and back extracted with DCM (3*25ml). Evaporation of the two DCM extracts did not reveal the desired product. It appears that the borate ester is hydrolyzed in the aqueous medium and remains in the aqueous phase as boric acid. The combined aqueous layers (approximately 100 ml) contained N,N -dimethyl-1-[3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Cyclopentan-2-yl)-1,3-benzothiazol-2-yl]oxypyran-3-yl]methanamine (1.85 g, 4.94 mmol, 100.00% yield) (theoretical product, most likely as boronic acid), which was used directly in the next step.

LCMS(ESI)：[M]+ m/z：計算值374.2；實測值375.2；Rt=2.586min。LCMS (ESI): [M] + m/z: calculated 374.2; found 375.2; Rt=2.586 min.

步驟5：(S)-6-(2-(3-((二甲胺基)甲基)氧呾-3-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-6-(2-(3-((dimethylamino)methyl)oxypyr-3-yl)benzo[d]thiazol-5-yl)-3-methyl-3 Synthesis of 3-butyl ,4-dihydropyridine-1(2H)-carboxylate

藉由一般程序方案H步驟3製備。產率：1.3g粗品。Prepared by General Procedure H, Step 3. Yield: 1.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值443.2；實測值444.2；Rt=1.279min。LCMS (ESI): [M] + m/z: calculated 443.2; found 444.2; Rt=1.279 min.

步驟6：(S)-N,N-二甲基-1-(3-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 6: (S)-N,N-Dimethyl-1-(3-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d] Synthesis of Thiazol-2-yl)oxo-3-yl)methanamine

藉由一 般程序方案H步驟4製備。產率：0. 45g粗品。 Prepared by General Procedure Scheme H, Step 4. Yield : 0.45 g crude .

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=0.624min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=0.624 min.

步驟7：N,N-二甲基-1-(3-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)氧呾-3-基)甲胺之合成Step 7: N,N-Dimethyl-1-(3-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)oxygen Synthesis of -3-yl)methylamine

藉由一般程序方案H步驟5製備。產率：0.33g(72.91%)。Prepared by General Procedure H, Step 5. Yield: 0.33 g (72.91%).

LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=0.574min。LCMS (ESI): [M] + m/z: calculated 345.2; found 346.2; Rt=0.574 min.

步驟8：5-(2-((2R,5S)-2-(2-(3-((二甲胺基)甲基)氧呾-3-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-2-甲氧基菸鹼醯胺(化合物1155 )之合成Step 8: 5-(2-((2R,5S)-2-(2-(3-((dimethylamino)methyl)oxon-3-yl)benzo[d]thiazol-5-yl )-5-methylpiperidin-1-yl)-2-oxyacetamido)-2-methoxynicotinamide ( compound 1155 ) synthesis

藉由一般程序方案H步驟6A製備。產率：27.3mg(11.1%)。Prepared by General Procedure H, Step 6A. Yield: 27.3 mg (11.1%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-5min 20-60%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-5min 20-60% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.09(m,3H),1.32-1.42(m,1H),1.70-1.77(m,1H),1.84-1.94(m,1H),2.08(s,6H),2.11-2.36(m,2H),2.83-3.37(m,3H),3.50-4.09(m,4H),4.70-4.78(m,2H),4.91-4.97(m,2H),5.28-5.75(m,1H),7.37-7.46(m,1H),7.66-7.78(m,2H),7.93-7.99(m,1H),8.04-8.12(m,1H),8.41-8.49(m,1H),8.49-8.60(m,1H),10.97-11.20(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.09(m,3H), 1.32-1.42(m,1H), 1.70-1.77(m,1H), 1.84-1.94(m,1H) ,2.08(s,6H),2.11-2.36(m,2H),2.83-3.37(m,3H),3.50-4.09(m,4H),4.70-4.78(m,2H),4.91-4.97(m, 2H), 5.28-5.75(m, 1H), 7.37-7.46(m, 1H), 7.66-7.78(m, 2H), 7.93-7.99(m, 1H), 8.04-8.12(m, 1H), 8.41- 8.49 (m, 1H), 8.49-8.60 (m, 1H), 10.97-11.20 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值566.2；實測值567.2；Rt=2.625min。LCMS (ESI): [M] + m/z: calculated 566.2; found 567.2; Rt=2.625min.

實例649. N-(6-胺基-5-乙基吡啶-3-基)-2-((5S)-5-甲基-2-(2-(3-甲基-3-氮雜雙環[3.2.0]庚-6-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1147)之合成Example 649. N-(6-Amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2-(3-methyl-3-azabicyclo Synthesis of [3.2.0]hept-6-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1147)

Figure 110128222-A0202-12-2153-681
Figure 110128222-A0202-12-2153-681

步驟1：2-(3-氮雜雙環[3.2.0]庚-6-基)-5-溴苯并[d]噻唑之合成Step 1: Synthesis of 2-(3-azabicyclo[3.2.0]hept-6-yl)-5-bromobenzo[d]thiazole

藉由一般程序方案H步驟1A製備。產率：2.3g(89.73%)。Prepared by General Procedure H, Step 1A. Yield: 2.3 g (89.73%).

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=0.815min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=0.815 min.

步驟2：5-溴-2-(3-甲基-3-氮雜雙環[3.2.0]庚-6-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-bromo-2-(3-methyl-3-azabicyclo[3.2.0]hept-6-yl)benzo[d]thiazole

在25℃下，將用7-8% MeOH穩定之37重量%甲醛水溶液(783.90mg，26.11mmol，723.82μL)及乙酸(893.33mg，14.88mmol，851.60μL)添加到2-(3-氮雜雙環[3.2.0 ]庚-6-基)-5-溴-1,3-苯并噻唑(2.3g，7.44mmol)於MeOH(60.07mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌0.5h，然後在25℃下一次性添加氰基硼氫化鈉(934.83mg，14.88mmol)(發泡！)。將反應混合物在25℃下攪拌17h，然後在真空中濃縮。將殘餘物用10%氫氧化鈉水溶液(20ml)稀釋且用DCM(2*20ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到粗品5-溴-2-(3-甲基-3-氮雜雙環[3.2.0 ]庚-6-基)-1,3-苯并噻唑(1.5g，4.64mmol，62.39%產率)。Aqueous 37 wt% formaldehyde stabilized with 7-8% MeOH (783.90 mg, 26.11 mmol, 723.82 μL) and acetic acid (893.33 mg, 14.88 mmol, 851.60 μL) were added to 2-(3-aza at 25°C) In a stirred solution of bicyclo[ 3.2.0 ]heptan-6-yl)-5-bromo-1,3-benzothiazole (2.3 g, 7.44 mmol) in MeOH (60.07 mL). The resulting mixture was stirred at 25 °C for 0.5 h, then sodium cyanoborohydride (934.83 mg, 14.88 mmol) was added in one portion at 25 °C (foaming!). The reaction mixture was stirred at 25 °C for 17 h, then concentrated in vacuo. The residue was diluted with 10% aqueous sodium hydroxide solution (20ml) and extracted with DCM (2*20ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give crude 5-bromo-2-(3-methyl-3-azabicyclo[ 3.2.0 ]heptan-6-yl)-1 , 3-benzothiazole (1.5 g, 4.64 mmol, 62.39% yield).

LCMS(ESI)：[M]+ m/z：計算值323.2；實測值324.2；Rt=0.840min。LCMS (ESI): [M] + m/z: calculated 323.2; found 324.2; Rt=0.840 min.

步驟3：2-(3-甲基-3-氮雜雙環[3.2.0]庚-6-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜Step 3: 2-(3-Methyl-3-azabicyclo[3.2.0]hept-6-yl)-5-(4,4,5,5-tetramethyl-1,3,2-di oxaborola 環戊烷-2-基)苯并[d]噻唑之合成Synthesis of cyclopentan-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟2製備。產率：1g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 1 g crude.

LCMS(ESI)：[M]+ m/z：計算值370.2；實測值371.2；Rt=0.886min。LCMS (ESI): [M] + m/z: calculated 370.2; found 371.2; Rt=0.886 min.

步驟4：(3S)-3-甲基-6-(2-(3-甲基-3-氮雜雙環[3.2.0]庚-6-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 4: (3S)-3-Methyl-6-(2-(3-methyl-3-azabicyclo[3.2.0]heptan-6-yl)benzo[d]thiazol-5-yl) Synthesis of -3,4-dihydropyridine-1(2H)-carboxylate tert-butyl ester

藉由一般程序方案H步驟3製備。產率：1.4g粗品。Prepared by General Procedure H, Step 3. Yield: 1.4 g crude.

LCMS(ESI)：[M]+ m/z：計算值439.2；實測值440.2；Rt=1.366min。LCMS (ESI): [M] + m/z: calculated 439.2; found 440.2; Rt=1.366 min.

步驟5：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(3-甲基-3-氮雜雙環[3.2.0]庚-6-基)苯并[d]噻唑之合成Step 5: 5-((S)-5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(3-methyl-3-azabicyclo[3.2.0] Synthesis of Hept-6-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：1g粗品。Prepared by General Procedure H, Step 4. Yield: 1 g crude.

LCMS(ESI)：[M]+ m/z：計算值339.2；實測值340.2；Rt=0.697min。LCMS (ESI): [M] + m/z: calculated 339.2; found 340.2; Rt=0.697 min.

步驟6：2-(3-甲基-3-氮雜雙環[3.2.0]庚-6-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 6: 2-(3-Methyl-3-azabicyclo[3.2.0]hept-6-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo Synthesis of [d]thiazole

藉由一般程序方案H步驟5製備。產率：0.7g粗品。Prepared by General Procedure H, Step 5. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值341.2；實測值342.2；Rt=0.658min。LCMS (ESI): [M] + m/z: calculated 341.2; found 342.2; Rt=0.658 min.

步驟7：N-(6-胺基-5-乙基吡啶-3-基)-2-((5S)-5-甲基-2-(2-(3-甲基-3-氮雜雙環[3.2.0]庚-6-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1147)之合成Step 7: N-(6-Amino-5-ethylpyridin-3-yl)-2-((5S)-5-methyl-2-(2-(3-methyl-3-azabicyclo) Synthesis of [3.2.0]hept-6-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1147)

藉由一般程序方案H步驟6A製備。產率：12.7mg(6.26%)。Prepared by General Procedure H, Step 6A. Yield: 12.7 mg (6.26%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 60-60-85%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 60-60-85% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH ).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.14(m,6H),1.30-1.39(m,1H),1.67-1.73(m,1H),1.82-2.15(m,5H),2.17-2.32(m,4H),2.39-2.43(m,2H),2.67-2.98(m,4H),3.06-3.21(m,2H),3.46-4.11(m,2H),5.25-5.73(m,3H),7.31-7.41(m, 1H),7.43-7.53(m,1H),7.82-7.92(m,1H),7.97-8.10(m,2H),10.49-10.63(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.02-1.14 (m, 6H), 1.30-1.39 (m, 1H), 1.67-1.73 (m, 1H), 1.82-2.15 (m, 5H) ,2.17-2.32(m,4H),2.39-2.43(m,2H),2.67-2.98(m,4H),3.06-3.21(m,2H),3.46-4.11(m,2H),5.25-5.73( m, 3H), 7.31-7.41 (m, 1H), 7.43-7.53 (m, 1H), 7.82-7.92 (m, 1H), 7.97-8.10 (m, 2H), 10.49-10.63 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值532.2；實測值533.2；Rt=2.075min。LCMS (ESI): [M] + m/z: calculated 532.2; found 533.2; Rt=2.075 min.

實例650. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(3-甲基-3-氮雜雙環[3.1.1]庚-1-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1212)之合成Example 650. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(3-methyl-3-nitrogen Synthesis of Heterobicyclo[3.1.1]heptan-1-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (Compound 1212)

Figure 110128222-A0202-12-2155-682
Figure 110128222-A0202-12-2155-682

步驟1：1-(5-溴苯并[d]噻唑-2-基)-3-氮雜雙環[3.1.1]庚烷-3-甲酸第三丁酯之合成Step 1: Synthesis of 1-(5-bromobenzo[d]thiazol-2-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester

藉由一般程序方案H步驟1B製備。產率：1.3g粗品。Prepared by General Procedure H, Step IB. Yield: 1.3 g crude.

LCMS(ESI)：[M-t -Bu]+ m/z：計算值353.2；實測值354.2；Rt=1.756min。LCMS (ESI): [M- t -Bu] + m/z: calculated 353.2; found 354.2; Rt=1.756 min.

步驟2：2-(3-氮雜雙環[3.1.1]庚-1-基)-5-溴苯并[d]噻唑之合成Step 2: Synthesis of 2-(3-azabicyclo[3.1.1]heptan-1-yl)-5-bromobenzo[d]thiazole

將1-(5-溴-1,3-苯并噻唑-2-基)-3-氮雜雙環[3.1.1 ]庚烷-3-甲酸第三丁酯(1.3g，3.18mmol)溶解於DCM(10mL)中且添加TFA(10mL)。將混合物在25℃下攪拌2h。然後將其蒸發，溶解於水中且添加Na2 CO3 。將混合物用DCM萃取兩次，將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以獲得2-(3-氮雜雙環[3.1.1 ]庚-1-基)-5-溴-1,3-苯并噻唑(930mg，粗品)。1-(5-Bromo-1,3-benzothiazol-2-yl)-3-azabicyclo[ 3.1.1 ]heptane-3-carboxylic acid tert-butyl ester (1.3 g, 3.18 mmol) was dissolved in DCM (10 mL) and TFA (10 mL) was added. The mixture was stirred at 25 °C for 2 h. It was then evaporated, dissolved in water and Na2CO3 added . The mixture was extracted twice with DCM, the combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 2-(3-azabicyclo[ 3.1.1 ]heptan-1-yl)-5 -Bromo-1,3-benzothiazole (930 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2；Rt=1.021min。LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=1.021 min.

步驟3：5-溴-2-(3-甲基-3-氮雜雙環[3.1.1]庚-1-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-bromo-2-(3-methyl-3-azabicyclo[3.1.1]heptan-1-yl)benzo[d]thiazole

將2-(3-氮雜雙環[3.1.1 ]庚-1-基)-5-溴-1,3-苯并噻唑(930mg，3.01 mmol)溶解於MeOH(30mL)中且依次添加乙酸(361.22mg，6.02mmol，344.34μL)、2-(3-氮雜雙環[3.1.1 ]庚-1-基)-5-溴-1,3-苯并噻唑(930mg，3.01mmol)、氰基硼氫化鈉(283.50mg，4.51mmol)。將反應物在25℃下攪拌12h。將反應混合物蒸發。添加水且將其用DCM萃取兩次。將經合併之有機相用鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得5-溴-2-(3-甲基-3-氮雜雙環[3.1.1 ]庚-1-基)-1,3-苯并噻唑(950mg，粗品)。2-(3-Azabicyclo[ 3.1.1 ]heptan-1-yl)-5-bromo-1,3-benzothiazole (930 mg, 3.01 mmol) was dissolved in MeOH (30 mL) and acetic acid ( 361.22 mg, 6.02 mmol, 344.34 μL), 2-(3-azabicyclo[ 3.1.1 ]heptan-1-yl)-5-bromo-1,3-benzothiazole (930 mg, 3.01 mmol), cyano Sodium borohydride (283.50 mg, 4.51 mmol). The reaction was stirred at 25 °C for 12 h. The reaction mixture was evaporated. Water was added and it was extracted twice with DCM. The combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 5-bromo-2-(3-methyl-3-azabicyclo[ 3.1.1 ]heptane-1 -yl)-1,3-benzothiazole (950 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值323.2；實測值324.2；Rt=0.835min。LCMS (ESI): [M] + m/z: calculated 323.2; found 324.2; Rt=0.835 min.

步驟4：2-(3-甲基-3-氮雜雙環[3.1.1]庚-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 4: 2-(3-Methyl-3-azabicyclo[3.1.1]heptan-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-di Synthesis of oxaborol-2-yl)benzo[d]thiazole

藉由一般程序方案H步驟2製備。產率：1.8g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 1.8 g crude.

LCMS(ESI)：[M]+ m/z：計算值370.2；實測值371.2；Rt=1.041min。LCMS (ESI): [M] + m/z: calculated 370.2; found 371.2; Rt=1.041 min.

步驟5：(S)-3-甲基-6-(2-(3-甲基-3-氮雜雙環[3.1.1]庚-1-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 5: (S)-3-Methyl-6-(2-(3-methyl-3-azabicyclo[3.1.1]heptan-1-yl)benzo[d]thiazol-5-yl) Synthesis of -3,4-dihydropyridine-1(2H)-carboxylate tert-butyl ester

藉由一般程序方案H步驟3製備。產率：0.94g粗品。Prepared by General Procedure H, Step 3. Yield: 0.94 g crude.

LCMS(ESI)：[M]+ m/z：計算值439.2；實測值440.2；Rt=1.288min。LCMS (ESI): [M] + m/z: calculated 439.2; found 440.2; Rt=1.288 min.

步驟6：(S)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(3-甲基-3-氮雜雙環[3.1.1]庚-1-基)苯并[d]噻唑之合成Step 6: (S)-5-(5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(3-methyl-3-azabicyclo[3.1.1] Synthesis of hept-1-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.8g粗品。Prepared by General Procedure H, Step 4. Yield: 0.8 g crude.

LCMS(ESI)：[M]+ m/z：計算值339.2；實測值340.2；Rt=0.768min。LCMS (ESI): [M] + m/z: calculated 339.2; found 340.2; Rt=0.768 min.

步驟7：2-(3-甲基-3-氮雜雙環[3.1.1]庚-1-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 7: 2-(3-Methyl-3-azabicyclo[3.1.1]heptan-1-yl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo Synthesis of [d]thiazole

藉由一般程序方案H步驟5製備。產率：0.65g(78.34%)。Prepared by General Procedure H, Step 5. Yield: 0.65 g (78.34%).

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(3-甲基-3-氮雜雙環[3.1.1]庚-1-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1212)之合Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(3-methyl-3-nitrogen) Combination of heterobicyclo[3.1.1]hept-1-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1212) 成to make

藉由一般程序方案H步驟6B製備。產率：19.7mg(19.43%)。Prepared by General Procedure H, Step 6B. Yield: 19.7 mg (19.43%).

HPLC條件： 管柱：SunFire C18 100*19mm，5微米；2-10min 40-50% MeOH+NH3 ，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-10 min 40-50% MeOH+ NH3 , flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.05-1.15(m,3H),1.29-1.41(m,1H),1.62-1.76(m,1H),1.82-1.93(m,1H),1.96-2.00(m,2H),2.04-2.23(m,1H),2.25-2.36(m,4H),2.38(s,3H),2.40-2.43(m,2H),2.75-2.78(m,0.3H),2.79(s,2H),3.02-3.12(m,2H),3.24-3.27(m,0.7H),3.47-4.05(m,1H),5.25-5.61(m,1H),5.61-5.74(m,2H),7.33-7.43(m,1H),7.42-7.54(m,1H),7.86-7.93(m,1H),7.97-8.11(m,2H),10.56(br s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.05(m,3H), 1.05-1.15(m,3H), 1.29-1.41(m,1H), 1.62-1.76(m,1H) ,1.82-1.93(m,1H),1.96-2.00(m,2H),2.04-2.23(m,1H),2.25-2.36(m,4H),2.38(s,3H),2.40-2.43(m, 2H), 2.75-2.78(m, 0.3H), 2.79(s, 2H), 3.02-3.12(m, 2H), 3.24-3.27(m, 0.7H), 3.47-4.05(m, 1H), 5.25- 5.61(m,1H),5.61-5.74(m,2H),7.33-7.43(m,1H),7.42-7.54(m,1H),7.86-7.93(m,1H),7.97-8.11(m,2H) ), 10.56(br s, 1H).

LCMS(ESI)：[M]+ m/z：計算值532.2；實測值533.2；Rt=0.990min。LCMS (ESI): [M] + m/z: calculated 532.2; found 533.2; Rt=0.990 min.

實例651. N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-((3aR,5r,6aS)-2-甲基八氫環戊[c]吡咯-5-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1338)之合成Example 651. N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-((3aR,5r,6aS)- Synthesis of 2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1338)

Figure 110128222-A0202-12-2157-683
Figure 110128222-A0202-12-2157-683

步驟1：(3aR,5s,6aS)-5-(5-溴苯并[d]噻唑-2-基)六氫環戊[c]吡咯-2(1H)-甲酸第三丁酯之合成Step 1: Synthesis of (3aR,5s,6aS)-5-(5-bromobenzo[d]thiazol-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester

將三苯基膦(6.17g，23.52mmol)一次性添加到(3aR,6aS )-2-第三丁氧基 羰基-3,3a,4,5,6,6a -六氫-1H -環戊[c ]吡咯-5-甲酸(2.50g，9.80mmol)、2-胺基-4- 溴苯硫酚(2g，9.80mmol)、四氯化碳(8.74g，56.84mmol)及TEA(4.96g，49.00mmol，6.83mL)之溶液中。由於放熱反應，所得反應混合物暫時升溫至大約50-60℃。此後，將其在20℃下攪拌18h。然後，在減壓下移除揮發物且將殘餘物用MTBE(100ml)研磨。過濾出所得淺色沉澱。在減壓下濃縮濾液且藉由梯度管柱層析(SiO2 ，己烷/MTBE)純化殘餘物，得到5-(5-溴-1,3-苯并噻唑-2-基)-3,3a,4,5,6,6a-六氫-1H -環戊[c ]吡咯-2-甲酸第三丁酯(1.55g，3.66mmol，37.36%產率)。Triphenylphosphine (6.17 g, 23.52 mmol) was added in one portion to ( 3aR,6aS )-2 -tert- butoxycarbonyl- 3,3a,4,5,6,6a -hexahydro- 1H -cyclopentane [ c ] Pyrrole-5-carboxylic acid (2.50 g, 9.80 mmol), 2-amino-4-bromothiophenol (2 g, 9.80 mmol), carbon tetrachloride (8.74 g, 56.84 mmol) and TEA (4.96 g) , 49.00 mmol, 6.83 mL) in solution. The resulting reaction mixture was briefly warmed to about 50-60°C due to the exothermic reaction. After this time, it was stirred at 20 °C for 18 h. Then, the volatiles were removed under reduced pressure and the residue was triturated with MTBE (100 ml). The resulting pale precipitate was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by gradient column chromatography ( SiO2 , hexane/MTBE) to give 5-(5-bromo-1,3-benzothiazol-2-yl)-3, 3a,4,5,6,6a-Hexahydro- 1H -cyclopenta[ c ]pyrrole-2-carboxylic acid tert-butyl ester (1.55 g, 3.66 mmol, 37.36% yield).

LCMS(ESI)：[M-t -Bu]+ m/z：計算值367.2；實測值368.2；Rt=1.737min。LCMS (ESI): [M- t -Bu] + m/z: calculated 367.2; found 368.2; Rt=1.737 min.

步驟2：5-溴-2-((3aR,5s,6aS)-八氫環戊[c]吡咯-5-基)苯并[d]噻唑之合成Step 2: Synthesis of 5-bromo-2-((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazole

將TFA(4.17g，36.61mmol，2.82mL)添加到5-(5-溴-1,3-苯并噻唑-2-基)-3,3a,4,5,6,6a-六氫-1H -環戊[c ]吡咯-2-甲酸第三丁酯(1.55g，3.66mmol)於DCM(7.18mL)中之溶液中。將所得混合物在20℃下攪拌5h。然後，將其在減壓下濃縮，留下5-溴-2-[(3aR,6aS )-1,2,3,3a,4,5,6,6a-八氫環戊[c ]吡咯-5-基]-1,3-苯并噻唑(1.2g，2.75mmol，75.13%產率，TFA)。TFA (4.17 g, 36.61 mmol, 2.82 mL) was added to 5-(5-bromo-1,3-benzothiazol-2-yl)-3,3a,4,5,6,6a-hexahydro- 1H - Cyclopenta[ c ]pyrrole-2-carboxylic acid tert-butyl ester (1.55 g, 3.66 mmol) in DCM (7.18 mL). The resulting mixture was stirred at 20 °C for 5 h. It was then concentrated under reduced pressure to leave 5-bromo-2-[( 3aR,6aS )-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[ c ]pyrrole- 5-yl]-1,3-benzothiazole (1.2 g, 2.75 mmol, 75.13% yield, TFA).

LCMS(ESI)：[M]+ m/z：計算值324.2；實測值325.2；Rt=0.999min。LCMS (ESI): [M] + m/z: calculated 324.2; found 325.2; Rt=0.999 min.

步驟3：5-溴-2-((3aR,5s,6aS)-2-甲基八氫環戊[c]吡咯-5-基)苯并[d]噻唑之合成Step 3: Synthesis of 5-bromo-2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazole

將用7-8% MeOH穩定之37重量%甲醛水溶液(222.93mg，7.42mmol，205.85μL)及乙酸鈉(609.07mg，7.42mmol，398.60μL)添加到5-溴-2-[(3aR,6aS )-1,2,3,3a,4,5,6,6a-八氫環戊[c ]吡咯-5-基]-1,3-苯并噻唑(1.2g，3.71mmol)於MeOH(19.40mL)中之溶液中。將所得混合物在20℃下攪拌1h，之後向其中添加氰基硼氫化鈉(466.58mg，7.42mmol)。此後，繼續攪拌16h。然後，在減壓下移除溶劑且將殘餘物分配於15%K2 CO4 水溶液(30ml)與DCM(50ml)之間。將有機層分離，經固體K2 CO3 乾燥且在減壓下濃縮，留下5-溴-2-[(3aR,6aS )-2-甲基-3,3a,4,5,6,6a-六氫-1H -環戊[c ]吡咯-5-基]-1,3-苯并噻唑(1.2g，3.56mmol， 95.84%產率)。37 wt% aqueous formaldehyde stabilized with 7-8% MeOH (222.93 mg, 7.42 mmol, 205.85 μL) and sodium acetate (609.07 mg, 7.42 mmol, 398.60 μL) were added to 5-bromo-2-[( 3aR,6aS )-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[ c ]pyrrol-5-yl]-1,3-benzothiazole (1.2 g, 3.71 mmol) in MeOH (19.40 mL) in the solution. The resulting mixture was stirred at 20 °C for 1 h, before adding sodium cyanoborohydride (466.58 mg, 7.42 mmol). Thereafter, stirring was continued for 16 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 15 % aqueous K2CO4 (30ml) and DCM (50ml). The organic layer was separated, dried over solid K2CO3 and concentrated under reduced pressure to leave 5 -bromo- 2 -[( 3aR,6aS )-2-methyl-3,3a,4,5,6,6a - Hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]-1,3-benzothiazole (1.2 g, 3.56 mmol, 95.84% yield).

LCMS(ESI)：[M]+ m/z：計算值337.2；實測值338.2；Rt=0.918min。LCMS (ESI): [M] + m/z: calculated 337.2; found 338.2; Rt=0.918 min.

步驟4：(2-((3aR,5s,6aS)-2-甲基八氫環戊[c]吡咯-5-基)苯并[d]噻唑-5-基)硼酸之合成Step 4: Synthesis of (2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazol-5-yl)boronic acid

藉由一般程序方案H步驟2製備。產率：0.5g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 0.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值302.2；實測值303.2；Rt=0.618min。LCMS (ESI): [M] + m/z: calculated 302.2; found 303.2; Rt=0.618 min.

步驟5：(S)-3-甲基-6-(2-((3aR,5s,6aS)-2-甲基八氫環戊[c]吡咯-5-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯(化合物1338)之合成Step 5: (S)-3-Methyl-6-(2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazole- Synthesis of 5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Compound 1338)

藉由一般程序方案H步驟3製備。產率：0.7g粗品。Prepared by General Procedure H, Step 3. Yield: 0.7 g crude.

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=1.152min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=1.152 min.

步驟6：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-((3aR,5s,6aS)-2-甲基八氫環戊[c]吡咯-5-基)苯并[d]噻唑之合成Step 6: 5-((S)-5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-((3aR,5s,6aS)-2-methyloctahydrocycle Synthesis of Penta[c]pyrrol-5-yl)benzo[d]thiazole

藉由一般程序方案H步驟4製備。產率：0.5g粗品。Prepared by General Procedure H, Step 4. Yield: 0.5 g crude.

LCMS(ESI)：[M]+ m/z：計算值353.2；實測值354.2；Rt=0.603min。LCMS (ESI): [M] + m/z: calculated 353.2; found 354.2; Rt=0.603 min.

步驟7：2-((3aR,5s,6aS)-2-甲基八氫環戊[c]吡咯-5-基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 7: 2-((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)-5-((2R,5S)-5-methylpiperidine-2- Synthesis of yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：0.3g粗品。Prepared by General Procedure H, Step 5. Yield: 0.3 g crude.

LCMS(ESI)：[M]+ m/z：計算值355.2；實測值356.2；Rt=0.710min。LCMS (ESI): [M] + m/z: calculated 355.2; found 356.2; Rt=0.710 min.

步驟8：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-((3aR,5r,6aS)-2-甲基八氫環戊[c]吡咯-5-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1338)之合成Step 8: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-((3aR,5r,6aS)- Synthesis of 2-methyloctahydrocyclopenta[c]pyrrol-5-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1338)

藉由一般程序方案H步驟6B製備。產率：7.4mg(2.61%)。Prepared by General Procedure H, Step 6B. Yield: 7.4 mg (2.61%).

HPLC條件： 管柱：SunFire C18 100*19mm，5微米；0-5min 50-100%水-MeCN+FA，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: SunFire C18 100*19mm, 5 microns; 0-5min 50-100% water-MeCN+FA, flow rate: 30ml/min; (loading pump 4ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.06-1.14(m,3H),1.27-1.40(m,1H),1.58-1.76(m,3H),1.79-2.05(m,3H),2.07-2.13(m,2H),2.19-2.23(m,3H),2.25-2.36(m,3H),2.38-2.43(m,3H),2.60-2.75(m,3H),2.76-2.89(m,1H),3.71-4.05(m,1H),5.25-5.71(m,3H),7.30-7.42(m,1H),7.42-7.55(m,1H),7.80-7.92(m,1H),7.97-8.08(m,2H),10.49-10.59(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.06-1.14(m,3H), 1.27-1.40(m,1H), 1.58-1.76(m,3H) ,1.79-2.05(m,3H),2.07-2.13(m,2H),2.19-2.23(m,3H),2.25-2.36(m,3H),2.38-2.43(m,3H),2.60-2.75( m,3H),2.76-2.89(m,1H),3.71-4.05(m,1H),5.25-5.71(m,3H),7.30-7.42(m,1H),7.42-7.55(m,1H), 7.80-7.92 (m, 1H), 7.97-8.08 (m, 2H), 10.49-10.59 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值546.2；實測值547.2；Rt=2.250min。LCMS (ESI): [M+1] + m/z: calculated 546.2; found 547.2; Rt=2.250 min.

實例652. 2-甲氧基-5-(2-((2R,5S)-5-甲基-2-(2-((S)-1-甲基哌啶-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1359)之合成Example 652. 2-Methoxy-5-(2-((2R,5S)-5-methyl-2-(2-((S)-1-methylpiperidin-3-yl)benzo[ d] Synthesis of thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 1359)

Figure 110128222-A0202-12-2160-684
Figure 110128222-A0202-12-2160-684

步驟1：5-溴-2-(1-甲基哌啶-3-基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(1-methylpiperidin-3-yl)benzo[d]thiazole

藉由一般程序方案H步驟1A製備。產率：4.3g(93.99%)。Prepared by General Procedure H, Step 1A. Yield: 4.3 g (93.99%).

LCMS(ESI)：[M]+ m/z：計算值311.2；實測值312.2；Rt=0.990min。LCMS (ESI): [M] + m/z: calculated 311.2; found 312.2; Rt=0.990 min.

步驟2：2-(1-甲基哌啶-3-基)-5-(4,4,5,5-四甲基1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(1-Methylpiperidin-3-yl)-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborol-2-yl ) Synthesis of Benzo[d]thiazole

藉由一般程序方案H步驟2製備。產率：4.9g粗品。Prepared by General Procedure Scheme H, Step 2. Yield: 4.9 g crude.

LCMS(ESI)：[M]+ m/z：計算值358.2；實測值359.2；Rt=0.965min。LCMS (ESI): [M] + m/z: calculated 358.2; found 359.2; Rt=0.965 min.

步驟3：(3S)-3-甲基-6-(2-(1-甲基哌啶-3-基)苯并[d]噻唑-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (3S)-3-Methyl-6-(2-(1-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1 Synthesis of (2H)-tert-butyl formate

藉由一般程序方案H步驟3製備。產率：5.8g粗品。Prepared by General Procedure H, Step 3. Yield: 5.8 g crude.

LCMS(ESI)：[M]+ m/z：計算值427.2；實測值428.2；Rt=1.150min。LCMS (ESI): [M] + m/z: calculated 427.2; found 428.2; Rt=1.150 min.

步驟4：5-((S)-5-甲基-3,4,5,6-四氫吡啶-2-基)-2-(1-甲基哌啶-3-基)苯并[d]噻唑之合成Step 4: 5-((S)-5-Methyl-3,4,5,6-tetrahydropyridin-2-yl)-2-(1-methylpiperidin-3-yl)benzo[d ]Synthesis of thiazole

藉由一般程序方案H步驟4製備。產率：3g粗品。Prepared by General Procedure H, Step 4. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值327.2；實測值328.2；Rt=0.656min。LCMS (ESI): [M] + m/z: calculated 327.2; found 328.2; Rt=0.656 min.

步驟5：5-((2R,5S)-5-甲基哌啶-2-基)-2-(1-甲基哌啶-3-基)苯并[d]噻唑之合成Step 5: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-(1-methylpiperidin-3-yl)benzo[d]thiazole

藉由一般程序方案H步驟5製備。產率：1.8g(59.63%)。Prepared by General Procedure H, Step 5. Yield: 1.8 g (59.63%).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.491min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.491 min.

步驟6：(2R,5S)-5-甲基-2-(2-(1-甲基哌啶-3-基)苯并[d]噻唑-5-基)哌啶-1-甲酸第三丁酯之合成Step 6: (2R,5S)-5-Methyl-2-(2-(1-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidine-1-carboxylic acid 3rd Synthesis of Butyl Ester

向2-(1-甲基-3-哌啶基)-5-[(2R,5S )-5-甲基-2-哌啶基]-1,3-苯并噻唑(1.5g，4.55mmol)於THF(4mL)中之溶液中添加二碳酸二-第三丁酯(993.53mg，4.55mmol，1.04mL)。將所得混合物在25℃下攪拌3h且藉由HPLC(裝置(流動相，管柱)：SYSTEM 55-95% 0-5min H2 O/MeCN/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeCN)，目標質量429，管柱：XBridge BEH C18 5um 130A)純化，以獲得(2R,5S )-5-甲基-2-[2-(1-甲基-3-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(0.99g，2.30mmol，50.62%產率)。To 2-(1-methyl-3-piperidinyl)-5-[( 2R,5S )-5-methyl-2-piperidinyl]-1,3-benzothiazole (1.5 g, 4.55 mmol ) in THF (4 mL) was added di-tert-butyl dicarbonate (993.53 mg, 4.55 mmol, 1.04 mL). The resulting mixture was stirred at 25°C for 3 h and was purified by HPLC (apparatus (mobile phase, column): SYSTEM 55-95% 0-5 min H2O /MeCN/0.1% NH4OH , flow rate: 30 ml/min (loading Pump 4ml/min MeCN), target mass 429, column: XBridge BEH C18 5um 130A) purification to obtain ( 2R,5S )-5-methyl-2-[2-(1-methyl-3-piperidine) (0.99 g, 2.30 mmol, 50.62% yield).

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=3.390min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=3.390 min.

步驟7：掌性分離Step 7: Palm Separation

對外消旋(2R,5S )-5-甲基-2-[2-(1-甲基-3-哌啶基)-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(0.99g，2.30mmol)進行掌性分離(管柱：Chiralpak AD-H-III(250*20mm，5mkm)，己烷-IPA-MeOH，80-10-10，12ml/min)，以獲得(2R,5S )-5-甲基-2-[2-[(3S )-1-甲基-3-哌啶基]-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(384mg，893.82μmol，77.58%產率)。Racemic ( 2R,5S )-5-methyl-2-[2-(1-methyl-3-piperidinyl)-1,3-benzothiazol-5-yl]piperidine-1-carboxylic acid Chiral separation of tert-butyl ester (0.99g, 2.30mmol) (column: Chiralpak AD-H-III (250*20mm, 5mkm), Hexane-IPA-MeOH, 80-10-10, 12ml/min) , to obtain ( 2R,5S )-5-methyl-2-[2-[( 3S )-1-methyl-3-piperidinyl]-1,3-benzothiazol-5-yl]piperidine - tert-butyl 1-carboxylate (384 mg, 893.82 μmol, 77.58% yield).

此異構物於分析條件下(管柱：AD-H，以己烷-IPA-MeOH，80-10-10,0.8ml/min為流動相)之保留時間為11.83min。The retention time of this isomer under analytical conditions (column: AD-H, hexane-IPA-MeOH, 80-10-10, 0.8 ml/min as mobile phase) was 11.83 min.

LCMS(ESI)：[M]+ m/z：計算值429.2；實測值430.2；Rt=1.099min。LCMS (ESI): [M] + m/z: calculated 429.2; found 430.2; Rt=1.099 min.

步驟8：5-((2R,5S)-5-甲基哌啶-2-基)-2-((S)-1-甲基哌啶-3-基)苯并[d]噻唑之合成Step 8: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-((S)-1-methylpiperidin-3-yl)benzo[d]thiazole

將(2R,5S )-5-甲基-2-[2-[(3S )-1-甲基-3-哌啶基]-1,3-苯并噻唑-5-基]哌啶-1-甲酸第三丁酯(384mg，893.82μmol)於MeOH(4mL)及於二噁烷中之4.0M氯化氫溶液(325.89mg，8.94mmol，407.37μL)中之溶液在25℃下攪拌3h。蒸發溶劑，以得到5-[(2R,5S )-5-甲基-2-哌啶基]-2-[(3S )-1-甲基-3-哌啶基]-1,3-苯并噻唑(392mg，893.17μmol，99.93%產率，3HCl)。(2R, 5S )-5-methyl-2-[2-[( 3S )-1-methyl-3-piperidinyl]-1,3-benzothiazol-5-yl]piperidin-1 - A solution of tert-butyl formate (384 mg, 893.82 μmol) in MeOH (4 mL) and a 4.0 M solution of hydrogen chloride in dioxane (325.89 mg, 8.94 mmol, 407.37 μL) was stirred at 25° C. for 3 h. The solvent was evaporated to give 5-[( 2R,5S )-5-methyl-2-piperidinyl]-2-[( 3S )-1-methyl-3-piperidinyl]-1,3-benzene Thiazole (392 mg, 893.17 μmol, 99.93% yield, 3HCl).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=0.729min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=0.729 min.

步驟9：2-甲氧基-5-(2-((2R,5S)-5-甲基-2-(2-((S)-1-甲基哌啶-3-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1359)之合成Step 9: 2-Methoxy-5-(2-((2R,5S)-5-methyl-2-(2-((S)-1-methylpiperidin-3-yl)benzo[ d] Synthesis of thiazol-5-yl)piperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 1359)

藉由一般程序方案H步驟6A製備。產率：77mg(62.62%)。Prepared by General Procedure H, Step 6A. Yield: 77 mg (62.62%).

HPLC條件： 管柱：XBridge C18 100*20mm，5微米；0-1-6min 40-40-90%水-MeOH+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: XBridge C18 100*20mm, 5 microns; 0-1-6min 40-40-90% water-MeOH+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeOH) .

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.04(m,3H),1.36(m,1H),1.59(m,2H),1.71(m,2H),1.88(m,1H),2.06(m,3H),2.21(s,3H),2.29(m,2H),2.63(m,2H),2.93(m,2H),3.79(m,4H),5.49(d,1H),7.38(dd,1H),7.72(m,2H),7.88(m,1H),8.05(dd,1H),8.55(m,2H),11.04(s,1H) 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.04(m, 3H), 1.36(m, 1H), 1.59(m, 2H), 1.71(m, 2H), 1.88(m, 1H), 2.06(m, 3H), 2.21(s, 3H), 2.29(m, 2H), 2.63(m, 2H), 2.93(m, 2H), 3.79(m, 4H), 5.49(d, 1H), 7.38 (dd,1H),7.72(m,2H),7.88(m,1H),8.05(dd,1H),8.55(m,2H),11.04(s,1H)

LCMS(ESI)：[M]+ m/z：計算值550.2；實測值551.2；Rt=2.550min。LCMS (ESI): [M] + m/z: calculated 550.2; found 551.2; Rt=2.550 min.

方案I-式9化合物之合成Scheme I - Synthesis of Compounds of Formula 9

式9化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 9 are compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as described herein.

一般程序9General Procedure 9

Figure 110128222-A0202-12-2163-685
Figure 110128222-A0202-12-2163-685

步驟1：9-A之合成Step 1: Synthesis of 9-A

8-H 描述於方案H中。 8-H is described in Scheme H.

將8-H(1當量)及TEA(1.1當量)溶解於THF中且冷卻至0℃，隨後在Ar下逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(1.1當量)且將反應混合物在室溫下攪拌12h且在減壓下蒸發，以得到9-A，其不經進一步純化即用於下一步驟中。8-H (1 equiv) and TEA (1.1 equiv) were dissolved in THF and cooled to 0°C, followed by dropwise addition of 2-chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl under Ar ester (1.1 equiv) and the reaction mixture was stirred at room temperature for 12 h and evaporated under reduced pressure to give 9-A, which was used in the next step without further purification.

步驟2：9-B之合成Step 2: Synthesis of 9-B

在0℃下，向9-A(1當量)於THF(10mL)中之溶液鼓泡氨(1當量)達10min。然後將反應混合物在室溫下攪拌18h。過濾出反應混合物且將濾液在真空中蒸發，以得到9-B，其不經進一步純化即用於下一步驟中。Ammonia (1 equiv) was bubbled through a solution of 9-A (1 equiv) in THF (10 mL) at 0°C for 10 min. The reaction mixture was then stirred at room temperature for 18 h. The reaction mixture was filtered off and the filtrate was evaporated in vacuo to give 9-B which was used in the next step without further purification.

步驟3A：式9之合成Step 3A: Synthesis of Formula 9

在氬氣下，將9-B(1當量)、R3 Br(1.1當量)、Cu(1當量)、CuI(1當量)、K2 CO3 (2當量)及N,N -二甲基環己-1,2-二胺(1.5當量)混合於二噁烷中，然後在小瓶中在95℃下攪拌隔夜達24h。藉由HPLC純化殘餘物，以獲得純產物(式9)。Under argon, 9-B (1 equiv), R3Br (1.1 equiv), Cu (1 equiv), CuI ( 1 equiv), K2CO3 ( 2 equiv) and N,N -dimethyl Cyclohexyl-1,2-diamine (1.5 equiv) was mixed in dioxane, then stirred in a vial at 95°C overnight for 24h. The residue was purified by HPLC to obtain pure product (Formula 9).

實例653. N-(6-胺基-5-(氧呾-3-基)吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1334)之合成Example 653. N-(6-Amino-5-(oxon-3-yl)pyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1- Synthesis of methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1334)

Figure 110128222-A0202-12-2163-686
Figure 110128222-A0202-12-2163-686

藉由一般程序方案9步驟3A製備。產率：67.6mg(30.46%)。Prepared by General Scheme 9, Step 3A. Yield: 67.6 mg (30.46%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-6min 15-35%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-6 min 15-35% water-MeCN + 0.1% NH4OH ; (loading pump 4 ml/min MeCN).

外消旋化合物1334：Racemic Compound 1334:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03-1.05(d,3H),1.32-1.40(m,1H),1.70-1.90(m,4H),2.01-2.07(m,4H),2.18(s,3H),2.29-2.31(m,1H),2.82-3.07(m,3H),3.51-4.24(m,4H),4.47-4.54(m,2H),4.88-4.95(m,2H),5.31-5.70(m,3H),7.34-7.42(m,1H),7.68-7.90(m,2H),8.03-8.14(m,2H),10.61-10.67(d,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03-1.05(d,3H), 1.32-1.40(m,1H), 1.70-1.90(m,4H), 2.01-2.07(m,4H) ,2.18(s,3H),2.29-2.31(m,1H),2.82-3.07(m,3H),3.51-4.24(m,4H),4.47-4.54(m,2H),4.88-4.95(m, 2H), 5.31-5.70(m, 3H), 7.34-7.42(m, 1H), 7.68-7.90(m, 2H), 8.03-8.14(m, 2H), 10.61-10.67(d, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=1.834min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=1.834 min.

藉由掌性HPLC(管柱：Chiralpak AS-H(250 x 20mm，5mkm)；流動相：己烷-IPA-MeOH，60-20-20；流速：13mL/min)純化N -[6-胺基-5-(氧呾-3-基)-3-吡啶基]-2-[(2R,5S )-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺，以獲得N -[6-胺基-5-(氧呾-3-基)-3-吡啶基]-2-[(2R,5S )-5-甲基-2-[2-(1-甲基-4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(52mg，94.77μmol，22.33%產率)(RT=11.43min)。 N- [6-amine was purified by chiral HPLC (column: Chiralpak AS-H (250 x 20 mm, 5 mkm); mobile phase: hexane-IPA-MeOH, 60-20-20; flow rate: 13 mL/min) base-5-(oxo-3-yl)-3-pyridyl]-2-[( 2R,5S )-5-methyl-2-[2-(1-methyl-4-piperidinyl) -1,3-Benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide to give N- [6-amino-5-(oxygen-3-yl) -3-Pyridinyl]-2-[( 2R,5S )-5-methyl-2-[2-(1-methyl-4-piperidinyl)-1,3-benzothiazol-5-yl ]-1-Piperidinyl]-2-oxoacetamide (52 mg, 94.77 μmol, 22.33% yield) (RT=11.43 min).

化合物1334於分析條件下(管柱：AS-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)10.48min。Compound 1334 was subjected to analytical conditions (column: AS-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) for 10.48 min.

化合物1334：Compound 1334:

保留時間：10.48minRetention time: 10.48min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.04(m,3H),1.34-1.39(m,1H),1.70(m,1H),1.79-1.86(m,3H),2.03-2.07(m,4H),2.18(s,3H),2.29-2.37(m,1H),2.60(m,1H),2.82-2.84(m,2H),3.05(m,1H),3.51-3.53(m,1H),4.04-4.23(m,2H),4.48-4.54(m,2H),4.88-4.93(m,2H),5.31-5.70(m,3H),7.34-7.42(m,1H),7.68-7.76(d,1H),7.87-7.90(d,1H),8.03-8.07(m,1H),8.14(s,1H),10.60-10.67 (m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.02-1.04 (m, 3H), 1.34-1.39 (m, 1H), 1.70 (m, 1H), 1.79-1.86 (m, 3H), 2.03 -2.07(m, 4H), 2.18(s, 3H), 2.29-2.37(m, 1H), 2.60(m, 1H), 2.82-2.84(m, 2H), 3.05(m, 1H), 3.51-3.53 (m,1H),4.04-4.23(m,2H),4.48-4.54(m,2H),4.88-4.93(m,2H),5.31-5.70(m,3H),7.34-7.42(m,1H) , 7.68-7.76(d, 1H), 7.87-7.90(d, 1H), 8.03-8.07(m, 1H), 8.14(s, 1H), 10.60-10.67 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=1.806min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=1.806 min.

實例654.N -(6-胺基-5-(氧呾-3-基)吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(2-(吡咯啶-1-基)乙基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1379)之合成Example 654. N- (6-amino-5-(oxo-3-yl)pyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(2- Synthesis of (pyrrolidin-1-yl)ethyl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1379)

Figure 110128222-A0202-12-2165-687
Figure 110128222-A0202-12-2165-687

藉由一般程序方案9步驟3A製備。產率：15.9mg(7.25%)。Prepared by General Scheme 9, Step 3A. Yield: 15.9 mg (7.25%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 10-10-65%水-MeCN+0.1% NH4 OH；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6 min 10-10-65% water-MeCN+0.1% NH4OH ; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94-1.14(m,3H),1.30-1.48(m,1H),1.66-1.69(m,3H),1.69-1.76(m,2H),1.83-1.95(m,1H),2.02-2.29(m,1H),2.29-2.37(m,1H),2.44-2.47(m,2H),2.53-2.58(m,2H),2.77-2.82(m,0.3H),2.83-2.88(m,2H),3.21-3.26(m,2H),3.26-3.28(m,0.7H),3.41-4.07(m,1H),4.13-4.29(m,1H),4.43-4.59(m,2H),4.87-4.99(m,2H),5.25-5.61(m,1H),5.61-5.75(m,2H),7.30-7.45(m,1H),7.65-7.80(m,1H),7.82-7.93(m,1H),7.99-8.06(m,1H),8.06-8.19(m,1H),10.54-10.77(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.94-1.14(m,3H), 1.30-1.48(m,1H), 1.66-1.69(m,3H), 1.69-1.76(m,2H) ,1.83-1.95(m,1H),2.02-2.29(m,1H),2.29-2.37(m,1H),2.44-2.47(m,2H),2.53-2.58(m,2H),2.77-2.82( m,0.3H),2.83-2.88(m,2H),3.21-3.26(m,2H),3.26-3.28(m,0.7H),3.41-4.07(m,1H),4.13-4.29(m,1H ), 4.43-4.59(m, 2H), 4.87-4.99(m, 2H), 5.25-5.61(m, 1H), 5.61-5.75(m, 2H), 7.30-7.45(m, 1H), 7.65-7.80 (m, 1H), 7.82-7.93 (m, 1H), 7.99-8.06 (m, 1H), 8.06-8.19 (m, 1H), 10.54-10.77 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值548.2；實測值549.2；Rt=2.110min。LCMS (ESI): [M] + m/z: calculated 548.2; found 549.2; Rt=2.110 min.

實例655.N -(6-胺基-5-甲氧基吡啶-3-基)-2-((2R,5S )-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d ]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1203)之合成Example 655. N- (6-amino-5-methoxypyridin-3-yl)-2-(( 2R,5S )-5-methyl-2-(2-(1-methylpiperidine- Synthesis of 4-yl)benzo[ d ]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1203)

Figure 110128222-A0202-12-2166-688
Figure 110128222-A0202-12-2166-688

藉由一般程序方案9步驟3A製備。產率：55mg(42.15%)。Prepared by General Scheme 9, Step 3A. Yield: 55 mg (42.15%).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.01-1.06(m,3H),1.31-1.42(m,1H),1.65-1.74(m,1H),1.78-1.93(m,3H),1.99-2.11(m,5H),2.18(s,3H),2.24-2.36(m,1H),2.83(d,2H),3.00-3.28(m,2H),3.49-4.06(m,4H),5.27-5.72(m,3H),7.28-7.44(m,2H),7.72-7.83(m,1H),7.85-7.92(m,1H),8.02-8.08(m,1H),10.48-10.70(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.01-1.06(m,3H), 1.31-1.42(m,1H), 1.65-1.74(m,1H), 1.78-1.93(m,3H) ,1.99-2.11(m,5H),2.18(s,3H),2.24-2.36(m,1H),2.83(d,2H),3.00-3.28(m,2H),3.49-4.06(m,4H) ,5.27-5.72(m,3H),7.28-7.44(m,2H),7.72-7.83(m,1H),7.85-7.92(m,1H),8.02-8.08(m,1H),10.48-10.70( m, 1H).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=2.451min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=2.451 min.

在掌性HPLC上使用以下條件純化初始批次：The initial batch was purified on chiral HPLC using the following conditions:

管柱：Chiralpak IC-III(250*20mm，5mkm)；流動相：MeOH-IPA 50-50流速：11mL/min，RT=45.776min。Column: Chiralpak IC-III (250*20mm, 5mkm); Mobile phase: MeOH-IPA 50-50 Flow rate: 11 mL/min, RT=45.776min.

化合物1203：Compound 1203:

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.02-1.05(m,3H),1.32-1.40(m,2H),1.69-1.88(m,4H),2.01-2.07(m,4H),2.18(s,3H),2.29-2.37(m,1H),2.82-2.84(m,2H),3.03-3.07(m,1H),3.49-4.05(m,5H),5.30-5.70(m,3H),7.31-7.42(m,2H),7.74-7.91(m,2H),8.04-8.07(m,1H),10.59-10.56(d,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.02-1.05(m,3H), 1.32-1.40(m,2H), 1.69-1.88(m,4H), 2.01-2.07(m,4H) ,2.18(s,3H),2.29-2.37(m,1H),2.82-2.84(m,2H),3.03-3.07(m,1H),3.49-4.05(m,5H),5.30-5.70(m, 3H), 7.31-7.42 (m, 2H), 7.74-7.91 (m, 2H), 8.04-8.07 (m, 1H), 10.59-10.56 (d, 1H).

LCMS(ESI)：[M]+ m/z：計算值522.2；實測值523.2；Rt=1.852min。LCMS (ESI): [M] + m/z: calculated 522.2; found 523.2; Rt=1.852 min.

方案J-式10化合物之合成Scheme J - Synthesis of Compounds of Formula 10

式10化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 10 are compounds of formula ( I ) wherein R1, R2, R3 , R4, R6, R7 and R8 are as described herein.

一般程序10General Procedure 10

Figure 110128222-A0202-12-2167-689
Figure 110128222-A0202-12-2167-689

步驟1A：10-C之合成Step 1A: Synthesis of 10-C

將磷酸(4當量)及五氧化二磷(4當量)混合在一起。將反應懸浮液在室溫下攪拌10min，然後在Ar下添加10a-A(1當量)，隨後添加10a-B(1.2當量)。將溶液在110℃下攪拌18h，然後將其用水研磨，鹼化(NaOH，10%水溶液)至pH=10，用DCM萃取兩次，乾燥且在真空中蒸發，以得到10-C。Phosphoric acid (4 equiv) and phosphorus pentoxide (4 equiv) were mixed together. The reaction suspension was stirred at room temperature for 10 min, then 10a-A (1 equiv) was added under Ar followed by 10a-B (1.2 equiv). The solution was stirred at 110 °C for 18 h, then it was triturated with water, basified (NaOH, 10% aq) to pH=10, extracted twice with DCM, dried and evaporated in vacuo to give 10-C.

步驟1B：10-C之合成Step 1B: Synthesis of 10-C

向10b-A(1當量)於DMSO中之經攪拌之溶液中添加4.1b-B(1當量)。將所得混合物在100℃下攪拌14h。將反應混合物倒入到冷水中且用MTBE萃取兩次。將經合併之有機層用水及鹽水洗滌，經Na2 SO4 乾燥。在真空中蒸發MTBE，以得到10-C。To a stirred solution of 10b-A (1 equiv) in DMSO was added 4.1bB (1 equiv). The resulting mixture was stirred at 100 °C for 14 h. The reaction mixture was poured into cold water and extracted twice with MTBE. The combined organic layers were washed with water and brine, dried over Na2SO4 . MTBE was evaporated in vacuo to give 10-C.

步驟1C：10-C之合成Step 1C: Synthesis of 10-C

向10c-A(1當量)於1,2-二氯乙烷中之經攪拌之溶液中添加10c-B(2當量)且使其在25℃下攪拌2h，添加(三乙醯氧基)硼氫化鈉(2當量)。將反應混合物在25℃下攪拌16h。完成之後，將反應混合物蒸發，用水萃取且藉由K2 CO3 中和 至pH=10。將水相用CHCl3 萃取兩次。將經合併之有機相經Na2 SO4 乾燥且在減壓下蒸發，以得到10-C。(將TEA(1.5當量/各酸當量，若使用胺鹽)添加到相應胺之溶液中)To a stirred solution of 10c-A (1 equiv) in 1,2-dichloroethane was added 10c-B (2 equiv) and allowed to stir at 25°C for 2 h, (triacetoxy) was added Sodium borohydride (2 equiv.). The reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was evaporated, extracted with water and neutralized to pH = 10 by K2CO3. The aqueous phase was extracted twice with CHCl3 . The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give 10-C. (TEA (1.5 equiv/equivalent of each acid, if amine salt is used) is added to the solution of the corresponding amine)

步驟2：10-D之合成Step 2: Synthesis of 10-D

將10-C(1當量)、B2 Pin2 (1.1當量)及KOAc(2當量)混合於二噁烷中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)C12 *DCM(0.05當量)。將反應混合物在氬氣、90℃下攪拌14h，然後冷卻且過濾。將濾餅用二噁烷洗滌兩次。蒸發溶劑，以得到10-D。10-C (1 equiv), B2Pin2 (1.1 equiv) and KOAc ( 2 equiv) were mixed in dioxane. The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf) C12 *DCM (0.05 equiv) was added under argon. The reaction mixture was stirred under argon at 90 °C for 14 h, then cooled and filtered. The filter cake was washed twice with dioxane. The solvent was evaporated to give 10-D.

步驟3：10-F之合成Step 3: Synthesis of 10-F

將10-D(1當量)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(1.2當量)、碳酸鈉(3當量)一起混合於二噁烷-水混合物(3：1)中。將所得混合物抽真空，然後用氬氣回填。將此操作重複兩次，然後添加Pd(dppf)Cl2 *DCM(819.86mg，1.00mmol)且將反應混合物在氬氣、90℃下攪拌隔夜，然後冷卻，且在真空中濃縮。將殘餘物用MTBE稀釋且攪拌0.5h。在大部分殘餘物已溶解之後，添加無水硫酸鈉，且過濾所得混合物。將濾餅另外用MTBE(5*50ml)洗滌且丟棄。將濾液在真空中濃縮，以得到10-F。10-D (1 equiv), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (1.2 equiv) , sodium carbonate (3 equiv) were mixed together in a dioxane-water mixture (3:1). The resulting mixture was evacuated and backfilled with argon. This was repeated twice, then Pd(dppf)Cl2*DCM ( 819.86 mg, 1.00 mmol) was added and the reaction mixture was stirred under argon at 90°C overnight, then cooled and concentrated in vacuo. The residue was diluted with MTBE and stirred for 0.5 h. After most of the residue had dissolved, anhydrous sodium sulfate was added, and the resulting mixture was filtered. The filter cake was additionally washed with MTBE (5*50ml) and discarded. The filtrate was concentrated in vacuo to give 10-F.

步驟4：10-G之合成Step 4: Synthesis of 10-G

將10-F(1當量)於TFA(15當量)中之溶液在室溫下攪拌1h，然後在真空中濃縮。將冷水添加到殘餘物中，且將所得混合物用DCM萃取兩次。丟棄DCM層，且將水層鹼化至pH 11。將所得混合物用DCM萃取兩次。將經合併之有機萃取物經硫酸鈉乾燥，且在真空中濃縮，以得到10-G。A solution of 10-F (1 equiv) in TFA (15 equiv) was stirred at room temperature for 1 h, then concentrated in vacuo. Cold water was added to the residue, and the resulting mixture was extracted twice with DCM. The DCM layer was discarded, and the aqueous layer was basified to pH 11. The resulting mixture was extracted twice with DCM. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 10-G.

步驟5：10-H之合成Step 5: Synthesis of 10-H

將10-G(1當量)溶解於MeOH中且將所得溶液在冰浴中冷卻至0℃。將硼氫化鈉(2當量)分批添加到先前溶液中。在添加完成之後，使反應混合物升溫至室溫 且攪拌隔夜。將水添加到反應混合物且將所得混合物在真空中濃縮。將殘餘物用水稀釋且將所得混合物用DCM萃取兩次，經Na2 SO4 乾燥，過濾且蒸發，以獲得10-H。10-G (1 equiv) was dissolved in MeOH and the resulting solution was cooled to 0 °C in an ice bath. Sodium borohydride (2 equiv) was added portionwise to the previous solution. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture and the resulting mixture was concentrated in vacuo. The residue was diluted with water and the resulting mixture was extracted twice with DCM, dried over Na2SO4 , filtered and evaporated to obtain 10-H.

步驟6A：式10之合成Step 6A: Synthesis of Formula 10

將10-H(1當量)、草醯胺酸(1當量)及TEA(2.5當量+1.0當量/各酸當量，若使用胺鹽)一起混合於DMF中。向其中添加HATU(1.5當量)且將所得混合物攪拌隔夜。將反應混合物在真空中濃縮且藉由HPLC純化殘餘物，以獲得式10。10-H (1 equiv), oxalic acid (1 equiv) and TEA (2.5 equiv + 1.0 equiv per acid equiv, if using amine salt) were mixed together in DMF. To this was added HATU (1.5 equiv) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to obtain formula 10.

步驟6B：式10之合成Step 6B: Synthesis of Formula 10

將DIPEA(2.5當量+1.0當量/各酸當量，若使用胺鹽)添加到相應胺或其鹽(10-H)(1當量)及草醯胺酸(1當量)於DMF中之溶液中。將所得混合物攪拌5min，隨後添加HATU(1.1當量)於DMF中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之濾液經歷HPLC(Waters SunFire C18 19*100 5mkm管柱且以H2 O-MeOH為流動相)，以得到純產物(式10)。DIPEA (2.5 equiv + 1.0 equiv per acid equiv, if an amine salt is used) was added to a solution of the corresponding amine or its salt (10-H) (1 equiv) and oxalic acid (1 equiv) in DMF. The resulting mixture was stirred for 5 min, then a solution of HATU (1.1 equiv) in DMF was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The filtrate obtained was subjected to HPLC (Waters SunFire C18 19*100 5mkm column with H2O -MeOH as mobile phase) to give pure product (Formula 10).

實例656. 外消旋-2-(2-甲氧基乙基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑Example 656. Racemic-2-(2-methoxyethyl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole 步驟1：5-溴-2-(2-甲氧基乙基)苯并[d]噻唑之合成Step 1: Synthesis of 5-bromo-2-(2-methoxyethyl)benzo[d]thiazole

Figure 110128222-A0202-12-2169-690
Figure 110128222-A0202-12-2169-690

將2-胺基-4-溴苯硫酚(5.5g，26.95mmol，170.94uL)、3-甲氧基丙腈(3.44g，40.42mmol，3.67mL)、乙酸銅(II)(489.49mg，2.69mmol)、TEA(2.73g，26.95mmol，3.76mL)溶解於EtOH(100mL)中。將混合物在70℃(油浴溫度)下攪拌13h。在反應完成(藉由LCMS監測)之後，將混合物冷卻至室溫且用Na2 CO3 水 溶液萃取，且將粗產物用EtOAc萃取。將有機萃取物在真空中濃縮，且藉由矽膠管柱層析使用己烷/EtOAc作為溶析液來純化所得殘餘物，以得到5-溴-2-(2-甲氧基乙基)-1,3-苯并噻唑(2.75g，10.10mmol，37.49%產率)。2-Amino-4-bromothiophenol (5.5 g, 26.95 mmol, 170.94 uL), 3-methoxypropionitrile (3.44 g, 40.42 mmol, 3.67 mL), copper(II) acetate (489.49 mg, 2.69 mmol), TEA (2.73 g, 26.95 mmol, 3.76 mL) were dissolved in EtOH (100 mL). The mixture was stirred at 70 °C (oil bath temperature) for 13 h. After completion of the reaction (monitored by LCMS ) , the mixture was cooled to room temperature and extracted with aqueous Na2CO3 , and the crude product was extracted with EtOAc. The organic extracts were concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using hexane/EtOAc as eluent to give 5-bromo-2-(2-methoxyethyl)- 1,3-benzothiazole (2.75 g, 10.10 mmol, 37.49% yield).

LCMS(ESI)：[M]+ m/z：計算值272.2；實測值273.2；Rt=1.369min。LCMS (ESI): [M] + m/z: calculated 272.2; found 273.2; Rt=1.369 min.

步驟2：2-(2-甲氧基乙基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑之合成Step 2: 2-(2-Methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene Synthesis of [d]thiazoles

Figure 110128222-A0202-12-2170-691
Figure 110128222-A0202-12-2170-691

藉由一般程序方案J步驟2製備。產率：3.2g粗品。Prepared by General Procedure J, Step 2. Yield: 3.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值319.2；實測值320.2；Rt=1.562min。LCMS (ESI): [M] + m/z: calculated 319.2; found 320.2; Rt=1.562 min.

步驟3：6-(2-(2-甲氧基乙基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: 6-(2-(2-Methoxyethyl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid 3rd Synthesis of Butyl Ester

Figure 110128222-A0202-12-2170-692
Figure 110128222-A0202-12-2170-692

藉由一般程序方案J步驟3製備。產率：3.2g粗品。Prepared by General Procedure J, Step 3. Yield: 3.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=1.577min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=1.577 min.

步驟4：2-(2-甲氧基乙基)-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑之合成Step 4: Synthesis of 2-(2-Methoxyethyl)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2171-693
Figure 110128222-A0202-12-2171-693

藉由一般程序方案J步驟4製備。產率：3.2g粗品。Prepared by General Procedure J, Step 4. Yield: 3.2 g crude.

LCMS(ESI)：[M]+ m/z：計算值288.2；實測值289.2；Rt=0.764min。LCMS (ESI): [M] + m/z: calculated 288.2; found 289.2; Rt=0.764 min.

步驟5：外消旋-2-(2-甲氧基乙基)-5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑之合成Step 5: Synthesis of racemic-2-(2-methoxyethyl)-5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole

Figure 110128222-A0202-12-2171-694
Figure 110128222-A0202-12-2171-694

藉由一般程序方案J步驟5製備。產率：3g粗品。Prepared by General Procedure J, Step 5. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值290.2；實測值291.2；Rt=0.877min。LCMS (ESI): [M] + m/z: calculated 290.2; found 291.2; Rt=0.877 min.

實例657. N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1279及鏡像異構化合物1279)之合成Example 657. N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazole-5 Synthesis of -yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1279 and Enantiomer 1279)

Figure 110128222-A0202-12-2171-695
Figure 110128222-A0202-12-2171-695

步驟1：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazole-5 Synthesis of -yl)-5-methylpiperidin-1-yl)-2-side oxyacetamide

藉由一般程序方案J步驟6A製備。產率：57mg(9.67%)。Prepared by General Scheme J, Step 6A. Yield: 57 mg (9.67%).

HPLC條件：管柱：YMC Triart C18 100*20mm，5微米；0-5min 30-55%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 30-55% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

LCMS(ESI)：[M]+ m/z：計算值480.2；實測值481.2；Rt=1.828min。LCMS (ESI): [M] + m/z: calculated 480.2; found 481.2; Rt=1.828 min.

步驟2：掌性分離(化合物1279及鏡像異構化合物1279)Step 2: Chiral separation (compound 1279 and enantiomer compound 1279)

對外消旋N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(57mg，118.60umol)進行掌性分離(管柱：Chiralpak IA-II(250*20，5mkm)，MeOH-IPA，50-50，10ml/min)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18.7mg，38.91umol，65.61%產率)(RT=33.47min)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(20mg，41.61umol，70.18%產率)(RT=57.96min)。Racemic N- (6-amino-5-methylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazole-5 -yl)-5-methylpiperidin-1-yl)-2-oxyacetamide (57mg, 118.60umol) for chiral separation (column: Chiralpak IA-II (250*20, 5mkm), MeOH-IPA, 50-50, 10 ml/min) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-[2-[2 -(Dimethylamino)ethyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (18.7 mg, 38.91 umol , 65.61% yield) (RT=33.47 min) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[2-[2-( Dimethylamino)ethyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (20 mg, 41.61 umol, 70.18% yield) (RT=57.96 min).

鏡像異構化合物1279於分析條件下(管柱：OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為15.71min且化合物1279之保留時間為37.52min。The retention time of enantiomer compound 1279 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 15.71 min and the retention time of compound 1279 is 37.52min.

鏡像異構化合物1279：Enantiomer 1279:

保留時間：15.71minRetention time: 15.71min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.04(m,3H),1.22-1.40(m,2H),1.66-1.90(m,3H),2.04-2.37(m,9H),2.68-2.78(m,2H),3.20-3.23(m,2H),3.47(d,1H),4.03(d,1H),5.27-5.69(m,3H),7.32-7.50(m,2H),7.84-8.04(m,3H),10.56(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.04(m,3H), 1.22-1.40(m,2H), 1.66-1.90(m,3H), 2.04-2.37(m,9H) ,2.68-2.78(m,2H),3.20-3.23(m,2H),3.47(d,1H),4.03(d,1H),5.27-5.69(m,3H),7.32-7.50(m,2H) , 7.84-8.04 (m, 3H), 10.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值480.2；實測值481.2；Rt=1.818min。LCMS (ESI): [M] + m/z: calculated 480.2; found 481.2; Rt=1.818 min.

化合物1279：Compound 1279:

保留時間：37.52minRetention time: 37.52min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02-1.04(m,3H),1.22-1.39(m,2H),1.66-1.71(m,2H),1.84-2.32(m,10H),2.69(m,1H),3.21(m,3H),3.47(d,1H),4.04(d,1H),5.27-5.69(m,3H),7.32-7.50(m,2H),7.84-8.04(m,3H),10.56(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02-1.04(m,3H), 1.22-1.39(m,2H), 1.66-1.71(m,2H), 1.84-2.32(m,10H) ,2.69(m,1H),3.21(m,3H),3.47(d,1H),4.04(d,1H),5.27-5.69(m,3H),7.32-7.50(m,2H),7.84-8.04 (m, 3H), 10.56 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值480.2；實測值481.2；Rt=1.818min。LCMS (ESI): [M] + m/z: calculated 480.2; found 481.2; Rt=1.818 min.

實例658. N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-(甲氧基甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1211及鏡像異構化合物1211)之合成Example 658. N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-(methoxymethyl)benzo[d]thiazol-5-yl)-5 Synthesis of -Methylpiperidin-1-yl)-2-oxoacetamide (Compound 1211 and Enantiomer Compound 1211)

Figure 110128222-A0202-12-2173-696
Figure 110128222-A0202-12-2173-696

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-(甲氧基甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-(methoxymethyl)benzo[d]thiazol-5-yl)-5 Synthesis of -methylpiperidin-1-yl)-2-oxyacetamide

藉由一般程序方案J步驟6B製備。產率：26.5mg(12.82%)。Prepared by General Scheme J, Step 6B. Yield: 26.5 mg (12.82%).

HPLC條件：管柱：SunFire C18 100*19mm，5微米；2-10min 0-100% MeCN+FA，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-10 min 0-100% MeCN+FA, flow rate: 30 ml/min; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.04(m,3H),1.33-1.40(m,2H),1.68-1.73(m,1H),1.86-1.92(m,2H),2.12(m,2H),2.18(s,3H),3.44(s,3H),4.01(m,1H),4.84(m,2H),5.26(m,1H),5.70(m,1H),7.38(d,1H),7.83(s,1H),7.89(m,1H),8.08(m,1H),8.30(s,1H),11.01(m,1H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 1.01-1.04 (m, 3H), 1.33-1.40 (m, 2H), 1.68-1.73 (m, 1H), 1.86-1.92 (m, 2H) ,2.12(m,2H),2.18(s,3H),3.44(s,3H),4.01(m,1H),4.84(m,2H),5.26(m,1H),5.70(m,1H), 7.38(d,1H), 7.83(s,1H), 7.89(m,1H), 8.08(m,1H), 8.30(s,1H), 11.01(m,1H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=2.765min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=2.765 min.

步驟7：掌性分離(化合物1211及鏡像異構化合物1211)Step 7: Chiral separation (compound 1211 and enantiomer compound 1211)

對外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-[2-(甲氧基甲基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(53mg，116.85umol)進行掌性分離(管柱：ChiraI ART(250*20mm，5mkm)；流動相：IPA-MeOH，50-50；流速：12ml/min)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-[2-(甲氧基甲基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(17.8mg，39.25umol，33.58%產率)(RT=13.11min)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[2-(甲氧基甲基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18mg，39.69umol，33.96%產率)(RT=17.54min)。Racemic N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-[2-(methoxymethyl)-1,3-benzo Thiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (53mg, 116.85umol) for chiral separation (column: ChiraI ART (250*20mm, 5mkm) ; mobile phase: IPA-MeOH, 50-50; flow rate: 12 ml/min) to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2 -[2-(Methoxymethyl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (17.8 mg, 39.25 umol, 33.58% yield) (RT=13.11 min) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[2-(methoxy ylmethyl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (18 mg, 39.69 umol, 33.96% yield) ( RT=17.54min).

鏡像異構化合物1211於分析條件下(管柱：IC，以IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為17.95min且化合物1211之保留時間為24.51min。The retention time of enantiomer compound 1211 under analytical conditions (column: IC, with IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 17.95 min and the retention time of compound 1211 was 24.51 min.

鏡像異構化合物1211：Enantiomer compound 1211:

保留時間：17.95minRetention time: 17.95min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.58-10.49(m,1H),8.13-8.07(m,1H),8.05-7.88(m,2H),7.51-7.36(m,2H),5.74-5.25(m,3H),4.85-4.81(m,2H),4.06-3.45(m,1H),3.44(s,3H),3.19-2.76(m,1H),2.35-2.27(m,1H),2.20-2.08(m,1H),2.05-1.96(m,3H),1.91-1.83(m,1H),1.73-1.66(m,1H),1.41-1.31(m,1H),1.04-1.01(m,3H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 10.58-10.49(m,1H), 8.13-8.07(m,1H), 8.05-7.88(m,2H), 7.51-7.36(m,2H) ,5.74-5.25(m,3H),4.85-4.81(m,2H),4.06-3.45(m,1H),3.44(s,3H),3.19-2.76(m,1H),2.35-2.27(m, 1H), 2.20-2.08(m, 1H), 2.05-1.96(m, 3H), 1.91-1.83(m, 1H), 1.73-1.66(m, 1H), 1.41-1.31(m, 1H), 1.04- 1.01 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=2.540min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=2.540 min.

化合物1211：Compound 1211:

保留時間：24.51minRetention time: 24.51min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.59-10.49(m,1H),8.13-7.88(m,3H),7.52-7.36(m,2H),5.73-5.26(m,3H),4.86-4.80(m,2H),4.06-3.46(m,1H),3.44(s,3H),3.25-2.75(m,1H),2.36-2.25(m,1H),2.24-2.07(m,1H),2.06-1.96(m,3H),1.93-1.82(m,1H),1.76-1.64(m,1H),1.41-1.30(m,1H),1.04-1.00(m,3H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 10.59-10.49(m,1H), 8.13-7.88(m,3H), 7.52-7.36(m,2H), 5.73-5.26(m,3H) ,4.86-4.80(m,2H),4.06-3.46(m,1H),3.44(s,3H),3.25-2.75(m,1H),2.36-2.25(m,1H),2.24-2.07(m, 1H), 2.06-1.96(m, 3H), 1.93-1.82(m, 1H), 1.76-1.64(m, 1H), 1.41-1.30(m, 1H), 1.04-1.00(m, 3H).

LCMS(ESI)：[M]+ m/z：計算值453.2；實測值454.2；Rt=2.549min。LCMS (ESI): [M] + m/z: calculated 453.2; found 454.2; Rt=2.549 min.

實例659. N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-((二甲胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1106、化合物1122及鏡像異構化合物1122)之合成Example 659. N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-((dimethylamino)methyl)benzo[d]thiazol-5-yl )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1106, Compound 1122 and Enantiomer Compound 1122) Synthesis

Figure 110128222-A0202-12-2175-697
Figure 110128222-A0202-12-2175-697

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-((二甲胺基)甲基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1106)之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(2-((dimethylamino)methyl)benzo[d]thiazol-5-yl )-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1106) Synthesis

藉由一般程序10步驟6A製備。產率：27mg(9.97%)。Prepared by General Procedure 10, Step 6A. Yield: 27 mg (9.97%).

HPLC條件：管柱：SunFire C18 100*19mm，5微米；2-8min 50-75%水-MeCN+NH3 ，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: SunFire C18 100*19 mm, 5 microns; 2-8 min 50-75% water-MeCN+ NH3 , flow rate: 30 ml/min; (loading pump 4 ml/min MeCN).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.71-0.78(m,2H),1.03(m,3H),1.32-1.39(m,1H),1.67-1.73(m,2H),1.85(m,1H),1.97(m,1H),2.08(m,2H),2.30(m,6H),2.78(m,1H),3.86(m,3H),5.62(m,2H),7.34-7.54(m,2H),7.85(s,1H),7.88-8.06(m,2H),10.51(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.71-0.78(m, 2H), 1.03(m, 3H), 1.32-1.39(m, 1H), 1.67-1.73(m, 2H), 1.85 (m,1H),1.97(m,1H),2.08(m,2H),2.30(m,6H),2.78(m,1H),3.86(m,3H),5.62(m,2H),7.34- 7.54 (m, 2H), 7.85 (s, 1H), 7.88-8.06 (m, 2H), 10.51 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值466.2；實測值467.2；Rt=2.007min。LCMS (ESI): [M] + m/z: calculated 466.2; found 467.2; Rt=2.007 min.

步驟7：掌性分離(化合物1122及鏡像異構化合物1122)Step 7: Chiral separation (compound 1122 and enantiomer compound 1122)

對外消旋N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-[2-[(二甲胺基)甲基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(60mg，128.59umol)進行掌性分離(管柱：Chiralpak AS-H(250*20mm，5mkm)；流動相：己烷-MeOH-IPA，60-20-20；流速：12ml/min)，以獲得N -(6-胺基-5-甲基-3-吡啶 基)-2-[(2S,5R )-2-[2-[(二甲胺基)甲基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18.9mg，40.51umol，31.50%產率)(RT=11.78min)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-[2-[(二甲胺基)甲基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(18.6mg，39.86umol，31.00%產率)(RT=18.73min)。Racemic N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-[2-[(dimethylamino)methyl]-1,3 - Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (60 mg, 128.59 umol) for chiral separation (column: Chiralpak AS-H (250 umol) *20mm, 5mkm); mobile phase: hexane-MeOH-IPA, 60-20-20; flow rate: 12ml/min) to obtain N- (6-amino-5-methyl-3-pyridyl)- 2-[( 2S,5R )-2-[2-[(dimethylamino)methyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]- 2-Oxyacetamide (18.9 mg, 40.51 umol, 31.50% yield) (RT=11.78 min) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-2-[2-[(dimethylamino)methyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxygen Ethylacetamide (18.6 mg, 39.86 umol, 31.00% yield) (RT=18.73 min).

鏡像異構化合物1122於分析條件下(管柱：AS-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為11.73min且化合物1122之保留時間為8.74min。The retention time of enantiomer compound 1122 under analytical conditions (column: AS-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 11.73 min and the retention time of compound 1122 is 8.74min.

鏡像異構化合物1122：Enantiomer compound 1122:

保留時間：11.73minRetention time: 11.73min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.57-10.49(m,1H),8.09-7.95(m,2H),7.91-7.83(m,1H),7.54-7.32(m,2H),5.74-5.25(m,3H),4.05-3.45(m,3H),3.25-2.75(m,1H),2.30(s,6H),2.29-2.05(m,2H),2.05-1.95(m,3H),1.93-1.82(m,1H),1.75-1.66(m,1H),1.41-1.29(m,1H),1.05-1.00(m,3H)。 1 H NMR (600MHz, DMSO- d 6 ) δ (ppm) 10.57-10.49 (m, 1H), 8.09-7.95 (m, 2H), 7.91-7.83 (m, 1H), 7.54-7.32 (m, 2H) ,5.74-5.25(m,3H),4.05-3.45(m,3H),3.25-2.75(m,1H),2.30(s,6H),2.29-2.05(m,2H),2.05-1.95(m, 3H), 1.93-1.82 (m, 1H), 1.75-1.66 (m, 1H), 1.41-1.29 (m, 1H), 1.05-1.00 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值466.2；實測值467.2；Rt=1.458min。LCMS (ESI): [M] + m/z: calculated 466.2; found 467.2; Rt=1.458 min.

化合物1122：Compound 1122:

保留時間：8.74minRetention time: 8.74min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.57-10.47(m,1H),8.08-7.94(m,2H),7.91-7.83(m,1H),7.52-7.32(m,2H),5.71-5.24(m,3H),4.05-3.44(m,3H),3.28-2.76(m,1H),2.30(s,6H),2.28-2.06(m,2H),2.04-1.96(m,3H),1.91-1.84(m,1H),1.76-1.67(m,1H),1.40-1.31(m,1H),1.04-1.01(m,3H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 10.57-10.47(m,1H), 8.08-7.94(m,2H), 7.91-7.83(m,1H), 7.52-7.32(m,2H) ,5.71-5.24(m,3H),4.05-3.44(m,3H),3.28-2.76(m,1H),2.30(s,6H),2.28-2.06(m,2H),2.04-1.96(m, 3H), 1.91-1.84 (m, 1H), 1.76-1.67 (m, 1H), 1.40-1.31 (m, 1H), 1.04-1.01 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值466.2；實測值467.2；Rt=1.460min。LCMS (ESI): [M] + m/z: calculated 466.2; found 467.2; Rt=1.460 min.

實例660.N -(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1196及化合物1133)之合成Example 660. N- (6-Amino-5-ethylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazole-5 Synthesis of -yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1196 and Compound 1133)

Figure 110128222-A0202-12-2177-698
Figure 110128222-A0202-12-2177-698

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazole-5 Synthesis of -yl)-5-methylpiperidin-1-yl)-2-side oxyacetamide

藉由一般程序方案J步驟6A製備。產率：264mg(48.35%)。Prepared by General Scheme J, Step 6A. Yield: 264 mg (48.35%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-1-5min 35-35-65%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-1-5min 35-35-65% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN) .

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=1.955min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=1.955 min.

步驟2：掌性分離(化合物1196及化合物1133)Step 2: Chiral separation (compound 1196 and compound 1133)

對外消旋N -(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(264mg，533.71umol)進行掌性分離(管柱：Chirapak IC-III(250*20mm，5mkm)，IPA-MeOH，50-50，10ml/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(60mg，121.30umol，45.45%產率)(RT=34.84min)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(53mg，107.15umol，40.15%產率)(RT=24.54min)。Racemic N- (6-amino-5-ethylpyridin-3-yl)-2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazole-5 -yl)-5-methylpiperidin-1-yl)-2-oxyacetamide (264mg, 533.71umol) for chiral separation (column: Chirapak IC-III (250*20mm, 5mkm), IPA-MeOH, 50-50, 10 ml/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-[2-[2 -(Dimethylamino)ethyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (60 mg, 121.30 umol, 45.45% yield) (RT=34.84 min) and N-(6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5R )-2-[2-[2-(di Methylamino)ethyl]-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (53 mg, 107.15 umol, 40.15% yield rate) (RT=24.54min).

化合物1196於分析條件下(管柱：IC，以IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為34.84min且化合物1133之保留時間為12.90min。The retention time of compound 1196 under analytical conditions (column: IC, with IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 34.84 min and the retention time of compound 1133 was 12.90 min.

化合物1196：Compound 1196:

保留時間：34.84minRetention time: 34.84min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.06-1.16(m,3H),1.31-1.41(m,1H),1.66-1.76(m,1H),1.82-1.92(m,1H),2.04-2.18(m,1H),2.23(s, 6H),2.26-2.32(m,1H),2.32-2.36(m,1H),2.40-2.43(m,1H),2.68-2.76(m,2H),2.76-3.27(m,3H),3.35-4.08(m,1H),5.26-5.61(m,1H),5.61-5.73(m,2H),7.30-7.42(m,1H),7.43-7.56(m,1H),7.81-7.91(m,1H),7.99-8.03(m,1H),8.03-8.09(m,1H),10.49-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.06-1.16(m,3H), 1.31-1.41(m,1H), 1.66-1.76(m,1H) ,1.82-1.92(m,1H),2.04-2.18(m,1H),2.23(s,6H),2.26-2.32(m,1H),2.32-2.36(m,1H),2.40-2.43(m, 1H), 2.68-2.76(m, 2H), 2.76-3.27(m, 3H), 3.35-4.08(m, 1H), 5.26-5.61(m, 1H), 5.61-5.73(m, 2H), 7.30- 7.42(m,1H),7.43-7.56(m,1H),7.81-7.91(m,1H),7.99-8.03(m,1H),8.03-8.09(m,1H),10.49-10.60(m,1H) ).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=1.745min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=1.745 min.

化合物1133：Compound 1133:

保留時間：12.90minRetention time: 12.90min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.06-1.16(m,3H),1.30-1.42(m,1H),1.63-1.77(m,1H),1.80-1.94(m,1H),2.03-2.18(m,1H),2.20(s,6H),2.27-2.33(m,1H),2.36-2.44(m,2H),2.65-2.72(m,2H),2.74-3.27(m,3H),3.36-4.11(m,1H),5.26-5.61(m,1H),5.61-5.75(m,2H),7.31-7.42(m,1H),7.42-7.54(m,1H),7.78-7.89(m,1H),7.98-8.03(m,1H),8.03-8.11(m,1H),10.51-10.66(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.06-1.16(m,3H), 1.30-1.42(m,1H), 1.63-1.77(m,1H) ,1.80-1.94(m,1H),2.03-2.18(m,1H),2.20(s,6H),2.27-2.33(m,1H),2.36-2.44(m,2H),2.65-2.72(m, 2H), 2.74-3.27(m, 3H), 3.36-4.11(m, 1H), 5.26-5.61(m, 1H), 5.61-5.75(m, 2H), 7.31-7.42(m, 1H), 7.42- 7.54(m,1H), 7.78-7.89(m,1H), 7.98-8.03(m,1H), 8.03-8.11(m,1H), 10.51-10.66(m,1H).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=1.730min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=1.730 min.

實例661.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(2-乙基苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1184)之合成Example 661. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(2-ethylbenzo[ d ]thiazol-5-yl)-5-methylpiperidine Synthesis of -1-yl)-2-oxoacetamide (Compound 1184)

Figure 110128222-A0202-12-2178-699
Figure 110128222-A0202-12-2178-699

藉由一般程序方案J步驟6B製備。產率：49mg(14.58%)。Prepared by General Scheme J, Step 6B. Yield: 49 mg (14.58%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-6min 40-65%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-6 min 40-65% water-MeCN+0.1% NH4OH , flow rate: 30 ml/min; (loading pump 4 ml/min MeOH).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.02(m,3H),1.36(m,4H),1.70(m,1H),1.87(m,1H),2.04(m,3H),2.25(m,2H),3.00(m,3H),3.85(m,1H),5.63(m,3H),7.40(m,2H),7.96(m,3H),10.54(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.02(m,3H), 1.36(m,4H), 1.70(m,1H), 1.87(m,1H), 2.04(m,3H), 2.25(m, 2H), 3.00(m, 3H), 3.85(m, 1H), 5.63(m, 3H), 7.40(m, 2H), 7.96(m, 3H), 10.54(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值437.2；實測值438.2；Rt=2.168min。LCMS (ESI): [M] + m/z: calculated 437.2; found 438.2; Rt=2.168 min.

實例662. 5-(2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1355、化合物1128及化合物1254)之合成Example 662. 5-(2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)- Synthesis of 2-oxyacetamido)nicotinamide (Compound 1355, Compound 1128 and Compound 1254)

Figure 110128222-A0202-12-2179-700
Figure 110128222-A0202-12-2179-700

步驟6：5-(2-(2-(2-(2-(二甲胺基)乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物1355)之合成Step 6: 5-(2-(2-(2-(2-(dimethylamino)ethyl)benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)- Synthesis of 2-oxyacetamido)nicotinamide (compound 1355)

藉由一般程序方案J步驟6A製備。產率：20mg(6.14%)。Prepared by General Scheme J, Step 6A. Yield: 20 mg (6.14%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-5min 15-40%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-5min 15-40% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

化合物1355：Compound 1355:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03-1.04(m,3H),1.33-1.40(m,2H),1.68-1.99(m,3H),2.08-2.30(m,6H),2.67-2.85(m,2H),3.19-3.23(m,2H),3.50-4.05(m,2H),5.30-5.70(m,2H),7.34-7.42(m,1H),7.53-7.59(m,1H),7.86-7.89(m,1H),8.00-8.16(m,2H),8.40-8.51(m,1H),8.69-8.90(m,2H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03-1.04(m,3H), 1.33-1.40(m,2H), 1.68-1.99(m,3H), 2.08-2.30(m,6H) ,2.67-2.85(m,2H),3.19-3.23(m,2H),3.50-4.05(m,2H),5.30-5.70(m,2H),7.34-7.42(m,1H),7.53-7.59( m, 1H), 7.86-7.89 (m, 1H), 8.00-8.16 (m, 2H), 8.40-8.51 (m, 1H), 8.69-8.90 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=1.914min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=1.914 min.

步驟7：掌性分離(化合物1128及化合物1254)Step 7: Chiral separation (compound 1128 and compound 1254)

對外消旋5-(2-(2-(2-(2-(二甲胺基)乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(235mg，475.12umol)進行掌性分離(管柱：Chiralcel OJ-H-II(250*20mm，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min)，以獲得5-[[2-[(2R,5S )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(90mg，181.96umol，76.60%產率)(RT=29.78min)及5-[[2-[(2S,5R )-2-[2-[2-(二甲胺基)乙基]-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(86mg，173.88umol，73.19%產率)(RT=14.44min)。Racemic 5-(2-(2-(2-(2-(dimethylamino)ethyl)benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)- Chiral separation (column: Chiralcel OJ-H-II (250*20mm, 5mkm), Hexane-IPA-MeOH, 50 -25-25, 12ml/min) to obtain 5-[[2-[( 2R,5S )-2-[2-[2-(dimethylamino)ethyl]-1,3-benzothiazole -5-yl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (90 mg, 181.96 umol, 76.60% yield) (RT =29.78min) and 5-[[2-[( 2S,5R )-2-[2-[2-(dimethylamino)ethyl]-1,3-benzothiazol-5-yl]-5 -Methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (86 mg, 173.88 umol, 73.19% yield) (RT=14.44 min).

化合物1128於分析條件下(管柱：OJ-H，己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為22.93min且化合物1254之保留時間為11.34min。The retention time of compound 1128 under analytical conditions (column: OJ-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 22.93 min and the retention time of compound 1254 was 11.34 min .

化合物1128：Compound 1128:

保留時間：22.93minRetention time: 22.93min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.05(m,3H),1.37(m,1H),1.72(m,1H),1.89(m,1H),2.08(m,1H),2.20(m,6H),2.31(m,1H),2.68(m,3H),3.22(m,2H),3.77(dd,1H),5.50(m,1H),7.38(dd,1H),7.58(m,1H),7.87(m,1H),8.03(m,1H),8.14(m,1H),8.47(m,1H),8.81(m,2H),11.08(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.05(m, 3H), 1.37(m, 1H), 1.72(m, 1H), 1.89(m, 1H), 2.08(m, 1H), 2.20(m,6H),2.31(m,1H),2.68(m,3H),3.22(m,2H),3.77(dd,1H),5.50(m,1H),7.38(dd,1H),7.58 (m, 1H), 7.87 (m, 1H), 8.03 (m, 1H), 8.14 (m, 1H), 8.47 (m, 1H), 8.81 (m, 2H), 11.08 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=2.340min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=2.340 min.

化合物1254Compound 1254

保留時間：11.34minRetention time: 11.34min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.05(m,3H),1.37(m,1H),1.72(m,1H),1.89(m,1H),2.09(m,1H),2.20(m,6H),2.31(m,1H),2.68(m,2H),3.21(m,3H),3.52(m,1H),5.30(s,1H),7.38(dd,1H),7.59(d,1H),7.87(m,1H),8.03(dd,1H),8.15(d,1H),8.49(m,1H),8.77(m,1H),8.89(m,1H),11.28(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.05(m, 3H), 1.37(m, 1H), 1.72(m, 1H), 1.89(m, 1H), 2.09(m, 1H), 2.20(m,6H),2.31(m,1H),2.68(m,2H),3.21(m,3H),3.52(m,1H),5.30(s,1H),7.38(dd,1H),7.59 (d,1H),7.87(m,1H),8.03(dd,1H),8.15(d,1H),8.49(m,1H),8.77(m,1H),8.89(m,1H),11.28( m, 1H).

LCMS(ESI)：[M]+ m/z：計算值494.2；實測值495.2；Rt=2.370min。LCMS (ESI): [M] + m/z: calculated 494.2; found 495.2; Rt=2.370 min.

實例663. N-(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-(2-甲氧基乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1375及化合物1386)之合成Example 663. N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-(2-(2-methoxyethyl)benzo[d]thiazol-5-yl) Synthesis of -5-methylpiperidin-1-yl)-2-oxoacetamide (Compound 1375 and Compound 1386)

Figure 110128222-A0202-12-2181-701
Figure 110128222-A0202-12-2181-701

步驟1：N-(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-(2-甲氧基乙基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethylpyridin-3-yl)-2-(2-(2-(2-methoxyethyl)benzo[d]thiazol-5-yl) Synthesis of -5-methylpiperidin-1-yl)-2-oxoacetamide

藉由一般程序方案J步驟6A製備。產率：207mg(62.41%)。Prepared by General Scheme J, Step 6A. Yield: 207 mg (62.41%).

HPLC條件： 管柱：XBridge C18 100*19mm，5微米；0-5min 5-55%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。 HPLC conditions: Column: XBridge C18 100*19 mm, 5 microns; 0-5 min 5-55% water-MeCN+0.1% NH4OH , flow rate: 30 ml/min; (loading pump 4 ml/min MeCN).

LCMS(ESI)：[M]+ m/z：計算值481.2；實測值482.2；Rt=2.923min。LCMS (ESI): [M] + m/z: calculated 481.2; found 482.2; Rt=2.923 min.

步驟2：掌性分離(化合物1375及化合物1386)Step 2: Chiral separation (compound 1375 and compound 1386)

對外消旋N -(6-胺基-5-乙基吡啶-3-基)-2-(2-(2-(2-甲氧基乙基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(170mg，352.98umol)進行掌性分離(管柱：ChiralART YMC(250*20mm，5mkm)，IPA-MeOH，50-50，10ml/min)，以獲得N -(6-胺基-5-乙基-3-吡啶基)-2-[(2S,5R )-2-[2-(2-甲氧基乙基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(53mg，110.05μmol，62.35%產率)(RT=14.57min)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S )-2-[2-(2-甲氧基乙基)-1,3-苯并噻唑-5-基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(55mg，114.20μmol，64.71%產率)(RT=18.81min)。化合物1375於分析條件下(管柱：IC，以IPA-MeOH，50-50，0.6ml/min為流動相)之保留時間為16.50min且化合物1386之保留時間為22.49min。Racemic N- (6-amino-5-ethylpyridin-3-yl)-2-(2-(2-(2-methoxyethyl)benzo[ d ]thiazol-5-yl) Chiral separation (column: ChiralART YMC (250*20mm, 5mkm), IPA-MeOH, 50 -50, 10ml/min) to obtain N- (6-amino-5-ethyl-3-pyridyl)-2-[( 2S,5R )-2-[2-(2-methoxyethyl) yl)-1,3-benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxyacetamide (53 mg, 110.05 μmol, 62.35% yield) (RT= 14.57min) and N-(6-amino-5-ethyl-3-pyridyl)-2-[( 2R,5S )-2-[2-(2-methoxyethyl)-1,3 - Benzothiazol-5-yl]-5-methyl-1-piperidinyl]-2-oxoacetamide (55 mg, 114.20 μmol, 64.71% yield) (RT=18.81 min). The retention time of compound 1375 under analytical conditions (column: IC, with IPA-MeOH, 50-50, 0.6 ml/min as mobile phase) was 16.50 min and the retention time of compound 1386 was 22.49 min.

化合物1375：Compound 1375:

保留時間：16.50minRetention time: 16.50min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.05-1.15(m,3H),1.30-1.42(m,1H),1.64-1.75(m,1H),1.81-1.95(m,1H),2.03-2.37(m,3H),2.39-2.42(m,1H),2.75-3.28(m,4H),3.31-3.35(m,2H),3.43-4.09(m,3H),5.25-5.75(m,3H),7.32-7.43(m,1H),7.43-7.53(m,1H),7.82-7.92(m,1H),7.97-8.09(m,2H),10.51-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.05-1.15(m,3H), 1.30-1.42(m,1H), 1.64-1.75(m,1H) ,1.81-1.95(m,1H),2.03-2.37(m,3H),2.39-2.42(m,1H),2.75-3.28(m,4H),3.31-3.35(m,2H),3.43-4.09( m,3H),5.25-5.75(m,3H),7.32-7.43(m,1H),7.43-7.53(m,1H),7.82-7.92(m,1H),7.97-8.09(m,2H), 10.51-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值481.2；實測值482.2；Rt=2.642min。LCMS (ESI): [M] + m/z: calculated 481.2; found 482.2; Rt=2.642 min.

化合物1386：Compound 1386:

保留時間：22.49minRetention time: 22.49min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01-1.06(m,3H),1.06-1.15(m,3H),1.30-1.39(m,1H),1.62-1.75(m,1H),1.81-1.92(m,1H),2.03-2.36(m,3H),2.39-2.43(m,1H),2.75-3.28(m,4H),3.31-3.34(m,2H),3.45-4.06(m,3H),5.24-5.72(m,3H),7.31-7.43(m,1H),7.43-7.54(m,1H),7.82-7.92(m,1H),7.98-8.08(m,2H),10.50-10.62(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01-1.06(m,3H), 1.06-1.15(m,3H), 1.30-1.39(m,1H), 1.62-1.75(m,1H) ,1.81-1.92(m,1H),2.03-2.36(m,3H),2.39-2.43(m,1H),2.75-3.28(m,4H),3.31-3.34(m,2H),3.45-4.06( m,3H),5.24-5.72(m,3H),7.31-7.43(m,1H),7.43-7.54(m,1H),7.82-7.92(m,1H),7.98-8.08(m,2H), 10.50-10.62 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值481.2；實測值482.2；Rt=2.658min。LCMS (ESI): [M] + m/z: calculated 481.2; found 482.2; Rt=2.658 min.

實例664. N-(6-胺基-5-(三氟甲基)吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物1117)之合成Example 664. N-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methyl) Synthesis of piperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (compound 1117)

Figure 110128222-A0202-12-2182-702
Figure 110128222-A0202-12-2182-702

藉由一般程序方案J步驟3A製備。產率：31mg(13.18%)。Prepared by General Scheme J, Step 3A. Yield: 31 mg (13.18%).

HPLC條件：管柱：XBridge C18 100*19mm，5微米；0-5min 25-45%水-MeCN+0.1% NH4 OH，流速：30ml/min；(裝載泵4ml/min MeCN)。HPLC conditions: Column: XBridge C18 100*19mm, 5 microns; 0-5min 25-45% water-MeCN+0.1% NH4OH , flow rate: 30ml/min; (loading pump 4ml/min MeCN).

化合物1117：Compound 1117:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.07(m,3H),1.28-1.41(m,1H),1.66-1.74(m,1H),1.76-1.91(m,3H),2.04-2.09(m,4H),2.10-2.24(m,4H),2.26-2.34(m,1H),2.83-2.87(m,2H),3.04-3.09(m,1H),3.26-3.31(m,1H),3.52-4.06(m,1H),5.29-5.75(m,1H),6.32-6.42(m,2H),7.32-7.42(m,1H),7.85-7.89(m,1H),7.98-8.12(m,2H),8.34-8.47(m,1H),10.81-10.96(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.97-1.07(m,3H), 1.28-1.41(m,1H), 1.66-1.74(m,1H), 1.76-1.91(m,3H) ,2.04-2.09(m,4H),2.10-2.24(m,4H),2.26-2.34(m,1H),2.83-2.87(m,2H),3.04-3.09(m,1H),3.26-3.31( m,1H),3.52-4.06(m,1H),5.29-5.75(m,1H),6.32-6.42(m,2H),7.32-7.42(m,1H),7.85-7.89(m,1H), 7.98-8.12 (m, 2H), 8.34-8.47 (m, 1H), 10.81-10.96 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值560.2；實測值561.2；Rt=2.547min。LCMS (ESI): [M] + m/z: calculated 560.2; found 561.2; Rt=2.547 min.

實例665.N -(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S )-2-(2-(2-(二甲胺基)丙-2-基)苯并[d ]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1237)之合成Example 665. N- (6-amino-5-ethylpyridin-3-yl)-2-(( 2R,5S )-2-(2-(2-(dimethylamino)propan-2-yl) ) Synthesis of benzo[ d ]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1237)

Figure 110128222-A0202-12-2183-703
Figure 110128222-A0202-12-2183-703

步驟1：2-(5-溴苯并[d]噻唑-2-基)-N,N-二甲基丙-2-胺之合成Step 1: Synthesis of 2-(5-Bromobenzo[d]thiazol-2-yl)-N,N-dimethylpropan-2-amine

藉由一般程序方案J步驟1B製備。產率：1.5g(20.46%)。Prepared by General Procedure J, Step IB. Yield: 1.5 g (20.46%).

LCMS(ESI)：[M]+ m/z：計算值299.2；實測值300.2；Rt=0.956min。LCMS (ESI): [M] + m/z: calculated 299.2; found 300.2; Rt=0.956 min.

步驟2：N,N-二甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 2: N,N-Dimethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo Synthesis of [d]thiazol-2-yl)propan-2-amine

藉由一般程序方案J步驟2製備。產率：1.74g粗品。Prepared by General Procedure J, Step 2. Yield: 1.74 g crude.

LCMS(ESI)：[M]+ m/z：計算值346.2；實測值347.2；Rt=0.945min。LCMS (ESI): [M] + m/z: calculated 346.2; found 347.2; Rt=0.945min.

步驟3：(S)-6-(2-(2-(二甲胺基)丙-2-基)苯并[d]噻唑-5-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 3: (S)-6-(2-(2-(Dimethylamino)prop-2-yl)benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydro Synthesis of tert-butyl pyridine-1(2H)-carboxylate

藉由一般程序方案J步驟3製備。產率：3g粗品。Prepared by General Procedure J, Step 3. Yield: 3 g crude.

LCMS(ESI)：[M]+ m/z：計算值415.2；實測值416.2；Rt=1.041min。LCMS (ESI): [M] + m/z: calculated 415.2; found 416.2; Rt=1.041 min.

步驟4：(S)-N,N-二甲基-2-(5-(5-甲基-3,4,5,6-四氫吡啶-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 4: (S)-N,N-Dimethyl-2-(5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole-2 Synthesis of -yl)propan-2-amine

藉由一般程序方案J步驟4製備。產率：0.44g粗品。Prepared by General Procedure J, Step 4. Yield: 0.44 g crude.

LCMS(ESI)：[M]+ m/z：計算值315.2；實測值316.2；Rt=0.524min。LCMS (ESI): [M] + m/z: calculated 315.2; found 316.2; Rt=0.524 min.

步驟5：N,N-二甲基-2-(5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑-2-基)丙-2-胺之合成Step 5: N,N-Dimethyl-2-(5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazol-2-yl)propan-2-amine synthesis

藉由一般程序方案J步驟5製備。產率：0.36g(81.30%)。Prepared by General Procedure J, Step 5. Yield: 0.36 g (81.30%).

LCMS(ESI)：[M]+ m/z：計算值317.2；實測值318.2；Rt=0.535min。LCMS (ESI): [M] + m/z: calculated 317.2; found 318.2; Rt=0.535 min.

步驟6：N-(6-胺基-5-乙基吡啶-3-基)-2-((2R,5S)-2-(2-(2-(二甲胺基)丙-2-基)苯并[d]噻唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1237)之合成Step 6: N-(6-Amino-5-ethylpyridin-3-yl)-2-((2R,5S)-2-(2-(2-(dimethylamino)propan-2-yl) ) Synthesis of benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound 1237)

藉由一般程序方案J步驟6A製備。產率：54.7mg(34.14%)。Prepared by General Scheme J, Step 6A. Yield: 54.7 mg (34.14%).

HPLC條件： 管柱：YMC Triart C18 100*20mm，5微米；0-1-6min 50-50-90%水-MeOH+0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min MeOH)。 HPLC conditions: Column: YMC Triart C18 100*20mm, 5 microns; 0-1-6min 50-50-90% water-MeOH+0.1% NH4OH , flow rate: 30mL/min; (loading pump 4mL/min MeOH ).

1 H NMR(600MHz,dmso)δ 1.00-1.06(m,3H),1.06-1.19(m,3H),1.28-1.40(m,1H),1.42(s,6H),1.62-1.76(m,1H),1.83-1.95(m,1H),2.03-2.18(m,1H),2.22(s,6H),2.26-2.33(m,1H),2.36-2.44(m,2H),2.76-3.29(m,1H),3.43-4.10(m,1H),5.18-5.61(m,1H),5.61-5.73(m,2H),7.31-7.42(m,1H),7.42-7.57(m,1H),7.82-7.91(m,1H),7.98-8.14(m,2H),10.43-10.65(m,1H)。 1 H NMR(600MHz,dmso)δ 1.00-1.06(m,3H),1.06-1.19(m,3H),1.28-1.40(m,1H),1.42(s,6H),1.62-1.76(m,1H) ),1.83-1.95(m,1H),2.03-2.18(m,1H),2.22(s,6H),2.26-2.33(m,1H),2.36-2.44(m,2H),2.76-3.29(m ,1H),3.43-4.10(m,1H),5.18-5.61(m,1H),5.61-5.73(m,2H),7.31-7.42(m,1H),7.42-7.57(m,1H),7.82 -7.91 (m, 1H), 7.98-8.14 (m, 2H), 10.43-10.65 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值508.2；實測值509.2；Rt=1.645min。LCMS (ESI): [M] + m/z: calculated 508.2; found 509.2; Rt=1.645 min.

方案K-式11化合物之合成Scheme K - Synthesis of Compounds of Formula 11

式11化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 11 are compounds of formula ( I ) wherein R1, R2, R3 , R4, R6, R7 and R8 are as described herein.

一般程序11General Procedures 11

Figure 110128222-A0202-12-2185-704
Figure 110128222-A0202-12-2185-704

步驟1：11B之合成Step 1: Synthesis of 11B

在氬氣下，將LiHMDS(1.3當量；1.08M於THF/乙苯中)逐滴添加到11A (1.0當量)於THF(400mL)中之經冷卻至-78℃之溶液中。將所得溶液在-78℃下攪拌1.5h，隨後添加1,1,1-三氟-N-苯基-N-(三氟甲基磺醯基)甲磺醯胺(1.05當量)。使反應混合物緩慢升溫(不移除冷卻浴！)至25℃且攪拌12h。然後，將混合物用水(100mL)及MTBE(700mL)稀釋。將有機層分離，將水層另外用MTBE(200mL)萃取。將經合併之有機萃取物用10%氫氧化鈉水溶液(2* 100mL)洗滌，經碳酸鉀(250g)乾燥且在真空中濃縮。將殘餘物用己烷/MTBE混合物稀釋(4/1,500ml，重複8次)且攪拌30min。將所得混濁溶液自油狀殘餘物傾析，透過短矽膠墊(150mL無水矽膠)過濾且在真空中蒸發，以得到11B。 Under argon, LiHMDS (1.3 equiv; 1.08 M in THF/ethylbenzene) was added dropwise to a cooled solution of 11A (1.0 equiv) in THF (400 mL) to -78 °C. The resulting solution was stirred at -78 °C for 1.5 h, followed by the addition of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.05 equiv.). The reaction mixture was slowly warmed (without removing the cooling bath!) to 25 °C and stirred for 12 h. Then, the mixture was diluted with water (100 mL) and MTBE (700 mL). The organic layer was separated and the aqueous layer was additionally extracted with MTBE (200 mL). The combined organic extracts were washed with 10% aqueous sodium hydroxide solution (2 * 100 mL), dried over potassium carbonate (250 g) and concentrated in vacuo. The residue was diluted with a hexane/MTBE mixture (4/1,500 ml, repeated 8 times) and stirred for 30 min. The resulting cloudy solution was decanted from the oily residue, filtered through a short pad of silica gel (150 mL of anhydrous silica) and evaporated in vacuo to give 11B.

步驟2：11C之合成Step 2: Synthesis of 11C

將11B (1.0當量)、(6-氟-3-吡啶基)硼酸(1.38當量)及碳酸鈉(3.05當量)添加到1,4-二噁烷(100mL)及水(30mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(0.05當 量)。將反應混合物在氬氣、85℃下攪拌18h。使所得混合物冷卻至室溫且過濾。將濾餅用二噁烷(2* 50mL)洗滌且丟棄。將濾液在真空中濃縮，且藉由矽膠管柱層析使用己烷/MTBE梯度(0-100% MTBE)純化殘餘物兩次，以得到11C。 11B (1.0 equiv), (6-fluoro-3-pyridyl)boronic acid (1.38 equiv) and sodium carbonate (3.05 equiv) were added to a mixture of 1,4-dioxane (100 mL) and water (30 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM (0.05 equiv ) was added under argon. The reaction mixture was stirred under argon at 85 °C for 18 h. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with dioxane (2 * 50 mL) and discarded. The filtrate was concentrated in vacuo and the residue was purified twice by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) to give 11C.

步驟3：11D之合成Step 3: Synthesis of 11D

將11C (1.0當量)於三氟乙酸(50.0mL)中之溶液在25℃下攪拌1h，然後在真空中濃縮。將碎冰(10g)添加到殘餘物中，且將所得混合物用10%碳酸鉀水溶液鹼化至pH 10且用二氯甲烷(2* 100.0mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在減壓下濃縮，以得到11D 。 A solution of 11C (1.0 equiv.) in trifluoroacetic acid (50.0 mL) was stirred at 25 °C for 1 h, then concentrated in vacuo. Crushed ice (10 g) was added to the residue, and the resulting mixture was basified to pH 10 with 10% aqueous potassium carbonate and extracted with dichloromethane (2 * 100.0 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give 11D .

步驟4：11E之合成Step 4: Synthesis of 11E

在-10℃下將硼氫化鈉(2.14當量)一次性添加到11D (1.0當量)於甲醇(50mL)中之經攪拌之溶液中。將所得混合物在-10℃下攪拌30min，且使其升溫至25℃且攪拌1h。在真空中濃縮反應混合物，將殘餘物用水(30.0mL)稀釋且用二氯甲烷(2* 100.0mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中濃縮，以得到11E。 Sodium borohydride (2.14 equiv) was added in one portion to a stirred solution of 11D (1.0 equiv) in methanol (50 mL) at -10°C. The resulting mixture was stirred at -10 °C for 30 min, and allowed to warm to 25 °C and stirred for 1 h. The reaction mixture was concentrated in vacuo, the residue was diluted with water (30.0 mL) and extracted with dichloromethane (2 * 100.0 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 11E.

步驟5：11F之合成Step 5: Synthesis of 11F

在25℃下，在30min內，將HATU(1.15當量)以小批量添加到11E (1.0當量)、2-[(6-胺基-5-甲基/乙基-3-吡啶基)胺基]-2-側氧基乙酸(1.25當量)及三乙胺(6.0當量)於DMSO(22.0mL)中之經攪拌之混合物中。將所得混合物在25℃下攪拌2h。使用LCMS分析混合物且將反應混合物直接用於下一步驟中。HATU (1.15 equiv) was added in small batches to 11E (1.0 equiv), 2-[(6-amino-5-methyl/ethyl-3-pyridyl)amino at 25°C over 30 min ]-2-Pendoxoacetic acid (1.25 equiv) and triethylamine (6.0 equiv) in a stirred mixture of DMSO (22.0 mL). The resulting mixture was stirred at 25 °C for 2 h. The mixture was analyzed using LCMS and the reaction mixture was used directly in the next step.

步驟6：式9之合成Step 6: Synthesis of Formula 9

方法A：Method A:

將相應胺 (2.5當量)添加到來自前一步驟且含有11F (1.0當量)之反應混合物中。將所得混合物在密封小瓶中在115℃下攪拌40-61h(LCMS對照)。然後，使混合物冷卻至室溫且提交至反相HPLC，以得到式9。The corresponding amine (2.5 equiv) was added to the reaction mixture from the previous step containing 11F (1.0 equiv). The resulting mixture was stirred in a sealed vial at 115°C for 40-61 h (LCMS control). The mixture was then cooled to room temperature and submitted to reverse phase HPLC to give formula 9.

方法B：Method B:

將相應胺 (2.5當量)及三乙胺(2.0當量)添加到11E (1.0當量)之經攪拌之混合物中。將所得混合物在密封小瓶中在115℃下攪拌60h，然後冷卻且倒入到冷水(40mL)中。使所得混合物靜置0.5h。將所得沉澱過濾，用水(3*5mL)洗滌，然後溶解於二氯甲烷(30mL)中。將溶液經硫酸鈉乾燥且在真空中濃縮。將殘餘物溶解於無水二氯甲烷(10mL)中且一次性添加於二噁烷中之4.0M氯化氫溶液(60.0當量)。將所得混合物在25℃下攪拌0.5h，然後在真空中蒸發至乾。將殘餘物提交至反相HPLC，以得到式9。The corresponding amine (2.5 equiv) and triethylamine (2.0 equiv) were added to a stirred mixture of 11E (1.0 equiv). The resulting mixture was stirred in a sealed vial at 115 °C for 60 h, then cooled and poured into cold water (40 mL). The resulting mixture was allowed to stand for 0.5 h. The resulting precipitate was filtered, washed with water (3*5 mL), and dissolved in dichloromethane (30 mL). The solution was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dry dichloromethane (10 mL) and a 4.0 M solution of hydrogen chloride in dioxane (60.0 equiv) was added in one portion. The resulting mixture was stirred at 25 °C for 0.5 h, then evaporated to dryness in vacuo. The residue was submitted to reverse phase HPLC to give formula 9.

實例666. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-[甲基-(1-甲基-4-哌啶基)胺基]-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1225)之合成Example 666. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-[methyl-(1-methyl Synthesis of -4-piperidinyl)amino]-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (compound 1225)

Figure 110128222-A0202-12-2187-705
Figure 110128222-A0202-12-2187-705

藉由一般程序方案K步驟6(方法A)製備Prepared by General Procedure K, Step 6 (Method A)

HPLC條件：管柱：XBridge BEH C18 5um 130A；流動相：30-30-75% 0-1-6min H2 O/MeOH/0.1% NH4 OH；流速：30mL/min(裝載泵4mL/min甲醇)HPLC conditions: Column: XBridge BEH C18 5um 130A; mobile phase: 30-30-75% 0-1-6 min H2O /MeOH/0.1% NH4OH ; flow rate: 30 mL/min (load pump 4 mL/min methanol )

產率：106.0mg(28.70%)Yield: 106.0 mg (28.70%)

1 H NMR(600MHz,dmso)δ 1.00(m,3H),1.29-1.36(m,2H),1.48(m,2H),1.70-1.74(m,3H),1.94-1.99(m,2H),2.03(s,3H),2.15(m,3H),2.80(m,5H),3.92-3.94(m,1H),4.38(m,2H),5.01(m,1H),5.49(m,1H),5.61(m,2H),6.58-6.62(m,1H),7.39-7.48(m,2H),7.97-8.02(m,2H),10.46(m,1H)。 1 H NMR (600MHz, dmso) δ 1.00 (m, 3H), 1.29-1.36 (m, 2H), 1.48 (m, 2H), 1.70-1.74 (m, 3H), 1.94-1.99 (m, 2H), 2.03(s, 3H), 2.15(m, 3H), 2.80(m, 5H), 3.92-3.94(m, 1H), 4.38(m, 2H), 5.01(m, 1H), 5.49(m, 1H) , 5.61 (m, 2H), 6.58-6.62 (m, 1H), 7.39-7.48 (m, 2H), 7.97-8.02 (m, 2H), 10.46 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值481.2；實測值481.2；Rt=1.552min。LCMS (ESI): [M+2H] + m/z: calculated 481.2; found 481.2; Rt=1.552 min.

實例667. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(3S)-3,4-二甲基哌嗪-1-Example 667. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-[6-[(3S)-3,4-dimethylpiperazine -1- 基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1289)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(3R)-3,4-二甲基哌嗪-1-基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1263)之合成yl]-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1289) and N-(6-amino-5-ethyl-3-pyridine yl)-2-[(2R,5S)-2-[6-[(3R)-3,4-dimethylpiperazin-1-yl]-3-pyridyl]-5-methyl-1- Synthesis of piperidinyl]-2-oxoacetamide (compound 1263)

步驟1：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-氟-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(6-fluoro-3-pyridyl)-5-methyl-1 -Piperidinyl]-2-Side Oxyacetamide Synthesis

Figure 110128222-A0202-12-2188-706
Figure 110128222-A0202-12-2188-706

藉由一般程序方案K步驟5製備Prepared by General Procedure K, Step 5

產率：1.79g(粗品)Yield: 1.79g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值386.2；實測值386.2；Rt=2.227min。LCMS (ESI): [M+H] + m/z: calculated 386.2; found 386.2; Rt=2.227 min.

步驟2：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-(3,4-二甲基哌嗪-1-基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-2-[6-(3,4-dimethylpiperazin-1-yl )-3-pyridyl]-5-methyl-1-piperidinyl]-2-side oxyacetamide synthesis

Figure 110128222-A0202-12-2188-707
Figure 110128222-A0202-12-2188-707

藉由一般程序方案K步驟6(方法A)製備Prepared by General Procedure K, Step 6 (Method A)

HPLC條件：管柱：YMC Triart C18 100x20mm，5um；流動相：30-30-45% 0-2-5min H2 O/乙腈/0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min甲醇)HPLC conditions: column: YMC Triart C18 100x20mm, 5um; mobile phase: 30-30-45% 0-2-5min H2O /acetonitrile/0.1% NH4OH , flow rate: 30mL/min; (loading pump 4mL/ min methanol)

產率：285mg(60.27%)Yield: 285 mg (60.27%)

LCMS(ESI)：[M+H]+ m/z：計算值480.4；實測值480.4；Rt=1.782min。LCMS (ESI): [M+H] + m/z: calculated 480.4; found 480.4; Rt=1.782 min.

步驟3：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(3S)-3,4-二甲基哌嗪-1-Step 3: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-2-[6-[(3S)-3,4-dimethylpiperazine -1- 基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1289)及N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-[6-[(3R)-3,4-二甲基哌嗪-1-基]-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1263)之合成yl]-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1289) and N-(6-amino-5-ethyl-3-pyridine yl)-2-[(2R,5S)-2-[6-[(3R)-3,4-dimethylpiperazin-1-yl]-3-pyridyl]-5-methyl-1- Synthesis of piperidinyl]-2-oxoacetamide (compound 1263)

Figure 110128222-A0202-12-2189-708
Figure 110128222-A0202-12-2189-708

藉由一般程序方案K步驟7製備Prepared by General Scheme K, Step 7

掌性分離條件：Chiralcel OJ-H，250*20mm，5mkm，MeOH，100%，18mL/min，注入體積：200.000μl；管柱溫度：25℃；波長：205nm、264nm)，保留時間(異構物A)=21.799min；保留時間(異構物B)=57.625minChiral separation conditions: Chiralcel OJ-H, 250*20mm, 5mkm, MeOH, 100%, 18mL/min, injection volume: 200.000μl; column temperature: 25°C; wavelength: 205nm, 264nm), retention time (isomerization) Compound A) = 21.799min; retention time (isomer B) = 57.625min

化合物1289：Compound 1289:

產率：46.0mg(36.80%)Yield: 46.0 mg (36.80%)

RT(Chiralcel OJ-H,250*20mm，5mkm，Hex-IPA-MeOH，50-25-25，0.6mL/min)=48.548min。RT (Chiralcel OJ-H, 250*20mm, 5mkm, Hex-IPA-MeOH, 50-25-25, 0.6mL/min)=48.548min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.01(m,6H),1.09(m,3H),1.32(m,1H),1.70(m,1H),1.85(m,1H),1.95(m,2H),2.12(m,2H),2.18(s,3H),2.39(m,2H),2.91(m,4H),3.69(m,1H),4.04(m,2H),5.58(m,3H),6.83(m,1H),7.45(m,2H),8.03(m,2H),10.47(s,1H) 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.01 (m, 6H), 1.09 (m, 3H), 1.32 (m, 1H), 1.70 (m, 1H), 1.85 (m, 1H) ,1.95(m,2H),2.12(m,2H),2.18(s,3H),2.39(m,2H),2.91(m,4H),3.69(m,1H),4.04(m,2H), 5.58(m, 3H), 6.83(m, 1H), 7.45(m, 2H), 8.03(m, 2H), 10.47(s, 1H)

LCMS(ESI)：[M+2H]+ m/z：計算值481.2；實測值481.2；Rt=1.804min。LCMS (ESI): [M+2H] + m/z: calculated 481.2; found 481.2; Rt=1.804 min.

化合物1263：Compound 1263:

產率：52.0mg(41.60%)Yield: 52.0 mg (41.60%)

RT(Chiralcel OJ-H,250*20mm，5mkm，Hex-IPA-MeOH，50-25-25，0.6mL/min) =81.723min。RT (Chiralcel OJ-H, 250*20mm, 5mkm, Hex-IPA-MeOH, 50-25-25, 0.6mL/min) =81.723min.

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.01(m,6H),1.10(m,3H),1.32(m,1H),1.70(m,1H),1.87(m,1H),2.00(m,2H),2.11(m,1H),2.18(s,3H),2.39(m,3H),2.88(m,4H),3.67(dd,1H),4.03(m,2H),5.58(m,3H),6.83(t,1H),7.45(m,2H),8.03(m,2H),10.48(s,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.01 (m, 6H), 1.10 (m, 3H), 1.32 (m, 1H), 1.70 (m, 1H), 1.87 (m, 1H) ,2.00(m,2H),2.11(m,1H),2.18(s,3H),2.39(m,3H),2.88(m,4H),3.67(dd,1H),4.03(m,2H), 5.58(m, 3H), 6.83(t, 1H), 7.45(m, 2H), 8.03(m, 2H), 10.48(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值480.2；實測值480.4；Rt=1.810min。LCMS (ESI): [M+H] + m/z: calculated 480.2; found 480.4; Rt=1.810 min.

實例668. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-[(1-甲基-4-哌啶基)胺基]-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1306)之合成Example 668. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-[(1-methyl-4- Synthesis of piperidinyl)amino]-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (compound 1306)

Figure 110128222-A0202-12-2190-709
Figure 110128222-A0202-12-2190-709

步驟1：(3S)-6-(6-氟-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (3S)-6-(6-fluoro-3-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

藉由一般程序方案K步驟2製備Prepared by General Procedure K, Step 2

產率：3.0g(44.30%)Yield: 3.0 g (44.30%)

LCMS(ESI)：[M+H]+ m/z：計算值293.2；實測值293.2；Rt=1.500min。LCMS (ESI): [M+H] + m/z: calculated 293.2; found 293.2; Rt=1.500 min.

步驟2：2-氟-5-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吡啶之合成Step 2: Synthesis of 2-fluoro-5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]pyridine

藉由一般程序方案K步驟3製備Prepared by General Procedure K, Step 3

產率：1.9g(96.32%)Yield: 1.9g (96.32%)

LCMS(ESI)：[M+H]+ m/z：計算值193.2；實測值193.2；Rt=0.634min。LCMS (ESI): [M+H] + m/z: calculated 193.2; found 193.2; Rt=0.634 min.

步驟3：2-氟-5-[(2R,5S)-5-甲基-2-哌啶基]吡啶之合成Step 3: Synthesis of 2-fluoro-5-[(2R,5S)-5-methyl-2-piperidinyl]pyridine

藉由一般程序方案K步驟4製備Prepared by General Scheme K, Step 4

產率：1.8g(93.75%)Yield: 1.8g (93.75%)

LCMS(ESI)：[M+H]+ m/z：計算值195.2；實測值195.2；Rt=0.544min。步驟4：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-2-(6-氟-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成 LCMS (ESI): [M+H] + m/z: calculated 195.2; found 195.2; Rt=0.544 min. Step 4: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-2-(6-fluoro-3-pyridyl)-5-methyl-1 -Piperidinyl]-2-Side Oxyacetamide Synthesis

藉由一般程序方案K步驟5製備Prepared by General Procedure K, Step 5

產率：1.79g(粗品)Yield: 1.79g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值386.2；實測值386.2；Rt=2.227min。LCMS (ESI): [M+H] + m/z: calculated 386.2; found 386.2; Rt=2.227 min.

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-[(1-甲基-4-哌啶基)胺基]-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1306)之合成Step 5: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-[(1-methyl-4- Synthesis of piperidinyl)amino]-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (compound 1306)

藉由一般程序方案K步驟6(方法A)製備Prepared by General Procedure K, Step 6 (Method A)

HPLC條件：管柱：YMC Triart C18 100x20mm，5um；流動相：5-95% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30mL/min；(裝載泵4mL/min甲醇)HPLC conditions: Column: YMC Triart C18 100x20mm, 5um; Mobile phase: 5-95% 0-5min H2O /MeOH/0.1% NH4OH , flow rate: 30mL/min; (loading pump 4mL/min methanol)

產率：83.0mg(26.68%)Yield: 83.0 mg (26.68%)

1 H NMR(600MHz,DMSO-d 6 )δ(ppm) 1 H NMR (600MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M+H]+ m/z：計算值480.2；實測值480.2；Rt=1.488min。LCMS (ESI): [M+H] + m/z: calculated 480.2; found 480.2; Rt=1.488 min.

方案L-式12化合物之合成Scheme L - Synthesis of Compounds of Formula 12

式11化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 11 are compounds of formula ( I ) wherein R1, R2, R3 , R4, R6, R7 and R8 are as described herein.

一般程序12General Procedure 12

方案LScheme L

Figure 110128222-A0202-12-2192-710
Figure 110128222-A0202-12-2192-710

步驟1：12B之一般程序Step 1: General Procedure for 12B

將2-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯甲醛(1.0當量)及12A (1.0當量，或其鹽)溶解於i-PrOH(140mL)中。將所得混合物在80℃下攪拌2小時，隨後添加三-正丁基膦(Bu3 P，3.0當量)。將反應混合物在回流下攪拌2小時。然後，在真空中移除揮發物。將殘餘物溶解於DCM且用水洗滌。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。藉由急驟層析純化殘餘物，以得到12B。 2-Nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzaldehyde (1.0 equiv.) and 12A (1.0 equivalent, or its salt) was dissolved in i-PrOH (140 mL). The resulting mixture was stirred at 80°C for 2 hours, then tri-n-butylphosphine ( Bu3P , 3.0 equiv) was added. The reaction mixture was stirred at reflux for 2 hours. Then, the volatiles were removed in vacuo. The residue was dissolved in DCM and washed with water. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give 12B.

步驟1A：12F之一般程序Step 1A: General Procedure for 12F

將5-溴-2-硝基苯甲醛(1.0當量)及12A (1.0當量)溶解於i-PrOH(400.0mL)中。將所得混合物在80℃下攪拌2h，隨後添加三-正丁基膦(3.0當量)。將反應混合物再回流16h。然後將反應混合物在減壓下蒸發且藉由急驟層析純化，以得到12F 。5-Bromo-2-nitrobenzaldehyde (1.0 equiv) and 12A (1.0 equiv) were dissolved in i-PrOH (400.0 mL). The resulting mixture was stirred at 80 °C for 2 h, then tri-n-butylphosphine (3.0 equiv) was added. The reaction mixture was refluxed for an additional 16 h. The reaction mixture was then evaporated under reduced pressure and purified by flash chromatography to give 12F .

步驟1B：12H之一般程序Step 1B: General Procedure for 12H

將5-溴-2-硝基苯甲醛(1.0當量)及12G (1.0當量)溶解於i-PrOH(80.0mL)中。將所得混合物在80℃下攪拌2h且添加三-正丁基膦(3.0當量)。將反應混 合物再回流16h。然後將反應混合物在減壓下蒸發且藉由急驟層析純化，以得到12H 。5-Bromo-2-nitrobenzaldehyde (1.0 equiv) and 12G (1.0 equiv) were dissolved in i-PrOH (80.0 mL). The resulting mixture was stirred at 80 °C for 2 h and tri-n-butylphosphine (3.0 equiv) was added. The reaction mixture was refluxed for an additional 16 h. The reaction mixture was then evaporated under reduced pressure and purified by flash chromatography to give 12H .

步驟1C：12J之一般程序Step 1C: General Procedure for 12J

將99%無水碳酸鉀(3.0當量)及碘甲烷(1.7當量)添加到12B(1.0當量)於MeCN(大約45.0mL)中之溶液中。將所得混合物在25℃下攪拌16h。然後，在減壓下移除溶劑。將殘餘物用水(40.0mL)稀釋且將所得混合物用DCM萃取，得到12J 。To a solution of 12B (1.0 equiv) in MeCN (approximately 45.0 mL) was added 99% anhydrous potassium carbonate (3.0 equiv) and iodomethane (1.7 equiv). The resulting mixture was stirred at 25 °C for 16 h. Then, the solvent was removed under reduced pressure. The residue was diluted with water (40.0 mL) and the resulting mixture was extracted with DCM to give 12J .

步驟2：12C之一般程序Step 2: General Procedure for 12C

在惰性氣氛、85℃下，將12B (1.0當量)、外消旋-(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.01當量)、碳酸鈉(3.0當量)及Pd(dppf)Cl2 DCM(0.05當量)在1,4-二噁烷(6.0mL)及水(2.0mL)之混合物中攪拌15h。完成之後，將反應混合物冷卻，用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮，以得到12C 。所獲得之材料不經額外純化即用於下一步驟中。 12B (1.0 equiv.), rac-(3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H under an inert atmosphere at 85°C - tert-butyl pyridine-1-carboxylate (1.01 equiv), sodium carbonate (3.0 equiv) and Pd(dppf) Cl2DCM (0.05 equiv) in 1,4-dioxane (6.0 mL) and water (2.0 mL) ) was stirred in the mixture for 15h. After completion, the reaction mixture was cooled, diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to give 12C . The obtained material was used in the next step without additional purification.

步驟2A：12B之一般程序Step 2A: General Procedure for 12B

將12F (1.0當量)、B2 Pin2 (1.1當量)及乙酸鉀(2.0當量)一起混合於1.4-二噁烷(大約20.0mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)2 Cl2 DCM(993.01mg，1.22mmol)。將反應混合物在氬氣氣氛、90℃下攪拌14h。然後使混合物冷卻至室溫且在真空中移除揮發物，以得到12B 。 12F (1.0 equiv), B2Pin2 (1.1 equiv) and potassium acetate ( 2.0 equiv) were mixed together in 1.4-dioxane (approximately 20.0 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf) 2Cl2DCM (993.01 mg , 1.22 mmol) was added under argon. The reaction mixture was stirred at 90 °C for 14 h under an argon atmosphere. The mixture was then cooled to room temperature and the volatiles were removed in vacuo to give 12B .

步驟2B：12I之一般程序Step 2B: General Procedure for 12I

將12H (1.0當量)溶解於TFA(1.0mL)及DCM(1.0mL)之混合物中。將反應混合物在室溫下攪拌30分鐘。然後，在真空中濃縮混合物，以得到12I 。所獲得之材料不經額外純化即用於下一步驟中。 12H (1.0 equiv) was dissolved in a mixture of TFA (1.0 mL) and DCM (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. Then, the mixture was concentrated in vacuo to give 12I . The obtained material was used in the next step without additional purification.

步驟2C：式12之一般程序Step 2C: General Procedure for Equation 12

將碳酸鈉(2.0當量)添加到12J(1.0當量)及外消旋-(5S)-5-甲基-2-(三氟甲基磺醯基氧基)哌啶-1-甲酸第三丁酯(1.1當量)於水(大約15.0mL)及1,4-二噁烷(大約50.0mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2 ‧CH2 Cl2 (0.05當量)。在惰性氣氛下將所得混合物在90℃下攪拌15h。反應完成之後，添加水(大約50.0mL)。將所得混合物用EtOAc(3*20.0mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得12C 。所獲得之材料不經額外純化即用於下一步驟中。Sodium carbonate (2.0 equiv) was added to 12J (1.0 equiv) and rac-(5S)-5-methyl-2-(trifluoromethylsulfonyloxy)piperidine-1-carboxylic acid tert-butyl A solution of ester (1.1 equiv) in water (approximately 15.0 mL) and 1,4-dioxane (approximately 50.0 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, Pd(dppf) Cl2.CH2Cl2 ( 0.05 equiv. ) was added under argon flow. The resulting mixture was stirred at 90 °C for 15 h under an inert atmosphere. After the reaction was complete, water (approximately 50.0 mL) was added. The resulting mixture was extracted with EtOAc (3*20.0 mL). The combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo to obtain 12C . The obtained material was used in the next step without additional purification.

步驟3：12D之一般程序Step 3: General Procedure for 12D

方法A：Method A:

將12C (1.0當量)溶解於TFA(1.0mL)及DCM(1.0mL)之混合物中。將反應混合物在室溫下攪拌30分鐘。然後，將混合物在真空中濃縮，得到12D 。所獲得之材料不經額外純化即用於下一步驟中。 12C (1.0 equiv) was dissolved in a mixture of TFA (1.0 mL) and DCM (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. Then, the mixture was concentrated in vacuo to give 12D . The obtained material was used in the next step without additional purification.

方法B：Method B:

將12C(1.0當量)溶解於HCl(於二噁烷中之4.0M溶液，1.0mL)及MeOH(1.0mL)之混合物中。在室溫下將反應混合物攪拌隔夜。然後，將混合物在真空中濃縮，得到12D 。所獲得之材料不經額外純化即用於下一步驟中。12C (1.0 equiv) was dissolved in a mixture of HCl (4.0 M in dioxane, 1.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at room temperature overnight. Then, the mixture was concentrated in vacuo to give 12D . The obtained material was used in the next step without additional purification.

步驟3B：12F之一般程序Step 3B: General Procedure for 12F

向12I(1.0當量)、乙酸(1.0當量)及用10-15%甲醇穩定之37%甲醛水溶液(ACS，36.5-38.0%)(1.0當量)於DCM(大約25.0mL)中之溶液中添加三乙醯氧基硼氫化鈉(1.0當量)。將所得混合物在25℃下攪拌16h。然後，在真空中移除溶劑。將殘餘物倒入到H2 O(50.0mL)中且用EtOAc(2x20.0mL)萃取。將經合併之有機萃取物用鹽水(2*20.0mL)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到12F 。To a solution of 12I (1.0 equiv.), acetic acid (1.0 equiv.), and 37% aqueous formaldehyde (ACS, 36.5-38.0%) stabilized with 10-15% methanol (1.0 equiv.) in DCM (approximately 25.0 mL) was added three Sodium acetoxyborohydride (1.0 equiv.). The resulting mixture was stirred at 25 °C for 16 h. Then, the solvent was removed in vacuo. The residue was poured into H2O (50.0 mL) and extracted with EtOAc (2 x 20.0 mL). The combined organic extracts were washed with brine (2*20.0 mL), dried over sodium sulfate and evaporated in vacuo to give 12F .

步驟4：12E之一般程序Step 4: General Procedure for 12E

將硼氫化鈉(2.0當量)分批添加到12D (1.0當量)於MeOH(5.0mL)中之溶液中。將反應混合物在室溫下攪拌17小時。然後，將混合物用HCl(於二噁烷中之4.0M溶液)酸化至pH 5且在真空中移除揮發物，以得到12E 。所獲得之材料不經額外純化即用於下一步驟中。Sodium borohydride (2.0 equiv) was added portionwise to a solution of 12D (1.0 equiv) in MeOH (5.0 mL). The reaction mixture was stirred at room temperature for 17 hours. The mixture was then acidified to pH 5 with HCl (4.0M in dioxane) and the volatiles were removed in vacuo to give 12E . The obtained material was used in the next step without additional purification.

步驟5：式12之一般程序Step 5: General Procedure of Equation 12

將HATU(1.4當量)添加到12E (1.0當量)、相應酸(1.1當量)及DIPEA(10.0當量)於DMSO(大約6.0mL)中之經攪拌之溶液中。將所得反應混合物在25℃下攪拌4h。完成之後，將反應混合物提交至反相HPLC，以得到式12。 HATU (1.4 equiv) was added to a stirred solution of 12E (1.0 equiv), the corresponding acid (1.1 equiv) and DIPEA (10.0 equiv) in DMSO (approximately 6.0 mL). The resulting reaction mixture was stirred at 25 °C for 4 h. After completion, the reaction mixture was submitted to reverse phase HPLC to give formula 12.

實例669. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1321)之合成Example 669. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Synthesis of pyridyl)indazol-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1321)

Figure 110128222-A0202-12-2195-711
Figure 110128222-A0202-12-2195-711

步驟1：4-(5-溴吲唑-2-基)哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-butyl 4-(5-bromoindazol-2-yl)piperidine-1-carboxylate

藉由一般程序方案L步驟1B製備Prepared by General Procedure L, Step 1B

FCC條件：Interchim；120g SiO2 ，HEX-ETOAC 0~100%，流速=70mL/min，cv=10.4FCC conditions: Interchim; 120g SiO 2 , HEX-ETOAC 0~100%, flow rate=70mL/min, cv=10.4

產率：4.2g(84.68%)Yield: 4.2g (84.68%)

LCMS(ESI)：[M+H]+ m/z：計算值382.0；實測值382.0；Rt=1.402min。LCMS (ESI): [M+H] + m/z: calculated 382.0; found 382.0; Rt=1.402 min.

步驟2：5-溴-2-(4-哌啶基)吲唑之合成Step 2: Synthesis of 5-bromo-2-(4-piperidinyl)indazole

藉由一般程序方案L步驟2B製備Prepared by General Procedure L, Step 2B

產率：0.42g(38.01%)Yield: 0.42g (38.01%)

LCMS(ESI)：[M+H]+ m/z：計算值280.0；實測值280.0；Rt=0.895min。LCMS (ESI): [M+H] + m/z: calculated 280.0; found 280.0; Rt=0.895 min.

步驟3：5-溴-2-(1-甲基-4-哌啶基)吲唑之合成Step 3: Synthesis of 5-bromo-2-(1-methyl-4-piperidinyl)indazole

藉由一般程序方案L步驟3B製備Prepared by General Procedure L, Step 3B

產率：0.42g(88.88%)Yield: 0.42g (88.88%)

LCMS(ESI)：[M+H]+ m/z：計算值294.0；實測值294.0；Rt=0.880min。LCMS (ESI): [M+H] + m/z: calculated 294.0; found 294.0; Rt=0.880 min.

步驟4：2-(1-甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 4: 2-(1-Methyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of base)indazole

藉由一般程序方案L步驟2A製備Prepared by General Procedure L, Step 2A

產率：0.45g(粗品)Yield: 0.45g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值342.2；Rt=0.916min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 342.2; Rt=0.916 min.

步驟5：(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 5: (3S)-3-Methyl-6-[2-(1-methyl-4-piperidinyl)indazol-5-yl]-3,4-dihydro-2H-pyridine-1- Synthesis of tert-butyl formate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

產率：0.38g(粗品)Yield: 0.38g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=1.048min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=1.048 min.

步驟6：2-(1-甲基-4-哌啶基)-5-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 6: Synthesis of 2-(1-Methyl-4-piperidinyl)-5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：0.25g(87.01%)Yield: 0.25g (87.01%)

LCMS(ESI)：[M+H]+ m/z：計算值311.2；實測值311.2；Rt=0.881min。LCMS (ESI): [M+H] + m/z: calculated 311.2; found 311.2; Rt=0.881 min.

步驟7：2-(1-甲基-4-哌啶基)-5-[(2R,5S)-5-甲基-2-哌啶基]吲唑之合成Step 7: Synthesis of 2-(1-Methyl-4-piperidinyl)-5-[(2R,5S)-5-methyl-2-piperidinyl]indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：0.22g(粗品)Yield: 0.22g (crude)

步驟8：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1321)之合成Step 8: N-(6-Amino-5-ethyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidine Synthesis of pyridyl)indazol-5-yl]-1-piperidinyl]-2-oxoacetamide (compound 1321)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-15min 40-60%甲醇+NH3 ，流速30mL/min(裝載泵4mL/min甲醇)，管柱：SunFire 100*19mm，5微米，及2-10min 0-30%乙腈+FA流速30mL/min(裝載泵4mL/min乙腈)，管柱Sun Fire C18 100*19mmHPLC conditions: 2-15min 40-60% methanol+ NH3 , flow rate 30mL/min (loading pump 4mL/min methanol), column: SunFire 100*19mm, 5 microns, and 2-10min 0-30% acetonitrile+FA Flow rate 30mL/min (loading pump 4mL/min acetonitrile), column Sun Fire C18 100*19mm

產率：0.006g(1.69%)Yield: 0.006g (1.69%)

1 H NMR(600MHz,dmso)δ 0.85-1.04(m,3H),1.06-1.14(m,3H),1.31-1.41(m,1H),1.69-1.93(m,2H),2.03-2.13(m,7H),2.22(s,3H),2.23-2.34(m,1H),2.37-2.43(m,2H),2.75-2.78(m,0H),2.87-2.90(m,2H),3.19-3.22(m,1H),3.49-4.03(m,1H),4.37-4.47(m,1H),5.15-5.70(m,3H),7.12-7.29(m,1H),7.41-7.54(m,1H),7.57-7.64(m,2H),7.97-8.10(m,1H),8.35-8.40(m,1H),10.45-10.69(m,1H)。 1 H NMR(600MHz,dmso)δ 0.85-1.04(m,3H),1.06-1.14(m,3H),1.31-1.41(m,1H),1.69-1.93(m,2H),2.03-2.13(m ,7H),2.22(s,3H),2.23-2.34(m,1H),2.37-2.43(m,2H),2.75-2.78(m,0H),2.87-2.90(m,2H),3.19-3.22 (m,1H),3.49-4.03(m,1H),4.37-4.47(m,1H),5.15-5.70(m,3H),7.12-7.29(m,1H),7.41-7.54(m,1H) , 7.57-7.64(m, 2H), 7.97-8.10(m, 1H), 8.35-8.40(m, 1H), 10.45-10.69(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值504.2；實測值504.2；Rt=1.976min。LCMS (ESI): [M+H] + m/z: calculated 504.2; found 504.2; Rt=1.976 min.

實例670. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1115)之合成Example 670. 2-Methoxy-5-[[2-Pendox-2-[racemic-(2R,5S)-5-methyl-2-[2-(1-methyl-4- Synthesis of piperidinyl)indazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 1115)

Figure 110128222-A0202-12-2198-712
Figure 110128222-A0202-12-2198-712

步驟1：5-溴-2-(1-甲基-4-哌啶基)吲唑之合成Step 1: Synthesis of 5-bromo-2-(1-methyl-4-piperidinyl)indazole

藉由一般程序方案L步驟1A製備Prepared by General Procedure L, Step 1A

產率：20g(78.19%)Yield: 20g (78.19%)

LCMS(ESI)：[M+H]+ m/z：計算值295.0；實測值295.0；Rt=0.785min。LCMS (ESI): [M+H] + m/z: calculated 295.0; found 295.0; Rt=0.785 min.

步驟2：2-(1-甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 2: 2-(1-Methyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of base)indazole

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

FCC條件：Interchim；330g SiO2 ，MTBE-MeOH 0~100%，流速=100mL/min，cv=9.4FCC conditions: Interchim; 330g SiO 2 , MTBE-MeOH 0~100%, flow rate=100mL/min, cv=9.4

產率：9.0g(77.59%)Yield: 9.0 g (77.59%)

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值342.2；Rt=0.799min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 342.2; Rt=0.799 min.

步驟3：(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: (3S)-3-Methyl-6-[2-(1-methyl-4-piperidinyl)indazol-5-yl]-3,4-dihydro-2H-pyridine-1- Synthesis of tert-butyl formate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

FCC條件：Interchim；120g SiO2 ，MTBE-MeOH 0~100%，流速=70mL/min，cv=15.3FCC conditions: Interchim; 120g SiO 2 , MTBE-MeOH 0~100%, flow rate=70mL/min, cv=15.3

產率：6.0g(55.41%)Yield: 6.0 g (55.41%)

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.5；Rt=1.019min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.5; Rt=1.019 min.

步驟4：2-(1-甲基-4-哌啶基)-5-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 4: Synthesis of 2-(1-Methyl-4-piperidinyl)-5-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]indazole

藉由一般程序方案L步驟3(方法B)製備Prepared by General Procedure L, Step 3 (Method B)

產率：1.2g(79.35%)Yield: 1.2g (79.35%)

LCMS(ESI)：[M+H]+ m/z：計算值311.2；實測值311.2；Rt=0.769min。LCMS (ESI): [M+H] + m/z: calculated 311.2; found 311.2; Rt=0.769 min.

步驟5：2-(1-甲基-4-哌啶基)-5-[(2R,5S)-5-甲基-2-哌啶基]吲唑之合成Step 5: Synthesis of 2-(1-Methyl-4-piperidinyl)-5-[(2R,5S)-5-methyl-2-piperidinyl]indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：3.2g(79.48%)Yield: 3.2g (79.48%)

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值313.2；Rt=0.664min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 313.2; Rt=0.664 min.

步驟6：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺之合成Step 6: 2-Methoxy-5-[[2-Pendoxyloxy-2-[racemic-(2R,5S)-5-methyl-2-[2-(1-methyl-4- Synthesis of piperidinyl)indazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide

(化合物1115)之合成Synthesis of (Compound 1115)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-10min 30-100%甲醇，流速30mL/min(裝載泵4mL/min甲醇)，管柱Sun Fire C18 100*19mmHPLC conditions: 2-10min 30-100% methanol, flow rate 30mL/min (loading pump 4mL/min methanol), column Sun Fire C18 100*19mm

產率：0.088g(35.52%)Yield: 0.088g (35.52%)

1 H NMR(600MHz,dmso)δ 1.01-1.05(m,3H),1.30-1.40(m,1H),1.73-1.94(m,2H),1.96-2.33(m,11H),2.80-2.90(m,2H),3.40-4.34(m,5H),4.38-4.47(m,1H),5.17-5.75(m,1H),7.07-7.30(m,1H),7.55-7.64(m,2H),7.66-7.80(m,2H),8.31-8.63(m,3H),10.94(s,1H)。 1 H NMR(600MHz, dmso)δ 1.01-1.05(m, 3H), 1.30-1.40(m, 1H), 1.73-1.94(m, 2H), 1.96-2.33(m, 11H), 2.80-2.90(m ,2H),3.40-4.34(m,5H),4.38-4.47(m,1H),5.17-5.75(m,1H),7.07-7.30(m,1H),7.55-7.64(m,2H),7.66 -7.80(m, 2H), 8.31-8.63(m, 3H), 10.94(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值534.2；實測值534.2；Rt=1.820min。LCMS (ESI): [M+H] + m/z: calculated 534.2; found 534.2; Rt=1.820 min.

實例671. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1091)之合成Example 671. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 Synthesis of -[rac-(3S)-1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1091)

Figure 110128222-A0202-12-2200-713
Figure 110128222-A0202-12-2200-713

步驟1：2-[外消旋-(3S)-1-甲基吡咯啶-3-基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 1: 2-[Rac-(3S)-1-methylpyrrolidin-3-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)indazole

藉由一般程序12製備Prepared by General Procedure 12

FCC條件：Interchim；120g SiO2 ，MTB-MeOH 0~100%，流速=70mL/min，cv=13.9FCC conditions: Interchim; 120g SiO 2 , MTB-MeOH 0~100%, flow rate=70mL/min, cv=13.9

產率：2.6g(31.45%)Yield: 2.6g (31.45%)

LCMS(ESI)：[M+H]+ m/z：計算值328.2；實測值328.2；Rt=0.904min。LCMS (ESI): [M+H] + m/z: calculated 328.2; found 328.2; Rt=0.904 min.

步驟2：外消旋-(3S)-3-甲基-6-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: rac-(3S)-3-methyl-6-[2-[rac-(3S)-1-methylpyrrolidin-3-yl]indazol-5-yl]-3 Synthesis of ,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

藉由一般程序12製備Prepared by General Procedure 12

產率：2.0g(粗品)Yield: 2.0g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值397.2；Rt=1.189min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 397.2; Rt=1.189 min.

步驟3：2-[外消旋-(3S)-1-甲基吡咯啶-3-基]-5-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 3: 2-[Rac-(3S)-1-methylpyrrolidin-3-yl]-5-[rac-(3S)-3-methyl-2,3,4,5- Synthesis of Tetrahydropyridin-6-yl]indazole

藉由一般程序12製備Prepared by General Procedure 12

產率：1.55g(粗品)Yield: 1.55g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值297.2；實測值297.2；Rt=0.668min。LCMS (ESI): [M+H] + m/z: calculated 297.2; found 297.2; Rt=0.668 min.

步驟4：5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑之合成Step 4: 5-[Rac-(2R,5S)-5-methyl-2-piperidinyl]-2-[rac-(3S)-1-methylpyrrolidin-3-yl] Synthesis of Indazole

藉由一般程序12製備Prepared by General Procedure 12

產率：1.5g(粗品，2HCl)Yield: 1.5 g (crude, 2HCl)

LCMS(ESI)：[M+H]+ m/z：計算值299.2；實測值299.2；Rt=0.680min。LCMS (ESI): [M+H] + m/z: calculated 299.2; found 299.2; Rt=0.680 min.

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1091)之合成Step 5: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[2 Synthesis of -[rac-(3S)-1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1091)

藉由一般程序12製備Prepared by General Procedure 12

HPLC條件：2-10min 40-100%甲醇+NH3 流速30mL/min(裝載泵4mL/min甲醇)，管柱Sun Fire C18 100*19mmHPLC conditions: 2-10min 40-100% methanol + NH3 flow rate 30mL/min (loading pump 4mL/min methanol), column Sun Fire C18 100*19mm

產率：0.057g，(14.41%)Yield: 0.057g, (14.41%)

1 H NMR(600MHz,dmso)δ 1.00-1.14(m,6H),1.29-1.40(m,1H),1.72-1.92(m,2H),2.02-2.25(m,3H),2.30(s,3H),2.38-2.44(m,2H),2.52-2.54(m,1H),2.75-3.24(m,5H),3.43-4.04(m,1H),5.15-5.68(m,4H),7.12-7.27(m,1H),7.42-7.53(m,1H),7.56-7.64(m,2H),7.97-8.08(m,1H),8.36-8.42(m,1H),10.51(s,1H)。 1 H NMR(600MHz,dmso)δ 1.00-1.14(m,6H),1.29-1.40(m,1H),1.72-1.92(m,2H),2.02-2.25(m,3H),2.30(s,3H) ), 2.38-2.44(m, 2H), 2.52-2.54(m, 1H), 2.75-3.24(m, 5H), 3.43-4.04(m, 1H), 5.15-5.68(m, 4H), 7.12-7.27 (m, 1H), 7.42-7.53 (m, 1H), 7.56-7.64 (m, 2H), 7.97-8.08 (m, 1H), 8.36-8.42 (m, 1H), 10.51 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值490.2；實測值490.4；Rt=2.198min。LCMS (ESI): [M+H] + m/z: calculated 490.2; found 490.4; Rt=2.198 min.

實例672. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1398)之合成Example 672. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 Synthesis of -[rac-(3R)-1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1398)

Figure 110128222-A0202-12-2202-714
Figure 110128222-A0202-12-2202-714

步驟1：2-[外消旋-(3R)-1-甲基吡咯啶-3-基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環成烷-2-基)吲唑之合成Step 1: 2-[Rac-(3R)-1-methylpyrrolidin-3-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borane-2-yl)indazoles

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

FCC條件：Interchim；120g SiO2 ，MTBE-MeOH 0~100%，流速=70mL/min，cv=13.7FCC conditions: Interchim; 120g SiO 2 , MTBE-MeOH 0~100%, flow rate=70mL/min, cv=13.7

產率：3.6g(43.55%)Yield: 3.6g (43.55%)

LCMS(ESI)：[M+H]+ m/z：計算值328.2；實測值328.2；Rt=0.897min。LCMS (ESI): [M+H] + m/z: calculated 328.2; found 328.2; Rt=0.897 min.

步驟2：外消旋-(3S)-3-甲基-6-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: rac-(3S)-3-methyl-6-[2-[rac-(3R)-1-methylpyrrolidin-3-yl]indazol-5-yl]-3 Synthesis of 3-butyl ,4-dihydro-2H-pyridine-1-carboxylate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

產率：3.5g(粗品)Yield: 3.5g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值397.4；Rt=1.010min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 397.4; Rt=1.010 min.

步驟3：2-[外消旋-(3R)-1-甲基吡咯啶-3-基]-5-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 3: 2-[Rac-(3R)-1-methylpyrrolidin-3-yl]-5-[rac-(3S)-3-methyl-2,3,4,5- Synthesis of Tetrahydropyridin-6-yl]indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：2.0g(粗品)Yield: 2.0g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值297.2；實測值297.1；Rt=0.380min。LCMS (ESI): [M+H] + m/z: calculated 297.2; found 297.1; Rt=0.380 min.

步驟4：5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑之合成Step 4: 5-[Rac-(2R,5S)-5-methyl-2-piperidinyl]-2-[rac-(3R)-1-methylpyrrolidin-3-yl] Synthesis of Indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：1.9g(粗品，2 HCl)Yield: 1.9 g (crude, 2 HCl)

LCMS(ESI)：[M+H]+ m/z：計算值299.2；實測值299.0；Rt=0.675min。LCMS (ESI): [M+H] + m/z: calculated 299.2; found 299.0; Rt=0.675 min.

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1398)之合成Step 5: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[2 Synthesis of -[rac-(3R)-1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1398)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-10min 50-70%甲醇+NH3 流速30mL/min(裝載泵4mL/min甲醇)，管柱：sun fire C18HPLC conditions: 2-10min 50-70% methanol + NH 3 flow rate 30mL/min (loading pump 4mL/min methanol), column: sun fire C18

產率：0.06g(15.17%)Yield: 0.06g (15.17%)

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.02(m,3H),1.10(m,3H),1.35(m,1H),1.82(m,2H),2.06(m,1H),2.19(m,2H),2.30(s,3H),2.38(m,3H),2.53(m,2H),2.84(m,2H),2.93(m,1H),3.83(m,1H),5.41(m,4H),7.20(m,1H),7.54(m,3H),8.03(m,1H),8.39(m,1H),10.50(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.02(m, 3H), 1.10(m, 3H), 1.35(m, 1H), 1.82(m, 2H), 2.06(m, 1H), 2.19(m, 2H), 2.30(s, 3H), 2.38(m, 3H), 2.53(m, 2H), 2.84(m, 2H), 2.93(m, 1H), 3.83(m, 1H), 5.41 (m, 4H), 7.20 (m, 1H), 7.54 (m, 3H), 8.03 (m, 1H), 8.39 (m, 1H), 10.50 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值490.2；實測值490.4；Rt=1.708min。LCMS (ESI): [M+H] + m/z: calculated 490.2; found 490.4; Rt=1.708 min.

實例673. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基Example 673. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl -2-[2-(1-甲基吖呾-3-基)吲唑-5-基]-1-哌啶基]乙醯胺(化合物1239)之合成- Synthesis of 2-[2-(1-Methylacridin-3-yl)indazol-5-yl]-1-piperidinyl]acetamide (Compound 1239)

Figure 110128222-A0202-12-2204-715
Figure 110128222-A0202-12-2204-715

步驟1：2-(1-甲基吖呾-3-基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 1: 2-(1-Methylacridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of base)indazole

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

FCC條件：Interchim；120g SiO2 ,MTB-MeOH 0~100%，流速=70mL/min，cv=8.1FCC conditions: Interchim; 120g SiO 2 , MTB-MeOH 0~100%, flow rate=70mL/min, cv=8.1

產率：3.0g(37.91%)Yield: 3.0 g (37.91%)

LCMS(ESI)：[M+H]+ m/z：計算值314.2；實測值314.2；Rt=0.898min。LCMS (ESI): [M+H] + m/z: calculated 314.2; found 314.2; Rt=0.898 min.

步驟2：外消旋-(3S)-3-甲基-6-[2-(1-甲基吖呾-3-基)吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Racemic-(3S)-3-methyl-6-[2-(1-methylacridin-3-yl)indazol-5-yl]-3,4-dihydro-2H- Synthesis of tert-butyl pyridine-1-carboxylate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

產率：0.7g(粗品)Yield: 0.7g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值383.0；實測值383.0；Rt=1.179min。LCMS (ESI): [M+H] + m/z: calculated 383.0; found 383.0; Rt=1.179 min.

步驟3：2-(1-甲基吖呾-3-基)-5-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 3: 2-(1-Methylacraz-3-yl)-5-[rac-(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl] Synthesis of Indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：0.6g(粗品)Yield: 0.6g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值283.2；實測值283.5；Rt=0.371min。LCMS (ESI): [M+H] + m/z: calculated 283.2; found 283.5; Rt=0.371 min.

步驟4：2-(1-甲基吖呾-3-基)-5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]吲唑之合成Step 4: Synthesis of 2-(1-Methylazrazin-3-yl)-5-[rac-(2R,5S)-5-methyl-2-piperidinyl]indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：0.6g(79.03%，2HCl)Yield: 0.6g (79.03%, 2HCl)

LCMS(ESI)：[M+H]+ m/z：計算值285.2；實測值285.2；Rt=0.660min。LCMS (ESI): [M+H] + m/z: calculated 285.2; found 285.2; Rt=0.660 min.

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基吖呾-3-基)吲唑-5-基]-1-哌啶基]乙醯胺(化合物1239)之合成Step 5: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[2 Synthesis of -(1-Methylacridin-3-yl)indazol-5-yl]-1-piperidinyl]acetamide (Compound 1239)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-10min 50-60%甲醇+NH3 流速30mL/min(裝載泵4mL/min甲醇)，管柱Sun Fire C18 100*19mmHPLC conditions: 2-10min 50-60% methanol + NH 3 flow rate 30mL/min (loading pump 4mL/min methanol), column Sun Fire C18 100*19mm

產率：0.047g(5.89%)Yield: 0.047g (5.89%)

1 H NMR(600MHz,dmso)δ 0.99-1.05(m,3H),1.06-1.13(m,3H),1.29-1.42(m,1H),1.66-1.79(m,1H),1.81-1.90(m,1H),2.02-2.18(m,1H),2.21-2.29(m,1H),2.34(s,3H),2.38-2.44(m,2H),2.76-3.19(m,1H),3.48-4.03(m,5H),5.21-5.28(m,1H),5.54-5.68(m,3H),7.15-7.29(m,1H),7.42-7.52(m,1H),7.59-7.65(m,2H),7.98-8.08(m,1H),8.41-8.48(m,1H),10.51(s,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.05(m,3H),1.06-1.13(m,3H),1.29-1.42(m,1H),1.66-1.79(m,1H),1.81-1.90(m ,1H),2.02-2.18(m,1H),2.21-2.29(m,1H),2.34(s,3H),2.38-2.44(m,2H),2.76-3.19(m,1H),3.48-4.03 (m,5H),5.21-5.28(m,1H),5.54-5.68(m,3H),7.15-7.29(m,1H),7.42-7.52(m,1H),7.59-7.65(m,2H) , 7.98-8.08(m, 1H), 8.41-8.48(m, 1H), 10.51(s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值477.2；實測值477.4；Rt=2.184min。LCMS (ESI): [M+2H] + m/z: calculated 477.2; found 477.4; Rt=2.184 min.

實例674. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基-3-哌啶基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1270)之Example 674. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 -[Rac-(3R)-1-methyl-3-piperidinyl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1270) 合成synthesis

Figure 110128222-A0202-12-2206-716
Figure 110128222-A0202-12-2206-716

步驟1：2-[外消旋-(3R)-1-甲基-3-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 1: 2-[Rac-(3R)-1-methyl-3-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)indazole

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

FCC條件：Interchim；120g SiO2 ，MTBE-MeOH 0~100%，流速=70mL/min，cv=6FCC conditions: Interchim; 120g SiO 2 , MTBE-MeOH 0~100%, flow rate=70mL/min, cv=6

產率：3g(34.80%)Yield: 3g (34.80%)

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值342.2；Rt=0.926min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 342.2; Rt=0.926 min.

步驟2：外消旋-(3S)-3-甲基-6-[2-[外消旋-(3R)-1-甲基-3-哌啶基]吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: rac-(3S)-3-methyl-6-[2-[rac-(3R)-1-methyl-3-piperidinyl]indazol-5-yl]-3 Synthesis of 3-butyl ,4-dihydro-2H-pyridine-1-carboxylate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

產率：0.7g(粗品)Yield: 0.7g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值411.4；實測值411.4；Rt=0.870min。LCMS (ESI): [M+H] + m/z: calculated 411.4; found 411.4; Rt=0.870 min.

步驟3：2-[外消旋-(3R)-1-甲基-3-哌啶基]-5-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 3: 2-[Rac-(3R)-1-methyl-3-piperidinyl]-5-[rac-(3S)-3-methyl-2,3,4,5- Synthesis of Tetrahydropyridin-6-yl]indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：0.45g(粗品)Yield: 0.45g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值311.2；實測值311.2；Rt=0.660min。LCMS (ESI): [M+H] + m/z: calculated 311.2; found 311.2; Rt=0.660 min.

步驟4：5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-2-[外消旋-(3R)-1-甲基-3-哌啶基]吲唑之合成Step 4: 5-[Rac-(2R,5S)-5-methyl-2-piperidinyl]-2-[rac-(3R)-1-methyl-3-piperidinyl] Synthesis of Indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：0.5g(粗品，2HCl)Yield: 0.5 g (crude, 2HCl)

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值313.2；Rt=0.687min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 313.2; Rt=0.687 min.

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基-3-哌啶基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1270)之合成Step 5: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[2 - Synthesis of [rac-(3R)-1-methyl-3-piperidinyl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1270)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-10min 50-100%甲醇+NH3 流速30mL/min(裝載泵4mL/min甲醇)，管柱：sun fire C18HPLC conditions: 2-10min 50-100% methanol + NH 3 flow rate 30mL/min (loading pump 4mL/min methanol), column: sun fire C18

產率：0.018g(2.75%)Yield: 0.018g (2.75%)

1 H NMR(600MHz,dmso)δ 0.99-1.05(m,3H),1.05-1.15(m,4H),1.29-1.41(m,1H),1.61-1.95(m,6H),1.98-2.09(m,3H),2.21-2.29(m,4H),2.66-3.03(m,4H),3.43-4.03(m,1H),4.55-4.63(m,1H),5.15-5.66(m,3H),7.12-7.26(m,1H),7.41-7.53(m,1H),7.55-7.64(m,2H),7.97-8.10(m,1H),8.40-8.46(m,1H),10.44-10.56(m,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.05(m,3H),1.05-1.15(m,4H),1.29-1.41(m,1H),1.61-1.95(m,6H),1.98-2.09(m ,3H),2.21-2.29(m,4H),2.66-3.03(m,4H),3.43-4.03(m,1H),4.55-4.63(m,1H),5.15-5.66(m,3H),7.12 -7.26(m,1H),7.41-7.53(m,1H),7.55-7.64(m,2H),7.97-8.10(m,1H),8.40-8.46(m,1H),10.44-10.56(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值504.2；實測值504.4；Rt=2.092min。LCMS (ESI): [M+H] + m/z: calculated 504.2; found 504.4; Rt=2.092 min.

實例675. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基Example 675. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl -2-[2-[外消旋-(3S)-1-甲基-3-哌啶基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1271)之合成- Synthesis of 2-[2-[rac-(3S)-1-methyl-3-piperidinyl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1271)

Figure 110128222-A0202-12-2208-717
Figure 110128222-A0202-12-2208-717

步驟1：2-[外消旋-(3S)-1-甲基-3-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 1: 2-[Rac-(3S)-1-methyl-3-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)indazole

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

FCC條件：Interchim；120g SiO2 ，MTB-MeOH 0~100%，流速=70mL/min，cv=6產率：3.1g(35.96%)FCC conditions: Interchim; 120 g SiO 2 , MTB-MeOH 0~100%, flow rate=70 mL/min, cv=6 Yield: 3.1 g (35.96%)

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值342.2；Rt=1.132min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 342.2; Rt=1.132 min.

步驟2：外消旋-(3S)-3-甲基-6-[2-[外消旋-(3S)-1-甲基-3-哌啶基]吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: rac-(3S)-3-methyl-6-[2-[rac-(3S)-1-methyl-3-piperidinyl]indazol-5-yl]-3 Synthesis of 3-butyl ,4-dihydro-2H-pyridine-1-carboxylate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

產率：1.2g(粗品)Yield: 1.2g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=1.062min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=1.062 min.

步驟3：2-[外消旋-(3S)-1-甲基-3-哌啶基]-5-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶Step 3: 2-[Rac-(3S)-1-methyl-3-piperidinyl]-5-[rac-(3S)-3-methyl-2,3,4,5- tetrahydropyridine -6-基]吲唑之合成Synthesis of -6-yl]indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：0.7g(粗品)Yield: 0.7g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值311.2；實測值311.2；Rt=0.937min。LCMS (ESI): [M+H] + m/z: calculated 311.2; found 311.2; Rt=0.937 min.

步驟4：5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-2-[外消旋-(3S)-1-甲基-3-哌啶基]吲唑之合成Step 4: 5-[Rac-(2R,5S)-5-methyl-2-piperidinyl]-2-[rac-(3S)-1-methyl-3-piperidinyl] Synthesis of Indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：0.5g(粗品，2HCl)Yield: 0.5 g (crude, 2HCl)

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值313.2；Rt=0.345min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 313.2; Rt=0.345 min.

步驟5：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基-3-哌啶基]吲唑-5-基]-1-哌啶基]乙醯胺(化合物1271)之合成Step 5: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[2 - Synthesis of [rac-(3S)-1-methyl-3-piperidinyl]indazol-5-yl]-1-piperidinyl]acetamide (compound 1271)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-10min 50-65%甲醇+NH3 流速30mL/min(裝載泵4mL/min甲醇)，管柱：sun fire C18HPLC conditions: 2-10min 50-65% methanol + NH 3 flow rate 30mL/min (loading pump 4mL/min methanol), column: sun fire C18

產率：0.06g(14.75%)Yield: 0.06g (14.75%)

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.07(m,6H),1.33(m,1H),1.69(m,3H),1.89(m,3H),2.04(m,3H),2.15(m,1H),2.22(s,4H),2.40(m,3H),2.74(m,1H),3.03(m,1H),3.83(m,1H),4.89(m,1H),5.61(m,2H),7.20(m,1H),7.54(m,3H),8.03(m,1H),8.43(m,1H),10.42(s,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.07(m, 6H), 1.33(m, 1H), 1.69(m, 3H), 1.89(m, 3H), 2.04(m, 3H), 2.15(m, 1H), 2.22(s, 4H), 2.40(m, 3H), 2.74(m, 1H), 3.03(m, 1H), 3.83(m, 1H), 4.89(m, 1H), 5.61 (m, 2H), 7.20 (m, 1H), 7.54 (m, 3H), 8.03 (m, 1H), 8.43 (m, 1H), 10.42 (s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值505.2；實測值505.2；Rt=1.707min。LCMS (ESI): [M+2H] + m/z: calculated 505.2; found 505.2; Rt=1.707 min.

實例676. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺( 化合物1141)之合成 Example 676. 2-Methoxy-5-[[2-Pendox-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R) Synthesis of -1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide ( compound 1141 )

Figure 110128222-A0202-12-2210-718
Figure 110128222-A0202-12-2210-718

步驟1：2-[外消旋-(3R)-1-甲基吡咯啶-3-基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 1: 2-[Rac-(3R)-1-methylpyrrolidin-3-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)indazole

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

FCC條件：Interchim；120g SiO2 ，MTBE-MeOH 0~100%，流速=70mL/min，cv=13.7FCC conditions: Interchim; 120g SiO 2 , MTBE-MeOH 0~100%, flow rate=70mL/min, cv=13.7

產率：3.6g(43.55%)Yield: 3.6g (43.55%)

LCMS(ESI)：[M+H]+ m/z：計算值328.2；實測值328.2；Rt=0.897min。LCMS (ESI): [M+H] + m/z: calculated 328.2; found 328.2; Rt=0.897 min.

步驟2：外消旋-(3S)-3-甲基-6-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: rac-(3S)-3-methyl-6-[2-[rac-(3R)-1-methylpyrrolidin-3-yl]indazol-5-yl]-3 Synthesis of 3-butyl ,4-dihydro-2H-pyridine-1-carboxylate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

產率：3.5g(粗品)Yield: 3.5g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值397.4；Rt=1.010min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 397.4; Rt=1.010 min.

步驟3：2-[外消旋-(3R)-1-甲基吡咯啶-3-基]-5-[外消旋-(3S)-3-甲基-2,3,4,5-四氫Step 3: 2-[Rac-(3R)-1-methylpyrrolidin-3-yl]-5-[rac-(3S)-3-methyl-2,3,4,5- tetrahydro 吡啶-6-基]吲唑之合成Synthesis of Pyridin-6-yl]indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：2.0g(粗品)Yield: 2.0g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值297.2；實測值297.1；Rt=0.380min。LCMS (ESI): [M+H] + m/z: calculated 297.2; found 297.1; Rt=0.380 min.

步驟4：5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑之合成Step 4: 5-[Rac-(2R,5S)-5-methyl-2-piperidinyl]-2-[rac-(3R)-1-methylpyrrolidin-3-yl] Synthesis of Indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：1.9g(粗品，2 HCl)Yield: 1.9 g (crude, 2 HCl)

LCMS(ESI)：[M+H]+ m/z：計算值299.2；實測值299.0；Rt=0.675min。LCMS (ESI): [M+H] + m/z: calculated 299.2; found 299.0; Rt=0.675 min.

步驟5：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3R)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1141)之合成Step 5: 2-Methoxy-5-[[2-Pendoxyloxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3R) Synthesis of -1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 1141)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-10min 45-60%甲醇+NH3 流速30mL/min(裝載泵4mL/min甲醇)，管柱：sun fire C18HPLC conditions: 2-10min 45-60% methanol + NH 3 flow rate 30mL/min (loading pump 4mL/min methanol), column: sun fire C18

產率：0.02g(9.53%)Yield: 0.02g (9.53%)

1 H NMR(600MHz,dmso)δ 0.96-1.09(m,3H),1.30-1.40(m,1H),1.57-2.07(m,3H),2.11-2.26(m,2H),2.31(s,3H),2.78-3.23(m,5H),3.47-4.00(m,5H),5.14-5.68(m,2H),7.13-7.28(m,1H),7.55-7.63(m,2H),7.68-7.76(m,2H),8.35-8.59(m,3H),10.94-11.13(m,1H)。 1 H NMR(600MHz,dmso)δ 0.96-1.09(m,3H),1.30-1.40(m,1H),1.57-2.07(m,3H),2.11-2.26(m,2H),2.31(s,3H) ), 2.78-3.23(m, 5H), 3.47-4.00(m, 5H), 5.14-5.68(m, 2H), 7.13-7.28(m, 1H), 7.55-7.63(m, 2H), 7.68-7.76 (m, 2H), 8.35-8.59 (m, 3H), 10.94-11.13 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值520.2；實測值520.4；Rt=2.407min。LCMS (ESI): [M+H] + m/z: calculated 520.2; found 520.4; Rt=2.407 min.

實例677. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1318)之合成Example 677. 2-Methoxy-5-[[2-Pendox-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S) Synthesis of -1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 1318)

Figure 110128222-A0202-12-2212-719
Figure 110128222-A0202-12-2212-719

步驟1：2-[外消旋-(3S)-1-甲基吡咯啶-3-基]-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 1: 2-[Rac-(3S)-1-methylpyrrolidin-3-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolalan-2-yl)indazole

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

FCC條件：Interchim；120g SiO2 ，MTB-MeOH 0~100%，流速=70mL/min，cv=13.9FCC conditions: Interchim; 120g SiO 2 , MTB-MeOH 0~100%, flow rate=70mL/min, cv=13.9

產率：2.6g(31.45%)Yield: 2.6g (31.45%)

LCMS(ESI)：[M+H]+ m/z：計算值328.2；實測值328.2；Rt=0.904min。LCMS (ESI): [M+H] + m/z: calculated 328.2; found 328.2; Rt=0.904 min.

步驟2：外消旋-(3S)-3-甲基-6-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: rac-(3S)-3-methyl-6-[2-[rac-(3S)-1-methylpyrrolidin-3-yl]indazol-5-yl]-3 Synthesis of 3-butyl ,4-dihydro-2H-pyridine-1-carboxylate

藉由一般程序方案L步驟2製備Prepared by General Procedure L, Step 2

產率：2.0g(粗品)Yield: 2.0g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值397.2；Rt=1.189min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found 397.2; Rt=1.189 min.

步驟3：2-[外消旋-(3S)-1-甲基吡咯啶-3-基]-5-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 3: 2-[Rac-(3S)-1-methylpyrrolidin-3-yl]-5-[rac-(3S)-3-methyl-2,3,4,5- Synthesis of Tetrahydropyridin-6-yl]indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：1.55g(粗品)Yield: 1.55g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值297.2；實測值297.2；Rt=0.668min。LCMS (ESI): [M+H] + m/z: calculated 297.2; found 297.2; Rt=0.668 min.

步驟4：5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]-2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑之合成Step 4: 5-[Rac-(2R,5S)-5-methyl-2-piperidinyl]-2-[rac-(3S)-1-methylpyrrolidin-3-yl] Synthesis of Indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：1.5g(粗品，2HCl)Yield: 1.5 g (crude, 2HCl)

LCMS(ESI)：[M+H]+ m/z：計算值299.2；實測值299.2；Rt=0.680min。LCMS (ESI): [M+H] + m/z: calculated 299.2; found 299.2; Rt=0.680 min.

步驟5：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-[外消旋-(3S)-1-甲基吡咯啶-3-基]吲唑-5-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1318)之合成Step 5: 2-Methoxy-5-[[2-Pendoxyloxy-2-[rac-(2R,5S)-5-methyl-2-[2-[rac-(3S) Synthesis of -1-methylpyrrolidin-3-yl]indazol-5-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 1318)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：2-10min 50-65%甲醇+NH3 流速30.0mL/min(裝載泵4mL/min甲醇)，管柱：SunFire C18HPLC conditions: 2-10 min 50-65% methanol + NH 3 flow rate 30.0 mL/min (loading pump 4 mL/min methanol), column: SunFire C18

產率：0.017g(8.10%)Yield: 0.017g (8.10%)

1 H NMR(600MHz,dmso)δ 0.99-1.07(m,3H),1.29-1.40(m,1H),1.72-1.83(m,1H),1.83-1.94(m,1H),2.03-2.27(m,3H),2.30(s,3H),2.75-3.20(m,5H),3.46-4.03(m,5H),5.13-5.68(m,2H),7.13-7.27(m,1H),7.55-7.65(m,2H),7.67-7.76(m,2H),8.36-8.42(m,1H),8.43-8.68(m,2H),10.93-11.10(m,1H)。 1 H NMR(600MHz,dmso)δ 0.99-1.07(m,3H),1.29-1.40(m,1H),1.72-1.83(m,1H),1.83-1.94(m,1H),2.03-2.27(m ,3H),2.30(s,3H),2.75-3.20(m,5H),3.46-4.03(m,5H),5.13-5.68(m,2H),7.13-7.27(m,1H),7.55-7.65 (m, 2H), 7.67-7.76 (m, 2H), 8.36-8.42 (m, 1H), 8.43-8.68 (m, 2H), 10.93-11.10 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值520.2；實測值520.2；Rt=2.393min。LCMS (ESI): [M+H] + m/z: calculated 520.2; found 520.2; Rt=2.393 min.

實例678. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基 -2-[2-(1,2,2,6,6-五甲基-4-哌啶基)吲唑-5-基]-1-哌啶基]乙醯胺( 化合物1140)之合成 Example 678. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl -2-[2 Synthesis of -(1,2,2,6,6-pentamethyl-4-piperidinyl)indazol-5-yl]-1-piperidinyl]acetamide ( compound 1140 )

Figure 110128222-A0202-12-2214-720
Figure 110128222-A0202-12-2214-720

步驟1：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-(2,2,6,6-四甲基-4-哌啶基)吲唑之合成Step 1: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-2-(2,2,6,6-tetra Synthesis of methyl-4-piperidinyl)indazole

藉由一般程序方案L步驟1製備Prepared by General Procedure L, Step 1

產率：2.8g(粗品)Yield: 2.8g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值384.2；實測值384.2；Rt=1.133minLCMS(ESI): [M+H] + m/z: Calculated 384.2; Found 384.2; Rt=1.133min

步驟2：2-(1,2,2,6,6-五甲基-4-哌啶基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 2: 2-(1,2,2,6,6-Pentamethyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Synthesis of Bororol-2-yl)indazole

藉由一般程序方案L步驟1C製備Prepared by General Procedure L, Step 1C

產率：3.0g(粗品)Yield: 3.0g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值398.2；實測值398.1；Rt=1.152min。LCMS (ESI): [M+H] + m/z: calculated 398.2; found 398.1; Rt=1.152 min.

步驟3：外消旋-(3S)-3-甲基-6-[2-(1,2,2,6,6-五甲基-4-哌啶基)吲唑-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: Racemic-(3S)-3-methyl-6-[2-(1,2,2,6,6-pentamethyl-4-piperidinyl)indazol-5-yl]- Synthesis of 3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

藉由一般程序方案L步驟2C製備Prepared by General Procedure L, Step 2C

產率：3.5g(粗品)Yield: 3.5g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值467.2；Rt=1.232min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 467.2; Rt=1.232 min.

步驟4：2-(1,2,2,6,6-五甲基-4-哌啶基)-5-[外消旋-(3S)-3-甲基-1,2,3,4-四氫吡啶-6-基]吲唑之合成Step 4: 2-(1,2,2,6,6-Pentamethyl-4-piperidinyl)-5-[rac-(3S)-3-methyl-1,2,3,4 -Synthesis of tetrahydropyridin-6-yl]indazole

藉由一般程序方案L步驟3(方法A)製備Prepared by General Procedure L, Step 3 (Method A)

產率：1.1g(粗品)Yield: 1.1 g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值367.2；Rt=0.725min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 367.2; Rt=0.725 min.

步驟5：2-(1,2,2,6,6-五甲基-4-哌啶基)-5-[外消旋-(2R,5S)-5-甲基-2-哌啶基]吲唑之合成Step 5: 2-(1,2,2,6,6-Pentamethyl-4-piperidinyl)-5-[rac-(2R,5S)-5-methyl-2-piperidinyl ] Synthesis of Indazole

藉由一般程序方案L步驟4製備Prepared by General Procedure L, Step 4

產率：1.3g(粗品)Yield: 1.3g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值369.2；實測值369.2；Rt=0.756min。LCMS (ESI): [M+H] + m/z: calculated 369.2; found 369.2; Rt=0.756 min.

步驟6：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1,2,2,6,6-五甲基-4-哌啶基)吲唑-5-基]-1-哌啶基]乙醯胺(化合物1140)之合成Step 6: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 Synthesis of -(1,2,2,6,6-Pentamethyl-4-piperidinyl)indazol-5-yl]-1-piperidinyl]acetamide (Compound 1140)

藉由一般程序方案L步驟5製備Prepared by General Procedure L, Step 5

HPLC條件：管柱：XBridge C18 100x19mm 5um；流動相：35-35-60% 0-1-6min H2 O/MeCN/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeCN)HPLC conditions: Column: XBridge C18 100x19mm 5um; Mobile phase: 35-35-60% 0-1-6min H2O /MeCN/0.1% NH4OH , flow rate: 30mL/min (loading pump 4mL/min MeCN)

產率：78.2mg(25.74%)Yield: 78.2 mg (25.74%)

1 H NMR(600MHz,dmso)δ 0.86-1.09(m,6H),1.10-1.12(m,6H),1.13-1.16(m,6H),1.32-1.46(m,2H),1.75-2.07(m,7H),2.11-2.19(m,1H),2.21-2.24(m,3H),2.39-2.43(m,1H),2.76-3.23(m,1H),3.45-4.05(m,1H),4.78-4.90(m,1H),5.14-5.71(m,3H),7.11-7.28(m,1H),7.41-7.54(m,1H),7.57-7.74(m,2H),7.98-8.11(m,1H),8.36-8.45(m,1H),10.52(s,1H)。 1 H NMR(600MHz,dmso)δ 0.86-1.09(m,6H),1.10-1.12(m,6H),1.13-1.16(m,6H),1.32-1.46(m,2H),1.75-2.07(m ,7H),2.11-2.19(m,1H),2.21-2.24(m,3H),2.39-2.43(m,1H),2.76-3.23(m,1H),3.45-4.05(m,1H),4.78 -4.90(m, 1H), 5.14-5.71(m, 3H), 7.11-7.28(m, 1H), 7.41-7.54(m, 1H), 7.57-7.74(m, 2H), 7.98-8.11(m, 1H), 8.36-8.45 (m, 1H), 10.52 (s, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值561.2；實測值561.1；Rt=2.193min。LCMS (ESI): [M+2H] + m/z: calculated 561.2; found 561.1; Rt=2.193 min.

方案M-式13化合物之合成Scheme M - Synthesis of Compounds of Formula 13

式11化合物為式(I)化合物，其中R1 、R2 、R3 、R4 、R6 、R7 及R8 如本文所述。Compounds of formula 11 are compounds of formula ( I ) wherein R1, R2, R3 , R4, R6, R7 and R8 are as described herein.

一般程序13General Procedures 13

Figure 110128222-A0202-12-2216-721
Figure 110128222-A0202-12-2216-721

步驟1：13B之一般程序Step 1: General Procedure for 13B

將2-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯甲醛(1.0當量)及13A (1.0當量，或其鹽)溶解於i-PrOH(140mL)中。將所得混合物在80℃下攪拌2小時，隨後添加三-正丁基膦(Bu3 P，3.0當量)。將反應混合物在回流下攪拌2小時。然後，在真空中移除揮發物。將殘餘物溶解於DCM且用水洗滌。將有 機層分離，經Na2 SO4 乾燥且在減壓下濃縮。藉由急驟層析純化殘餘物，以得到13B。 2-Nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzaldehyde (1.0 equiv.) and 13A (1.0 equivalent, or its salt) was dissolved in i-PrOH (140 mL). The resulting mixture was stirred at 80°C for 2 hours, then tri-n-butylphosphine ( Bu3P , 3.0 equiv) was added. The reaction mixture was stirred at reflux for 2 hours. Then, the volatiles were removed in vacuo. The residue was dissolved in DCM and washed with water. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give 13B.

步驟1A：13F之一般程序Step 1A: General Procedure for 13F

將5-溴-2-硝基苯甲醛(1.0當量)及13A (1.0當量)溶解於i-PrOH(400.0mL)中。將所得混合物在80℃下攪拌2h，隨後添加三-正丁基膦(3.0當量)。將反應混合物再回流16h。然後將反應混合物在減壓下蒸發且藉由急驟層析純化，以得到13F。5-Bromo-2-nitrobenzaldehyde (1.0 equiv) and 13A (1.0 equiv) were dissolved in i-PrOH (400.0 mL). The resulting mixture was stirred at 80 °C for 2 h, then tri-n-butylphosphine (3.0 equiv) was added. The reaction mixture was refluxed for an additional 16 h. The reaction mixture was then evaporated under reduced pressure and purified by flash chromatography to give 13F.

步驟1B：13H之一般程序Step 1B: General Procedure for 13H

將5-溴-2-硝基苯甲醛(1.0當量)及13G (1.0當量)溶解於i-PrOH(80.0mL)中。將所得混合物在80℃下攪拌2h且添加三-正丁基膦(3.0當量)。將反應混合物再回流16h。然後將反應混合物在減壓下蒸發且藉由急驟層析純化，以得到13H 。5-Bromo-2-nitrobenzaldehyde (1.0 equiv) and 13G (1.0 equiv) were dissolved in i-PrOH (80.0 mL). The resulting mixture was stirred at 80 °C for 2 h and tri-n-butylphosphine (3.0 equiv) was added. The reaction mixture was refluxed for an additional 16 h. The reaction mixture was then evaporated under reduced pressure and purified by flash chromatography to give 13H .

步驟1C：13J之一般程序Step 1C: General Procedure for 13J

將99%無水碳酸鉀(3.0當量)及碘甲烷(1.7當量)添加到13B (1.0當量)於MeCN(大約45.0mL)中之溶液中。將所得混合物在25℃下攪拌16h。然後，在減壓下移除溶劑。將殘餘物用水(40.0mL)稀釋且將所得混合物用DCM萃取，得到13J 。To a solution of 13B (1.0 equiv) in MeCN (approximately 45.0 mL) was added 99% anhydrous potassium carbonate (3.0 equiv) and iodomethane (1.7 equiv). The resulting mixture was stirred at 25 °C for 16 h. Then, the solvent was removed under reduced pressure. The residue was diluted with water (40.0 mL) and the resulting mixture was extracted with DCM to give 13J .

步驟2：13C之一般程序Step 2: General Procedure for 13C

在惰性氣氛、85℃下，將13B (1.0當量)、外消旋-(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.01當量)、碳酸鈉(3.0當量)及Pd(dppf)Cl2 DCM(0.05當量)在1,4-二噁烷(6.0mL)及水(2.0mL)之混合物中攪拌15h。完成之後，將反應混合物冷卻，用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮，以得到13C 。所獲得之材料不經額外純化即用於下一步驟中。 13B (1.0 equiv.), rac-(3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H under inert atmosphere at 85°C - tert-butyl pyridine-1-carboxylate (1.01 equiv), sodium carbonate (3.0 equiv) and Pd(dppf) Cl2DCM (0.05 equiv) in 1,4-dioxane (6.0 mL) and water (2.0 mL) ) was stirred in the mixture for 15h. After completion, the reaction mixture was cooled, diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to give 13C . The obtained material was used in the next step without additional purification.

步驟2A：13B之一般程序Step 2A: General Procedure for 13B

將13F (1.0當量)、B2 Pin2 (1.1當量)及乙酸鉀(2.0當量)一起混合於1.4-二噁烷(大約20.0mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)2 Cl2 DCM(993.01mg，1.22mmol)。將反應混合物在氬氣氣氛、90℃下攪拌14h。然後使混合物冷卻至室溫且在真空中移除揮發物，以得到13B 。 13F (1.0 equiv), B2Pin2 (1.1 equiv) and potassium acetate ( 2.0 equiv) were mixed together in 1.4-dioxane (approximately 20.0 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf) 2Cl2DCM (993.01 mg , 1.22 mmol) was added under argon. The reaction mixture was stirred at 90 °C for 14 h under an argon atmosphere. The mixture was then cooled to room temperature and the volatiles were removed in vacuo to give 13B .

步驟2B：13I之一般程序Step 2B: General Procedure for 13I

將13H (1.0當量)溶解於TFA(1.0mL)及DCM(1.0mL)之混合物中。將反應混合物在室溫下攪拌30分鐘。然後，將混合物在真空中濃縮，得到13I 。所獲得之材料不經額外純化即用於下一步驟中。 13H (1.0 equiv) was dissolved in a mixture of TFA (1.0 mL) and DCM (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. Then, the mixture was concentrated in vacuo to give 13I . The obtained material was used in the next step without additional purification.

步驟2C：13C之一般程序Step 2C: General Procedure for 13C

將碳酸鈉(2.0當量)添加到13J (1.0當量)及外消旋-(5S)-5-甲基-2-(三氟甲基磺醯基氧基)哌啶-1-甲酸第三丁酯(1.1當量)於水(大約15.0mL)及1,4-二噁烷(大約50.0mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2 ‧CH2 Cl2 (0.05當量)。在惰性氣氛下將所得混合物在90℃下攪拌15h。反應完成之後，添加水(大約50.0mL)。將所得混合物用EtOAc(3*20.0mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中濃縮，以獲得13C 。所獲得之材料不經額外純化即用於下一步驟中。Sodium carbonate (2.0 equiv) was added to 13J (1.0 equiv) and rac-(5S)-5-methyl-2-(trifluoromethylsulfonyloxy)piperidine-1-carboxylic acid tert-butyl A solution of ester (1.1 equiv) in water (approximately 15.0 mL) and 1,4-dioxane (approximately 50.0 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, Pd(dppf) Cl2.CH2Cl2 ( 0.05 equiv. ) was added under argon flow. The resulting mixture was stirred at 90 °C for 15 h under an inert atmosphere. After the reaction was complete, water (approximately 50.0 mL) was added. The resulting mixture was extracted with EtOAc (3*20.0 mL). The combined organic layers were dried over Na2SO4 , filtered and concentrated in vacuo to obtain 13C . The obtained material was used in the next step without additional purification.

步驟3：13D之一般程序Step 3: General Procedure for 13D

方法A：Method A:

將13C (1.0當量)溶解於TFA(1.0mL)及DCM(1.0mL)之混合物中。將反應混合物在室溫下攪拌30分鐘。然後，將混合物在真空中濃縮，得到13D 。所獲得之材料不經額外純化即用於下一步驟中。 13C (1.0 equiv) was dissolved in a mixture of TFA (1.0 mL) and DCM (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. Then, the mixture was concentrated in vacuo to give 13D . The obtained material was used in the next step without additional purification.

方法B：Method B:

將13C (1.0當量)溶解於HCl(於二噁烷中之4.0M溶液，1.0mL)及MeOH(1.0mL)之混合物中。將反應混合物在室溫下攪拌隔夜。然後，將混合物在真空中濃縮，得到13D 。所獲得之材料不經額外純化即用於下一步驟中。 13C (1.0 equiv.) was dissolved in a mixture of HCl (4.0 M in dioxane, 1.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at room temperature overnight. Then, the mixture was concentrated in vacuo to give 13D . The obtained material was used in the next step without additional purification.

步驟3B：13F之一般程序Step 3B: General Procedure for 13F

向13I (1.0當量)、乙酸(1.0當量)及用10-15%甲醇穩定之37%甲醛水溶液(ACS，36.5-38.0%)(1.0當量)於DCM(大約25.0mL)中之溶液中添加三乙醯氧基硼氫化鈉(1.0當量)。將所得混合物在25℃下攪拌16h。然後，在真空中移除溶劑。將殘餘物倒入到H2 O(50.0mL)中且用EtOAc(2x20.0mL)萃取。將經合併之有機萃取物用鹽水(2* 20.0mL)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到13F 。To a solution of 13I (1.0 equiv.), acetic acid (1.0 equiv.), and 37% aqueous formaldehyde (ACS, 36.5-38.0%) stabilized with 10-15% methanol (1.0 equiv.) in DCM (approximately 25.0 mL) was added three Sodium acetoxyborohydride (1.0 equiv.). The resulting mixture was stirred at 25 °C for 16 h. Then, the solvent was removed in vacuo. The residue was poured into H2O (50.0 mL) and extracted with EtOAc (2 x 20.0 mL). The combined organic extracts were washed with brine (2 * 20.0 mL), dried over sodium sulfate and evaporated in vacuo to give 13F .

步驟4：13E之一般程序Step 4: General Procedure for 13E

將硼氫化鈉(2.0當量)分批添加到13D (1.0當量)於MeOH(5.0mL)中之溶液中。將反應混合物在室溫下攪拌17小時。然後，將混合物用HCl(於二噁烷中之4.0M溶液)酸化至pH5且在真空中移除揮發物，以得到13E 。所獲得之材料不經額外純化即用於下一步驟中。Sodium borohydride (2.0 equiv) was added portionwise to a solution of 13D (1.0 equiv) in MeOH (5.0 mL). The reaction mixture was stirred at room temperature for 17 hours. The mixture was then acidified to pH 5 with HCl (4.0M in dioxane) and the volatiles were removed in vacuo to give 13E . The obtained material was used in the next step without additional purification.

步驟5：式13之一般程序Step 5: General Procedure of Equation 13

將HATU(1.4當量)添加到13E (1.0當量)、相應酸(1.1當量)及DIPEA(10.0當量)於DMSO(大約6.0mL)中之經攪拌之溶液中。將所得反應混合物在25℃下攪拌4h。將所得混合物提交至反相HPLC，以得到式E。 HATU (1.4 equiv) was added to a stirred solution of 13E (1.0 equiv), the corresponding acid (1.1 equiv) and DIPEA (10.0 equiv) in DMSO (approximately 6.0 mL). The resulting reaction mixture was stirred at 25 °C for 4 h. The resulting mixture was submitted to reverse phase HPLC to give formula E.

實例679. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1,2,2,6,6-五甲基-4-哌啶基)吲唑-6-基]-1-哌啶基]乙醯胺(化合物1295)之合成Example 679. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 Synthesis of -(1,2,2,6,6-Pentamethyl-4-piperidinyl)indazol-6-yl]-1-piperidinyl]acetamide (Compound 1295)

步驟1：6-溴-2-(2,2,6,6-四甲基-4-哌啶基)吲唑之合成Step 1: Synthesis of 6-bromo-2-(2,2,6,6-tetramethyl-4-piperidinyl)indazole

藉由一般程序方案M步驟1A製備Prepared by General Procedure M, Step 1A

產率：3.6g(82.08%)Yield: 3.6g (82.08%)

LCMS(ESI)：[M+H]+ m/z：計算值336.2；實測值336.2；Rt=1.061min。LCMS (ESI): [M+H] + m/z: calculated 336.2; found 336.2; Rt=1.061 min.

步驟2：6-溴-2-(1,2,2,6,6-五甲基-4-哌啶基)吲唑之合成Step 2: Synthesis of 6-bromo-2-(1,2,2,6,6-pentamethyl-4-piperidinyl)indazole

藉由一般程序方案M步驟1C製備Prepared by General Scheme M, Step 1C

產率：2.7g(72.0%)Yield: 2.7g (72.0%)

LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值350.2；Rt=1.015min。LCMS (ESI): [M+H] + m/z: calculated 352.2; found 350.2; Rt=1.015 min.

步驟3：2-(1,2,2,6,6-五甲基-4-哌啶基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 3: 2-(1,2,2,6,6-Pentamethyl-4-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxo Synthesis of Bororol-2-yl)indazole

藉由一般程序方案M步驟2A製備Prepared by General Procedure M, Step 2A

產率：1.8g(58.77%)Yield: 1.8g (58.77%)

LCMS(ESI)：[M+H]+ m/z：計算值398.2；實測值398.0；Rt=1.118min。LCMS (ESI): [M+H] + m/z: calculated 398.2; found 398.0; Rt=1.118 min.

步驟4：外消旋-(3S)-3-甲基-6-[2-(1,2,2,6,6-五甲基-4-哌啶基)吲唑-6-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 4: Racemic-(3S)-3-methyl-6-[2-(1,2,2,6,6-pentamethyl-4-piperidinyl)indazol-6-yl]- Synthesis of 3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

藉由一般程序方案M步驟2製備Prepared by General Procedure M, Step 2

產率：2.0g(粗品)Yield: 2.0g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值467.2；實測值467.4；Rt=1.276min。LCMS (ESI): [M+H] + m/z: calculated 467.2; found 467.4; Rt=1.276 min.

步驟5：2-(1,2,2,6,6-五甲基-4-哌啶基)-6-[外消旋-(3S)-3-甲基-1,2,3,4-四氫吡啶-6-基]吲唑之合成Step 5: 2-(1,2,2,6,6-Pentamethyl-4-piperidinyl)-6-[rac-(3S)-3-methyl-1,2,3,4 -Synthesis of tetrahydropyridin-6-yl]indazole

藉由一般程序方案M步驟3(方法A)製備Prepared by General Scheme M, Step 3 (Method A)

產率：0.9g(57.29%)Yield: 0.9g (57.29%)

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值367.2；Rt=0.727min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 367.2; Rt=0.727 min.

步驟6：2-(1,2,2,6,6-五甲基-4-哌啶基)-6-[外消旋-(2R,5S)-5-甲基-2-哌啶基]吲唑之合成Step 6: 2-(1,2,2,6,6-Pentamethyl-4-piperidinyl)-6-[rac-(2R,5S)-5-methyl-2-piperidinyl ] Synthesis of Indazole

藉由一般程序方案M步驟4製備Prepared by General Procedure M, Step 4

產率：0.8g(93.60%)Yield: 0.8g (93.60%)

LCMS(ESI)：[M+H]+ m/z：計算值369.2；實測值369.2；Rt=0.767min。LCMS (ESI): [M+H] + m/z: calculated 369.2; found 369.2; Rt=0.767 min.

步驟7：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1,2,2,6,6-五甲基-4-哌啶基)吲唑-6-基]-1-哌啶基]乙醯胺(化合物1295)之合成Step 7: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[racemic-(2R,5S)-5-methyl-2-[2 Synthesis of -(1,2,2,6,6-Pentamethyl-4-piperidinyl)indazol-6-yl]-1-piperidinyl]acetamide (Compound 1295)

藉由一般程序方案M步驟5製備Prepared by General Procedure M, Step 5

HPLC條件：管柱：XBridge C18 100x19mm 5um；流動相：50-100% 0-5minH2 O/MeOH/0.1% NH4 OH，流速：30mL/min(裝載泵4mL/min MeCN)HPLC conditions: Column: XBridge C18 100x19mm 5um; Mobile phase: 50-100% 0-5minH2O /MeOH/0.1% NH4OH , flow rate: 30mL/min (load pump 4mL/min MeCN)

產率：79.9mg(35.07%)Yield: 79.9 mg (35.07%)

1 H NMR(600MHz,dmso)δ 1.02-1.07(m,3H),1.10-1.17(m,15H),1.31-1.43(m,1H),1.69-1.80(m,1H),1.82-1.92(m,1H),1.93-2.00(m,4H),2.02-2.12(m,1H),2.13-2.22(m,1H),2.22(s,3H),2.37-2.45(m,2H),2.78-3.10(m,1H),3.43-4.07(m,1H),4.79-4.89(m,1H),5.19-5.70(m,3H),6.94-7.09(m,1H),7.41-7.53(m,2H),7.64-7.71(m,1H),7.97-8.10(m,1H),8.41(s,1H),10.36-10.71(m,1H)。 1 H NMR(600MHz,dmso)δ 1.02-1.07(m,3H),1.10-1.17(m,15H),1.31-1.43(m,1H),1.69-1.80(m,1H),1.82-1.92(m ,1H),1.93-2.00(m,4H),2.02-2.12(m,1H),2.13-2.22(m,1H),2.22(s,3H),2.37-2.45(m,2H),2.78-3.10 (m,1H),3.43-4.07(m,1H),4.79-4.89(m,1H),5.19-5.70(m,3H),6.94-7.09(m,1H),7.41-7.53(m,2H) , 7.64-7.71(m, 1H), 7.97-8.10(m, 1H), 8.41(s, 1H), 10.36-10.71(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值560.2；實測值560.2；Rt=2.166min。LCMS (ESI): [M+H] + m/z: calculated 560.2; found 560.2; Rt=2.166 min.

實例680. 2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-6-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1299)之合成Example 680. 2-Methoxy-5-[[2-Pendox-2-[racemic-(2R,5S)-5-methyl-2-[2-(1-methyl-4- Synthesis of piperidinyl)indazol-6-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 1299)

Figure 110128222-A0202-12-2222-722
Figure 110128222-A0202-12-2222-722

步驟1：6-溴-2-(1-甲基-4-哌啶基)吲唑之合成Step 1: Synthesis of 6-bromo-2-(1-methyl-4-piperidinyl)indazole

藉由一般程序方案M步驟1A製備Prepared by General Procedure M, Step 1A

FCC條件：Interchim；330g SiO2 ，MTBE-MeOH 0~100%，流速=100mL/min，cv=10FCC conditions: Interchim; 330g SiO 2 , MTBE-MeOH 0~100%, flow rate=100mL/min, cv=10

產率：38.0g(74.28%)Yield: 38.0 g (74.28%)

LCMS(ESI)：[M+2H]+ m/z：計算值296.2；實測值296.2；Rt=0.808min。LCMS (ESI): [M+2H] + m/z: calculated 296.2; found 296.2; Rt=0.808 min.

步驟2：2-(1-甲基-4-哌啶基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 2: 2-(1-Methyl-4-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of base)indazole

藉由一般程序方案M步驟2A製備Prepared by General Procedure M, Step 2A

FCC條件：Interchim；120g SiO2 ，MTBE-MeOH 0~100%，流速=70mL/min，cv=7FCC conditions: Interchim; 120g SiO 2 , MTBE-MeOH 0~100%, flow rate=70mL/min, cv=7

產率：21.0g(47.64%)Yield: 21.0 g (47.64%)

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值342.0；Rt=1.045min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 342.0; Rt=1.045 min.

步驟3：外消旋-(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)吲唑-6-基]-3,4-二氫-2H-吡啶Step 3: Racemic-(3S)-3-methyl-6-[2-(1-methyl-4-piperidinyl)indazol-6-yl]-3,4-dihydro-2H- Pyridine -1-甲酸第三丁酯之合成-Synthesis of tert-butyl 1-carboxylate

藉由一般程序方案M步驟2製備Prepared by General Procedure M, Step 2

FCC條件：Interchim；120g SiO2 ，MTBE-MeOH 0~100%，流速=70mL/min，cv=11FCC conditions: Interchim; 120g SiO 2 , MTBE-MeOH 0~100%, flow rate=70mL/min, cv=11

產率：9.0g(74.81%)Yield: 9.0 g (74.81%)

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.4；Rt=1.165min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.4; Rt=1.165 min.

步驟4：2-(1-甲基-4-哌啶基)-6-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 4: 2-(1-Methyl-4-piperidinyl)-6-[rac-(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl] Synthesis of Indazole

藉由一般程序方案M步驟3(方法B)製備Prepared by General Scheme M, Step 3 (Method B)

產率：6.0g(71.40%，2HCl)Yield: 6.0 g (71.40%, 2HCl)

LCMS(ESI)：[M+H]+ m/z：計算值311.2；實測值311.2；Rt=0.578min。LCMS (ESI): [M+H] + m/z: calculated 311.2; found 311.2; Rt=0.578 min.

步驟5：2-(1-甲基-4-哌啶基)-6-[外消旋-(2R,5S)-5-甲基-2-哌啶基]吲唑之合成Step 5: Synthesis of 2-(1-Methyl-4-piperidinyl)-6-[rac-(2R,5S)-5-methyl-2-piperidinyl]indazole

藉由一般程序方案M步驟4製備Prepared by General Procedure M, Step 4

產率：4.9g(粗品)Yield: 4.9g (crude)

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值313.2；Rt=0.543min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 313.2; Rt=0.543 min.

步驟6：2-甲氧基-5-[[2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-6-基]-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物1299)之合成Step 6: 2-Methoxy-5-[[2-Pendoxyloxy-2-[racemic-(2R,5S)-5-methyl-2-[2-(1-methyl-4- Synthesis of piperidinyl)indazol-6-yl]-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 1299)

藉由一般程序方案M步驟5製備Prepared by General Procedure M, Step 5

HPLC條件：2-10min 50-100%水-MeOH+NH3 流速30mL/min(裝載泵4mL甲醇)，管柱：sun fire C18HPLC conditions: 2-10min 50-100% water-MeOH+NH 3 flow rate 30mL/min (loading pump 4mL methanol), column: sun fire C18

產率：0.22g(44.40%)Yield: 0.22g (44.40%)

1 H NMR(600MHz,dmso)δ 0.73-1.06(m,3H),1.27-1.43(m,1H),1.65-1.82(m,1H),1.82-1.94(m,1H),2.02-2.15(m,7H),2.21(s,3H),2.24-2.34(m,1H),2.80-3.13(m,3H),3.46-3.51(m,0.7H),3.91-3.97(m,3H),4.01-4.05(m,0.3H),4.38- 4.45(m,1H),5.17-5.73(m,1H),6.95-7.10(m,1H),7.53(s,1H),7.64-7.73(m,2H),7.74(s,1H),8.35-8.39(m,1H),8.39-8.49(m,1H),8.49-8.64(m,1H),10.76(br s,1H)。 1 H NMR(600MHz,dmso)δ 0.73-1.06(m,3H),1.27-1.43(m,1H),1.65-1.82(m,1H),1.82-1.94(m,1H),2.02-2.15(m ,7H),2.21(s,3H),2.24-2.34(m,1H),2.80-3.13(m,3H),3.46-3.51(m,0.7H),3.91-3.97(m,3H),4.01- 4.05(m,0.3H),4.38- 4.45(m,1H),5.17-5.73(m,1H),6.95-7.10(m,1H),7.53(s,1H),7.64-7.73(m,2H) , 7.74(s, 1H), 8.35-8.39(m, 1H), 8.39-8.49(m, 1H), 8.49-8.64(m, 1H), 10.76(br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值534.2；實測值534.2；Rt=2.454min。LCMS (ESI): [M+H] + m/z: calculated 534.2; found 534.2; Rt=2.454 min.

實例681. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-3-側氧基異吲哚啉-5-基]-1-哌啶基]乙醯胺(化合物1272)之合成Example 681. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 Synthesis of -(1-methyl-4-piperidinyl)-3-oxyisoindolin-5-yl]-1-piperidinyl]acetamide (Compound 1272)

Figure 110128222-A0202-12-2224-723
Figure 110128222-A0202-12-2224-723

步驟1：6-溴-2-(1-甲基-4-哌啶基)異吲哚啉-1-酮Step 1: 6-Bromo-2-(1-methyl-4-piperidinyl)isoindolin-1-one

將5-溴-2-(溴甲基)苯甲酸甲酯(5g，16.24mmol)及1-甲基哌啶-4-胺(1.85g，16.24mmol)溶解於MeCN(69.35mL)中，向其中添加DIPEA(4.20g，32.47mmol，5.66mL)。將此混合物回流24h。然後將其蒸發且藉由CC(SiO2，將MTBE/MeOH用作溶析液混合物)純化，以得到6-溴-2-(1-甲基-4-哌啶基)異吲哚啉-1-酮(1.3g，4.20mmol，25.90%產率)。Methyl 5-bromo-2-(bromomethyl)benzoate (5 g, 16.24 mmol) and 1-methylpiperidin-4-amine (1.85 g, 16.24 mmol) were dissolved in MeCN (69.35 mL). To this was added DIPEA (4.20 g, 32.47 mmol, 5.66 mL). The mixture was refluxed for 24h. It was then evaporated and purified by CC (SiO2, MTBE/MeOH was used as eluent mixture) to give 6-bromo-2-(1-methyl-4-piperidinyl)isoindoline-1 - Ketone (1.3 g, 4.20 mmol, 25.90% yield).

LCMS(ESI)：[M+1 ]+ m/z：計算值309.2；實測值311.0；Rt=0.845min。LCMS (ESI): [M+ 1 ] + m/z: calculated 309.2; found 311.0; Rt=0.845 min.

步驟2：2-(1-甲基-4-哌啶基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異吲哚啉-1-酮Step 2: 2-(1-Methyl-4-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)isoindolin-1-one

向6-溴-2-(1-甲基-4-哌啶基)異吲哚啉-1-酮(1.3g，4.20mmol)之溶液中添加乙酸鉀(825.26mg，8.41mmol，525.64μL)及雙(頻哪醇)二硼(1.07g，4.20mmol)。將反應混合物除氣且一次性添加Pd(dppf)Cl2．DCM(171.67mg，210.22 μmol)。將混合物用Ar進一步除氣且在90℃下加熱16h。在此時間之後，使反應混合物冷卻至室溫，過濾且在真空中移除溶劑，以得到2-(1-甲基-4-哌啶基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異吲哚啉-1-酮(1.50g，4.21mmol，100.00%產率)。To a solution of 6-bromo-2-(1-methyl-4-piperidinyl)isoindolin-1-one (1.3 g, 4.20 mmol) was added potassium acetate (825.26 mg, 8.41 mmol, 525.64 μL) and bis(pinacol)diboron (1.07 g, 4.20 mmol). The reaction mixture was degassed and Pd(dppf)Cl2 was added in one portion. DCM (171.67 mg, 210.22 μmol). The mixture was further degassed with Ar and heated at 90 °C for 16 h. After this time, the reaction mixture was cooled to room temperature, filtered and the solvent was removed in vacuo to give 2-(1-methyl-4-piperidinyl)-6-(4,4,5,5- Tetramethyl-1,3,2-dioxaborol-2-yl)isoindolin-1-one (1.50 g, 4.21 mmol, 100.00% yield).

LCMS(ESI)：[M+1]+ m/z：計算值356.2；實測值357.2；Rt=0.869min。LCMS (ESI): [M+1] + m/z: calculated 356.2; found 357.2; Rt=0.869 min.

步驟3：(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)-3-側氧基異吲哚啉-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯Step 3: (3S)-3-Methyl-6-[2-(1-methyl-4-piperidinyl)-3-oxyisoindolin-5-yl]-3,4-di Hydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.45g，4.21mmol)、2-(1-甲基-4-哌啶基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異吲哚啉-1-酮(1.5g，4.21mmol)及碳酸鈉(1.34g，12.63mmol，528.73μL)添加到二噁烷(29.60mL)及水(9.87mL)之混合物中。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2．DCM(171.92mg，210.52μmol)。將反應混合物在氬氣、70℃下攪拌16h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)-3-側氧基異吲哚啉-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.58g，3.71mmol，88.18%產率)，其不經純化即用於下一步驟中。(3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.45 g, 4.21 mmol), 2-(1-Methyl-4-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)iso Indolin-1-one (1.5 g, 4.21 mmol) and sodium carbonate (1.34 g, 12.63 mmol, 528.73 μL) were added to a mixture of dioxane (29.60 mL) and water (9.87 mL). The resulting mixture was evacuated and then backfilled with argon. This operation was repeated three times, and then Pd(dppf)Cl2 was added under argon. DCM (171.92 mg, 210.52 μmol). The reaction mixture was stirred under argon at 70 °C for 16 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give (3S)-3-methyl-6-[2-(1-methyl-4-piperidinyl)-3-oxyisoindoline as a brown oil -5-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.58 g, 3.71 mmol, 88.18% yield) was used in the next step without purification.

LCMS(ESI)：[M+1]+ m/z：計算值425.2；實測值426.4；Rt=1.146min。LCMS (ESI): [M+1] + m/z: calculated 425.2; found 426.4; Rt=1.146 min.

步驟4：2-(1-甲基-4-哌啶基)-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]異吲哚啉-1-酮Step 4: 2-(1-Methyl-4-piperidinyl)-6-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]isoindoline -1-keto

將(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)-3-側氧基異吲哚啉-5-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.58g，3.71mmol)於TFA(6.35g，55.69mmol，4.29mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2*30 ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之2-(1-甲基-4-哌啶基)-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]異吲哚啉-1-酮(1.18g，3.63mmol，97.66%產率)，其直接用於下一步驟中。(3S)-3-methyl-6-[2-(1-methyl-4-piperidinyl)-3-oxyisoindolin-5-yl]-3,4-dihydro- A solution of tert-butyl 2H-pyridine-1-carboxylate (1.58 g, 3.71 mmol) in TFA (6.35 g, 55.69 mmol, 4.29 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was diluted with dichloromethane (2*30 ml) extraction. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-(1-methyl-4-piperidinyl)-6-[(3S)-3-methyl as a brown oil yl-2,3,4,5-tetrahydropyridin-6-yl]isoindolin-1-one (1.18 g, 3.63 mmol, 97.66% yield), which was used directly in the next step.

LCMS(ESI)：[M+1]+ m/z：計算值325.2；實測值326.0；Rt=0.596min。LCMS (ESI): [M+1] + m/z: calculated 325.2; found 326.0; Rt=0.596 min.

步驟5：2-(1-甲基-4-哌啶基)-6-[(5S)-5-甲基-2-哌啶基]異吲哚啉-1-酮之合成Step 5: Synthesis of 2-(1-Methyl-4-piperidinyl)-6-[(5S)-5-methyl-2-piperidinyl]isoindolin-1-one

在0℃下，向2-(1-甲基-4-哌啶基)-6-[(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]異吲哚啉-1-酮(1.18g，3.63mmol)於MeOH(19.74mL)中之經攪拌之溶液中添加硼氫化鈉(274.35mg，7.25mmol，255.44μL)。將所得反應混合物在25℃下攪拌16h。完成之後，將反應混合物在減壓下濃縮，然後用水20mL及50ml EtOAc萃取。將經合併之有機相用鹽水20mL洗滌，經Na2SO4乾燥且在減壓下濃縮，以獲得2-(1-甲基-4-哌啶基)-6-[(5S)-5-甲基-2-哌啶基]異吲哚啉-1-酮(1.1g，3.36mmol，92.65%產率)，其不經進一步純化即用於下一步驟中。To 2-(1-methyl-4-piperidinyl)-6-[(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl]iso at 0 °C To a stirred solution of indolin-1-one (1.18 g, 3.63 mmol) in MeOH (19.74 mL) was added sodium borohydride (274.35 mg, 7.25 mmol, 255.44 μL). The resulting reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure, then extracted with 20 mL of water and 50 mL of EtOAc. The combined organic phases were washed with brine 20 mL, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 2-(1-methyl-4-piperidinyl)-6-[(5S)-5-methyl- 2-Piperidinyl]isoindolin-1-one (1.1 g, 3.36 mmol, 92.65% yield) was used in the next step without further purification.

LCMS(ESI)：[M+1]+ m/z：計算值327.2；實測值328.2；Rt=0.656min。LCMS (ESI): [M+1] + m/z: calculated 327.2; found 328.2; Rt=0.656 min.

步驟6：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-3-側氧基異吲哚啉-5-基]-1-哌啶基]乙醯胺(化合物1272)之合成Step 6: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[(2R,5S)-5-methyl-2-[2-(1- Synthesis of methyl-4-piperidinyl)-3-oxoisoindolin-5-yl]-1-piperidinyl]acetamide (compound 1272)

將DIPEA(308.90mg，2.39mmol，416.30μL)添加到相應2-[(6-胺基-5-乙基-3-吡啶基)胺基]-2-側氧基乙酸(0.2g，956.02μmol)及2-(1-甲基-4-哌啶基)-6-[(2R,5S)-5-甲基-2-哌啶基]異吲哚啉-1-酮(313.06mg，956.02μmol)於DMF(19.58mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(399.86mg，1.05mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以水-MeOH+NH3 為溶析液混合物)，以得到N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)-3-側氧基異吲哚啉-5-基]-1-哌啶基]乙醯胺(54.9mg，105.85μmol，11.07%產 率)。DIPEA (308.90 mg, 2.39 mmol, 416.30 μL) was added to the corresponding 2-[(6-amino-5-ethyl-3-pyridyl)amino]-2-oxoacetic acid (0.2 g, 956.02 μmol ) and 2-(1-methyl-4-piperidinyl)-6-[(2R,5S)-5-methyl-2-piperidinyl]isoindolin-1-one (313.06 mg, 956.02 μmol) in DMF (19.58 mL). The resulting mixture was stirred for 5 min before HATU (399.86 mg, 1.05 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with water-MeOH+ NH3 as eluent mixture) to give N-(6-amino-5-ethyl-3-pyridine base)-2-oxy-2-[(2R,5S)-5-methyl-2-[2-(1-methyl-4-piperidinyl)-3-oxyisoindoline -5-yl]-1-piperidinyl]acetamide (54.9 mg, 105.85 μmol, 11.07% yield).

1 H NMR(600MHz,dmso)δ 0.98-1.04(m,3H),1.06-1.13(m,3H),1.30-1.38(m,1H),1.62-1.70(m,3H),1.77-1.87(m,3H),2.01-2.12(m,3H),2.21-2.29(m,4H),2.35-2.41(m,2H),2.73-2.91(m,3H),3.96-4.06(m,2H),4.41-4.45(m,2H),5.22-5.65(m,3H),7.42-7.54(m,2H),7.57-7.59(m,1H),7.60-7.63(m,1H),7.98-8.08(m,1H),10.53-10.58(m,1H)。 1 H NMR(600MHz,dmso)δ 0.98-1.04(m,3H),1.06-1.13(m,3H),1.30-1.38(m,1H),1.62-1.70(m,3H),1.77-1.87(m ,3H),2.01-2.12(m,3H),2.21-2.29(m,4H),2.35-2.41(m,2H),2.73-2.91(m,3H),3.96-4.06(m,2H),4.41 -4.45(m, 2H), 5.22-5.65(m, 3H), 7.42-7.54(m, 2H), 7.57-7.59(m, 1H), 7.60-7.63(m, 1H), 7.98-8.08(m, 1H), 10.53-10.58 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值518.6；實測值517.2；Rt=1.935min。LCMS (ESI): [M+1] + m/z: calculated 518.6; found 517.2; Rt=1.935 min.

實例682. N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-6-基]-1-哌啶基]乙醯胺(化合物1096)之合成Example 682. N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 Synthesis of -(1-methyl-4-piperidinyl)indazol-6-yl]-1-piperidinyl]acetamide (compound 1096)

Figure 110128222-A0202-12-2227-724
Figure 110128222-A0202-12-2227-724

步驟1：4-(6-溴吲唑-2-基)哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-butyl 4-(6-bromoindazol-2-yl)piperidine-1-carboxylate

藉由一般程序13製備。步驟1BPrepared by General Procedure 13. Step 1B

FCC條件：Interchim 120g SiO2 ，HEX-EtOAc 0~100%，流速=70mL/min，cv=17.1FCC conditions: Interchim 120g SiO 2 , HEX-EtOAc 0~100%, flow rate=70mL/min, cv=17.1

產率：2.98g(60.08%)Yield: 2.98g (60.08%)

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值380.0；Rt=1.540min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 380.0; Rt=1.540 min.

步驟2：6-溴-2-(4-哌啶基)吲唑之合成Step 2: Synthesis of 6-bromo-2-(4-piperidinyl)indazole

藉由一般程序13製備。步驟2BPrepared by General Procedure 13. Step 2B

產率：0.57g(77.37%)Yield: 0.57g (77.37%)

LCMS(ESI)：[M+H]+ m/z：計算值282.2；實測值282.2；Rt=0.770min。LCMS (ESI): [M+H] + m/z: calculated 282.2; found 282.2; Rt=0.770 min.

步驟3：6-溴-2-(1-甲基-4-哌啶基)吲唑之合成Step 3: Synthesis of 6-bromo-2-(1-methyl-4-piperidinyl)indazole

藉由一般程序13製備。步驟3BPrepared by General Procedure 13. Step 3B

產率：0.27g(45.11%)Yield: 0.27g (45.11%)

LCMS(ESI)：[M+H]+ m/z：計算值294.2；實測值294.0；Rt=0.866min。LCMS (ESI): [M+H] + m/z: calculated 294.2; found 294.0; Rt=0.866 min.

步驟4：2-(1-甲基-4-哌啶基)-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑之合成Step 4: 2-(1-Methyl-4-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of base)indazole

藉由一般程序13製備。步驟2APrepared by General Procedure 13. Step 2A

產率：0.35g(84.35%)Yield: 0.35g (84.35%)

LCMS(ESI)：[M+H]+ m/z：計算值342.2；實測值342.2；Rt=0.947min。LCMS (ESI): [M+H] + m/z: calculated 342.2; found 342.2; Rt=0.947 min.

步驟5：外消旋-(3S)-3-甲基-6-[2-(1-甲基-4-哌啶基)吲唑-6-基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 5: Racemic-(3S)-3-methyl-6-[2-(1-methyl-4-piperidinyl)indazol-6-yl]-3,4-dihydro-2H- Synthesis of tert-butyl pyridine-1-carboxylate

藉由一般程序13製備。步驟2Prepared by General Procedure 13. Step 2

HPLC條件：2-10min 20-100%水-甲醇+FA；流速30mL/min(裝載泵4mL/min甲醇)，管柱Sun Fire C18 100*19mmHPLC conditions: 2-10min 20-100% water-methanol+FA; flow rate 30mL/min (loading pump 4mL/min methanol), column Sun Fire C18 100*19mm

產率：0.07g(16.62%)Yield: 0.07g (16.62%)

LCMS(ESI)：[M+H]+ m/z：計算值411.2；實測值411.2；Rt=0.910min。LCMS (ESI): [M+H] + m/z: calculated 411.2; found 411.2; Rt=0.910 min.

步驟6：2-(1-甲基-4-哌啶基)-6-[外消旋-(3S)-3-甲基-2,3,4,5-四氫吡啶-6-基]吲唑之合成Step 6: 2-(1-Methyl-4-piperidinyl)-6-[rac-(3S)-3-methyl-2,3,4,5-tetrahydropyridin-6-yl] Synthesis of Indazole

藉由一般程序13製備。步驟3(方法A)Prepared by General Procedure 13. Step 3 (Method A)

產率：0.05g(94.46%)Yield: 0.05g (94.46%)

LCMS(ESI)：[M+H]+ m/z：計算值311.2；實測值311.2；Rt=0.542min。LCMS (ESI): [M+H] + m/z: calculated 311.2; found 311.2; Rt=0.542 min.

步驟7：2-(1-甲基-4-哌啶基)-6-[外消旋-(2R,5S)-5-甲基-2-哌啶基]吲唑之合成Step 7: Synthesis of 2-(1-Methyl-4-piperidinyl)-6-[rac-(2R,5S)-5-methyl-2-piperidinyl]indazole

藉由一般程序13製備。步驟4Prepared by General Procedure 13. Step 4

產率：0.041g(81.47%)Yield: 0.041 g (81.47%)

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值313.2；Rt=0.613min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 313.2; Rt=0.613 min.

步驟8：N-(6-胺基-5-乙基-3-吡啶基)-2-側氧基-2-[外消旋-(2R,5S)-5-甲基-2-[2-(1-甲基-4-哌啶基)吲唑-6-基]-1-哌啶基]乙醯胺(化合物1096)之合成Step 8: N-(6-Amino-5-ethyl-3-pyridyl)-2-oxy-2-[rac-(2R,5S)-5-methyl-2-[2 Synthesis of -(1-methyl-4-piperidinyl)indazol-6-yl]-1-piperidinyl]acetamide (compound 1096)

藉由一般程序13製備。步驟5Prepared by General Procedure 13. Step 5

HPLC條件：2-10min 40-100%水-甲醇+NH3 30ml/min(裝載泵4ml甲醇)，管柱：sun fire c18HPLC conditions: 2-10min 40-100% water-methanol+NH3 30ml/min (loading pump 4ml methanol), column: sun fire c18

產率：8.2mg(21.92%)Yield: 8.2 mg (21.92%)

1 H NMR(600MHz,dmso)δ 0.74-1.05(m,3H),1.05-1.17(m,3H),1.29-1.40(m,1H),1.70-1.81(m,1H),1.82-1.92(m,1H),2.01-2.15(m,7H),2.21(s,3H),2.26-2.35(m,1H),2.37-2.44(m,2H),2.75-3.21(m,3H),3.45-4.07(m,1H),4.34-4.48(m,1H),5.17-5.76(m,3H),6.91-7.08(m,1H),7.42-7.57(m,2H),7.62-7.71(m,1H),7.98-8.12(m,1H),8.37(s,1H),10.53(br s,1H)。 1 H NMR(600MHz,dmso)δ 0.74-1.05(m,3H),1.05-1.17(m,3H),1.29-1.40(m,1H),1.70-1.81(m,1H),1.82-1.92(m ,1H),2.01-2.15(m,7H),2.21(s,3H),2.26-2.35(m,1H),2.37-2.44(m,2H),2.75-3.21(m,3H),3.45-4.07 (m,1H),4.34-4.48(m,1H),5.17-5.76(m,3H),6.91-7.08(m,1H),7.42-7.57(m,2H),7.62-7.71(m,1H) , 7.98-8.12 (m, 1H), 8.37 (s, 1H), 10.53 (br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值504.2；實測值504.2；Rt=1.667min。LCMS (ESI): [M+H] + m/z: calculated 504.2; found 504.2; Rt=1.667 min.

其他實例Other instances

實例683. N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基-2-(2-(噻吩-2-基)哌啶-1-基)乙Example 683. N-(6-Amino-5-methylpyridin-3-yl)-2-oxy-2-(2-(thiophen-2-yl)piperidin-1-yl)ethyl 醯胺(化合物9)之合成Synthesis of amide (compound 9)

Figure 110128222-A0202-12-2230-550
Figure 110128222-A0202-12-2230-550

步驟1：2-[(6-溴-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1: Synthesis of 2-[(6-bromo-5-methyl-3-pyridyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester

在0℃下，向6-溴-5-甲基吡啶-3-胺(5g，26.73mmol)及三乙胺(2.71g，26.73mmol，3.73mL)於THF(250mL)中之溶液中添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(5.09g，26.73mmol)。在室溫下攪拌1h之後，過濾所得混合物且蒸發至乾，以得到呈米色固體之2-[(6-溴-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(9g，26.39mmol，98.71%產率)且其不經進一步純化即用於下一步驟中。To a solution of 6-bromo-5-methylpyridin-3-amine (5 g, 26.73 mmol) and triethylamine (2.71 g, 26.73 mmol, 3.73 mL) in THF (250 mL) at 0 °C was added 2 - 2,2,2-trifluoroethyl chloro-2-pendoxoacetic acid (5.09 g, 26.73 mmol). After stirring at room temperature for 1 h, the resulting mixture was filtered and evaporated to dryness to give 2-[(6-bromo-5-methyl-3-pyridyl)amino]-2-pendoxoacetic acid as a beige solid 2,2,2-Trifluoroethyl ester (9 g, 26.39 mmol, 98.71% yield) and this was used in the next step without further purification.

1 H NMR(500MHz,DMSO-d6 )δ 2.33(s,3H),4.99(q,2H),8.13(s,1H),8.59(s,1H),11.28(s,1H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.33(s,3H), 4.99(q,2H), 8.13(s,1H), 8.59(s,1H), 11.28(s,1H).

LCMS(ESI)：[M+H]+ m/z：計算值341.0；實測值342.2；Rt=1.277min。LCMS (ESI): [M+H] + m/z: calculated 341.0; found 342.2; Rt=1.277 min.

步驟2：N-(6-溴-5-甲基吡啶-3-基)-2-側氧基-2-(2-噻吩-2-基哌啶-1-基)乙醯胺之合成Step 2: Synthesis of N-(6-bromo-5-methylpyridin-3-yl)-2-oxy-2-(2-thiophen-2-ylpiperidin-1-yl)acetamide

向2-[(6-溴-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(3g，8.80mmol)及2-(2-噻吩基)哌啶(1.47g，7.22mmol，HCl)於乙腈(50mL)中之溶液中添加DIPEA(3.41g，26.40mmol，4.60mL)。將所得混合物加熱至回流達18h。將反應混合物蒸發至乾且使其經歷管柱層析(Companion combiflash；120g SiO2 ，石油醚/乙酸乙酯，其中乙酸乙酯為10~35%，流速=85mL/min，Rv=6CV)。獲得呈淺黃色膠狀物之N-(6-溴-5-甲基吡啶-3-基)-2-側氧基-2-(2-噻吩-2-基哌啶-1-基)乙醯胺(1.5g，3.67mmol，41.75%產率)。To 2-[(6-bromo-5-methyl-3-pyridinyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (3 g, 8.80 mmol) and 2-(2 -Thienyl)piperidine (1.47 g, 7.22 mmol, HCl) in acetonitrile (50 mL) was added DIPEA (3.41 g, 26.40 mmol, 4.60 mL). The resulting mixture was heated to reflux for 18 h. The reaction mixture was evaporated to dryness and subjected to column chromatography (Companion combiflash; 120 g SiO2 , petroleum ether/ethyl acetate with 10-35% ethyl acetate, flow rate=85 mL/min, Rv=6CV). N-(6-bromo-5-methylpyridin-3-yl)-2-oxy-2-(2-thiophen-2-ylpiperidin-1-yl)ethyl was obtained as a pale yellow gum Amide (1.5 g, 3.67 mmol, 41.75% yield).

1 H NMR(400MHz,CDCl3 )δ 1.56(m,5H),1.76(m,1H),2.36(m,4H),3.22(m,1H),4.80(m,1H),6.05(m,1H),6.93(m,2H),8.05(m,1H),8.33(d,1H),9.32(d,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.56(m, 5H), 1.76(m, 1H), 2.36(m, 4H), 3.22(m, 1H), 4.80(m, 1H), 6.05(m, 1H) ), 6.93(m, 2H), 8.05(m, 1H), 8.33(d, 1H), 9.32(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值407.0；實測值408.0；Rt=1.426min。LCMS (ESI): [M+H] + m/z: calculated 407.0; found 408.0; Rt=1.426 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基-2-(2-(噻吩-2-基)哌啶-1-基)乙醯胺(化合物9 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-oxy-2-(2-(thiophen-2-yl)piperidin-1-yl)acetamide Synthesis of ( Compound 9 )

在Ar下，向N-(6-溴-5-甲基-3-吡啶基)-2-側氧基-2-[2-(2-噻吩基)-1-哌啶基]乙醯胺(0.5g，1.22mmol)、胺甲酸第三丁酯(286.90mg，2.45mmol)及碳酸銫(797.97mg，2.45mmol)於二噁烷(10mL)中之混合物中添加XantPhos(35.43mg，61.23μmol)及XantPhos Pd G3(87.10mg，91.84μmol)。將混合物在100℃下加熱42h。過濾最終混合物且蒸發，以得到N-[3-甲基-5-[[2-側氧基-2-[2-(2-噻吩基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.95g，粗品)。將所獲得之固體溶解於HCl(於二噁烷中之4.0M溶液，2ml)且攪拌1h。然後，在真空中濃縮混合物。使殘餘物經歷HPLC(SunFire C18 19* 100 5mkm管柱；25-70% H2 O-MeCN，10min，流速：30mL/min，裝載泵4ml/min MeCN)，以得到呈黃色油狀物之N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(2-噻吩基)-1-哌啶基]乙醯胺(0.007g，20.32μmol，1.66%產率)。To N-(6-bromo-5-methyl-3-pyridinyl)-2-oxy-2-[2-(2-thienyl)-1-piperidinyl]acetamide under Ar (0.5 g, 1.22 mmol), tert-butyl carbamate (286.90 mg, 2.45 mmol) and cesium carbonate (797.97 mg, 2.45 mmol) in dioxane (10 mL) was added XantPhos (35.43 mg, 61.23 μmol) ) and XantPhos Pd G3 (87.10 mg, 91.84 μmol). The mixture was heated at 100 °C for 42 h. The final mixture was filtered and evaporated to give N-[3-methyl-5-[[2-oxy-2-[2-(2-thienyl)-1-piperidinyl]acetoxy]amino ]-2-Pyridinyl]carbamic acid tert-butyl ester (0.95 g, crude). The obtained solid was dissolved in HCl (4.0M solution in dioxane, 2ml) and stirred for 1 h. Then, the mixture was concentrated in vacuo. The residue was subjected to HPLC (SunFire C18 19 * 100 5mkm column; 25-70% H2O -MeCN, 10min, flow rate: 30mL/min, loading pump 4ml/min MeCN) to give N as a yellow oil -(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[2-(2-thienyl)-1-piperidinyl]acetamide (0.007 g, 20.32 g μmol, 1.66% yield).

1 H NMR(400MHz,CD3 OD)δ 1.69(m,2H),1.78(m,2H),2.00(m,1H),2.13(m,3H),2.33(m,1H),2.65(s,3H),3.01(m,1H),4.07(m,1H),5.86(m,1H),7.01(m,2H),7.35(m,1H),7.59(m,1H),8.06(m,1H)。 1 H NMR (400MHz, CD 3 OD) δ 1.69(m, 2H), 1.78(m, 2H), 2.00(m, 1H), 2.13(m, 3H), 2.33(m, 1H), 2.65(s, 3H), 3.01(m, 1H), 4.07(m, 1H), 5.86(m, 1H), 7.01(m, 2H), 7.35(m, 1H), 7.59(m, 1H), 8.06(m, 1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值344.1；實測值345.2；Rt=0.982min。LCMS (ESI): [M+H] + m/z: calculated 344.1; found 345.2; Rt=0.982 min.

實例684. N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(2-噻吩基)-1-哌啶基]乙醯胺(化合物24)及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(2-噻吩基)-1-哌啶基]乙醯胺(化合物22)之合成Example 684. N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(2S)-2-(2-thienyl)-1-piperidinyl] Acetamide (compound 24) and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-(2-thienyl)-1 Synthesis of -Piperidinyl]acetamide (Compound 22)

Figure 110128222-A0202-12-2232-551
Figure 110128222-A0202-12-2232-551
步驟1-3與化合物9 相同。Steps 1-3 are the same as compound 9 .

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(2-噻吩基)-1-哌啶基]乙醯胺(化合物24 )及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(2-噻吩基)-1-哌啶基]乙醯胺(化合物22 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[(2S)-2-(2-thienyl)-1-piperidinyl] Acetamide ( compound 24 ) and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-(2-thienyl)-1 Synthesis of -Piperidinyl]acetamide ( Compound 22 )

使用(IB(250* 20，5mkm)Chiralpak管柱，己烷-IPA-MeOH，90-5-5，流速15ml/min)進行掌性分離，得到化合物24 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2S)-2-(2-噻吩基)-1-哌啶基]乙醯胺(8.84mg，32.74%產率；RT=54.098min)及化合物22 N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[(2R)-2-(2-噻吩基)-1-哌啶基]乙醯胺(9.35mg，34.63%產率；RT=51.528min)。Chiral separation using (IB (250 * 20, 5mkm) Chiralpak column, hexane-IPA-MeOH, 90-5-5, flow rate 15ml/min) gave compound 24 N-(6-amino-5- Methyl-3-pyridyl)-2-oxy-2-[(2S)-2-(2-thienyl)-1-piperidinyl]acetamide (8.84 mg, 32.74% yield; RT =54.098min) and compound 22 N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[(2R)-2-(2-thienyl)-1- Piperidinyl]acetamide (9.35 mg, 34.63% yield; RT=51.528 min).

化合物22： RT(IB，己烷-IPA-MeOH，90-5-5，0.6ml/min)=50.937min。 Compound 22: RT (IB, Hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 50.937 min.

1 H NMR(500MHz,CDCl3 )δ 1.76(m,4H),1.84(m,1H),2.05(m,1H),2.15(m,3H),2.33(m,1H),3.08(m,1H),4.40(m,2H),4.73(m,1H),6.43(m,1H),6.95(m,1H),7.00(m,1H),7.78(m,1H),8.07(m,1H),9.01(m,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.76 (m, 4H), 1.84 (m, 1H), 2.05 (m, 1H), 2.15 (m, 3H), 2.33 (m, 1H), 3.08 (m, 1H) ), 4.40(m, 2H), 4.73(m, 1H), 6.43(m, 1H), 6.95(m, 1H), 7.00(m, 1H), 7.78(m, 1H), 8.07(m, 1H) ,9.01(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.1；實測值345.0；Rt=3.711min。LCMS (ESI): [M+H] + m/z: calculated 344.1; found 345.0; Rt=3.711 min.

化合物24： RT(IB，己烷-IPA-MeOH，90-5-5，0.6ml/min)=46.420min。 Compound 24: RT (IB, Hexane-IPA-MeOH, 90-5-5, 0.6 ml/min) = 46.420 min.

1 H NMR(500MHz,CDCl3 )δ 1.76(m,4H),1.84(m,1H),2.05(m,1H),2.15(m,3H), 2.33(m,1H),3.10(m,1H),4.40(m,2H),4.74(m,1H),6.43(m,1H),6.95(m,1H),7.00(m,1H),7.78(m,1H),8.07(m,1H),9.00(m,1H)。 1 H NMR (500MHz, CDCl 3 ) δ 1.76 (m, 4H), 1.84 (m, 1H), 2.05 (m, 1H), 2.15 (m, 3H), 2.33 (m, 1H), 3.10 (m, 1H) ), 4.40(m, 2H), 4.74(m, 1H), 6.43(m, 1H), 6.95(m, 1H), 7.00(m, 1H), 7.78(m, 1H), 8.07(m, 1H) ,9.00(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.1；實測值345.0；Rt=3.707min。LCMS (ESI): [M+H] + m/z: calculated 344.1; found 345.0; Rt=3.707 min.

實例685. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物415)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,6S)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物417)之合成Example 685. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2- Pendant oxyacetamide (compound 415) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,6S)-2-methyl-6-phenyl-1 Synthesis of -piperidinyl]-2-oxoacetamide (compound 417)

Figure 110128222-A0202-12-2233-552
Figure 110128222-A0202-12-2233-552

步驟1：N-[3-甲基-5-[[2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[3-Methyl-5-[[2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl] Synthesis of tertiary butyl amino]-2-pyridyl]carbamate

向2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸甲酯(0.74g，2.83mmol)於MeOH(10mL)中之溶液中添加氫氧化鈉珠粒(113.26mg，2.83mmol，53.18μL)且將所得混合物攪拌1h。然後，蒸發溶劑且將殘餘物與EtOH一起再蒸發。此後，將固體溶解於DMF中且添加TATU(1.09g，3.40mmol)，隨後添加N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(632.26mg，2.83mmol)且將所得混合物攪拌12h。將反應混合物倒入到水中，用EtOAc萃取3次。將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(40-60% 0.5-5min；水(hcl)-乙腈30mL/min；裝載泵4mL/min；管柱SunFire 19* 100mm)。獲得呈白色固體之 N-[3-甲基-5-[[2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.2964g，654.96μmol，23.13%產率)。1 H NMR(500MHz,CDCl3 )δ 0.94(m,3H),1.52(s,9H),1.87(m,4H),2.31(s,3H),2.59(m,1H),5.02(m,1H),6.78(m,1H),7.25(m,2H),7.34(m,3H),8.09(s,1H),8.37(s,1H),9.33(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值452.2；實測值453.2；Rt=1.427min。To a solution of methyl 2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxoacetate (0.74 g, 2.83 mmol) in MeOH (10 mL) Sodium hydroxide beads (113.26 mg, 2.83 mmol, 53.18 μL) were added and the resulting mixture was stirred for 1 h. Then, the solvent was evaporated and the residue was re-evaporated with EtOH. After this time, the solid was dissolved in DMF and TATU (1.09 g, 3.40 mmol) was added followed by 3-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (632.26 mg, 2.83 mmol) mmol) and the resulting mixture was stirred for 12 h. The reaction mixture was poured into water and extracted 3 times with EtOAc. The combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (40-60% 0.5-5 min; water (hcl)-acetonitrile 30 mL/min; loading pump 4 mL/min; column SunFire 19 * 100 mm). Obtained as a white solid N-[3-methyl-5-[[2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxoacetyl tert-butyl]amino]-2-pyridyl]carbamate (0.2964 g, 654.96 μmol, 23.13% yield). 1 H NMR (500MHz, CDCl 3 )δ 0.94(m, 3H), 1.52(s, 9H), 1.87(m, 4H), 2.31(s, 3H), 2.59(m, 1H), 5.02(m, 1H) ), 6.78(m, 1H), 7.25(m, 2H), 7.34(m, 3H), 8.09(s, 1H), 8.37(s, 1H), 9.33(m, 1H). LCMS (ESI): [M+H]+ m/z: calculated 452.2; found 453.2; Rt=1.427 min.

步驟2：N-[3-甲基-5-[[2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之掌性拆分Step 2: N-[3-Methyl-5-[[2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl] Chiral Resolution of 3-Butyl Amino]-2-pyridyl]carbamate

使用(IA(250* 20，5mkm)Chiralpak管柱；以己烷-IPA-MeOH 70-15-15為流動相；流速12mL/min)進行掌性拆分；得到N-[3-甲基-5-[[2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(147.1mg，325.05μmol，49.63%產率)(RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=9.7692min)及N-[3-甲基-5-[[2-[(2S,6S)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(123.99mg，273.98μmol，41.83%產率)(RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=16.8562min。RT(IA，己烷-IPA-MeOH，50-25-25，0.6mL/min)=9.7692min。1 H NMR(500MHz,CDCl3 )δ 0.94(m,3H),1.25(m,1H),1.49(s,9H),1.64(m,2H),1.96(m,3H),2.30(s,3H),2.61(m,1H),5.02(m,1H),6.82(m,1H),7.32(m,2H),7.38(m,3H),8.10(s,1H),8.41(s,1H),9.38(m,1H)。LCMS(ESI)：[M+2H]+ m/z：計算值452.2；實測值454.2；Rt=5.688miChiralpak column using (IA (250 * 20, 5mkm) Chiralpak column; hexane-IPA-MeOH 70-15-15 as mobile phase; flow rate 12mL/min) for chiral resolution; N-[3-methyl- 5-[[2-[(2R,6R)-2-Methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid Tertiary butyl ester (147.1 mg, 325.05 μmol, 49.63% yield) (RT(IA, hexane-IPA-MeOH, 50-25-25, 0.6 mL/min)=9.7692 min) and N-[3-methyl yl-5-[[2-[(2S,6S)-2-methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl] 3-Butyl carbamate (123.99 mg, 273.98 μmol, 41.83% yield) (RT(IA, hexane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 16.8562 min. RT(IA, hexane Alkane-IPA-MeOH, 50-25-25, 0.6 mL/min) = 9.7692 min. 1 H NMR (500 MHz, CDCl 3 ) δ 0.94 (m, 3H), 1.25 (m, 1H), 1.49 (s, 9H ), 1.64(m, 2H), 1.96(m, 3H), 2.30(s, 3H), 2.61(m, 1H), 5.02(m, 1H), 6.82(m, 1H), 7.32(m, 2H) , 7.38(m, 3H), 8.10(s, 1H), 8.41(s, 1H), 9.38(m, 1H). LCMS(ESI): [M+2H] + m/z: calculated 452.2; found 454.2; Rt=5.688mi

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物415 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 415 )

在21℃下，向N-[3-甲基-5-[[2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(147.1mg，325.05μmol)於二噁烷(5mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(59.26mg，1.63mmol，74.07μL)。使所得混合物攪拌2h。將所得混合物蒸發至乾且使其經歷HPLC(C18 管柱，H2 O-MeCN，30-50% MeCN，30mL/min)，以獲得呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(40.84mg，115.88μmol，35.65%產率)。1 H NMR(500MHz,DMSO-d6 )δ(ppm)0.65-0.80(m,3H),1.49-1.57(m,1H),1.57-1.67(m,1H),1.70-1.84(m,3H),2.01-2.13(m,3H),4.05-4.75(m,1H),5.13-5.73(m,3H),7.16-7.42(m,5H),7.42-7.60(m,2H),7.91-8.19(m,1H),10.38-10.63(m,1H)。LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.2；Rt=2.577min。At 21 °C, to N-[3-methyl-5-[[2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-side oxyethyl To a solution of acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (147.1 mg, 325.05 μmol) in dioxane (5 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (59.26 mg) , 1.63 mmol, 74.07 μL). The resulting mixture was stirred for 2 h. The resulting mixture was evaporated to dryness and subjected to HPLC (C18 column, H2O -MeCN, 30-50% MeCN, 30 mL/min) to obtain N-(6-amino-5-methane as a white solid) yl-3-pyridyl)-2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxyacetamide (40.84 mg, 115.88 μmol, 35.65 %Yield). 1 H NMR (500MHz, DMSO-d 6 )δ(ppm) 0.65-0.80(m,3H), 1.49-1.57(m,1H), 1.57-1.67(m,1H), 1.70-1.84(m,3H) ,2.01-2.13(m,3H),4.05-4.75(m,1H),5.13-5.73(m,3H),7.16-7.42(m,5H),7.42-7.60(m,2H),7.91-8.19( m, 1H), 10.38-10.63 (m, 1H). LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.2; Rt=2.577 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,6S)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物417 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,6S)-2-methyl-6-phenyl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 417 )

在21℃下，向N-[3-甲基-5-[[2-[(2S,6S)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(123.99mg，273.98μmol)於二噁烷(5mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(49.95mg，1.37mmol，62.44μL)。使所得混合物攪拌2h。將所得混合物蒸發至乾且使其經歷HPLC(C18管柱，H2 O-MeCN，30-50% MeCN，30mL/min)，得到呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,6S)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(48.4mg，137.33μmol，50.12%產率)。1 H NMR(500MHz,DMSO-d6 )δ(ppm)0.64-0.86(m,3H),1.46-1.57(m,1H),1.57-1.66(m,1H),1.70-1.97(m,3H),1.99-2.10(m,3H),2.56-2.60(m,1H),3.91-4.84(m,1H),5.06-5.76(m,3H),7.22-7.30(m,1H),7.33-7.41(m,3H),7.40-7.62(m,2H),7.91-8.15(m,1H),10.39-10.65(m,1H)。At 21 °C, to N-[3-methyl-5-[[2-[(2S,6S)-2-methyl-6-phenyl-1-piperidinyl]-2-side oxyethyl To a solution of acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (123.99 mg, 273.98 μmol) in dioxane (5 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (49.95 mg) , 1.37 mmol, 62.44 μL). The resulting mixture was stirred for 2 h. The resulting mixture was evaporated to dryness and subjected to HPLC (C18 column, H2O -MeCN, 30-50% MeCN, 30 mL/min) to give N-(6-amino-5-methyl as a white solid) -3-Pyridinyl)-2-[(2S,6S)-2-methyl-6-phenyl-1-piperidinyl]-2-oxyacetamide (48.4 mg, 137.33 μmol, 50.12% Yield). 1 H NMR (500MHz, DMSO-d 6 )δ(ppm) 0.64-0.86(m,3H), 1.46-1.57(m,1H), 1.57-1.66(m,1H), 1.70-1.97(m,3H) ,1.99-2.10(m,3H),2.56-2.60(m,1H),3.91-4.84(m,1H),5.06-5.76(m,3H),7.22-7.30(m,1H),7.33-7.41( m, 3H), 7.40-7.62 (m, 2H), 7.91-8.15 (m, 1H), 10.39-10.65 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.2；Rt=2.569min。LCMS (ESI): [M+H] + m/z: calculated 352.2; found 353.2; Rt=2.569 min.

實例686. N-(6-胺基-5-甲基-3-吡啶基)-2-[外消旋-(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物112)之合成Example 686. N-(6-Amino-5-methyl-3-pyridyl)-2-[rac-(2R,6R)-2-methyl-6-phenyl-1-piperidinyl Synthesis of ]-2-oxoacetamide (Compound 112)

Figure 110128222-A0202-12-2236-553
在21℃下，向N-[3-甲基-5-[[2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(141.73mg，234.89μmol)(如實例685中所述製備)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(400.00mg，10.97mmol，0.5mL)。使所得混合物攪拌6h。將所得混合物蒸發至乾且藉由HPLC(2-7min，40-90min，R1 30mL/min；Sunfire C18，100x19x5um；裝載泵：5mL/min R1)純化，以得到呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,6R)-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(17.7mg，50.22μmol，21.38%產率)。1 H NMR(DMSO-d6,500MHz)：δ(ppm)0.91(m,5H),1.54(m,3H),1.79(m,3H),2.10(m,3H),4.77(m,1H),6.09(m,2H),7.40(m,6H),8.19(m,1H),10.71(s,1H)LCMS(ESI)：[M+H]+ m/z：計算值352.2；實測值353.2；Rt=2.737min。
Figure 110128222-A0202-12-2236-553
 At 21 °C, to N-[3-methyl-5-[[2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (141.73 mg, 234.89 μmol) (prepared as described in Example 685) in dioxane (2 mL) was added to dioxane 4.0 M hydrogen chloride solution (400.00 mg, 10.97 mmol, 0.5 mL) in the solution. The resulting mixture was stirred for 6 h. The resulting mixture was evaporated to dryness and purified by HPLC (2-7 min, 40-90 min, R1 30 mL/min; Sunfire C18, 100x19x5um; loading pump: 5 mL/min R1) to give N-(6- as a white solid Amino-5-methyl-3-pyridyl)-2-[(2R,6R)-2-methyl-6-phenyl-1-piperidinyl]-2-oxyacetamide (17.7 mg, 50.22 μmol, 21.38% yield). 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 0.91(m, 5H), 1.54(m, 3H), 1.79(m, 3H), 2.10(m, 3H), 4.77(m, 1H), 6.09(m, 2H), 7.40(m, 6H), 8.19(m, 1H), 10.71(s, 1H) LCMS(ESI): [M+H] + m/z: calculated 352.2; found 353.2; Rt=2.737min.

實例687. 5-(2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物240)之合成Example 687. Synthesis of 5-(2-(2-cyclopentylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 240)

Figure 110128222-A0202-12-2236-554
Figure 110128222-A0202-12-2236-554

步驟1：2-(2-環戊基哌啶-1-基)-2-側氧基乙酸2,2,2-三氟乙酯之合成 在-10℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(1.14g，5.98mmol)逐滴添加到2-環戊基-5-甲基哌啶(1g，5.98mmol)及TEA(604.88mg，5.98mmol，833.16μL)於THF(30mL)中之溶液中。使所得混合物升溫至室溫且攪拌12h。過濾出所得沉澱。蒸發濾液，以獲得2-(2-環戊基-5-甲基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(2g， 粗品)，其不經純化即用於下一步驟中。 Step 1: Synthesis of 2-(2-cyclopentylpiperidin-1-yl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester Pendant 2,2,2-trifluoroethyl acetate (1.14 g, 5.98 mmol) was added dropwise to 2-cyclopentyl-5-methylpiperidine (1 g, 5.98 mmol) and TEA (604.88 mg, 5.98 mmol, 833.16 μL) in THF (30 mL). The resulting mixture was warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered off. The filtrate was evaporated to obtain 2,2,2-trifluoroethyl 2-(2-cyclopentyl-5-methyl-1-piperidinyl)-2-oxyacetate (2 g, crude), which was not Purified and used in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.25(m,6H),1.68(m,8H),3.14(m,1H),3.26(m,1H),3.59(m,1H),4.15(m,1H),5.05(m,2H)。LCMS(ESI)：[M+1]m/z：計算值307.3；實測值308.2；Rt=1.548min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.25(m, 6H), 1.68(m, 8H), 3.14(m, 1H), 3.26(m, 1H), 3.59(m, 1H), 4.15(m, 1H), 5.05(m, 2H). LCMS (ESI): [M+1] m/z: calculated 307.3; found 308.2; Rt=1.548 min.

步驟2：2-(2-環戊基哌啶-1-基)-2-側氧基乙酸鋰之合成Step 2: Synthesis of lithium 2-(2-cyclopentylpiperidin-1-yl)-2-oxoacetate

將98%氫氧化鋰單水合物(261.18mg，6.22mmol，172.97μL)添加到2-(2-環戊基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(1.91g，6.22mmol)於水(2mL)及THF(20mL)中之溶液中且將所得混合物在20℃下攪拌12h。將所得混合物蒸發至乾，以獲得[2-(2-環戊基-1-哌啶基)-2-側氧基乙醯基]氧基鋰(1.3g，5.62mmol，90.33%產率)，其不經純化即用於下一步驟中。98% Lithium hydroxide monohydrate (261.18 mg, 6.22 mmol, 172.97 μL) was added to 2-(2-cyclopentyl-1-piperidinyl)-2-oxoacetic acid 2,2,2-tris A solution of fluoroethyl ester (1.91 g, 6.22 mmol) in water (2 mL) and THF (20 mL) and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was evaporated to dryness to obtain lithium [2-(2-cyclopentyl-1-piperidinyl)-2-oxyethanoyl]oxylithium (1.3 g, 5.62 mmol, 90.33% yield) , which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.25(m,6H),1.68(m,8H),2.36(m,1H),3.27(m,1H),3.89(m,1H),4.13(m,1H)。LCMS(ESI)：[M+1]m/z：計算值225.3；實測值226.2；Rt=1.121min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.25(m, 6H), 1.68(m, 8H), 2.36(m, 1H), 3.27(m, 1H), 3.89(m, 1H), 4.13 (m, 1H). LCMS (ESI): [M+1] m/z: calculated 225.3; found 226.2; Rt=1.121 min.

步驟3：5-(2-(2-環戊基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成 將[2-(2-環戊基-1-哌啶基)-2-側氧基乙醯基]氧基鋰(0.5g，2.16mmol)與HATU(904.46mg，2.38mmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加5-胺基吡啶-3-甲醯胺(296.56mg，2.16mmol)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(管柱SunFire 19*100mm，以水-MeCN為流動相)，以獲得5-[[2-(2-環戊基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.194g，563.29μmol，26.05%產率)。 Step 3: Synthesis of 5-(2-(2-cyclopentylpiperidin-1-yl)-2-oxyacetamido)nicotinamide [2-(2-cyclopentyl-1 Lithium -piperidinyl)-2-oxyacetoxy]oxide (0.5 g, 2.16 mmol) and HATU (904.46 mg, 2.38 mmol) were mixed in DMF (5 mL) and the resulting mixture was stirred at 20 °C After 10 min, 5-aminopyridine-3-carboxamide (296.56 mg, 2.16 mmol) was added. The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (column SunFire 19*100 mm, with water-MeCN as mobile phase) to obtain 5-[[2-(2-cyclopentyl-1-piperidinyl)-2-pentoxyethyl Acyl]amino]pyridine-3-carboxamide (0.194 g, 563.29 μmol, 26.05% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.23(m,2H),1.33-1.42(m,1H),1.42-1.78(m,12H),2.75-3.19(m,1H),3.49-3.60(m,1H),4.18-4.25(m,1H),7.50-7.65(m,1H),8.09-8.18(m,1H),8.43-8.55(m,1H),8.73-8.78(m,1H),8.83-8.92(m,1H),11.02-11.12(m,1H)。LCMS(ESI)：[M+1]m/z：計算值344.4；實測值 345.2；Rt=3.146min。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.23(m, 2H), 1.33-1.42(m, 1H), 1.42-1.78(m, 12H), 2.75-3.19(m, 1H) ,3.49-3.60(m,1H),4.18-4.25(m,1H),7.50-7.65(m,1H),8.09-8.18(m,1H),8.43-8.55(m,1H),8.73-8.78( m, 1H), 8.83-8.92 (m, 1H), 11.02-11.12 (m, 1H). LCMS (ESI): [M+1] m/z: calculated 344.4; found 345.2; Rt=3.146 min.

實例688.N -甲基-4-(5-甲基-1-(2-((5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)哌啶-2-基)苯甲醯胺(化合物92)之合成Example 688. N -Methyl-4-(5-methyl-1-(2-((5-methylpyridin-3-yl)amino)-2-oxyacetyl)piperidine-2 Synthesis of -yl)benzamide (compound 92)

Figure 110128222-A0202-12-2238-555
Figure 110128222-A0202-12-2238-555

步驟1：4-(5-甲基吡啶-2-基)苯甲酸甲酯之合成Step 1: Synthesis of methyl 4-(5-methylpyridin-2-yl)benzoate

將2-溴-5-甲基吡啶(1.82g，10.57mmol)及(4-甲氧基羰基苯基)硼酸(2g，11.11mmol)溶解於二噁烷(40mL)及水(5mL)中。向其中添加碳酸銫(8.23g，25.26mmol)。然後，添加肆(三苯基磷烷)鈀(0)(583.73mg，505.15μmol)且將反應燒瓶快速抽真空且用氬氣再填充。將所得混合物在65℃下攪拌12h。此後，將其冷卻且蒸發。將殘餘物分配於EtOAc(100ml)與水(100ml)之間。收集有機相，將其經Na2 SO4 乾燥且蒸發。使殘餘物經歷管柱層析，以獲得4-(5-甲基-2-吡啶基)苯甲酸甲酯(0.3g，1.32mmol，13.07%產率)。2-Bromo-5-methylpyridine (1.82 g, 10.57 mmol) and (4-methoxycarbonylphenyl)boronic acid (2 g, 11.11 mmol) were dissolved in dioxane (40 mL) and water (5 mL). To this was added cesium carbonate (8.23 g, 25.26 mmol). Then, tetrakis(triphenylphosphine)palladium(0) (583.73 mg, 505.15 μmol) was added and the reaction flask was quickly evacuated and refilled with argon. The resulting mixture was stirred at 65 °C for 12 h. After that, it was cooled and evaporated. The residue was partitioned between EtOAc (100ml) and water (100ml). The organic phase was collected, dried over Na2SO4 and evaporated. The residue was subjected to column chromatography to obtain methyl 4-(5-methyl-2-pyridyl)benzoate (0.3 g, 1.32 mmol, 13.07% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)2.35(s,3H),3.87(s,3H),7.74(d,1H),7.96(d,1H),8.04(d,2H),8.20(d,2H),8.55(s,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 2.35(s,3H), 3.87(s,3H), 7.74(d,1H), 7.96(d,1H), 8.04(d,2H), 8.20(d, 2H), 8.55(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值227.2；實測值228.2；Rt=1.255min。LCMS (ESI): [M] + m/z: calculated 227.2; found 228.2; Rt=1.255 min.

步驟2：4-(5-甲基吡啶-2-基)苯甲酸之合成Step 2: Synthesis of 4-(5-methylpyridin-2-yl)benzoic acid

將氫氧化鈉珠粒(105.60mg，2.64mmol，49.58μL)添加到4-(5-甲基-2-吡啶基)苯甲酸甲酯(0.3g，1.32mmol)於MeOH(20mL)中之溶液且將所得混合 物在65℃下加熱12h。將所得溶液冷卻至室溫且蒸發。將殘餘物分配於DCM(10ml)與水(10ml)之間。收集水層且用硫酸氫鈉(316.98mg，2.64mmol)酸化。將所得混合物用EtOAc(2x30ml)萃取。蒸發經合併之有機層，以獲得4-(5-甲基-2-吡啶基)苯甲酸(0.28g，1.31mmol，99.47%產率)。Sodium hydroxide beads (105.60 mg, 2.64 mmol, 49.58 μL) were added to a solution of methyl 4-(5-methyl-2-pyridyl)benzoate (0.3 g, 1.32 mmol) in MeOH (20 mL) and mix the resulting The material was heated at 65°C for 12h. The resulting solution was cooled to room temperature and evaporated. The residue was partitioned between DCM (10ml) and water (10ml). The aqueous layer was collected and acidified with sodium bisulfate (316.98 mg, 2.64 mmol). The resulting mixture was extracted with EtOAc (2x30ml). The combined organic layers were evaporated to obtain 4-(5-methyl-2-pyridyl)benzoic acid (0.28 g, 1.31 mmol, 99.47% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)2.32(s,3H),7.65(d,1H),7.83(d,1H),7.93(m,4H),8.48(s,1H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 2.32 (s, 3H), 7.65 (d, 1H), 7.83 (d, 1H), 7.93 (m, 4H), 8.48 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值213.2；實測值214.2；Rt=0.881min。LCMS (ESI): [M] + m/z: calculated 213.2; found 214.2; Rt=0.881 min.

步驟3：N-甲基-4-(5-甲基吡啶-2-基)苯甲醯胺之合成Step 3: Synthesis of N-methyl-4-(5-methylpyridin-2-yl)benzamide

將4-(5-甲基-2-吡啶基)苯甲酸(0.28g，1.31mmol)、甲胺(177.32mg，2.63mmol，197.24μL，HCl)、HATU(549.22mg，1.44mmol)及三乙胺(465.06mg，4.60mmol，640.58μL)混合於DMF(5mL)中且將所得混合物在20℃下攪拌12h。將所得混合物分配於EtOAc(50ml)與水(50ml)之間。收集有機層，將其用水、鹽水洗滌且蒸發。使殘餘物經歷管柱層析，以獲得N -甲基-4-(5-甲基-2-吡啶基)苯甲醯胺(0.2g，883.89μmol，67.31%產率)。Combine 4-(5-methyl-2-pyridyl)benzoic acid (0.28 g, 1.31 mmol), methylamine (177.32 mg, 2.63 mmol, 197.24 μL, HCl), HATU (549.22 mg, 1.44 mmol) and triethylamine The amine (465.06 mg, 4.60 mmol, 640.58 μL) was mixed in DMF (5 mL) and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was partitioned between EtOAc (50ml) and water (50ml). The organic layer was collected, washed with water, brine and evaporated. The residue was subjected to column chromatography to obtain N -methyl-4-(5-methyl-2-pyridyl)benzamide (0.2 g, 883.89 μmol, 67.31% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)2.34(s,3H),2.80(d,3H),7.71(d,1H),7.93(m,3H),8.13(d,2H),8.50(m,2H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 2.34(s, 3H), 2.80(d, 3H), 7.71(d, 1H), 7.93(m, 3H), 8.13(d, 2H), 8.50 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值226.2；實測值227.2；Rt=0.783min。LCMS (ESI): [M] + m/z: calculated 226.2; found 227.2; Rt=0.783 min.

步驟4：N-甲基-4-(5-甲基哌啶-2-基)苯甲醯胺之合成Step 4: Synthesis of N-methyl-4-(5-methylpiperidin-2-yl)benzamide

將乾燥的487型鈀(10%於碳上)(1.88mg，17.68μmol)添加到N -甲基-4-(5-甲基-2-吡啶基)苯甲醯胺(0.2g，883.89μmol)於MeOH(30mL)中之溶液中且將所得混合物在50atm壓力及50℃下氫化72h。在起始材料消耗(H-NMR對照)之後，將所得混合物冷卻至室溫且過濾。將濾液蒸發至乾。使殘餘物經歷HPLC(管柱SunFire 100*19mm 5um，以水-MeCN+NH3 為溶析液混合物)，以獲得N -甲基-4-(5-甲基-2-哌啶基)苯甲醯胺(0.012g，51.65μmol，5.84%產率)。Dry palladium type 487 (10% on carbon) (1.88 mg, 17.68 μmol) was added to N -methyl-4-(5-methyl-2-pyridyl)benzamide (0.2 g, 883.89 μmol) ) in MeOH (30 mL) and the resulting mixture was hydrogenated at 50 atm pressure and 50 °C for 72 h. After consumption of starting material (H-NMR control), the resulting mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness. The residue was subjected to HPLC (column SunFire 100*19mm 5um with water-MeCN+ NH3 as eluent mixture) to obtain N -methyl-4-(5-methyl-2-piperidinyl)benzene Formamide (0.012 g, 51.65 μmol, 5.84% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值232.3；實測值233.2；Rt=1.556min。LCMS (ESI): [M] + m/z: calculated 232.3; found 233.2; Rt=1.556 min.

步驟5：N-甲基-4-(5-甲基-1-(2-((5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)哌啶-2-基)苯甲醯胺(化合物92 )之合成Step 5: N-Methyl-4-(5-methyl-1-(2-((5-methylpyridin-3-yl)amino)-2-oxyethanoyl)piperidine-2 Synthesis of -yl)benzamide ( compound 92 )

將[2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]氧基鋰(9.61mg，51.65μmol)及HATU(19.64mg，51.65μmol)混合於DMF(2mL)中且將所得混合物在20℃下攪拌20min，隨後添加N -甲基-4-(5-甲基-2-哌啶基)苯甲醯胺(0.012g，51.65μmol)且將所得混合物在20℃下攪拌12h。使所得混合物經歷HPLC(管柱SunFire 100*19mm 5um，以水-MeCN為溶析液混合物)，以獲得N -甲基-4-[5-甲基-1-[2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-2-哌啶基]苯甲醯胺(0.005g，12.68μmol，24.54%產率)。Lithium [2-[(5-methyl-3-pyridyl)amino]-2-oxyethanoyl]oxide (9.61 mg, 51.65 μmol) and HATU (19.64 mg, 51.65 μmol) were mixed in DMF (2 mL) and the resulting mixture was stirred at 20 °C for 20 min, then N -methyl-4-(5-methyl-2-piperidinyl)benzamide (0.012 g, 51.65 μmol) was added and the The resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was subjected to HPLC (column SunFire 100*19mm 5um with water-MeCN as eluent mixture) to obtain N -methyl-4-[5-methyl-1-[2-[(5-methyl (0.005 g, 12.68 μmol, 24.54% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.12(m,3H),1.41(m,1H),2.00(m,2H),2.25(m,2H),2.38(m,3H),3.20(m,4H),4.47(m,1H),6.18(m,2H),7.36(d,2H),7.78(d,2H),8.13(m,1H),8.25(m,1H),8.62(m,1H),9.57(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.12(m, 3H), 1.41(m, 1H), 2.00(m, 2H), 2.25(m, 2H), 2.38(m, 3H), 3.20( m, 4H), 4.47(m, 1H), 6.18(m, 2H), 7.36(d, 2H), 7.78(d, 2H), 8.13(m, 1H), 8.25(m, 1H), 8.62(m , 1H), 9.57 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值394.5；實測值395.2；Rt=2.496min。LCMS (ESI): [M] + m/z: calculated 394.5; found 395.2; Rt=2.496 min.

實例689.N -甲基-3-[(2R ,5S )-5-甲基-1-[2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-2-哌啶基]苯甲醯胺(化合物48)之合成Example 689. N -methyl-3-[( 2R , 5S )-5-methyl-1-[2-[(5-methyl-3-pyridinyl)amino]-2-pendantoxy Synthesis of Acetyl]-2-piperidinyl]benzamide (Compound 48)

Figure 110128222-A0202-12-2240-556
Figure 110128222-A0202-12-2240-556

步驟1：3-(5-甲基-2-吡啶基)苯甲酸甲酯之合成Step 1: Synthesis of methyl 3-(5-methyl-2-pyridyl)benzoate

向2-溴-5-甲基吡啶(2g，11.63mmol)及(3-甲氧基羰基苯基)硼酸(2.30g，12.79mmol)於二噁烷(40mL)及水(4mL)中之經攪拌之溶液中添加碳酸銫(9.47g，29.07mmol)。將所得懸浮液用氬氣除氣。添加肆(三苯基磷烷)鈀(0)(671.75mg，581.32μmol)。將反應混合物在65℃下攪拌12小時。完成之後，將反應混合物過濾且將濾液在真空中蒸發。將殘餘物分配於EtOAc(100mL)與水(100mL)之間。將有機相經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由管柱層析純化粗產物，以獲得3-(5-甲基-2-吡啶基)苯甲酸甲酯(1g，4.40mmol，37.85%產率)。To 2-bromo-5-methylpyridine (2 g, 11.63 mmol) and (3-methoxycarbonylphenyl)boronic acid (2.30 g, 12.79 mmol) in dioxane (40 mL) and water (4 mL) To the stirred solution was added cesium carbonate (9.47 g, 29.07 mmol). The resulting suspension was degassed with argon. Add tetrakis(triphenylphosphine)palladium(0) (671.75 mg, 581.32 μmol). The reaction mixture was stirred at 65°C for 12 hours. After completion, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic phase was dried over Na2SO4 , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 3-(5-methyl-2-pyridyl)benzoate (1 g, 4.40 mmol, 37.85% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)2.35(s,3H),3.89(s,3H),7.63(t,1H),7.72(d,1H),7.93(d,1H),7.99(d,1H),8.32(m,1H),8.54(s,1H),8.67(s,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ(ppm) 2.35(s,3H), 3.89(s,3H), 7.63(t,1H), 7.72(d,1H), 7.93(d,1H) , 7.99(d, 1H), 8.32(m, 1H), 8.54(s, 1H), 8.67(s, 1H).

步驟2：3-(5-甲基-2-吡啶基)苯甲酸之合成Step 2: Synthesis of 3-(5-methyl-2-pyridyl)benzoic acid

向3-(5-甲基-2-吡啶基)苯甲酸甲酯(1g，4.40mmol)於MeOH(20mL)中之經攪拌之溶液中添加氫氧化鈉(352.00mg，8.80mmol)。將所得反應混合物在65℃下攪拌12小時。完成之後，使反應混合物冷卻至室溫且在減壓下濃縮。將所獲得之殘餘物分配於DCM(10mL)與水(10mL)之間。將水層用硫酸氫鈉(1.06g，8.80mmol)酸化。將所得混合物用EtOAc(2 x 30mL)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，以獲得3-(5-甲基-2-吡啶基)苯甲酸(0.9g，4.22mmol，95.92%產率)。To a stirred solution of methyl 3-(5-methyl-2-pyridyl)benzoate (1 g, 4.40 mmol) in MeOH (20 mL) was added sodium hydroxide (352.00 mg, 8.80 mmol). The resulting reaction mixture was stirred at 65°C for 12 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was partitioned between DCM (10 mL) and water (10 mL). The aqueous layer was acidified with sodium bisulfate (1.06 g, 8.80 mmol). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain 3-(5-methyl-2-pyridyl)benzoic acid (0.9 g, 4.22 mmol, 95.92% yield) .

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)2.34(s,3H),7.59(t,1H),7.72(d,1H),7.96(m,2H),8.27(d,1H),8.53(s,1H),8.64(s,1H),13.05(brs,1H)。 1 H NMR (DMSO- d 6 , 500MHz): δ(ppm) 2.34(s, 3H), 7.59(t, 1H), 7.72(d, 1H), 7.96(m, 2H), 8.27(d, 1H) , 8.53(s, 1H), 8.64(s, 1H), 13.05(brs, 1H).

步驟3：N-甲基-3-(5-甲基-2-吡啶基)苯甲醯胺之合成Step 3: Synthesis of N-methyl-3-(5-methyl-2-pyridyl)benzamide

向3-(5-甲基-2-吡啶基)苯甲酸(1g，4.69mmol)、甲胺(鹽酸鹽，633.28mg，9.38mmol)及HATU(1.96g，5.16mmol)於DMF(5mL)中之經攪拌之溶液中添加三乙胺(1.66g，16.41mmol，2.29mL)。將所得反應混合物在20℃下攪拌12 小時。12小時之後，將反應混合物分配於EtOAc(50mL)與水(50mL)之間。將有機層用水、鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析純化粗產物，以獲得N -甲基-3-(5-甲基-2-吡啶基)苯甲醯胺(1.05g，4.64mmol，98.95%產率)。To 3-(5-methyl-2-pyridyl)benzoic acid (1 g, 4.69 mmol), methylamine (hydrochloride, 633.28 mg, 9.38 mmol) and HATU (1.96 g, 5.16 mmol) in DMF (5 mL) To the stirred solution was added triethylamine (1.66 g, 16.41 mmol, 2.29 mL). The resulting reaction mixture was stirred at 20°C for 12 hours. After 12 hours, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain N -methyl-3-(5-methyl-2-pyridyl)benzamide (1.05 g, 4.64 mmol, 98.95% yield).

1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)2.35(s,3H),2.81(d,3H),7.55(t,1H),7.74(m,1H),7.85(d,1H),7.93(m,1H),8.18(d,1H),8.52(m,3H)。 1 H NMR (DMSO- d 6 , 500MHz): δ(ppm) 2.35(s,3H), 2.81(d,3H), 7.55(t,1H), 7.74(m,1H), 7.85(d,1H) , 7.93 (m, 1H), 8.18 (d, 1H), 8.52 (m, 3H).

LCMS(ESI)：[M+H]+ m/z：計算值226.1；實測值227.2；Rt=0.852min。LCMS (ESI): [M+H] + m/z: calculated 226.1; found 227.2; Rt=0.852 min.

步驟4：N-甲基-3-(5-甲基-2-哌啶基)苯甲醯胺之合成Step 4: Synthesis of N-methyl-3-(5-methyl-2-piperidinyl)benzamide

在50atm H2 壓力、50℃下，將N -甲基-3-(5-甲基-2-吡啶基)苯甲醯胺(1.05g，4.64mmol)於MeOH(30mL)中之溶液經乾燥的487型鈀(10%於碳上)(493.83mg，4.64mmol)氫化52小時。完成之後，過濾反應混合物；將殘餘物用MeOH洗滌。在減壓下濃縮濾液且藉由反相HPLC(溶析液：水-乙腈，0-10%，0.5-6min；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFire 100*19mm，5um)純化粗產物，以獲得N -甲基-3-(5-甲基-2-哌啶基)苯甲醯胺(210mg)。A solution of N -methyl-3-(5-methyl- 2 -pyridyl)benzamide (1.05 g, 4.64 mmol) in MeOH (30 mL) was dried at 50 atm H pressure at 50 °C of Palladium Form 487 (10% on carbon) (493.83 mg, 4.64 mmol) was hydrogenated for 52 h. After completion, the reaction mixture was filtered; the residue was washed with MeOH. The filtrate was concentrated under reduced pressure and analyzed by reverse phase HPLC (eluent: water-acetonitrile, 0-10%, 0.5-6 min; flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile; column: SunFire 100 *19mm, 5um) The crude product was purified to obtain N -methyl-3-(5-methyl-2-piperidinyl)benzamide (210 mg).

LCMS(ESI)：[M+H]+ m/z：計算值232.2；實測值233.2；Rt=1.668min。LCMS (ESI): [M+H] + m/z: calculated 232.2; found 233.2; Rt=1.668 min.

步驟5：N-甲基-3-[(2R,5S)-5-甲基-1-[2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-2-哌啶基]苯甲醯胺(化合物48 )之合成Step 5: N-Methyl-3-[(2R,5S)-5-methyl-1-[2-[(5-methyl-3-pyridyl)amino]-2-oxoacetone Synthesis of yl]-2-piperidinyl]benzamide ( compound 48 )

向[2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]氧基鋰(104.13mg，559.57μmol)及HATU(212.77mg，559.57μmol)於DMF(3mL)中之經攪拌之溶液中添加N -甲基-3-(5-甲基-2-哌啶基)苯甲醯胺(0.13g，559.57μmol)。將所得反應混合物在20℃下攪拌12小時。使所得混合物經歷反相HPLC純化(溶析液：水-乙腈，20-25%，0.5-6min；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFire 100*19mm，5um)，以獲得呈灰白色固體之N -甲基-3-[(2R ,5S )-5-甲基-1-[2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-2-哌啶基]苯甲醯胺(化合物48 ， 40.10mg，101.66μmol，18.17%產率)。To lithium [2-[(5-methyl-3-pyridinyl)amino]-2-oxyethanoyl]oxylithium (104.13 mg, 559.57 μmol) and HATU (212.77 mg, 559.57 μmol) in DMF To the stirred solution in (3 mL) was added N -methyl-3-(5-methyl-2-piperidinyl)benzamide (0.13 g, 559.57 μmol). The resulting reaction mixture was stirred at 20°C for 12 hours. The resulting mixture was subjected to reverse phase HPLC purification (eluent: water-acetonitrile, 20-25%, 0.5-6 min; flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile; column: SunFire 100*19 mm, 5um ) to obtain N -methyl-3-[( 2R , 5S )-5-methyl-1-[2-[(5-methyl-3-pyridyl)amino]- 2-Pendant oxyacetyl]-2-piperidinyl]benzamide ( compound 48 , 40.10 mg, 101.66 μmol, 18.17% yield).

1 H NMR(DMSO-d 6 +CCl4 ,400MHz)：δ(ppm)1.12(m,3H),1.43(m,1H),1.92(m,2H),2.15(m,1H),2.35(m,3H),2.84(m,3H),3.03(m,1H),3.30(m,1H),3.88(m,1H),5.49(m,1H),7.44(m,2H),7.74(m,2H),7.97(m,1H),8.08(m,1H),8.25(m,1H),8.55(m,1H),10.92(m,1H)。 1 H NMR (DMSO- d 6 +CCl 4 , 400MHz): δ (ppm) 1.12 (m, 3H), 1.43 (m, 1H), 1.92 (m, 2H), 2.15 (m, 1H), 2.35 (m ,3H),2.84(m,3H),3.03(m,1H),3.30(m,1H),3.88(m,1H),5.49(m,1H),7.44(m,2H),7.74(m, 2H), 7.97 (m, 1H), 8.08 (m, 1H), 8.25 (m, 1H), 8.55 (m, 1H), 10.92 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值394.2；實測值395.2；Rt=1.013min。LCMS (ESI): [M+H] + m/z: calculated 394.2; found 395.2; Rt=1.013 min.

實例690.N -(6-胺基-4,5-二甲基吡啶-3-基)-2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物383、化合物391)之合成Example 690. N- (6-Amino-4,5-lutidine-3-yl)-2-(2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide (Compound 383, Compound 391)

Figure 110128222-A0202-12-2243-557
Figure 110128222-A0202-12-2243-557

步驟1：2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1: Synthesis of 2-(2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester

在-40℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(996.01mg，5.23mmol)逐滴添加到4-(5-甲基-2-哌啶基)苯酚(1g，5.23mmol)及TEA(529.05mg，5.23mmol，728.71μL)於THF(20mL)中之溶液中。使所得混合物升溫至室溫且攪拌12h。過濾出所得沉澱。蒸發濾液，以獲得2-[2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.2g，3.48mmol，66.47%產率)，其不經純化即用於下一步驟中。2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (996.01 mg, 5.23 mmol) was added dropwise to 4-(5-methyl-2-piperidine at -40°C) yl)phenol (1 g, 5.23 mmol) and TEA (529.05 mg, 5.23 mmol, 728.71 μL) in THF (20 mL). The resulting mixture was warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered off. The filtrate was evaporated to obtain 2-[2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-trifluoroethyl acetate (1.2 g, 3.48 mmol, 66.47% yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.92(d,3H),1.28(m,1H),1.67(m,1H),1.89(m,1H),2.11(m,1H),3.18(m,1H),3.79(m,2H),4.62(m,1H),5.04(m,2H),6.77 (m,2H),7.05(m,2H),9.44(m,1H)。LCMS(ESI)：[M]+ m/z：計算值345.2；實測值346.2；Rt=1.354min 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.92(d,3H), 1.28(m,1H), 1.67(m,1H), 1.89(m,1H), 2.11(m,1H), 3.18 (m, 1H), 3.79 (m, 2H), 4.62 (m, 1H), 5.04 (m, 2H), 6.77 (m, 2H), 7.05 (m, 2H), 9.44 (m, 1H). LCMS(ESI): [M] + m/z: Calculated 345.2; Measured 346.2; Rt=1.354min

步驟2：2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙酸之合成Step 2: Synthesis of 2-(2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl)-2-oxoacetic acid

將98%氫氧化鋰單水合物(145.83mg，3.48mmol，96.57μL)添加到2-[2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.2g，3.48mmol)於THF(20mL)及水(2mL)中之溶液中且將所得混合物在20℃下攪拌12h。將所得混合物蒸發至乾，以獲得2-[2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(0.8g，2.96mmol，85.19%產率，Li+ )，其不經純化即用於下一步驟中。98% Lithium hydroxide monohydrate (145.83 mg, 3.48 mmol, 96.57 μL) was added to 2-[2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxo 2,2,2-trifluoroethyl acetate (1.2 g, 3.48 mmol) in THF (20 mL) and water (2 mL) and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was evaporated to dryness to obtain 2-[2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-pendoxoacetic acid (0.8 g, 2.96 mmol, 85.19% yield). yield, Li + ), which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.18(m,1H),1.38(m,1H),1.98(m,3H),2.84(m,1H),3.12(m,1H),4.65(m,1H),5.04(m,1H),6.78(m,2H),7.17(m,2H),9.55(m,1H)。LCMS(ESI)：[M]+ m/z：計算值263.2；實測值264.2；Rt=0.885min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.98(d,3H), 1.18(m,1H), 1.38(m,1H), 1.98(m,3H), 2.84(m,1H), 3.12 (m, 1H), 4.65 (m, 1H), 5.04 (m, 1H), 6.78 (m, 2H), 7.17 (m, 2H), 9.55 (m, 1H). LCMS (ESI): [M] + m/z: calculated 263.2; found 264.2; Rt=0.885min.

步驟3：3,4-二甲基-5-硝基吡啶-2-胺之合成Step 3: Synthesis of 3,4-Dimethyl-5-nitropyridin-2-amine

將3-溴-4-甲基-5-硝基吡啶-2-胺(5g，15.98mmol，HBr)及甲基硼酸(4.78g，79.89mmol)溶解於THF(100mL)及水(10mL)中。向其中添加碳酸銫(33.84g，103.85mmol)。然後，添加Pd(dppf)Cl2 *DCM(798.86μmol)且將反應燒瓶快速抽真空且用氬氣再填充。將所得混合物在80℃下攪拌12h。此後，將其冷卻且蒸發。將殘餘物分配於EtOAc(100ml)與水(100ml)之間。收集有機相，將其經Na2 SO4 乾燥且蒸發，以獲得3,4-二甲基-5-硝基吡啶-2-胺(2g，11.96mmol，74.88%產率)。3-Bromo-4-methyl-5-nitropyridin-2-amine (5 g, 15.98 mmol, HBr) and methylboronic acid (4.78 g, 79.89 mmol) were dissolved in THF (100 mL) and water (10 mL) . To this was added cesium carbonate (33.84 g, 103.85 mmol). Then, Pd(dppf)Cl 2 *DCM (798.86 μmol) was added and the reaction flask was quickly evacuated and refilled with argon. The resulting mixture was stirred at 80 °C for 12 h. After that, it was cooled and evaporated. The residue was partitioned between EtOAc (100ml) and water (100ml). The organic phase was collected, dried over Na2SO4 and evaporated to obtain 3,4-dimethyl-5-nitropyridin-2-amine (2 g, 11.96 mmol, 74.88% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)2.64(s,3H),2.99(s,3H),7.65(bds,2H),9.16(s,1H)。LCMS(ESI)：[M]+ m/z：計算值167.2；實測值168.2；Rt=0.881min。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 2.64 (s, 3H), 2.99 (s, 3H), 7.65 (bds, 2H), 9.16 (s, 1H). LCMS (ESI): [M] + m/z: calculated 167.2; found 168.2; Rt=0.881 min.

步驟4：3,4-二甲基吡啶-2,5-二胺之合成Step 4: Synthesis of 3,4-lutidine-2,5-diamine

將乾燥的487型鈀(10%於碳上)(636.62mg，5.98mmol)添加到3,4-二甲基-5-硝基吡啶-2-胺(1g，5.98mmol)於MeOH(30mL)中之溶液且將所得混合物 在50atm壓力及20℃下氫化12h。過濾所得混合物且將其蒸發，以獲得3,4-二甲基吡啶-2,5-二胺(0.7g，5.10mmol，85.30%產率)，其不經純化即用於下一步驟中。Dry palladium Form 487 (10% on carbon) (636.62 mg, 5.98 mmol) was added to 3,4-dimethyl-5-nitropyridin-2-amine (1 g, 5.98 mmol) in MeOH (30 mL) solution in and the resulting mixture Hydrogenate at 50 atm pressure and 20 °C for 12 h. The resulting mixture was filtered and evaporated to give 3,4-lutidine-2,5-diamine (0.7 g, 5.10 mmol, 85.30% yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.90(s,3H),1.93(s,3H),4.01(bds,2H),4.60(bds,2H),7.27(s,1H)。LCMS(ESI)：[M]+ m/z：計算值137.2；實測值138.2；Rt=min。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 1.90 (s, 3H), 1.93 (s, 3H), 4.01 (bds, 2H), 4.60 (bds, 2H), 7.27 (s, 1H). LCMS (ESI): [M] + m/z: calculated 137.2; found 138.2; Rt=min.

步驟5：N-(6-胺基-4,5-二甲基吡啶-3-基)-2-(2-(4-羥基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺之合成Step 5: N-(6-Amino-4,5-lutidine-3-yl)-2-(2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide

將2-[2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(0.4g，1.48mmol，Li+ )與HATU(562.83mg，1.48mmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加3,4-二甲基吡啶-2,5-二胺(203.06mg，1.48mmol)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(管柱：TRIART 100*20，5微米，水/ACN+NH3 為溶析液混合物)，以獲得N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.057g，149.04μmol，10.07%產率)。2-[2-(4-Hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxoacetic acid (0.4 g, 1.48 mmol, Li + ) was mixed with HATU (562.83 mg, 1.48 mmol ) in DMF (5 mL) and the resulting mixture was stirred at 20 °C for 10 min, followed by the addition of 3,4-lutidine-2,5-diamine (203.06 mg, 1.48 mmol). The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (column: TRIART 100*20, 5 microns, water/ACN+NH as eluent mixture) to obtain N- (6-amino-4,5-dimethyl-3- Pyridyl)-2-[2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.057 g, 149.04 μmol, 10.07% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm) 1 H NMR (500MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值382.5；實測值383.2；Rt=0.811min。LCMS (ESI): [M] + m/z: calculated 382.5; found 383.2; Rt=0.811 min.

步驟6：掌性分離(化合物383 及化合物391 )Step 6: Chiral separation ( compound 383 and compound 391 )

使用(Chiralpak OD-H 250*30，5mkm管柱；以己烷-IPA-MeOH，70-15-15為流動相；流速30mL/min；注入體積：900mkl)分離N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(57mg，149.04μmol)，得到呈黃色固體之化合物383 N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2R,5S )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(21mg，54.91μmol，36.84%產率)(RT(OD-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=14.05 min)及呈黃色固體之化合物391 N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2S,5R )-2-(4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(22mg，57.52μmol，38.60%產率)(RT(OD-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=8.29min)。Separation of N- (6-amino- 4,5-Dimethyl-3-pyridyl)-2-[2-(4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (57 mg, 149.04 μmol) to give compound 383 as a yellow solid N- (6-amino-4,5-dimethyl-3-pyridyl)-2-[( 2R,5S )-2-(4-hydroxyphenyl) )-5-methyl-1-piperidinyl]-2-oxyacetamide (21 mg, 54.91 μmol, 36.84% yield) (RT(OD-H, hexane-IPA-MeOH, 60-20 -20, 0.6ml/min)=14.05min) and compound 391 as a yellow solid N- (6-amino-4,5-dimethyl-3-pyridyl)-2-[( 2S,5R )- 2-(4-Hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (22 mg, 57.52 μmol, 38.60% yield) (RT (OD-H, hexane) -IPA-MeOH, 60-20-20, 0.6ml/min)=8.29min).

化合物383：保留時間：14.05minCompound 383: retention time: 14.05min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.26-1.34(m,1H),1.65-1.73(m,1H),1.83(d,1H),1.87-2.04(m,7H),2.11-2.19(m,1H),2.70-3.13(m,1H),3.40-4.02(m,1H),4.97-5.54(m,1H),5.56-5.85(m,2H),6.67-6.80(m,2H),7.02-7.22(m,2H),7.43-7.68(m,1H),9.16-9.45(m,1H),9.48-10.14(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.04(m,3H), 1.26-1.34(m,1H), 1.65-1.73(m,1H), 1.83(d,1H), 1.87 -2.04(m, 7H), 2.11-2.19(m, 1H), 2.70-3.13(m, 1H), 3.40-4.02(m, 1H), 4.97-5.54(m, 1H), 5.56-5.85(m, 2H), 6.67-6.80(m, 2H), 7.02-7.22(m, 2H), 7.43-7.68(m, 1H), 9.16-9.45(m, 1H), 9.48-10.14(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值382.4；實測值383.2；Rt=1.974min。LCMS (ESI): [M] + m/z: calculated 382.4; found 383.2; Rt=1.974 min.

化合物391：保留時間：8.29minCompound 391: retention time: 8.29min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.91-1.06(m,3H),1.18-1.38(m,1H),1.59-1.74(m,1H),1.76-1.87(m,1H),1.87-2.04(m,7H),2.08-2.20(m,1H),2.66-3.18(m,1H),3.41-4.00(m,1H),5.00-5.55(m,1H),5.57-5.85(m,2H),6.71-6.78(m,2H),7.03-7.19(m,2H),7.46-7.67(m,1H),9.16-9.38(m,1H),9.51-10.14(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.91-1.06(m,3H), 1.18-1.38(m,1H), 1.59-1.74(m,1H), 1.76-1.87(m,1H) ,1.87-2.04(m,7H),2.08-2.20(m,1H),2.66-3.18(m,1H),3.41-4.00(m,1H),5.00-5.55(m,1H),5.57-5.85( m, 2H), 6.71-6.78 (m, 2H), 7.03-7.19 (m, 2H), 7.46-7.67 (m, 1H), 9.16-9.38 (m, 1H), 9.51-10.14 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值382.4；實測值383.2；Rt=1.980min。LCMS (ESI): [M] + m/z: calculated 382.4; found 383.2; Rt=1.980 min.

實例691. 2-甲氧基-5-(2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺基)菸鹼醯胺(化合物138、化合物199及化合物202)之合成Example 691. 2-Methoxy-5-(2-oxo-2-(2-phenylpiperidin-1-yl)acetamido)nicotinamide (Compound 138, Compound 199 and Compound 202 ) synthesis

Figure 110128222-A0202-12-2246-558
Figure 110128222-A0202-12-2246-558

步驟1：2-甲氧基-5-(2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺基)菸鹼醯胺(化合物138 )之合成Step 1: Synthesis of 2-methoxy-5-(2-pendoxo-2-(2-phenylpiperidin-1-yl)acetamido)nicotinamide ( compound 138 )

將DIPEA(138.52mg，1.07mmol，186.68μL)添加到相應2-側氧基-2-(2-苯基-1-哌啶基)乙酸(0.1g，428.70μmol)及5-胺基-2-甲氧基吡啶-3-甲醯胺 (71.66mg，428.70μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(179.31mg，471.57μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到純的2-甲氧基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(117.4mg，307.00μmol，71.61%產率)。DIPEA (138.52 mg, 1.07 mmol, 186.68 μL) was added to the corresponding 2-oxo-2-(2-phenyl-1-piperidinyl)acetic acid (0.1 g, 428.70 μmol) and 5-amino-2 -Methoxypyridine-3-carboxamide (71.66 mg, 428.70 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (179.31 mg, 471.57 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure 2-methoxy-5-[[2-oxy-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine -3-Carboxamide (117.4 mg, 307.00 μmol, 71.61% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.44(m,2H),1.61(m,2H),1.92(m,1H),3.00(m,2H),3.96(m,4H),5.69(m,1H),7.33(m,3H),7.41(m,2H),7.73(m,1H),7.77(m,1H),8.51(m,1H),8.57(m,1H),11.08(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.44(m, 2H), 1.61(m, 2H), 1.92(m, 1H), 3.00(m, 2H), 3.96(m, 4H), 5.69(m,1H),7.33(m,3H),7.41(m,2H),7.73(m,1H),7.77(m,1H),8.51(m,1H),8.57(m,1H),11.08 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值382.4；實測值383.2；Rt=3.030min。LCMS (ESI): [M] + m/z: calculated 382.4; found 383.2; Rt=3.030 min.

步驟2：掌性分離(化合物199 及化合物202 )Step 2: Chiral separation ( compound 199 and compound 202 )

使用(Chiralpak IB 250*20，5mkm管柱；CO2 -MeOH，70-30為流動相；流速2mL/min)分離2-甲氧基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(46.2mg，120.81μmol)；得到呈米色固體之化合物199 2-甲氧基-5-[[2-側氧基-2-[(2R)-2-苯基-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(22mg，57.53μmol，47.62%產率)(RT=7.02min)及呈米色固體之化合物202 2-甲氧基-5-[[2-側氧基-2-[(2S )-2-苯基-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(24.15mg，63.15μmol，52.27%產率)(RT=7.71min)。2-Methoxy-5-[[2-Pendoxyl-2-(2 was isolated using (Chiralpak IB 250*20, 5mkm column; CO2 -MeOH, 70-30 as mobile phase; flow rate 2mL/min) -Phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (46.2 mg, 120.81 μmol); gave compound 199 as a beige solid 2-methoxy-5-[[2 - Pendant oxy-2-[(2R)-2-phenyl-1-piperidinyl]acetoxy]amino]pyridine-3-carboxamide (22 mg, 57.53 μmol, 47.62% yield) (RT = 7.02min ) and compound 202 as a beige solid yl]pyridine-3-carboxamide (24.15 mg, 63.15 μmol, 52.27% yield) (RT=7.71 min).

化合物199：保留時間：7.02minCompound 199: retention time: 7.02min

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.53(m,4H),1.87(m,1H),3.01(m,1H),3.70(m,1H),3.95(m,3H),4.23(m,1H),5.44(m,1H),7.37(m,5H),7.76(m,2H),8.52(m,2H),11.09(m,1H)。 1 H NMR (400MHz, DMSO- d 6 ) δ(ppm) 1.53(m, 4H), 1.87(m, 1H), 3.01(m, 1H), 3.70(m, 1H), 3.95(m, 3H), 4.23 (m, 1H), 5.44 (m, 1H), 7.37 (m, 5H), 7.76 (m, 2H), 8.52 (m, 2H), 11.09 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值382.2；實測值383.2；Rt=3.359min。LCMS (ESI): [M] + m/z: calculated 382.2; found 383.2; Rt=3.359 min.

化合物202：保留時間：7.71minCompound 202: retention time: 7.71min

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.55(m,4H),1.83(m,1H),3.01(m,1H),3.70(m,1H),3.95(m,3H),4.30(m,1H),5.45(m,1H),7.37(m,5H),7.75(m,2H),8.53(m,2H),11.09(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.55(m, 4H), 1.83(m, 1H), 3.01(m, 1H), 3.70(m, 1H), 3.95(m, 3H), 4.30 (m, 1H), 5.45 (m, 1H), 7.37 (m, 5H), 7.75 (m, 2H), 8.53 (m, 2H), 11.09 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值382.2；實測值383.2；Rt=3.360min。LCMS (ESI): [M] + m/z: calculated 382.2; found 383.2; Rt=3.360 min.

實例692.N -(5-(羥基甲基)吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物136)及N-(5-甲醯基吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物147)之合成Example 692. N- (5-(Hydroxymethyl)pyridin-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide (Compound 136) and N- Synthesis of (5-Methylpyridin-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide (Compound 147)

Figure 110128222-A0202-12-2248-559
Figure 110128222-A0202-12-2248-559

步驟1：N-(5-(羥基甲基)吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物136 )之合成Step 1: Synthesis of N-(5-(hydroxymethyl)pyridin-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide ( compound 136 )

將DIPEA(138.52mg，1.07mmol，186.68μL)添加到相應2-側氧基-2-(2-苯基-1-哌啶基)乙酸(0.1g，428.70μmol)及(5-胺基-3-吡啶基)甲醇(53.22mg，428.70μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(179.31mg，471.57μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC，以得到純的N -[5-(羥基甲基)-3-吡啶基]-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(0.1g，294.65μmol，68.73%產率)。DIPEA (138.52 mg, 1.07 mmol, 186.68 μL) was added to the corresponding 2-oxo-2-(2-phenyl-1-piperidinyl)acetic acid (0.1 g, 428.70 μmol) and (5-amino- 3-Pyridinyl)methanol (53.22 mg, 428.70 [mu]mol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (179.31 mg, 471.57 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC to give pure N- [5-(hydroxymethyl)-3-pyridinyl]-2-oxy-2-(2-phenyl-1-piperidinyl)ethyl Amide (0.1 g, 294.65 μmol, 68.73% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.42(m,2H),1.61(m,2H),1.82(m,1H),2.98(m,2H),3.96(m,1H),4.49(m,2H),5.42(m,2H),7.26(m,1H),7.33(m,2H),7.39(m,2H),8.05(m,1H),8.24(m,1H),8.64(m,1H),11.10(m,1H)。LCMS(ESI)：[M]+ m/z：計算值339.4；實測值340.2；Rt=2.490min。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.42(m, 2H), 1.61(m, 2H), 1.82(m, 1H), 2.98(m, 2H), 3.96(m, 1H), 4.49(m, 2H), 5.42(m, 2H), 7.26(m, 1H), 7.33(m, 2H), 7.39(m, 2H), 8.05(m, 1H), 8.24(m, 1H), 8.64 (m, 1H), 11.10 (m, 1H). LCMS (ESI): [M] + m/z: calculated 339.4; found 340.2; Rt=2.490 min.

步驟2：N-(5-甲醯基吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物147 )Step 2: N-(5-Methylpyridin-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide ( Compound 147 ) 之合成synthesis

將N -[5-(羥基甲基)-3-吡啶基]-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(84.4mg，248.68μmol)及2-碘氧基苯甲酸(90.53mg，323.29μmol)溶解於MeCN(10mL)中且在回流下攪拌3h。使所得溶液冷卻至室溫且透過濾紙過濾。在減壓下蒸發溶劑。藉由HPLC使用水-MeOH作為流動相純化固體殘餘物，以得到N -(5-甲醯基-3-吡啶基)-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(14.6mg，43.28μmol，17.40%產率)。 N- [5-(Hydroxymethyl)-3-pyridyl]-2-oxy-2-(2-phenyl-1-piperidinyl)acetamide (84.4 mg, 248.68 μmol) and 2 - Iodooxybenzoic acid (90.53 mg, 323.29 μmol) was dissolved in MeCN (10 mL) and stirred at reflux for 3 h. The resulting solution was cooled to room temperature and filtered through filter paper. The solvent was evaporated under reduced pressure. The solid residue was purified by HPLC using water-MeOH as mobile phase to give N- (5-carboxy-3-pyridyl)-2-oxy-2-(2-phenyl-1-piperidine) yl)acetamide (14.6 mg, 43.28 μmol, 17.40% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.63(m,2H),2.01(m,2H),2.50(m,1H),2.99(m,1H),3.70(m,1H),4.68(m,1H),6.19(m,1H),7.27(m,3H),7.36(m,2H),8.72(m,1H),8.86(m,1H),9.01(m,1H),9.76(m,1H),10.10(m,1H)。LCMS(ESI)：[M]+ m/z：計算值337.4；實測值338.2；Rt=3.284min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.63(m, 2H), 2.01(m, 2H), 2.50(m, 1H), 2.99(m, 1H), 3.70(m, 1H), 4.68( m, 1H), 6.19(m, 1H), 7.27(m, 3H), 7.36(m, 2H), 8.72(m, 1H), 8.86(m, 1H), 9.01(m, 1H), 9.76(m , 1H), 10.10(m, 1H). LCMS (ESI): [M] + m/z: calculated 337.4; found 338.2; Rt=3.284 min.

實例693.N -(5,6-二甲基吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物139、化合物189及化合物188)之合成Example 693. N- (5,6-Lutidine-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide (Compound 139, Compound 189 and Synthesis of compound 188)

Figure 110128222-A0202-12-2249-560
Figure 110128222-A0202-12-2249-560

步驟1：N-(5,6-二甲基吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物139 )之合成Step 1: Synthesis of N-(5,6-lutidine-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide ( compound 139 )

將DIPEA(138.52mg，1.07mmol，186.68μL)添加到相應5,6-二甲基吡啶-3-胺(52.37mg，428.70μmol)及2-側氧基-2-(2-苯基-1-哌啶基)乙酸(0.1g，428.70μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(179.31mg，471.57μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters SunFire C18 19*100 5mkm管柱且以40-60% MeCN為流動相)，以得到純的N -(5,6-二甲基-3-吡啶基)-2-側氧基-2-(2-苯 基-1-哌啶基)乙醯胺(99.6mg，295.19μmol，68.86%產率)。DIPEA (138.52 mg, 1.07 mmol, 186.68 μL) was added to the corresponding 5,6-lutidine-3-amine (52.37 mg, 428.70 μmol) and 2-Pendox-2-(2-phenyl-1 -Piperidinyl)acetic acid (0.1 g, 428.70 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (179.31 mg, 471.57 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters SunFire C18 19*100 5mkm column with 40-60% MeCN as mobile phase) to give pure N- (5,6-dimethyl-3-pyridinyl)- 2-Pendoxo-2-(2-phenyl-1-piperidinyl)acetamide (99.6 mg, 295.19 μmol, 68.86% yield).

1 H NMR(400MHz,DMSO-d 6 +CCl4 )δ(ppm)1.44(m,2H),1.62(m,2H),1.82(m,1H),2.23(m,3H),2.37(m,3H),2.98(m,2H),3.67(m,1H),5.68(m,1H),7.33(m,3H),7.41(m,2H),7.86(m,1H),8.53(m,1H),10.97(m,1H)。 1 H NMR (400MHz, DMSO- d 6 +CCl 4 )δ(ppm) 1.44(m, 2H), 1.62(m, 2H), 1.82(m, 1H), 2.23(m, 3H), 2.37(m, 3H), 2.98(m, 2H), 3.67(m, 1H), 5.68(m, 1H), 7.33(m, 3H), 7.41(m, 2H), 7.86(m, 1H), 8.53(m, 1H) ), 10.97(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值337.4；實測值338.2；Rt=2.510min。LCMS (ESI): [M] + m/z: calculated 337.4; found 338.2; Rt=2.510 min.

步驟2：掌性分離(化合物189 及化合物188 )Step 2: Chiral separation ( Compound 189 and Compound 188 )

使用(Chiralpak OJ-H 250*20，5mkm管柱；以己烷-IPA-MeOH，60-20-20為流動相；流速12mL/min；注入體積：900mkl)分離N -(5,6-二甲基-3-吡啶基)-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(52.93mg，156.87μmol)；得到呈米色固體之化合物189 N -(5,6-二甲基-3-吡啶基)-2-側氧基-2-[(2R )-2-苯基-1-哌啶基]乙醯胺(26.84mg，79.55μmol，50.71%產率)(RT(OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=24.48min)及呈米色固體之化合物188 N -(5,6-二甲基-3-吡啶基)-2-側氧基-2-[(2S )-2-苯基-1-哌啶基]乙醯胺(26.09mg，77.32μmol，49.29%產率)(RT(OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=10.69min)。Using (Chiralpak OJ-H 250*20, 5mkm column; hexane-IPA-MeOH, 60-20-20 as mobile phase; flow rate 12mL/min; injection volume: 900mkl) to separate N- (5,6-di Methyl-3-pyridyl)-2-oxy-2-(2-phenyl-1-piperidinyl)acetamide (52.93 mg, 156.87 μmol); gave compound 189 as a beige solid N- ( 5,6-Dimethyl-3-pyridyl)-2-oxy-2-[( 2R )-2-phenyl-1-piperidinyl]acetamide (26.84 mg, 79.55 μmol, 50.71% Yield) (RT(OJ-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min) = 24.48 min) and compound 188 N- (5,6-dimethyl- 3-Pyridinyl)-2-oxy-2-[( 2S )-2-phenyl-1-piperidinyl]acetamide (26.09 mg, 77.32 μmol, 49.29% yield) (RT (OJ- H, Hexane-IPA-MeOH, 60-20-20, 0.6 ml/min) = 10.69 min).

化合物189：保留時間：24.48minCompound 189: retention time: 24.48min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.49(m,4H),1.85(m,1H),2.20(m,3H),2.34(m,3H),2.43(m,1H),2.96(m,1H),4.02(m,1H),5.39(m,1H),7.33(m,5H),7.80(m,1H),8.46(m,1H),10.94(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.49(m, 4H), 1.85(m, 1H), 2.20(m, 3H), 2.34(m, 3H), 2.43(m, 1H), 2.96(m, 1H), 4.02(m, 1H), 5.39(m, 1H), 7.33(m, 5H), 7.80(m, 1H), 8.46(m, 1H), 10.94(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值337.2；實測值338.2；Rt=3.802min。LCMS (ESI): [M] + m/z: calculated 337.2; found 338.2; Rt=3.802 min.

化合物188：保留時間：10.69minCompound 188: retention time: 10.69min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.51(m,4H),1.83(m,1H),2.20(m,3H),2.34(m,3H),2.43(m,1H),2.96(m,1H),4.12(m,1H),5.40(m,1H),7.34(m,5H),7.80(m,1H),8.46(m,1H),10.93(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.51(m, 4H), 1.83(m, 1H), 2.20(m, 3H), 2.34(m, 3H), 2.43(m, 1H), 2.96(m,1H), 4.12(m,1H), 5.40(m,1H), 7.34(m,5H), 7.80(m,1H), 8.46(m,1H), 10.93(m,1H).

LCMS(ESI)：[M]+ m/z：計算值337.2；實測值338.2；Rt=3.808min。LCMS (ESI): [M] + m/z: calculated 337.2; found 338.2; Rt=3.808 min.

實例694.N -羥基-5-(2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺基)菸鹼醯胺(化合物378)之合成Example 694. Synthesis of N -hydroxy-5-(2-oxo-2-(2-phenylpiperidin-1-yl)acetamido)nicotinamide (compound 378)

Figure 110128222-A0202-12-2251-561
Figure 110128222-A0202-12-2251-561

步驟1：5-((第三丁氧基羰基)胺基)菸鹼酸甲酯之合成Step 1: Synthesis of methyl 5-((tertiary butoxycarbonyl)amino)nicotinate

將一部分5-甲氧基羰基吡啶-3-甲酸(4.23g，23.35mmol)溶解於無水第三丁醇(98.25g，1.33mol，125mL)中且依次用99% TEA(3.54g，35.03mmol，4.88mL)及疊氮磷酸二苯酯(8.52g，35.03mmol)處理。將混合物回流8h。在減壓下移除溶劑且將殘餘物分配於水與DCM之間。分離各層且用DCM萃取水相兩次。將經合併之有機相乾燥且濃縮，以產生5-(第三丁氧基 羰基胺基)吡啶-3-甲酸甲酯(8g，粗品)，其不經進一步純化即使用。A portion of 5-methoxycarbonylpyridine-3-carboxylic acid (4.23 g, 23.35 mmol) was dissolved in anhydrous 3-butanol (98.25 g, 1.33 mol, 125 mL) and successively treated with 99% TEA (3.54 g, 35.03 mmol, 4.88 mL) and diphenylphosphoryl azide (8.52 g, 35.03 mmol). The mixture was refluxed for 8 h. The solvent was removed under reduced pressure and the residue was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried and concentrated to give methyl 5-( tert- butoxycarbonylamino)pyridine-3-carboxylate (8 g, crude) which was used without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.49(s,9H),3.96(s,3H),8.49(s,1H),8.69(s,1H),8.84(s,1H),12.06(bds,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.49(s, 9H), 3.96(s, 3H), 8.49(s, 1H), 8.69(s, 1H), 8.84(s, 1H), 12.06( bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值252.2；實測值253.2；Rt=1.216min。LCMS (ESI): [M] + m/z: calculated 252.2; found 253.2; Rt=1.216 min.

步驟2：5-((第三丁氧基羰基)胺基)菸鹼酸之合成Step 2: Synthesis of 5-((3rd-butoxycarbonyl)amino)nicotinic acid

將5-(第三丁氧基 羰基胺基)吡啶-3-甲酸甲酯(8g，31.71mmol)溶解於MeOH(128mL)及水(32mL)中，一次性添加氫氧化鈉珠粒(1.90g，47.57mmol，893.25μL)，將混合物在室溫下攪拌8h，將混合物濃縮，將殘餘物用1N HCl處理，直到所得漿液達到pH 3。收集殘餘物且用水洗滌，乾燥。使粗品經歷CC(SiO2 ，梯度ACN/CHCl3 )，以產生5-(第三丁氧基 羰基胺基)吡啶-3-甲酸(1.1g，4.62mmol，14.56%產率)。Methyl 5-( tert- butoxycarbonylamino)pyridine-3-carboxylate (8 g, 31.71 mmol) was dissolved in MeOH (128 mL) and water (32 mL), and sodium hydroxide beads (1.90 g) were added in one portion. , 47.57 mmol, 893.25 μL), the mixture was stirred at room temperature for 8 h, the mixture was concentrated, and the residue was treated with 1 N HCl until the resulting slurry reached pH 3. The residue was collected and washed with water and dried. The crude product was subjected to CC ( SiO2 , gradient ACN/ CHCl3 ) to give 5-( tert- butoxycarbonylamino)pyridine-3-carboxylic acid (1.1 g, 4.62 mmol, 14.56% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.49(s,9H),8.48(s,1H),8.69(s,1H),8.78 (s,1H),9.82(bds,1H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 1.49 (s, 9H), 8.48 (s, 1H), 8.69 (s, 1H), 8.78 (s, 1H), 9.82 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值238.2；實測值239.2；Rt=0.964min。LCMS (ESI): [M] + m/z: calculated 238.2; found 239.2; Rt=0.964 min.

步驟3：(5-((苯甲醯基氧基)胺甲醯基)吡啶-3-基)胺甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl (5-((benzyloxy)aminocarbamoyl)pyridin-3-yl)carbamate

將5-(第三丁氧基 羰基胺基)吡啶-3-甲酸(0.2g，839.49μmol)溶解於DMF(4mL)中且一次性添加O -苯甲基羥基胺(200.99mg，1.26mmol，HCl)、EDC(321.86mg，1.68mmol)、HOBt(124.78mg，923.44μmol)及DIPEA(336.35mg，2.60mmol，453.30μL)。將混合物在室溫下攪拌8h且藉由LCMS控制。將混合物用EtOAc(30mL)稀釋且用鹽水(3*10mL)洗滌，經Na2 SO4 乾燥且濃縮，以產生N -[5-(苯甲基氧基胺甲醯基)-3-吡啶基]胺甲酸第三丁 酯(0.3g，粗品)，其不經進一步純化即使用。5-( Third- butoxycarbonylamino)pyridine-3-carboxylic acid (0.2 g, 839.49 μmol) was dissolved in DMF (4 mL) and O -benzylhydroxylamine (200.99 mg, 1.26 mmol, 0-benzylhydroxylamine) was added in one portion. HCl), EDC (321.86 mg, 1.68 mmol), HOBt (124.78 mg, 923.44 μmol) and DIPEA (336.35 mg, 2.60 mmol, 453.30 μL). The mixture was stirred at room temperature for 8 h and controlled by LCMS. The mixture was diluted with EtOAc (30 mL) and washed with brine (3*10 mL), dried over Na2SO4 and concentrated to give N- [5-(benzyloxyaminocarboxy)-3-pyridyl ] tert -butyl carbamate (0.3 g, crude), which was used without further purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.49(s,9H),4.84(s,2H),5.45(bds,2H),7.40(m,5H),8.01(s,1H),8.57(s,1H),8.65(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.49(s, 9H), 4.84(s, 2H), 5.45(bds, 2H), 7.40(m, 5H), 8.01(s, 1H), 8.57( s, 1H), 8.65 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值343.2；實測值344.2；Rt=1.221min。LCMS (ESI): [M] + m/z: calculated 343.2; found 344.2; Rt=1.221 min.

步驟4：5-胺基-N-(苯甲醯基氧基)菸鹼醯胺之合成Step 4: Synthesis of 5-amino-N-(benzyloxy)nicotinamide

將N -[5-(苯甲基氧基胺甲醯基)-3-吡啶基]胺甲酸第三丁 酯(0.3g，873.68μmol)溶解於二噁烷(1mL)中且添加於二噁烷中之4.0M氯化氫溶液(318.55mg，8.74mmol，398.19μL)，將混合物在室溫下攪拌4h且濃縮，以產生5-胺基-N -苯甲基氧基吡啶-3-甲醯胺(0.3g，粗品，HCl)，其不經進一步純化即使用。3-Butyl N- [5-(benzyloxyaminocarbamoyl)-3-pyridyl] carbamate (0.3 g, 873.68 μmol) was dissolved in dioxane (1 mL) and added to dioxane 4.0 M hydrogen chloride solution in alkane (318.55 mg, 8.74 mmol, 398.19 μL), the mixture was stirred at room temperature for 4 h and concentrated to give 5-amino- N -benzyloxypyridine-3-carboxamide (0.3 g, crude, HCl), which was used without further purification.

LCMS(ESI)：[M]+ m/z：計算值243.2；實測值244.2；Rt=0.780min。LCMS (ESI): [M] + m/z: calculated 243.2; found 244.2; Rt=0.780 min.

步驟5：N-(苯甲醯基氧基)-5-(2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺基)菸鹼醯胺之合成Step 5: Synthesis of N-(benzyloxy)-5-(2-oxo-2-(2-phenylpiperidin-1-yl)acetamido)nicotinamide

將5-胺基-N -苯甲基氧基吡啶-3-甲醯胺(0.3g，1.07mmol，HCl)、2-側氧基-2-(2-苯基-1-哌啶基)乙酸(250.17mg，1.07mmol)、TEA(325.58mg，3.22 mmol，448.45μL)及HATU(611.69mg，1.61mmol)於DMF(5mL)中之溶液在25℃下攪拌12h。將反應混合物用EtOAc(30ml)稀釋且用鹽水(3x30ml)洗滌。將有機層經Na2 SO4 乾燥，過濾且在真空下濃縮。使殘餘物經歷HPLC(30-55% 2-7min；水-MecN；30ml/min；管柱SunFire 19*100mm)，以產生N -苯甲基氧基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(24.4mg，53.22μmol，4.96%產率)。5-Amino- N -benzyloxypyridine-3-carboxamide (0.3 g, 1.07 mmol, HCl), 2-oxy-2-(2-phenyl-1-piperidinyl) A solution of acetic acid (250.17 mg, 1.07 mmol), TEA (325.58 mg, 3.22 mmol, 448.45 μL) and HATU (611.69 mg, 1.61 mmol) in DMF (5 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with EtOAc (30ml) and washed with brine (3x30ml). The organic layer was dried over Na2SO4 , filtered and concentrated in vacuo. The residue was subjected to HPLC (30-55% 2-7min; water-MecN; 30ml/min; column SunFire 19*100mm) to yield N -benzyloxy-5-[[2-endoxy- 2-(2-Phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (24.4 mg, 53.22 μmol, 4.96% yield).

LCMS(ESI)：[M]+ m/z：計算值458.4；實測值459.2；Rt=1.349min。LCMS (ESI): [M] + m/z: calculated 458.4; found 459.2; Rt=1.349 min.

步驟6：N-羥基-5-(2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺基)菸鹼醯胺(化合物378 )之合成Step 6: Synthesis of N-hydroxy-5-(2-oxo-2-(2-phenylpiperidin-1-yl)acetamido)nicotinamide ( compound 378 )

將N -苯甲基氧基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(24.4mg，53.22μmol)溶解於MeOH(2mL)中且添加鈀(5%於活性碳糊上)5R437(1.13mg，10.64μmol)。將混合物抽真空且添加具有氫氣之氣球。藉由LCMS控制混合物。將混合物過濾且使溶液經歷HPLC(10-50% 0.5-6.5min；水-MeCN；30ml/min；管柱SunFire 19*100mm)，以產生N -[5-(羥基胺甲醯基)-3-吡啶基]-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(4.1mg，11.13μmol，20.91%產率)。 N -benzyloxy-5-[[2-oxo-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (24.4 mg , 53.22 μmol) was dissolved in MeOH (2 mL) and palladium (5% on activated carbon paste) 5R437 (1.13 mg, 10.64 μmol) was added. The mixture was evacuated and a balloon with hydrogen gas was added. The mixture was controlled by LCMS. The mixture was filtered and the solution was subjected to HPLC (10-50% 0.5-6.5 min; water-MeCN; 30 ml/min; column SunFire 19*100 mm) to yield N- [5-(hydroxylaminecarboxy)-3 -Pyridinyl]-2-Pendoxyloxy-2-(2-phenyl-1-piperidinyl)acetamide (4.1 mg, 11.13 μmol, 20.91% yield).

LCMS(ESI)：[M]+ m/z：計算值368.2；實測值369.2；Rt=2.523min。LCMS (ESI): [M] + m/z: calculated 368.2; found 369.2; Rt=2.523 min.

實例695.N -(6-胺基-4,5-二甲基吡啶-3-基)-2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺(化合物368、化合物367)之合成Example 695. N- (6-Amino-4,5-lutidine-3-yl)-2-(5-methyl-2-phenylpiperidin-1-yl)-2-pendoxyl Synthesis of Acetamide (Compound 368, Compound 367)

Figure 110128222-A0202-12-2253-562
Figure 110128222-A0202-12-2253-562

步驟1：N-(6-胺基-4,5-二甲基吡啶-3-基)-2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺之合成Step 1: N-(6-Amino-4,5-lutidine-3-yl)-2-(5-methyl-2-phenylpiperidin-1-yl)-2-pendoxyl Synthesis of Acetamide

將2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸(0.4g，1.57mmol，Li+ ) 與HATU(598.25mg，1.57mmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加3,4-二甲基吡啶-2,5-二胺(215.84mg，1.57mmol)(如上文所製備)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(2-10min 45-60%水+NH3 /MeOH+NH3 (裝載泵4ml MeOH+NH3 )；管柱：TRIART 100*20 5微米)，以獲得N -(6-胺基-4,5-二甲基-3-吡啶基)-2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(0.19g，518.48μmol，32.95%產率)。2-(5-Methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid (0.4 g, 1.57 mmol, Li + ) and HATU (598.25 mg, 1.57 mmol) were mixed in DMF ( 5 mL) and the resulting mixture was stirred at 20 °C for 10 min, followed by the addition of 3,4-lutidine-2,5-diamine (215.84 mg, 1.57 mmol) (prepared as above). The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (2-10 min 45-60% water+ NH3 /MeOH+ NH3 (load pump 4 ml MeOH+ NH3 ); column: TRIART 100*20 5 microns) to obtain N- (6- Amino-4,5-dimethyl-3-pyridyl)-2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetamide (0.19 g, 518.48 g μmol, 32.95% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=1.082min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=1.082 min.

步驟2：掌性分離(化合物368、化合物368 及化合物367 )Step 2: Chiral separation ( Compound 368, Compound 368 and Compound 367 )

使用(Chiralpak IA-II 250*20，5mkm管柱；己烷-IPA-MeOH，40-30-30為流動相；流速11mL/min；注入體積：900mkl)分離N -(6-胺基-4,5-二甲基-3-吡啶基)-2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯胺(190mg，518.48μmol)；得到呈黃色固體之化合物368 及化合物368 N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(83mg，226.49μmol，43.68%產率)(RT(OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=12.09min)及呈黃色固體之化合物367 N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(68.49mg，186.90μmol，36.05%產率)(RT(OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=15.44min)。在以下條件下再純化樣品：管柱：Chiralpak OJ-H；流動相：己烷-MeOH-IPA，70-15-15，13mL/min；45mg純的化合物368 。 N- (6-amino-4) was isolated using (Chiralpak IA-II 250*20, 5mkm column; hexane-IPA-MeOH, 40-30-30 as mobile phase; flow rate 11mL/min; injection volume: 900mkl) ,5-dimethyl-3-pyridyl)-2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyacetamide (190 mg, 518.48 μmol); obtained as Compound 368 and Compound 368 as yellow solid N- (6-amino-4,5-dimethyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-phenyl-1 -Piperidinyl]-2-oxoacetamide (83 mg, 226.49 μmol, 43.68% yield) (RT (OJ-H, Hexane-IPA-MeOH, 60-20-20, 0.6 ml/min) =12.09min) and compound 367 N- (6-amino-4,5-dimethyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-benzene as a yellow solid yl-1-piperidinyl]-2-oxyacetamide (68.49 mg, 186.90 μmol, 36.05% yield) (RT(OJ-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min)=15.44min). The sample was repurified under the following conditions: Column: Chiralpak OJ-H; Mobile Phase: Hexane-MeOH-IPA, 70-15-15, 13 mL/min; 45 mg of pure compound 368 .

化合物368：保留時間：12.09minCompound 368: retention time: 12.09min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94-1.06(m,3H),1.27-1.38(m,1H),1.38-1.85(m,2H),1.85-2.07(m,7H),2.12-2.25(m,1H),2.68-3.24(m,1H),3.35-4.07(m,1H),5.12-5.57(m,1H),5.58-6.47(m,2H),7.07-7.26(m,1H),7.26-7.42(m, 4H),7.46-7.68(m,1H),9.47-10.19(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.94-1.06(m,3H), 1.27-1.38(m,1H), 1.38-1.85(m,2H), 1.85-2.07(m,7H) ,2.12-2.25(m,1H),2.68-3.24(m,1H),3.35-4.07(m,1H),5.12-5.57(m,1H),5.58-6.47(m,2H),7.07-7.26( m, 1H), 7.26-7.42 (m, 4H), 7.46-7.68 (m, 1H), 9.47-10.19 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=2.550min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=2.550 min.

化合物367：保留時間：15.44minCompound 367: retention time: 15.44min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.95-1.07(m,3H),1.24-1.39(m,1H),1.40-1.85(m,2H),1.86-2.12(m,7H),2.12-2.27(m,1H),2.53-2.73(m,1H),2.89-3.24(m,1H),3.41-4.13(m,1H),5.10-5.57(m,1H),5.57-5.89(m,2H),7.12-7.26(m,1H),7.27-7.31(m,1H),7.35-7.38(m,2H),7.38-7.69(m,1H),9.39-10.29(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.95-1.07(m,3H), 1.24-1.39(m,1H), 1.40-1.85(m,2H), 1.86-2.12(m,7H) ,2.12-2.27(m,1H),2.53-2.73(m,1H),2.89-3.24(m,1H),3.41-4.13(m,1H),5.10-5.57(m,1H),5.57-5.89( m, 2H), 7.12-7.26 (m, 1H), 7.27-7.31 (m, 1H), 7.35-7.38 (m, 2H), 7.38-7.69 (m, 1H), 9.39-10.29 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=2.544min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=2.544 min.

實例696.N -(6-胺基-4,5-二甲基吡啶-3-基)-2-(2-甲基-6-苯基哌啶-1-基)-2-側氧基乙醯胺(化合物425、化合物439)之合成Example 696. N- (6-Amino-4,5-lutidine-3-yl)-2-(2-methyl-6-phenylpiperidin-1-yl)-2-pendoxyl Synthesis of Acetamide (Compound 425, Compound 439)

Figure 110128222-A0202-12-2255-563
Figure 110128222-A0202-12-2255-563

步驟1：外消旋-2-((2R,6R)-2-甲基-6-苯基哌啶-1-基)-2-側氧基乙酸鈉之合成Step 1: Synthesis of rac-2-((2R,6R)-2-methyl-6-phenylpiperidin-1-yl)-2-oxoacetate sodium

向2-[(2R,6R )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸甲酯(0.92g，3.52mmol)於MeOH(25mL)中之溶液中添加氫氧化鈉珠粒(154.90mg，3.87mmol，72.72μL)且使所得混合物在室溫下攪拌1h。然後，將所得混合物蒸發至乾且呈鈉鹽([2-[(2R,6R )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]氧基鈉(0.9g，3.34mmol，94.94%產率)用於下一步驟中。To a solution of methyl 2-[( 2R,6R )-2-methyl-6-phenyl-1-piperidinyl]-2-oxyacetate (0.92 g, 3.52 mmol) in MeOH (25 mL) Sodium hydroxide beads (154.90 mg, 3.87 mmol, 72.72 μL) were added and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then evaporated to dryness as the sodium salt ([2-[( 2R,6R )-2-methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]oxy Base sodium (0.9 g, 3.34 mmol, 94.94% yield) was used in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm) 1 H NMR (500MHz, CDCl 3 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值247.2；實測值248.2；Rt=1.181min。LCMS (ESI): [M] + m/z: calculated 247.2; found 248.2; Rt=1.181 min.

步驟2：N-(6-胺基-4,5-二甲基吡啶-3-基)-2-(2-甲基-6-苯基哌啶-1-基)-2-側氧基乙醯胺之合成Step 2: N-(6-Amino-4,5-lutidine-3-yl)-2-(2-methyl-6-phenylpiperidin-1-yl)-2-pendoxyl Synthesis of Acetamide

在21℃下，將[2-[(2R,6R )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]氧基鈉(0.45，1.67mmol)、TATU(645.88mg，2.01mmol)及TEA(169.11mg，1.67mmol，232.93μL)混合於無水DMF(8mL)中且將所得混合物攪拌15min。向其中添加3,4-二甲基吡啶-2,5-二胺(229.26mg，1.67mmol)(如上文所製備)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(0.5-6.5min；水-MeOH(+NH3 )；30ml/min；裝載泵4ml/min R1；管柱YMC-Actus Triat 20*100mm)。獲得呈棕色固體之N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2R,6R )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(122.3mg，333.74μmol，19.97%產率)。At 21 °C, sodium [2-[( 2R,6R )-2-methyl-6-phenyl-1-piperidinyl]-2-oxyacetoxy]oxysodium (0.45, 1.67 mmol ), TATU (645.88 mg, 2.01 mmol) and TEA (169.11 mg, 1.67 mmol, 232.93 μL) were mixed in dry DMF (8 mL) and the resulting mixture was stirred for 15 min. To this was added 3,4-lutidine-2,5-diamine (229.26 mg, 1.67 mmol) (prepared as above) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (0.5-6.5 min; water-MeOH (+ NH3 ); 30 ml/min; loading pump 4 ml/min Rl; column YMC-Actus Triat 20*100 mm). N- (6-amino-4,5-dimethyl-3-pyridinyl)-2-[( 2R,6R )-2-methyl-6-phenyl-1-piperidine was obtained as a brown solid yl]-2-oxoacetamide (122.3 mg, 333.74 μmol, 19.97% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.92(d,3H),1.87(m,3H),2.08(s,3H),2.18(s,3H),2.58(m,1H),4.46(m,2H),4.97(m,1H),6.17(m,1H),7.24(m,2H),7.36(m,5H),8.05(s,1H),8.59(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.92(d,3H), 1.87(m,3H), 2.08(s,3H), 2.18(s,3H), 2.58(m,1H), 4.46( m, 2H), 4.97 (m, 1H), 6.17 (m, 1H), 7.24 (m, 2H), 7.36 (m, 5H), 8.05 (s, 1H), 8.59 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=0.954min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=0.954 min.

步驟3：掌性分離(化合物425 及化合物439 )Step 3: Chiral separation ( compound 425 and compound 439 )

使用(Chiralpak OJ-H 250*20，5mkm管柱；己烷-IPA-MeOH，60-20-20為流動相；流速12mL/min；注入體積：900mkl)分離N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2R,6R )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(120mg，327.46μmol)；得到呈白色固體之化合物425 N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(52.57mg，143.46μmol，43.81%產率)(RT(OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=31.68min)及呈白色固體之化合物439 N -(6-胺基-4,5-二甲基-3-吡啶基)-2-[(2R,6R )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯胺(50.39mg，137.51μmol，41.99%產率)(RT (OJ-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)=13.17min)。 N- (6-amino-4) was isolated using (Chiralpak OJ-H 250*20, 5mkm column; hexane-IPA-MeOH, 60-20-20 as mobile phase; flow rate 12mL/min; injection volume: 900mkl) ,5-dimethyl-3-pyridyl)-2-[( 2R,6R )-2-methyl-6-phenyl-1-piperidinyl]-2-oxyacetamide (120 mg, 327.46 μmol); compound 425 was obtained as a white solid N- (6-amino-4,5-dimethyl-3-pyridyl)-2-[( 2S,6S )-2-methyl-6-benzene yl-1-piperidinyl]-2-oxyacetamide (52.57 mg, 143.46 μmol, 43.81% yield) (RT(OJ-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min)=31.68min) and compound 439 as a white solid N- (6-amino-4,5-dimethyl-3-pyridyl)-2-[( 2R,6R )-2-methyl -6-Phenyl-1-piperidinyl]-2-oxyacetamide (50.39 mg, 137.51 μmol, 41.99% yield) (RT (OJ-H, Hexane-IPA-MeOH, 60-20 -20, 0.6ml/min)=13.17min).

化合物425Compound 425

保留時間：31.68minRetention time: 31.68min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.67-0.91(m,3H),1.47-1.62(m,2H),1.68-1.85(m,3H),1.87-2.16(m,7H),3.99-4.86(m,1H),5.07-5.62(m,1H),5.62-5.91(m,2H),7.25(t,1H),7.30-7.38(m,2H),7.38-7.52(m,2H),7.52-7.70(m,1H),9.54-10.21(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.67-0.91(m,3H), 1.47-1.62(m,2H), 1.68-1.85(m,3H), 1.87-2.16(m,7H) ,3.99-4.86(m,1H),5.07-5.62(m,1H),5.62-5.91(m,2H),7.25(t,1H),7.30-7.38(m,2H),7.38-7.52(m, 2H), 7.52-7.70 (m, 1H), 9.54-10.21 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=3.980min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=3.980 min.

化合物439：保留時間：13.17minCompound 439: retention time: 13.17min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.62-0.84(m,3H),1.48-1.64(m,2H),1.65-1.84(m,3H),1.85-2.20(m,7H),3.94-4.78(m,1H),5.13-5.61(m,1H),5.62-5.83(m,2H),7.22-7.28(t,1H),7.30-7.38(m,2H),7.38-7.54(m,2H),7.57-7.72(m,1H),9.49-10.27(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.62-0.84(m,3H), 1.48-1.64(m,2H), 1.65-1.84(m,3H), 1.85-2.20(m,7H) ,3.94-4.78(m,1H),5.13-5.61(m,1H),5.62-5.83(m,2H),7.22-7.28(t,1H),7.30-7.38(m,2H),7.38-7.54( m, 2H), 7.57-7.72 (m, 1H), 9.49-10.27 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=3.971min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=3.971 min.

實例697. 5-(2-(2-甲基-6-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物278、化合物274)之合成Example 697. Synthesis of 5-(2-(2-methyl-6-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 278, Compound 274)

Figure 110128222-A0202-12-2257-564
Figure 110128222-A0202-12-2257-564

步驟1：外消旋-2-((2S,6S)-2-甲基-6-苯基哌啶-1-基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1: Mixture of racemic-2-((2S,6S)-2-methyl-6-phenylpiperidin-1-yl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester synthesis

向(2S,6S )-2-甲基-6-苯基哌啶(0.23g，1.31mmol)於DCM(10mL)中之 溶液中添加TEA(159.35mg，1.57mmol，219.48μL)，隨後在0℃、惰性氣氛下，添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(274.99mg，1.44mmol)。1h之後，將反應混合物用水淬滅，將DCM乾燥且蒸發，以得到呈黃色固體之2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(0.43g，1.31mmol，99.50%產率)。To a solution of ( 2S,6S )-2-methyl-6-phenylpiperidine (0.23 g, 1.31 mmol) in DCM (10 mL) was added TEA (159.35 mg, 1.57 mmol, 219.48 μL), followed by At °C, under an inert atmosphere, 2,2,2-trifluoroethyl 2-chloro-2-oxoacetate (274.99 mg, 1.44 mmol) was added. After 1 h, the reaction mixture was quenched with water, dried with DCM and evaporated to give 2-[( 2S,6S )-2-methyl-6-phenyl-1-piperidinyl]-2- as a yellow solid Pendant 2,2,2-trifluoroethyl acetate (0.43 g, 1.31 mmol, 99.50% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.84(d,3H),1.68(m,2H),1.96(m,2H),2.58(d,1H),3.11(m,1H),3.82(m,1H),4.76(m,2H),5.89(m,1H),7.26(m,1H),7.37(m,4H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.84(d,3H), 1.68(m,2H), 1.96(m,2H), 2.58(d,1H), 3.11(m,1H), 3.82( m, 1H), 4.76 (m, 2H), 5.89 (m, 1H), 7.26 (m, 1H), 7.37 (m, 4H).

LCMS(ESI)：[M]+ m/z：計算值329.2；實測值330.2；Rt=1.532min。LCMS (ESI): [M] + m/z: calculated 329.2; found 330.2; Rt=1.532 min.

步驟2：外消旋-2-((2S,6S)-2-甲基-6-苯基哌啶-1-基)-2-側氧基乙酸之合成Step 2: Synthesis of racemic-2-((2S,6S)-2-methyl-6-phenylpiperidin-1-yl)-2-oxoacetic acid

向2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(0.43g，1.31mmol)於THF(25mL)中之溶液中添加氫氧化鋰水合物(65.75mg，1.57mmol，43.54μL)且使所得混合物在室溫下攪拌1h。然後將所得混合物蒸發至乾，溶解於水中，用DCM洗滌三次。將水酸化至pH=1且用EtOAc萃取兩次，將有機物用鹽水洗滌，經Na2 SO4 乾燥且蒸發。獲得呈淺黃色固體之2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸(0.26g，1.05mmol，80.52%產率)。To 2-[( 2S,6S )-2-methyl-6-phenyl-1-piperidinyl]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (0.43 g, 1.31 mmol) To a solution in THF (25 mL) was added lithium hydroxide hydrate (65.75 mg, 1.57 mmol, 43.54 μL) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then evaporated to dryness, dissolved in water and washed three times with DCM. The water was acidified to pH=1 and extracted twice with EtOAc, the organics were washed with brine, dried over Na2SO4 and evaporated. 2-[( 2S,6S )-2-methyl-6-phenyl-1-piperidinyl]-2-oxoacetic acid was obtained as a pale yellow solid (0.26 g, 1.05 mmol, 80.52% yield) .

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.68(m,2H),1.96(m,3H),2.61(d,1H),4.68(m,1H),5.89(m,1H),7.36(m,5H),7.87(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d,3H), 1.68(m,2H), 1.96(m,3H), 2.61(d,1H), 4.68(m,1H), 5.89( m, 1H), 7.36 (m, 5H), 7.87 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值247.2；實測值248.2；Rt=1.028min。LCMS (ESI): [M] + m/z: calculated 247.2; found 248.2; Rt=1.028 min.

步驟3：5-(2-(2-甲基-6-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 3: Synthesis of 5-(2-(2-Methyl-6-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide

在21℃下，將2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙酸(0.26g，1.05mmol)、TATU(372.49mg，1.16mmol)及TEA(212.78mg，2.10mmol，293.09μL)混合於無水DMF(15mL)中且將所得混合物攪拌15min。向其中添加5-胺基吡啶-3-甲醯胺(144.19mg，1.05mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽 水洗滌且蒸發。使殘餘物經歷HPLC(2-7min 25-50% MeCN，30ml/min Sunfire c18 5μM)。獲得呈微黃色固體之5-[[2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(166.2mg，453.59μmol，43.14%產率)。At 21°C, 2-[( 2S,6S )-2-methyl-6-phenyl-1-piperidinyl]-2-oxoacetic acid (0.26 g, 1.05 mmol), TATU (372.49 mg , 1.16 mmol) and TEA (212.78 mg, 2.10 mmol, 293.09 μL) were mixed in dry DMF (15 mL) and the resulting mixture was stirred for 15 min. To this was added 5-aminopyridine-3-carboxamide (144.19 mg, 1.05 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (2-7 min 25-50% MeCN, 30 ml/min Sunfire c18 5 μM). 5-[[2-[( 2S,6S )-2-methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- 3-Carboxamide (166.2 mg, 453.59 μmol, 43.14% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.91(d,3H),1.61(m,2H),1.91(m,3H),2.55(m,2H),4.88(m,1H),6.42(m,2H),7.36(m,5H),8.68(s,1H),8.87(s,1H),9.04(s,1H),9.91(s,1H), 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.91(d,3H), 1.61(m,2H), 1.91(m,3H), 2.55(m,2H), 4.88(m,1H), 6.42( m, 2H), 7.36(m, 5H), 8.68(s, 1H), 8.87(s, 1H), 9.04(s, 1H), 9.91(s, 1H),

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=1.233min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=1.233 min.

步驟4：掌性分離(化合物278 及化合物274 )Step 4: Chiral separation ( compound 278 and compound 274 )

使用(Chiralpak AS-H 250*20，5mkm管柱；CO2 -MeOH，60-40為流動相；流速2mL/min)分離5-[[2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(166.2mg，453.59μmol)，得到呈米色固體之化合物278 5-[[2-[(2R,6R )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(47.87mg，130.64μmol，28.80%產率)(RT=4.54min)及呈米色固體之化合物274 5-[[2-[(2S,6S )-2-甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(51.47mg，140.36μmol，30.94%產率)(RT=3.59min)。5-[[ 2 -[( 2S,6S )-2-methyl- 6-Phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxamide (166.2 mg, 453.59 μmol) to give compound 278 as a beige solid 5-[[ 2-[( 2R,6R )-2-methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (47.87mg, 130.64 g μmol, 28.80% yield) (RT=4.54 min) and compound 274 as a beige solid 5-[[2-[( 2S,6S )-2-methyl-6-phenyl-1-piperidinyl]- 2-Pendant oxyacetoxy]amino]pyridine-3-carboxamide (51.47 mg, 140.36 μmol, 30.94% yield) (RT=3.59 min).

化合物278：保留時間：4.54minCompound 278: retention time: 4.54min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.64-0.82(m,3H),1.48-1.55(m,1H),1.55-1.67(m,1H),1.69-1.96(m,3H),2.53-2.62(m,1H),3.98-4.83(m,1H),5.05-5.82(m,1H),7.19-7.29(m,1H),7.30-7.50(m,4H),7.56-7.68(m,1H),8.09-8.25(m,1H),8.40-8.54(m,1H),8.69-8.80(m,1H),8.80-8.97(m,1H),11.25(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.64-0.82(m,3H), 1.48-1.55(m,1H), 1.55-1.67(m,1H), 1.69-1.96(m,3H) ,2.53-2.62(m,1H),3.98-4.83(m,1H),5.05-5.82(m,1H),7.19-7.29(m,1H),7.30-7.50(m,4H),7.56-7.68( m, 1H), 8.09-8.25 (m, 1H), 8.40-8.54 (m, 1H), 8.69-8.80 (m, 1H), 8.80-8.97 (m, 1H), 11.25 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=3.046min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=3.046 min.

化合物274：保留時間：3.59minCompound 274: retention time: 3.59min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.66-0.86(m,3H),1.46-1.55(m,1H),1.55-1.63(m,1H),1.70-1.92(m,3H),2.55-2.64(m,1H),4.00-4.80(m,1H),5.05-5.80 (m,1H),7.17-7.28(m,1H),7.31-7.52(m,4H),7.54-7.67(m,1H),8.08-8.22(m,1H),8.42-8.54(m,1H),8.68-8.80(m,1H),8.80-8.96(m,1H),11.25(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.66-0.86(m,3H), 1.46-1.55(m,1H), 1.55-1.63(m,1H), 1.70-1.92(m,3H) ,2.55-2.64(m,1H),4.00-4.80(m,1H),5.05-5.80(m,1H),7.17-7.28(m,1H),7.31-7.52(m,4H),7.54-7.67( m, 1H), 8.08-8.22 (m, 1H), 8.42-8.54 (m, 1H), 8.68-8.80 (m, 1H), 8.80-8.96 (m, 1H), 11.25 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值366.2；實測值367.2；Rt=3.048min。LCMS (ESI): [M] + m/z: calculated 366.2; found 367.2; Rt=3.048 min.

實例698.外消旋 -5-[[2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、外消旋 -5-[[2-[(2R ,3R ,6R )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及外消旋 -5-[[2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物154、化合物163及化合物181)之合成；5-[[2-[(2S ,3S ,6R )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物435及化合物433)之掌性分離；-[[2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,3S ,6R )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物482及化合物483)之掌性分離Example 698. Racemic -5-[[2-[( 2R , 3R ,6S)-2,3-dimethyl-6-phenyl-1-piperidinyl]-2- pendoxyl Acetyl]amino]pyridine-3-carboxamide, rac -5-[[2-[( 2R , 3R , 6R )-2,3-dimethyl-6-phenyl- 1-Piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide and racemic -5-[[2-[(2 S ,3 R ,6 S )-2 Synthesis of ,3-dimethyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 154, Compound 163 and Compound 181) ; 5-[[2-[( 2S ,3S, 6R )-2,3-dimethyl-6-phenyl-1-piperidinyl]-2- oxyethanoyl ]amino ] Pyridine-3-carboxamide and 5-[[2-[(2 R ,3 R ,6 S )-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-side Chiral isolation of oxyacetyl]amino]pyridine-3-carbamide (compound 435 and compound 433); -[[2-[( 2S , 3R , 6S )-2,3-di Methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide and 5-[[2-[(2 R ,3 S ,6 R )-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 482 and compound 483) palmar separation

Figure 110128222-A0202-12-2261-565
Figure 110128222-A0202-12-2261-565

步驟1：2-(2,3-二甲基-6-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1: Synthesis of 2-(2,3-Dimethyl-6-phenyl-1-piperidinyl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester

在-10℃下，向2,3-二甲基-6-苯基哌啶(0.5g，2.64mmol)及三乙胺(267.28mg，2.64mmol，368.15μL)於THF(10mL)中之經攪拌之溶液中逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(503.19mg，2.64mmol)。使所得反應混合物升溫至室溫且在同一溫度下攪拌12小時。12小時之後，過濾反應混合物且在減壓下濃縮濾液，以獲得2-(2,3-二甲基-6-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(0.8g，粗品)。粗產物不經任何進一步純化即用於下一步反應。To 2,3-dimethyl-6-phenylpiperidine (0.5 g, 2.64 mmol) and triethylamine (267.28 mg, 2.64 mmol, 368.15 μL) in THF (10 mL) at -10 °C To the stirred solution was added 2,2,2-trifluoroethyl 2-chloro-2-oxoacetate (503.19 mg, 2.64 mmol) dropwise. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(2,3-dimethyl-6-phenyl-1-piperidinyl)-2-oxoacetic acid 2,2, 2-Trifluoroethyl ester (0.8 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值343.2；實測值344.0；Rt=1.571min。LCMS (ESI): [M+H] + m/z: calculated 343.2; found 344.0; Rt=1.571 min.

步驟2：[2-(2,3-二甲基-6-苯基-1-哌啶基)-2-側氧基乙醯基]氧基鋰之合成Step 2: Synthesis of lithium [2-(2,3-dimethyl-6-phenyl-1-piperidinyl)-2-oxyethanoyl]oxylithium

向2-(2,3-二甲基-6-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(0.8g，2.33mmol)於水(2mL)及THF(20mL)中之經攪拌之溶液中添加98%氫氧化鋰 單水合物(97.78mg，2.33mmol)。將所得反應混合物在20℃下攪拌24小時。24小時之後，將反應混合物蒸發至乾，以獲得[2-(2,3-二甲基-6-苯基-1-哌啶基)-2-側氧基乙醯基]氧基鋰(0.5g，粗品)，其不經任何進一步純化即用於下一步驟反應。To 2-(2,3-dimethyl-6-phenyl-1-piperidinyl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester (0.8 g, 2.33 mmol) in water ( 2 mL) and THF (20 mL) were added 98% lithium hydroxide to a stirred solution Monohydrate (97.78 mg, 2.33 mmol). The resulting reaction mixture was stirred at 20°C for 24 hours. After 24 hours, the reaction mixture was evaporated to dryness to obtain lithium [2-(2,3-dimethyl-6-phenyl-1-piperidinyl)-2-oxoacetoxy]oxylithium ( 0.5 g, crude), which was used in the next step reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值261.1；實測值262.2；Rt=1.109min。LCMS (ESI): [M+H] + m/z: calculated 261.1; found 262.2; Rt=1.109 min.

步驟3：外消旋-5-[[2-[(2R,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、外消旋-5-[[2-[(2R,3R,6R)-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及外消旋-5-[[2-[(2S,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物154 、化合物163 及化合物181 )之合成Step 3: Racemic-5-[[2-[(2R,3R,6S)-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-pendoxetyl ]amino]pyridine-3-carboxamide, rac-5-[[2-[(2R,3R,6R)-2,3-dimethyl-6-phenyl-1-piperidinyl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide and racemic-5-[[2-[(2S,3R,6S)-2,3-dimethyl-6- Synthesis of Phenyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide ( Compound 154 , Compound 163 and Compound 181 )

向[2-(2,3-二甲基-6-苯基-1-哌啶基)-2-側氧基乙醯基]氧基鋰(0.5g，1.87mmol)於DMF(5mL)中之經攪拌之溶液中添加HATU(711.38mg，1.87mmol)。將所得反應混合物在20℃下攪拌10分鐘。10分鐘之後，添加5-胺基吡啶-3-甲醯胺(256.58mg，1.87mmol)且使所得反應混合物在20℃下攪拌12小時。藉由反相HPLC(流動相：0.5-6.5min；水-乙腈，流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFire 19*100mm，5um)純化所得反應混合物，以獲得呈黃色固體之外消旋 -5-[[2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物154 ，27.7mg)、外消旋 -5-[[2-[(2R ,3R ,6R )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物163 ，24.30mg)及外消旋 -5-[[2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物181 ，35.2mg)。To lithium [2-(2,3-dimethyl-6-phenyl-1-piperidinyl)-2-oxyethanoyl]oxylithium (0.5 g, 1.87 mmol) in DMF (5 mL) To the stirred solution was added HATU (711.38 mg, 1.87 mmol). The resulting reaction mixture was stirred at 20°C for 10 minutes. After 10 minutes, 5-aminopyridine-3-carboxamide (256.58 mg, 1.87 mmol) was added and the resulting reaction mixture was stirred at 20°C for 12 hours. The resulting reaction mixture was purified by reverse phase HPLC (mobile phase: 0.5-6.5 min; water-acetonitrile, flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile; column: SunFire 19*100 mm, 5 um) to obtain Racemic -5-[[2-[(2 R ,3 R ,6 S )-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-oxygen as a yellow solid Acetyl]amino]pyridine-3-carboxamide ( compound 154 , 27.7mg ), rac -5-[[2-[( 2R , 3R ,6R)-2,3-di Methyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 163 , 24.30mg) and rac -5-[[ 2-[(2 S ,3 R ,6 S )-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3- Formamide ( compound 181 , 35.2 mg).

化合物154：Compound 154:

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)0.85(m,3H),1.26(m,3H),1.48(m,1H),1.95(m,1H),2.23(m,3H),4.30(m,1H),5.20(m,1H),7.28(m,5H),7.62(m,1H), 8.43(m,3H),8.88(m,1H),10.98(m,1H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 0.85 (m, 3H), 1.26 (m, 3H), 1.48 (m, 1H), 1.95 (m, 1H), 2.23 (m, 3H) , 4.30(m, 1H), 5.20(m, 1H), 7.28(m, 5H), 7.62(m, 1H), 8.43(m, 3H), 8.88(m, 1H), 10.98(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=1.199min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=1.199 min.

化合物163：Compound 163:

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)0.54(m,3H),0.80(m,3H),1.57(m,2H),2.62(m,2H),4.07(m,1H),5.44(m,1H),7.26(m,1H),7.39(m,4H),7.57(m,1H),8.18(m,1H),8.50(m,1H),8.83(m,2H),11.30(m,1H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 0.54 (m, 3H), 0.80 (m, 3H), 1.57 (m, 2H), 2.62 (m, 2H), 4.07 (m, 1H) ,5.44(m,1H),7.26(m,1H),7.39(m,4H),7.57(m,1H),8.18(m,1H),8.50(m,1H),8.83(m,2H), 11.30 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=1.222min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=1.222 min.

化合物181：Compound 181:

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)0.82(m,3H),1.00(m,3H),1.35(m,1H),1.70(m,1H),2.13(m,3H),3.99(m,1H),5.41(m,1H),7.32(m,5H),7.66(m,1H),8.20(m,1H),8.51(m,1H),8.84(m,2H),11.29(s,1H)。 1 H NMR (DMSO- d 6 , 400MHz): δ (ppm) 0.82 (m, 3H), 1.00 (m, 3H), 1.35 (m, 1H), 1.70 (m, 1H), 2.13 (m, 3H) ,3.99(m,1H),5.41(m,1H),7.32(m,5H),7.66(m,1H),8.20(m,1H),8.51(m,1H),8.84(m,2H), 11.29(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=1.215min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=1.215 min.

步驟4：5-[[2-[(2S,3S,6R)-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之掌性分離Step 4: 5-[[2-[(2S,3S,6R)-2,3-Dimethyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide and 5-[[2-[(2R,3R,6S)-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-oxoacetamide Chiral separation of [methyl]amino]pyridine-3-carboxamide

使外消旋 -5-[[2-[(2R ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物154 )經歷掌性分離(管柱：Chiralpak IC-I，250 * 20mm，5um；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min)，以獲得呈黃色固體之(化合物435 )及(化合物433 )。make rac -5-[[2-[(2 R ,3 R ,6 S )-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-oxoacetone yl]amino]pyridine-3-carboxamide ( compound 154 ) was subjected to chiral separation (column: Chiralpak IC-I, 250*20mm, 5um; mobile phase: Hexane-IPA-MeOH, 50-25-25 ; flow rate: 12 mL/min) to obtain ( Compound 435 ) and ( Compound 433 ) as yellow solids.

化合物435： LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=3.039min。 Compound 435: LCMS (ESI): [M+H] + m/z: calcd 380.2; found 381.2; Rt=3.039 min.

掌性HPLC：Rt=18.22min(管柱：IA；流動相：己烷-MeOH-IPA，60-20-20；流速：0.6mL/min)。Chiral HPLC: Rt=18.22 min (column: IA; mobile phase: Hexane-MeOH-IPA, 60-20-20; flow rate: 0.6 mL/min).

化合物433： LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=3.030 min Compound 433: LCMS (ESI): [M+H] + m/z: calcd 380.2; found 381.2; Rt=3.030 min

掌性HPLC：Rt=17.00min(管柱：IA；流動相：己烷-MeOH-IPA，60-20-20；流速：0.6mL/min)。Chiral HPLC: Rt=17.00 min (column: IA; mobile phase: Hexane-MeOH-IPA, 60-20-20; flow rate: 0.6 mL/min).

步驟5：5-[[2-[(2S,3R,6S)-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,3S,6R)-2,3-二甲基-6-苯基-1-哌啶基]-2- 側基乙醯基]胺基]吡啶-3-甲醯胺(化合物482及化合物483)之掌性分離 Step 5: 5-[[2-[(2S,3R,6S)-2,3-Dimethyl-6-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide and 5-[[2-[(2R,3S,6R)-2,3-dimethyl-6-phenyl-1-piperidinyl]-2- pendant acetylene Chiral separation of ]amino]pyridine-3-carboxamide (compound 482 and compound 483)

使外消旋 -5-[[2-[(2S ,3R ,6S )-2,3-二甲基-6-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物181 )經歷掌性分離(Chiralpak OJ，250 * 30mm，20um；流動相：CO2 -MeOH，60-40；流速：90mL/min)，以獲得呈黃色固體之(化合物482 )及(化合物483 )。Make rac -5-[[2-[(2 S ,3 R ,6 S )-2,3-dimethyl-6-phenyl-1-piperidinyl]-2-side oxyacetyl yl]amino]pyridine-3-carboxamide ( compound 181 ) was subjected to chiral separation (Chiralpak OJ, 250*30mm, 20um; mobile phase: CO2 -MeOH, 60-40; flow rate: 90 mL/min) as ( Compound 482 ) and ( Compound 483 ) were obtained as yellow solids.

化合物482： LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=4.815min。 Compound 482: LCMS (ESI): [M+H] + m/z: calcd 380.2; found 381.2; Rt=4.815 min.

掌性HPLC：Rt=2.61min(管柱：OJ-H；流動相：CO2 -MeOH，60-40；流速：2.0mL/min)。Chiral HPLC: Rt=2.61 min (column: OJ-H; mobile phase: CO2 -MeOH, 60-40; flow rate: 2.0 mL/min).

化合物483： LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=4.817min。 Compound 483: LCMS (ESI): [M+H] + m/z: calcd 380.2; found 381.2; Rt=4.817 min.

掌性HPLC：Rt=4.13min(管柱：OJ-H；流動相：CO2 -MeOH，60-40；流速：2.0mL/min)。Chiral HPLC: Rt=4.13 min (column: OJ-H; mobile phase: CO2 -MeOH, 60-40; flow rate: 2.0 mL/min).

實例699. N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物254)及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物258)之合成Example 699. N-(5,6-Dimethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxygen Ethylacetamide (Compound 254) and N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-phenyl-1-piperidinyl Synthesis of ]-2-oxoacetamide (Compound 258)

Figure 110128222-A0202-12-2265-566
Figure 110128222-A0202-12-2265-566

步驟1：2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1: Synthesis of 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester

在-10℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(5.43g，28.53mmol)逐滴添加到5-甲基-2-苯基哌啶(5g，28.53mmol)及三乙胺(2.89g，28.53mmol，3.98mL)於THF(50mL)中之溶液中。將所得混合物升溫至室溫且攪拌12h。過濾出所得沉澱。將濾液蒸發，以獲得2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(9g，27.33mmol，95.80%產率)，其不經純化即用於下一步驟。2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (5.43 g, 28.53 mmol) was added dropwise to 5-methyl-2-phenylpiperidine ( 5 g, 28.53 mmol) and triethylamine (2.89 g, 28.53 mmol, 3.98 mL) in THF (50 mL). The resulting mixture was warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered off. The filtrate was evaporated to obtain 2,2,2-trifluoroethyl 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyacetate (9 g, 27.33 mmol, 95.80%) yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.19(m,3H),1.33(m,1H),1.91(m,4H),3.10(m,2H),5.10(m,3H),7.19(d,1H),7.21(d,1H),7.40(m,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.19(m, 3H), 1.33(m, 1H), 1.91(m, 4H), 3.10(m, 2H), 5.10(m, 3H), 7.19(d , 1H), 7.21 (d, 1H), 7.40 (m, 3H).

LCMS(ESI)：[M+H]+ m/z：計算值329.1；實測值330.1；Rt=1.496min。LCMS (ESI): [M+H] + m/z: calculated 329.1; found 330.1; Rt=1.496 min.

步驟2：2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸之合成Step 2: Synthesis of 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid

將氫氧化鋰(654.50mg，27.33mmol)添加到2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸2,2,2-三氟乙酯(9g，27.33mmol)於THF(100mL)及水(10mL)中之溶液中。將所得混合物在20℃下攪拌12h。然後，將混合物蒸發至乾，以獲得2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸(5g，19.67mmol，71.96%產率，Li+)，其不經純化即用於下一步驟。Lithium hydroxide (654.50 mg, 27.33 mmol) was added to 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester ( 9 g, 27.33 mmol) in THF (100 mL) and water (10 mL). The resulting mixture was stirred at 20 °C for 12 h. Then, the mixture was evaporated to dryness to obtain 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid (5 g, 19.67 mmol, 71.96% yield, Li+), It was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.13(m,3H),1.30(m,1H),1.63(m,2H),2.01(m,2H),3.56(m,2H),5.04(m,1H),7.16(m,3H),7.32(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.13(m, 3H), 1.30(m, 1H), 1.63(m, 2H), 2.01(m, 2H), 3.56(m, 2H), 5.04(m , 1H), 7.16 (m, 3H), 7.32 (m, 2H).

LCMS(ESI)：酸[M+H]+ m/z：計算值247.1.1；實測值248.2；Rt=1.133min。LCMS (ESI): acid [M+H] + m/z: calculated 247.1.1; found 248.2; Rt=1.133 min.

步驟3：N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺之合成Step 3: N-(5,6-Dimethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxygen Synthesis of Acetamide

將DIPEA(261.32mg，2.02mmol，352.18μL)添加到相應2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸(0.2g，808.77μmol)及5,6-二甲基吡啶-3-胺(98.81mg，808.77μmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(338.27mg，889.65μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters SunFire C18 19* 100mm 5mkm管柱，以H2 O-MeOH為流動相)，以得到純的N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(70mg，199.18μmol，24.63%產率)。DIPEA (261.32 mg, 2.02 mmol, 352.18 μL) was added to the corresponding 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxoacetic acid (0.2 g, 808.77 μmol) and 5 , 6-Lutidine-3-amine (98.81 mg, 808.77 μmol) in DMF (5 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (338.27 mg, 889.65 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters SunFire C18 19 * 100mm 5mkm column with H2O -MeOH as mobile phase) to give pure N-(5,6-dimethyl-3-pyridinyl)- 2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyacetamide (70 mg, 199.18 μmol, 24.63% yield).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.4；Rt=2.702min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.4; Rt=2.702 min.

步驟4：N-(5,6-二甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物254 )及N-(5,6-二甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物258 )之合成Step 4: N-(5,6-Dimethyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-oxygen Ethylacetamide ( Compound 254 ) and N-(5,6-dimethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-phenyl-1-piperidinyl Synthesis of ]-2-oxyacetamide ( Compound 258 )

掌性分離條件：反相及梯度：己烷-IPA-MeOH，70-15-15，12ml/min管柱：OJ-H(250*20，5mkm)；化合物254 之保留時間為15.77min，化合物258 之保留時間為10.18minChiral separation conditions: reverse phase and gradient: hexane-IPA-MeOH, 70-15-15, 12ml/min Column: OJ-H (250*20, 5mkm); the retention time of compound 254 is 15.77min, the compound The retention time of 258 is 10.18min

化合物254： RT(OJ-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=15.778min。 Compound 254: RT (OJ-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 15.778 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.96-1.04(m,3H),1.26-1.36(m,1H),1.59-1.72(m,1H),1.80-1.94(m,1H),1.99-2.14(m,1H),2.16-2.25(m,4H),2.32-2.37(m,3H),2.72-3.23(m,1H),3.40-4.07(m,1H),5.11-5.62(m,1H),7.23-7.28(m,1H),7.28-7.31(m,1H),7.31-7.38(m,2H),7.38-7.41(m,1H),7.70-7.86(m,1H),8.37-8.60(m,1H),10.85-11.01(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.96-1.04(m,3H), 1.26-1.36(m,1H), 1.59-1.72(m,1H), 1.80-1.94(m,1H), 1.99- 2.14(m,1H), 2.16-2.25(m,4H), 2.32-2.37(m,3H), 2.72-3.23(m,1H), 3.40-4.07(m,1H), 5.11-5.62(m,1H) ),7.23-7.28(m,1H),7.28-7.31(m,1H),7.31-7.38(m,2H),7.38-7.41(m,1H),7.70-7.86(m,1H),8.37-8.60 (m, 1H), 10.85-11.01 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=4.089min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.2; Rt=4.089 min.

化合物258： RT(OJ-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=10.184min。 Compound 258: RT (OJ-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 10.184 min.

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.04(m,3H),1.28-1.38(m,1H),1.59-1.70(m,1H),1.81-1.93(m,1H),2.00-2.16(m,1H),2.17-2.26(m,4H),2.32-2.38(m,3H),2.73-3.25(m,1H),3.41-4.05(m,1H),5.03-5.68(m,1H),7.23-7.28(m,1H),7.28-7.31(m,1H),7.31-7.38(m,2H),7.38-7.41(m,1H),7.73-7.86(m,1H),8.36-8.54(m,1H),10.84-11.00(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.04(m,3H), 1.28-1.38(m,1H), 1.59-1.70(m,1H), 1.81-1.93(m,1H), 2.00- 2.16(m, 1H), 2.17-2.26(m, 4H), 2.32-2.38(m, 3H), 2.73-3.25(m, 1H), 3.41-4.05(m, 1H), 5.03-5.68(m, 1H ),7.23-7.28(m,1H),7.28-7.31(m,1H),7.31-7.38(m,2H),7.38-7.41(m,1H),7.73-7.86(m,1H),8.36-8.54 (m, 1H), 10.84-11.00 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.2；Rt=4.081min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.2; Rt=4.081 min.

實例700. 2-甲基-5-[[2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物200)及2-甲基-5-[[2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺Example 700. 2-Methyl-5-[[2-[(2R,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (compound 200) and 2-methyl-5-[[2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide

(化合物196)之合成Synthesis of (Compound 196)

Figure 110128222-A0202-12-2267-567
Figure 110128222-A0202-12-2267-567

步驟1：2-甲基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 2-Methyl-5-[[2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxylate Synthesis of Amines

將5-胺基-2-甲基吡啶-3-甲醯胺(213.95mg，1.42mmol)、2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙酸(350mg，1.42mmol)、HATU(591.97mg，1.56mmol)及TEA(157.54mg，1.56mmol，217.00μL)混合於DMSO(5mL)中。將反應混合物在室溫下攪拌16h。使於DMSO中之溶液經歷HPLC(2-10min35-60%水-MeCN+NH3 (裝載泵4ml MeCN+NH3 )；管柱：TRIART 100* 20 5微米)，以得到2-甲基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(302mg，793.82μmol，56.09%產率)。在HPLC之後獲得呈三種級分之最終產物。使級分1及2在下一步驟時經歷掌性分離。5-Amino-2-methylpyridine-3-carboxamide (213.95 mg, 1.42 mmol), 2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxygen Acetic acid (350 mg, 1.42 mmol), HATU (591.97 mg, 1.56 mmol) and TEA (157.54 mg, 1.56 mmol, 217.00 [mu]L) were mixed in DMSO (5 mL). The reaction mixture was stirred at room temperature for 16 h. The solution in DMSO was subjected to HPLC (2-10 min 35-60% water-MeCN+ NH3 (load pump 4 ml MeCN+ NH3 ); column: TRIART 100 * 20 5 microns) to give 2-methyl-5 -[[2-(5-Methyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (302 mg, 793.82 μmol, 56.09% Yield). The final product was obtained in three fractions after HPLC. Fractions 1 and 2 were subjected to chiral separation in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=3.064min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=3.064 min.

步驟2：2-甲基-5-[[2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物200 )及2-甲基-5-[[2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺Step 2: 2-Methyl-5-[[2-[(2R,5S)-5-methyl-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino] Pyridine-3-carboxamide ( compound 200 ) and 2-methyl-5-[[2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-side Oxyacetyl]amino]pyridine-3-carboxamide

(化合物196 )之合成Synthesis of ( Compound 196 )

對2-甲基-5-[[2-(5-甲基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(142.3mg，374.04μmol)進行掌性分離(樣品資訊：AD-H，己烷-IPA-MeOH，60-20-20，0.6ml/min)，得到化合物200 2-甲基-5-[[2-[(2R,5S)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(46.9mg，123.28μmol，32.96%產率)及化合物196 2-甲基-5-[[2-[(2S,5R)-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(35.7mg，142.30μmol，25.09%產率)。p-2-Methyl-5-[[2-(5-methyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide ( 142.3 mg, 374.04 μmol) for chiral separation (sample information: AD-H, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min) to obtain compound 200 2-methyl-5-[[2 -[(2R,5S)-5-Methyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (46.9 mg, 123.28 μmol , 32.96% yield) and compound 196 2-methyl-5-[[2-[(2S,5R)-5-methyl-2-phenyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carboxamide (35.7 mg, 142.30 μmol, 25.09% yield).

化合物196： RT(AD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=29.9min。 Compound 196: RT (AD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 29.9 min.

1 H NMR(dmso,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.66(m,1H),1.87(m,1H),2.05(m,1H),2.22(m,1H),2.51(m,3H),3.08(m,1H),3.73(m,1H),5.37(m,1H),7.27(t,1H),7.30(d,1H),7.37(m,3H),7.54(m,1H),7.88(m,1H),8.01(m,1H),8.69(m,1H),11.10(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.66 (m, 1H), 1.87 (m, 1H), 2.05 (m, 1H), 2.22 ( m, 1H), 2.51(m, 3H), 3.08(m, 1H), 3.73(m, 1H), 5.37(m, 1H), 7.27(t, 1H), 7.30(d, 1H), 7.37(m , 3H), 7.54 (m, 1H), 7.88 (m, 1H), 8.01 (m, 1H), 8.69 (m, 1H), 11.10 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=4.332min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=4.332 min.

化合物200： RT(AD-H，己烷-IPA-MeOH，60-20-20，0.6mL/min)=12.8min。 Compound 200: RT (AD-H, Hexane-IPA-MeOH, 60-20-20, 0.6 mL/min) = 12.8 min.

1 H NMR(dmso,600MHz)：δ(ppm)1.01(m,3H),1.33(m,1H),1.65(m,1H),1.84(m,1H),2.00(m,1H),2.18(m,1H),2.44(m,3H),2.99(m,1H),3.73(m,1H),5.37(m,1H),7.27(t,1H),7.30(d,1H),7.38(m,3H),7.54(m,1H),7.87(m,1H),8.01(m,1H),8.68(m,1H),11.10(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 1.01 (m, 3H), 1.33 (m, 1H), 1.65 (m, 1H), 1.84 (m, 1H), 2.00 (m, 1H), 2.18 ( m, 1H), 2.44(m, 3H), 2.99(m, 1H), 3.73(m, 1H), 5.37(m, 1H), 7.27(t, 1H), 7.30(d, 1H), 7.38(m , 3H), 7.54 (m, 1H), 7.87 (m, 1H), 8.01 (m, 1H), 8.68 (m, 1H), 11.10 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=4.330min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=4.330 min.

實例701.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-Example 701. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(4-(trifluoromethyl)phenyl)piperidine-1- 基)-2-側氧基乙醯胺(化合物548、化合物575)之合成Synthesis of yl)-2-oxoacetamide (Compound 548, Compound 575)

Figure 110128222-A0202-12-2269-568
Figure 110128222-A0202-12-2269-568

步驟1：(3-甲基-5-(2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (3-Methyl-5-(2-(5-methyl-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoacetamide Synthesis of tert-butyl)pyridin-2-yl)carbamate

將2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸(0.3g，931.02μmol，Li+ )與HATU(389.40mg，1.02mmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加N -(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁 酯(207.87mg，931.02μmol)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(管柱：SunFire 19*100mm，5mkl；以水-MeCN為溶析液混合物)，以獲得N -[3-甲基-5-[[2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.1555g，298.73μmol，32.09%產率)。2-[5-Methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetic acid (0.3 g, 931.02 μmol, Li + ) was mixed with HATU ( 389.40 mg, 1.02 mmol) in DMF (5 mL) and the resulting mixture was stirred at 20 °C for 10 min, followed by the addition of 3-butyl N- (5-amino-3-methyl-2-pyridyl) carbamate (207.87 mg, 931.02 μmol). The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (column: SunFire 19*100mm, 5mkl; water-MeCN as eluent mixture) to obtain N- [3-methyl-5-[[2-[5-methyl-2 tert-butyl -[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid ( 0.1555 g, 298.73 g μmol, 32.09% yield).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=4.261min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=4.261 min.

步驟2：掌性分離Step 2: Palm Separation

使用(Chiralpak IC 200*20，5mkm管柱；以己烷-IPA-MeOH，80-10-10為流動相；流速15mL/min；注入體積：300mkl)分離N -[3-甲基-5-[[2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(217.2mg，417.26μmol)；得到E1N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(52.94mg，101.70μmol，24.37%產率)(RT=21.62min)及E2N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第 三丁 酯(61.88mg，118.88μmol，28.49%產率)(RT=25.74min)。E1於分析條件下(管柱：IC-3，以己烷-IPA-MeOH，80-10-10，0.155ml/min為流動相)之保留時間為15.75min且E2之保留時間為19.80min。Separation of N- [3-methyl-5- [[2-[5-Methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl] tert -butyl carbamate (217.2 mg, 417.26 μmol); yields El N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-[4-(trifluoro) Methyl)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (52.94 mg, 101.70 μmol, 24.37% yield) (RT=21.62min) and E2 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-[4-(trifluoromethyl)phenyl]-1 -Piperidinyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert - butyl ester (61.88 mg, 118.88 μmol, 28.49% yield) (RT=25.74 min). The retention time of E1 under analytical conditions (column: IC-3, hexane-IPA-MeOH, 80-10-10, 0.155 ml/min as mobile phase) was 15.75 min and that of E2 was 19.80 min.

E1：保留時間：15.75minE1: retention time: 15.75min

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=1.301min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=1.301 min.

E2：保留時間：19.80minE2: retention time: 19.80min

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=1.302min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=1.302 min.

步驟3：N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物548及化合物575)之合成Step 3: N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl )-2-oxyacetamide (Compound 548 and Compound 575) Synthesis

將N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(61.88mg，118.88μmol)及N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.05294g，101.70μmol)溶解於水(3mL)及二噁烷(1mL)中且將所得混合物加熱至100℃達12h。將所得混合物冷卻至室溫且使其經歷HPLC(管柱：SunFire 19*100mm，5mkl；以水-MeCN為溶析液混合物)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯胺(0.022g，52.33μmol，44.02%產率)及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯胺(0.0255g，60.65μmol，59.64%產率)。 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (61.88 mg, 118.88 μmol) and N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2- oxyethanoyl ]amino]-2-pyridyl]carbamic acid Tributyl ester (0.05294 g, 101.70 μmol) was dissolved in water (3 mL) and dioxane (1 mL) and the resulting mixture was heated to 100 °C for 12 h. The resulting mixture was cooled to room temperature and subjected to HPLC (column: SunFire 19*100mm, 5mkl; water-MeCN as eluent mixture) to obtain N- (6-amino-5-methyl-3 -pyridyl)-2-[( 2R,5S )-5-methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetamide ( 0.022 g, 52.33 μmol, 44.02% yield) and N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-[4- (Trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetamide (0.0255 g, 60.65 μmol, 59.64% yield).

化合物548： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.26-1.40(m,1H),1.56-1.67(m,1H),1.81-1.92(m,1H),1.96-2.03(m,3H),2.03-2.15(m,1H),2.16-2.29(m,1H),2.70-3.23(m,1H),3.45-4.08(m,1H),5.20-5.67(m,3H),7.40-7.49(m,1H),7.50-7.59(m,2H),7.71-7.77(m,2H),7.93-8.04(m,1H),10.30-10.61(m,1H)。 Compound 548: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98-1.05 (m, 3H), 1.26-1.40 (m, 1H), 1.56-1.67 (m, 1H), 1.81-1.92 (m) ,1H),1.96-2.03(m,3H),2.03-2.15(m,1H),2.16-2.29(m,1H),2.70-3.23(m,1H),3.45-4.08(m,1H),5.20 -5.67(m, 3H), 7.40-7.49(m, 1H), 7.50-7.59(m, 2H), 7.71-7.77(m, 2H), 7.93-8.04(m, 1H), 10.30-10.61(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值420.2；實測值421.2；Rt=2.728min。LCMS (ESI): [M] + m/z: calculated 420.2; found 421.2; Rt=2.728 min.

化合物575： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.03(m,3H),1.24-1.39(m,1H),1.55-1.67(m,1H),1.75-1.93(m,1H),1.94-2.03(m,3H),2.03-2.15(m,1H),2.16-2.29(m,1H),2.75-3.24(m,1H),3.46-4.06(m,1H),5.19-5.64(m,3H),7.41-7.49(m,1H),7.49-7.60(m,2H),7.69-7.80(m,2H),7.90-8.06(m,1H),10.45-10.55(m,1H)。 Compound 575: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.97-1.03 (m, 3H), 1.24-1.39 (m, 1H), 1.55-1.67 (m, 1H), 1.75-1.93 (m) ,1H),1.94-2.03(m,3H),2.03-2.15(m,1H),2.16-2.29(m,1H),2.75-3.24(m,1H),3.46-4.06(m,1H),5.19 -5.64(m, 3H), 7.41-7.49(m, 1H), 7.49-7.60(m, 2H), 7.69-7.80(m, 2H), 7.90-8.06(m, 1H), 10.45-10.55(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值420.2；實測值421.2；Rt=2.647min。LCMS (ESI): [M] + m/z: calculated 420.2; found 421.2; Rt=2.647 min.

實例702. 5-(2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物511、化合物508)之合成Example 702. 5-(2-(5-Methyl-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of (Compound 511, Compound 508)

Figure 110128222-A0202-12-2271-569
Figure 110128222-A0202-12-2271-569

步驟1：5-(2-(5-甲基-2-(4-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide synthesis

將2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸(0.3g，931.02μmol，Li+ )與HATU(389.40mg，1.02mmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加5-胺基吡啶-3-甲醯胺(127.68mg，931.02μmol)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(管柱：SunFire 19*100mm，5mkl；以水-MeCN為溶析液混合物)，以獲得5-[[2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1145.g，263.58μmol，28.31%產率)。2-[5-Methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetic acid (0.3 g, 931.02 μmol, Li + ) was mixed with HATU ( 389.40 mg, 1.02 mmol) was mixed in DMF (5 mL) and the resulting mixture was stirred at 20 °C for 10 min, then 5-aminopyridine-3-carboxamide (127.68 mg, 931.02 μmol) was added. The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (column: SunFire 19*100mm, 5mkl; with water-MeCN as eluent mixture) to obtain 5-[[2-[5-methyl-2-[4-(trifluoromethane (0.1145.g, 263.58 μmol, 28.31% yield).

LCMS(ESI)：[M]+ m/z：計算值434.2；實測值435.2；Rt=3.492min。LCMS (ESI): [M] + m/z: calculated 434.2; found 435.2; Rt=3.492 min.

步驟2：掌性分離(化合物511 及化合物508 )Step 2: Chiral separation ( Compound 511 and Compound 508 )

使用(Chiralpak IC 250*20，5mkm管柱；以己烷-IPA-MeOH，60-20-20 為流動相；流速12mL/min；注入體積：300mkl)分離5-[[2-[5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(114.5mg，263.58μmol)；得到化合物511 5-[[2-[(2S,5R )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50.03mg，115.17μmol，43.69%產率)(RT=22.82min)及化合物508 5-[[2-[(2R,5S )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(58.4mg，134.43μmol，51%產率)(RT=38.04min)。化合物511 於分析條件下(管柱：IC-3，以己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為16.70min且化合物508 之保留時間為27.34min。Using (Chiralpak IC 250*20, 5mkm column; hexane-IPA-MeOH, 60-20-20 as mobile phase; flow rate 12mL/min; injection volume: 300mkl) was used to separate 5-[[2-[5-methanone yl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (114.5 mg, 263.58 μmol) ; yield compound 511 5-[[2-[( 2S,5R )-5-methyl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carboxamide (50.03 mg, 115.17 μmol, 43.69% yield) (RT=22.82 min) and compound 508 5-[[2-[( 2R,5S )-5-methyl yl-2-[4-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (58.4 mg, 134.43 μmol, 51% yield) (RT=38.04 min). The retention time of compound 511 under analytical conditions (column: IC-3, with hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 16.70 min and the retention time of compound 508 was 27.34 min.

化合物511：保留時間：16.70minCompound 511: retention time: 16.70min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.00-1.04(m,3H),1.27-1.40(m,1H),1.58-1.69(m,1H),1.83-1.95(m,1H),2.01-2.18(m,1H),2.18-2.30(m,1H),2.78-3.27(m,1H),3.50-4.09(m,1H),5.20-5.68(m,1H),7.50-7.65(m,3H),7.68-7.83(m,2H),8.05-8.19(m,1H),8.42-8.55(m,1H),8.70-8.81(m,1H),8.81-8.97(m,1H),11.15-11.36(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.00-1.04(m,3H), 1.27-1.40(m,1H), 1.58-1.69(m,1H), 1.83-1.95(m,1H) ,2.01-2.18(m,1H),2.18-2.30(m,1H),2.78-3.27(m,1H),3.50-4.09(m,1H),5.20-5.68(m,1H),7.50-7.65( m,3H),7.68-7.83(m,2H),8.05-8.19(m,1H),8.42-8.55(m,1H),8.70-8.81(m,1H),8.81-8.97(m,1H), 11.15-11.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值434.2；實測值435.2；Rt=2.927min。LCMS (ESI): [M] + m/z: calculated 434.2; found 435.2; Rt=2.927 min.

化合物508：保留時間：27.34minCompound 508: retention time: 27.34min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.05(m,3H),1.28-1.40(m,1H),1.58-1.71(m,1H),1.83-1.94(m,1H),2.03-2.18(m,1H),2.18-2.28(m,1H),2.74-3.26(m,1H),3.49-4.10(m,1H),5.22-5.88(m,1H),7.50-7.64(m,3H),7.69-7.79(m,2H),8.08-8.24(m,1H),8.40-8.54(m,1H),8.72-8.81(m,1H),8.81-8.94(m,1H),11.11-11.40(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.05(m,3H), 1.28-1.40(m,1H), 1.58-1.71(m,1H), 1.83-1.94(m,1H) ,2.03-2.18(m,1H),2.18-2.28(m,1H),2.74-3.26(m,1H),3.49-4.10(m,1H),5.22-5.88(m,1H),7.50-7.64( m,3H),7.69-7.79(m,2H),8.08-8.24(m,1H),8.40-8.54(m,1H),8.72-8.81(m,1H),8.81-8.94(m,1H), 11.11-11.40 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值434.2；實測值435.2；Rt=2.929min。LCMS (ESI): [M] + m/z: calculated 434.2; found 435.2; Rt=2.929 min.

實例703. 5-(2-(2-(4-氟-3-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物307、化合物293)之合成Example 703. 5-(2-(2-(4-Fluoro-3-methylphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of (Compound 307, Compound 293)

Figure 110128222-A0202-12-2273-570
Figure 110128222-A0202-12-2273-570

步驟1：(5-(4-氟-3-甲基苯基)-2-甲基-5-側氧基戊基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (5-(4-fluoro-3-methylphenyl)-2-methyl-5-oxypentyl)carbamate

在-78℃下，將5-甲基-2-側氧基哌啶-1-甲酸第三丁 酯(5.64g，26.45mmol)(15%於THF溶液中)冷卻至室溫且逐滴添加到4-溴-1-氟-2-甲基苯(5g，26.45mmol，3.36mL)於THF(50mL)中之溶液中。使所得混合物升溫至室溫然後倒入到NH4 Cl水溶液中。將所得混合物用EtOAc(2x40ml)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以獲得N -[5-(4-氟-3-甲基苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(5g，15.46mmol，58.45%產率)，其不經純化即用於下一步驟中。At -78°C, tert- butyl 5-methyl-2-oxypiperidine-1-carboxylate (5.64 g, 26.45 mmol) (15% in THF) was cooled to room temperature and added dropwise to a solution of 4-bromo-1-fluoro-2-methylbenzene (5 g, 26.45 mmol, 3.36 mL) in THF (50 mL). The resulting mixture was allowed to warm to room temperature and poured into aqueous NH4Cl . The resulting mixture was extracted with EtOAc (2x40ml). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated to give N- [5-(4-fluoro-3-methylphenyl)-2-methyl-5-pendoxyloxy 3 -Butyl pentyl]carbamate (5 g, 15.46 mmol, 58.45% yield) was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.49(s,9H),1.85(m,4H),2.22(s,3H),2.95(m,2H),3.80(m,1H),5.55(m,1H),7.12(m,3H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.98(d,3H), 1.49(s,9H), 1.85(m,4H), 2.22(s,3H), 2.95(m,2H), 3.80 (m, 1H), 5.55 (m, 1H), 7.12 (m, 3H).

LCMS(ESI)：[M-Boc]+ m/z：計算值223.2；實測值224.2；Rt=1.556minLCMS(ESI): [M-Boc] + m/z: Calculated 223.2; Measured 224.2; Rt=1.556min

步驟2：2-(4-氟-3-甲基苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(4-fluoro-3-methylphenyl)-5-methylpiperidine

將N -[5-(4-氟-3-甲基苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁 酯(5g，15.46mmol)溶解於三氟乙酸(44.07g，386.52mmol，29.78mL)中且將所得混合物攪拌1h。向其中添加50%NaOH水溶液，直至pH 11-12。將所得混合物用DCM(4x40ml)萃取，將經合併之有機層蒸發至乾。將殘餘物溶解於MeOH(50mL)中且添加硼氫化鈉(584.92mg，15.46mmol，546.65μL)。將所得混合物在20℃下攪拌12h且蒸發。將50%NaOH水溶液添加到殘餘物中。將所得混合物用DCM(4x40ml)萃取，將經合併之有機層蒸發至乾，以獲得2-(4-氟-3-甲基苯基)-5-甲基 哌啶(1.4g，6.75mmol，43.68%產率)，其不經純化即用於下一步驟中。 N- [5-(4-Fluoro-3-methylphenyl)-2-methyl-5-oxypentyl]carbamic acid tert- butyl ester (5 g, 15.46 mmol) was dissolved in trifluoroacetic acid ( 44.07 g, 386.52 mmol, 29.78 mL) and the resulting mixture was stirred for 1 h. To this was added 50% aqueous NaOH until pH 11-12. The resulting mixture was extracted with DCM (4x40ml) and the combined organic layers were evaporated to dryness. The residue was dissolved in MeOH (50 mL) and sodium borohydride (584.92 mg, 15.46 mmol, 546.65 μL) was added. The resulting mixture was stirred at 20 °C for 12 h and evaporated. Aqueous 50% NaOH was added to the residue. The resulting mixture was extracted with DCM (4x40ml) and the combined organic layers were evaporated to dryness to give 2-(4-fluoro-3-methylphenyl)-5-methylpiperidine (1.4g, 6.75mmol, 43.68% yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.82(d,3H),1.46(m,1H),1.50(m,1H),1.66(m,1H),1.76(m,1H),2.19(m,2H),2.25(s,3H),2.98(d,1H),3.40(d,1H),4.17(bds,1H),7.00(m,1H),7.22(m,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.82(d,3H), 1.46(m,1H), 1.50(m,1H), 1.66(m,1H), 1.76(m,1H), 2.19(m, 2H), 2.25(s, 3H), 2.98(d, 1H), 3.40(d, 1H), 4.17(bds, 1H), 7.00(m, 1H), 7.22(m, 2H).

LCMS(ESI)：[M]+ m/z：計算值207.2；實測值208.2；Rt=0.950min。LCMS (ESI): [M] + m/z: calculated 207.2; found 208.2; Rt=0.950 min.

步驟3：2-(2-(4-氟-3-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 3: 2-(2-(4-Fluoro-3-methylphenyl)-5-methylpiperidin-1-yl)-2-oxoacetic acid 2,2,2-trifluoroethyl ester synthesis

在-10℃下，將2-氯-2-側氧基乙酸2,2,2-三氟乙酯(919.04mg，4.82mmol)逐滴添加到2-(4-氟-3-甲基苯基)-5-甲基哌啶(1g，4.82mmol)及TEA(488.17mg，4.82mmol，672.40μL)於THF(20mL)中之溶液中。使所得混合物升溫至室溫且攪拌12h。過濾出所得沉澱。蒸發濾液，以獲得2-[2-(4-氟-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.7g，4.70mmol，97.52%產率)，其不經純化即用於下一步驟中。2-Chloro-2-pendoxoacetic acid 2,2,2-trifluoroethyl ester (919.04 mg, 4.82 mmol) was added dropwise to 2-(4-fluoro-3-methylbenzene at -10°C) yl)-5-methylpiperidine (1 g, 4.82 mmol) and TEA (488.17 mg, 4.82 mmol, 672.40 μL) in THF (20 mL). The resulting mixture was warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered off. The filtrate was evaporated to give 2-[2-(4-fluoro-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxoacetic acid 2,2,2-trifluoroethyl Ester (1.7 g, 4.70 mmol, 97.52% yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.96(d,3H),1.45(m,2H),1.68(m,2H),1.98(m,2H),2.25(s,3H),3.09(m,1H),3.62(s,2H),5.13(m,1H),7.20(m,3H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.96(d, 3H), 1.45(m, 2H), 1.68(m, 2H), 1.98(m, 2H), 2.25(s, 3H), 3.09 (m, 1H), 3.62 (s, 2H), 5.13 (m, 1H), 7.20 (m, 3H).

LCMS(ESI)：[M]+ m/z：計算值361.2；實測值362.2；Rt=1.645minLCMS(ESI): [M] + m/z: Calculated 361.2; Measured 362.2; Rt=1.645min

步驟4：2-(2-(4-氟-3-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙酸鋰之合成Step 4: Synthesis of lithium 2-(2-(4-fluoro-3-methylphenyl)-5-methylpiperidin-1-yl)-2-oxoacetate

將98%氫氧化鋰單水合物(197.43mg，4.70mmol，130.75μL)添加到2-[2-(4-氟-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.7g，4.70mmol)於水(3mL)及THF(30mL)中之溶液中且將所得混合物在20℃下攪拌12h。將所得混合物蒸發至乾，以獲得[2-[2-(4-氟-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]氧基鋰(1g，3.51mmol，74.52%產率)，其不經純化即用於下一步驟中。98% Lithium hydroxide monohydrate (197.43 mg, 4.70 mmol, 130.75 μL) was added to 2-[2-(4-fluoro-3-methylphenyl)-5-methyl-1-piperidinyl] - A solution of 2,2,2-trifluoroethyl 2-pendoxoacetic acid (1.7 g, 4.70 mmol) in water (3 mL) and THF (30 mL) and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was evaporated to dryness to obtain [2-[2-(4-fluoro-3-methylphenyl)-5-methyl-1-piperidinyl]-2-pendoxetyl]oxy base lithium (1 g, 3.51 mmol, 74.52% yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值285.2；實測值286.2；Rt=min。LCMS (ESI): [M] + m/z: calculated 285.2; found 286.2; Rt=min.

步驟5：5-(2-(2-(4-氟-3-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 5: 5-(2-(2-(4-Fluoro-3-methylphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide synthesis

將[2-[2-(4-氟-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]氧基鋰(0.3g，1.05mmol)與HATU(399.91mg，1.05mmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加5-胺基吡啶-3-甲醯胺(144.24mg，1.05mmol)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以MeCN-水為溶析液混合物)，以獲得5-[[2-[2-(4-氟-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1354g，339.83μmol，32.31%產率)。Lithium [2-[2-(4-fluoro-3-methylphenyl)-5-methyl-1-piperidinyl]-2-oxyacetoxy]oxyl (0.3 g, 1.05 mmol ) was mixed with HATU (399.91 mg, 1.05 mmol) in DMF (5 mL) and the resulting mixture was stirred at 20 °C for 10 min before 5-aminopyridine-3-carboxamide (144.24 mg, 1.05 mmol) was added. The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with MeCN-water as eluent mixture) to obtain 5-[[2-[2-(4-fluoro-3-methylphenyl) -5-Methyl-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.1354 g, 339.83 μmol, 32.31% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm) 1 H NMR (400MHz, DMSO- d 6 )δ(ppm)

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=3.091minLCMS(ESI): [M] + m/z: Calculated 398.2; Measured 399.2; Rt=3.091min

步驟6：掌性分離(化合物307 及化合物293 )Step 6: Chiral separation ( compound 307 and compound 293 )

使用(Chiralpak IC-I 250*20，5mkm管柱；以己烷-IPA-MeOH，50-5-25為流動相；流速10mL/min；注入體積：900mkl)分離5-(2-(2-(4-氟-3-甲基苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(135.4mg，339.83μmol)；得到呈黃色固體之化合物307 5-[[2-[(2S,5R )-2-(4-氟-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(41mg，102.90μmol，30.28%產率)(RT(IC-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=9.67min)及呈黃色固體之化合物293 5-[[2-[(2R,5S )-2-(4-氟-3-甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(60.8mg，143.91μmol，35.87%產率)(RT(IC-3，己烷-IPA-MeOH，50-25-25，0.155ml/min)=15.26min)。Separation of 5-(2-(2- (4-Fluoro-3-methylphenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (135.4 mg, 339.83 μmol); obtained as yellow Solid compound 307 5-[[2-[( 2S,5R )-2-(4-fluoro-3-methylphenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide (41 mg, 102.90 μmol, 30.28% yield) (RT(IC-3, hexane-IPA-MeOH, 50-25-25, 0.155 ml/min) = 9.67min) and compound 293 as a yellow solid 5-[[2-[( 2R,5S )-2-(4-fluoro-3-methylphenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (60.8 mg, 143.91 μmol, 35.87% yield) (RT (IC-3, hexane-IPA-MeOH, 50-25-25 , 0.155ml/min)=15.26min).

化合物307：保留時間：9.67minCompound 307: retention time: 9.67min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.00-1.05(m,3H),1.30-1.42(m,1H),1.63 -1.74(m,1H),1.84-1.96(m,1H),2.01-2.15(m,1H),2.16-2.27(m,4H),2.80-3.19(m,1H),3.47-4.03(m,1H),5.07-5.61(m,1H),7.11-7.29(m,3H),7.57-7.69(m,1H),8.10-8.23(m,1H),8.43-8.56(m,1H),8.74-8.83(m,1H),8.83-9.00(m,1H),11.16-11.32(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.00-1.05(m,3H), 1.30-1.42(m,1H), 1.63-1.74(m,1H), 1.84-1.96(m,1H) ,2.01-2.15(m,1H),2.16-2.27(m,4H),2.80-3.19(m,1H),3.47-4.03(m,1H),5.07-5.61(m,1H),7.11-7.29( m,3H),7.57-7.69(m,1H),8.10-8.23(m,1H),8.43-8.56(m,1H),8.74-8.83(m,1H),8.83-9.00(m,1H), 11.16-11.32 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=3.274min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=3.274 min.

化合物293：保留時間：15.26minCompound 293: retention time: 15.26min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.01-1.06(m,3H),1.23-1.41(m,1H),1.63-1.79(m,1H),1.84-1.96(m,1H),2.00-2.12(m,1H),2.16-2.28(m,4H),2.79-3.24(m,1H),3.49-4.05(m,1H),5.08-5.62(m,1H),7.11-7.30(m,3H),7.53-7.68(m,1H),8.07-8.29(m,1H),8.41-8.53(m,1H),8.74-8.82(m,1H),8.82-8.94(m,1H),11.15-11.35(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.01-1.06(m,3H), 1.23-1.41(m,1H), 1.63-1.79(m,1H), 1.84-1.96(m,1H) ,2.00-2.12(m,1H),2.16-2.28(m,4H),2.79-3.24(m,1H),3.49-4.05(m,1H),5.08-5.62(m,1H),7.11-7.30( m,3H),7.53-7.68(m,1H),8.07-8.29(m,1H),8.41-8.53(m,1H),8.74-8.82(m,1H),8.82-8.94(m,1H), 11.15-11.35 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=3.264min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=3.264 min.

實例704. 5-[[2-[(2S ,5R )-5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,5S )-5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物227及化合物219)之合成Example 704. 5-[[2-[( 2S , 5R )-5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide and 5-[[2-[(2 R ,5 S )-5-methyl-2-( m-tolyl )-1-piperidinyl]-2-side oxyacetamide Synthesis of yl]amino]pyridine-3-carboxamide (compound 227 and compound 219)

Figure 110128222-A0202-12-2276-571
Figure 110128222-A0202-12-2276-571

N-[2-甲基-5-(間甲苯基)-5-側氧基戊基]胺甲酸第三丁酯之合成Synthesis of N-[2-methyl-5-(m-tolyl)-5-oxypentyl]carbamic acid tert-butyl ester

在-10℃下，向5-甲基-2-(間甲苯基 )哌啶(1g，5.28mmol)及三乙胺 (534.56mg，5.28mmol，736.31μL)於THF(30mL)中之經攪拌之溶液中逐滴添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(1.01g，5.28mmol)。使所得反應混合物升溫至室溫且在同一溫度下攪拌12小時。12小時之後，過濾反應混合物。在減壓下濃縮濾液，以獲得2-[5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.6g，4.66mmol，88.21%產率)。粗產物不經任何進一步純化即用於下一步反應。To a stirred mixture of 5-methyl-2-( m-tolyl )piperidine (1 g, 5.28 mmol) and triethylamine (534.56 mg, 5.28 mmol, 736.31 μL) in THF (30 mL) at -10 °C To this solution was added 2,2,2-trifluoroethyl 2-chloro-2-oxoacetate (1.01 g, 5.28 mmol) dropwise. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 2,2,2-trifluoroethyl 2-[5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyacetate (1.6 g, 4.66 mmol, 88.21% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值343.2；實測值344.2；Rt=1.590min。LCMS (ESI): [M+H] + m/z: calculated 343.2; found 344.2; Rt=1.590 min.

步驟2：[2-[5-甲基-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯基]氧基鋰之合成Step 2: Synthesis of lithium [2-[5-methyl-2-(m-tolyl)-1-piperidinyl]-2-oxyethanoyl]oxylithium

向2-[5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.6g，4.66mmol)於THF(20mL)及水(2mL)中之經攪拌之溶液中添加98%氫氧化鋰單水合物(195.55mg，4.66mmol)。使所得反應混合物在20℃下攪拌12小時。完成之後，在減壓下濃縮反應混合物，以獲得[2-[5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]氧基鋰(0.9g，3.37mmol，72.27%產率)。粗產物不經任何進一步純化即用於下一步反應。To 2-[5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyacetate 2,2,2-trifluoroethyl ester (1.6 g, 4.66 mmol) in THF ( To a stirred solution in 20 mL) and water (2 mL) was added 98% lithium hydroxide monohydrate (195.55 mg, 4.66 mmol). The resulting reaction mixture was stirred at 20°C for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain lithium [2-[5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyethanoyl]oxylithium ( 0.9 g, 3.37 mmol, 72.27% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值261.1；實測值262.2；Rt=1.110min。LCMS (ESI): [M+H] + m/z: calculated 261.1; found 262.2; Rt=1.110 min.

步驟3：5-[[2-[5-甲基-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 3: Compound of 5-[[2-[5-methyl-2-(m-tolyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide synthesis

向[2-[5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]氧基鋰(0.3g，1.12mmol)於DMF(5mL)中之經攪拌之溶液中添加HATU(426.83mg，1.12mmol)。將所得反應混合物在20℃下攪拌10分鐘。10分鐘之後，添加5-胺基吡啶-3-甲醯胺(153.95mg，1.12mmol)。將所得反應混合物在20℃下攪拌12小時。使所得反應混合物經歷反相HPLC純化(溶析液：水-乙腈，28%，0.5-6.5min；流速：30mL/min；裝載泵：4mL/min；管柱：SunFire 19*100mm，5um)，以獲得5-[[2-[5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺 (0.0844g，221.85μmol，19.76%產率)。To lithium [2-[5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyethanoyl]oxylithium (0.3 g, 1.12 mmol) in DMF (5 mL) To the stirred solution was added HATU (426.83 mg, 1.12 mmol). The resulting reaction mixture was stirred at 20°C for 10 minutes. After 10 minutes, 5-aminopyridine-3-carboxamide (153.95 mg, 1.12 mmol) was added. The resulting reaction mixture was stirred at 20°C for 12 hours. The resulting reaction mixture was subjected to reverse phase HPLC purification (eluent: water-acetonitrile, 28%, 0.5-6.5 min; flow rate: 30 mL/min; loading pump: 4 mL/min; column: SunFire 19*100 mm, 5 um), to obtain 5-[[2-[5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.0844 g, 221.85 μmol, 19.76% yield).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=3.375min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=3.375 min.

5-[[2-[(2S,5R)-5-甲基-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,5S)-5-甲基-2-(間甲苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物227 及化合物219 )之掌性分離5-[[2-[(2S,5R)-5-methyl-2-(m-tolyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Amide and 5-[[2-[(2R,5S)-5-methyl-2-(m-tolyl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- Chiral separation of 3-formamide ( compound 227 and compound 219 )

使5-[[2-[5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.084g，220.80μmol)經歷掌性層析(管柱：Chiralpak IA II，250*20mm，5um，溶析液：己烷-MeOH-IPA，70-15-15，流速：12mL/min)，以得到呈黃色固體之5-[[2-[(2S ,5R )-5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物227 ，33mg)及5-[[2-[(2R ,5S )-5-甲基-2-(間甲苯基 )-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物219 ，31mg)。Make 5-[[2-[5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.084g , 220.80 μmol) was subjected to chiral chromatography (column: Chiralpak IA II, 250*20 mm, 5um, eluent: hexane-MeOH-IPA, 70-15-15, flow rate: 12 mL/min) to obtain a 5-[[2-[(2 S ,5 R )-5-methyl-2-( m-tolyl )-1-piperidinyl]-2-oxyethanoyl]amino] as a yellow solid Pyridine-3-carboxamide ( compound 227 , 33 mg) and 5-[[2-[( 2R , 5S )-5-methyl-2-( m-tolyl )-1-piperidinyl]-2 -Pendant oxyacetoxy]amino]pyridine-3-carboxamide ( compound 219 , 31 mg).

化合物227： 1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.05(m,3H),1.35(m,1H),1.71(m,1H),1.89(m,1H),2.04(m,1H),2.21(m,1H),2.32(m,3H),3.13(m,1H),3.76(m,1H),5.36(m,1H),7.18(m,4H),7.63(m,1H),8.18(m,1H),8.50(m,1H),8.83(m,2H),11.26(m,1H)。 Compound 227: 1 H NMR (DMSO- d 6 , 400 MHz): δ (ppm) 1.05 (m, 3H), 1.35 (m, 1H), 1.71 (m, 1H), 1.89 (m, 1H), 2.04 (m ,1H),2.21(m,1H),2.32(m,3H),3.13(m,1H),3.76(m,1H),5.36(m,1H),7.18(m,4H),7.63(m, 1H), 8.18 (m, 1H), 8.50 (m, 1H), 8.83 (m, 2H), 11.26 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.4；Rt=3.232min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.4; Rt=3.232 min.

掌性HPLC：Rt=24.77min(管柱：IA；溶析液：己烷-MeOH-IPA，70-15-15；流速：0.6mL/min)。Chiral HPLC: Rt=24.77 min (column: IA; eluent: hexane-MeOH-IPA, 70-15-15; flow rate: 0.6 mL/min).

化合物219： 1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.04(m,3H),1.36(m,1H),1.69(m,1H),1.90(m,1H),2.13(m,2H),2.32(m,3H),3.11(m,1H),3.76(m,1H),5.36(m,1H),7.13(m,3H),7.27(m,1H),7.63(m,1H),8.18(m,1H),8.50(m,1H),8.78(m,1H),8.89(m,1H),11.26(m,1H)。 Compound 219: 1 H NMR (DMSO- d 6 , 400 MHz): δ (ppm) 1.04 (m, 3H), 1.36 (m, 1H), 1.69 (m, 1H), 1.90 (m, 1H), 2.13 (m ,2H),2.32(m,3H),3.11(m,1H),3.76(m,1H),5.36(m,1H),7.13(m,3H),7.27(m,1H),7.63(m, 1H), 8.18 (m, 1H), 8.50 (m, 1H), 8.78 (m, 1H), 8.89 (m, 1H), 11.26 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值380.2；實測值381.2；Rt=3.248min。LCMS (ESI): [M+H] + m/z: calculated 380.2; found 381.2; Rt=3.248 min.

掌性HPLC：Rt=31.95min(管柱：IA；溶析液：己烷-MeOH-IPA，70-15-15； 流速：0.6mL/min)。Chiral HPLC: Rt=31.95min (column: IA; eluent: hexane-MeOH-IPA, 70-15-15; Flow rate: 0.6 mL/min).

實例705. 5-(2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物509、化合物510)之合成Example 705. 5-(2-(5-Methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide Synthesis of (Compound 509, Compound 510)

Figure 110128222-A0202-12-2279-572
Figure 110128222-A0202-12-2279-572

步驟1：5-(2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 1: 5-(2-(5-Methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide synthesis

將2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸(0.3g，931.02μmol，Li+ )與HATU(354.00mg，931.02μmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加5-胺基吡啶-3-甲醯胺(127.68mg，931.02μmol)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(管柱：SunFire 19*100mm，5mkl；以水-MeCN為溶析液混合物)，以獲得5-[[2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.166g，382.13μmol，41.04%產率)。2-[5-Methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetic acid (0.3 g, 931.02 μmol, Li + ) was mixed with HATU ( 354.00 mg, 931.02 μmol) was mixed in DMF (5 mL) and the resulting mixture was stirred at 20° C. for 10 min before 5-aminopyridine-3-carboxamide (127.68 mg, 931.02 μmol) was added. The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (column: SunFire 19*100mm, 5mkl; with water-MeCN as eluent mixture) to obtain 5-[[2-[5-methyl-2-[3-(trifluoromethane (0.166 g, 382.13 μmol, 41.04% yield).

LCMS(ESI)：[M]+ m/z：計算值434.2；實測值435.2；Rt=3.308min。LCMS (ESI): [M] + m/z: calculated 434.2; found 435.2; Rt=3.308 min.

步驟2：掌性分離(化合物509 及化合物510 )Step 2: Chiral separation ( Compound 509 and Compound 510 )

使用(Chiralpak IC-I 250*20，5mkm管柱；以己烷-IPA-MeOH，60-20-20為流動相；流速12mL/min；注入體積：400mkl)分離5-[[2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(166mg，382.13μmol)；得到化合物509 5-[[2-[(2R,5S )-5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(60.41mg，139.06μmol，36.39%產率)(RT=22.68min)及化合物510 5-[[2-[(2S,5R )-5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(54.87mg，166μmol，33.05%產率)(RT=15.63 min)。化合物509 於分析條件下(管柱：IC，己烷-IPA-MeOH，60-20-20，0.6ml/min為流動相)之保留時間為23.08min且化合物510 之保留時間為15.71min。5-[[2-[5 was isolated using (Chiralpak IC-I 250*20, 5mkm column; hexane-IPA-MeOH, 60-20-20 as mobile phase; flow rate 12mL/min; injection volume: 400mkl) -Methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (166 mg, 382.13 μmol ); obtain compound 509 5-[[2-[( 2R,5S )-5-methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide (60.41 mg, 139.06 μmol, 36.39% yield) (RT=22.68 min) and compound 510 5-[[2-[( 2S,5R )-5- Methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (54.87 mg, 166 μmol, 33.05% yield) (RT=15.63 min). The retention time of compound 509 under analytical conditions (column: IC, hexane-IPA-MeOH, 60-20-20, 0.6 ml/min as mobile phase) was 23.08 min and that of compound 510 was 15.71 min.

化合物509：保留時間：23.08minCompound 509: retention time: 23.08min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99-1.06(m,3H),1.27-1.38(m,1H),1.56-1.66(m,1H),1.84-1.96(m,1H),2.06-2.18(m,1H),2.20-2.30(m,1H),2.74-3.28(m,1H),3.49-4.07(m,1H),5.20-5.64(m,1H),7.57-7.69(m,5H),8.06-8.25(m,1H),8.41-8.56(m,1H),8.68-8.80(m,1H),8.80-8.93(m,1H),11.21-11.32(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.99-1.06(m,3H), 1.27-1.38(m,1H), 1.56-1.66(m,1H), 1.84-1.96(m,1H) ,2.06-2.18(m,1H),2.20-2.30(m,1H),2.74-3.28(m,1H),3.49-4.07(m,1H),5.20-5.64(m,1H),7.57-7.69( m, 5H), 8.06-8.25 (m, 1H), 8.41-8.56 (m, 1H), 8.68-8.80 (m, 1H), 8.80-8.93 (m, 1H), 11.21-11.32 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值434.2；實測值435.2；Rt=3.363min。LCMS (ESI): [M] + m/z: calculated 434.2; found 435.2; Rt=3.363 min.

化合物510：保留時間：15.71minCompound 510: retention time: 15.71min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.06(m,3H),1.27-1.41(m,1H),1.57-1.67(m,1H),1.85-1.95(m,1H),2.06-2.20(m,1H),2.20-2.32(m,1H),2.74-3.27(m,1H),3.48-4.10(m,1H),5.24-5.65(m,1H),7.55-7.70(m,5H),8.07-8.22(m,1H),8.38-8.53(m,1H),8.69-8.80(m,1H),8.80-8.94(m,1H),11.17-11.37(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.06(m,3H), 1.27-1.41(m,1H), 1.57-1.67(m,1H), 1.85-1.95(m,1H) ,2.06-2.20(m,1H),2.20-2.32(m,1H),2.74-3.27(m,1H),3.48-4.10(m,1H),5.24-5.65(m,1H),7.55-7.70( m, 5H), 8.07-8.22 (m, 1H), 8.38-8.53 (m, 1H), 8.69-8.80 (m, 1H), 8.80-8.94 (m, 1H), 11.17-11.37 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值434.2；實測值435.2；Rt=3.367min。LCMS (ESI): [M] + m/z: calculated 434.2; found 435.2; Rt=3.367 min.

實例706.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物507、化合物496)之合成Example 706. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl )-2-oxyacetamide (Compound 507, Compound 496) Synthesis

Figure 110128222-A0202-12-2280-573
Figure 110128222-A0202-12-2280-573

步驟1：(3-甲基-5-(2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺基)Step 1: (3-Methyl-5-(2-(5-methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoacetamide base) 吡啶-2-基)胺甲酸第三丁酯之合成Synthesis of tert-butyl pyridin-2-yl)carbamate

將2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙酸(0.3g，931.02μmol，Li+ )與HATU(389.40mg，1.02mmol)混合於DMF(5mL)中且將所得混合物在20℃下攪拌10min，隨後添加N -(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁 酯(207.87mg，931.02μmol)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC(管柱：SunFire 19*100mm，5mkl；以水-MeCN為溶析液混合物)，以獲得N -[3-甲基-5-[[2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(323.90mg，622.24μmol，66.83%產率)。2-[5-Methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetic acid (0.3 g, 931.02 μmol, Li + ) was mixed with HATU ( 389.40 mg, 1.02 mmol) in DMF (5 mL) and the resulting mixture was stirred at 20 °C for 10 min, followed by the addition of 3-butyl N- (5-amino-3-methyl-2-pyridyl) carbamate (207.87 mg, 931.02 μmol). The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC (column: SunFire 19*100mm, 5mkl; with water-MeCN as eluent mixture) to obtain N- [3-methyl-5-[[2-[5-methyl-2 -[3-(Trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert- butyl ester (323.90 mg, 622.24 mg μmol, 66.83% yield).

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=4.245min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=4.245 min.

步驟2：掌性分離Step 2: Palm Separation

使用(Chiralpak IC 250*20，5mkm管柱；以己烷-IPA-MeOH，80-10-10為流動相；流速12mL/min；注入體積：300mkl)分離N-[3-甲基-5-[[2-[5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(217.2mg，417.26μmol)；得到E1N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[4-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(132.86mg，255.23μmol，41.13%產率)(RT=39.76min)及E2N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(107.18mg，205.90μmol，33.18%產率)(RT=32.18min)。E1於分析條件下(管柱：IC，以己烷-IPA-MeOH，80-10-10，0.6ml/min為流動相)之保留時間為25.79min且E2之保留時間為23.60min。Separation of N-[3-methyl-5- [[2-[5-Methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl] tert-butyl carbamate (217.2 mg, 417.26 μmol); yields El N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-[4-(trifluoro) Methyl)phenyl]-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (132.86 mg, 255.23 μmol, 41.13% yield) (RT=39.76min) and E2 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-[3-(trifluoromethyl)phenyl]-1 -Piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert -butyl ester (107.18 mg, 205.90 μmol, 33.18% yield) (RT=32.18 min). The retention time of E1 under analytical conditions (column: IC, with hexane-IPA-MeOH, 80-10-10, 0.6 ml/min as mobile phase) was 25.79 min and that of E2 was 23.60 min.

E1：保留時間：25.79minE1: retention time: 25.79min

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=6.125min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=6.125 min.

E2：保留時間：23.60minE2: retention time: 23.60min

LCMS(ESI)：[M]+ m/z：計算值520.2；實測值521.2；Rt=6.199min。LCMS (ESI): [M] + m/z: calculated 520.2; found 521.2; Rt=6.199 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(3-(三氟甲基)苯基)哌啶-1-基)-2-側氧基乙醯胺(Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(3-(trifluoromethyl)phenyl)piperidin-1-yl )-2-side oxyacetamide ( 化合物507及化合物496)之合成Synthesis of compound 507 and compound 496)

將N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.107g，205.55μmol)及N -[3-甲基-5-[[2-[(2S,5R )-5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.132g，253.58μmol)溶解於二噁烷/HCl(3mL)中且將所得混合物在20℃下攪拌12h。將所得混合物蒸發且使殘餘物經歷HPLC(管柱：Triart 20*100mm，5mkl；以水-MeOH+NH3 為溶析液混合物)，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯胺(0.0582g，138.43μmol，67.34%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-[3-(三氟甲基)苯基]-1-哌啶基]-2-側氧基乙醯胺(0.0156g，37.11μmol，14.63%產率)。 N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (0.107g, 205.55μmol) and N- [3-methyl-5-[[2-[( 2S,5R )-5-methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2- oxyethanoyl ]amino]-2-pyridyl]carbamic acid Tributyl ester (0.132 g, 253.58 μmol) was dissolved in dioxane/HCl (3 mL) and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was evaporated and the residue was subjected to HPLC (column: Triart 20*100mm, 5mkl; water-MeOH+ NH3 as eluent mixture) to obtain N- (6-amino-5-methyl- 3-Pyridinyl)-2-[( 2R,5S )-5-methyl-2-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetamide (0.0582 g, 138.43 μmol, 67.34% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5-methyl-2-[3 -(Trifluoromethyl)phenyl]-1-piperidinyl]-2-oxoacetamide (0.0156 g, 37.11 μmol, 14.63% yield).

化合物507： LCMS(ESI)：[M]+ m/z：計算值420.2；實測值421.2；Rt=1.063min。 Compound 507: LCMS (ESI): [M] + m/z: calcd 420.2; found 421.2; Rt=1.063 min.

化合物496： LCMS(ESI)：[M]+ m/z：計算值420.2；實測值421.2；Rt=1.072min。 Compound 496: LCMS (ESI): [M] + m/z: calcd 420.2; found 421.2; Rt=1.072 min.

實例707. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物606)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物596)之合成Example 707. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide (Compound 606) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- Synthesis of (3-chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 596)

Figure 110128222-A0202-12-2283-574
Figure 110128222-A0202-12-2283-574

步驟1：2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯之合成Step 1: Synthesis of methyl 2-[2-(3-chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetate

在0℃下，向2-(3-氯-4-氟苯基)-5-甲基哌啶(0.5g，2.20mmol)及三乙胺(266.63mg，2.63mmol，367.27μL)於DCM中之溶液中添加2-氯-2-側氧基乙酸甲酯(295.90mg，2.42mmol)。在室溫下攪拌1h之後，將所得混合物用Et2O稀釋且過濾，然後蒸發至乾，以得到呈黃色固體之2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.75g，粗品)，其不經進一步純化即用於下一步驟中。To 2-(3-chloro-4-fluorophenyl)-5-methylpiperidine (0.5 g, 2.20 mmol) and triethylamine (266.63 mg, 2.63 mmol, 367.27 μL) in DCM at 0 °C To this solution was added methyl 2-chloro-2-oxoacetate (295.90 mg, 2.42 mmol). After stirring at room temperature for 1 h, the resulting mixture was diluted with Et2O and filtered, then evaporated to dryness to give 2-[2-(3-chloro-4-fluorophenyl)-5-methyl- Methyl 1-piperidinyl]-2-oxoacetate (0.75 g, crude) was used in the next step without further purification.

1 H NMR(CDCl3 ,500MHz)：δ 1.08(d,3H),1.47(m,1H),1.79(m,1H),1,94(m,1H),2.17-2.24(m,2H),3.23(dd,2H),3.80-3.91(兩個單峰，3H),5.72(s,1H),7.17-7.29(m,3H)。 1 H NMR (CDCl 3 , 500MHz): δ 1.08 (d, 3H), 1.47 (m, 1H), 1.79 (m, 1H), 1,94 (m, 1H), 2.17-2.24 (m, 2H), 3.23 (dd, 2H), 3.80-3.91 (two singlets, 3H), 5.72 (s, 1H), 7.17-7.29 (m, 3H).

LCMS(ESI)：[M+H]+ m/z：計算值313.1；實測值314.2；Rt=1.453min。LCMS (ESI): [M+H] + m/z: calculated 313.1; found 314.2; Rt=1.453 min.

步驟2：N-[5-[[2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of tert-butyl ]-3-methyl-2-pyridyl]carbamate

向2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.75g，2.39mmol)於MeOH(12.50mL)中之溶液中添加羥基鈉(105.17mg，2.63mmol，49.38μL)且將所得混合物攪拌1h。然後，蒸發溶劑且將殘餘物與EtOH一起再蒸發。此後，將固體溶解於DMF中且添加HATU(908.91mg，2.39mmol)，隨後添加N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(533.71mg，2.39mmol)且將所得混合物攪拌12h。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(55-80% 2-7min水-乙腈；流速：30ml/min；(裝載泵4ml/min，乙腈)；管柱：SunFireC18 100x19mm 5um)。獲得兩種級分之N-[5-[[2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(654.6mg，1.30mmol，54.23%產率)：385.7mg(藉由LCMS測得100%，幾乎單一非鏡像異構物)及268.9mg(藉由LCMS為100%，3：1=反式/順式)。To methyl 2-[2-(3-chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetate (0.75 g, 2.39 mmol) in MeOH (12.50 mL) To the solution in ) was added sodium hydroxyde (105.17 mg, 2.63 mmol, 49.38 μL) and the resulting mixture was stirred for 1 h. Then, the solvent was evaporated and the residue was re-evaporated with EtOH. After this time, the solid was dissolved in DMF and HATU (908.91 mg, 2.39 mmol) was added followed by tert-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (533.71 mg, 2.39 mmol) mmol) and the resulting mixture was stirred for 12 h. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (55-80% 2-7 min water-acetonitrile; flow rate: 30 ml/min; (loading pump 4 ml/min, acetonitrile); column: SunFire C18 100x19mm 5um). Two fractions of N-[5-[[2-[2-(3-chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (654.6 mg, 1.30 mmol, 54.23% yield): 385.7 mg (100% by LCMS, almost single non-mirror isomeric structure) and 268.9 mg (100% by LCMS, 3:1=trans/cis).

1 H NMR(CDCl3 ,400MHz)：δ 1.06(m,3H),1.47(m,10H),1.79(m,1H),1,94(m,1H),2.17-2.24(m,2H),3.23(dd,2H),3.80-3.91(兩個單峰，3H),5.72(s,1H),7.17-7.29(m,3H)。 1 H NMR (CDCl 3 , 400MHz): δ 1.06 (m, 3H), 1.47 (m, 10H), 1.79 (m, 1H), 1,94 (m, 1H), 2.17-2.24 (m, 2H), 3.23 (dd, 2H), 3.80-3.91 (two singlets, 3H), 5.72 (s, 1H), 7.17-7.29 (m, 3H).

LCMS(ESI)：[M+H]+ m/z：計算值504.2；實測值505.4；Rt=3.312min。LCMS (ESI): [M+H] + m/z: calculated 504.2; found 505.4; Rt=3.312 min.

步驟3：N-[5-[[2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P1)及N-[5-[[2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(P2)之合成Step 3: N-[5-[[2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (P1) and N-[5-[[2-[(2S,5R)-2-(3-chloro) -4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester ( Synthesis of P2)

對N-[5-[[2-[2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(385.7mg，763.79μmol)進行掌性分離(管柱：Chiralpak IC(250* 20mm，5mkm)；以己烷-IPA-MeOH，70-15-15為流動相；流速：14mL/min；管柱溫度：20℃；波長：205nm)，得到rel-N-[5-[[2-[(2R,5S)-2-(3- 氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(106.44mg，27.60%產率；P1 )及rel-N-[5-[[2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(131.29mg，34.04%產率；P2 )。p-N-[5-[[2-[2-(3-Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]- Chiral separation (column: Chiralpak IC (250 * 20mm, 5mkm); hexane-IPA-MeOH, 70 -15-15 is the mobile phase; flow rate: 14mL/min; column temperature: 20°C; wavelength: 205nm) to obtain rel-N-[5-[[2-[(2R,5S)-2-(3- Chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (106.44 mg, 27.60% yield; P1 ) and rel-N-[5-[[2-[(2S,5R)-2-(3-chloro-4-fluorophenyl)-5-methyl-1 -Piperidinyl]-2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (131.29 mg, 34.04% yield; P2 ).

P2： LCMS(ESI)：[M+H]+ m/z：計算值504.9；實測值505.2；Rt=6.158min。 P2: LCMS (ESI): [M+H] + m/z: calculated 504.9; found 505.2; Rt=6.158 min.

RT(IA-3，己烷-IPA-MeOH，70-15-15，14ml/min)=29.07minRT(IA-3, Hexane-IPA-MeOH, 70-15-15, 14ml/min)=29.07min

P1： LCMS(ESI)：[M-BOC]+ m/z：計算值504.9；實測值449.2；Rt=6.163min。 P1: LCMS (ESI): [M-BOC] + m/z: calculated 504.9; found 449.2; Rt=6.163 min.

RT(IA-3，己烷-IPA-MeOH，70-15-15，14ml/min)=25.61minRT(IA-3, Hexane-IPA-MeOH, 70-15-15, 14ml/min)=25.61min

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物606 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 606 )

在21℃下，向N-[5-[[2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(106.44mg，210.78μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(38.43mg，1.05mmol，48.03μL)。使所得混合物攪拌2h。將所得混合物蒸發至乾且使其經歷HPLC(40-100% 2-7min水-MeOH-NH3 ；流速：30mL/min；(裝載泵4mL/min，MeOH+NH3 )；管柱：ymc-actus triat 100* 19mm 5um(L))。獲得呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(43.6mg，107.69μmol，51.09%產率)。At 21 °C, to N-[5-[[2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (106.44 mg, 210.78 μmol) in dioxane (2 mL) was added to dioxane 4.0 M hydrogen chloride solution (38.43 mg, 1.05 mmol, 48.03 μL) in the solution. The resulting mixture was stirred for 2 h. The resulting mixture was evaporated to dryness and subjected to HPLC (40-100% 2-7 min water-MeOH- NH3 ; flow rate: 30 mL/min; (load pump 4 mL/min, MeOH+ NH3 ); column: ymc- actus triat 100 * 19mm 5um(L)). N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(3-chloro-4-fluorophenyl)-5-methyl was obtained as a white solid yl-1-piperidinyl]-2-oxoacetamide (43.6 mg, 107.69 μmol, 51.09% yield).

1 H NMR(600MHz,DMSO-d6)δ 0.97-1.01(m,3H),1.24-1.37(m,1H),1.59-1.68(m,1H),1.81-1.93(m,1H),1.95-2.07(m,4H),2.12-2.24(m,1H),2.69-3.26(m,1H),3.42-4.03(m,1H),5.09-5.54(m,1H),5.58-5.66(m,2H),7.26-7.37(m,1H),7.39-7.46(m,2H),7.46-7.54(m,1H),7.92-8.04(m,1H),10.38-10.60(m,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.97-1.01(m,3H), 1.24-1.37(m,1H), 1.59-1.68(m,1H), 1.81-1.93(m,1H), 1.95-2.07 (m,4H), 2.12-2.24(m,1H), 2.69-3.26(m,1H), 3.42-4.03(m,1H), 5.09-5.54(m,1H), 5.58-5.66(m,2H) , 7.26-7.37(m, 1H), 7.39-7.46(m, 2H), 7.46-7.54(m, 1H), 7.92-8.04(m, 1H), 10.38-10.60(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值404.1；實測值405.2；Rt=2.663min。LCMS (ESI): [M+H] + m/z: calculated 404.1; found 405.2; Rt=2.663 min.

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3-chloro-4-fluorophenyl)-5-methyl- 1-piperidine 基]-2-側氧基乙醯胺(化合物596 )之合成Synthesis of yl]-2-oxoacetamide ( Compound 596 )

在21℃下，向N-[5-[[2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(131.29mg，259.99μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(47.40mg，1.30mmol，59.25μL)。使所得混合物攪拌2h。將所得混合物蒸發至乾且使其經歷HPLC(40-100% 2-7min水-MeOH-NH3 ；流速：30ml/min；(裝載泵4ml/min，MeOH+NH3 )；管柱：ymc-actus triat 100x19mm 5um(L))。獲得呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3-氯-4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(55.7mg，137.58μmol，52.92%產率)。At 21 °C, to N-[5-[[2-[(2S,5R)-2-(3-chloro-4-fluorophenyl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (131.29 mg, 259.99 μmol) in dioxane (2 mL) was added to dioxane 4.0 M hydrogen chloride solution (47.40 mg, 1.30 mmol, 59.25 μL) in the solution. The resulting mixture was stirred for 2 h. The resulting mixture was evaporated to dryness and subjected to HPLC (40-100% 2-7 min water-MeOH- NH3 ; flow rate: 30 ml/min; (load pump 4 ml/min, MeOH+ NH3 ); column: ymc- actus triat 100x19mm 5um(L)). N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3-chloro-4-fluorophenyl)-5-methyl was obtained as a white solid yl-1-piperidinyl]-2-oxoacetamide (55.7 mg, 137.58 μmol, 52.92% yield).

1 H NMR(600MHz,DMSO-d6)δ 0.96-1.02(m,3H),1.24-1.38(m,1H),1.56-1.71(m,1H),1.81-1.92(m,1H),1.96-2.10(m,4H),2.11-2.25(m,1H),2.68-3.24(m,1H),3.41-4.04(m,1H),5.08-5.54(m,1H),5.55-5.69(m,2H),7.27-7.37(m,1H),7.39-7.46(m,2H),7.46-7.53(m,1H),7.93-8.04(m,1H),10.45-10.65(m,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.96-1.02(m,3H), 1.24-1.38(m,1H), 1.56-1.71(m,1H), 1.81-1.92(m,1H), 1.96-2.10 (m,4H), 2.11-2.25(m,1H), 2.68-3.24(m,1H), 3.41-4.04(m,1H), 5.08-5.54(m,1H), 5.55-5.69(m,2H) ,7.27-7.37(m,1H),7.39-7.46(m,2H),7.46-7.53(m,1H),7.93-8.04(m,1H),10.45-10.65(m,1H).

LCMS(ESI)：[M+H]+ m/z：計算值404.1；實測值405.2；Rt=2.654min。LCMS (ESI): [M+H] + m/z: calculated 404.1; found 405.2; Rt=2.654 min.

實例708. 2-胺基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(化合物126)之合成Example 708. 2-Amino-5-[[2-oxy-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (Compound 126) synthesis

Figure 110128222-A0202-12-2286-575
Figure 110128222-A0202-12-2286-575

步驟1：2-氯-5-硝基吡啶-3-羰基氯之合成Step 1: Synthesis of 2-chloro-5-nitropyridine-3-carbonyl chloride

將2-氯-5-硝基吡啶-3-甲酸(5.00g，24.69mmol)與亞硫醯氯(29.37g，246.85mmol)混合。添加3滴DMF且在劇烈攪拌之情況下將所得混合物在90℃下加熱12h。在真空中移除過量亞硫醯氯，以獲得2-氯-5-硝基吡啶-3-羰基氯(5g，22.62mmol，91.65%產率)，其不經純化即用於下一步驟中。2-Chloro-5-nitropyridine-3-carboxylic acid (5.00 g, 24.69 mmol) was combined with thionine chloride (29.37 g, 246.85 mmol). 3 drops of DMF were added and the resulting mixture was heated at 90 °C for 12 h with vigorous stirring. The excess thionium chloride was removed in vacuo to give 2-chloro-5-nitropyridine-3-carbonyl chloride (5 g, 22.62 mmol, 91.65% yield) which was used in the next step without purification .

1 H NMR(400MHz,CDCl3 )δ 9.09(s,1H),9.38(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (s, 1H), 9.38 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值219.9；實測值221.0；Rt=0.431min。LCMS (ESI): [M+H] + m/z: calculated 219.9; found 221.0; Rt=0.431 min.

步驟2：2-胺基-5-硝基吡啶-3-甲醯胺之合成Step 2: Synthesis of 2-amino-5-nitropyridine-3-carboxamide

將2-氯-5-硝基吡啶-3-羰基氯(5g，22.62mmol)溶解於THF(100mL)中。使氨(385.31mg，22.62mmol)穿過溶液達10分鐘且將所得混合物在20℃下攪拌12h。等分試樣之LCMS顯示63%所要產物。將反應混合物蒸發至乾。添加50ml飽和氨水溶液。將所得混合物在20℃下再攪拌12h。過濾所獲得之沉澱，將其用水洗滌且乾燥，以獲得2-胺基-5-硝基吡啶-3-甲醯胺(2.25g，粗品)，其不經純化即用於下一步驟中。2-Chloro-5-nitropyridine-3-carbonyl chloride (5 g, 22.62 mmol) was dissolved in THF (100 mL). Ammonia (385.31 mg, 22.62 mmol) was passed through the solution for 10 min and the resulting mixture was stirred at 20 °C for 12 h. LCMS of an aliquot showed 63% of the desired product. The reaction mixture was evaporated to dryness. 50 ml of saturated aqueous ammonia solution were added. The resulting mixture was stirred at 20 °C for an additional 12 h. The obtained precipitate was filtered, washed with water and dried to obtain 2-amino-5-nitropyridine-3-carboxamide (2.25 g, crude), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 7.64(m,2H),8.39(m,2H),8.79(s,1H),8.96(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.64 (m, 2H), 8.39 (m, 2H), 8.79 (s, 1H), 8.96 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值182.0；實測值183.0；Rt=0.643min。LCMS (ESI): [M+H] + m/z: calculated 182.0; found 183.0; Rt=0.643 min.

步驟3：2,5-二胺基吡啶-3-甲醯胺之合成Step 3: Synthesis of 2,5-diaminopyridine-3-carboxamide

使用Noblyst P8078 2%V 1% Pt/碳(54.90μmol)作為催化劑在1atm壓力下將2-胺基-5-硝基吡啶-3-甲醯胺(1g，5.49mmol)於AcOH(3mL)中之溶液氫化12h。過濾所得混合物且蒸發濾液，以獲得呈乙酸酯形式之乙酸過量的粗產物(1.5g)。將0.4g此材料再溶解於6N HCl中且蒸發至乾，以獲得2,5-二胺基吡啶-3-甲醯胺(0.3g，1.33mmol，24.28%產率，2HCl)，其不經純化即用於下一步驟中。2-Amino-5-nitropyridine-3-carboxamide (1 g, 5.49 mmol) in AcOH (3 mL) at 1 atm pressure using Noblyst P8078 2% V 1% Pt/carbon (54.90 μmol) as catalyst The solution was hydrogenated for 12h. The resulting mixture was filtered and the filtrate was evaporated to obtain the crude product in excess of acetic acid as acetate (1.5 g). 0.4 g of this material was redissolved in 6N HCl and evaporated to dryness to give 2,5-diaminopyridine-3-carboxamide (0.3 g, 1.33 mmol, 24.28% yield, 2HCl) which was not treated with Purification was used in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值152.1；實測值153.2；Rt=0.169min。LCMS (ESI): [M+H] + m/z: calculated 152.1; found 153.2; Rt=0.169 min.

步驟4：2-胺基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺Step 4: 2-Amino-5-[[2-oxo-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (EN-TG-3082)之合成Synthesis of (EN-TG-3082)

將[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]氧基鋰(318.82mg，1.33mmol)與HATU(557.48mg，1.47mmol)及三乙胺(337.19mg，3.33mmol，464.44μL)混合於DMF(5mL)中。將所得混合物在20℃下攪拌10min，隨後添加2,5-二胺基吡啶-3-甲醯胺(0.3g，1.33mmol，2HCl)。將所得混合物在20℃下攪拌12h。使所獲得之溶液經歷HPLC(16_水-MeOH+NH3 ；以20-55%水-MeOH+NH3 為流動相；Waters SunFire C18 19* 100 5mkm管柱，流速12ml/min)，以獲得2-胺基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(0.0579g，157.59μmol，11.82%產率)。Lithium [2-oxy-2-(2-phenyl-1-piperidinyl)acetoxy]oxide (318.82 mg, 1.33 mmol) was combined with HATU (557.48 mg, 1.47 mmol) and triethylamine ( 337.19 mg, 3.33 mmol, 464.44 μL) were mixed in DMF (5 mL). The resulting mixture was stirred at 20 °C for 10 min, followed by the addition of 2,5-diaminopyridine-3-carboxamide (0.3 g, 1.33 mmol, 2HCl). The resulting mixture was stirred at 20 °C for 12 h. The obtained solution was subjected to HPLC (16-water-MeOH+ NH3 ; 20-55% water-MeOH+ NH3 as mobile phase; Waters SunFire C18 19 * 100 5mkm column, flow rate 12ml/min) to obtain 2-Amino-5-[[2-oxo-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (0.0579 g, 157.59 μmol, 11.82% yield).

1 H NMR(400MHz,DMSO-d 6 )δ 1.52(m,4H),1.90(m,1H),2.99(m,1H),3.40(m,1H),3.75(m,1H),5.46(m,1H),7.02(m,2H),7.31(m,3H),7.40(m,3H),7.99(m,1H),8.09(m,1H),8.18(m,1H),10.68(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ 1.52(m, 4H), 1.90(m, 1H), 2.99(m, 1H), 3.40(m, 1H), 3.75(m, 1H), 5.46(m ,1H),7.02(m,2H),7.31(m,3H),7.40(m,3H),7.99(m,1H),8.09(m,1H),8.18(m,1H),10.68(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.2；Rt=2.596min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.2; Rt=2.596 min.

實例709.N -(4-胺基-5-甲基吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物184)之合成Example 709. Of N- (4-amino-5-methylpyridin-3-yl)-2-oxy-2-(2-phenylpiperidin-1-yl)acetamide (Compound 184) synthesis

Figure 110128222-A0202-12-2288-576
Figure 110128222-A0202-12-2288-576

步驟1：5-甲基吡啶-3,4-二胺之合成Step 1: Synthesis of 5-methylpyridine-3,4-diamine

將3-甲基-5-硝基吡啶-4-胺(0.5g，3.27mmol)、Fe粉(0.72g，12.89mmol，91.60μL)及5ml HCl混合於乙醇(25mL)中且將其回流2h。將乙醇蒸餾。將所得懸浮液用水稀釋且藉由添加2N NaOH將pH調節至13。用乙酸乙酯萃取，用無水硫酸鈉乾燥經合併之有機相且蒸發溶劑，得到5-甲基吡啶-3,4-二胺(90mg，粗品)。3-Methyl-5-nitropyridin-4-amine (0.5 g, 3.27 mmol), Fe powder (0.72 g, 12.89 mmol, 91.60 μL) and 5 ml HCl were mixed in ethanol (25 mL) and refluxed for 2 h . Distill the ethanol. The resulting suspension was diluted with water and the pH was adjusted to 13 by adding 2N NaOH. It was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and the solvent was evaporated to give 5-picoline-3,4-diamine (90 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值123.3；實測值124.2；Rt=0.225min。LCMS (ESI): [M] + m/z: calculated 123.3; found 124.2; Rt=0.225min.

步驟2：N-(4-胺基-5-甲基吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺之合成Step 2: Synthesis of N-(4-amino-5-methylpyridin-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide

將5-甲基吡啶-3,4-二胺(90mg，365.39μmol)、2-側氧基-2-(2-苯基-1-哌啶基)乙酸(45.00mg，192.92μmol)、HATU(138.93mg，365.39μmol)及TEA(36.97mg，365.39μmol，50.93μL)混合於DMSO(1mL)中。使未分離所需化合物之於DMSO中之溶液經歷HPLC(管柱：SUNFIRE C18 100*19mm，5微米且以MeCN+FA為流動相)，以得到純的N -(4-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(15.2mg，44.92μmol，12.29%產率)。5-Methylpyridine-3,4-diamine (90 mg, 365.39 μmol), 2-oxo-2-(2-phenyl-1-piperidinyl)acetic acid (45.00 mg, 192.92 μmol), HATU (138.93 mg, 365.39 μmol) and TEA (36.97 mg, 365.39 μmol, 50.93 μL) were mixed in DMSO (1 mL). A solution in DMSO that did not isolate the desired compound was subjected to HPLC (column: SUNFIRE C18 100*19 mm, 5 microns with MeCN+FA as mobile phase) to give pure N- (4-amino-5- Methyl-3-pyridyl)-2-oxy-2-(2-phenyl-1-piperidinyl)acetamide (15.2 mg, 44.92 μmol, 12.29% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.66(m,5H),2.02(m,1H),2.14(m,3H),2.42(m,1H),2.90(m,1H),4.16(m,1H),5.64(m,1H),6.35(m,2H),7.35(m,4H),7.78(m,1H),8.39(m,1H),8.58(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.66(m, 5H), 2.02(m, 1H), 2.14(m, 3H), 2.42(m, 1H), 2.90(m, 1H), 4.16( m, 1H), 5.64 (m, 1H), 6.35 (m, 2H), 7.35 (m, 4H), 7.78 (m, 1H), 8.39 (m, 1H), 8.58 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值338.4；實測值339.2；Rt=2.527min。LCMS (ESI): [M] + m/z: calculated 338.4; found 339.2; Rt=2.527 min.

N-(2-胺基-5-甲基吡啶-3-基)-2-側氧基-2-(2-苯基哌啶-1-基)乙醯胺(化合物160 )之合成Synthesis of N-(2-amino-5-methylpyridin-3-yl)-2-oxo-2-(2-phenylpiperidin-1-yl)acetamide ( Compound 160 )

將TEA(1.23g，12.18mmol，1.70mL)添加到5-甲基吡啶-2,3-二胺(150mg，1.22mmol)、2-側氧基-2-(2-苯基-1-哌啶基)乙酸(284.11mg，1.22mmol)及HATU(509.42mg，1.34mmol)於DMF(5mL)中之經攪拌之混合物中。將反應混合物在25℃下攪拌2h，然後藉由反相HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)使用0-5min 30-75%水-甲醇(NH3 0.1%)直接純化，以得到呈棕色固體之N -(2-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-苯基-1-哌啶基)乙醯胺(156mg，460.99μmol，37.85%產率)。TEA (1.23 g, 12.18 mmol, 1.70 mL) was added to 5-methylpyridine-2,3-diamine (150 mg, 1.22 mmol), 2-Pendoxo-2-(2-phenyl-1-piperidine) In a stirred mixture of pyridyl)acetic acid (284.11 mg, 1.22 mmol) and HATU (509.42 mg, 1.34 mmol) in DMF (5 mL). The reaction mixture was stirred at 25°C for 2h, then by reverse phase HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um) using 0-5min 30-75% water-methanol ( NH3 0.1%) Purified directly to give N- (2-amino-5-methyl-3-pyridyl)-2-oxy-2-(2-phenyl-1-piperidinyl)acetone as a brown solid Amine (156 mg, 460.99 μmol, 37.85% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.53(m,4H),1.89(m,1H),2.11(m,3H),3.00(m,1H),3.99(m,1H),5.58(m,3H),7.36(m,6H),7.62(m,2H),10.10(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.53(m, 4H), 1.89(m, 1H), 2.11(m, 3H), 3.00(m, 1H), 3.99(m, 1H), 5.58 (m, 3H), 7.36 (m, 6H), 7.62 (m, 2H), 10.10 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值338.4；實測值339.2；Rt=2.530min。LCMS (ESI): [M] + m/z: calculated 338.4; found 339.2; Rt=2.530 min.

實例710. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物410)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物419)之合成Example 710. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl -1-Piperidinyl]-2-oxyacetamide (Compound 410) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2 Synthesis of -[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 419)

Figure 110128222-A0202-12-2290-577
Figure 110128222-A0202-12-2290-577

步驟1：N-[5-[[2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of tert-butyl]-3-methyl-2-pyridyl]carbamate

在21℃下，將[2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]氧基鈉(0.45g，1.41mmol)、TATU(544.72mg，1.69mmol)(如上文所製備)及三乙胺(142.62mg，1.41mmol，196.45μL)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(314.68mg，1.41mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-75% 2-7min；水-乙腈30ml/min；裝載泵：乙腈4ml/min；管柱SunFire 19* 100mm)。獲得呈淺黃色膠狀物之N-[5-[[2-[2-[4-(二氟甲基)苯基]-5- 甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.44g，875.53μmol，62.12%產率)。At 21 °C, sodium [2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]oxylate ( 0.45 g, 1.41 mmol), TATU (544.72 mg, 1.69 mmol) (prepared as above) and triethylamine (142.62 mg, 1.41 mmol, 196.45 μL) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added tert-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (314.68 mg, 1.41 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-75% 2-7 min; water-acetonitrile 30 ml/min; loading pump: acetonitrile 4 ml/min; column SunFire 19 * 100 mm). N-[5-[[2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-pendoxyl was obtained as a pale yellow gum Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.44 g, 875.53 μmol, 62.12% yield).

1 H NMR(400MHz,CDCl3 )δ 1.07(d,3H),1.48(s,9H),1.97(m,4H),2.28(m,5H),3.20(m,1H),4.80(m,1H),5.77(m,2H),7.36(m,2H),7.50(m,2H),8.02(s,1H),8.32(m,1H),9.33(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.07(d,3H), 1.48(s,9H), 1.97(m,4H), 2.28(m,5H), 3.20(m,1H), 4.80(m,1H) ), 5.77(m, 2H), 7.36(m, 2H), 7.50(m, 2H), 8.02(s, 1H), 8.32(m, 1H), 9.33(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值502.2；實測值503.2；Rt=1.341min。LCMS (ESI): [M+H] + m/z: calculated 502.2; found 503.2; Rt=1.341 min.

步驟2：N-[5-[[2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2S,5R)-2-[4-(difluoro Synthesis of Methyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

掌性拆分IC_II(250* 20，5mkm)，己烷-IPA-MeOH，60-20-20，12ml/minChiral resolution IC_II (250 * 20, 5mkm), Hexane-IPA-MeOH, 60-20-20, 12ml/min

異構物1 N-[5-[[2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(83.83mg，166.81μmol，20.55%產率)之RT為18.493(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)。 Isomer 1 N-[5-[[2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-side RT of 18.493 (IC, hexane-IPA- MeOH, 50-25-25, 0.6 ml/min).

異構物2 N-[5-[[2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(83.83mg，166.81μmol，20.55%產率)之RT為14.346min(IC，己烷-IPA-MeOH，50-25-25，0.6ml/min)。 Isomer 2 N-[5-[[2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-side RT of 14.346 min (IC, hexane-IPA) for tert-butyl oxyacetoxy]amino]-3-methyl-2-pyridyl]carbamate (83.83 mg, 166.81 μmol, 20.55% yield) -MeOH, 50-25-25, 0.6 ml/min).

異構物1：Isomer 1:

LCMS(ESI)：[M+H]+ m/z：計算值502.2；實測值503.2；Rt=5.806min。LCMS (ESI): [M+H] + m/z: calculated 502.2; found 503.2; Rt=5.806 min.

異構物2：Isomer 2:

LCMS(ESI)：[M+H]+ m/z：計算值502.2；實測值503.2；Rt=5.806min。LCMS (ESI): [M+H] + m/z: calculated 502.2; found 503.2; Rt=5.806 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物419 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl Synthesis of -1-piperidinyl]-2-oxoacetamide ( compound 419 )

在21℃下，向N-[5-[[2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶 基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(83.83mg，166.81μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(30.41mg，834.04μmol，38.01μL)。使所得混合物攪拌8h。將所得混合物蒸發至乾且使其經歷HPLC(C18，H2 O-MeCN，34-50% MeCN，30ml/min)。獲得呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(24.32mg，60.43μmol，36.23%產率)。To N-[5-[[2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2 at 21 °C - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (83.83 mg, 166.81 μmol) in dioxane (2 mL) was added to dioxane 4.0 M hydrogen chloride solution in alkane (30.41 mg, 834.04 μmol, 38.01 μL). The resulting mixture was stirred for 8 h. The resulting mixture was evaporated to dryness and subjected to HPLC (C18, H2O -MeCN, 34-50% MeCN, 30 ml/min). N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5- was obtained as a white solid Methyl-1-piperidinyl]-2-oxoacetamide (24.32 mg, 60.43 μmol, 36.23% yield).

1 H NMR(500MHz,DMSO-d 6 )δ 0.99-1.05(m,3H),1.27-1.44(m,1H),1.57-1.70(m,1H),1.81-1.93(m,1H),1.97-2.10(m,4H),2.17-2.28(m,1H),2.71-3.17(m,1H),3.49-4.14(m,1H),5.22-5.67(m,3H),6.92-7.17(m,1H),7.44-7.54(m,3H),7.57-7.66(m,2H),7.94-8.11(m,1H),10.45-10.65(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 0.99-1.05(m,3H), 1.27-1.44(m,1H), 1.57-1.70(m,1H), 1.81-1.93(m,1H), 1.97- 2.10(m, 4H), 2.17-2.28(m, 1H), 2.71-3.17(m, 1H), 3.49-4.14(m, 1H), 5.22-5.67(m, 3H), 6.92-7.17(m, 1H) ), 7.44-7.54(m, 3H), 7.57-7.66(m, 2H), 7.94-8.11(m, 1H), 10.45-10.65(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值403.0；Rt=2.740min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 403.0; Rt=2.740 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物410 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-[4-(difluoromethyl)phenyl]-5-methyl Synthesis of -1-piperidinyl]-2-oxoacetamide ( compound 410 )

在21℃下，向N-[5-[[2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(87.01mg，173.14μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(31.56mg，865.68μmol，39.45μL)。使所得混合物攪拌8h。將所得混合物蒸發至乾且使其經歷HPLC(50-100% 0.5-6min；水-MeOH+NH3 30ml/min；裝載泵MeOH+NH3 4ml/min；管柱xbridge 20* 100mm；然後C18，H2 O-MeCN，34-50% MeCN，30ml/min)。獲得呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(33.34mg，82.85μmol，47.85%產率)。At 21 °C, to N-[5-[[2-[(2S,5R)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (87.01 mg, 173.14 μmol) in dioxane (2 mL) was added to dioxane 4.0 M hydrogen chloride solution in alkane (31.56 mg, 865.68 μmol, 39.45 μL). The resulting mixture was stirred for 8 h. The resulting mixture was evaporated to dryness and subjected to HPLC (50-100% 0.5-6 min; water-MeOH+ NH3 30ml/min; loading pump MeOH+ NH3 4ml/min; column xbridge 20 * 100mm; then C18, H2O -MeCN, 34-50% MeCN, 30 ml/min). N-(6-amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-2-[4-(difluoromethyl)phenyl]-5- was obtained as a white solid Methyl-1-piperidinyl]-2-oxoacetamide (33.34 mg, 82.85 μmol, 47.85% yield).

1 H NMR(500MHz,DMSO-d 6 )δ 1.00-1.11(m,3H),1.30-1.41(m,1H),1.57-1.76(m,1H),1.83-1.95(m,1H),1.97-2.12(m,4H),2.13-2.30(m,1H),2.72-3.23(m, 1H),3.48-4.14(m,1H),5.20-5.67(m,3H),6.88-7.15(m,1H),7.42-7.53(m,3H),7.56-7.66(m,2H),7.85-8.12(m,1H),10.47-10.65(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ 1.00-1.11(m,3H), 1.30-1.41(m,1H), 1.57-1.76(m,1H), 1.83-1.95(m,1H), 1.97- 2.12(m, 4H), 2.13-2.30(m, 1H), 2.72-3.23(m, 1H), 3.48-4.14(m, 1H), 5.20-5.67(m, 3H), 6.88-7.15(m, 1H) ), 7.42-7.53(m, 3H), 7.56-7.66(m, 2H), 7.85-8.12(m, 1H), 10.47-10.65(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值402.2；實測值403.0；Rt=2.753min。LCMS (ESI): [M+H] + m/z: calculated 402.2; found 403.0; Rt=2.753 min.

實例711. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物283)之合成及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物284)之合成Example 711. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidine Synthesis of N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3 Synthesis of -chlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (compound 284)

Figure 110128222-A0202-12-2293-578
Figure 110128222-A0202-12-2293-578

步驟1：2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯之合成Step 1: Synthesis of methyl 2-[2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetate

在0℃下，向2-(3-氯苯基)-5-甲基哌啶(0.5g，2.38mmol)及三乙胺(265.38mg，2.62mmol，365.54μL)於DCM(25mL)中之溶液中添加2-氯-2-側氧基乙酸甲酯(292.08mg，2.38mmol)。在室溫下攪拌1h之後，將所得混合物過濾且蒸發至乾，以得到呈黃色固體之2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.9g，粗品)，其不經進一步純化即用於下一步驟中。To 2-(3-chlorophenyl)-5-methylpiperidine (0.5 g, 2.38 mmol) and triethylamine (265.38 mg, 2.62 mmol, 365.54 μL) in DCM (25 mL) at 0 °C To the solution was added methyl 2-chloro-2-oxoacetate (292.08 mg, 2.38 mmol). After stirring at room temperature for 1 h, the resulting mixture was filtered and evaporated to dryness to give 2-[2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2- as a yellow solid Methyl oxyacetate (0.9 g, crude) was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ 0.789-1.07(m,3H),1.37(m,2H),1.56-2.00(m,2H),2.16(m,1H),2.84-3.08(m,1H),3.20(dd,1H),3.79-3.88(m,3H),4.83(s,0.5H),6.71(s,0.5H),7.24(m,4H) 1 H NMR (400MHz, CDCl 3 )δ 0.789-1.07(m,3H), 1.37(m,2H), 1.56-2.00(m,2H), 2.16(m,1H), 2.84-3.08(m,1H) ,3.20(dd,1H),3.79-3.88(m,3H),4.83(s,0.5H),6.71(s,0.5H),7.24(m,4H)

LCMS(ESI)：[M+H]+ m/z：計算值295.2；實測值296.2；Rt=1.443min。LCMS (ESI): [M+H] + m/z: calculated 295.2; found 296.2; Rt=1.443 min.

步驟2：N-[5-[[2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[2-(3-Chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3- Synthesis of tert-butyl methyl-2-pyridyl]carbamate

向2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.9g，3.04mmol)於MeOH(12.50mL)中之溶液中添加羥基鈉(121.71mg，3.04mmol，57.14μL)且將所得混合物攪拌1h。然後，蒸發溶劑且將殘餘物與EtOH一起再蒸發。此後，將固體溶解於DMF中且添加HATU(1.16g，3.04mmol)，隨後添加N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(679.41mg，3.04mmol)且將所得混合物攪拌12h。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-75% 2-7min；水-乙腈；30ml/min；裝載泵4ml/min；乙腈；管柱SunFire 19*100mm)。獲得兩種級分之N-[5-[[2-[2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(495.2mg，1.02mmol，33.42%產率)：131mg(藉由LCMS為80.66%，單一非鏡像異構物)及364.2mg(藉由LCMS為94.21%，約4：1非鏡像異構物之混合物)。To a solution of methyl 2-[2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetate (0.9 g, 3.04 mmol) in MeOH (12.50 mL) Sodium hydroxy (121.71 mg, 3.04 mmol, 57.14 μL) was added and the resulting mixture was stirred for 1 h. Then, the solvent was evaporated and the residue was re-evaporated with EtOH. After this time, the solid was dissolved in DMF and HATU (1.16 g, 3.04 mmol) was added followed by 3-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (679.41 mg, 3.04 mmol) mmol) and the resulting mixture was stirred for 12 h. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-75% 2-7 min; water-acetonitrile; 30 ml/min; loading pump 4 ml/min; acetonitrile; column SunFire 19*100 mm). Two fractions of N-[5-[[2-[2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (495.2 mg, 1.02 mmol, 33.42% yield): 131 mg (80.66% by LCMS, single diastereomer) and 364.2 mg ( 94.21% by LCMS, about 4:1 mixture of diastereoisomers).

1H NMR(400MHz,CDCl3 )δ 0.85-1.07(m,3H),1.36(m,1H),1.48(s,9H),1.85(m,1H),1.99(m,1H),2.15(m,1H),2.29(s,3H),2.96-3.33(m,1H),3.76(s,1H),4.24-4.80(m,1H),5.73-6.41(m,1H),6.80(m,1H),7.15-7.25(m,4H),8.03(s,1H),8.34-8.36(m,1H),9.41(m,1H)。1H NMR (400MHz, CDCl 3 )δ 0.85-1.07(m, 3H), 1.36(m, 1H), 1.48(s, 9H), 1.85(m, 1H), 1.99(m, 1H), 2.15(m, 1H), 2.29(s, 3H), 2.96-3.33(m, 1H), 3.76(s, 1H), 4.24-4.80(m, 1H), 5.73-6.41(m, 1H), 6.80(m, 1H) , 7.15-7.25(m, 4H), 8.03(s, 1H), 8.34-8.36(m, 1H), 9.41(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值486.2；實測值487.2；Rt=3.523min。LCMS (ESI): [M+H] + m/z: calculated 486.2; found 487.2; Rt=3.523 min.

步驟3：N-[5-[[2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯及N-[5-[[2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 3: N-[5-[[2-[(2S,5R)-2-(3-Chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester and N-[5-[[2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl Synthesis of tert-butyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid

在以下條件下分離外消旋物：管柱：IC-II(250*20，5mkm)，流動相：己烷-IPA-MeOH，60-20-20；流速：14ml/min。24℃，波長：205nm，215nmThe racemates were separated under the following conditions: Column: IC-II (250*20, 5mkm), Mobile phase: Hexane-IPA-MeOH, 60-20-20; Flow rate: 14ml/min. 24℃, wavelength: 205nm, 215nm

N-[5-[[2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺 基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(133.55mg，274.24μmol，36.67%產率)之RT=27.9min且N-[5-[[2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.14g，287.48μmol，38.44%產率)之RT=20.6minN-[5-[[2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amine tert-butyl]-3-methyl-2-pyridyl]carbamate (133.55 mg, 274.24 μmol, 36.67% yield) at RT=27.9 min and N-[5-[[2-[(2R, 5S)-2-(3-Chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid RT=20.6 min for tertiary butyl ester (0.14 g, 287.48 μmol, 38.44% yield)

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物283 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidine [Synthesis of]-2-oxoacetamide ( Compound 283 )

在21℃下，向N-[5-[[2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(133.55mg，274.24μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(49.99mg，1.37mmol，62.49μL)。使所得混合物攪拌1h。將所得混合物蒸發至乾且使其經歷HPLC(50-100% 2-7min水-乙腈；流速30ml/min(裝載泵4ml/min；MeOH+NH3 )；管柱YMC-actus triat 100x19mm 5um)。獲得呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(56.8mg，146.82μmol，53.54%產率)(呈兩種級分)。At 21 °C, to N-[5-[[2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (133.55 mg, 274.24 μmol) in dioxane (2 mL) was added 4.0 M in dioxane Hydrogen chloride solution (49.99 mg, 1.37 mmol, 62.49 [mu]L). The resulting mixture was stirred for 1 h. The resulting mixture was evaporated to dryness and subjected to HPLC (50-100% 2-7 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min; MeOH+ NH3 ); column YMC-actus triat 100x19mm 5um). N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(3-chlorophenyl)-5-methyl-1- was obtained as a white solid Piperidinyl]-2-oxoacetamide (56.8 mg, 146.82 μmol, 53.54% yield) (in two fractions).

1 H NMR(600MHz,DMSO-d 6 )δ 0.94-1.02(m,3H),1.25-1.38(m,1H),1.56-1.66(m,1H),1.81-1.91(m,1H),1.91-2.06(m,4H),2.14-2.24(m,1H),2.70-3.22(m,1H),3.33-4.05(m,1H),5.09-5.56(m,1H),5.57-5.64(m,2H),7.21-7.37(m,3H),7.37-7.42(m,1H),7.42-7.50(m,1H),7.93-8.04(m,1H),10.45-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.94-1.02(m,3H), 1.25-1.38(m,1H), 1.56-1.66(m,1H), 1.81-1.91(m,1H), 1.91- 2.06(m, 4H), 2.14-2.24(m, 1H), 2.70-3.22(m, 1H), 3.33-4.05(m, 1H), 5.09-5.56(m, 1H), 5.57-5.64(m, 2H ), 7.21-7.37(m, 3H), 7.37-7.42(m, 1H), 7.42-7.50(m, 1H), 7.93-8.04(m, 1H), 10.45-10.58(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值386.2；實測值387.2；Rt=2.528min。LCMS (ESI): [M+H]+ m/z: calculated 386.2; found 387.2; Rt=2.528 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物284 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1-piperidine Synthesis of [methyl]-2-oxoacetamide ( Compound 284 )

在21℃下，向N-[5-[[2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(140.00mg，287.48μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(52.41mg，1.44 mmol，65.51μL)。使所得混合物攪拌1h。將所得混合物蒸發至乾且使其經歷HPLC(40-65% 2-7min水-乙腈；流速30ml/min(裝載泵4ml/min；乙腈)；管柱SunFireC18 100x19mm 5um)。獲得呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(40.7mg，105.20μmol，36.59%產率)(呈兩種級分)。At 21 °C, to N-[5-[[2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (140.00 mg, 287.48 μmol) in dioxane (2 mL) was added 4.0 M in dioxane Hydrogen chloride solution (52.41 mg, 1.44 mmol, 65.51 μL). The resulting mixture was stirred for 1 h. The resulting mixture was evaporated to dryness and subjected to HPLC (40-65% 2-7 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min; acetonitrile); column SunFire C18 100x19mm 5um). N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3-chlorophenyl)-5-methyl-1- was obtained as a white solid Piperidinyl]-2-oxyacetamide (40.7 mg, 105.20 μmol, 36.59% yield) (in two fractions).

1 H NMR(600MHz,DMSO-d 6 )δ 0.95-1.04(m,3H),1.25-1.38(m,1H),1.56-1.66(m,1H),1.79-1.92(m,1H),1.94-2.11(m,4H),2.13-2.26(m,1H),2.70-3.22(m,1H),3.43-4.05(m,1H),5.11-5.56(m,1H),5.56-5.66(m,2H),7.18-7.42(m,4H),7.42-7.50(m,1H),7.91-8.04(m,1H),10.47-10.58(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.95-1.04(m,3H), 1.25-1.38(m,1H), 1.56-1.66(m,1H), 1.79-1.92(m,1H), 1.94- 2.11(m, 4H), 2.13-2.26(m, 1H), 2.70-3.22(m, 1H), 3.43-4.05(m, 1H), 5.11-5.56(m, 1H), 5.56-5.66(m, 2H ), 7.18-7.42(m, 4H), 7.42-7.50(m, 1H), 7.91-8.04(m, 1H), 10.47-10.58(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值386.2；實測值387.2；Rt=1.615min。LCMS (ESI): [M+H] + m/z: calculated 386.2; found 387.2; Rt=1.615 min.

實例712. 5-[[2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物358)及5-[[2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物359)之合成Example 712. 5-[[2-[(2S,5R)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide (Compound 358) and 5-[[2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl- Synthesis of 1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 359)

Figure 110128222-A0202-12-2296-579
Figure 110128222-A0202-12-2296-579

步驟1：2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯之合成Step 1: Synthesis of methyl 2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetate

在0℃下，向2-[4-(二氟甲基)苯基]-5-甲基哌啶(0.63g，2.80mmol)及三乙胺(339.58mg，3.36mmol，467.74μL)於DCM(15mL)中之溶液中添加2-氯-2-側氧基乙酸甲酯(376.86mg，3.08mmol)。在室溫下攪拌1h之後，過濾所得混 合物且將其蒸發至乾，以得到呈黃色固體之2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.88g，粗品)，其不經進一步純化即用於下一步驟中。To 2-[4-(difluoromethyl)phenyl]-5-methylpiperidine (0.63 g, 2.80 mmol) and triethylamine (339.58 mg, 3.36 mmol, 467.74 μL) in DCM at 0 °C To the solution in (15 mL) was added methyl 2-chloro-2-oxoacetate (376.86 mg, 3.08 mmol). After stirring for 1 h at room temperature, the resulting mixture was filtered compound and evaporated to dryness to give 2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-pendoxyl as a yellow solid Methyl acetate (0.88 g, crude) was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ 1.08(d,3H),1.44(m,2H),1.80(m,2H),2.17(m,2H),3.20(m,1H),3.89(s,3H),5.78(m,2H),7.34(m,2H),7.51(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ 1.08(d,3H), 1.44(m,2H), 1.80(m,2H), 2.17(m,2H), 3.20(m,1H), 3.89(s,3H) ), 5.78 (m, 2H), 7.34 (m, 2H), 7.51 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值311.2；實測值312.0；Rt=1.426min。LCMS (ESI): [M+H] + m/z: calculated 311.2; found 312.0; Rt=1.426 min.

步驟2：[2-[2[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]氧基鈉之合成Step 2: Synthesis of sodium [2-[2[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]oxysodium

向2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.88g，2.83mmol)於MeOH(10mL)中之溶液中添加氫氧化鈉(124.36mg，3.11mmol，58.39μL)且使所得混合物在室溫下攪拌1h。然後將所得混合物蒸發至乾，以得到[2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]氧基鈉(0.9g，2.82mmol，99.72%產率)，其呈鈉鹽用於下一步驟中。To methyl 2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetate (0.88 g, 2.83 mmol) in MeOH (10 mL) ) was added sodium hydroxide (124.36 mg, 3.11 mmol, 58.39 μL) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then evaporated to dryness to give [2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl] Sodium oxide (0.9 g, 2.82 mmol, 99.72% yield) was used as the sodium salt in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值297.1；實測值298.2；Rt=1.537min。LCMS (ESI): [M+H] + m/z: calculated 297.1; found 298.2; Rt=1.537 min.

步驟3：5-[[2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 3: 5-[[2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -Synthesis of 3-formamide

在21℃下，將[2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]氧基鈉(0.45g，1.41mmol)、TATU(544.72mg，1.69mmol)及三乙胺(142.62mg，1.41mmol，196.45μL)混合於無水DMF(5mL)中且將所得混合物攪拌1h。向其中添加5-胺基吡啶-3-甲醯胺(193.29mg，1.41mmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(30-65% 2-7min；水-MeOH(+NH3 )；30ml/min；裝載泵4ml/min；乙腈；管柱xbridge 19* 100mm)。獲得呈黃色膠狀物之5-[[2-[2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(156.2mg，375.10μmol，26.61%產率)。At 21 °C, sodium [2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]oxylate ( 0.45 g, 1.41 mmol), TATU (544.72 mg, 1.69 mmol) and triethylamine (142.62 mg, 1.41 mmol, 196.45 μL) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 1 h. To this was added 5-aminopyridine-3-carboxamide (193.29 mg, 1.41 mmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (30-65% 2-7 min; water-MeOH (+ NH3 ); 30 ml/min; loading pump 4 ml/min; acetonitrile; column xbridge 19 * 100 mm). 5-[[2-[2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl] was obtained as a yellow gum Amino]pyridine-3-carboxamide (156.2 mg, 375.10 μmol, 26.61% yield).

1 H NMR(400MHz,CDCl3 )δ 0.95(m,3H),1.39(m,1H),1.77(m,4H),2.20(m,2H),3.37(m,1H),4.30(m,1H),5.77(m,2H),7.37(m,2H),7.49(m,2H),8.60(m,1H),8.81(s,1H),9.01(m,1H),9.87(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.95(m,3H), 1.39(m,1H), 1.77(m,4H), 2.20(m,2H), 3.37(m,1H), 4.30(m,1H) ), 5.77(m, 2H), 7.37(m, 2H), 7.49(m, 2H), 8.60(m, 1H), 8.81(s, 1H), 9.01(m, 1H), 9.87(s, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值416.2；實測值417.2；Rt=1.136min。LCMS (ESI): [M+H] + m/z: calculated 416.2; found 417.2; Rt=1.136 min.

步驟4：5-[[2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物358 )及5-[[2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物359 )之合成Step 4: 5-[[2-[(2S,5R)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide ( compound 358 ) and 5-[[2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl- Synthesis of 1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide ( compound 359 )

掌性拆分：IA(250*20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/minPalmar resolution: IA (250*20, 5mkm), hexane-IPA-MeOH, 50-25-25, 12ml/min

5-[[2-[(2S,5R)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(62.76mg，150.71μmol，40.18%產率)之RT 為24.9482min(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)5-[[2-[(2S,5R)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (62.76 mg, 150.71 μmol, 40.18% yield) RT of 24.9482 min (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)

5-[[2-[(2R,5S)-2-[4-(二氟甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(65.89mg，158.23μmol，42.18%產率)之RT 為33.4822min(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)5-[[2-[(2R,5S)-2-[4-(difluoromethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (65.89 mg, 158.23 μmol, 42.18% yield) RT of 33.4822 min (IA, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)

化合物358： 1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.04(m,3H),1.28-1.38(m,1H),1.60-1.68(m,1H),1.82-1.95(m,1H),2.05-2.18(m,1H),2.19-2.30(m,1H),2.75-3.24(m,1H),3.38-4.11(m,1H),5.19-5.67(m,1H),6.90-7.12(m,1H),7.43-7.51(m,2H),7.55-7.65(m,3H),8.09-8.20(m,1H),8.41-8.52(m,1H),8.71-8.80(m,1H),8.81-8.93(m,1H),11.13-11.39(m,1H)。 Compound 358: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.04 (m, 3H), 1.28-1.38 (m, 1H), 1.60-1.68 (m, 1H), 1.82-1.95 (m, 1H) ,2.05-2.18(m,1H),2.19-2.30(m,1H),2.75-3.24(m,1H),3.38-4.11(m,1H),5.19-5.67(m,1H),6.90-7.12( m,1H),7.43-7.51(m,2H),7.55-7.65(m,3H),8.09-8.20(m,1H),8.41-8.52(m,1H),8.71-8.80(m,1H), 8.81-8.93 (m, 1H), 11.13-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值416.2；實測值417.2；Rt=3.134min。LCMS (ESI): [M+H] + m/z: calculated 416.2; found 417.2; Rt=3.134 min.

化合物359： 1 H NMR(600MHz,DMSO-d 6 )δ 1.00-1.04(m,3H),1.28-1.38(m,1H),1.60-1.68(m,1H),1.82-1.95(m,1H),2.05-2.18(m,1H),2.19-2.30(m,1H),2.75-3.24(m,1H),3.38-4.11(m,1H),5.19-5.67(m,1H),6.90-7.12(m,1H),7.43-7.51(m,2H),7.55-7.65(m,3H),8.09-8.20(m,1H),8.41-8.52(m,1H),8.71-8.80 (m,1H),8.81-8.93(m,1H),11.13-11.39(m,1H)。 Compound 359: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.00-1.04 (m, 3H), 1.28-1.38 (m, 1H), 1.60-1.68 (m, 1H), 1.82-1.95 (m, 1H) ,2.05-2.18(m,1H),2.19-2.30(m,1H),2.75-3.24(m,1H),3.38-4.11(m,1H),5.19-5.67(m,1H),6.90-7.12( m,1H),7.43-7.51(m,2H),7.55-7.65(m,3H),8.09-8.20(m,1H),8.41-8.52(m,1H),8.71-8.80(m,1H), 8.81-8.93 (m, 1H), 11.13-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值416.2；實測值417.2；Rt=3.135min。LCMS (ESI): [M+H] + m/z: calculated 416.2; found 417.2; Rt=3.135 min.

實例713. 4-胺基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(化合物119)之合成Example 713. 4-Amino-5-[[2-oxo-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide (Compound 119) synthesis

Figure 110128222-A0202-12-2299-580
Figure 110128222-A0202-12-2299-580

步驟1：4-羥基-5-硝基吡啶-3-甲酸之合成Step 1: Synthesis of 4-hydroxy-5-nitropyridine-3-carboxylic acid

在0℃下，將硝酸(18.36g，291.37mmol，12mL)逐滴添加到4-羥基吡啶-3-甲酸(6g，43.13mmol)於硫酸(50mL)中之經攪拌之溶液中。將所得混合物在100℃下攪拌24小時。24小時之後，使反應混合物冷卻且倒入到碎冰(500g)中。過濾所沉澱之固體，將其用水(5 x 20mL)洗滌且在真空中乾燥，以獲得呈白色固體之4-羥基-5-硝基吡啶-3-甲酸(4.90g，26.62mmol，61.71%產率)。粗產物直接用於下一步驟。Nitric acid (18.36 g, 291.37 mmol, 12 mL) was added dropwise to a stirred solution of 4-hydroxypyridine-3-carboxylic acid (6 g, 43.13 mmol) in sulfuric acid (50 mL) at 0 °C. The resulting mixture was stirred at 100°C for 24 hours. After 24 hours, the reaction mixture was cooled and poured into crushed ice (500 g). The precipitated solid was filtered, washed with water (5 x 20 mL) and dried in vacuo to give 4-hydroxy-5-nitropyridine-3-carboxylic acid (4.90 g, 26.62 mmol, 61.71% yield) as a white solid Rate). The crude product was used directly in the next step.

LCMS(ESI)：[M-H]- m/z：計算值184.0；實測值183.0；Rt=0.508min。LCMS (ESI): [MH] - m/z: calculated 184.0; found 183.0; Rt=0.508 min.

步驟2：4-氯-5-硝基吡啶-3-羰基氯之合成Step 2: Synthesis of 4-chloro-5-nitropyridine-3-carbonyl chloride

向4-羥基-5-硝基吡啶-3-甲酸(4.90g，26.62mmol)及二甲基甲醯胺(194.54mg，2.66mmol，206.08μL)於氯仿(100mL)中之經攪拌之懸浮液中添加亞硫醯氯(31.66g，266.15mmol)。將所得反應混合物在70℃下攪拌24小時。然後在減壓下濃縮所得溶液，以獲得呈淡黃色油狀物之粗產物4-氯-5-硝基吡啶-3-羰基氯(5.80g，26.24mmol，98.61%產率)，其直接用於下一步驟中。To a stirred suspension of 4-hydroxy-5-nitropyridine-3-carboxylic acid (4.90 g, 26.62 mmol) and dimethylformamide (194.54 mg, 2.66 mmol, 206.08 μL) in chloroform (100 mL) To this was added thionium chloride (31.66 g, 266.15 mmol). The resulting reaction mixture was stirred at 70°C for 24 hours. The resulting solution was then concentrated under reduced pressure to obtain crude 4-chloro-5-nitropyridine-3-carbonyl chloride (5.80 g, 26.24 mmol, 98.61% yield) as a pale yellow oil, which was used directly with in the next step.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)9.17(s,1H),9.33(s,1H)。 1 H NMR (CDCl 3 , 400 MHz): δ (ppm) 9.17 (s, 1H), 9.33 (s, 1H).

步驟3：4-胺基-5-硝基吡啶-3-甲醯胺之合成Step 3: Synthesis of 4-amino-5-nitropyridine-3-carboxamide

在0℃下，將氣態氨鼓泡穿過4-氯-5-硝基吡啶-3-羰基氯(5.80g，26.24mmol)於乙腈(100mL)中之溶液。反應混合物之顏色立即自無色轉變成黃色。移除冷卻浴且在25℃下進一步鼓泡氨達1小時。過濾所沉澱之固體，用乙腈(2 x 20mL)及水(2 x 20mL)洗滌，且在真空中乾燥，以得到呈黃色固體之4-胺基-5-硝基吡啶-3-甲醯胺(3.80g，20.86mmol，79.50%產率)。Gaseous ammonia was bubbled through a solution of 4-chloro-5-nitropyridine-3-carbonyl chloride (5.80 g, 26.24 mmol) in acetonitrile (100 mL) at 0 °C. The color of the reaction mixture immediately changed from colorless to yellow. The cooling bath was removed and ammonia was further bubbled at 25°C for 1 hour. The precipitated solid was filtered, washed with acetonitrile (2 x 20 mL) and water (2 x 20 mL), and dried in vacuo to give 4-amino-5-nitropyridine-3-carboxamide as a yellow solid (3.80 g, 20.86 mmol, 79.50% yield).

LCMS(ESI)：[M+H]+ m/z：計算值182.0；實測值183.0；Rt=0.499min。LCMS (ESI): [M+H] + m/z: calculated 182.0; found 183.0; Rt=0.499 min.

步驟4：4,5-二胺基吡啶-3-甲醯胺之合成Step 4: Synthesis of 4,5-diaminopyridine-3-carboxamide

在氫氣氣氛、25℃下將4-胺基-5-硝基吡啶-3-甲醯胺(500mg，2.75mmol)於甲醇(20mL)中之溶液經鈀(10%於碳上)(200mg，2.75mmol)氫化12小時。12小時之後，過濾催化劑且將濾餅用甲醇(2 x 20mL)洗滌。在減壓下濃縮濾液，以獲得呈白色固體之4,5-二胺基吡啶-3-甲醯胺(350mg，2.30mmol，83.79%產率)。A solution of 4-amino-5-nitropyridine-3-carboxamide (500 mg, 2.75 mmol) in methanol (20 mL) was treated with palladium (10% on carbon) (200 mg, 2.75 mmol) hydrogenated for 12 hours. After 12 hours, the catalyst was filtered and the filter cake was washed with methanol (2 x 20 mL). The filtrate was concentrated under reduced pressure to obtain 4,5-diaminopyridine-3-carboxamide (350 mg, 2.30 mmol, 83.79% yield) as a white solid.

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)4.71(s,2H),6.80(s,2H),7.16(s,1H),7.66(s,1H),7.80(s,1H),8.05(d,1H)。 1 H NMR (DMSO- d 6 , 400MHz): δ(ppm) 4.71(s, 2H), 6.80(s, 2H), 7.16(s, 1H), 7.66(s, 1H), 7.80(s, 1H) , 8.05(d,1H).

步驟5：4-胺基-5-[[2-側氧基-2-(2-苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(化合物119 )之合成Step 5: 4-Amino-5-[[2-oxo-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3-carboxamide ( compound 119 ) synthesis

向4,5-二胺基吡啶-3-甲醯胺(200mg，1.31mmol)、2-側氧基-2-(2-苯基-1-哌啶基)乙酸(306.61mg，1.31mmol)及HATU(549.78mg，1.45mmol)於DMF(10mL)中之經攪拌之混合物中添加三乙胺(1.33g，13.14mmol，1.83mL)。將所得反應混合物在25℃下攪拌2小時。2小時之後，將反應混合物在減壓下濃縮，且藉由反相HPLC純化(溶析液：25-70%，水-甲醇(0.1% NH3 )；管柱：SunFireC18 100*19mm，5um)純化殘餘物，以得到呈灰白色固體之4-胺基-5-[[2-側氧基-2-(2- 苯基-1-哌啶基)乙醯基]胺基]吡啶-3-甲醯胺(化合物119 ，26mg，70.77μmol，5.38%產率)。To 4,5-diaminopyridine-3-carboxamide (200 mg, 1.31 mmol), 2-oxy-2-(2-phenyl-1-piperidinyl)acetic acid (306.61 mg, 1.31 mmol) To a stirred mixture of and HATU (549.78 mg, 1.45 mmol) in DMF (10 mL) was added triethylamine (1.33 g, 13.14 mmol, 1.83 mL). The resulting reaction mixture was stirred at 25°C for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC (eluent: 25-70%, water-methanol (0.1% NH3 ); column: SunFire C18 100*19mm, 5um) The residue was purified to give 4-amino-5-[[2-oxy-2-(2-phenyl-1-piperidinyl)acetyl]amino]pyridine-3- as an off-white solid Formamide ( compound 119 , 26 mg, 70.77 μmol, 5.38% yield).

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.4；Rt=2.198min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.4; Rt=2.198 min.

實例714. 5-[[2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物745)之合成Example 714. 5-[[2-[(2R,4S)-4-Acetylamino-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 -Synthesis of carboxamide (compound 745)

Figure 110128222-A0202-12-2301-581
Figure 110128222-A0202-12-2301-581

步驟1：5-[[2-[(2R,4S)-4-(苯甲基胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 1: 5-[[2-[(2R,4S)-4-(benzylamino)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Synthesis of pyridine-3-carboxamide

將(2R,4S)-N-苯甲基-2-苯基哌啶-4-胺(0.5g，1.47mmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(308.22mg，1.25mmol，HCl)及三乙胺(671.01mg，6.63mmol，924.26μL)混合於DMF(5mL)中。在劇烈攪拌之情況下，向其中小批量添加HATU(616.34mg，1.62mmol)且將所得混合物在20℃下攪拌12h。使反應混合物經歷HPLC，以獲得5-[[2-[(2R,4S)-4-(苯甲基胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1896g，414.41μmol，28.12%產率)。(2R,4S)-N-benzyl-2-phenylpiperidin-4-amine (0.5 g, 1.47 mmol, 2HCl), 2-[(5-aminocarbamoyl-3-pyridinyl)amine [00110] [00100] [00110] [00110] [00110] [00110] [00111] [00101] [00106]-2-Pendant oxyacetic acid (308.22 mg, 1.25 mmol, HCl) and triethylamine (671.01 mg, 6.63 mmol, 924.26 [mu]L) were mixed in DMF (5 mL). With vigorous stirring, HATU (616.34 mg, 1.62 mmol) was added to it in small batches and the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was subjected to HPLC to obtain 5-[[2-[(2R,4S)-4-(benzylamino)-2-phenyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide (0.1896 g, 414.41 μmol, 28.12% yield).

HPLC條件：24% 0.5-6.5min水-乙腈；流速：30ml/min；(裝載泵4ml/min乙腈)；目標質量457；管柱SunFire 100x19mm 5um(L)HPLC conditions: 24% 0.5-6.5min water-acetonitrile; flow rate: 30ml/min; (loading pump 4ml/min acetonitrile); target mass 457; column SunFire 100x19mm 5um (L)

1 H NMR(DMSO-d6,400MHz)：1.75(m,2H),2.21(m,2H),2.95(m,1H),3.20(s, 2H),3.66(m,4H),4.13(m,1H),5.16(m,1H),7.40(m,9H),8.30(m,4H),11.28(m,1H)。 1 H NMR (DMSO-d6, 400MHz): 1.75 (m, 2H), 2.21 (m, 2H), 2.95 (m, 1H), 3.20 (s, 2H), 3.66 (m, 4H), 4.13 (m, 1H), 5.16 (m, 1H), 7.40 (m, 9H), 8.30 (m, 4H), 11.28 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值457.2；實測值458.2；Rt=1.263min。LCMS (ESI): [M+H] + m/z: calculated 457.2; found 458.2; Rt=1.263 min.

步驟2：5-[[2-[(2R,4S)-4-胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 2: 5-[[2-[(2R,4S)-4-amino-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-methyl Synthesis of Amide

在1atm壓力下使用乾燥的487型鈀(10%於碳上)(2.21mg，20.72μmol)作為催化劑將5-[[2-[(2R,4S)-4-(苯甲基胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.1896g，414.41μmol)於MeOH(10mL)中之溶液氫化24h。過濾所得混合物且將濾液蒸發至乾，以獲得5-[[2-[(2R,4S)-4-胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.12g，326.62μmol，78.82%產率)，其不經純化即用於下一步驟中。5-[[2-[(2R,4S)-4-(benzylamino)- 5-[[2-[(2R,4S)-4-(benzylamino)- A solution of 2-phenyl-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (0.1896 g, 414.41 μmol) in MeOH (10 mL) was hydrogenated for 24 h. The resulting mixture was filtered and the filtrate was evaporated to dryness to obtain 5-[[2-[(2R,4S)-4-amino-2-phenyl-1-piperidinyl]-2-pendoxetylacetone ]amino]pyridine-3-carboxamide (0.12 g, 326.62 μmol, 78.82% yield), which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值367.2；實測值368.0；Rt=0.746min。LCMS (ESI): [M+H] + m/z: calculated 367.2; found 368.0; Rt=0.746 min.

步驟3：5-[[2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物745 )之合成Step 3: 5-[[2-[(2R,4S)-4-Acetylamino-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 -Synthesis of carboxamide ( compound 745 )

將5-[[2-[(2R,4S)-4-胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.12g，326.62μmol)與乙酸乙醯酯(66.69mg，653.24μmol，61.75μL)混合於DCM(5mL)中且將所得混合物在20℃下攪拌12h。將所得混合物蒸發且使殘餘物經歷HPLC，以獲得5-[[2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(33.30mg，81.33μmol，24.90%產率)Convert 5-[[2-[(2R,4S)-4-amino-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.12 g, 326.62 μmol) and acetyl acetate (66.69 mg, 653.24 μmol, 61.75 μL) were mixed in DCM (5 mL) and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was evaporated and the residue was subjected to HPLC to obtain 5-[[2-[(2R,4S)-4-acetamido-2-phenyl-1-piperidinyl]-2- pendantoxy Acetyl]amino]pyridine-3-carboxamide (33.30 mg, 81.33 μmol, 24.90% yield)

HPLC條件：0-10% 0.5-6.5min水-乙腈；流速30ml/min；(裝載泵4ml/min乙腈)；目標質量409；管柱SunFireC18 100x19mm 5um(L)HPLC conditions: 0-10% 0.5-6.5min water-acetonitrile; flow rate 30ml/min; (loading pump 4ml/min acetonitrile); target mass 409; column SunFireC18 100x19mm 5um (L)

1 H NMR(400MHz,TFA)δ 3.02-3.25(m,2H),3.25-3.34(m,3H),3.36-3.75(m,3H),3.76-3.96(m,1H),4.84-5.15(m,1H),5.45-6.19(m,3H),6.73-7.24(m,1H),8.34-8.45(m,3H),8.47-8.58(m,3H),10.26-10.51(m,2H),10.62-10.88(m,1H)。 1 H NMR (400MHz, TFA)δ 3.02-3.25(m, 2H), 3.25-3.34(m, 3H), 3.36-3.75(m, 3H), 3.76-3.96(m, 1H), 4.84-5.15(m ,1H),5.45-6.19(m,3H),6.73-7.24(m,1H),8.34-8.45(m,3H),8.47-8.58(m,3H),10.26-10.51(m,2H),10.62 -10.88(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.4；Rt=1.411min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.4; Rt=1.411 min.

實例715. 2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物831)之合成Example 715. 2-[(2R,4S)-4-acetamido-2-phenyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)- Synthesis of 2-Pendant Oxyacetamide (Compound 831)

Figure 110128222-A0202-12-2303-582
Figure 110128222-A0202-12-2303-582

步驟1：N-[5-[[2-[(2R,4S)-4-(苯甲基胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 1: N-[5-[[2-[(2R,4S)-4-(benzylamino)-2-phenyl-1-piperidinyl]-2-oxoacetyl] Synthesis of tert-butyl amino]-3-methyl-2-pyridyl]carbamate

在輕微加熱下，將(2R,4S)-N-苯甲基-2-苯基哌啶-4-胺(392.54mg，1.47mmol，2HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(435.14mg，1.47mmol)及DIPEA(761.81mg，5.89mmol，1.03mL)溶解於DMSO(5mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(672.37mg，1.77mmol)。在反應完成之後，藉由HPLC純化混合物，以得到N-[5-[[2-[(2R,4S)-4-(苯甲基胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯 (0.5g，919.70μmol，62.41%產率)。(2R,4S)-N-benzyl-2-phenylpiperidin-4-amine (392.54 mg, 1.47 mmol, 2HCl), 2-[[6-(tert-butoxy Carbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (435.14 mg, 1.47 mmol) and DIPEA (761.81 mg, 5.89 mmol, 1.03 mL) were dissolved in DMSO (5 mL) middle. With vigorous stirring and occasional heating, HATU (672.37 mg, 1.77 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC to give N-[5-[[2-[(2R,4S)-4-(benzylamino)-2-phenyl-1-piperidinyl] -2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.5 g, 919.70 μmol, 62.41% yield).

HPLC條件：(2-4 58-62% 0.5-6.5min水-MeOH+NH3 ；流速30ml/min；(裝載泵4ml/min MeOH)；目標質量543；管柱SunFireC18 100x19mm 5um(L))。HPLC conditions: (2-4 58-62% 0.5-6.5 min water-MeOH+ NH3 ; flow rate 30 ml/min; (loading pump 4 ml/min MeOH); target mass 543; column SunFire C18 100x19mm 5um(L)).

LCMS(ESI)：[M+H]+ m/z：計算值543.3；實測值544.0；Rt=2.183min。LCMS (ESI): [M+H] + m/z: calculated 543.3; found 544.0; Rt=2.183 min.

步驟2：N-[5-[[2-[(2R,4S)-4-胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[(2R,4S)-4-Amino-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3 -Synthesis of tert-butyl methyl-2-pyridyl]carbamate

將N-[5-[[2-[(2R,4S)-4-(苯甲基胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(80.00mg，147.15μmol)溶解於MeOH(5mL)中，隨後添加Pd/C(1.79mg，14.72μmol)。在氫氣氣氛(1atm)下攪拌所獲得之混合物隔夜。在反應完成之後，過濾出固體且蒸發有機溶劑，以得到N-[5-[[2-[(2R,4S)-4-胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(60mg，132.29μmol，89.90%產率)。N-[5-[[2-[(2R,4S)-4-(benzylamino)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino ]- tert-butyl 3-methyl-2-pyridyl]carbamate (80.00 mg, 147.15 μmol) was dissolved in MeOH (5 mL) followed by the addition of Pd/C (1.79 mg, 14.72 μmol). The resulting mixture was stirred under a hydrogen atmosphere (1 atm) overnight. After the reaction was completed, the solid was filtered off and the organic solvent was evaporated to give N-[5-[[2-[(2R,4S)-4-amino-2-phenyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (60 mg, 132.29 μmol, 89.90% yield).

LCMS(ESI)：[M+H]+ m/z：計算值453.3；實測值454.2；Rt=0.982min。LCMS (ESI): [M+H] + m/z: calculated 453.3; found 454.2; Rt=0.982 min.

步驟3：N-[5-[[2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 3: N-[5-[[2-[(2R,4S)-4-acetamido-2-phenyl-1-piperidinyl]-2-oxyacetamido]amino] Synthesis of -3-methyl-2-pyridyl]carbamic acid tert-butyl ester

將N-[5-[[2-[(2R,4S)-4-胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(30mg，66.15μmol)溶解於DCM(3mL)中，隨後添加乙酸酐(8.10mg，79.38μmol，7.50μL)。在反應完成之後，在減壓下蒸發有機溶劑，以得到N-[5-[[2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(60mg，粗品)，其不經純化即用於下一步驟中。N-[5-[[2-[(2R,4S)-4-amino-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl tert-butyl-2-pyridyl]carbamate (30 mg, 66.15 μmol) was dissolved in DCM (3 mL) followed by the addition of acetic anhydride (8.10 mg, 79.38 μmol, 7.50 μL). After the reaction was completed, the organic solvent was evaporated under reduced pressure to obtain N-[5-[[2-[(2R,4S)-4-acetamido-2-phenyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (60 mg, crude), which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值409.2；實測值410.4；Rt=1.411min。LCMS (ESI): [M+H] + m/z: calculated 409.2; found 410.4; Rt=1.411 min.

步驟4：2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物831 )之合成Step 4: 2-[(2R,4S)-4-Acetylamino-2-phenyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridinyl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 831 )

將N-[5-[[2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(60mg，60.54μmol)溶解於H2 O(1mL)/二噁烷(2mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑且藉由HPLC(10-60% 0.5-7.5min水-MeOH+NH3 流速30ml/min(裝載泵4ml/min MeCN)目標質量396管柱：sunfire C18 100*19mm 5um)純化，得到2-[(2R,4S)-4-乙醯胺基-2-苯基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(10mg，25.29μmol，41.77%產率)。N-[5-[[2-[(2R,4S)-4-acetamido-2-phenyl-1-piperidinyl]-2-oxyacetamido]amino]-3 -Methyl-2-pyridyl]carbamic acid tert-butyl ester (60 mg, 60.54 μmol) was dissolved in a mixture of H2O (1 mL)/dioxane (2 mL) and stirred at reflux overnight. Aliquots showed complete consumption of starting material; solvent was evaporated under reduced pressure and target mass by HPLC (10-60% 0.5-7.5 min water-MeOH+NH flow 30 ml/min (loading pump 4 ml/min MeCN) 396 column: sunfire C18 100*19mm 5um) purified to give 2-[(2R,4S)-4-acetamido-2-phenyl-1-piperidinyl]-N-(6-amino- 5-Methyl-3-pyridyl)-2-oxoacetamide (10 mg, 25.29 μmol, 41.77% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.43-1.55(m,4H),1.94-2.07(m,5H),2.26-2.35(m,1H),3.47-3.59(m,1H),3.67-3.79(m,1H),3.82-4.27(m,1H),5.13-5.35(m,1H),5.52-5.66(m,2H),7.17-7.24(m,3H),7.28-7.34(m,2H),7.34-7.56(m,2H),7.80-8.07(m,1H),10.26-10.56(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.43-1.55 (m, 4H), 1.94-2.07 (m, 5H), 2.26-2.35 (m, 1H), 3.47-3.59 (m, 1H), 3.67- 3.79(m, 1H), 3.82-4.27(m, 1H), 5.13-5.35(m, 1H), 5.52-5.66(m, 2H), 7.17-7.24(m, 3H), 7.28-7.34(m, 2H) ), 7.34-7.56(m, 2H), 7.80-8.07(m, 1H), 10.26-10.56(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.2；實測值396.4；Rt=1.286min。LCMS (ESI): [M+H] + m/z: calculated 395.2; found 396.4; Rt=1.286 min.

實例716. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S)-4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物975)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S)-4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物906)之合成Example 716. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,4S)-4-(dimethylamino)-2-phenyl-1-piperidinyl ]-2-Oxyacetamide (Compound 975) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4S)-4-(dimethylamino) )-2-phenyl-1-piperidinyl]-2-oxoacetamide (compound 906) synthesis

Figure 110128222-A0202-12-2306-583
Figure 110128222-A0202-12-2306-583

步驟1：4-(二甲胺基)-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 4-(dimethylamino)-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

將4-側氧基-2-苯基哌啶-1-甲酸第三丁酯(0.5g，1.82mmol)溶解於甲醇(20mL)/40%二甲胺水溶液(818.68mg，18.16mmol，1.06mL)混合物中且在高壓釜中、在氫氣氣氛下氫化。在反應完成之後，過濾出固體且將有機溶劑蒸發至乾，得到粗品4-(二甲胺基)-2-苯基哌啶-1-甲酸第三丁酯(0.6g，1.97mmol，108.54%產率)，其不經純化即用於下一步驟中。4-Pendox-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.82 mmol) was dissolved in methanol (20 mL)/40% aqueous dimethylamine (818.68 mg, 18.16 mmol, 1.06 mL) ) mixture and hydrogenated in an autoclave under a hydrogen atmosphere. After the reaction was completed, the solid was filtered off and the organic solvent was evaporated to dryness to give crude 3-butyl 4-(dimethylamino)-2-phenylpiperidine-1-carboxylate (0.6 g, 1.97 mmol, 108.54%) yield), which was used in the next step without purification.

注意：獲得非鏡像異構物之混合物。Note: A mixture of diastereoisomers was obtained.

LCMS(ESI)：[M+H]+ m/z：計算值304.3；實測值305.2；Rt=0.986min。LCMS (ESI): [M+H] + m/z: calculated 304.3; found 305.2; Rt=0.986 min.

步驟2：N,N-二甲基-2-苯基哌啶-4-胺之合成Step 2: Synthesis of N,N-dimethyl-2-phenylpiperidin-4-amine

將4-(二甲胺基)-2-苯基哌啶-1-甲酸第三丁酯(0.6g，1.97mmol)溶解於二噁烷(3mL)中，隨後添加HCl(10M，1.97mL)且攪拌隔夜。在反應完成之後，過濾所獲得之固體，用MTBE(10mL)洗滌且風乾，以得到N,N-二甲基-2-苯基哌 啶-4-胺(0.4g，1.44mmol，73.21%產率，2HCl)。4-(Dimethylamino)-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.97 mmol) was dissolved in dioxane (3 mL) followed by the addition of HCl (10 M, 1.97 mL) and stirred overnight. After completion of the reaction, the obtained solid was filtered, washed with MTBE (10 mL) and air-dried to give N,N-dimethyl-2-phenylpiperidine Pyridin-4-amine (0.4 g, 1.44 mmol, 73.21% yield, 2HCl).

1 H NMR(DMSO-d6,400MHz)：2.10(m,4H),2.37(s,3H),2.41(s,3H),2.62(m,2H),4.32(m,1H),7.43(m,5H),9.97(m,2H),11.43(s,1H)。 1 H NMR (DMSO-d6, 400MHz): 2.10(m, 4H), 2.37(s, 3H), 2.41(s, 3H), 2.62(m, 2H), 4.32(m, 1H), 7.43(m, 5H), 9.97 (m, 2H), 11.43 (s, 1H).

步驟3：N-[5-[[2-[4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 3: N-[5-[[2-[4-(Dimethylamino)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl Synthesis of tert-butyl-2-pyridyl]carbamate

在輕微加熱下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(426.05mg，1.44mmol)、N,N-二甲基-2-苯基哌啶-4-胺(0.4g，1.44mmol，2HCl)及DIPEA(559.41mg，4.33mmol，753.93μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(658.33mg，1.73mmol)。在反應完成之後，藉由HPLC(24% 0.5-6.5min水-乙腈+NH3 ；流速30ml/min(裝載泵4ml/min乙腈)；目標質量481；管柱XBridge 100x19mm 5um(R))純化混合物，以得到N-[5-[[2-[4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.55g，1.14mmol，79.15%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (426.05 mg, 1.44 mmol) was added with gentle heating , N,N-dimethyl-2-phenylpiperidin-4-amine (0.4 g, 1.44 mmol, 2HCl) and DIPEA (559.41 mg, 4.33 mmol, 753.93 μL) were dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (658.33 mg, 1.73 mmol) was added in small batches. After the reaction was complete, the mixture was purified by HPLC (24% 0.5-6.5 min water-acetonitrile + NH3 ; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 481; column XBridge 100x19 mm 5um (R)) , to give N-[5-[[2-[4-(dimethylamino)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl tert-butyl-2-pyridyl]carbamate (0.55 g, 1.14 mmol, 79.15% yield).

LCMS(ESI)：[M+H]+ m/z：計算值481.3；實測值482.2；Rt=1.952min。LCMS (ESI): [M+H] + m/z: calculated 481.3; found 482.2; Rt=1.952 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S)-4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物975 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,4S)-4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯胺(化合物906 )之合成Step 4: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,4S)-4-(dimethylamino)-2-phenyl-1-piperidinyl ]-2-Oxyacetamide ( Compound 975 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,4S)-4-(dimethylamino) )-2-phenyl-1-piperidinyl]-2-side oxyacetamide ( compound 906 ) synthesis

將N-[5-[[2-[4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.5g，1.04mmol)溶解於二噁烷(5mL)/水(1mL)混合物中且在回流下攪拌隔夜。等分試樣顯示起始材料完全消耗；在減壓下蒸發溶劑且藉由HPLC(5-40% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量382；管柱SunFireC18 100x19mm 5um(R))純化，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4S)-4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯胺(140mg，367.00μmol，35.35%產率)及N-(6-胺基-5-甲基-3-吡啶 基)-2-[(2R,4S)-4-(二甲胺基)-2-苯基-1-哌啶基]-2-側氧基乙醯胺(90mg，235.93μmol，22.72%產率)藉由2D NMR確定相對組態。The N-[5-[[2-[4-(dimethylamino)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl- 3-Butyl 2-pyridyl]carbamate (0.5 g, 1.04 mmol) was dissolved in a mixture of dioxane (5 mL)/water (1 mL) and stirred at reflux overnight. Aliquots showed complete consumption of starting material; solvent was evaporated under reduced pressure and analyzed by HPLC (5-40% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 382 ; column SunFire C18 100x19mm 5um (R)) purification to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,4S)-4-(dimethylamino)- 2-Phenyl-1-piperidinyl]-2-oxoacetamide (140 mg, 367.00 μmol, 35.35% yield) and N-(6-amino-5-methyl-3-pyridine) yl)-2-[(2R,4S)-4-(dimethylamino)-2-phenyl-1-piperidinyl]-2-oxyacetamide (90 mg, 235.93 μmol, 22.72% yield ratio) relative configuration was determined by 2D NMR.

化合物975： 1 H NMR(600MHz,DMSO-d6)δ 1.54-1.64(m,1H),1.70-1.79(m,1H),1.93-1.97(m,1H),1.97-2.04(m,3H),2.05-2.12(m,6H),2.11-2.24(m,3H),3.43-3.61(m,1H),3.77-4.30(m,1H),4.95-5.21(m,1H),5.47-5.69(m,2H),7.14-7.33(m,5H),7.49(s,1H),7.66-8.10(m,1H),9.93-10.50(m,1H)。 Compound 975: 1 H NMR (600 MHz, DMSO-d6) δ 1.54-1.64 (m, 1H), 1.70-1.79 (m, 1H), 1.93-1.97 (m, 1H), 1.97-2.04 (m, 3H), 2.05-2.12(m, 6H), 2.11-2.24(m, 3H), 3.43-3.61(m, 1H), 3.77-4.30(m, 1H), 4.95-5.21(m, 1H), 5.47-5.69(m , 2H), 7.14-7.33 (m, 5H), 7.49 (s, 1H), 7.66-8.10 (m, 1H), 9.93-10.50 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.3；實測值382.4；Rt=0.846min。LCMS (ESI): [M+H] + m/z: calculated 381.3; found 382.4; Rt=0.846 min.

化合物906： 1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.36(m,1H),1.70(m,2H),2.00(m,4H),2.15(d,6H),2.27(m,1H),2.86(m,1H),4.05(m,1H),5.66(m,3H),7.29(m,3H),7.38(m,2H),7.47(m,1H),7.99(m,1H),10.54(s,1H)。 Compound 906: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 1.36 (m, 1H), 1.70 (m, 2H), 2.00 (m, 4H), 2.15 (d, 6H), 2.27 (m, 1H), 2.86(m, 1H), 4.05(m, 1H), 5.66(m, 3H), 7.29(m, 3H), 7.38(m, 2H), 7.47(m, 1H), 7.99(m, 1H) ), 10.54(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值381.3；實測值382.2；Rt=1.061min。LCMS (ESI): [M+H] + m/z: calculated 381.3; found 382.2; Rt=1.061 min.

實例717. 5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-(三氟甲氧基)吡啶-3-甲醯胺(化合物1039)之合成Example 717. 5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] - Synthesis of 2-(trifluoromethoxy)pyridine-3-carboxamide (Compound 1039)

Figure 110128222-A0202-12-2308-584
Figure 110128222-A0202-12-2308-584

步驟1A.2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯之合成Step 1A. 2,2,2-trifluoroethyl 2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetic synthesis

在0℃下，向(2R,5S)-2-(4-氟苯基)-5-甲基哌啶(3.00g，15.52mmol)(中間物4A)及TEA(1.88g，18.63mmol，2.60mL)於DCM(50mL)中之溶液中添加2-氯-2-側氧基乙酸2,2,2-三氟乙酯(3.25g，17.08mmol)。在室溫下攪拌1h，將所得 混合物過濾且蒸發至乾，以得到呈黃色膠狀物之2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(5.72g，粗品)，其不經進一步純化即用於下一步驟中。To (2R,5S)-2-(4-fluorophenyl)-5-methylpiperidine (3.00 g, 15.52 mmol) (Intermediate 4A) and TEA (1.88 g, 18.63 mmol, 2.60 g) at 0 °C mL) in DCM (50 mL) was added 2,2,2-trifluoroethyl 2-chloro-2-pendoxoacetic acid (3.25 g, 17.08 mmol). After stirring for 1 h at room temperature, the resulting The mixture was filtered and evaporated to dryness to give 2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxo as a yellow gum 2,2,2-trifluoroethyl acetate (5.72 g, crude), which was used in the next step without further purification.

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.06(m,3H),1.43(m,1H),1.86-2.00(m,2H),2.17(m,2H),2.89(dd,0.3H，旋轉異構性)，3.08(m,1H),3.30(dd,0.7H),4.09(d,0.3H),4.58(m,1H),4.77(m,1H),5.73(s,0.7H),7.04(m,2H),7.20(m,2H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.06 (m, 3H), 1.43 (m, 1H), 1.86-2.00 (m, 2H), 2.17 (m, 2H), 2.89 (dd, 0.3H) , rotational isomerism), 3.08(m, 1H), 3.30(dd, 0.7H), 4.09(d, 0.3H), 4.58(m, 1H), 4.77(m, 1H), 5.73(s, 0.7H ), 7.04 (m, 2H), 7.20 (m, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值347.1；實測值348.2；Rt=3.756min。LCMS (ESI): [M+1] + m/z: calculated 347.1; found 348.2; Rt=3.756 min.

步驟2A.2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸之合成Step 2A. Synthesis of 2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxoacetic acid

向2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(3.81g，10.97mmol)於MeOH(50mL)中之溶液中添加98%氫氧化鋰單水合物(598.45mg，14.26mmol，396.33μL)且使所得混合物在室溫下攪拌1h。然後將所得混合物蒸發至乾，溶解於水中，將水酸化至pH=1且用DCM萃取兩次，將有機物用鹽水洗滌，經Na2 SO4 乾燥且蒸發。獲得呈白色固體之2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(2.5g，9.42mmol，85.91%產率)。To 2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (3.81 g, 10.97 mmol) in MeOH (50 mL) was added 98% lithium hydroxide monohydrate (598.45 mg, 14.26 mmol, 396.33 μL) and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then evaporated to dryness, dissolved in water, acidified to pH=1 and extracted twice with DCM, the organics were washed with brine, dried over Na2SO4 and evaporated. 2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetic acid (2.5g, 9.42mmol, 85.91 g) was obtained as a white solid %Yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)1.06(m,3H),1.40(m,1H),1.83(m,1H),1.95(m,1H),2.18(m,2H),2.90-3.30(兩個雙峰，1H，旋轉異構性)，4.18(m,1H),5.79(m,1H),7.04(t,2H),7.23(m,2H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 1.06 (m, 3H), 1.40 (m, 1H), 1.83 (m, 1H), 1.95 (m, 1H), 2.18 (m, 2H), 2.90 -3.30 (two doublets, 1H, rotamer), 4.18 (m, 1H), 5.79 (m, 1H), 7.04 (t, 2H), 7.23 (m, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值265.1；實測值266.2；Rt=1.212min。LCMS (ESI): [M+1] + m/z: calculated 265.1; found 266.2; Rt=1.212 min.

步驟1 2-苯甲基氧基-5-溴-吡啶之合成Step 1 Synthesis of 2-benzyloxy-5-bromo-pyridine

在-78℃下，將丁基鋰(1.20g，18.75mmol，7.51mL)逐滴添加到6-(三氟甲氧基)吡啶-3-胺(1.67g，9.38mmol)於THF(20mL)中之溶液中，接著在1min後添加氯三甲基矽烷(2.14g，19.69mmol，2.50mL)。使反應混合物達到25℃達2h，之後過濾到矽藻土墊上。移除溶劑且在真空(101-103 0C/1毫巴)下蒸餾粗品油狀物，以得到6-(三氟甲氧基)-N,N-雙(三甲基矽基)吡啶-3-胺(2.93g，粗品)。在0 ℃下，將丁基鋰(1.18g，18.43mmol，7.38mL)逐滴添加到二異丙胺(1.95g，19.31mmol，2.72mL)於THF(56mL)中之溶液中。在-78 0℃下，逐滴添加6-(三氟甲氧基)-N,N-雙(三甲基矽基)吡啶-3-胺(2.83g，8.78mmol)於THF(2mL)中之溶液且將反應混合物在此溫度下攪拌1h。然後透過具有硫酸之乾燥容器將CO2鼓泡到溶液中達15min。在-78℃下30min之後，使溶液達到室溫。蒸發溶劑。藉由管柱層析(MTBE/甲醇)純化所得粗材料，以獲得5-胺基-2-(三氟甲氧基)吡啶-3-甲酸(0.1g，450.20μmol，5.13%產率)。Butyllithium (1.20 g, 18.75 mmol, 7.51 mL) was added dropwise to 6-(trifluoromethoxy)pyridin-3-amine (1.67 g, 9.38 mmol) in THF (20 mL) at -78 °C To the solution, chlorotrimethylsilane (2.14 g, 19.69 mmol, 2.50 mL) was then added after 1 min. The reaction mixture was allowed to reach 25 °C for 2 h before being filtered onto a pad of celite. The solvent was removed and the crude oil was distilled under vacuum (101-103 OC/1 mbar) to give 6-(trifluoromethoxy)-N,N-bis(trimethylsilyl)pyridine-3 - Amine (2.93 g, crude). at 0 To a solution of diisopropylamine (1.95 g, 19.31 mmol, 2.72 mL) in THF (56 mL) was added butyllithium (1.18 g, 18.43 mmol, 7.38 mL) dropwise at °C. 6-(Trifluoromethoxy)-N,N-bis(trimethylsilyl)pyridin-3-amine (2.83 g, 8.78 mmol) in THF (2 mL) was added dropwise at -78 0°C solution and the reaction mixture was stirred at this temperature for 1 h. CO2 was then bubbled into the solution through a drying vessel with sulfuric acid for 15 min. After 30 min at -78°C, the solution was allowed to reach room temperature. Evaporate the solvent. The resulting crude material was purified by column chromatography (MTBE/methanol) to obtain 5-amino-2-(trifluoromethoxy)pyridine-3-carboxylic acid (0.1 g, 450.20 μmol, 5.13% yield).

1 H NMR(500MHz,DMSO-d6)δ(ppm)5.20-5.30(brs,2H),7.35(s,1H),7.65(s,1H)。 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 5.20-5.30 (brs, 2H), 7.35 (s, 1H), 7.65 (s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值222.0；實測值223.0；Rt=0.641min。LCMS (ESI): [M+1] + m/z: calculated 222.0; found 223.0; Rt=0.641 min.

步驟2.5-胺基-2-(三氟甲氧基)吡啶-3-甲醯胺之合成Step 2. Synthesis of 5-amino-2-(trifluoromethoxy)pyridine-3-carboxamide

將5-胺基-2-(三氟甲氧基)吡啶-3-甲酸(90mg，405.18μmol)、碳酸銨(116.80mg，1.22mmol)、三乙胺(205.00mg，2.03mmol，282.37μL)混合到DMF(2mL)中，然後添加HATU(231.09mg，607.78μmol)。將所得混合物在25℃下攪拌13h。將溶劑蒸發，以獲得粗產物，其藉由HPLC(35-55%(甲醇)-2-10min，流速：30ml/min)進行純化，以獲得5-胺基-2-(三氟甲氧基)吡啶-3-甲醯胺(18.9mg，85.47μmol，21.09%產率)。5-amino-2-(trifluoromethoxy)pyridine-3-carboxylic acid (90 mg, 405.18 μmol), ammonium carbonate (116.80 mg, 1.22 mmol), triethylamine (205.00 mg, 2.03 mmol, 282.37 μL) Mix into DMF (2 mL), then add HATU (231.09 mg, 607.78 μmol). The resulting mixture was stirred at 25 °C for 13 h. The solvent was evaporated to obtain crude product, which was purified by HPLC (35-55% (methanol)-2-10 min, flow rate: 30 ml/min) to obtain 5-amino-2-(trifluoromethoxy) ) pyridine-3-carboxamide (18.9 mg, 85.47 μmol, 21.09% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)5.19(d,1H),5.37(s,2H),5.65(d,1H),6.63(m,1H),6.78(d,1H),7.24-7.63(m,5),7.71(d,1H),8.19(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 5.19(d,1H), 5.37(s,2H), 5.65(d,1H), 6.63(m,1H), 6.78(d,1H), 7.24- 7.63(m,5), 7.71(d,1H), 8.19(s,1H).

LCMS(ESI)：[M+1]+ m/z：計算值221.0；實測值222.0；Rt=0.727min。LCMS (ESI): [M+1] + m/z: calculated 221.0; found 222.0; Rt=0.727 min.

步驟3.5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-(三氟甲氧基)吡啶-3-甲醯胺(化合物1039 )之合成Step 3. 5-[[2-[(2R,5S)-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-2 Synthesis of -(trifluoromethoxy)pyridine-3-carboxamide ( Compound 1039 )

將5-胺基-2-(三氟甲氧基)吡啶-3-甲醯胺(0.154g，696.40μmol)、2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(184.74mg，696.40 μmol)、三乙胺(704.69mg，6.96mmol，970.65μL)混合於DMF(5mL)中，然後添加HATU(397.19mg，1.04mmol)。將所得混合物在25℃下攪拌12h。將溶劑蒸發且將所得混合物與於甲醇(10ml)中之SiliaMetS® DMT(50mg)一起攪拌。將混合物過濾且在減壓下蒸發。藉由HPLC(2-10min 50-100%甲醇/H2 O)純化所得粗材料，以獲得5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-(三氟甲氧基)吡啶-3-甲醯胺(104.80mg，223.74μmol，32.13%產率)5-Amino-2-(trifluoromethoxy)pyridine-3-carboxamide (0.154 g, 696.40 μmol), 2-[(2R,5S)-2-(4-fluorophenyl)-5 -Methyl-1-piperidinyl]-2-oxoacetic acid (184.74 mg, 696.40 μmol), triethylamine (704.69 mg, 6.96 mmol, 970.65 μL) were mixed in DMF (5 mL), then HATU ( 397.19 mg, 1.04 mmol). The resulting mixture was stirred at 25 °C for 12 h. The solvent was evaporated and the resulting mixture was stirred with SiliaMetS® DMT (50 mg) in methanol (10 ml). The mixture was filtered and evaporated under reduced pressure. The resulting crude material was purified by HPLC (2-10 min 50-100% methanol/ H2O ) to obtain 5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methan (104.80 mg, 223.74 μmol, 32.13% yield)

1 H NMR(dmso,600MHz)：δ(ppm)0.97-1.06(m,3H),1.27-1.39(m,1H),1.59-1.73(m,1H),1.82-1.94(m,1H),2.00-2.13(m,1H),2.14-2.24(m,1H),2.74-3.23(m,1H),3.44-4.07(m,1H),5.11-5.65(m,1H),7.16-7.26(m,2H),7.30-7.40(m,2H),7.74-7.85(m,1H),7.91-8.04(m,1H),8.29-8.37(m,1H),8.54-8.67(m,1H),11.23-11.60(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.97-1.06 (m, 3H), 1.27-1.39 (m, 1H), 1.59-1.73 (m, 1H), 1.82-1.94 (m, 1H), 2.00 -2.13(m, 1H), 2.14-2.24(m, 1H), 2.74-3.23(m, 1H), 3.44-4.07(m, 1H), 5.11-5.65(m, 1H), 7.16-7.26(m, 2H), 7.30-7.40(m, 2H), 7.74-7.85(m, 1H), 7.91-8.04(m, 1H), 8.29-8.37(m, 1H), 8.54-8.67(m, 1H), 11.23- 11.60 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值468.0；實測值469.0；Rt=3.289min。LCMS (ESI): [M+1] + m/z: calculated 468.0; found 469.0; Rt=3.289 min.

實例718. 外消旋5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-(三氟甲氧基)吡啶-3-甲醯胺(化合物818)之合成Example 718. Racemic 5-[[2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Synthesis of Amino]-2-(trifluoromethoxy)pyridine-3-carboxamide (Compound 818)

Figure 110128222-A0202-12-2311-585
Figure 110128222-A0202-12-2311-585

將5-胺基-2-(三氟甲氧基)吡啶-3-甲醯胺(18.9mg，85.47μmol)(如上文所製備)、外消旋2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(22.67mg，85.47μmol)(以與上文鏡像異構純之材料之程序類似的方式製備)、三乙胺(43.24mg，427.34μmol，59.56μL)混合於DMF(2mL)中然後添加HATU(48.75mg，128.20μmol)。將所得混合物在25℃下攪拌11h。將溶劑蒸發且將所得混合物與於甲醇(10ml)中之SiliaMetS® DMT(50mg)一起攪拌。將混合物過濾且在減 壓下蒸發。藉由HPLC(2-10min 50-100%甲醇/H2 O)純化所得粗材料，以獲得外消旋5-[[2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-(三氟甲氧基)吡啶-3-甲醯胺(14.1mg，30.10μmol，35.22%產率)5-Amino-2-(trifluoromethoxy)pyridine-3-carboxamide (18.9 mg, 85.47 μmol) (prepared as above), racemic 2-[(2R,5S)-2- (4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxoacetic acid (22.67 mg, 85.47 μmol) (prepared in a similar manner to the procedure above for the enantiomerically pure material) ), triethylamine (43.24 mg, 427.34 μmol, 59.56 μL) were mixed in DMF (2 mL) and then HATU (48.75 mg, 128.20 μmol) was added. The resulting mixture was stirred at 25 °C for 11 h. The solvent was evaporated and the resulting mixture was stirred with SiliaMetS® DMT (50 mg) in methanol (10 ml). The mixture was filtered and evaporated under reduced pressure. The resulting crude material was purified by HPLC (2-10 min 50-100% methanol/ H2O ) to obtain racemic 5-[[2-[(2R,5S)-2-(4-fluorophenyl)- 5-Methyl-1-piperidinyl]-2-oxyacetyl]amino]-2-(trifluoromethoxy)pyridine-3-carboxamide (14.1 mg, 30.10 μmol, 35.22% Yield)

1 H NMR(dmso,600MHz)：δ(ppm)0.97-1.06(m,3H),1.27-1.39(m,1H),1.59-1.73(m,1H),1.82-1.94(m,1H),2.00-2.13(m,1H),2.14-2.24(m,1H),2.74-3.23(m,1H),3.44-4.07(m,1H),5.11-5.65(m,1H),7.16-7.26(m,2H),7.30-7.40(m,2H),7.74-7.85(m,1H),7.91-8.04(m,1H),8.29-8.37(m,1H),8.54-8.67(m,1H),11.23-11.60(m,1H)。 1 H NMR (dmso, 600MHz): δ (ppm) 0.97-1.06 (m, 3H), 1.27-1.39 (m, 1H), 1.59-1.73 (m, 1H), 1.82-1.94 (m, 1H), 2.00 -2.13(m, 1H), 2.14-2.24(m, 1H), 2.74-3.23(m, 1H), 3.44-4.07(m, 1H), 5.11-5.65(m, 1H), 7.16-7.26(m, 2H), 7.30-7.40(m, 2H), 7.74-7.85(m, 1H), 7.91-8.04(m, 1H), 8.29-8.37(m, 1H), 8.54-8.67(m, 1H), 11.23- 11.60 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值468.0；實測值469.0；Rt=3.289min。LCMS (ESI): [M+1] + m/z: calculated 468.0; found 469.0; Rt=3.289 min.

實例719.N -(5-氯-6-甲基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物622)之合成Example 719. N- (5-Chloro-6-methylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxygen Synthesis of Acetamide (Compound 622)

Figure 110128222-A0202-12-2312-586
Figure 110128222-A0202-12-2312-586

將外消旋-2-[(2S,5R )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(300.00mg，1.13mmol)(以與上文針對鏡像異構純之材料所述之方式類似的方式製備)、5-氯-6-甲基吡啶-3-胺(161.25mg，1.13mmol)及TEA(1.14g，11.31mmol，1.58mL)一起混合於DMF(5mL)中。將HATU(644.99mg，1.70mmol)添加到前一混合物中且將所得混合物攪拌18h。在真空中濃縮反應混合物且藉由HPLC(2-10min 50-60%水/MeOH(裝載泵4ml MeOH)管柱：TRIART 100*20 5微米)純化殘餘物，以獲得N -(5-氯-6-甲基-3-吡啶基)-2-[(2S,5R )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.1985g，509.17μmol，45.02%產率)。Racemic-2-[( 2S,5R )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetic acid (300.00 mg, 1.13 mmol) ( Prepared in a manner similar to that described above for the enantiomerically pure material), 5-chloro-6-methylpyridin-3-amine (161.25 mg, 1.13 mmol) and TEA (1.14 g, 11.31 mmol, 1.58 mL) were mixed together in DMF (5 mL). HATU (644.99 mg, 1.70 mmol) was added to the previous mixture and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 50-60% water/MeOH (load pump 4 ml MeOH) column: TRIART 100*20 5 microns) to obtain N- (5-chloro- 6-Methyl-3-pyridyl)-2-[( 2S,5R )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.1985 g, 509.17 μmol, 45.02% yield).

化合物622： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.68-1.02(m,3H),1.22-1.38 (m,1H),1.61-1.71(m,1H),1.80-1.95(m,1H),1.98-2.13(m,1H),2.13-2.30(m,1H),2.42-2.46(m,3H),2.73-3.26(m,1H),3.43-4.25(m,1H),5.08-5.67(m,1H),7.15-7.28(m,2H),7.30-7.40(m,2H),8.11-8.27(m,1H),8.53-8.69(m,1H),11.05-11.34(m,1H)。 Compound 622: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.68-1.02 (m, 3H), 1.22-1.38 (m, 1H), 1.61-1.71 (m, 1H), 1.80-1.95 (m ,1H),1.98-2.13(m,1H),2.13-2.30(m,1H),2.42-2.46(m,3H),2.73-3.26(m,1H),3.43-4.25(m,1H),5.08 -5.67(m,1H),7.15-7.28(m,2H),7.30-7.40(m,2H),8.11-8.27(m,1H),8.53-8.69(m,1H),11.05-11.34(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值389.2；實測值390.2；Rt=1.504min。LCMS (ESI): [M] + m/z: calculated 389.2; found 390.2; Rt=1.504 min.

實例720.N -(6-胺基-5-(二氟甲基)吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物867)之合成Example 720. N- (6-Amino-5-(difluoromethyl)pyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl) - Synthesis of 2-oxoacetamide (compound 867)

Figure 110128222-A0202-12-2313-587
Figure 110128222-A0202-12-2313-587

將2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(590mg，2.23mmol)、5-溴-3-(二氟甲基)吡啶-2-胺(497.86mg，2.23mmol)、銅(70.93mg，1.12mmol)、碘化銅(I)(42.52mg，223.24μmol，7.56μL)、(S,S )-(+)-N,N '-二甲基-1,2-環己烷二胺(31.75mg，223.24μmol，35.20μL)及碳酸鉀(617.05mg，4.46mmol，269.45μL)一起混合於甲苯(12mL)中。將氬氣流鼓泡穿過反應混合物達2min，此後將其在密封燒瓶中在105℃下攪拌18h。然後，將其用乙酸乙酯(20ml)及5%NH3 水溶液(15ml)稀釋。透過弗羅裡墊(florisil pad)過濾所得雙相混合物。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。藉由HPLC(第1次運行：50-70% 0-5min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；第2次運行：50-60% 0-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min；管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，得到N -[6-胺基-5-(二氟甲基)-3-吡啶基]-2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(190mg，467.52μmol，20.94%產率)。2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetamide (590 mg, 2.23 mmol), 5-bromo -3-(difluoromethyl)pyridin-2-amine (497.86 mg, 2.23 mmol), copper (70.93 mg, 1.12 mmol), copper(I) iodide (42.52 mg, 223.24 μmol, 7.56 μL), ( S ,S )-(+)- N,N' -dimethyl-1,2-cyclohexanediamine (31.75 mg, 223.24 μmol, 35.20 μL) and potassium carbonate (617.05 mg, 4.46 mmol, 269.45 μL) together Mix in toluene (12 mL). A stream of argon was bubbled through the reaction mixture for 2 min, after which it was stirred in a sealed flask at 105 °C for 18 h. It was then diluted with ethyl acetate (20ml) and 5% aqueous NH3 (15ml). The resulting biphasic mixture was filtered through a florisil pad. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. by HPLC (1st run: 50-70% 0-5min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min; 2nd run: 50-60% 0-6min H2O / MeOH/0.1% NH4OH , flow rate: 30ml/min; column: YMC Triart C18 100x20mm, 5um) The residue was purified to give N- [6-amino-5-(difluoromethyl)-3-pyridyl ]-2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (190 mg, 467.52 μmol, 20.94% yield Rate).

化合物867： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.72-1.05(m,3H),1.21-1.38 (m,1H),1.58-1.69(m,1H),1.78-1.93(m,1H),1.96-2.08(m,1H),2.09-2.26(m,1H),2.71-3.20(m,1H),3.47-4.05(m,1H),5.09-5.68(m,1H),6.10-6.23(m,2H),6.87-7.13(m,1H),7.14-7.25(m,2H),7.30-7.42(m,2H),7.87-8.00(m,1H),8.20-8.32(m,1H),10.64-10.91(m,1H)。 Compound 867: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.72-1.05 (m, 3H), 1.21-1.38 (m, 1H), 1.58-1.69 (m, 1H), 1.78-1.93 (m ,1H),1.96-2.08(m,1H),2.09-2.26(m,1H),2.71-3.20(m,1H),3.47-4.05(m,1H),5.09-5.68(m,1H),6.10 -6.23(m,2H),6.87-7.13(m,1H),7.14-7.25(m,2H),7.30-7.42(m,2H),7.87-8.00(m,1H),8.20-8.32(m, 1H), 10.64-10.91 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=2.966min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=2.966 min.

實例721.N -(6-胺基-5-(三氟甲基)吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物872)之合成Example 721. N- (6-Amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl) - Synthesis of 2-oxoacetamide (compound 872)

Figure 110128222-A0202-12-2314-588
Figure 110128222-A0202-12-2314-588

步驟1：5-硝基-3-(三氟甲基)吡啶-2-胺之合成Step 1: Synthesis of 5-nitro-3-(trifluoromethyl)pyridin-2-amine

將2-氯-5-硝基-3-(三氟甲基)吡啶(4.5g，19.86mmol)及氨(338.29mg，19.86mmol)於THF(50mL)溶液中之溶液在室溫下攪拌14h。在反應完成之後，將反應混合物過濾且在真空下濃縮，以得到呈白色固體之5-硝基-3-(三氟甲基)吡啶-2-胺(3.5g，粗品)。A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (4.5 g, 19.86 mmol) and ammonia (338.29 mg, 19.86 mmol) in THF (50 mL) was stirred at room temperature for 14 h . After completion of the reaction, the reaction mixture was filtered and concentrated under vacuum to give 5-nitro-3-(trifluoromethyl)pyridin-2-amine (3.5 g, crude) as a white solid.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.96(bds,2H),8.35(s,1H),9.01(s,1H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 7.96 (bds, 2H), 8.35 (s, 1H), 9.01 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值207.2；實測值208.2；Rt=0.985min。LCMS (ESI): [M] + m/z: calculated 207.2; found 208.2; Rt=0.985min.

步驟2：(5-硝基-3-(三氟甲基)吡啶-2-基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl (5-nitro-3-(trifluoromethyl)pyridin-2-yl)carbamate

在0℃下，向5-硝基-3-(三氟甲基)吡啶-2-胺(3.5g，16.90mmol)於DMF(15mL)中之溶液中分批添加於礦物油中之氫化鈉(油分散物)60%分散物(743.50mg，18.59mmol，60%純度)。將所得混合物攪拌0.5h(直至氣體逸出結束)且逐 滴添加二碳酸二-第三丁酯(4.06g，18.59mmol，4.27mL)於DMF(5mL)中之溶液。將所得混合物在25℃下攪拌16h。將混合物用水(1000mL)淬滅，用水萃取3次，將經合併之有機物用水、鹽水洗滌，乾燥且蒸發，以得到呈棕色固體之N -[5-硝基-3-(三氟甲基)-2-吡啶基]胺甲酸第三丁 酯(6.8g，粗品)，其不經進一步純化即用於下一步驟中。To a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-amine (3.5 g, 16.90 mmol) in DMF (15 mL) was added portionwise sodium hydride in mineral oil at 0 °C (Oil dispersion) 60% dispersion (743.50 mg, 18.59 mmol, 60% pure). The resulting mixture was stirred for 0.5 h (until gas evolution ceased) and a solution of di-tert-butyl dicarbonate (4.06 g, 18.59 mmol, 4.27 mL) in DMF (5 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (1000 mL), extracted 3 times with water, the combined organics were washed with water, brine, dried and evaporated to give N- [5-nitro-3-(trifluoromethyl) as a brown solid - 3 -Butyl 2-pyridyl]carbamate (6.8 g, crude), which was used in the next step without further purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.42(s,9H),8.69(s,1H),9.35(s,1H),10.12(s,1H)。LCMS(ESI)：[M]+ m/z：計算值307.2；實測值308.2；Rt=1.222min。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 1.42 (s, 9H), 8.69 (s, 1H), 9.35 (s, 1H), 10.12 (s, 1H). LCMS (ESI): [M] + m/z: calculated 307.2; found 308.2; Rt=1.222 min.

步驟3：(5-胺基-3-(三氟甲基)吡啶-2-基)胺甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl (5-amino-3-(trifluoromethyl)pyridin-2-yl)carbamate

在三頸圓底燒瓶中向N -[5-硝基-3-(三氟甲基)-2-吡啶基]胺甲酸第三丁 酯(0.65g，2.12mmol)於MeOH(25mL)中之溶液中添加Pd/C(0.06g，2.12mmol)。將反應燒瓶抽真空且用分子氫(4.26mg，2.12mmol)回填且使混合物攪拌隔夜。透過薄矽膠墊過濾，隨後濃縮且在真空下乾燥，得到呈米色固體之N -[5-胺基-3-(三氟甲基)-2-吡啶基]胺甲酸第三丁 酯(0.5g，1.80mmol，85.24%產率)。To a solution of tert-butyl N- [5-nitro-3-(trifluoromethyl)-2-pyridyl] carbamate (0.65 g, 2.12 mmol) in MeOH (25 mL) in a three neck round bottom flask To the solution was added Pd/C (0.06 g, 2.12 mmol). The reaction flask was evacuated and backfilled with molecular hydrogen (4.26 mg, 2.12 mmol) and the mixture was allowed to stir overnight. Filtration through a thin pad of silica gel followed by concentration and drying under vacuum gave tert-butyl N- [5-amino-3-(trifluoromethyl)-2-pyridyl] carbamate (0.5 g) as a beige solid , 1.80 mmol, 85.24% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.38(s,9H),5.78(bds,2H),7.23(s,1H),7.97(s,1H),8.73(s,1H)。LCMS(ESI)：[M]+ m/z：計算值277.2；實測值278.2；Rt=1.091min。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.38 (s, 9H), 5.78 (bds, 2H), 7.23 (s, 1H), 7.97 (s, 1H), 8.73 (s, 1H). LCMS (ESI): [M] + m/z: calculated 277.2; found 278.2; Rt=1.091 min.

步驟4：外消旋-(5-(2-((2R,5S)-2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-(三氟甲基)吡啶-2-基)胺甲酸第三丁酯之合成Step 4: Racemic-(5-(2-((2R,5S)-2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide Synthesis of tert-butyl)-3-(trifluoromethyl)pyridin-2-yl)carbamate

在21℃下，將N -[5-胺基-3-(三氟甲基)-2-吡啶基]胺甲酸第三丁 酯(252.91mg，912.24μmol)、TEA(184.62mg，1.82mmol，254.30μL)及HATU(346.86mg，912.24μmol)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(0.242g，912.24μmol)且將所得混合物在21℃下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(50-75% 2-7min 水-MeCN流速30ml/min(裝載泵4ml/min acn；管柱sunfire 100x19mm 5um(R))。獲得呈灰白色固體之N -[5-[[2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-(三氟甲基)-2-吡啶基]胺甲酸第三丁 酯(256.7mg，489.41μmol，53.65%產率)(存在順式雜質)。At 21 °C, N- [5-amino-3-(trifluoromethyl)-2-pyridyl]carbamic acid tert- butyl ester (252.91 mg, 912.24 μmol), TEA (184.62 mg, 1.82 mmol, 254.30 μL) and HATU (346.86 mg, 912.24 μmol) were mixed in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added 2-[2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxoacetic acid (0.242 g, 912.24 μmol) and the resulting mixture was stirred at 21 °C overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (50-75% 2-7min water-MeCN flow rate 30ml/min (loading pump 4ml/min acn; column sunfire 100x19mm 5um(R)). N- [5-[[ was obtained as an off-white solid 2-[2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-(trifluoromethyl)-2-pyridine tert -butyl ]carbamate (256.7 mg, 489.41 μmol, 53.65% yield) (cis impurity present).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.38(s,9H),5.78(bds,2H),7.23(s,1H),7.97(s,1H),8.73(s,1H)。LCMS(ESI)：[M]+ m/z：計算值524.2；實測值525.2；Rt=4.018min。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.38 (s, 9H), 5.78 (bds, 2H), 7.23 (s, 1H), 7.97 (s, 1H), 8.73 (s, 1H). LCMS (ESI): [M] + m/z: calculated 524.2; found 525.2; Rt=4.018 min.

步驟5：N-(6-胺基-5-(三氟甲基)吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物872 )之合成Step 5: N-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl) Synthesis of -2-oxoacetamide ( compound 872 )

在21℃下，向N -[5-[[2-[(2S,5R )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-(三氟甲基)-2-吡啶基]胺甲酸第三丁 酯(0.2567g，489.41μmol)於二噁烷(5mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(89.22mg，2.45mmol，111.53μL)。使所得混合物攪拌2h。將所得混合物蒸發至乾且使其經歷HPLC(40-65% 2-7min水-MeCN；流速30ml/min；(裝載泵4ml/min MeCN)；管柱sunfire 100x19mm 5um(L))。獲得呈米色固體之呈三種級分之N -[6-胺基-5-(三氟甲基)-3-吡啶基]-2-[(2S,5R )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(114.2mg，269.09μmol，54.98%產率)：第1級分-29.5mg(藉由LCMS為100%，單一非鏡像異構物)；第2級分-70.4mg(藉由LCMS為84.06%，15.94%順式)；第3級分-14.3mg(藉由LCMS為59.51%，40.49%順式)。At 21 °C, to N- [5-[[2-[( 2S,5R )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-(trifluoromethyl)-2-pyridyl]carbamic acid tert- butyl ester (0.2567 g, 489.41 μmol) in dioxane (5 mL) was added to dioxane 4.0 M hydrogen chloride solution (89.22 mg, 2.45 mmol, 111.53 μL) in the solution. The resulting mixture was stirred for 2 h. The resulting mixture was evaporated to dryness and subjected to HPLC (40-65% 2-7 min water-MeCN; flow rate 30 ml/min; (loading pump 4 ml/min MeCN); column sunfire 100x19 mm 5um(L)). N- [6-amino-5-(trifluoromethyl)-3-pyridyl]-2-[( 2S,5R )-2-(4-fluorophenyl) was obtained as a beige solid in three fractions )-5-methyl-1-piperidinyl]-2-oxoacetamide (114.2 mg, 269.09 μmol, 54.98% yield): Fraction 1 - 29.5 mg (100% by LCMS, single diastereomer); Fraction 2 - 70.4 mg (84.06% by LCMS, 15.94% cis); Fraction 3 - 14.3 mg (59.51% by LCMS, 40.49% cis).

化合物872： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.20-1.37(m,1H),1.59-1.70(m,1H),1.80-1.94(m,1H),1.99-2.13(m,1H),2.13-2.24(m,1H),2.70-3.20(m,1H),3.44-4.02(m,1H),5.12-5.60(m,1H),6.32-6.41(m,2H),7.15-7.24(m,2H),7.27-7.40(m,2H),7.96-8.11(m,1H),8.32-8.45(m,1H),10.70-10.93(m,1H)。 Compound 872: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.96-1.03 (m, 3H), 1.20-1.37 (m, 1H), 1.59-1.70 (m, 1H), 1.80-1.94 (m) ,1H),1.99-2.13(m,1H),2.13-2.24(m,1H),2.70-3.20(m,1H),3.44-4.02(m,1H),5.12-5.60(m,1H),6.32 -6.41(m, 2H), 7.15-7.24(m, 2H), 7.27-7.40(m, 2H), 7.96-8.11(m, 1H), 8.32-8.45(m, 1H), 10.70-10.93(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=3.503min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=3.503 min.

N -(6-胺基-5-甲氧基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物979)之合成 N- (6-Amino-5-methoxypyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-pendoxyl Synthesis of Acetamide (Compound 979)

Figure 110128222-A0202-12-2317-589
Figure 110128222-A0202-12-2317-589

步驟1：(3-甲氧基-5-硝基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl (3-methoxy-5-nitropyridin-2-yl)carbamate

將3-甲氧基-5-硝基吡啶-2-胺(2.00g，11.82mmol)、碳酸第三丁氧基 羰基第三丁酯 (3.87g，17.74mmol，4.07mL)及DMAP(72.23mg，591.23μmol)在DCM(50mL)中回流16h。在冷卻之後，將反應混合物用水洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到N -(3-甲氧基-5-硝基-2-吡啶基)胺甲酸第三丁 酯(1.2g，粗品)，其不經純化即用於下一步驟中。3-Methoxy-5-nitropyridin-2-amine (2.00 g, 11.82 mmol), 3- butoxycarbonyl tert- butyl carbonate (3.87 g, 17.74 mmol, 4.07 mL) and DMAP (72.23 mg) were combined , 591.23 μmol) was refluxed in DCM (50 mL) for 16 h. After cooling, the reaction mixture was washed with water, dried over Na 2 SO 4 and concentrated in vacuo to give tert-butyl N- (3-methoxy-5-nitro-2-pyridyl) carbamate ( 1.2 g, crude), which was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值269.2；實測值270.2；Rt=1.128min。LCMS (ESI): [M] + m/z: calculated 269.2; found 270.2; Rt=1.128 min.

步驟2：(5-胺基-3-甲氧基吡啶-2-基)胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl (5-amino-3-methoxypyridin-2-yl)carbamate

將粗品N -(3-甲氧基-5-硝基-2-吡啶基)胺甲酸第三丁 酯(250.00mg，928.49μmol)溶解於MeOH(20mL)中，隨後一次性添加氯化銨(695.33mg，13.00mmol，454.46μL)及鋅(425.00mg，6.50mmol，59.52μL)。將反應混合物在23℃下攪拌48h然後過濾。在減壓下濃縮濾液且將殘餘物溶解於DCM及水之混合物中。將有機層分離，經Na2 SO4 乾燥且在旋轉蒸發器上濃縮，以得到N -(5-胺基-3-甲氧基-2-吡啶基)胺甲酸第三丁 酯(0.18g，粗品)，其不經純化即用於下一步驟 中。The crude tert-butyl N- (3-methoxy-5-nitro-2-pyridyl) carbamate (250.00 mg, 928.49 μmol) was dissolved in MeOH (20 mL), followed by the addition of ammonium chloride ( 695.33 mg, 13.00 mmol, 454.46 μL) and zinc (425.00 mg, 6.50 mmol, 59.52 μL). The reaction mixture was stirred at 23 °C for 48 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in a mixture of DCM and water. The organic layer was separated, dried over Na 2 SO 4 and concentrated on a rotary evaporator to give 3-butyl N- (5-amino-3-methoxy-2-pyridyl) carbamate (0.18 g, crude product), which was used in the next step without purification.

LCMS(ESI)：[M]+ m/z：計算值239.2；實測值240.2；Rt=0.906min。LCMS (ESI): [M] + m/z: calculated 239.2; found 240.2; Rt=0.906 min.

步驟3：外消旋-(5-(2-((2R,5S)-2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲氧基吡啶-2-基)胺甲酸第三丁酯之合成Step 3: Racemic-(5-(2-((2R,5S)-2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxoacetamide Synthesis of tert-butyl)-3-methoxypyridin-2-yl)carbamate

向N -(5-胺基-3-甲氧基-2-吡啶基)胺甲酸第三丁 酯(0.18g，752.29μmol)、2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(199.57mg，752.29μmol)及DIPEA(97.23mg，752.29μmol，131.03μL)於DMSO(2mL)中之經攪拌之溶液中添加HATU(286.04mg，752.29μmol)。將所得反應混合物在25℃下攪拌14h。完成之後，將反應混合物用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮，以得到N -[5-[[2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲氧基-2-吡啶基]胺甲酸第三丁 酯(0.3g，粗品)，其不經純化即用於下一步驟中。To N- (5-amino-3-methoxy-2-pyridyl)carbamic acid tert -butyl ester (0.18 g, 752.29 μmol), 2-[( 2R,5S )-2-(4-fluorobenzene (199.57 mg, 752.29 μmol) and DIPEA (97.23 mg, 752.29 μmol, 131.03 μL) in DMSO (2 mL) with stirring To the solution was added HATU (286.04 mg, 752.29 μmol). The resulting reaction mixture was stirred at 25 °C for 14 h. After completion, the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried over Na 2 SO 4 and concentrated under reduced pressure to give N- [5-[[2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl -1-Piperidinyl]-2-oxyacetoxy]amino]-3-methoxy-2-pyridyl]carbamic acid tert- butyl ester (0.3 g, crude), which was obtained without purification used in the next step.

LCMS(ESI)：[M]+ m/z：計算值486.2；實測值487.2；Rt=1.331min。LCMS (ESI): [M] + m/z: calculated 486.2; found 487.2; Rt=1.331 min.

步驟4：N-(6-胺基-5-甲氧基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物979 )之合成Step 4: N-(6-Amino-5-methoxypyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2- Synthesis of Pendant Oxyacetamide ( Compound 979 )

將N -[5-[[2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲氧基-2-吡啶基]胺甲酸第三丁 酯(0.3g，616.61μmol)溶解於水(1mL)及1,4-二噁烷(2.5mL)之混合物中且將反應混合物在80℃下攪拌17h。在冷卻之後，在減壓下濃縮反應混合物且將殘餘物提交至反相HPLC(2-10min 0-100% MeOH/水+FA，30ml/min(裝載泵4ml MeOH)；管柱：SunFire 100*19mm，5微米)，以得到N -(6-胺基-5-甲氧基-3-吡啶基)-2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.056g，144.92μmol，23.50%產率)。 N- [5-[[2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]-3-methoxy-2-pyridyl]carbamic acid tert- butyl ester (0.3 g, 616.61 μmol) was dissolved in a mixture of water (1 mL) and 1,4-dioxane (2.5 mL) and the reaction was allowed to The mixture was stirred at 80 °C for 17 h. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was submitted to reverse phase HPLC (2-10 min 0-100% MeOH/water+FA, 30 ml/min (load pump 4 ml MeOH); column: SunFire 100* 19 mm, 5 microns) to give N- (6-amino-5-methoxy-3-pyridyl)-2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl yl-1-piperidinyl]-2-oxoacetamide (0.056 g, 144.92 μmol, 23.50% yield).

化合物979： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.97-1.05(m,3H),1.25-1.39(m,1H),1.59-1.71(m,1H),1.80-1.92(m,1H),1.97-2.13(m,1H),2.13-2.25(m, 1H),2.69-3.21(m,1H),3.43-3.47(m,0.6H),3.70-3.77(m,3H),3.96-4.04(m,0.4H),5.13-5.56(m,1H),5.56-5.64(m,2H),7.16-7.24(m,2H),7.28-7.34(m,2H),7.34-7.41(m,1H),7.71-7.81(m,1H),10.47-10.64(m,1H)。 Compound 979: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.97-1.05 (m, 3H), 1.25-1.39 (m, 1H), 1.59-1.71 (m, 1H), 1.80-1.92 (m ,1H),1.97-2.13(m,1H),2.13-2.25(m,1H),2.69-3.21(m,1H),3.43-3.47(m,0.6H),3.70-3.77(m,3H), 3.96-4.04(m, 0.4H), 5.13-5.56(m, 1H), 5.56-5.64(m, 2H), 7.16-7.24(m, 2H), 7.28-7.34(m, 2H), 7.34-7.41( m, 1H), 7.71-7.81 (m, 1H), 10.47-10.64 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值386.2；實測值387.2；Rt=2.282min。LCMS (ESI): [M] + m/z: calculated 386.2; found 387.2; Rt=2.282 min.

實例722. 2-(二氟甲氧基)-5-(2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物889)之合成Example 722. 2-(Difluoromethoxy)-5-(2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido ) Synthesis of Nicotinamide (Compound 889)

Figure 110128222-A0202-12-2319-590
Figure 110128222-A0202-12-2319-590

步驟1：2-(二氟甲氧基)-5-硝基菸鹼酸甲酯之合成Step 1: Synthesis of methyl 2-(difluoromethoxy)-5-nitronicotinate

向2-羥基-5-硝基吡啶-3-甲酸甲酯(5g，25.24mmol)於無水MeCN(100mL)中之經攪拌之溶液中添加2,2-二氟-2-氟磺醯基乙酸(22.47g，126.18mmol，13.06mL)及硫酸鈉(11.95g，50.47mmol，4.46mL，60%純度)，且將混合物在室溫下在氮氣氣氛下攪拌120h。藉由添加飽和NaHCO3 水溶液來淬滅反應物且將混合物用乙酸乙酯萃取。將有機層用鹽水洗滌，經硫酸鈉乾燥且濃縮。藉由CC(Companion combiflash；120g SiO2 ，氯仿/MeCN，其中MeCN為0~5%，流速=85mL/min，Rv=2-2.5CV)純化殘餘物，以得到呈淡黃色固體之2-(二氟甲氧基)-5-硝基吡啶-3-甲酸甲酯(1g，4.03mmol，15.97%產率)。To a stirred solution of methyl 2-hydroxy-5-nitropyridine-3-carboxylate (5 g, 25.24 mmol) in dry MeCN (100 mL) was added 2,2-difluoro-2-fluorosulfonylacetic acid (22.47 g, 126.18 mmol, 13.06 mL) and sodium sulfate (11.95 g, 50.47 mmol, 4.46 mL, 60% purity), and the mixture was stirred at room temperature under nitrogen atmosphere for 120 h. The reaction was quenched by addition of saturated aqueous NaHCO3 and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by CC (Companion combiflash; 120 g SiO 2 , chloroform/MeCN with 0-5% MeCN, flow rate=85 mL/min, Rv=2-2.5 CV) to give 2-( Difluoromethoxy)-5-nitropyridine-3-carboxylic acid methyl ester (1 g, 4.03 mmol, 15.97% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)3.90(s,3H),7.78(t,1H),8.91(s,1H),9.23(s,1H)。LCMS(ESI)：[M]+ m/z：計算值248.2；實測值249.2；Rt=1.249min。 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm) 3.90 (s, 3H), 7.78 (t, 1H), 8.91 (s, 1H), 9.23 (s, 1H). LCMS (ESI): [M] + m/z: calculated 248.2; found 249.2; Rt=1.249 min.

步驟2：5-胺基-2-(二氟甲氧基)菸鹼酸甲酯之合成Step 2: Synthesis of methyl 5-amino-2-(difluoromethoxy)nicotinate

在三頸圓底燒瓶中向2-(二氟甲氧基)-5-硝基吡啶-3-甲酸甲酯(0.91g，3.67mmol)於MeOH(25mL)中之溶液中添加鈀(10%於碳上)(91.00mg，855.10μmol)。將反應燒瓶抽真空且用分子氫(7.39mg，3.67mmol)回填且使混合物攪拌隔夜。透過薄矽膠墊過濾，得到甲醇溶液，其不經蒸發即用於下一步驟中。計算質量，如同產率為80%一般。To a solution of methyl 2-(difluoromethoxy)-5-nitropyridine-3-carboxylate (0.91 g, 3.67 mmol) in MeOH (25 mL) was added palladium (10%) in a three-necked round bottom flask on carbon) (91.00 mg, 855.10 μmol). The reaction flask was evacuated and backfilled with molecular hydrogen (7.39 mg, 3.67 mmol) and the mixture was allowed to stir overnight. Filtration through a thin pad of silica gel gave methanol solution which was used in the next step without evaporation. The mass was calculated as if the yield was 80%.

LCMS(ESI)：[M]+ m/z：計算值218.2；實測值219.2；Rt=0.780min。LCMS (ESI): [M] + m/z: calculated 218.2; found 219.2; Rt=0.780 min.

步驟3：5-胺基-2-(二氟甲氧基)菸鹼醯胺之合成Step 3: Synthesis of 5-amino-2-(difluoromethoxy)nicotinamide

將氨(49.96mg，2.93mmol)鼓泡穿過5-胺基-2-(二氟甲氧基)吡啶-3-甲酸甲酯(0.64g，2.93mmol)之溶液。16h之後，將反應混合物蒸發至乾，以得到呈米色固體之5-胺基-2-(二氟甲氧基)吡啶-3-甲醯胺(700mg，粗品)，其不經進一步純化即用於下一步驟中。Ammonia (49.96 mg, 2.93 mmol) was bubbled through a solution of methyl 5-amino-2-(difluoromethoxy)pyridine-3-carboxylate (0.64 g, 2.93 mmol). After 16 h, the reaction mixture was evaporated to dryness to give 5-amino-2-(difluoromethoxy)pyridine-3-carboxamide (700 mg, crude) as a beige solid, which was used without further purification in the next step.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)5.35(bds,2H),7.44(m,5H)。LCMS(ESI)：[M]+ m/z：計算值203.2；實測值204.2；Rt=0.644min。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 5.35 (bds, 2H), 7.44 (m, 5H). LCMS (ESI): [M] + m/z: calculated 203.2; found 204.2; Rt=0.644 min.

步驟4：2-(二氟甲氧基)-5-(2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物889 )之合成Step 4: 2-(Difluoromethoxy)-5-(2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido ) Synthesis of Nicotinamide ( Compound 889 )

在室溫下將5-胺基-2-(二氟甲氧基)吡啶-3-甲醯胺(114.87mg，565.44μmol)、HATU(215.00mg，565.44μmol)及TEA(57.22mg，565.44μmol，78.81μL)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加2-[2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(0.15g，565.44μmol)且將所得混合物在室溫下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(35-60% 0.5-6min水-MeCN；流速30ml/min(裝載泵4ml/min；MeCN)；管柱SunFire 100x19mm 5um(R))。獲得呈米色固體之三種級分：第1級分-13.4mg(94.68%反式、5.32%順式)，第2級分- 37.3mg(90.84%反式、9.16%順式)，第3級分-13.5mg(68.57%反式、31.43%順式)。5-Amino-2-(difluoromethoxy)pyridine-3-carboxamide (114.87 mg, 565.44 μmol), HATU (215.00 mg, 565.44 μmol) and TEA (57.22 mg, 565.44 μmol) were mixed at room temperature , 78.81 μL) in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added 2-[2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetic acid (0.15 g, 565.44 μmol) and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (35-60% 0.5-6 min water-MeCN; flow rate 30 ml/min (loading pump 4 ml/min; MeCN); column SunFire 100x19 mm 5um(R)). Three fractions were obtained as beige solids: Fraction 1 - 13.4 mg (94.68% trans, 5.32% cis), Fraction 2 - 37.3 mg (90.84% trans, 9.16% cis), fraction 3 - 13.5 mg (68.57% trans, 31.43% cis).

化合物889： 1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.32(m,1H),1.66(m,1H),1.89(m,1H),2.14(m,2H),3.23(m,1H),3.74(m,1H),5.36(m,1H),7.22(m,2H),7.35(m,2H),7.67(m,3H),8.32(d,1H),8.54(d,1H),11.23(m,1H)。 Compound 889: 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.01 (m, 3H), 1.32 (m, 1H), 1.66 (m, 1H), 1.89 (m, 1H), 2.14 (m, 2H), 3.23(m, 1H), 3.74(m, 1H), 5.36(m, 1H), 7.22(m, 2H), 7.35(m, 2H), 7.67(m, 3H), 8.32(d, 1H) ), 8.54(d, 1H), 11.23(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值450.2；實測值451.2；Rt=3.172min。LCMS (ESI): [M] + m/z: calculated 450.2; found 451.2; Rt=3.172 min.

實例723.N -(5-(二氟甲基)-6-甲氧基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1057)之合成Example 723. N- (5-(Difluoromethyl)-6-methoxypyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl )-2-side oxyacetamide (compound 1057) synthesis

Figure 110128222-A0202-12-2321-591
Figure 110128222-A0202-12-2321-591

步驟1：5-(二氟甲基)-N-(二苯基亞甲基)-6-甲氧基吡啶-3-胺之合成Step 1: Synthesis of 5-(difluoromethyl)-N-(diphenylmethylene)-6-methoxypyridin-3-amine

藉由將氬氣鼓泡到5-溴-3-(二氟甲基)-2-甲氧基吡啶(1g，4.20mmol)、二苯基甲亞胺(837.53mg，4.62mmol，775.49μL)、Xantphos(729.26mg，1.26mmol)、Pd2 (dba)3 (192.36mg，210.06μmol)及碳酸銫(4.11g，12.60mmol)於二噁烷(50mL)中之混合物若干分鐘來將混合物除氣。在90℃、Ar氣氛下，將反應混合物攪拌12h。將反應混合物冷卻至室溫且過濾。在真空中濃縮濾液且將殘餘物用水稀釋。將混合物用乙酸乙酯萃取。將經合併之有機層用水稀釋，經Na2 SO4 乾燥，過濾且濃縮，以得到N -[5-(二氟甲基)-6-甲氧基-3-吡啶基]-1,1-二苯基-甲亞胺(1.65g，粗品)，其不經進一步純化即用於下一步驟中。By bubbling argon through 5-bromo-3-(difluoromethyl)-2-methoxypyridine (1 g, 4.20 mmol), diphenylmethaneimine (837.53 mg, 4.62 mmol, 775.49 μL) , Xantphos (729.26 mg, 1.26 mmol), Pd 2 (dba) 3 (192.36 mg, 210.06 μmol) and a mixture of cesium carbonate (4.11 g, 12.60 mmol) in dioxane (50 mL) for several minutes to degas the mixture . The reaction mixture was stirred for 12 h at 90 °C under Ar atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was diluted with water. The mixture was extracted with ethyl acetate. The combined organic layers were diluted with water, dried over Na 2 SO 4 , filtered and concentrated to give N- [5-(difluoromethyl)-6-methoxy-3-pyridinyl]-1,1- Diphenyl-methylimine (1.65 g, crude) was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)3.89(s,3H),6.69(t,1H),7.32(m,10H),7.74(m,2H)。LCMS(ESI)：[M]+ m/z：計算值338.2；實測值339.2；Rt=1.549min。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 3.89 (s, 3H), 6.69 (t, 1H), 7.32 (m, 10H), 7.74 (m, 2H). LCMS (ESI): [M] + m/z: calculated 338.2; found 339.2; Rt=1.549 min.

步驟2：5-(二氟甲基)-6-甲氧基吡啶-3-胺之合成Step 2: Synthesis of 5-(difluoromethyl)-6-methoxypyridin-3-amine

將36% w/w鹽酸水溶液(8.00g，219.41mmol，10mL)添加到N -[5-(二 氟甲基)-6-甲氧基-3-吡啶基]-1,1-二苯基-甲亞胺(1.65g，4.88mmol)於THF(20mL)及水(10mL)中之溶液中。將所得混合物在20℃下攪拌15h。然後，將其用水(20ml)稀釋且用MTBE(2x20ml)萃取。收集有機層且丟棄。將水層用固體K2 CO3 鹼化至pH

Figure 110128222-A0202-12-2322-459
10-11且用DCM(4x10ml)萃取。將經合併之DCM層經K2 CO3 乾燥且在減壓下濃縮，得到呈紅色油狀物之5-(二氟甲基)-6-甲氧基吡啶-3-胺(0.64g，3.68mmol，75.36%產率)。36% w/w aqueous hydrochloric acid (8.00 g, 219.41 mmol, 10 mL) was added to N- [5-(difluoromethyl)-6-methoxy-3-pyridyl]-1,1-diphenyl - A solution of methylimine (1.65 g, 4.88 mmol) in THF (20 mL) and water (10 mL). The resulting mixture was stirred at 20 °C for 15 h. It was then diluted with water (20ml) and extracted with MTBE (2x20ml). The organic layer was collected and discarded. The aqueous layer was basified to pH with solid K2CO3
Figure 110128222-A0202-12-2322-459
10-11 and extracted with DCM (4x10ml). The combined DCM layers were dried over K2CO3 and concentrated under reduced pressure to give 5-(difluoromethyl)-6-methoxypyridin-3-amine (0.64 g, 3.68 g) as a red oil mmol, 75.36% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)3.52(bds,2H),3.89(s,3H),6.77(t,1H),7.25(s,1H),7.72(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 3.52 (bds, 2H), 3.89 (s, 3H), 6.77 (t, 1H), 7.25 (s, 1H), 7.72 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值174.2；實測值175.2；Rt=0.744min。LCMS (ESI): [M] + m/z: calculated 174.2; found 175.2; Rt=0.744 min.

步驟3：N-(5-(二氟甲基)-6-甲氧基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1057 )之合成Step 3: N-(5-(Difluoromethyl)-6-methoxypyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl )-2-side oxyacetamide ( compound 1057 ) synthesis

在室溫下將5-(二氟甲基)-6-甲氧基吡啶-3-胺(0.05g，287.11μmol)、HATU(109.17mg，287.11μmol)及TEA(29.05mg，287.11μmol，40.02μL)混合於無水DMF(5mL)中且將所得混合物攪拌15min。向其中添加2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸(76.17mg，287.11μmol)且將所得混合物在室溫下攪拌隔夜。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(第1次運行：45-70% 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min；MeCN)；管柱SunFireC18 100x19mm 5um(R)，第2次運行：50-100% 0.5-6.5min水-MeOH；流速30ml/min(裝載泵4ml/min MeOH)；管柱xbridge C18 100x19mm 5um(R))。獲得呈黃色膠狀物之N -[5-(二氟甲基)-6-甲氧基-3-吡啶基]-2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(63.5mg，150.68μmol，52.48%產率)。5-(difluoromethyl)-6-methoxypyridin-3-amine (0.05 g, 287.11 μmol), HATU (109.17 mg, 287.11 μmol) and TEA (29.05 mg, 287.11 μmol, 40.02 μmol) were mixed at room temperature μL) was mixed in dry DMF (5 mL) and the resulting mixture was stirred for 15 min. To this was added 2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxoacetic acid (76.17 mg, 287.11 μmol) and the resulting The mixture was stirred at room temperature overnight. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (1st run: 45-70% 0.5-6.5min water-MeCN; flow rate 30ml/min (load pump 4ml/min; MeCN); column SunFire C18 100x19mm 5um(R), 2nd run : 50-100% 0.5-6.5min water-MeOH; flow rate 30ml/min (load pump 4ml/min MeOH); column xbridge C18 100x19mm 5um(R)). N- [5-(difluoromethyl)-6-methoxy-3-pyridyl]-2-[( 2R,5S )-2-(4-fluorophenyl)- 5-Methyl-1-piperidinyl]-2-oxoacetamide (63.5 mg, 150.68 μmol, 52.48% yield).

化合物1057： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(d,3H),1.32(m,1H),1.66(m,1H),1.91(m,1H),2.03(m,1H),2.17(m,1H),3.21(m,1H),3.48(m,1H),3.92(s, 3H),5.48(m,1H),7.03(m,1H),7.21(m,2H),7.35(m,2H),8.23(m,1H),8.55(m,1H),11.12(m,1H)。 Compound 1057: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.01 (d, 3H), 1.32 (m, 1H), 1.66 (m, 1H), 1.91 (m, 1H), 2.03 (m, 1H), 2.17(m, 1H), 3.21(m, 1H), 3.48(m, 1H), 3.92(s, 3H), 5.48(m, 1H), 7.03(m, 1H), 7.21(m, 2H) ), 7.35(m, 2H), 8.23(m, 1H), 8.55(m, 1H), 11.12(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值421.2；實測值422.2；Rt=3.962min。LCMS (ESI): [M] + m/z: calculated 421.2; found 422.2; Rt=3.962 min.

實例724. N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物989)之合成Example 724. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidine Synthesis of pyridyl]-2-oxoacetamide (compound 989)

Figure 110128222-A0202-12-2323-592
Figure 110128222-A0202-12-2323-592

步驟1.3-環丙基吡啶-2-胺之合成Step 1. Synthesis of 3-cyclopropylpyridin-2-amine

向3-溴吡啶-2-胺(50g，289.00mmol)於甲苯(500mL)及水(100mL)中之溶液中添加環丙基硼酸(32.27g，375.70mmol)、三環己基膦(8.10g，28.90mmol)、無水磷酸鉀(184.03g，867.00mmol)及乙酸鈀(II)(3.24g，14.45mmol)。將反應混合物用Ar吹掃2min且加熱至90℃達16h且隨後在真空中濃縮至乾。將所得黏性物質用水稀釋且用MTBE(3 x 500mL)萃取。將經合併之有機層經硫酸鈉乾燥且在真空中濃縮至乾。獲得呈棕色油狀物之3-環丙基吡啶-2-胺(59g，粗品)，其不經進一步純化即用於下一步驟中。To a solution of 3-bromopyridin-2-amine (50 g, 289.00 mmol) in toluene (500 mL) and water (100 mL) was added cyclopropylboronic acid (32.27 g, 375.70 mmol), tricyclohexylphosphine (8.10 g, 28.90 mmol), anhydrous potassium phosphate (184.03 g, 867.00 mmol) and palladium(II) acetate (3.24 g, 14.45 mmol). The reaction mixture was purged with Ar for 2 min and heated to 90 °C for 16 h and then concentrated to dryness in vacuo. The resulting viscous material was diluted with water and extracted with MTBE (3 x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. 3-Cyclopropylpyridin-2-amine (59 g, crude) was obtained as a brown oil which was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.57(m,2H),0.92(m,2H),1.61(m,1H),4.88(brs,2H),6.58(m,1H),7.23(m,1H),7.94(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.57(m, 2H), 0.92(m, 2H), 1.61(m, 1H), 4.88(brs, 2H), 6.58(m, 1H), 7.23( m, 1H), 7.94 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值134,1；實測值135.2；Rt=0.609min。LCMS (ESI): [M+1] + m/z: calculated 134,1; found 135.2; Rt=0.609 min.

步驟2.5-溴-3-環丙基吡啶-2-胺之合成Step 2. Synthesis of 5-bromo-3-cyclopropylpyridin-2-amine

將NBS(50.87g，285.81mmol，24.22mL)分批添加到3-環丙基吡啶-2-胺(59g，285.81mmol)於無水DCM中之溶液中且將反應混合物在室溫下攪拌3h。將其用水(1×)洗滌且將水層用二氯甲烷(3×)再萃取。將經合併之有機萃取物 用鹽水洗滌(1×)且乾燥(Na2 SO4 )。在減壓下移除溶劑，以得到殘餘物，其藉由CC(Interchim；800g SiO2，氯仿/乙腈，其中乙腈為0~40%，流速=150mL/min，Rv=5-6CV)進行純化，以得到呈棕色固體之5-溴-3-環丙基吡啶-2-胺(30.4g，142.67mmol，49.92%產率)。NBS (50.87 g, 285.81 mmol, 24.22 mL) was added portionwise to a solution of 3-cyclopropylpyridin-2-amine (59 g, 285.81 mmol) in dry DCM and the reaction mixture was stirred at room temperature for 3 h. It was washed with water (1×) and the aqueous layer was re-extracted with dichloromethane (3×). The combined organic extracts were washed with brine ( 1x ) and dried ( Na2SO4 ). The solvent was removed under reduced pressure to give a residue, which was purified by CC (Interchim; 800 g SiO2, chloroform/acetonitrile with 0-40% acetonitrile, flow rate=150 mL/min, Rv=5-6 CV), to give 5-bromo-3-cyclopropylpyridin-2-amine as a brown solid (30.4 g, 142.67 mmol, 49.92% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.59(m,2H),0.94(m,2H),1.59(m,1H),4.78(brs,2H),7.32(s,1H),7.96(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.59(m, 2H), 0.94(m, 2H), 1.59(m, 1H), 4.78(brs, 2H), 7.32(s, 1H), 7.96( s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值212.1；實測值213.2；Rt=0.834min。LCMS (ESI): [M+1] + m/z: calculated 212.1; found 213.2; Rt=0.834 min.

步驟3.6-[5-[第三丁氧基羰基(甲基)胺基]-2-吡啶基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3. 6-[5-[Third-butoxycarbonyl(methyl)amino]-2-pyridyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester synthesis

在室溫下將氨(93.66mg，5.50mmol)鼓泡穿過2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙酸2,2,2-三氟乙酯(1.91g，5.50mmol)(如上文所述製備)於MeOH(50mL)中之溶液。1h之後，將所得混合物蒸發至乾且與苯一起再蒸發。獲得呈白色半固體之2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(1.35g，粗品)。Ammonia (93.66 mg, 5.50 mmol) was bubbled through 2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2- at room temperature A solution of pendant oxyacetic acid 2,2,2-trifluoroethyl ester (1.91 g, 5.50 mmol) (prepared as described above) in MeOH (50 mL). After 1 h, the resulting mixture was evaporated to dryness and re-evaporated with benzene. 2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (1.35 g, crude) was obtained as a white semi-solid ).

1 H NMR(500MHz,DMSO)δ(ppm)0.98(m,3H),1.32(m,1H),1.65-1.97(m,3H),2.60(m,1H),3.14(d,1H),3.39-3.96(m,1H),5.04 and 5.51(two singles rotamers,1H),7.21(m,3H),7.29(m,1H),7.72(m,1H),8.21(m,1H)。 1 H NMR(500MHz,DMSO)δ(ppm)0.98(m,3H),1.32(m,1H),1.65-1.97(m,3H),2.60(m,1H),3.14(d,1H),3.39 -3.96(m,1H),5.04 and 5.51(two singles rotamers,1H),7.21(m,3H),7.29(m,1H),7.72(m,1H),8.21(m,1H).

LCMS(ESI)：[M+1]+ m/z：計算值264.1；實測值265.2；Rt=2.369min。LCMS (ESI): [M+1] + m/z: calculated 264.1; found 265.2; Rt=2.369 min.

步驟4.N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物989 )之合成Step 4. N-(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidine Synthesis of pyridyl]-2-oxoacetamide ( compound 989 )

將2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.1g，378.37μmol)、5-溴-3-環丙基吡啶-2-胺(120.93mg，567.55μmol)、銅(12.02mg，189.18μmol)、碘化銅(I)(7.21mg，37.84μmol，1.28μL)、(S,S)-(+)-N,N'-二甲基-1,2-環己烷二胺(5.38mg，37.84μmol，5.97μL)及碳酸鉀(104.59mg，756.73 μmol，45.67μL)一起混合於甲苯(12mL)中。將氬氣流鼓泡穿過反應混合物達2min，此後將其在密封燒瓶中在105℃下攪拌18h。然後，將其用乙酸乙酯(20ml)及5%NH3 溶液(15ml)稀釋，透過弗羅裡墊過濾所得雙相混合物。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。藉由HPLC(35-60% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；管柱SunFireC18 100x19mm 5um(R))純化殘餘物，得到呈黃色膠狀物之N-(6-胺基-5-環丙基-3-吡啶基)-2-[(2R,5S)-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(2.7mg，6.81μmol，1.80%產率)。2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.1 g, 378.37 μmol), 5- Bromo-3-cyclopropylpyridin-2-amine (120.93 mg, 567.55 μmol), copper (12.02 mg, 189.18 μmol), copper(I) iodide (7.21 mg, 37.84 μmol, 1.28 μL), (S,S )-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (5.38 mg, 37.84 μmol, 5.97 μL) and potassium carbonate (104.59 mg, 756.73 μmol, 45.67 μL) were mixed together in In toluene (12 mL). A stream of argon was bubbled through the reaction mixture for 2 min, after which it was stirred in a sealed flask at 105 °C for 18 h. It was then diluted with ethyl acetate (20ml) and 5% NH3 solution (15ml) and the resulting biphasic mixture was filtered through a pad of Flory. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by HPLC (35-60% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); column SunFire C18 100x19 mm 5um(R)) to give N as a yellow gum -(6-Amino-5-cyclopropyl-3-pyridyl)-2-[(2R,5S)-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetamide (2.7 mg, 6.81 μmol, 1.80% yield).

LCMS(ESI)：[M+1]+ m/z：計算值396.2；實測值397.2；Rt=2.41min。LCMS (ESI): [M+1] + m/z: calculated 396.2; found 397.2; Rt=2.41 min.

實例725.N -(6-胺基-5-(二氟甲氧基)吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1026)之合成Example 725. N- (6-Amino-5-(difluoromethoxy)pyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl )-2-oxyacetamide (Compound 1026) Synthesis

Figure 110128222-A0202-12-2325-593
Figure 110128222-A0202-12-2325-593

步驟1：5-溴-3-(二氟甲氧基)吡啶-2-胺之合成Step 1: Synthesis of 5-bromo-3-(difluoromethoxy)pyridin-2-amine

向3-(二氟甲氧基)吡啶-2-胺(3g，18.74mmol)於MeCN(25mL)中之經攪拌之溶液中添加N -溴琥珀醯亞胺(3.50g，19.67mmol，1.67mL)。將所得混合物在25℃下攪拌12h。在減壓下蒸發MeCN。將殘餘物用水(50ml)稀釋且用EtOAc(2*50ml)萃取。將經合併之有機層用水及鹽水洗滌，經Na2 SO4 乾燥。在減壓下蒸發EtOAc，以得到5-溴-3-(二氟甲氧基)吡啶-2-胺(4g，16.74mmol，89.32%產率)。To a stirred solution of 3-(difluoromethoxy)pyridin-2-amine (3 g, 18.74 mmol) in MeCN (25 mL) was added N -bromosuccinimide (3.50 g, 19.67 mmol, 1.67 mL) ). The resulting mixture was stirred at 25 °C for 12 h. MeCN was evaporated under reduced pressure. The residue was diluted with water (50ml) and extracted with EtOAc (2*50ml). The combined organic layers were washed with water and brine, dried over Na2SO4 . EtOAc was evaporated under reduced pressure to give 5-bromo-3-(difluoromethoxy)pyridin-2-amine (4 g, 16.74 mmol, 89.32% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)4.75(bds,2H),6.52(t,1H),7.41(s,1H),7.98(s,1H)。LCMS(ESI)：[M]+ m/z：計算值239.2；實測值240.2；Rt=1.192min。 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 4.75 (bds, 2H), 6.52 (t, 1H), 7.41 (s, 1H), 7.98 (s, 1H). LCMS (ESI): [M] + m/z: calculated 239.2; found 240.2; Rt=1.192 min.

步驟2：N-(6-胺基-5-(二氟甲氧基)吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物1026 )之合成Step 2: N-(6-Amino-5-(difluoromethoxy)pyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl )-2-side oxyacetamide ( compound 1026 ) synthesis

在裝備有回流冷凝器及玻璃塞之100ml單頸圓底燒瓶中將5-溴-3-(二氟甲氧基)吡啶-2-胺(0.2g，836.76μmol)、2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(221.15mg，836.76μmol)(如上文所示製備)、碘化銅(I)(31.87mg，167.35μmol，5.67μL)、無水碳酸鉀99%(231.30mg，1.67mmol，101.00μL)、N 1 ,N 2 -二甲基環己烷-1,2-二胺(23.80mg，167.35μmol)、銅(2.66mg，41.84μmol)及MeCN(10mL)之混合物抽真空然後用氬氣回填。然後將反應混合物在氬氣、100℃下攪拌36h。然後藉由反相HPLC(50-65% 0-6min H2 O/MeOH/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)目標質量423管柱：YMC Triart C18 100x20mm，5um)純化反應混合物，以得到N -[6-胺基-5-(二氟甲氧基)-3-吡啶基]-2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(19mg，44.98μmol，5.38%產率)。5-Bromo-3-(difluoromethoxy)pyridin-2-amine (0.2 g, 836.76 μmol), 2-[( 2R, 5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (221.15 mg, 836.76 μmol) (prepared as shown above), iodinated Copper(I) (31.87 mg, 167.35 μmol, 5.67 μL), anhydrous potassium carbonate 99% (231.30 mg, 1.67 mmol, 101.00 μL), N 1 ,N 2 -dimethylcyclohexane-1,2-diamine A mixture of (23.80 mg, 167.35 μmol), copper (2.66 mg, 41.84 μmol) and MeCN (10 mL) was evacuated and backfilled with argon. The reaction mixture was then stirred under argon at 100 °C for 36 h. Then by reverse phase HPLC (50-65% 0-6 min H2O /MeOH/0.1% NH4OH , flow rate: 30ml/min (load pump 4ml/min MeOH) target mass 423 column: YMC Triart C18 100x20mm, 5um) purify the reaction mixture to give N- [6-amino-5-(difluoromethoxy)-3-pyridyl]-2-[( 2R,5S )-2-(4-fluorophenyl) -5-Methyl-1-piperidinyl]-2-oxoacetamide (19 mg, 44.98 μmol, 5.38% yield).

化合物1026： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.31(m,1H),2.01(m,3H),3.20(m,1H),3.65(m,2H),5.53(m,1H),5.98(m,2H),7.18(m,1H),7.21(m,2H),7.31(m,2H),7.68(m,1H),8.07(m,1H),10.74(s,1H)。 Compound 1026: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98 (d, 3H), 1.31 (m, 1H), 2.01 (m, 3H), 3.20 (m, 1H), 3.65 (m, 2H), 5.53(m, 1H), 5.98(m, 2H), 7.18(m, 1H), 7.21(m, 2H), 7.31(m, 2H), 7.68(m, 1H), 8.07(m, 1H) ), 10.74(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=2.925min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=2.925 min.

實例726.N -(6-胺基-5-異丙基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物993)之合成Example 726. N- (6-Amino-5-isopropylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2- Synthesis of Pendant Oxyacetamide (Compound 993)

Figure 110128222-A0202-12-2326-594
Figure 110128222-A0202-12-2326-594

步驟1：5-溴-3-異丙基吡啶-2-胺之合成Step 1: Synthesis of 5-bromo-3-isopropylpyridin-2-amine

將NBS(1.37g，7.71mmol，653.42μL)一次性添加到3-異丙基吡啶-2-胺(1g，7.34mmol)於無水DCM(25mL)中之溶液中且將反應混合物在室溫下攪拌2h。將其用水洗滌且將水層用二氯甲烷再萃取。將經合併之有機萃取物用鹽 水洗滌且經Na2 SO4 乾燥。在減壓下移除溶劑，以得到呈棕色固體之粗品5-溴-3-異丙基吡啶-2-胺(1.44g，粗品)。NBS (1.37 g, 7.71 mmol, 653.42 μL) was added in one portion to a solution of 3-isopropylpyridin-2-amine (1 g, 7.34 mmol) in dry DCM (25 mL) and the reaction mixture was allowed to cool at room temperature Stir for 2h. It was washed with water and the aqueous layer was re-extracted with dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4 . The solvent was removed under reduced pressure to give crude 5-bromo-3-isopropylpyridin-2-amine (1.44 g, crude) as a brown solid.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.26(d,6H),2.73(m,1H),5.02(bds,2H),7.45(s,1H),7.96(s,1H)。LCMS(ESI)：[M]+ m/z：計算值215.2；實測值216.2；Rt=0.902min。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.26 (d, 6H), 2.73 (m, 1H), 5.02 (bds, 2H), 7.45 (s, 1H), 7.96 (s, 1H). LCMS (ESI): [M] + m/z: calculated 215.2; found 216.2; Rt=0.902 min.

步驟2：N-(6-胺基-5-異丙基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物993 )之合成Step 2: N-(6-Amino-5-isopropylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2- Synthesis of Pendant Oxyacetamide ( Compound 993 )

將2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.1g，378.37μmol)、5-溴-3-異丙基吡啶-2-胺(81.38mg，378.37μmol)、銅(12.02mg，189.18μmol)、碘化銅(I)(7.21mg，37.84μmol，1.28μL)、(S,S )-(+)-N,N' -二甲基-1,2-環己烷二胺(5.38mg，37.84μmol，5.97μL)及碳酸鉀(104.59mg，756.73μmol，45.67μL)一起混合於甲苯(12mL)中。將氬氣流鼓泡穿過反應混合物達2min，此後將其在密封燒瓶中在105℃下攪拌18h。然後，將其用乙酸乙酯(20ml)及5%NH3 水溶液(15ml)稀釋。透過矽藻土墊過濾所得雙相混合物。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。藉由HPLC(40-70 0.5-6.5min水-MeCN；流速30ml/min(裝載泵4ml/min；MeCN)；管柱SunFireC18 100x19mm 5um(R))純化殘餘物，得到呈黃色膠狀物之N -(6-胺基-5-異丙基-3-吡啶基)-2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(7.4mg，18.57μmol，4.91%產率)。獲得兩種級分：第1級分-1.7mg(藉由LCMS為93.81%)；第2級分-5.7mg(96.8%反式；3.2%順式)。2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.1 g, 378.37 μmol), 5- Bromo-3-isopropylpyridin-2-amine (81.38 mg, 378.37 μmol), copper (12.02 mg, 189.18 μmol), copper(I) iodide (7.21 mg, 37.84 μmol, 1.28 μL), ( S,S )-(+) -N,N' -dimethyl-1,2-cyclohexanediamine (5.38 mg, 37.84 μmol, 5.97 μL) and potassium carbonate (104.59 mg, 756.73 μmol, 45.67 μL) were mixed together in In toluene (12 mL). A stream of argon was bubbled through the reaction mixture for 2 min, after which it was stirred in a sealed flask at 105 °C for 18 h. It was then diluted with ethyl acetate (20ml) and 5% aqueous NH3 (15ml). The resulting biphasic mixture was filtered through a pad of celite. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by HPLC (40-70 0.5-6.5min water-MeCN; flow rate 30ml/min (loading pump 4ml/min; MeCN); column SunFire C18 100x19mm 5um(R)) to give N as a yellow gum -(6-Amino-5-isopropyl-3-pyridyl)-2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetamide (7.4 mg, 18.57 μmol, 4.91% yield). Two fractions were obtained: Fraction 1 - 1.7 mg (93.81% by LCMS); Fraction 2 - 5.7 mg (96.8% trans; 3.2% cis).

化合物993： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.04(m,3H),1.06-1.15(m,6H),1.26-1.38(m,1H),1.59-1.71(m,1H),1.79-1.94(m,1H),1.96-2.12(m,1H),2.13-2.26(m,1H),2.67-2.74(m,0.3H),2.84-2.91(m,1H),3.17-3.22(m,0.7H),3.44-4.05(m,1H),5.11-5.60(m,1H),5.61-5.71(m,2H),7.17-7.24(m, 2H),7.31-7.41(m,2H),7.47-7.57(m,1H),7.98-8.11(m,1H),10.39-1化合物0.69(m,1H)。 Compound 993: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.96-1.04 (m, 3H), 1.06-1.15 (m, 6H), 1.26-1.38 (m, 1H), 1.59-1.71 (m) ,1H),1.79-1.94(m,1H),1.96-2.12(m,1H),2.13-2.26(m,1H),2.67-2.74(m,0.3H),2.84-2.91(m,1H), 3.17-3.22(m, 0.7H), 3.44-4.05(m, 1H), 5.11-5.60(m, 1H), 5.61-5.71(m, 2H), 7.17-7.24(m, 2H), 7.31-7.41( m, 2H), 7.47-7.57 (m, 1H), 7.98-8.11 (m, 1H), 10.39-1 compound 0.69 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值398.2；實測值399.2；Rt=2.635min。LCMS (ESI): [M] + m/z: calculated 398.2; found 399.2; Rt=2.635 min.

實例727.N -(5-乙基-6-甲基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物779)之合成Example 727. N- (5-ethyl-6-methylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide (Compound 779)

Figure 110128222-A0202-12-2328-595
Figure 110128222-A0202-12-2328-595

步驟1：2-(3-溴-5-硝基吡啶-2-基)丙二酸二乙酯之合成Step 1: Synthesis of diethyl 2-(3-bromo-5-nitropyridin-2-yl)malonate

將丙二酸二乙酯(20.24g，126.35mmol，19.09mL)逐滴添加到於礦物油中之氫化鈉(油分散物)60%分散物(5.81g，145.30mmol，60%純度)於DMF(200mL)中之懸浮液中。在H2 逸出停止之後，在30分鐘期間分批添加3-溴-2-氯-5-硝基吡啶(15g，63.17mmol)。將所得混合物在20℃下攪拌15h。然後，將其倒入到硫酸氫鈉單水合物(21.81g，157.94mmol)於水(800mL)中之冰冷溶液中。將所得混合物用乙酸乙酯(2x250ml)萃取。將有機層分離且依次用水(2x150ml)及鹽水(100ml)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。將殘餘物用冷(-5-0℃)己烷(150ml)稀釋。藉由過濾收集沉澱之橙色固體且乾燥，得到2-(3-溴-5-硝基-2-吡啶基)丙二酸二乙酯(21.8g，60.36mmol，95.55%產率)。Diethyl malonate (20.24 g, 126.35 mmol, 19.09 mL) was added dropwise to a 60% dispersion of sodium hydride (oil dispersion) in mineral oil (5.81 g, 145.30 mmol, 60% pure) in DMF (200 mL). After H2 evolution ceased, 3-bromo-2-chloro-5-nitropyridine (15 g, 63.17 mmol) was added portionwise over 30 minutes. The resulting mixture was stirred at 20 °C for 15 h. It was then poured into an ice-cold solution of sodium bisulfate monohydrate (21.81 g, 157.94 mmol) in water (800 mL). The resulting mixture was extracted with ethyl acetate (2x250ml). The organic layer was separated and washed sequentially with water (2x150ml) and brine (100ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was diluted with cold (-5-0°C) hexanes (150ml). The precipitated orange solid was collected by filtration and dried to give diethyl 2-(3-bromo-5-nitro-2-pyridyl)malonate (21.8 g, 60.36 mmol, 95.55% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.30(t,6H),4.31(m,4H),5.28(s,1H),8.68(s,1H),9.33(s,1H)。LCMS(ESI)：[M]+ m/z：計算值361.2；實測值362.2；Rt=1.373min。 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 1.30 (t, 6H), 4.31 (m, 4H), 5.28 (s, 1H), 8.68 (s, 1H), 9.33 (s, 1H). LCMS (ESI): [M] + m/z: calculated 361.2; found 362.2; Rt=1.373 min.

步驟2：3-溴-2-甲基-5-硝基吡啶之合成Step 2: Synthesis of 3-bromo-2-methyl-5-nitropyridine

將2-(3-溴-5-硝基-2-吡啶基)丙二酸二乙酯(21.8g，60.36mmol)懸浮於硫酸(10%)(214.00g，218.19mmol，200mL，10%純度)中且將所得混合物在110℃下攪拌5h。然後，將其冷卻且用DCM(3x60ml)萃取。將經合併之有機層經Na2 SO4 乾燥且在減壓下濃縮，得到3-溴-2-甲基-5-硝基吡啶(12.5g，57.60mmol，95.42%產率)。Diethyl 2-(3-bromo-5-nitro-2-pyridyl)malonate (21.8 g, 60.36 mmol) was suspended in sulfuric acid (10%) (214.00 g, 218.19 mmol, 200 mL, 10% pure ) and the resulting mixture was stirred at 110 °C for 5 h. It was then cooled and extracted with DCM (3x60ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 3-bromo-2-methyl-5-nitropyridine (12.5 g, 57.60 mmol, 95.42% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)2.78(s,3H),8.58(s,1H),9.22(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 2.78 (s, 3H), 8.58 (s, 1H), 9.22 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值217.2；實測值218.2；Rt=1.188min。LCMS (ESI): [M] + m/z: calculated 217.2; found 218.2; Rt=1.188 min.

步驟3：2-甲基-5-硝基-3-乙烯基吡啶之合成Step 3: Synthesis of 2-methyl-5-nitro-3-vinylpyridine

將碳酸鈉(7.33g，69.12mmol，2.90mL)添加到3-溴-2-甲基-5-硝基吡啶(6g，27.65mmol)及三氟(乙烯基)硼氫化物(5.18g，38.71mmol，K+ )於二噁烷(80mL)及水(30mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2 *DCM(903.11mg，1.11mmol)。在惰性氣氛下將所得混合物在90℃下攪拌24h。然後，將其在減壓下濃縮且將殘餘物用50：50混合物己烷/MTBE(100ml)萃取。透過短矽膠墊過濾所獲得之溶液且在減壓下蒸發，得到2-甲基-5-硝基-3-乙烯基吡啶(3.2g，19.49mmol，70.51%產率)。Sodium carbonate (7.33 g, 69.12 mmol, 2.90 mL) was added to 3-bromo-2-methyl-5-nitropyridine (6 g, 27.65 mmol) and trifluoro(vinyl)borohydride (5.18 g, 38.71 mmol) mmol, K + ) in dioxane (80 mL) and water (30 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, Pd(dppf)Cl2*DCM ( 903.11 mg, 1.11 mmol) was added under argon flow. The resulting mixture was stirred at 90 °C for 24 h under an inert atmosphere. It was then concentrated under reduced pressure and the residue was extracted with a 50:50 mixture hexane/MTBE (100 ml). The resulting solution was filtered through a short pad of silica gel and evaporated under reduced pressure to give 2-methyl-5-nitro-3-vinylpyridine (3.2 g, 19.49 mmol, 70.51% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)2.69(s,3H),5.61(d,1H),5.86(d,1H),6.92(m,1H),8.47(s,1H),9.20(s,1H)。LCMS(ESI)：[M]+ m/z：計算值164.2；實測值165.2；Rt=1.132min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 2.69(s, 3H), 5.61(d, 1H), 5.86(d, 1H), 6.92(m, 1H), 8.47(s, 1H), 9.20( s, 1H). LCMS (ESI): [M] + m/z: calculated 164.2; found 165.2; Rt=1.132 min.

步驟4：5-乙基-6-甲基吡啶-3-胺之合成Step 4: Synthesis of 5-ethyl-6-methylpyridin-3-amine

將鈀(10%於碳上)(400mg，375.87μmol，10%純度)添加到2-甲基-5-硝基-3-乙烯基吡啶(3.2g，19.49mmol)於MeOH(60mL)中之溶液中。將反應燒瓶抽真空且用來自所附氣球之氫氣(785.88mg，389.86mmol)回填。將所得混合物在20℃下攪拌16h。然後，過濾出催化劑且在減壓下濃縮濾液，得到5-乙基-6-甲基吡啶-3-胺(2.6g，19.09mmol，97.93%產率)。Palladium (10% on carbon) (400 mg, 375.87 μmol, 10% pure) was added to 2-methyl-5-nitro-3-vinylpyridine (3.2 g, 19.49 mmol) in MeOH (60 mL) in solution. The reaction flask was evacuated and backfilled with hydrogen (785.88 mg, 389.86 mmol) from the attached balloon. The resulting mixture was stirred at 20 °C for 16 h. Then, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 5-ethyl-6-methylpyridin-3-amine (2.6 g, 19.09 mmol, 97.93% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.15(t,3H),2.38(s,3H),2.52(m,2H),3.45(m,2H),6.77(s,1H),7.82(s,1H)。LCMS(ESI)：[M]+ m/z：計算值136.2；實測值137.2；Rt=0.568min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.15(t, 3H), 2.38(s, 3H), 2.52(m, 2H), 3.45(m, 2H), 6.77(s, 1H), 7.82( s, 1H). LCMS (ESI): [M] + m/z: calculated 136.2; found 137.2; Rt=0.568 min.

步驟5：2-((5-乙基-6-甲基吡啶-3-基)胺基)-2-側氧基乙酸苯甲酯之合成Step 5: Synthesis of benzyl 2-((5-ethyl-6-methylpyridin-3-yl)amino)-2-oxoacetate

在0℃下，將2-氯-2-側氧基乙酸苯甲酯(4.17g，21.00mmol)於MeCN(15mL)中之溶液逐滴添加到5-乙基-6-甲基吡啶-3-胺(2.6g，19.09mmol)及N,N -二異丙基乙胺(2.96g，22.91mmol，3.99mL)於MeCN(30mL)中之經攪拌之溶液中。使反應混合物升溫至25℃且攪拌4h，然後在真空中蒸發。將殘餘物用水(60ml)稀釋且攪拌0.5h。過濾沉澱，將其依次用水(2x30ml)及己烷(30ml)洗滌且風乾，以得到呈淡棕色固體之2-[(5-乙基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸苯甲酯(5.06g，16.96mmol，88.84%產率)。A solution of benzyl 2-chloro-2-oxoacetate (4.17 g, 21.00 mmol) in MeCN (15 mL) was added dropwise to 5-ethyl-6-methylpyridine-3 at 0 °C - A stirred solution of amine (2.6 g, 19.09 mmol) and N,N -diisopropylethylamine (2.96 g, 22.91 mmol, 3.99 mL) in MeCN (30 mL). The reaction mixture was warmed to 25 °C and stirred for 4 h, then evaporated in vacuo. The residue was diluted with water (60 ml) and stirred for 0.5 h. The precipitate was filtered, washed with water (2x30ml) followed by hexanes (30ml) and air-dried to give 2-[(5-ethyl-6-methyl-3-pyridinyl)amino]- as a light brown solid Benzyl 2-oxoacetate (5.06 g, 16.96 mmol, 88.84% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.15(t,3H),2.41(s,3H),2.59(m,2H),5.33(s,2H),7.46(m,5H),7.88(s,1H),8.62(s,1H),10.94(s,1H)。LCMS(ESI)：[M]+ m/z：計算值298.2；實測值299.2；Rt=1.002min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.15(t, 3H), 2.41(s, 3H), 2.59(m, 2H), 5.33(s, 2H), 7.46(m, 5H), 7.88(s, 1H), 8.62(s, 1H), 10.94(s, 1H). LCMS (ESI): [M] + m/z: calculated 298.2; found 299.2; Rt=1.002 min.

步驟6：2-((5-乙基-6-甲基吡啶-3-基)胺基)-2-側氧基乙酸之合成Step 6: Synthesis of 2-((5-ethyl-6-methylpyridin-3-yl)amino)-2-oxoacetic acid

將2-[(5-乙基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸苯甲酯(5.06g，16.96mmol)及鈀(10%於碳上)(0.6g，563.80μmol，10%純度)於MeOH(100mL)中之混合物在氫氣氣氛、20℃下攪拌12h。然後，添加TEA(3.43g，33.92mmol，4.73mL)且繼續攪拌5分鐘。過濾出催化劑，且在減壓下將濾液蒸發至乾，得到2-[(5-乙基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸(5.06g，16.35mmol，96.42%產率，Et3 N)。Benzyl 2-[(5-ethyl-6-methyl-3-pyridinyl)amino]-2-oxoacetate (5.06 g, 16.96 mmol) and palladium (10% on carbon) ( A mixture of 0.6 g, 563.80 μmol, 10% pure) in MeOH (100 mL) was stirred at 20 °C for 12 h under a hydrogen atmosphere. Then, TEA (3.43 g, 33.92 mmol, 4.73 mL) was added and stirring was continued for 5 minutes. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure to give 2-[(5-ethyl-6-methyl-3-pyridinyl)amino]-2-pendoxoacetic acid (5.06 g, 16.35 g mmol, 96.42% yield, Et3N ).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.13(t,3H),2.34(s,3H),2.52(m,2H),7.88(s,1H),8.59(s,1H),10.13(s,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.13(t, 3H), 2.34(s, 3H), 2.52(m, 2H), 7.88(s, 1H), 8.59(s, 1H), 10.13(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值208.2；實測值209.2；Rt=0.636min。LCMS (ESI): [M] + m/z: calculated 208.2; found 209.2; Rt=0.636 min.

步驟7：N-(5-乙基-6-甲基吡啶-3-基)-2-(2-(4-氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物779 )之合成Step 7: N-(5-Ethyl-6-methylpyridin-3-yl)-2-(2-(4-fluorophenyl)-5-methylpiperidin-1-yl)-2-side Synthesis of Oxyacetamide ( Compound 779 )

向2-[(5-乙基-6-甲基-3-吡啶基)胺基]-2-側氧基乙酸(128mg，413.70μmol，Et3 N)、(2R,5S )-2-(4-氟苯基)-5-甲基哌啶(80mg，413.95μmol)及TEA(62.79mg，620.55μmol，86.49μL)於DMF(2mL)中之經攪拌之混合物中添加HATU(173.03mg，455.07μmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC Triart C18 100x20mm，5um 50-90% 0-5min；H2 O-MeOH(0.1% NH3 )，流速：30ml/min)且隨後使其經歷掌性HPLC(管柱：Chiralpak AD-H(250x20mm，5um)；流動相：己烷-IPA-MeOH，50-25-25；流速：12mL/min；管柱溫度：24℃)，得到N -(5-乙基-6-甲基-3-吡啶基)-2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(96mg，250.35μmol，60.52%產率)。To 2-[(5-ethyl-6-methyl-3-pyridinyl)amino]-2-oxoacetic acid (128 mg, 413.70 μmol, Et3N ), ( 2R,5S )-2-( To a stirred mixture of 4-fluorophenyl)-5-methylpiperidine (80 mg, 413.95 μmol) and TEA (62.79 mg, 620.55 μmol, 86.49 μL) in DMF (2 mL) was added HATU (173.03 mg, 455.07 μmol). The resulting reaction mixture was stirred at 20 °C for 4 h. It was then subjected to HPLC (column: YMC Triart C18 100x20mm, 5um 50-90% 0-5min; H2O -MeOH (0.1% NH3 ), flow rate: 30ml/min) and then chiral HPLC (column: Chiralpak AD-H (250x20mm, 5um); mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 12 mL/min; column temperature: 24°C) to give N- (5- Ethyl-6-methyl-3-pyridyl)-2-[( 2R,5S )-2-(4-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetamide (96 mg, 250.35 μmol, 60.52% yield).

化合物779： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.03(m,3H),1.08-1.17(m,3H),1.27-1.38(m,1H),1.59-1.71(m,1H),1.81-1.91(m,1H),1.98-2.13(m,1H),2.14-2.24(m,1H),2.36-2.42(m,3H),2.50-2.58(m,2H),2.70-3.25(m,1H),3.38-4.04(m,1H),5.07-5.62(m,1H),7.15-7.26(m,2H),7.31-7.42(m,2H),7.75-7.85(m,1H),8.37-8.57(m,1H),10.83-11.03(m,1H)。 Compound 779: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.96-1.03 (m, 3H), 1.08-1.17 (m, 3H), 1.27-1.38 (m, 1H), 1.59-1.71 (m) ,1H),1.81-1.91(m,1H),1.98-2.13(m,1H),2.14-2.24(m,1H),2.36-2.42(m,3H),2.50-2.58(m,2H),2.70 -3.25(m, 1H), 3.38-4.04(m, 1H), 5.07-5.62(m, 1H), 7.15-7.26(m, 2H), 7.31-7.42(m, 2H), 7.75-7.85(m, 1H), 8.37-8.57 (m, 1H), 10.83-11.03 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值383.2；實測值384.2；Rt=1.088min。LCMS (ESI): [M] + m/z: calculated 383.2; found 384.2; Rt=1.088 min.

實例728.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(5-(1-(四氫-2H -哌喃-2-基)-1H -吡唑-5-基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺(化合物556及化合物577)之合成Example 728. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(5-(1-(tetrahydro- 2H -pyran-2- yl)-1H-pyrazol-5- yl )thiophen-2-yl)piperidin-1-yl)-2-oxoacetamide (Compound 556 and Compound 577)

Figure 110128222-A0202-12-2332-596
Figure 110128222-A0202-12-2332-596

步驟1：(5-(2-(2-(5-溴噻吩-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 1: (5-(2-(2-(5-Bromothiophen-2-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methyl Synthesis of tert-butyl pyridin-2-yl)carbamate

將2-(5-溴-2-噻吩基)-5-甲基哌啶(0.35g，1.35mmol)(如中間物3C之合成中所述製備)及2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(397.21mg，1.35mmol)混合於DMF(30mL)中。將反應懸浮液冷卻至20℃且添加HATU(511.47mg，1.35mmol)，隨後添加TEA(136.12mg，1.35mmol，187.49μL)，且在環境溫度下攪拌15h。將反應混合物在真空中蒸發且倒入到水(200ml)中且用EtOAc(2x60ml)萃取。將經合併之有機萃取物用水(2*30ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物N -[5-[[2-[2-(5-溴-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.5g，930.29μmol，69.16%產率)。2-(5-Bromo-2-thienyl)-5-methylpiperidine (0.35 g, 1.35 mmol) (prepared as described in the synthesis of intermediate 3C) and 2-[[6-( tertiary butyl Oxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (397.21 mg, 1.35 mmol) was mixed in DMF (30 mL). The reaction suspension was cooled to 20°C and HATU (511.47 mg, 1.35 mmol) was added followed by TEA (136.12 mg, 1.35 mmol, 187.49 μL) and stirred at ambient temperature for 15 h. The reaction mixture was evaporated in vacuo and poured into water (200ml) and extracted with EtOAc (2x60ml). The combined organic extracts were washed with water (2*30ml), dried over sodium sulfate and evaporated in vacuo to give the product N- [5-[[2-[2-(5-bromo-2-thienyl) -5-Methyl-1-piperidinyl]-2-oxoacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.5 g, 930.29 μmol, 69.16 g %Yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.26(d,3H),1.49(s,9H),2.02(s,3H),2.27(m,4H),2.77(m,1H),3.69(m,1H),4.76(m,2H),6.71(m,2H),6.93(m,1H),8.04(m,1H),8.32(m,1H),9.20(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.26(d,3H), 1.49(s,9H), 2.02(s,3H), 2.27(m,4H), 2.77(m,1H), 3.69( m, 1H), 4.76 (m, 2H), 6.71 (m, 2H), 6.93 (m, 1H), 8.04 (m, 1H), 8.32 (m, 1H), 9.20 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值537.2；實測值538.2；Rt=1.443min。LCMS (ESI): [M] + m/z: calculated 537.2; found 538.2; Rt=1.443 min.

步驟2：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-2-(5-(1-(四氫-2H-哌喃-2-基)-1H-吡唑-5-基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之Step 2: Racemic-(3-Methyl-5-(2-((2R,5S)-5-methyl-2-(5-(1-(tetrahydro-2H-pyran-2-yl) )-1H-pyrazol-5-yl)thiophen-2-yl)piperidin-1-yl)-2-oxyacetamido)pyridin-2-yl)carbamic acid tert-butyl ester 合成synthesis

將N -[5-[[2-[2-(5-溴-2-噻吩基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.5g，930.29μmol)及1-四氫哌喃-2-基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑(258.76mg，930.29μmol)一起混合於水(2mL)中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加水(2mL)中之碳酸鈉(197.20mg，1.86mmol，77.95μL)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(37.99mg，46.51μmol)。將反應混合物在氬氣、100℃下攪拌18h，然後冷卻且在真空中蒸發，將其倒入水(50ml)中且用EtOAc(2x20ml)萃取。將經合併之有機萃取物用水(2*10ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到產物N -[3-甲基-5-[[2-[5-甲基-2-[5-(2-四氫哌喃-2-基吡唑-3-基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.63g，粗品)。 N- [5-[[2-[2-(5-bromo-2-thienyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3 -Methyl-2-pyridyl]carbamic acid tert- butyl ester (0.5g, 930.29μmol) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborol-2-yl)pyrazole (258.76 mg, 930.29 μmol) were mixed together in water (2 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then sodium carbonate (197.20 mg, 1.86 mmol, 77.95 μL) and [1,1′-bis(1,1′-bis() in water (2 mL) were added under argon Diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (37.99 mg, 46.51 [mu]mol). The reaction mixture was stirred under argon at 100°C for 18h, then cooled and evaporated in vacuo, poured into water (50ml) and extracted with EtOAc (2x20ml). The combined organic extracts were washed with water (2*10ml), dried over sodium sulfate and evaporated in vacuo to give the product N- [3-methyl-5-[[2-[5-methyl-2- [5-(2-Tetrahydropyran-2-ylpyrazol-3-yl)-2-thienyl]-1-piperidinyl]-2-oxyacetyl]amino]-2- 3-Butyl pyridyl]carbamate (0.63 g, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.09(d,3H),1.23(s,9H),1.57(m,5H),2.02(s,3H),3.36(m,1H),3.68(m,4H),4.09(m,4H),4.36(m,2H),5.34(m,2H),6.93(m,2H),7.72(m,3H),8.04(m,1H),9.04(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.09(d, 3H), 1.23(s, 9H), 1.57(m, 5H), 2.02(s, 3H), 3.36(m, 1H), 3.68( m, 4H), 4.09(m, 4H), 4.36(m, 2H), 5.34(m, 2H), 6.93(m, 2H), 7.72(m, 3H), 8.04(m, 1H), 9.04(m , 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值508.2；實測值509.2；Rt=1.054min。LCMS (ESI): [M-Boc] + m/z: calculated 508.2; found 509.2; Rt=1.054 min.

步驟3：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(5-(1-(四氫-2H-哌喃-2-基)-1H-吡唑-5-基)噻吩-2-基)哌啶-1-基)-2-側氧基乙醯胺(化合物556 及化合物577 )之合成Step 3: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(5-(1-(tetrahydro-2H-pyran-2-yl) )-1H-pyrazol-5-yl)thiophen-2-yl)piperidin-1-yl)-2-oxoacetamide ( compound 556 and compound 577 ) synthesis

將於二噁烷中之4.0M氯化氫溶液(2.40g，65.82mmol，3mL)添加到N -[3-甲基-5-[[2-[5-甲基-2-[5-(2-四氫哌喃-2-基吡唑-3-基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.63g，1.03mmol)於MeOH(20mL)中之溶液中。將反應混合物在25℃下攪拌14h，然後在真空中蒸發且藉由製備型(50-100% 0-9.5min水-MeOH(NH3 0.1%)，流速30ml/min)純化0.36g所獲得 之粗產物，以得到產物N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-[5-(1H -吡唑-5-基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯胺(0.0159g，37.45μmol，3.62%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5R )-5-甲基-2-[5-(1H -吡唑-5-基)-2-噻吩基]-1-哌啶基]-2-側氧基乙醯胺(0.0045g，10.60μmol，1.02%產率)。A 4.0 M solution of hydrogen chloride in dioxane (2.40 g, 65.82 mmol, 3 mL) was added to N- [3-methyl-5-[[2-[5-methyl-2-[5-(2- Tetrahydropyran-2-ylpyrazol- 3 -yl)-2-thienyl]-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid A solution of tributyl ester (0.63 g, 1.03 mmol) in MeOH (20 mL). The reaction mixture was stirred at 25 °C for 14 h, then evaporated in vacuo and 0.36 g of obtained was purified by preparative (50-100% 0-9.5 min water-MeOH ( NH3 0.1%), flow rate 30 ml/min) crude product to give the product N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-[5-( 1H -pyrazole- 5-yl)-2-thienyl]-1-piperidinyl]-2-oxyacetamide (0.0159 g, 37.45 μmol, 3.62% yield) and N-(6-amino-5-methyl) yl-3-pyridyl)-2-[( 2R,5R )-5-methyl-2-[5-( 1H -pyrazol-5-yl)-2-thienyl]-1-piperidinyl] -2-Pendant oxyacetamide (0.0045 g, 10.60 μmol, 1.02% yield).

化合物556： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.75-1.00(m,3H),1.27-1.43(m,1H),1.64-1.93(m,2H),1.97-2.04(m,4H),2.05-2.29(m,1H),2.59-2.96(m,1H),3.44-4.23(m,1H),5.36-5.81(m,3H),6.86-6.93(m,1H),7.03-7.10(m,1H),7.45-7.52(m,1H),7.66-7.75(m,1H),7.97-8.06(m,2H),10.43-10.53(m,1H),12.95(s,1H)。 Compound 556: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.75-1.00 (m, 3H), 1.27-1.43 (m, 1H), 1.64-1.93 (m, 2H), 1.97-2.04 (m) ,4H),2.05-2.29(m,1H),2.59-2.96(m,1H),3.44-4.23(m,1H),5.36-5.81(m,3H),6.86-6.93(m,1H),7.03 -7.10(m,1H),7.45-7.52(m,1H),7.66-7.75(m,1H),7.97-8.06(m,2H),10.43-10.53(m,1H),12.95(s,1H) .

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=0.873min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=0.873 min.

化合物577： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.84(d,3H),1.85(m,1H),1.97(m,1H),2.00(s,3H),2.17(m,1H),3.03(m,1H),3.13(m,1H),5.68(m,2H),5.91(m,1H),6.53(d,1H),6.85(d,1H),7.01(d,1H),7.59(m,1H),7.70(s,1H),8.00(s,1H),8.16(d,1H),8.88(t,1H),10.34(s,1H),12.96(s,1H)。 Compound 577: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.84 (d, 3H), 1.85 (m, 1H), 1.97 (m, 1H), 2.00 (s, 3H), 2.17 (m, 1H), 3.03(m, 1H), 3.13(m, 1H), 5.68(m, 2H), 5.91(m, 1H), 6.53(d, 1H), 6.85(d, 1H), 7.01(d, 1H) ), 7.59(m, 1H), 7.70(s, 1H), 8.00(s, 1H), 8.16(d, 1H), 8.88(t, 1H), 10.34(s, 1H), 12.96(s, 1H) .

LCMS(ESI)：[M]+ m/z：計算值424.2；實測值425.2；Rt=2.092min。LCMS (ESI): [M] + m/z: calculated 424.2; found 425.2; Rt=2.092 min.

實例729. 2-(1'-乙醯基-5-甲基-[2,4'-聯哌啶]-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物737)、N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-[2,4'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物708)及1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-N ,5-二甲基-[2,4'-聯哌啶]-1'-甲醯胺(化合物781)之合成Example 729. 2-(1'-Acetyl-5-methyl-[2,4'-bipiperidin]-1-yl)-N-(6-amino - 5-methylpyridine-3- yl)-2-oxyacetamide (Compound 737), N- (6-amino-5-methylpyridin-3-yl)-2-(5-methyl-[2,4'-biphenyl] Piperidin]-1-yl)-2-oxoacetamide (Compound 708) and 1-(2-((6-amino-5-methylpyridin-3-yl)amino)-2- Synthesis of pendant oxyacetyl) -N ,5-dimethyl-[2,4'-bipiperidine]-1'-carboxamide (Compound 781)

Figure 110128222-A0202-12-2335-597
Figure 110128222-A0202-12-2335-597

步驟1：外消旋-4-((2R,5S)-1-(2-((6-((第三丁氧基羰基)胺基)-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)-5,6-二氫吡啶-1(2H)-甲酸苯甲酯之合成Step 1: Racemic-4-((2R,5S)-1-(2-((6-((3rd-butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino )-2-oxyethanoyl)-5-methylpiperidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid benzyl

在室溫下將HATU(3.39g，8.91mmol)分批添加到2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(2.63g，8.91mmol)、4-[(2R,5S )-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(7g，8.91mmol)及DIPEA(6.91g，53.43mmol，9.31mL)於DMF(100mL)中之懸浮液中。將澄清溶液在25℃下攪拌32h且在真空中蒸發溶劑。將殘餘物溶解於EtOAc(300mL)中，用水(5x100mL)洗滌，在真空中蒸發且藉由矽膠急驟層析使用0至100% MTB-氯仿梯度溶析來純化，以得到4-[(2R,5S )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(3.3g，5.58mmol，62.63%產率)。HATU (3.39 g, 8.91 mmol) was added portionwise to 2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2- at room temperature Pendant oxyacetic acid (2.63 g, 8.91 mmol), 4-[( 2R,5S )-5-methyl-2-piperidinyl]-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (7 g, 8.91 mmol) and DIPEA (6.91 g, 53.43 mmol, 9.31 mL) in a suspension of DMF (100 mL). The clear solution was stirred at 25 °C for 32 h and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc (300 mL), washed with water (5 x 100 mL), evaporated in vacuo and purified by silica gel flash chromatography using a 0 to 100% MTB-chloroform gradient to give 4-[( 2R, 5S )-1-[2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-side oxyacetyl]-5-methyl yl-2-piperidinyl]-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (3.3 g, 5.58 mmol, 62.63% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.06(d,3H),1.39(s,9H),2.14(m,8H),2.36(m,4H),3.89(m,4H),4.36(m,1H),5.06(s,2H),5.86(m,1H),7.31(m,5H),7.86(m,1H),8.38(m,1H),9.03(m,1H),10.89(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.06(d,3H), 1.39(s,9H), 2.14(m,8H), 2.36(m,4H), 3.89(m,4H), 4.36(m, 1H), 5.06(s, 2H), 5.86(m, 1H), 7.31(m, 5H), 7.86(m, 1H), 8.38(m, 1H), 9.03(m, 1H), 10.89 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值591.2；實測值592.2；Rt=1.390min。LCMS (ESI): [M] + m/z: calculated 591.2; found 592.2; Rt=1.390 min.

步驟2：外消旋-(3-甲基-5-(2-((2R,5S)-5-甲基-[2,4'-聯哌啶]-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 2: Racemic-(3-methyl-5-(2-((2R,5S)-5-methyl-[2,4'-bipiperidin]-1-yl)-2-oxygen Synthesis of tert-butyl acetamido)pyridin-2-yl)carbamate

向4-[(2R,5S )-1-[2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-3,6-二氫-2H -吡啶-1-甲酸苯甲酯(3.5g，5.92mmol)於MeOH(350mL)中之溶液中添加鈀(10%於碳上)(629.50mg，5.92mmol)。在氫氣氣氛(1bar)下進行反應且在45℃下劇烈攪拌。48h之後，藉由過濾移除催化劑，且在真空中濃縮濾液，以得到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(4-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(2.5g，5.44mmol，91.96%產率)。to 4-[( 2R,5S )-1-[2-[[6-( tert- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoethyl Acyl]-5-methyl-2-piperidinyl]-3,6-dihydro- 2H -pyridine-1-carboxylic acid benzyl ester (3.5 g, 5.92 mmol) in MeOH (350 mL) was added Palladium (10% on carbon) (629.50 mg, 5.92 mmol). The reaction was carried out under a hydrogen atmosphere (1 bar) with vigorous stirring at 45°C. After 48 h, the catalyst was removed by filtration and the filtrate was concentrated in vacuo to give N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(4- Piperidinyl)-1-piperidinyl]-2-oxoacetyl]amino]-2-pyridyl]carbamic acid tert -butyl ester (2.5 g, 5.44 mmol, 91.96% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.92(d,3H),1.36(s,3H),1.41(s,9H),1.96(m,4H),2.19(m,4H),2.96(m,3H),3.14(m,4H),4.26(m,1H),7.91(m,2H),8.38(m,1H),9.02(m,2H),11.05(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.92(d,3H), 1.36(s,3H), 1.41(s,9H), 1.96(m,4H), 2.19(m,4H), 2.96(m,3H), 3.14(m,4H), 4.26(m,1H), 7.91(m,2H), 8.38(m,1H), 9.02(m,2H), 11.05(m,1H).

LCMS(ESI)：[M]+ m/z：計算值459.2；實測值460.2；Rt=1.014min。LCMS (ESI): [M] + m/z: calculated 459.2; found 460.2; Rt=1.014 min.

步驟3：2-(1'-乙醯基-5-甲基-[2,4'-聯哌啶]-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物737 )之合成Step 3: 2-(1'-Acetyl-5-methyl-[2,4'-bipiperidin]-1-yl)-N-(6-amino-5-methylpyridine-3- Synthesis of yl)-2-oxoacetamide ( Compound 737 )

在室溫下將HATU(413.67mg，1.09mmol)分批添加到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(4-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.5g，1.09mmol)、乙酸(65.33mg，1.09mmol，62.22μL)及DIPEA(843.64mg，6.53mmol，1.14mL)於DMF(50mL)中之懸浮液中。將澄清溶液在25℃下攪拌32h且在真空中蒸發溶劑。藉由RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；25-65% 0-5min水-MeOH(NH3 0.1%)，流速30ml/min)純化殘餘物，以得到N -[5-[[2-[(2R,5S )-2-(1-乙醯基-4-哌啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(26mg，51.83μmol，4.76%產率)及化合物737 2-[(2R,5S )-2-(1-乙醯基-4-哌啶基)-5-甲基-1-哌啶基]-N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(222mg，552.93μmol，50.82%產率)。HATU (413.67 mg, 1.09 mmol) was added portionwise to N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(4-piperidine) at room temperature (0.5 g, 1.09 mmol), acetic acid ( 65.33 mg, 1.09 mmol, 62.22 μL) and DIPEA (843.64 mg, 6.53 mmol, 1.14 mL) in suspension in DMF (50 mL). The clear solution was stirred at 25 °C for 32 h and the solvent was evaporated in vacuo. The residue was purified by RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 25-65% 0-5min water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N- [5-[[2-[( 2R,5S )-2-(1-acetyl-4-piperidinyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (26 mg, 51.83 μmol, 4.76% yield) and compound 737 2-[( 2R,5S )-2-(1 -Acetyl-4-piperidinyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2- oxoacetyl Amine (222 mg, 552.93 μmol, 50.82% yield).

化合物737： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.94(m,3H),0.96(m,1H),1.33 (m,1H),1.61(m,2H),1.85(m,2H),1.95(m,7H),2.11(m,2H),2.91(m,3H),3.70(m,3H),4.05(m,1H),4.36(m,1H),5.59(s,2H),7.44(m,1H),7.97(m,1H),10.28(m,1H)。 Compound 737: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.94 (m, 3H), 0.96 (m, 1H), 1.33 (m, 1H), 1.61 (m, 2H), 1.85 (m, 2H), 1.95(m, 7H), 2.11(m, 2H), 2.91(m, 3H), 3.70(m, 3H), 4.05(m, 1H), 4.36(m, 1H), 5.59(s, 2H ), 7.44 (m, 1H), 7.97 (m, 1H), 10.28 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值401.2；實測值402.2；Rt=1.215min。LCMS (ESI): [M] + m/z: calculated 401.2; found 402.2; Rt=1.215 min.

步驟4：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-[2,4'-聯哌啶]-1-基)-2-側氧基乙醯胺(化合物708 )之合成Step 4: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-[2,4'-bipiperidin]-1-yl)-2-oxygen Synthesis of Ethylacetamide ( Compound 708 )

在室溫下將於二噁烷中之4.0M氯化氫溶液(1.98g，7.62mmol，1.89mL，14%純度)小心添加到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(4-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.35g，761.56μmol)於DCM(3.5mL)中之溶液中。然後將反應混合物在室溫下攪拌12h且在真空中蒸發溶劑。使殘餘物經歷RP-HPLC(管柱：YMC Triart C18 100x20mm，5um；以40-60% 0-5min 0.1% NH3 -MeOH為流動相)，以得到化合物708 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-(4-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(62mg，172.48μmol，22.65%產率)。A 4.0 M solution of hydrogen chloride in dioxane (1.98 g, 7.62 mmol, 1.89 mL, 14% purity) was carefully added to N- [3-methyl-5-[[2-[( 2R, 5S )-5-methyl-2-(4-piperidinyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester ( 0.35 g, 761.56 μmol) in DCM (3.5 mL). The reaction mixture was then stirred at room temperature for 12 h and the solvent was evaporated in vacuo. The residue was subjected to RP-HPLC (column: YMC Triart C18 100x20mm, 5um; 40-60% 0-5 min 0.1% NH3 -MeOH as mobile phase) to give compound 708 N- (6-amino-5 -Methyl-3-pyridyl)-2-[( 2R,5S )-5-methyl-2-(4-piperidinyl)-1-piperidinyl]-2-oxoacetamide ( 62 mg, 172.48 μmol, 22.65% yield).

化合物708： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.93(m,5H),1.27(m,1H),1.41(m,1H),1.58(m,3H),1.85(m,4H),2.00(m,3H),2.37(m,2H),2.88(m,3H),3.46(m,1H),4.03(m,1H),5.58(m,2H),7.45(m,1H),7.98(m,1H),10.27(m,1H)。 Compound 708: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.93 (m, 5H), 1.27 (m, 1H), 1.41 (m, 1H), 1.58 (m, 3H), 1.85 (m, 4H), 2.00(m, 3H), 2.37(m, 2H), 2.88(m, 3H), 3.46(m, 1H), 4.03(m, 1H), 5.58(m, 2H), 7.45(m, 1H) ), 7.98 (m, 1H), 10.27 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值359.2；實測值360.2；Rt=0.997min。LCMS (ESI): [M] + m/z: calculated 359.2; found 360.2; Rt=0.997 min.

步驟5：1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-N,5-二甲基-[2,4'-聯哌啶]-1'-甲醯胺(化合物781 )之合成Step 5: 1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-N,5-dimethyl-[2, Synthesis of 4'-bipiperidine]-1'-carboxamide ( Compound 781 )

在室溫下將DIPEA(140.61mg，1.09mmol，189.50μL)分批添加到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(4-哌啶基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.5g，1.09mmol)、DIPEA(140.61mg，1.09mmol，189.50μL)於ACN(50mL)中之懸浮液中。將澄清溶液在25℃下攪拌18h且在真 空中蒸發溶劑。藉由RP-HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；以0-5min 30-50%水-MeOH(NH3 0.1%)，流速30ml/min為流動相，然後另一個管柱：C18，以水-ACN 5-95% 30ml/min為流動相)純化殘餘物，以得到化合物781 4-[(2R,5S )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-N-甲基哌啶-1-甲醯胺(38mg，91.23μmol，8.39%產率)。DIPEA (140.61 mg, 1.09 mmol, 189.50 μL) was added portionwise to N- [3-methyl-5-[[[2-[( 2R,5S )-5-methyl-2-(4 at room temperature -Piperidinyl)-1-piperidinyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.5g, 1.09mmol), DIPEA (140.61mg, 1.09 mmol, 189.50 μL) in ACN (50 mL). The clear solution was stirred at 25 °C for 18 h and the solvent was evaporated in vacuo. By RP-HPLC (column: YMC-Actus Triart C18 100*20mml.DS-5um; 0-5min 30-50% water-MeOH (NH 3 0.1%), flow rate 30ml/min as mobile phase, and then another One column: C18, the residue was purified with water-ACN 5-95% 30 ml/min as mobile phase) to give compound 781 4-[( 2R,5S )-1-[2-[(6-amino- 5-Methyl-3-pyridyl)amino]-2-oxyacetyl]-5-methyl-2-piperidinyl]-N-methylpiperidine-1-carboxamide (38mg , 91.23 μmol, 8.39% yield).

化合物781： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.74-0.92(m,2H),0.92-0.97(m,3H),1.22-1.32(m,1H),1.38-1.48(m,1H),1.48-1.74(m,3H),1.74-1.99(m,3H),1.99-2.08(m,4H),2.51-2.57(m,4H),2.83-3.28(m,1H),3.32-3.49(m,1H),3.84-4.14(m,3H),5.55-5.63(m,2H),6.29-6.37(m,1H),7.40-7.49(m,1H),7.94-8.02(m,1H),10.24-10.36(m,1H)。 Compound 781: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.74-0.92 (m, 2H), 0.92-0.97 (m, 3H), 1.22-1.32 (m, 1H), 1.38-1.48 (m ,1H),1.48-1.74(m,3H),1.74-1.99(m,3H),1.99-2.08(m,4H),2.51-2.57(m,4H),2.83-3.28(m,1H),3.32 -3.49(m, 1H), 3.84-4.14(m, 3H), 5.55-5.63(m, 2H), 6.29-6.37(m, 1H), 7.40-7.49(m, 1H), 7.94-8.02(m, 1H), 10.24-10.36 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值416.2；實測值417.2；Rt=1.658min。LCMS (ESI): [M] + m/z: calculated 416.2; found 417.2; Rt=1.658 min.

實例730. 外消旋-2-[(2R,5S)-2-[4-(乙醯胺基甲基)苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物1036)之合成Example 730. Racemic-2-[(2R,5S)-2-[4-(acetamidomethyl)phenyl]-5-methyl-1-piperidinyl]-N-(6- Synthesis of amino-5-methyl-3-pyridyl)-2-oxyacetamide (compound 1036)

Figure 110128222-A0202-12-2338-598
Figure 110128222-A0202-12-2338-598

步驟1：(2R,5S)-2-(4-氰基苯基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (2R,5S)-2-(4-cyanophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將98+%六氰基高鐵酸鉀(II)三水合物(741.85mg，1.01mmol，401.00 μL)及乙酸鉀(24.76mg，252.27μmol，15.77μL)添加到(2R,5S)-2-(4-溴苯基)-5-甲基哌啶-1-甲酸第三丁酯(715mg，2.02mmol)於二噁烷(5mL)及水(5mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。在氬氣流下向其中添加XPhos-Pd-G3(17.08mg，20.18μmol)及XPhos(9.62mg，20.18μmol)且將所得混合物在100℃下攪拌2h。然後，在減壓下移除揮發物且將殘餘物再溶解於乙酸乙酯(20ml)中。透過短矽膠墊過濾此溶液且在真空中蒸發，得到(2R,5S)-2-(4-氰基苯基)-5-甲基哌啶-1-甲酸第三丁酯(887mg，粗品)。98+% Potassium hexacyanoferrate (II) trihydrate (741.85 mg, 1.01 mmol, 401.00 μL) and potassium acetate (24.76 mg, 252.27 μmol, 15.77 μL) were added to tert-butyl (2R,5S)-2-(4-bromophenyl)-5-methylpiperidine-1-carboxylate (715 mg, 2.02 mmol) in dioxane (5 mL) and water (5 mL). The reaction flask was evacuated and refilled with argon 3 times. To this were added XPhos-Pd-G3 (17.08 mg, 20.18 μmol) and XPhos (9.62 mg, 20.18 μmol) under argon flow and the resulting mixture was stirred at 100° C. for 2 h. Then, the volatiles were removed under reduced pressure and the residue was redissolved in ethyl acetate (20 ml). The solution was filtered through a short pad of silica gel and evaporated in vacuo to give tert-butyl (2R,5S)-2-(4-cyanophenyl)-5-methylpiperidine-1-carboxylate (887 mg, crude) .

1 H NMR(CDCl3 ,500MHz)：1.05(d,3H),1.30(m,1H),1.43(s,9H),1.65(m,H),1.84(m,1H),1.96(m,1H),2.15(m,1H),2.99(m,1H),3.70(m,1H),5.28(s,1H),7.34(m,2H),7.62(m,2H)。 1 H NMR (CDCl 3 , 500MHz): 1.05(d,3H), 1.30(m,1H), 1.43(s,9H), 1.65(m,H), 1.84(m,1H), 1.96(m,1H) ), 2.15(m, 1H), 2.99(m, 1H), 3.70(m, 1H), 5.28(s, 1H), 7.34(m, 2H), 7.62(m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值300.2；實測值301.8；Rt=1.619min。LCMS (ESI): [M+H] + m/z: calculated 300.2; found 301.8; Rt=1.619 min.

步驟2：外消旋-(2R,5S)-2-[4-(胺基甲基)苯基]-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of racemic-(2R,5S)-2-[4-(aminomethyl)phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester

將外消旋-(2R,5S)-2-(4-氰基苯基)-5-甲基哌啶-1-甲酸第三丁酯(0.9g，3.00mmol)添加到雷氏鎳(149.80μmol)於MeOH(20mL)中之懸浮液中且在室溫下、在高壓釜中、在氫氣氣氛下攪拌2h。在反應完成之後，過濾出混合物且在減壓下蒸發，以得到(2R,5S)-2-[4-(胺基甲基)苯基]-5-甲基哌啶-1-甲酸第三丁酯(1g，粗品)，其不經純化即用於下一步驟中。Racemic-(2R,5S)-2-(4-cyanophenyl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (0.9 g, 3.00 mmol) was added to Reinhardt nickel (149.80 μmol) in MeOH (20 mL) and stirred at room temperature in the autoclave under hydrogen atmosphere for 2 h. After the reaction was completed, the mixture was filtered off and evaporated under reduced pressure to give (2R,5S)-2-[4-(aminomethyl)phenyl]-5-methylpiperidine-1-carboxylic acid third Butyl ester (1 g, crude) was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值247.0；實測值247.0；Rt=1.573min。LCMS (ESI): [M+H] + m/z: calculated 247.0; found 247.0; Rt=1.573 min.

步驟3：外消旋-(2R,5S)-5-甲基-2-[4-[[(2,2,2-三氟乙醯基)胺基]甲基]苯基]哌啶-1-甲酸第三丁酯之合成Step 3: Racemic-(2R,5S)-5-methyl-2-[4-[[(2,2,2-trifluoroacetamido)amino]methyl]phenyl]piperidine- Synthesis of 3-butyl 1-formate

將外消旋-(2R,5S)-2-[4-(胺基甲基)苯基]-5-甲基哌啶-1-甲酸第三丁酯(1g，3.28mmol)溶解於DCM(20mL)中且冷卻至-30℃，隨後以逐滴方式添加三乙胺(498.59mg，4.93mmol，686.77μL)及TFAA(827.91mg，3.94mmol，555.65μL)。再攪拌15min之後，用H2 O(2mL)淬滅，且將有機層用10% NaHCO3 水溶液 洗滌。經Na2 SO4 乾燥有機溶劑且在減壓下蒸發，得到外消旋-(2R,5S)-5-甲基-2-[4-[[(2,2,2-三氟乙醯基)胺基]甲基]苯基]哌啶-1-甲酸第三丁酯(1.1g，2.75mmol，83.63%產率)。Racemic-(2R,5S)-2-[4-(aminomethyl)phenyl]-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1 g, 3.28 mmol) was dissolved in DCM ( 20 mL) and cooled to -30°C, then triethylamine (498.59 mg, 4.93 mmol, 686.77 μL) and TFAA (827.91 mg, 3.94 mmol, 555.65 μL) were added dropwise. After stirring for an additional 15 min, it was quenched with H2O ( 2 mL), and the organic layer was washed with 10% aqueous NaHCO3 . The organic solvent was dried over Na 2 SO 4 and evaporated under reduced pressure to give rac-(2R,5S)-5-methyl-2-[4-[[((2,2,2-trifluoroacetonitrile )amino]methyl]phenyl]piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.75 mmol, 83.63% yield).

LCMS(ESI)：[M-Boc]+ m/z：計算值300.2；實測值301.2；Rt=1.602min。LCMS (ESI): [M-Boc] + m/z: calculated 300.2; found 301.2; Rt=1.602 min.

步驟4：外消旋-2,2,2-三氟-N-[[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]甲基]乙醯胺之合成Step 4: Rac-2,2,2-trifluoro-N-[[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]methyl]acetamide synthesis

將外消旋-(2R,5S)-5-甲基-2-[4-[[(2,2,2-三氟乙醯基)胺基]甲基]苯基]哌啶-1-甲酸第三丁酯(1.1g，2.75mmol)溶解於DCM(30mL)中，隨後添加TFA(3.13g，27.47mmol，2.12mL)且再攪拌12h。在反應完成之後，在減壓下蒸發有機溶劑且將混合物與甲苯(100mL)一起再蒸發，以得到粗品外消旋-2,2,2-三氟-N-[[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]甲基]乙醯胺(1.3g，粗品，TFA)，其不經純化即用於下一步驟中。rac-(2R,5S)-5-methyl-2-[4-[[(2,2,2-trifluoroacetamido)amino]methyl]phenyl]piperidine-1- 3-Butyl formate (1.1 g, 2.75 mmol) was dissolved in DCM (30 mL), then TFA (3.13 g, 27.47 mmol, 2.12 mL) was added and stirred for an additional 12 h. After completion of the reaction, the organic solvent was evaporated under reduced pressure and the mixture was re-evaporated with toluene (100 mL) to give crude rac-2,2,2-trifluoro-N-[[4-[(2R, 5S)-5-Methyl-2-piperidinyl]phenyl]methyl]acetamide (1.3 g, crude, TFA), which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值300.2；實測值301.0；Rt=0.795min。LCMS (ESI): [M+H] + m/z: calculated 300.2; found 301.0; Rt=0.795 min.

步驟5：外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[4-[[(2,2,2-三氟乙醯基)胺基]甲基]苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 5: Racemic-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-[4-[[(2,2,2-trifluoroethyl Synthesis of 3-butyl Acyl)amino]methyl]phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

在輕微加熱下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(287.67mg，974.21μmol)、外消旋-2,2,2-三氟-N-[[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]甲基]乙醯胺(292.57mg，974.21μmol)及DIPEA(377.73mg，2.92mmol，509.07μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(444.51mg，1.17mmol)。在反應完成之後，藉由HPLC純化混合物，以得到外消旋產物，使其經歷掌性HPLC，以得到外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[4-[[(2,2,2-三氟乙醯基)胺基]甲基]苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(60mg，103.88μmol，10.66%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (287.67 mg, 974.21 μmol) was added with gentle heating , rac-2,2,2-trifluoro-N-[[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]methyl]acetamide (292.57mg , 974.21 μmol) and DIPEA (377.73 mg, 2.92 mmol, 509.07 μL) were dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (444.51 mg, 1.17 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC to give the racemic product, which was subjected to chiral HPLC to give rac-N-[3-methyl-5-[[2-[(2R,5S )-5-methyl-2-[4-[[(2,2,2-trifluoroacetoxy)amino]methyl]phenyl]-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (60 mg, 103.88 μmol, 10.66% yield).

HPLC條件：(42% 0.5-6.5min水-乙腈；流速30mL/min(裝載泵4mL/min乙腈)； 目標質量577；管柱SunFireC18 100x19mm 5um(R))HPLC conditions: (42% 0.5-6.5 min water-acetonitrile; flow rate 30 mL/min (loading pump 4 mL/min acetonitrile); Target mass 577; pipe string SunFireC18 100x19mm 5um(R))

LCMS(ESI)：[M+H]+ m/z：計算值577.2；實測值578.2；Rt=3.417min。LCMS (ESI): [M+H] + m/z: calculated 577.2; found 578.2; Rt=3.417 min.

步驟6：外消旋-N-[5-[[2-[(2R,5S)-2-[4-(胺基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 6: Racemic-N-[5-[[2-[(2R,5S)-2-[4-(aminomethyl)phenyl]-5-methyl-1-piperidinyl]- Synthesis of 3-butyl 2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

將外消旋-N-[3-甲基-5-[[2-[(2R,5S)-5-甲基-2-[4-[[(2,2,2-三氟乙醯基)胺基]甲基]-苯基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(60mg，103.88μmol)溶解於MeOH(5mL)/H2 O(1mL)混合物中，隨後添加99%無水碳酸鉀(71.78mg，519.40μmol，31.35μL)。在攪拌72h之後，將有機溶劑蒸發至乾且將粗殘餘物分配於DCM(6mL)與水(1mL)之間。將水層丟棄；將有機層分成2個部分，其用於合成2個目標。The rac-N-[3-methyl-5-[[2-[(2R,5S)-5-methyl-2-[4-[[((2,2,2-trifluoroacetone )amino]methyl]-phenyl]-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (60 mg, 103.88 μmol) was dissolved In a mixture of MeOH (5 mL)/H 2 O (1 mL), 99% anhydrous potassium carbonate (71.78 mg, 519.40 μmol, 31.35 μL) was then added. After stirring for 72 h, the organic solvent was evaporated to dryness and the crude residue was partitioned between DCM (6 mL) and water (1 mL). The aqueous layer was discarded; the organic layer was split into 2 parts, which were used to synthesize 2 targets.

LCMS(ESI)：[M+H]+ m/z：計算值481.2；實測值482.4；Rt=0.894min。LCMS (ESI): [M+H] + m/z: calculated 481.2; found 482.4; Rt=0.894 min.

步驟7：外消旋-N-[5-[[2-[(2R,5S)-2-[4-(乙醯胺基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 7: Racemic-N-[5-[[2-[(2R,5S)-2-[4-(acetamidomethyl)phenyl]-5-methyl-1-piperidinyl Synthesis of 3-butyl ]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid

將先前獲得之外消旋-N-[5-[[2-[(2R,5S)-2-[4-(胺基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(25mg，51.91μmol)於DCM中之溶液冷卻至0℃且一次性添加乙酸酐(5.30mg，51.91μmol，4.91μL)。在反應完成之後，將有機溶劑蒸發至乾且粗殘餘物不經純化即用於下一步驟中。The previously obtained rac-N-[5-[[2-[(2R,5S)-2-[4-(aminomethyl)phenyl]-5-methyl-1-piperidinyl] A solution of tert-butyl-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate (25 mg, 51.91 μmol) in DCM was cooled to 0 °C and ethyl acetate was added in one portion Acid anhydride (5.30 mg, 51.91 μmol, 4.91 μL). After the reaction was complete, the organic solvent was evaporated to dryness and the crude residue was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值523.2；實測值524.4；Rt=0.674min。LCMS (ESI): [M+H] + m/z: calculated 523.2; found 524.4; Rt=0.674 min.

步驟8：外消旋-2-[(2R,5S)-2-[4-(乙醯胺基甲基)苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物1036 )之合成Step 8: Racemic-2-[(2R,5S)-2-[4-(acetamidomethyl)phenyl]-5-methyl-1-piperidinyl]-N-(6- Synthesis of amino-5-methyl-3-pyridyl)-2-oxyacetamide ( compound 1036 )

將外消旋-N-[5-[[2-[(2R,5S)-2-[4-(乙醯胺基甲基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(25mg，47.74μmol)溶解於二噁烷(2mL)及H2 O(0.5mL)中且在100℃下攪拌3h。在反應完成之後， 使粗品RM經歷HPLC(12-14% 0.5-6.5min水-乙腈+NH3 ；流速30mL/min(裝載泵4mL/min乙腈)；目標質量423；管柱XBridge 100x19mm 5um(R))，以得到外消旋-2-[(2R,5S)-2-[4-(乙醯胺基甲基)苯基]-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(7mg，16.53μmol，34.62%產率)。The racemic-N-[5-[[2-[(2R,5S)-2-[4-(acetamidomethyl)phenyl]-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (25 mg, 47.74 μmol) was dissolved in dioxane (2 mL) and H 2 O (0.5 mL) ) and stirred at 100 °C for 3 h. After the reaction was complete, the crude RM was subjected to HPLC (12-14% 0.5-6.5 min water-acetonitrile + NH3 ; flow rate 30 mL/min (loading pump 4 mL/min acetonitrile); target mass 423; column XBridge 100x19mm 5um (R )) to give rac-2-[(2R,5S)-2-[4-(acetamidomethyl)phenyl]-5-methyl-1-piperidinyl]-N-( 6-Amino-5-methyl-3-pyridyl)-2-oxyacetamide (7 mg, 16.53 μmol, 34.62% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.95-1.02(m,3H),1.26-1.37(m,1H),1.59-1.67(m,1H),1.79-1.87(m,4H),1.97-2.10(m,4H),2.15-2.25(m,1H),2.66-3.21(m,1H),3.40-4.03(m,1H),4.18-4.23(m,2H),5.07-5.56(m,1H),5.56-5.65(m,2H),7.20-7.31(m,4H),7.41-7.52(m,1H),7.93-8.04(m,1H),8.26-8.32(m,1H),10.47(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.95-1.02(m,3H), 1.26-1.37(m,1H), 1.59-1.67(m,1H), 1.79-1.87(m,4H), 1.97- 2.10(m, 4H), 2.15-2.25(m, 1H), 2.66-3.21(m, 1H), 3.40-4.03(m, 1H), 4.18-4.23(m, 2H), 5.07-5.56(m, 1H) ),5.56-5.65(m,2H),7.20-7.31(m,4H),7.41-7.52(m,1H),7.93-8.04(m,1H),8.26-8.32(m,1H),10.47(s , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值423.2；實測值424.4；Rt=1.634min。LCMS (ESI): [M+H] + m/z: calculated 423.2; found 424.4; Rt=1.634 min.

實例731. 外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙醯胺(化合物977)之合成Example 731. Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(3-thienyl)-1 Synthesis of -piperidinyl]-2-oxoacetamide (compound 977)

Figure 110128222-A0202-12-2342-599
Figure 110128222-A0202-12-2342-599

步驟1：N-[2-甲基-5-側氧基-5-(3-噻吩基)戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl N-[2-methyl-5-oxo-5-(3-thienyl)pentyl]carbamate

在-78℃、Ar氣氛下，向3-溴噻吩(5g，30.67mmol，2.91mL)於THF(50mL)中之溶液中添加正丁基鋰(8.54g，30.67mmol，12.33mL，23%純度)。1h之後，在-78℃下，將所得混合物逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(5.45g，25.56mmol)於THF中之溶液中。此後，使其升溫至室溫。將所得混合物用NH4 Cl水溶液淬滅，將水用EtOAc萃取，將經合併之有機物用鹽水洗滌，乾燥且蒸發。獲得呈淡黃色油狀物之N-[2-甲基-5-側氧基-5-(3-噻吩基)戊基]胺甲酸 第三丁酯(6.55g，粗品)且其不經進一步純化即用於下一步驟中。To a solution of 3-bromothiophene (5 g, 30.67 mmol, 2.91 mL) in THF (50 mL) was added n-butyllithium (8.54 g, 30.67 mmol, 12.33 mL, 23% purity) at -78 °C under Ar atmosphere ). After 1 h, the resulting mixture was added dropwise to a solution of tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (5.45 g, 25.56 mmol) in THF at -78 °C. Thereafter, it was allowed to warm to room temperature. The resulting mixture was quenched with aqueous NH4Cl , the water was extracted with EtOAc, the combined organics were washed with brine, dried and evaporated. 3-Butyl N-[2-methyl-5-oxy-5-(3-thienyl)pentyl]carbamate (6.55 g, crude) was obtained as a pale yellow oil and was not treated further Purification was used in the next step.

步驟2：5-甲基-2-(3-噻吩基)哌啶之合成Step 2: Synthesis of 5-methyl-2-(3-thienyl)piperidine

將N-[2-甲基-5-側氧基-5-(3-噻吩基)戊基]胺甲酸第三丁酯(6.55g，22.02mmol)溶解於TFA(7.53g，66.07mmol，5.09mL)中且將所得反應混合物攪拌1小時。1小時之後，將50%NaOH水溶液添加到反應混合物中，直到pH=13-14。將所得混合物用DCM(4 x 20mL)萃取。將經合併之有機相經MgSO4乾燥且在減壓下濃縮。將所獲得之殘餘物溶解於水(25mL)及MeOH(100mL)中且分批添加硼氫化鈉(833.19mg，22.02mmol，778.69μL)。將所得反應混合物在氬氣氣氛、21℃下攪拌16小時。16小時之後，將反應混合物用1-2M HCl酸化，直到pH為1-3且攪拌30分鐘。然後，添加50%NaOH水溶液，直到pH=13-14。將所得混合物用DCM(4 x 100mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。藉由CC(Companion combiflash；220g SiO2，氯仿/乙腈，其中乙腈為10至100%，另外為乙腈/甲醇，其中甲醇為0至25%，流速=85mL/min，Rv=14CV)純化殘餘物，以獲得呈淡黃色油狀物之5-甲基-2-(3-噻吩基)哌啶(0.15g，827.37μmol，3.76%產率)。粗產物不經任何進一步純化即用於下一步反應。3-butyl N-[2-methyl-5-oxy-5-(3-thienyl)pentyl]carbamate (6.55 g, 22.02 mmol) was dissolved in TFA (7.53 g, 66.07 mmol, 5.09 mL) and the resulting reaction mixture was stirred for 1 hour. After 1 hour, 50% aqueous NaOH was added to the reaction mixture until pH=13-14. The resulting mixture was extracted with DCM (4 x 20 mL). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The obtained residue was dissolved in water (25 mL) and MeOH (100 mL) and sodium borohydride (833.19 mg, 22.02 mmol, 778.69 μL) was added portionwise. The resulting reaction mixture was stirred under an argon atmosphere at 21 °C for 16 hours. After 16 hours, the reaction mixture was acidified with 1-2M HCl until pH 1-3 and stirred for 30 minutes. Then, 50% NaOH aqueous solution was added until pH=13-14. The resulting mixture was extracted with DCM (4 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by CC (Companion combiflash; 220 g SiO2, chloroform/acetonitrile with 10 to 100% acetonitrile and additionally acetonitrile/methanol with 0 to 25% methanol, flow rate = 85 mL/min, Rv = 14 CV), This gave 5-methyl-2-(3-thienyl)piperidine (0.15 g, 827.37 μmol, 3.76% yield) as a pale yellow oil. The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值181.2；實測值182.0；Rt=0.637min。LCMS (ESI): [M+H] + m/z: calculated 181.2; found 182.0; Rt=0.637 min.

步驟3：2-[5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙酸甲酯之合成Step 3: Synthesis of methyl 2-[5-methyl-2-(3-thienyl)-1-piperidinyl]-2-oxoacetate

在0℃下，向5-甲基-2-(3-噻吩基)哌啶(0.15g，827.37μmol)及三乙胺(100.47mg，992.84μmol，138.38μL)於DCM(25mL)中之溶液中添加2-氯-2-側氧基乙酸甲酯(111.49mg，910.11μmol)。在室溫下攪拌1h之後，將所得混合物過濾且蒸發至乾，以得到呈微棕色油狀物之2-[5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙酸甲酯(200mg，粗品)，其不經進一步純化即用於下一步驟中。To a solution of 5-methyl-2-(3-thienyl)piperidine (0.15 g, 827.37 μmol) and triethylamine (100.47 mg, 992.84 μmol, 138.38 μL) in DCM (25 mL) at 0 °C To this was added methyl 2-chloro-2-oxoacetate (111.49 mg, 910.11 μmol). After stirring at room temperature for 1 h, the resulting mixture was filtered and evaporated to dryness to give 2-[5-methyl-2-(3-thienyl)-1-piperidinyl]- Methyl 2-oxoacetate (200 mg, crude) was used in the next step without further purification.

LCMS(ESI)：[M+H]+ m/z：計算值267.2；實測值268.2；Rt=1.305min。LCMS (ESI): [M+H] + m/z: calculated 267.2; found 268.2; Rt=1.305 min.

步驟4：N-[3-甲基-5-[[2-[5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙醯基]胺Step 4: N-[3-Methyl-5-[[2-[5-methyl-2-(3-thienyl)-1-piperidinyl]-2-oxyethanoyl]amine 基]-2-吡啶基]胺甲酸第三丁酯之合成Synthesis of tert-butyl]-2-pyridyl]carbamate

向2-[5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙酸甲酯(200mg，748.10μmol)於MeOH(5mL)中之溶液中添加氫氧化鈉珠粒(29.92mg，748.10μmol，14.05μL)且將所得混合物攪拌1h。然後，蒸發溶劑且將殘餘物與EtOH一起再蒸發。此後，將固體溶解於DMF中且添加HATU(284.45mg，748.10μmol)，隨後添加N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(167.03mg，748.10μmol)且將所得混合物攪拌12h。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(45-70% 0.5-6.5min水-乙腈；流速30mL/min(裝載泵4mL/min乙腈)；管柱SunFireC18 100x19mm 5um(R))，以得到呈灰白色固體之N-[3-甲基-5-[[2-[5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(91.8mg，200.19μmol，26.76%產率)。To a solution of methyl 2-[5-methyl-2-(3-thienyl)-1-piperidinyl]-2-oxoacetate (200 mg, 748.10 μmol) in MeOH (5 mL) was added hydrogen Sodium oxide beads (29.92 mg, 748.10 μmol, 14.05 μL) and the resulting mixture was stirred for 1 h. Then, the solvent was evaporated and the residue was re-evaporated with EtOH. After this time, the solid was dissolved in DMF and HATU (284.45 mg, 748.10 μmol) was added, followed by tert-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (167.03 mg, 748.10 μmol) μmol) and the resulting mixture was stirred for 12 h. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (45-70% 0.5-6.5 min water-acetonitrile; flow rate 30 mL/min (loading pump 4 mL/min acetonitrile); column SunFire C18 100x19 mm 5um(R)) to give N-[ as an off-white solid 3-Methyl-5-[[2-[5-methyl-2-(3-thienyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl ] tert-butyl carbamate (91.8 mg, 200.19 μmol, 26.76% yield).

LCMS(ESI)：[M+H]+ m/z：計算值458.2；實測值459.2；Rt=3.517min。LCMS (ESI): [M+H] + m/z: calculated 458.2; found 459.2; Rt=3.517 min.

步驟5：外消旋-N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙醯胺(化合物977 )之合成Step 5: Racemic-N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(3-thienyl)-1 Synthesis of -piperidinyl]-2-oxoacetamide ( compound 977 )

在21℃下，向N-[3-甲基-5-[[2-[5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(91.8mg，200.19μmol)於二噁烷(5mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(36.49mg，1.00mmol，45.62μL)。使所得混合物攪拌21h。將所得混合物蒸發至乾且使其經歷HPLC(0-30% 0.5-6.5min水-乙腈；流速30mL/min(裝載泵4mL/min水)；管柱SunFireC18 100x19mm 5um(R))。獲得呈黃色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(3-噻吩基)-1-哌啶基]-2-側氧基乙醯胺(17.2mg，47.98μmol，23.97%產率)。At 21 °C, to N-[3-methyl-5-[[2-[5-methyl-2-(3-thienyl)-1-piperidinyl]-2-side oxyacetyl ]amino]-2-pyridyl]carbamic acid tert-butyl ester (91.8 mg, 200.19 μmol) in dioxane (5 mL) was added to a 4.0 M solution of hydrogen chloride in dioxane (36.49 mg, 1.00 mmol, 45.62 μL). The resulting mixture was stirred for 21 h. The resulting mixture was evaporated to dryness and subjected to HPLC (0-30% 0.5-6.5 min water-acetonitrile; flow rate 30 mL/min (loading pump 4 mL/min water); column SunFire C18 100x19mm 5um(R)). N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-(3-thienyl)-1-piperidine was obtained as a yellow solid Peridyl]-2-Pendant oxyacetamide (17.2 mg, 47.98 μmol, 23.97% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 0.97-1.04(m,3H),1.31-1.42(m,1H),1.65-1.80(m,1H),1.82-1.93(m,1H),1.96-2.09(m,1H),2.11-2.14(m,3H),2.73-3.16(m, 1H),3.39-4.01(m,2H),5.07-5.64(m,1H),6.96-7.05(m,1H),7.05-7.33(m,2H),7.34-7.41(m,1H),7.51-7.59(m,1H),7.74(s,1H),8.17-8.23(m,1H),10.75-11.03(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.97-1.04(m,3H), 1.31-1.42(m,1H), 1.65-1.80(m,1H), 1.82-1.93(m,1H), 1.96- 2.09(m, 1H), 2.11-2.14(m, 3H), 2.73-3.16(m, 1H), 3.39-4.01(m, 2H), 5.07-5.64(m, 1H), 6.96-7.05(m, 1H) ),7.05-7.33(m,2H),7.34-7.41(m,1H),7.51-7.59(m,1H),7.74(s,1H),8.17-8.23(m,1H),10.75-11.03(m , 1H).

LCMS(ESI)：[M+H]+ m/z：計算值358.2；實測值359.2；Rt=2.187min。LCMS (ESI): [M+H] + m/z: calculated 358.2; found 359.2; Rt=2.187 min.

實例732. 2-乙基-5-(2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物747)之合成Example 732. Of 2-ethyl-5-(2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (compound 747) synthesis

Figure 110128222-A0202-12-2345-600
Figure 110128222-A0202-12-2345-600

步驟1：5-胺基-2-乙基菸鹼酸甲酯之合成Step 1: Synthesis of methyl 5-amino-2-ethylnicotinate

在20℃下，向5-胺基-2-乙基吡啶-3-甲酸(1.05g，6.32mmol)於MeOH(20mL)中之經攪拌之溶液中逐滴添加亞硫醯氯(826.89mg，6.95mmol，504.20μL)。將混合物在70℃下回流16h。將混合物冷卻，在真空中濃縮，以得到5-胺基-2-乙基吡啶-3-甲酸甲酯(1.25g，5.77mmol，91.31%產率，HCl)。To a stirred solution of 5-amino-2-ethylpyridine-3-carboxylic acid (1.05 g, 6.32 mmol) in MeOH (20 mL) at 20 °C was added thionyl chloride (826.89 mg, 6.95 mmol, 504.20 μL). The mixture was refluxed at 70 °C for 16 h. The mixture was cooled and concentrated in vacuo to give methyl 5-amino-2-ethylpyridine-3-carboxylate (1.25 g, 5.77 mmol, 91.31% yield, HCl).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.16(t,3H),3.06(m,2H),3.85(s,3H),6.45(m,2H),8.01(s,1H),8.04(s,1H)。LCMS(ESI)：[M]+ m/z：計算值180.2；實測值181.2；Rt=0.465min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.16(t, 3H), 3.06(m, 2H), 3.85(s, 3H), 6.45(m, 2H), 8.01(s, 1H), 8.04(s, 1H). LCMS (ESI): [M] + m/z: calculated 180.2; found 181.2; Rt=0.465 min.

步驟2：5-胺基-2-乙基菸鹼醯胺之合成Step 2: Synthesis of 5-amino-2-ethylnicotinamide

將5-胺基-2-乙基吡啶-3-甲酸甲酯(1.1g，5.08mmol，HCl)溶解於28% NH3 氫氧化銨(5.40g，154.07mmol，6mL)中且在70℃下加熱隔夜。將反應混合物蒸發且使其經歷HPLC(2-10min 0-60% acn/H2 O 30ml/min(裝載泵4ml MeCN)管柱：SunFire 100*19mm，5微米)純化粗產物。獲得5-胺基-2-乙基吡啶-3-甲醯胺(220mg，1.33mmol，26.23%產率)。Methyl 5-amino-2-ethylpyridine-3-carboxylate (1.1 g, 5.08 mmol, HCl) was dissolved in 28% NH3ammonium hydroxide (5.40 g, 154.07 mmol, 6 mL) and at 70 °C Heat overnight. The reaction mixture was evaporated and subjected to HPLC (2-10 min 0-60% acn/ H2O 30 ml/min (loading pump 4 ml MeCN) column: SunFire 100*19 mm, 5 microns) to purify the crude product. 5-Amino-2-ethylpyridine-3-carboxamide (220 mg, 1.33 mmol, 26.23% yield) was obtained.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.12(t,3H),2.68(m,2H),5.28(m,2H),6.89(s,1H),7.32(s,1H),7.78(s,1H),7.92(s,1H)。LCMS(ESI)：[M]+ m/z：計算值 165.2；實測值166.2；Rt=0.141min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.12(t, 3H), 2.68(m, 2H), 5.28(m, 2H), 6.89(s, 1H), 7.32(s, 1H), 7.78(s, 1H), 7.92(s, 1H). LCMS (ESI): [M] + m/z: calculated 165.2; found 166.2; Rt=0.141 min.

步驟3：2-乙基-5-(2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物747 )之合成Step 3: Compound of 2-ethyl-5-(2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide ( compound 747 ) synthesis

將5-胺基-2-乙基吡啶-3-甲醯胺(220mg，1.33mmol)、[2-[(2S,5R )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]氧基鋰(337.24mg，1.33mmol)、HATU(557.02mg，1.46mmol)及TEA(336.91mg，3.33mmol，464.06μL)混合於DMSO(4mL)中且攪拌1h。使DMSO中之溶液經歷HPLC(2-10min 45-60%水/MeCN(裝載泵4ml MeCN)管柱：TRIART 100*20 5微米)。2-乙基-5-[[2-[(2S,5R )-5-甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(303.3mg，768.89μmol，57.73%產率)。5-Amino-2-ethylpyridine-3-carboxamide (220 mg, 1.33 mmol), [2-[( 2S,5R )-5-methyl-2-phenyl-1-piperidinyl] Lithium-2-oxoacetoxy]oxide (337.24 mg, 1.33 mmol), HATU (557.02 mg, 1.46 mmol) and TEA (336.91 mg, 3.33 mmol, 464.06 μL) were mixed in DMSO (4 mL) and stirred 1h. The solution in DMSO was subjected to HPLC (2-10 min 45-60% water/MeCN (loading pump 4 ml MeCN) column: TRIART 100*20 5 microns). 2-Ethyl-5-[[2-[( 2S,5R )-5-methyl-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 - Formamide (303.3 mg, 768.89 μmol, 57.73% yield).

化合物747： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.03(m,3H),1.14(dt,3H),1.33(dd,1H),1.66(d,1H),1.87(d,1H),2.01-2.16(m,1H),2.17-2.29(m,1H),2.73-2.81(m,2H),3.22-3.26(m,1H),3.37-4.06(m,1H),5.09-5.64(m,1H),7.22-7.31(m,2H),7.33-7.43(m,3H),7.49-7.60(m,1H),7.84-7.94(m,1H),7.94-8.02(m,1H),8.66-8.78(m,1H),11.03-11.25(m,1H)。 Compound 747: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98-1.03 (m, 3H), 1.14 (dt, 3H), 1.33 (dd, 1H), 1.66 (d, 1H), 1.87 ( d,1H), 2.01-2.16(m,1H), 2.17-2.29(m,1H), 2.73-2.81(m,2H), 3.22-3.26(m,1H), 3.37-4.06(m,1H), 5.09-5.64(m, 1H), 7.22-7.31(m, 2H), 7.33-7.43(m, 3H), 7.49-7.60(m, 1H), 7.84-7.94(m, 1H), 7.94-8.02(m , 1H), 8.66-8.78 (m, 1H), 11.03-11.25 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值394.2；實測值395.2；Rt=1.088min。LCMS (ESI): [M] + m/z: calculated 394.2; found 395.2; Rt=1.088 min.

實例733.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(3,5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物712及化合物734)之合成Example 733. N- (6-Amino-5-methylpyridin-3-yl)-2-(2-(3,5-difluorophenyl)-5-methylpiperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide (Compound 712 and Compound 734)

Figure 110128222-A0202-12-2346-601
Figure 110128222-A0202-12-2346-601

步驟1：6-(3,5-二氟苯基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3,5-difluorophenyl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(5g，14.48mmol)、(3,5-二氟苯基)硼酸(2.29g，14.48mmol)及碳酸鈉(4.60g，43.44mmol，1.82mL)添加到水(15mL)及二噁烷(45mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(591.19mg，723.94μmol)。將反應混合物在氬氣、70℃下攪拌14h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，以得到呈棕色油狀物之6-(3,5-二氟苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁酯(4g，12.93mmol，89.31%產率)，其不經純化即用於下一步驟。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (5 g, 14.48 mmol), (3,5- Difluorophenyl)boronic acid (2.29 g, 14.48 mmol) and sodium carbonate (4.60 g, 43.44 mmol, 1.82 mL) were added to a mixture of water (15 mL) and dioxane (45 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM (591.19 mg , 723.94 μmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 14 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo to give 6-(3,5-difluorophenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert-butyl ester as a brown oil (4 g, 12.93 mmol, 89.31% yield), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.89(d,3H),1.04(s,9H),1.81(m,1H),2.33(m,1H),2.96(m,1H),3.80(d,1H),5.46(m,1H),6.87(m,2H),7.06(m,1H),7.53(m,1H)。LCMS(ESI)：[M-Boc]+ m/z：計算值209.2；實測值210.2；Rt=1.626min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.89(d,3H), 1.04(s,9H), 1.81(m,1H), 2.33(m,1H), 2.96(m,1H), 3.80 (d, 1H), 5.46 (m, 1H), 6.87 (m, 2H), 7.06 (m, 1H), 7.53 (m, 1H). LCMS (ESI): [M-Boc] + m/z: calculated 209.2; found 210.2; Rt=1.626 min.

步驟2：6-(3,5-二氟苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3,5-difluorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(3,5-二氟苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(4g，12.93mmol)於TFA(22.12g，193.96mmol，14.94mL)中之溶液在25℃下攪拌1h，然後在真空中蒸發。將碎冰(15g)添加到殘餘物中且用10%氫氧化鈉水溶液將pH調節至10。將所得混合物用二氯甲烷(2*30ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈棕色油狀物之6-(3,5-二氟苯基)-3-甲基-1,2,3,4-四氫吡啶(2.5g，11.95mmol，92.41%產率)，其直接用於下一步驟中。6-(3,5-Difluorophenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (4 g, 12.93 mmol) in TFA (22.12 g, 193.96 mmol, 14.94 mL) was stirred at 25 °C for 1 h, then evaporated in vacuo. Crushed ice (15 g) was added to the residue and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2*30ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 6-(3,5-difluorophenyl)-3-methyl-1,2,3,4 as a brown oil - Tetrahydropyridine (2.5 g, 11.95 mmol, 92.41% yield), which was used directly in the next step.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.93(d,3H),1.36(m,1H),1.77(m,2H),2.80(m,1H),3.21(m,1H),3.82(d,1H),4.31(m,1H),7.20(m,1H),7.34(m,1H),8.39(m,1H)。LCMS(ESI)：[M]+ m/z：計算值209.2；實測值210.2；Rt=0.832min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.93(d, 3H), 1.36(m, 1H), 1.77(m, 2H), 2.80(m, 1H), 3.21(m, 1H), 3.82(d,1H), 4.31(m,1H), 7.20(m,1H), 7.34(m,1H), 8.39(m,1H). LCMS (ESI): [M] + m/z: calculated 209.2; found 210.2; Rt=0.832 min.

步驟3：2-(3,5-二氟苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(3,5-difluorophenyl)-5-methylpiperidine

在0℃下，將硼氫化鈉(723.26mg，19.12mmol，675.94μL)一次性添加到6-(3,5-二氟苯基)-3-甲基-1,2,3,4-四氫吡啶(2g，9.56mmol)於MeOH(25mL)中之經攪拌之溶液中。將所得混合物在25℃下攪拌2h，然後在真空中蒸發。將 殘餘物用水(20ml)稀釋且用DCM(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以H2 O-MeOH+HCl為溶析液混合物)，以得到2-(3,5-二氟苯基)-5-甲基哌啶(0.85g，3.43mmol，35.90%產率，HCl)。Sodium borohydride (723.26 mg, 19.12 mmol, 675.94 μL) was added in one portion to 6-(3,5-difluorophenyl)-3-methyl-1,2,3,4-tetrakis at 0 °C Hydropyridine (2 g, 9.56 mmol) in a stirred solution of MeOH (25 mL). The resulting mixture was stirred at 25 °C for 2 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with DCM (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The oil obtained was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with H2O -MeOH+HCl as eluent mixture) to give 2-(3,5-difluorophenyl)- 5-Methylpiperidine (0.85 g, 3.43 mmol, 35.90% yield, HCl).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.88(d,3H),1.27(m,1H),1.84(m,3H),2.07(m,1H),2.62(m,1H),3.19(d,1H),4.18(m,1H),7.24(m,1H),7.42(m,2H),9.53(m,1H)。LCMS(ESI)：[M]+ m/z：計算值211.2；實測值212.2；Rt=1.447min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.88(d,3H), 1.27(m,1H), 1.84(m,3H), 2.07(m,1H), 2.62(m,1H), 3.19 (d, 1H), 4.18 (m, 1H), 7.24 (m, 1H), 7.42 (m, 2H), 9.53 (m, 1H). LCMS (ESI): [M] + m/z: calculated 211.2; found 212.2; Rt=1.447 min.

步驟4：(5-(2-(2-(3,5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 4: (5-(2-(2-(3,5-Difluorophenyl)-5-methylpiperidin-1-yl)-2-oxyacetamido)-3-methyl Synthesis of tert-butyl pyridin-2-yl)carbamate

將DIPEA(615.66mg，4.76mmol，829.73μL)添加到相應2-(3,5-二氟苯基)-5-甲基哌啶(0.295g，1.19mmol，HCl)及2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(351.66mg，1.19mmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(498.10mg，1.31mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeCN為溶析液混合物)，以得到N -[5-[[2-[2-(3,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.32g，655.03μmol，55.00%產率)。DIPEA (615.66 mg, 4.76 mmol, 829.73 μL) was added to the corresponding 2-(3,5-difluorophenyl)-5-methylpiperidine (0.295 g, 1.19 mmol, HCl) and 2-[[6- ( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (351.66 mg, 1.19 mmol) in DMF (10 mL). The resulting mixture was stirred for 5 min before HATU (498.10 mg, 1.31 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeCN as eluent mixture) to give N- [5-[[2-[2-(3,5- Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.32 g , 655.03 μmol, 55.00% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.25(m,2H),1.39(s,9H),1.59(m,1H),1.87(m,1H),2.04(m,1H),2.13(s,3H),3.24(m,1H),3.46(m,1H),5.51(m,1H),7.03(m,3H),7.88(m,1H),8.39(m,1H),9.03(m,1H),11.03(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.98(d,3H), 1.25(m,2H), 1.39(s,9H), 1.59(m,1H), 1.87(m,1H), 2.04(m, 1H), 2.13(s, 3H), 3.24(m, 1H), 3.46(m, 1H), 5.51(m, 1H), 7.03(m, 3H), 7.88(m, 1H), 8.39 (m, 1H), 9.03 (m, 1H), 11.03 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值488.2；實測值489.2；Rt=3.673min。LCMS (ESI): [M] + m/z: calculated 488.2; found 489.2; Rt=3.673 min.

步驟5：掌性分離Step 5: Palm Separation

藉由掌性HPLC(管柱：IC(250*20，5mkm)，以CO2 -MeOH，55-45， 15ml/min為流動相)分離鏡像異構物，以得到兩種單獨的鏡像異構物E1N -[5-[[2-[(2S,5R )-2-(3,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(50.82mg，104.03μmol，15.88%產率)及E2N -[5-[[2-[(2R,5S )-2-(3,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(32.01mg，65.52μmol，10%產率)。The enantiomers were separated by chiral HPLC (column: IC (250*20, 5mkm) with CO2 -MeOH, 55-45, 15ml/min as mobile phase) to give two separate enantiomers Compound E1 N- [5-[[2-[( 2S,5R )-2-(3,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-side oxyacetyl tert -butyl]amino]-3-methyl-2-pyridyl]carbamate (50.82 mg, 104.03 μmol, 15.88% yield) and E2N- [5-[[2-[( 2R,5S )-2-(3,5-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl] tert -butyl carbamate (32.01 mg, 65.52 [mu]mol, 10% yield).

E1於分析條件下(管柱：IC，以CO2 -MeOH，60-40，2ml/min為流動相)之保留時間為5.90min且E2之保留時間為4.60min。The retention time of E1 under analytical conditions (column: IC, with CO2-MeOH, 60-40, 2 ml/min as mobile phase) was 5.90 min and the retention time of E2 was 4.60 min.

E1： LCMS(ESI)：[M]+ m/z：計算值488.2；實測值489.2；Rt=1.478min。 E1: LCMS (ESI): [M] + m/z: calculated 488.2; found 489.2; Rt=1.478 min.

E2： LCMS(ESI)：[M]+ m/z：計算值488.2；實測值489.2；Rt=1.479min。 E2: LCMS (ESI): [M] + m/z: calculated 488.2; found 489.2; Rt=1.479 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(3,5-二氟苯基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物712 及化合物734 )之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(3,5-difluorophenyl)-5-methylpiperidin-1-yl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 712 and Compound 734 )

將N -[5-[[2-[(2R,5S )-2-(3,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(32.01mg，65.52μmol)及N -[5-[[2-[(2S,5R )-2-(3,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(50.82mg，104.03μmol)溶解於水(5mL)及二噁烷(2mL)之混合物中。然後，將反應混合物在100℃下攪拌17h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeOH(100-50%)+FA為溶析液混合物)，以得到純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(3,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(10.7mg，27.55μmol，42.04%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(3,5-二氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(24.7mg，63.59μmol，61.13%產率)。 N- [5-[[2-[( 2R,5S )-2-(3,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-pendant oxyacetyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (32.01 mg, 65.52 μmol) and N- [5-[[2-[( 2S,5R )-2-(3, 5-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester ( 50.82 mg, 104.03 μmol) was dissolved in a mixture of water (5 mL) and dioxane (2 mL). Then, the reaction mixture was stirred at 100 °C for 17 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeOH (100-50%)+FA as eluent mixture) to give pure N- (6-amino -5-Methyl-3-pyridyl)-2-[( 2R,5S )-2-(3,5-difluorophenyl)-5-methyl-1-piperidinyl]-2-oxygen Ethylacetamide (10.7 mg, 27.55 μmol, 42.04% yield) and N-(6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(3, 5-Difluorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (24.7 mg, 63.59 μmol, 61.13% yield).

化合物712： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.30(m,1H),1.61(m,1H),1.84(m,1H),2.00(m,4H),2.17(m,1H),2.72(m,1H),3.72(m,1H),5.57 (m,3H),7.05(m,3H),7.45(m,1H),7.97(m,1H),10.52(m,1H)。 Compound 712: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.99 (m, 3H), 1.30 (m, 1H), 1.61 (m, 1H), 1.84 (m, 1H), 2.00 (m, 4H), 2.17(m, 1H), 2.72(m, 1H), 3.72(m, 1H), 5.57(m, 3H), 7.05(m, 3H), 7.45(m, 1H), 7.97(m, 1H) ), 10.52 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.308min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.308 min.

化合物734： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.99(m,3H),1.31(m,1H),1.60(m,1H),1.86(m,1H),2.00(m,4H),2.19(m,1H),2.71(m,1H),3.62(m,1H),5.57(m,3H),7.05(m,3H),7.45(m,1H),7.97(m,1H),10.52(m,1H)。 Compound 734: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.99 (m, 3H), 1.31 (m, 1H), 1.60 (m, 1H), 1.86 (m, 1H), 2.00 (m, 4H), 2.19(m, 1H), 2.71(m, 1H), 3.62(m, 1H), 5.57(m, 3H), 7.05(m, 3H), 7.45(m, 1H), 7.97(m, 1H) ), 10.52 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值388.2；實測值389.2；Rt=2.319min。LCMS (ESI): [M] + m/z: calculated 388.2; found 389.2; Rt=2.319 min.

實例734. 5-(2-(5-甲基-2-(2-甲基-2,3-二氫苯并呋喃-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物329、化合物376、化合物345、化合物377)之合成Example 734. 5-(2-(5-Methyl-2-(2-methyl-2,3-dihydrobenzofuran-5-yl)piperidin-1-yl)-2-side oxyethyl Synthesis of amide group) nicotinamide (compound 329, compound 376, compound 345, compound 377)

Figure 110128222-A0202-12-2350-602
Figure 110128222-A0202-12-2350-602

步驟1：3-甲基-6-(2-甲基-2,3-二氫苯并呋喃-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: 3-methyl-6-(2-methyl-2,3-dihydrobenzofuran-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester synthesis

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.5g，13.03mmol)、(2-甲基-2,3-二氫苯并呋喃-5-基)硼酸(2.78g，15.64mmol)及碳酸鈉(4.14g，39.09mmol，1.64mL)添加到1,4-二噁烷(60mL)及水(20mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 DCM(425.33mg，521.23μmol)。將反應混合物在氬氣、75℃下攪拌12h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析，使用己烷/MTBE梯度(0-100% MTBE)純化殘餘物，以得到呈淡黃色膠狀物之3-甲基-6-(2-甲基-2,3-二氫苯并呋喃-5-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.1g，3.34mmol，25.62%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.5 g, 13.03 mmol), (2-methyl) yl-2,3-dihydrobenzofuran-5-yl)boronic acid (2.78 g, 15.64 mmol) and sodium carbonate (4.14 g, 39.09 mmol, 1.64 mL) were added to 1,4-dioxane (60 mL) and in a mixture of water (20 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2 DCM (425.33 mg, 521.23 μmol) was added under argon. The reaction mixture was stirred under argon at 75 °C for 12 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/MTBE gradient (0-100% MTBE) to give 3-methyl-6-(2 as a pale yellow gum - Methyl-2,3-dihydrobenzofuran-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.1 g, 3.34 mmol, 25.62% yield).

1H NMR(400MHz,CDCl3 )δ(ppm)1.02(d,3H),1.12(s,9H),1.48(d,3H),1.86(m,2H),2.39(d,1H),2.96(m,2H),3.30(m,1H),4.08(d,1H),4.93(m,1H),5.20(m,1H),6.67(d,1H),7.05(d,1H),7.09(s,1H)。1H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.12(s,9H), 1.48(d,3H), 1.86(m,2H), 2.39(d,1H), 2.96(m ,2H),3.30(m,1H),4.08(d,1H),4.93(m,1H),5.20(m,1H),6.67(d,1H),7.05(d,1H),7.09(s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值229.2；實測值230.2；Rt=1.798min。LCMS (ESI): [M-Boc]+ m/z: calculated 229.2; found 230.2; Rt=1.798 min.

步驟2：5-(2-(5-甲基-2-(2-甲基-2,3-二氫苯并呋喃-5-基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物329 、化合物376 及化合物345 、化合物377 )之合成Step 2: 5-(2-(5-Methyl-2-(2-methyl-2,3-dihydrobenzofuran-5-yl)piperidin-1-yl)-2-pendoxoethyl Synthesis of amide group) nicotinamide ( compound 329 , compound 376 , compound 345 , compound 377 )

在25℃下，將HATU(328.73mg，864.56μmol)一次性添加到5-甲基-2-(2-甲基-2,3-二氫苯并呋喃-5-基)哌啶(200mg，864.56μmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(268.31mg，864.56μmol)及TEA(87.48mg，864.56μmol，120.50μL)於DMF(10mL)中之經攪拌之混合物中。將反應混合物在25℃下攪拌2h，然後在真空中濃縮至大約5ml且將其提交至反相HPLC(管柱：YMC Triart C18 100x20mm，5um；流動相45-75% 0-5min 0.1% NH3 -MeOH，流速：30ml/min)，以得到100mg呈淡黃色膠狀物之外消旋醯胺，然後將其提交至掌性HPLC(管柱：Chiralpak OJ-H(250*20mm，5mkm)；流動相：己烷-IPA-MeOH，40-30-30流速：10mL/min；管柱溫度：24℃；波長：205nm，236nm)，以得到呈混合物之前兩種鏡像異構物(分別地，rt=14.67及16.566min)及兩種粗品鏡像異構物(分別地，R.T.36.105及68.199min)。然後再次藉由掌性HPLC純化前兩種鏡像異構物之混合物(其中分別地，R.T.=14.67及16.566min)(管柱：Chiralpak OJ-H(250*20mm，5mkm)；流動相：己烷-IPA-MeOH，70-15-15流速：12mL/min；管柱溫度：24℃；波長：205nm，236nm)，以得到呈白色固體之化合物329 5-[[2-[(2S,5R )-5-甲基-2-[(2R )-2-甲基-2,3-二氫苯并呋喃-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(16.8mg，39.77μmol，4.60%產率)(R.T.=25.258min)及呈白色固體之化合物345 5-[[2-[(2S,5R )-5-甲基-2-[(2S )-2-甲基-2,3-二氫苯并呋喃-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(17.6mg，41.66μmol， 4.82%產率)(R.T.=31.452min)。藉由反相HPLC純化粗品第三鏡像異構物(其中R.T.36.105(藉由LCMS為87%純度))(管柱C18，流動相H2 O-MeCN，35-60% MeCN，流速30ml/min)，以得到化合物376 5-[[2-[(2R,5S )-5-甲基-2-[(2S )-2-甲基-2,3-二氫苯并呋喃-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(14.5mg，34.32μmol，3.97%產率)。第四鏡像異構物(其中R.T.=68.199min)不經進一步純化即提交為化合物377 5-[[2-[(2R,5S )-5-甲基-2-[(2R )-2-甲基-2,3-二氫苯并呋喃-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(17.1mg，40.48μmol，4.68%產率)。化合物329 於分析條件下(管柱：OJ-H，以CO2 -MeOH，60-40，2ml/min為流動相)之保留時間為3.66min，化合物376 之保留時間為5.68min，化合物345 之保留時間為4.09min且化合物377 之保留時間為8.90min。At 25°C, HATU (328.73 mg, 864.56 μmol) was added in one portion to 5-methyl-2-(2-methyl-2,3-dihydrobenzofuran-5-yl)piperidine (200 mg, 864.56 μmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (268.31 mg, 864.56 μmol) and TEA (87.48 mg, 864.56 μmol, 120.50 μL) in into the stirred mixture in DMF (10 mL). The reaction mixture was stirred at 25°C for 2h, then concentrated in vacuo to approximately 5ml and submitted to reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um; mobile phase 45-75% 0-5min 0.1% NH3 -MeOH, flow rate: 30ml/min) to give 100mg of racemic amide as a pale yellow gum, which was then submitted to chiral HPLC (column: Chiralpak OJ-H (250*20mm, 5mkm); Mobile phase: Hexane-IPA-MeOH, 40-30-30 Flow rate: 10 mL/min; Column temperature: 24°C; Wavelength: 205nm, 236nm) to obtain two enantiomers (respectively, rt=14.67 and 16.566 min) and two crude enantiomers (RT 36.105 and 68.199 min, respectively). The mixture of the first two enantiomers was then purified again by chiral HPLC (where RT=14.67 and 16.566 min, respectively) (column: Chiralpak OJ-H (250*20 mm, 5 mkm); mobile phase: hexane -IPA-MeOH, 70-15-15 flow rate: 12 mL/min; column temperature: 24 °C; wavelength: 205 nm, 236 nm) to give compound 329 as a white solid 5-[[2-[( 2S,5R ) -5-Methyl-2-[( 2R )-2-methyl-2,3-dihydrobenzofuran-5-yl]-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide (16.8 mg, 39.77 μmol, 4.60% yield) (RT=25.258 min) and compound 345 as a white solid 5-[[2-[( 2S,5R )-5-methyl yl-2-[( 2S )-2-methyl-2,3-dihydrobenzofuran-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine- 3-Carboxamide (17.6 mg, 41.66 μmol, 4.82% yield) (RT=31.452 min). The crude third enantiomer was purified by reverse phase HPLC with RT 36.105 (87% purity by LCMS) (column C18, mobile phase H2O -MeCN, 35-60% MeCN, flow rate 30ml/ min) to give compound 376 5-[[2-[( 2R,5S )-5-methyl-2-[( 2S )-2-methyl-2,3-dihydrobenzofuran-5-yl ]-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (14.5 mg, 34.32 μmol, 3.97% yield). The fourth enantiomer (where RT=68.199 min) was submitted without further purification as compound 377 5-[[2-[( 2R,5S )-5-methyl-2-[( 2R )-2-methyl yl-2,3-dihydrobenzofuran-5-yl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (17.1 mg, 40.48 μmol, 4.68% yield). Under the analytical conditions (column: OJ-H, with CO 2 -MeOH, 60-40, 2ml/min as mobile phase), the retention time of compound 329 was 3.66 min, the retention time of compound 376 was 5.68 min, and the retention time of compound 345 was 5.68 min. The retention time was 4.09 min and the retention time for compound 377 was 8.90 min.

化合物329：保留時間：3.66minCompound 329: retention time: 3.66min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.01(m,3H),1.29(m,1H),1.35(m,3H),1.71(m,1H),1.87(m,1H),1.97(m,1H),2.14(m,1H),2.77(m,1H),3.24(m,1H),3.52(m,2H),4.87(m,1H),5.27(m,1H),6.68(m,1H),7.02(m,1H),7.14(m,1H),7.59(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.85(m,1H),11.18(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.01(m, 3H), 1.29(m, 1H), 1.35(m, 3H), 1.71(m, 1H), 1.87(m, 1H), 1.97(m, 1H), 2.14(m, 1H), 2.77(m, 1H), 3.24(m, 1H), 3.52(m, 2H), 4.87(m, 1H), 5.27(m, 1H), 6.68 (m,1H),7.02(m,1H),7.14(m,1H),7.59(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.85( m, 1H), 11.18 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=3.143min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=3.143 min.

化合物376：保留時間：5.68minCompound 376: retention time: 5.68min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98-1.04(m,3H),1.19-1.32(m,2H),1.32-1.39(m,3H),1.69-1.78(m,1H),1.82-1.93(m,1H),1.99-2.10(m,1H),2.12-2.21(m,1H),2.67-2.79(m,1H),2.83-3.22(m,1H),3.32-3.99(m,1H),4.79-4.95(m,1H),4.99-5.54(m,1H),6.65-6.75(m,1H),6.98-7.05(m,1H),7.11-7.18(m,1H),7.52-7.63(m,1H),8.09-8.21(m,1H),8.43-8.51(m,1H),8.71-8.81(m,1H),8.81-8.94(m,1H),11.07-11.29(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.98-1.04(m,3H), 1.19-1.32(m,2H), 1.32-1.39(m,3H), 1.69-1.78(m,1H) ,1.82-1.93(m,1H),1.99-2.10(m,1H),2.12-2.21(m,1H),2.67-2.79(m,1H),2.83-3.22(m,1H),3.32-3.99( m,1H),4.79-4.95(m,1H),4.99-5.54(m,1H),6.65-6.75(m,1H),6.98-7.05(m,1H),7.11-7.18(m,1H), 7.52-7.63(m, 1H), 8.09-8.21(m, 1H), 8.43-8.51(m, 1H), 8.71-8.81(m, 1H), 8.81-8.94(m, 1H), 11.07-11.29(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=3.184min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=3.184 min.

化合物345：保留時間：4.09minCompound 345: retention time: 4.09min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.03(m,3H),1.35(m,3H),1.72(m,1H),1.86(m,1H),2.01(m,1H),2.14(m,1H),2.74(m,1H),3.00(m,1H),3.42(m,2H),4.22(m,1H),4.87(m,1H),5.27(m,1H),6.69(m,1H),7.02(m,1H),7.14(m,1H),7.59(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.85(m,1H),11.17(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.03(m, 3H), 1.35(m, 3H), 1.72(m, 1H), 1.86(m, 1H), 2.01(m, 1H), 2.14(m, 1H), 2.74(m, 1H), 3.00(m, 1H), 3.42(m, 2H), 4.22(m, 1H), 4.87(m, 1H), 5.27(m, 1H), 6.69 (m,1H),7.02(m,1H),7.14(m,1H),7.59(m,1H),8.14(m,1H),8.46(m,1H),8.75(m,1H),8.85( m, 1H), 11.17 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=3.139min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=3.139 min.

化合物377：保留時間：8.90minCompound 377: retention time: 8.90min

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.97-1.03(m,3H),1.19-1.32(m,2H),1.33-1.41(m,3H),1.69-1.78(m,1H),1.83-1.93(m,1H),1.97-2.10(m,1H),2.13-2.20(m,1H),2.69-2.79(m,1H),2.79-3.24(m,1H),3.39-3.97(m,1H),4.83-4.92(m,1H),5.00-5.55(m,1H),6.64-6.73(m,1H),6.98-7.06(m,1H),7.11-7.18(m,1H),7.56-7.66(m,1H),8.09-8.20(m,1H),8.41-8.51(m,1H),8.71-8.78(m,1H),8.81-8.92(m,1H),11.06-11.31(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.97-1.03(m,3H), 1.19-1.32(m,2H), 1.33-1.41(m,3H), 1.69-1.78(m,1H) ,1.83-1.93(m,1H),1.97-2.10(m,1H),2.13-2.20(m,1H),2.69-2.79(m,1H),2.79-3.24(m,1H),3.39-3.97( m,1H),4.83-4.92(m,1H),5.00-5.55(m,1H),6.64-6.73(m,1H),6.98-7.06(m,1H),7.11-7.18(m,1H), 7.56-7.66(m, 1H), 8.09-8.20(m, 1H), 8.41-8.51(m, 1H), 8.71-8.78(m, 1H), 8.81-8.92(m, 1H), 11.06-11.31(m , 1H).

LCMS(ESI)：[M]+ m/z：計算值422.2；實測值423.2；Rt=3.184min。LCMS (ESI): [M] + m/z: calculated 422.2; found 423.2; Rt=3.184 min.

實例735. 2-[(2S ,5S )-5-乙基-2-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺、2-[(2S ,5R )-5-乙基-2-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2R ,5S )-5-乙基-2-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物20、化合物17及化合物18)之合成Example 735. 2-[( 2S , 5S )-5-ethyl-2-phenyl - 1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-side oxy Acetamide, 2-[( 2S , 5R )-5-ethyl-2-phenyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2-oxygen Ethylacetamide and 2-[( 2R , 5S )-5-ethyl-2-phenyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2-side Synthesis of Oxyacetamide (Compound 20, Compound 17 and Compound 18)

Figure 110128222-A0202-12-2354-603
Figure 110128222-A0202-12-2354-603

步驟1：5-乙基-2-苯基吡啶之合成Step 1: Synthesis of 5-ethyl-2-phenylpyridine

向2-溴-5-乙基吡啶(1g，5.37mmol)及苯基硼酸(655.36mg，5.37mmol)於二噁烷(10mL)中之經攪拌之溶液中添加碳酸銫(5.25g，16.12mmol)。將所得懸浮液用氬氣除氣。添加肆(三苯基膦)鈀(0)(620mg，0.537mmol)將反應混合物在65℃下攪拌隔夜。完成之後，將反應混合物過濾且在真空中蒸發濾液，以獲得油狀殘餘物。藉由反相HPLC(49%水-乙腈；0.5-6.5min；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFire 100*19mm，5um)純化殘餘物，以得到呈黃色油狀物之產物5-乙基-2-苯基吡啶(0.56g，3.06mmol，56.86%產率)。To a stirred solution of 2-bromo-5-ethylpyridine (1 g, 5.37 mmol) and phenylboronic acid (655.36 mg, 5.37 mmol) in dioxane (10 mL) was added cesium carbonate (5.25 g, 16.12 mmol) ). The resulting suspension was degassed with argon. Forth(triphenylphosphine)palladium(0) (620 mg, 0.537 mmol) was added and the reaction mixture was stirred at 65°C overnight. After completion, the reaction mixture was filtered and the filtrate was evaporated in vacuo to obtain an oily residue. The residue was purified by reverse phase HPLC (49% water-acetonitrile; 0.5-6.5 min; flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile; column: SunFire 100*19 mm, 5 um) to give a yellow color Product 5-ethyl-2-phenylpyridine (0.56 g, 3.06 mmol, 56.86% yield) as an oil.

1 H NMR(DMSO-d 6 ,400MHz)：δ(ppm)1.22(t,3H),2.65(q,2H),7.44(m,3H),7.71(dd,1H),7.87(d,1H),8.06(d,2H),8.53(d,1H)。 1 H NMR (DMSO- d 6 , 400 MHz): δ (ppm) 1.22 (t, 3H), 2.65 (q, 2H), 7.44 (m, 3H), 7.71 (dd, 1H), 7.87 (d, 1H) , 8.06(d, 2H), 8.53(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值183.1；實測值184.2；Rt=2.645min。LCMS (ESI): [M+H] + m/z: calculated 183.1; found 184.2; Rt=2.645 min.

步驟2：5-乙基-2-苯基哌啶之合成Step 2: Synthesis of 5-ethyl-2-phenylpiperidine

在100atm H2 壓力、50℃下，將5-乙基-2-苯基吡啶(0.5g，2.73mmol)於MeOH(20mL)中之溶液經5% Pd(OH)2 /碳(16.84mg，136.43μmol)氫化18小時。完成之後，過濾反應混合物，將殘餘物用MeOH(10mL)洗滌且在減壓下濃縮濾液，以獲得5-乙基-2-苯基哌啶(0.38g，2.01mmol，73.57%產率)。粗產物不 經任何進一步純化即用於下一步。A solution of 5-ethyl- 2 -phenylpyridine (0.5 g, 2.73 mmol) in MeOH (20 mL) was treated with 5% Pd(OH) 2 on carbon (16.84 mg, 136.43 μmol) hydrogenated for 18 hours. After completion, the reaction mixture was filtered, the residue was washed with MeOH (10 mL) and the filtrate was concentrated under reduced pressure to obtain 5-ethyl-2-phenylpiperidine (0.38 g, 2.01 mmol, 73.57% yield). The crude product was used in the next step without any further purification.

步驟3：2-[(2S,5S)-5-乙基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺，2-[(2S,5R)-5-乙基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺及2-[(2R,5S)-5-乙基-2-苯基-1-哌啶基]-N-(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物20 、化合物17 及化合物18 )之合成Step 3: 2-[(2S,5S)-5-Ethyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxoacetyl Amine, 2-[(2S,5R)-5-ethyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxoacetamide and 2-[(2R,5S)-5-ethyl-2-phenyl-1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxoacetamide ( Synthesis of compound 20 , compound 17 and compound 18 )

在氬氣氣氛、-78℃下，向5-乙基-2-苯基哌啶(0.38g，2.01mmol)於THF(10mL)中之經攪拌之溶液中添加正丁基鋰 (2.5M於己烷中，385.76mg，6.02mmol，2.4mL)。將所得混合物在同一溫度下攪拌5分鐘。5分鐘之後，將溶解於THF(10mL)中之2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(526.32mg，2.01mmol)添加到反應混合物中。使所得混合物升溫至室溫且在同一溫度下攪拌隔夜。完成之後，添加MeOH(5mL)且在真空中蒸發反應混合物。藉由反相HPLC(溶析液：44%水-乙腈，0.5-6.5min；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFire 100*19mm，5um)及掌性管柱層析(管柱：IA，250*20mm，5um，溶析液：己烷-MeOH-IPA，80-10-10，流速：12mL/min)純化所獲得之粗殘餘物，以得到呈黃色固體之產物2-[(2S ,5S )-5-乙基-2-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物20 )(2mg，5.69μmol，2.83-1%產率)、2-[(2S ,5R )-5-乙基-2-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物17 )(24mg，68.29μmol，3.40%產率)及2-[(2R ,5S )-5-乙基-2-苯基-1-哌啶基]-N -(5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物18 )(28mg，79.67μmol，3.97%產率)。To a stirred solution of 5-ethyl-2-phenylpiperidine (0.38 g, 2.01 mmol) in THF (10 mL) was added n-butyllithium (2.5 M in THF) under argon at -78 °C. in hexane, 385.76 mg, 6.02 mmol, 2.4 mL). The resulting mixture was stirred at the same temperature for 5 minutes. After 5 minutes, 2,2,2-trifluoroethyl 2-[(5-methyl-3-pyridyl)amino]-2-oxoacetic acid (526.32 mg) was dissolved in THF (10 mL). , 2.01 mmol) was added to the reaction mixture. The resulting mixture was warmed to room temperature and stirred at the same temperature overnight. After completion, MeOH (5 mL) was added and the reaction mixture was evaporated in vacuo. By reversed-phase HPLC (eluent: 44% water-acetonitrile, 0.5-6.5min; flow rate: 30mL/min; loading pump: 4mL/min, acetonitrile; column: SunFire 100*19mm, 5um) and chiral tube The obtained crude residue was purified by column chromatography (column: IA, 250*20mm, 5um, eluent: hexane-MeOH-IPA, 80-10-10, flow rate: 12 mL/min) to give a yellow color Solid product 2-[(2S, 5S )-5-ethyl-2-phenyl-1-piperidinyl]-N-(5-methyl - 3-pyridyl)-2- pendantoxy Acetamide ( Compound 20 ) (2 mg, 5.69 μmol, 2.83-1 % yield), 2-[(2S, 5R )-5-ethyl-2-phenyl-1-piperidinyl] -N -(5-Methyl-3-pyridyl)-2-oxoacetamide ( Compound 17 ) (24 mg, 68.29 μmol, 3.40% yield) and 2-[( 2R , 5S )-5-ethyl yl-2-phenyl - 1-piperidinyl]-N-(5-methyl-3-pyridyl)-2-oxyacetamide ( Compound 18 ) (28 mg, 79.67 μmol, 3.97% yield ).

化合物18： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.92(m,3H),1.44(m,1H),1.50(m,1H),1.61(m,2H),1.74(m,1H),2.16(m,2H),2.33(m,3H),2.76(m,0.4H)3.26(m,0.6H),3.99(m,1H),5.46(m,1H),7.24(m,1H),7.30(m,1H),7.36(m,3H),7.96(m,1H),8.07(m,1H),8.56(m,1H),10.86(m,1H)。 Compound 18: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.92 (m, 3H), 1.44 (m, 1H), 1.50 (m, 1H), 1.61 (m, 2H), 1.74 (m ,1H),2.16(m,2H),2.33(m,3H),2.76(m,0.4H)3.26(m,0.6H),3.99(m,1H),5.46(m,1H),7.24(m , 1H), 7.30 (m, 1H), 7.36 (m, 3H), 7.96 (m, 1H), 8.07 (m, 1H), 8.56 (m, 1H), 10.86 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.0；Rt=4.946min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.0; Rt=4.946 min.

掌性HPLC：Rt=24.87min(管柱：IA；流動相：己烷-MeOH-IPA，80-10-10；流速：0.8mL/min)。Chiral HPLC: Rt=24.87 min (column: IA; mobile phase: hexane-MeOH-IPA, 80-10-10; flow rate: 0.8 mL/min).

化合物17： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.92(m,3H),1.44(m,1H),1.50(m,1H),1.61(m,2H),1.74(m,1H),2.16(m,2H),2.33(m,3H),2.76(m,0.4H),3.26(m,0.6H),3.99(m,1H),5.46(m,1H),7.24(m,1H),7.30(m,1H),7.36(m,3H),7.96(m,1H),8.07(m,1H),8.56(m,1H),10.86(m,1H)。 Compound 17: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.92 (m, 3H), 1.44 (m, 1H), 1.50 (m, 1H), 1.61 (m, 2H), 1.74 (m ,1H),2.16(m,2H),2.33(m,3H),2.76(m,0.4H),3.26(m,0.6H),3.99(m,1H),5.46(m,1H),7.24( m, 1H), 7.30 (m, 1H), 7.36 (m, 3H), 7.96 (m, 1H), 8.07 (m, 1H), 8.56 (m, 1H), 10.86 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.0；Rt=4.996min。LCMS (ESI): [M+H] + m/z: calculated 351.2; found 352.0; Rt=4.996 min.

掌性HPLC：Rt=32.61min(管柱：IA；流動相：己烷-MeOH-IPA，80-10-10；流速：0.8mL/min)。Chiral HPLC: Rt=32.61 min (column: IA; mobile phase: hexane-MeOH-IPA, 80-10-10; flow rate: 0.8 mL/min).

化合物20： LCMS(ESI)：[M+H]+ m/z：計算值351.2；實測值352.0；Rt=5.027min。 Compound 20: LCMS (ESI): [M+H] + m/z: calcd 351.2; found 352.0; Rt=5.027 min.

掌性HPLC：Rt=17.96min(管柱：IA；流動相：己烷-MeOH-IPA，80-10-10；流速：0.8mL/min)。Chiral HPLC: Rt=17.96 min (column: IA; mobile phase: hexane-MeOH-IPA, 80-10-10; flow rate: 0.8 mL/min).

實例736. 5-(2-(5-乙基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物547、化合物576及化合物565)之合成Example 736. 5-(2-(5-Ethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 547, Compound 576 and Compound 565) synthesis

Figure 110128222-A0202-12-2356-604
Figure 110128222-A0202-12-2356-604

步驟1：1-(第三丁氧基羰基)-5-乙基哌啶-2-甲酸之合成Step 1: Synthesis of 1-(3-butoxycarbonyl)-5-ethylpiperidine-2-carboxylic acid

將5-乙基哌啶-2-甲酸(5g，25.82mmol，HCl)溶解於水(50mL)中且向其中添加氫氧化鈉珠粒(4.13g，103.27mmol，1.94mL)。將所得混合物用THF(50mL)稀釋且將二碳酸二-第三丁酯(8.45g，38.73mmol，8.89mL)逐滴添加到先前 的混合物中。將反應混合物攪拌18h。將反應混合物在真空中濃縮且將殘餘物用水(50ml)稀釋。將所得混合物用MTBE(3*50ml)洗滌，然後用NaHSO4 酸化。將所得混合物用DCM(3*50ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得1-第三丁氧基 羰基-5-乙基哌啶-2-甲酸(4.03g，15.65mmol，60.62%產率)。5-Ethylpiperidine-2-carboxylic acid (5 g, 25.82 mmol, HCl) was dissolved in water (50 mL) and sodium hydroxide beads (4.13 g, 103.27 mmol, 1.94 mL) were added thereto. The resulting mixture was diluted with THF (50 mL) and di-tert-butyl dicarbonate (8.45 g, 38.73 mmol, 8.89 mL) was added dropwise to the previous mixture. The reaction mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (50 ml). The resulting mixture was washed with MTBE (3*50ml), then acidified with NaHSO4 . The resulting mixture was extracted with DCM (3*50ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to obtain 1 -tert- butoxycarbonyl-5-ethylpiperidine-2-carboxylic acid (4.03 g, 15.65 mmol, 60.62% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.87(m,3H),1.26(m,2H),1.38(s,9H),1.48(m,3H),1.79(m,2H),3.06(m,1H),3.68(m,1H),4.53(m,1H),12.55(bds,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.87(m, 3H), 1.26(m, 2H), 1.38(s, 9H), 1.48(m, 3H), 1.79(m, 2H), 3.06 (m, 1H), 3.68 (m, 1H), 4.53 (m, 1H), 12.55 (bds, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值157.2；實測值158.2；Rt=1.289min。LCMS (ESI): [M-Boc] + m/z: calculated 157.2; found 158.2; Rt=1.289 min.

步驟2：5-乙基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl 5-ethyl-2-phenylpiperidine-1-carboxylate

將Ir[dF(CF3 )ppy]2 (dtbbpy)PF6 (43.60mg，38.86μmol)、NiCl2 ．甘醇二甲醚(85.39mg，388.61μmol)及dtbbpy(156.45mg，582.92μmol)一起混合於DMF(50mL)中。將1-第三丁氧基 羰基-5-乙基哌啶-2-甲酸(1g，3.89mmol)、2-第三丁基 -1,1,3,3-四甲基(665.62mg，3.89mmol)及碘苯(792.80mg，3.89mmol，433.22μL)添加到前一混合物中且藉由用氬氣吹掃將所得混合物除氣15min。將小瓶密封，用石蠟膜纏繞且置於藍色LED光反應器中。將反應混合物在50℃下攪拌48h。在真空中濃縮反應混合物且將水(50ml)添加到殘餘物中。將所得混合物用EtOAc(2*50ml)萃取。將經合併之有機層用水(3*50ml)、鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由HPLC(2-10min 50-70% MeOH/H2 O 30ml/min(裝載泵4ml MeOH)，管柱：SunFire 100*19mm，5微米)純化殘餘物，以獲得5-乙基-2-苯基哌啶-1-甲酸第三丁 酯(0.2822g，975.08μmol，25.09%產率)及5-乙基-2-苯基哌啶-1-甲酸第三丁 酯(112.20mg，387.68μmol，9.98%產率)。Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (43.60 mg, 38.86 μmol), NiCl 2 . Glyme (85.39 mg, 388.61 μmol) and dtbbpy (156.45 mg, 582.92 μmol) were mixed together in DMF (50 mL). Combine 1 -tert- butoxycarbonyl-5-ethylpiperidine-2-carboxylic acid (1 g, 3.89 mmol), 2 -tert-butyl- 1,1,3,3-tetramethyl (665.62 mg, 3.89 mmol) and iodobenzene (792.80 mg, 3.89 mmol, 433.22 μL) were added to the previous mixture and the resulting mixture was degassed by purging with argon for 15 min. The vial was sealed, wrapped with parafilm and placed in a blue LED photoreactor. The reaction mixture was stirred at 50 °C for 48 h. The reaction mixture was concentrated in vacuo and water (50 ml) was added to the residue. The resulting mixture was extracted with EtOAc (2*50ml). The combined organic layers were washed with water (3*50ml), brine, dried over Na2SO4 , filtered and evaporated. The residue was purified by HPLC (2-10 min 50-70% MeOH/H 2 O 30 ml/min (loading pump 4 ml MeOH), column: SunFire 100*19 mm, 5 microns) to obtain 5-ethyl-2- 3-butyl phenylpiperidine-1-carboxylate (0.2822 g, 975.08 μmol, 25.09% yield) and tert- butyl 5-ethyl-2-phenylpiperidine-1-carboxylate (112.20 mg, 387.68 μmol , 9.98% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.89(t,3H),1.08(m,1H),1.40(s,9H),1.61(m,1H),1.79(m,1H),1.97(m,1H),2.28(m,2H),2.90(d,1H),3.77(d,1H),3.96(m,1H),5.25(m,1H),7.22(m,3H),7.36(m,2H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.89(t, 3H), 1.08(m, 1H), 1.40(s, 9H), 1.61(m, 1H), 1.79(m, 1H), 1.97(m, 1H), 2.28(m, 2H), 2.90(d, 1H), 3.77(d, 1H), 3.96(m, 1H), 5.25(m, 1H), 7.22(m, 3H), 7.36 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值189.2；實測值190.2；Rt=1.550min。LCMS (ESI): [M-Boc] + m/z: calculated 189.2; found 190.2; Rt=1.550 min.

步驟3：5-乙基-2-苯基哌啶之合成Step 3: Synthesis of 5-ethyl-2-phenylpiperidine

將5-乙基-2-苯基哌啶-1-甲酸第三丁 酯(0.464g，1.60mmol)溶解於MeOH(5mL)中且向其中添加於二噁烷中之4.0M氯化氫溶液(584.56mg，16.03mmol，730.70μL)。將所得混合物攪拌18h，然後蒸發至乾，以獲得5-乙基-2-苯基哌啶(0.337g，1.49mmol，93.11%產率，HCl)。 3-Butyl 5-ethyl-2-phenylpiperidine-1-carboxylate (0.464 g, 1.60 mmol) was dissolved in MeOH (5 mL) and to it was added a 4.0 M solution of hydrogen chloride in dioxane (584.56 g mg, 16.03 mmol, 730.70 μL). The resulting mixture was stirred for 18 h, then evaporated to dryness to obtain 5-ethyl-2-phenylpiperidine (0.337 g, 1.49 mmol, 93.11% yield, HCl).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.90(d,3H),1.68(m,6H),2.72(m,1H),3.06(m,1H),3.26(m,1H),4.22(m,1H),7.42(m,3H),7.54(m,2H),9.52(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.90(d, 3H), 1.68(m, 6H), 2.72(m, 1H), 3.06(m, 1H), 3.26(m, 1H), 4.22 (m, 1H), 7.42 (m, 3H), 7.54 (m, 2H), 9.52 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值189.2；實測值190.2；Rt=0.775min。LCMS (ESI): [M] + m/z: calculated 189.2; found 190.2; Rt=0.775 min.

步驟4：5-(2-(5-乙基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 4: Synthesis of 5-(2-(5-ethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide

將5-乙基-2-苯基哌啶(0.337g，1.49mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(366.65mg，1.49mmol，HCl)及TEA(1.51g，14.93mmol，2.08mL)一起混合於DMF(6mL)中且向其中添加HATU(851.39mg，2.24mmol)。將反應混合物攪拌18h。在真空中濃縮反應混合物且藉由HPLC(2-10min 50-70% MeOH/H2 O 30ml/min(裝載泵4ml MeOH)，管柱：SunFire 100*19mm，5微米)純化殘餘物，以獲得5-[[2-(5-乙基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2344g，616.13μmol，41.27%產率)Combine 5-ethyl-2-phenylpiperidine (0.337 g, 1.49 mmol, HCl), 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (366.65 mg, 1.49 mmol, HCl) and TEA (1.51 g, 14.93 mmol, 2.08 mL) were mixed together in DMF (6 mL) and to this was added HATU (851.39 mg, 2.24 mmol). The reaction mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 50-70% MeOH/ H2O 30 ml/min (loading pump 4 ml MeOH), column: SunFire 100*19 mm, 5 microns) to obtain 5-[[2-(5-Ethyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.2344 g, 616.13 μmol, 41.27% yield)

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.82(m,3H),1.22(m,2H),1.86(m,4H),2.70(m,1H),3.18(m,2H),3.68(m,1H),4.32(m,1H),5.55(m,1H),7.34(m,4H),7.58(m,1H),8.22(m,1H),8.48(m,1H),8.76(m,1H),11.38(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.82(m, 3H), 1.22(m, 2H), 1.86(m, 4H), 2.70(m, 1H), 3.18(m, 2H), 3.68(m, 1H), 4.32(m, 1H), 5.55(m, 1H), 7.34(m, 4H), 7.58(m, 1H), 8.22(m, 1H), 8.48(m, 1H), 8.76 (m, 1H), 11.38 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值380.2；實測值381.2；Rt=1.129min。LCMS (ESI): [M] + m/z: calculated 380.2; found 381.2; Rt=1.129 min.

步驟5：掌性分離(化合物547、化合物576 及化合物565 )Step 5: Chiral separation ( Compound 547, Compound 576 and Compound 565 )

對5-[[2-(5-乙基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2344g，616.13μmol)進行掌性分離(順式/反式 分離：C18，19*100， H2 O-ACN，70-30，30ml/min，10次注入，23mg/注入，保留時間=15.166；反式異構物分離：Chiralpak IA II(250*20mm，5mkm)己烷-IPA-MeOH，50-25-25，13ml/min，2次注入，20mg/注入，保留時間=20.247)，以獲得5-[[2-[(2S,5R )-5-乙基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.02606g，68.50μmol，11.12%產率)。p-5-[[2-(5-Ethyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.2344 g, 616.13 μmol ) for chiral separation ( cis/trans separation: C18, 19*100, H 2 O-ACN, 70-30, 30ml/min, 10 injections, 23mg/injection, retention time=15.166; trans isomerism Isolation: Chiralpak IA II (250*20mm, 5mkm) Hexane-IPA-MeOH, 50-25-25, 13ml/min, 2 injections, 20mg/injection, retention time=20.247) to obtain 5-[[ 2-[( 2S,5R )-5-ethyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.02606 g, 68.50 g μmol, 11.12% yield).

對5-[[2-(5-乙基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2344g，616.13μmol)進行掌性分離(順式/反式 分離：C18，19*100，H2 O-ACN，70-30，30ml/min，10次注入，23mg/注入，保留時間=15.166；反式異構物分離：Chiralpak IA II(250*20mm，5mkm)己烷-IPA-MeOH，50-25-25，13ml/min，2次注入，20mg/注入，保留時間=34.381)，以獲得5-[[2-[(2R,5S )-5-乙基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.02981g，78.36μmol，12.72%產率)。p-5-[[2-(5-Ethyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.2344 g, 616.13 μmol ) for chiral separation ( cis/trans separation: C18, 19*100, H 2 O-ACN, 70-30, 30ml/min, 10 injections, 23mg/injection, retention time=15.166; trans isomerism Isolation: Chiralpak IA II (250*20mm, 5mkm) Hexane-IPA-MeOH, 50-25-25, 13ml/min, 2 injections, 20mg/injection, retention time=34.381) to obtain 5-[[ 2-[( 2R,5S )-5-ethyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.02981 g, 78.36 g μmol, 12.72% yield).

對5-[[2-(5-乙基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.2344g，616.13μmol)進行掌性分離(C18,19*100，H2 O-ACN，70-30，30ml/min，10次注入，23mg/注入，保留時間=18.860)，以獲得5-[[2-[(2R,5R )-5-乙基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(97.35mg，255.89μmol，41.53%產率)。p-5-[[2-(5-Ethyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.2344 g, 616.13 μmol ) for chiral separation (C18, 19*100, H 2 O-ACN, 70-30, 30 ml/min, 10 injections, 23 mg/injection, retention time = 18.860) to obtain 5-[[2-[( 2R,5R )-5-ethyl-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (97.35 mg, 255.89 μmol, 41.53% Yield).

化合物547：保留時間：34.38minCompound 547: retention time: 34.38min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.74-0.94(m,3H),1.32-1.47(m,2H),1.47-1.57(m,2H),1.59-1.68(m,1H),1.91-2.09(m,1H),2.14-2.28(m,1H),2.75-3.23(m,1H),3.59-4.20(m,1H),5.10-5.61(m,1H),7.23-7.29(m,1H),7.29-7.32(m,1H),7.32-7.42(m,3H),7.54-7.70(m,1H),8.05-8.20(m,1H),8.40-8.55(m,1H),8.70-8.80(m,1H),8.80-8.96(m,1H),11.06-11.38(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.74-0.94(m,3H), 1.32-1.47(m,2H), 1.47-1.57(m,2H), 1.59-1.68(m,1H) ,1.91-2.09(m,1H),2.14-2.28(m,1H),2.75-3.23(m,1H),3.59-4.20(m,1H),5.10-5.61(m,1H),7.23-7.29( m,1H),7.29-7.32(m,1H),7.32-7.42(m,3H),7.54-7.70(m,1H),8.05-8.20(m,1H),8.40-8.55(m,1H), 8.70-8.80 (m, 1H), 8.80-8.96 (m, 1H), 11.06-11.38 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值380.2；實測值381.2；Rt=1.077min。LCMS (ESI): [M] + m/z: calculated 380.2; found 381.2; Rt=1.077 min.

化合物576：保留時間：20.25minCompound 576: retention time: 20.25min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.71-0.93(m,3H),1.30-1.48(m,2H),1.48-1.58(m,2H),1.59-1.69(m,1H),1.92-2.10(m,1H),2.14-2.27(m,1H),2.74-3.26(m,1H),3.56-4.26(m,1H),5.12-5.59(m,1H),7.23-7.29(m,1H),7.29-7.32(m,1H),7.32-7.41(m,3H),7.53-7.67(m,1H),8.09-8.22(m,1H),8.39-8.53(m,1H),8.70-8.80(m,1H),8.81-8.94(m,1H),11.01-11.46(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.71-0.93(m,3H), 1.30-1.48(m,2H), 1.48-1.58(m,2H), 1.59-1.69(m,1H) ,1.92-2.10(m,1H),2.14-2.27(m,1H),2.74-3.26(m,1H),3.56-4.26(m,1H),5.12-5.59(m,1H),7.23-7.29( m,1H),7.29-7.32(m,1H),7.32-7.41(m,3H),7.53-7.67(m,1H),8.09-8.22(m,1H),8.39-8.53(m,1H), 8.70-8.80 (m, 1H), 8.81-8.94 (m, 1H), 11.01-11.46 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值380.2；實測值381.2；Rt=1.073min。LCMS (ESI): [M] + m/z: calculated 380.2; found 381.2; Rt=1.073 min.

化合物565：保留時間：18.86minCompound 565: retention time: 18.86min

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.71-0.85(m,3H),0.99-1.13(m,3H),1.41-1.57(m,1H),1.69-1.75(m,1H),1.84-1.96(m,1H),2.54-2.63(m,2H),3.64-4.36(m,1H),5.14-5.76(m,1H),7.24-7.29(m,1H),7.29-7.32(m,1H),7.32-7.36(m,1H),7.36-7.42(m,2H),7.53-7.66(m,1H),8.11-8.20(m,1H),8.39-8.54(m,1H),8.70-8.80(m,1H),8.80-8.96(m,1H),11.26(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.71-0.85(m,3H), 0.99-1.13(m,3H), 1.41-1.57(m,1H), 1.69-1.75(m,1H) ,1.84-1.96(m,1H),2.54-2.63(m,2H),3.64-4.36(m,1H),5.14-5.76(m,1H),7.24-7.29(m,1H),7.29-7.32( m,1H),7.32-7.36(m,1H),7.36-7.42(m,2H),7.53-7.66(m,1H),8.11-8.20(m,1H),8.39-8.54(m,1H), 8.70-8.80(m, 1H), 8.80-8.96(m, 1H), 11.26(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值380.2；實測值381.2；Rt=2.860min。LCMS (ESI): [M] + m/z: calculated 380.2; found 381.2; Rt=2.860 min.

實例737. 5-[[2-[(2S,5R)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物571)及5-[[2-[(2R,5S)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物553)之合成Example 737. 5-[[2-[(2S,5R)-2-(6-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carboxamide (Compound 571) and 5-[[2-[(2R,5S)-2-(6-fluoro-1H-indazol-5-yl)-5 Synthesis of -Methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 553)

Figure 110128222-A0202-12-2361-605
Figure 110128222-A0202-12-2361-605

步驟1：1-(5-溴-6-氟-1H-吲唑-1-基)乙酮之合成Step 1: Synthesis of 1-(5-bromo-6-fluoro-1H-indazol-1-yl)ethanone

在冰浴冷卻下，將乙酸酐(10.01g，98.02mmol，9.27mL)添加到4-溴-5-氟-2-甲基苯胺(10g，49.01mmol)於氯仿(100mL)中之懸浮液中且將混合物在室溫下攪拌5min。然後添加乙酸鉀(5.29g，53.91mmol，3.37mL)、18-冠-6(25.91g，98.02mmol，21.96mL)於氯仿(30mL)中之溶液及亞硝酸第三丁酯(10.61g，102.92mmol，12.24mL)且將混合物在75℃下加熱16h。然後將深棕色混合物冷卻，添加DCM(20mL)且將有機層用飽和碳酸氫鈉水溶液洗滌。藉由管柱層析純化粗產物。Acetic anhydride (10.01 g, 98.02 mmol, 9.27 mL) was added to a suspension of 4-bromo-5-fluoro-2-methylaniline (10 g, 49.01 mmol) in chloroform (100 mL) under ice cooling And the mixture was stirred at room temperature for 5 min. Then potassium acetate (5.29 g, 53.91 mmol, 3.37 mL), 18-crown-6 (25.91 g, 98.02 mmol, 21.96 mL) in chloroform (30 mL) and tert-butyl nitrite (10.61 g, 102.92 mL) were added mmol, 12.24 mL) and the mixture was heated at 75 °C for 16 h. The dark brown mixture was then cooled, DCM (20 mL) was added and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The crude product was purified by column chromatography.

1 H NMR(400MHz,CDCl3 )δ 2.76(s,3H),7.92(s,1H),8.04(s,1H),8.23(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 2.76 (s, 3H), 7.92 (s, 1H), 8.04 (s, 1H), 8.23 (s, 1H).

步驟2：1-[6-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-基]乙酮之合成Step 2: 1-[6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazol-1-yl ] Synthesis of ethyl ketone

將乙酸鉀(1.68g，17.12mmol，1.07mL)添加到1-(5-溴-6-氟-吲唑-1-基)乙酮(2g，7.78mmol)於二噁烷(20mL)中之溶液中，隨後添加雙(頻哪醇)二硼(2.17g，8.56mmol)及Pd(dppf)Cl2 (284.64mg，389.02μmol)。將所得溶液在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋，過濾且蒸發。藉由 管柱層析(己烷/MTBE，流速：85ml/min)純化所得粗沉澱，以獲得1-[6-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-基]乙酮(1.29g，4.24mmol，54.52%產率)。Potassium acetate (1.68 g, 17.12 mmol, 1.07 mL) was added to a solution of 1-(5-bromo-6-fluoro-indazol-1-yl)ethanone (2 g, 7.78 mmol) in dioxane (20 mL) To the solution, bis(pinacol)diboron (2.17 g, 8.56 mmol) and Pd(dppf)Cl2 ( 284.64 mg, 389.02 [mu]mol) were then added. The resulting solution was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc, filtered and evaporated. The obtained crude precipitate was purified by column chromatography (hexane/MTBE, flow rate: 85 ml/min) to obtain 1-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborol-2-yl)indazol-1-yl]ethanone (1.29 g, 4.24 mmol, 54.52% yield).

1 H NMR(500MHz,CDCl3 )δ 1.40(s,12H),2.79(s,3H),8.10(s,1H),8.11(s,1H),8.13(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.40 (s, 12H), 2.79 (s, 3H), 8.10 (s, 1H), 8.11 (s, 1H), 8.13 (s, 1H).

步驟3：6-(6-氟-1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 6-(6-fluoro-1H-indazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鉀(1.76g，12.73mmol，768.01μL)於水(15mL)中之溶液中添加到3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.46g，4.24mmol)於二噁烷(15mL)中之溶液中，隨後添加1-[6-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-基]乙酮(1.29g，4.24mmol)及Pd(dppf)Cl2 (155.18mg，212.08μmol)。將所得混合物在90℃、Ar下攪拌隔夜。將所得混合物在真空下濃縮，用EtOAc稀釋，過濾且蒸發。藉由HPLC(2-10min 10-50% MeCN，30ml/min)純化粗產物，以獲得6-(6-氟-1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.8g，粗品)。A solution of potassium carbonate (1.76 g, 12.73 mmol, 768.01 μL) in water (15 mL) was added to 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H-pyridine-1-carboxylic acid tert-butyl ester (1.46 g, 4.24 mmol) in dioxane (15 mL) followed by the addition of 1-[6-fluoro-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborol-2-yl)indazol-1-yl]ethanone (1.29 g, 4.24 mmol) and Pd(dppf)Cl 2 (155.18 mg, 212.08 μmol). The resulting mixture was stirred at 90°C under Ar overnight. The resulting mixture was concentrated in vacuo, diluted with EtOAc, filtered and evaporated. The crude product was purified by HPLC (2-10 min 10-50% MeCN, 30 ml/min) to obtain 6-(6-fluoro-1H-indazol-5-yl)-3-methyl-3,4-di Hydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.8 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值331.2；實測值332.2；Rt=1.312min。LCMS (ESI): [M+H] + m/z: calculated 331.2; found 332.2; Rt=1.312 min.

步驟4：6-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑之合成Step 4: Synthesis of 6-fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole

將6-(6-氟-1H-吲唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.8g，5.43mmol)於TFA(10mL)及DCM(10mL)中之溶液在25℃下攪拌3h。將飽和碳酸鉀水溶液添加到該溶液(50ml)中，然後用DCM(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得6-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(1.45g，粗品)。所獲得之產物不經另外處理即用於下一步驟中。6-(6-Fluoro-1H-indazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.8 g, 5.43 mmol) in TFA (10 mL) and a solution in DCM (10 mL) was stirred at 25 °C for 3 h. Saturated aqueous potassium carbonate solution was added to the solution (50ml), then extracted with DCM (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 6-fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indazole (1.45 g ,Crude). The product obtained was used in the next step without further treatment.

步驟5：6-氟-5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑之合成Step 5: Synthesis of 6-fluoro-5-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole

將硼氫化鈉(170.79mg，4.51mmol，159.61μL)分批添加到6-氟-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H-吲唑(1.45g，3.76mmol)於甲醇(15mL)中之溶液 中。將混合物在室溫下攪拌12h。添加水(50ml)且將所得混合物用EtOAc(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得6-氟-5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(753mg，粗品)。Sodium borohydride (170.79 mg, 4.51 mmol, 159.61 μL) was added portionwise to 6-fluoro-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-1H-indone A solution of azole (1.45 g, 3.76 mmol) in methanol (15 mL) middle. The mixture was stirred at room temperature for 12 h. Water (50ml) was added and the resulting mixture was extracted with EtOAc (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 6-fluoro-5-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (753 mg, crude).

1 H NMR(500MHz,CDCl3 )δ 0.94(d,3H),1.25(m,2H),1.58(m,2H),1.93(m,2H),2.51(m,1H),3.20(m,1H),3.93(m,1H),7.10(s,1H),7.86(s,1H),7.99(s,1H),10.51(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.94(d,3H), 1.25(m,2H), 1.58(m,2H), 1.93(m,2H), 2.51(m,1H), 3.20(m,1H) ), 3.93(m, 1H), 7.10(s, 1H), 7.86(s, 1H), 7.99(s, 1H), 10.51(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值233.2；實測值234.0；Rt=0.802min。LCMS (ESI): [M+H] + m/z: calculated 233.2; found 234.0; Rt=0.802 min.

步驟6：5-[[2-[(2S,5R)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 6: 5-[[2-[(2S,5R)-2-(6-fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-pendoxyl Synthesis of Acetyl] Amino] Pyridine-3-Carboxyamide

將6-氟-5-[(2S,5R)-5-甲基-2-哌啶基]-1H-吲唑(450mg，1.93mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(473.80mg，1.93mmol，HCl)、三乙胺(975.97mg，9.64mmol，1.34mL)混合於DMF(10mL)中然後添加HATU(1.10g，2.89mmol)。將所得混合物在25℃下攪拌12h。將混合物在減壓下蒸發且藉由HPLC(2-10min 30-100%甲醇/H2 O，30ml/min)純化，以獲得5-[[2-[(2S,5R)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(127.3mg，299.93μmol，15.55%產率)。6-Fluoro-5-[(2S,5R)-5-methyl-2-piperidinyl]-1H-indazole (450 mg, 1.93 mmol), 2-[(5-aminocarbamoyl-3- Pyridyl)amino]-2-oxoacetic acid (473.80 mg, 1.93 mmol, HCl), triethylamine (975.97 mg, 9.64 mmol, 1.34 mL) were mixed in DMF (10 mL) then HATU (1.10 g, 2.89 mmol). The resulting mixture was stirred at 25 °C for 12 h. The mixture was evaporated under reduced pressure and purified by HPLC (2-10 min 30-100% methanol/ H2O , 30 ml/min) to obtain 5-[[2-[(2S,5R)-2-(6 -Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (127.3 mg, 299.93 μmol , 15.55% yield).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=1.081min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=1.081 min.

步驟7：5-[[2-[(2S,5R)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物571 )及5-[[2-[(2R,5S)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物553 )之合成Step 7: 5-[[2-[(2S,5R)-2-(6-fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide ( Compound 571 ) and 5-[[2-[(2R,5S)-2-(6-fluoro-1H-indazol-5-yl)-5 Synthesis of -Methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 553 )

藉由掌性層析(Chiralpak IB 250* 20，5B己烷-IPA-MeOH，50-25-25，15ml/min 0,1131)分離非鏡像異構物之混合物，以獲得化合物571 5-[[2-[(2S,5R)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(49.4mg，116.39μmol，38.81%產率)(RT=9.988)及化合物553 5-[[2-[(2R,5S)-2-(6-氟-1H-吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(46.71mg，110.05μmol，36.69%產率)(RT=14.543)。The mixture of diastereomers was separated by chiral chromatography (Chiralpak IB 250 * 20, 5B Hexane-IPA-MeOH, 50-25-25, 15 ml/min 0,1131) to obtain compound 571 5-[ [2-[(2S,5R)-2-(6-Fluoro-1H-indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ]pyridine-3-carboxamide (49.4 mg, 116.39 μmol, 38.81% yield) (RT=9.988) and compound 553 5-[[2-[(2R,5S)-2-(6-fluoro-1H- Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (46.71 mg, 110.05 μmol, 36.69% yield ) (RT=14.543).

化合物571： 1 H NMR(600MHz,DMSO-d 6 )δ 0.93-1.02(m,3H),1.18-1.42(m,1H),1.82-1.91(m,1H),1.91-2.07(m,2H),2.10-2.27(m,1H),3.37-3.67(m,1H),3.69-3.97(m,1H),5.44-5.55(m,1H),7.19-7.41(m,1H),7.49-7.65(m,1H),7.68-7.83(m,1H),7.90-8.24(m,2H),8.26-8.57(m,1H),8.60-8.93(m,2H),10.70-11.34(m,1H),12.95-13.22(m,1H)。 Compound 571: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.93-1.02 (m, 3H), 1.18-1.42 (m, 1H), 1.82-1.91 (m, 1H), 1.91-2.07 (m, 2H) ,2.10-2.27(m,1H),3.37-3.67(m,1H),3.69-3.97(m,1H),5.44-5.55(m,1H),7.19-7.41(m,1H),7.49-7.65( m,1H),7.68-7.83(m,1H),7.90-8.24(m,2H),8.26-8.57(m,1H),8.60-8.93(m,2H),10.70-11.34(m,1H), 12.95-13.22 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=2.168min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=2.168 min.

化合物553： 1 H NMR(600MHz,DMSO-d 6 )δ 0.99-1.02(m,3H),1.19-1.39(m,1H),1.82-1.91(m,1H),1.93-2.10(m,2H),2.11-2.26(m,1H),3.38-3.65(m,1H),3.71-3.97(m,1H),5.46-5.55(m,1H),7.18-7.38(m,1H),7.50-7.64(m,1H),7.70-7.81(m,1H),7.97-8.19(m,2H),8.28-8.54(m,1H),8.61-8.93(m,2H),10.81-11.31(m,1H),12.91-13.20(m,1H)。 Compound 553: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.02 (m, 3H), 1.19-1.39 (m, 1H), 1.82-1.91 (m, 1H), 1.93-2.10 (m, 2H) ,2.11-2.26(m,1H),3.38-3.65(m,1H),3.71-3.97(m,1H),5.46-5.55(m,1H),7.18-7.38(m,1H),7.50-7.64( m,1H),7.70-7.81(m,1H),7.97-8.19(m,2H),8.28-8.54(m,1H),8.61-8.93(m,2H),10.81-11.31(m,1H), 12.91-13.20 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=2.168min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=2.168 min.

實例738. 5-[[2-[(2R ,5S )-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S ,5R )-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物355及化合物354)之合成Example 738. 5-[[2-[( 2R , 5S )-2-(3-fluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Acrylo]amino]pyridine-3-carboxamide and 5-[[2-[( 2S , 5R )-2-(3-fluoro-4-hydroxyphenyl)-5-methyl-1- Synthesis of piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 355 and compound 354)

Figure 110128222-A0202-12-2364-606
Figure 110128222-A0202-12-2364-606

步驟1：6-(3-氟-4-甲氧基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(3-fluoro-4-methoxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.8g，11.00mmol)、(3-氟-4-甲氧基苯基)硼酸(1.87g，11.00mmol)及碳酸鈉(3.50g，33.01mmol，1.38mL)於1,4-二噁烷(30mL)及水(10mL)中之正攪拌懸浮液用氬氣吹掃10分鐘。10分鐘之後，在氬氣下添加Pd(dppf)Cl2 ‧CH2 Cl2 (450mg，550.19μmol)。將反應混合物在氬氣、70℃下攪拌13小時。13小時之後，將反應混合物冷卻至室溫且過濾。將濾餅用1.4-二噁烷(2 x 20mL)洗滌且丟棄。在減壓下蒸發濾液，以獲得呈黃色油狀物之6-(3-氟-4-甲氧基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3g，9.33mmol，84.83%產率)。粗產物不經任何進一步純化即用於下一步反應。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (3.8 g, 11.00 mmol), (3- Fluoro-4-methoxyphenyl)boronic acid (1.87 g, 11.00 mmol) and sodium carbonate (3.50 g, 33.01 mmol, 1.38 mL) in 1,4-dioxane (30 mL) and water (10 mL) The stirred suspension was purged with argon for 10 minutes. After 10 minutes, Pd(dppf)Cl2 - CH2Cl2 ( 450 mg, 550.19 [mu]mol) was added under argon. The reaction mixture was stirred under argon at 70°C for 13 hours. After 13 hours, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with 1.4-dioxane (2 x 20 mL) and discarded. The filtrate was evaporated under reduced pressure to obtain 6-(3-fluoro-4-methoxyphenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1- as a yellow oil 3-Butyl formate (3 g, 9.33 mmol, 84.83% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值321.2；實測值266.0(t -Bu裂解之產物質量)；Rt=1.528minLCMS (ESI): [M+Boc] + m/z: calculated value 321.2; found value 266.0 ( t -Bu cleavage product mass); Rt=1.528min

步驟2：6-(3-氟-4-甲氧基苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(3-Fluoro-4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將三氟乙酸(21.29g，186.69mmol，14.38mL)添加到6-(3-氟-4-甲氧基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3g，9.33mmol)中且將所得反應混合物在25℃下攪拌1小時。1小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物溶解於20mL冰冷水中且逐滴添加10% NaOH溶液，直到pH=10。將所得懸浮液用二氯甲烷(2 x 30mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈黃色膠狀物之6-(3-氟-4-甲氧基苯基)-3-甲基-2,3,4,5-四氫吡啶(1.5g，6.78mmol，72.62%產率)，其直接用於下一步驟中。Trifluoroacetic acid (21.29 g, 186.69 mmol, 14.38 mL) was added to 6-(3-fluoro-4-methoxyphenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1 - tert -butyl formate (3 g, 9.33 mmol) and the resulting reaction mixture was stirred at 25°C for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in 20 mL of ice-cold water and 10% NaOH solution was added dropwise until pH=10. The resulting suspension was extracted with dichloromethane (2 x 30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 6-(3-fluoro-4-methoxyphenyl)-3-methyl-2 as a yellow gum, 3,4,5-Tetrahydropyridine (1.5 g, 6.78 mmol, 72.62% yield) was used directly in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值221.2；實測值222.2；Rt=0.828min。LCMS (ESI): [M+H] + m/z: calculated 221.2; found 222.2; Rt=0.828 min.

步驟3：2-(3-氟-4-甲氧基苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(3-Fluoro-4-methoxyphenyl)-5-methylpiperidine

在0℃下，將硼氫化鈉(512.94mg，13.56mmol)一次性添加到6-(3-氟-4-甲氧基苯基)-3-甲基-2,3,4,5-四氫吡啶(1.5g，6.78mmol)於甲醇(30mL)中之經攪拌之溶液中。將反應混合物在0℃下攪拌1小時。1小時之後，在減壓下濃縮反 應混合物。將所獲得之殘餘物溶解於水(20mL)中且用二氯甲烷(2 x 40mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析純化所獲得之粗產物，以獲得2-(3-氟-4-甲氧基苯基)-5-甲基哌啶(0.8g，3.58mmol，52.85%產率)。Sodium borohydride (512.94 mg, 13.56 mmol) was added in one portion to 6-(3-fluoro-4-methoxyphenyl)-3-methyl-2,3,4,5-tetrakis at 0 °C Hydropyridine (1.5 g, 6.78 mmol) in a stirred solution of methanol (30 mL). The reaction mixture was stirred at 0°C for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in water (20 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 2-(3-fluoro-4-methoxyphenyl)-5-methylpiperidine (0.8 g, 3.58 mmol, 52.85% yield).

LCMS(ESI)：[M+H]+ m/z：計算值223.2；實測值224.1；Rt=0.873min。LCMS (ESI): [M+H] + m/z: calculated 223.2; found 224.1; Rt=0.873 min.

步驟4：2-氟-4-(5-甲基-2-哌啶基)苯酚之合成Step 4: Synthesis of 2-fluoro-4-(5-methyl-2-piperidinyl)phenol

將2-(3-氟-4-甲氧基苯基)-5-甲基哌啶(0.4g，1.79mmol)於HBr(1.48g，18.27mmol，992.26μL)之混合物在100℃下攪拌24小時。在真空中蒸發所得反應混合物。使所獲得之粗產物經歷HPLC純化，以得到呈棕色膠狀物之2-氟-4-(5-甲基-2-哌啶基)苯酚(0.26g，1.24mmol，69.36%產率)。A mixture of 2-(3-fluoro-4-methoxyphenyl)-5-methylpiperidine (0.4 g, 1.79 mmol) in HBr (1.48 g, 18.27 mmol, 992.26 μL) was stirred at 100 °C for 24 Hour. The resulting reaction mixture was evaporated in vacuo. The crude product obtained was subjected to HPLC purification to give 2-fluoro-4-(5-methyl-2-piperidinyl)phenol (0.26 g, 1.24 mmol, 69.36% yield) as a brown gum.

LCMS(ESI)：[M+H]+ m/z：計算值209.2；實測值210.4；Rt=1.766min。LCMS (ESI): [M+H] + m/z: calculated 209.2; found 210.4; Rt=1.766 min.

步驟5：外消旋-5-[[2-[(2S,5R)-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺)之合成Step 5: Racemic-5-[[2-[(2S,5R)-2-(3-fluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxygen Synthesis of Acetyl]amino]pyridine-3-carbamoylamine)

在25℃下，向2-氟-4-(5-甲基-2-哌啶基)苯酚(0.26g，1.24mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(259.88mg，1.06mmol，鹽酸鹽)及DIPEA(562.04mg，4.35mmol，757.46μL)於DMF(10mL)中之經攪拌之溶液中分批添加HATU(519.67mg，1.37mmol)。將所得反應混合物在25℃下攪拌。完成之後，在減壓下濃縮反應混合物，以獲得粗產物，其藉由反相HPLC進行純化，以得到呈淡黃色固體之外消旋 -5-[[2-[(2S ,5R )-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.15g，374.62μmol，30.15%產率)。To 2-fluoro-4-(5-methyl-2-piperidinyl)phenol (0.26 g, 1.24 mmol), 2-[(5-aminocarboxy-3-pyridinyl)amine at 25°C yl]-2-oxyacetic acid (259.88 mg, 1.06 mmol, hydrochloride salt) and DIPEA (562.04 mg, 4.35 mmol, 757.46 μL) in DMF (10 mL) was added portionwise HATU (519.67 μL) mg, 1.37 mmol). The resulting reaction mixture was stirred at 25°C. After completion, the reaction mixture was concentrated under reduced pressure to obtain crude product, which was purified by reverse phase HPLC to give rac -5-[[2-[( 2S , 5R ) as a pale yellow solid -2-(3-Fluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (0.15 g, 374.62 μmol, 30.15% yield).

LCMS(ESI)：[M+H]+ m/z：計算值400.2；實測值401.2；Rt=2.593min。LCMS (ESI): [M+H] + m/z: calculated 400.2; found 401.2; Rt=2.593 min.

步驟6：5-[[2-[(2R,5S)-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S,5R)-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物355 及化合物354 )之掌性分離Step 6: 5-[[2-[(2R,5S)-2-(3-Fluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-pendoxyloxyacetyl ]amino]pyridine-3-carboxamide and 5-[[2-[(2S,5R)-2-(3-fluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl] Chiral Separation of -2-Pendant Oxyacetyl]amino]pyridine-3-carboxyamide ( Compound 355 and Compound 354 )

使外消旋 -5-[[2-[(2S ,5R )-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺經歷掌性HPLC純化(管柱：Chiralpak IA-I(250 x 20mm，5um)；流動相：己烷-IPA-MeOH，75-15-15；流速：12mL/min)，以得到呈米色固體之5-[[2-[(2R ,5S )-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物355 ，54.5mg)及5-[[2-[(2S ,5R )-2-(3-氟-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物354 ，54.6mg)。Make rac -5-[[2-[( 2S , 5R )-2-(3-fluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carbamoylamine was purified by chiral HPLC (column: Chiralpak IA-I (250 x 20 mm, 5um); mobile phase: Hexane-IPA-MeOH, 75-15- 15; flow rate: 12 mL/min) to give 5-[[2-[( 2R , 5S )-2-(3-fluoro-4-hydroxyphenyl)-5-methyl-1 as a beige solid -Piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 355 , 54.5mg ) and 5-[[2-[(2S, 5R )-2- (3-Fluoro-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( Compound 354 , 54.6 mg) .

化合物355：Compound 355:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.99-1.03(m,3H),1.28-1.35(m,1H),1.63-1.73(m,1H),1.81-1.94(m,1H),1.97-2.06(m,1H),2.10-2.18(m,1H),2.71-3.21(m,1H),3.41-4.02(m,1H),5.00-5.53(m,1H),6.90-6.99(m,2H),7.01-7.15(m,1H),7.53-7.66(m,1H),8.10-8.19(m,1H),8.42-8.50(m,1H),8.73-8.81(m,1H),8.81-8.91(m,1H),9.77-9.83(m,1H),11.17-11.28(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.99-1.03 (m, 3H), 1.28-1.35 (m, 1H), 1.63-1.73 (m, 1H), 1.81-1.94 (m, 1H) ),1.97-2.06(m,1H),2.10-2.18(m,1H),2.71-3.21(m,1H),3.41-4.02(m,1H),5.00-5.53(m,1H),6.90-6.99 (m,2H),7.01-7.15(m,1H),7.53-7.66(m,1H),8.10-8.19(m,1H),8.42-8.50(m,1H),8.73-8.81(m,1H) , 8.81-8.91 (m, 1H), 9.77-9.83 (m, 1H), 11.17-11.28 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值400.2；實測值401.4；Rt=2.596min。LCMS (ESI): [M+H] + m/z: calculated 400.2; found 401.4; Rt=2.596 min.

掌性HPLC：Rt=12.14min(管柱：IA；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt = 12.14 min (column: IA; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

化合物354：Compound 354:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.98-1.02(m,3H),1.27-1.37(m,1H),1.63-1.73(m,1H),1.82-1.92(m,1H),1.94-2.04(m,1H),2.11-2.17(m,1H),2.75-3.21(m,1H),3.36-4.00(m,1H),5.01-5.52(m,1H),6.91-6.97(m,2H),7.02-7.14(m,1H),7.54-7.65(m,1H),8.12-8.24(m,1H),8.43-8.51(m,1H),8.71-8.81(m,1H),8.81-8.90(m,1H),9.80(s,1H),11.16-11.31(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.98-1.02 (m, 3H), 1.27-1.37 (m, 1H), 1.63-1.73 (m, 1H), 1.82-1.92 (m, 1H) ),1.94-2.04(m,1H),2.11-2.17(m,1H),2.75-3.21(m,1H),3.36-4.00(m,1H),5.01-5.52(m,1H),6.91-6.97 (m,2H),7.02-7.14(m,1H),7.54-7.65(m,1H),8.12-8.24(m,1H),8.43-8.51(m,1H),8.71-8.81(m,1H) , 8.81-8.90(m, 1H), 9.80(s, 1H), 11.16-11.31(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值400.2；實測值401.4；Rt=2.605min。LCMS (ESI): [M+H] + m/z: calculated 400.2; found 401.4; Rt=2.605 min.

掌性HPLC：Rt=16.37min(管柱：IA；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=16.37 min (column: IA; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

實例739. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1012)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1015)之合成Example 739. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(trifluoromethyl)-3- Pyridyl]-1-piperidinyl]-2-oxoacetamide (Compound 1012) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R )-5-methyl-2-[6-(trifluoromethyl)-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (compound 1015) synthesis

Figure 110128222-A0202-12-2368-607
Figure 110128222-A0202-12-2368-607

步驟1：3-甲基-6-[6-(三氟甲基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

向圓底燒瓶中添加[6-(三氟甲基)-3-吡啶基]硼酸(500mg，2.62mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.00g，2.90mmol)、Pd(dppf)Cl2 -DCM(450mg，0.551mmol)、Na2 CO3 (850mg，8.02mmol)、H2 O(5mL)及二噁烷(20mL)。將混合物除氣且用氮氣回填三次，然後在80℃、氮氣下攪拌12小時。所得混合物藉由添加水(30mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用鹽水(20mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；20g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~40%，流速：30mL/min)純化殘餘物，以得到呈黃色固體之3-甲基-6-[6-(三氟甲基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(720mg，80.3%產率)。1 H NMR(400MHz，氯仿-d )δ ppm 8.65(d,J =1.5Hz,1 H),7.73(dd,J =8.1,1.5Hz,1 H),7.62(d,J =8.1Hz,1 H),5.44(t,J =3.7Hz,1 H),4.08(br dd,J =12.5,2.8Hz,1 H),3.05(dd,J =12.5,9.5Hz,1 H),2.38-2.54(m,1 H),1.98 -2.17(m,1 H),1.84-1.97(m,1 H),1.12(br s,9 H),1.05(d,J =6.6Hz,3 H)；19 F NMR(377MHz，氯仿-d )δ ppm -67.63。To a round bottom flask was added [6-(trifluoromethyl)-3-pyridyl]boronic acid (500 mg, 2.62 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3, 4-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.00 g, 2.90 mmol), Pd(dppf)Cl2 - DCM (450 mg, 0.551 mmol), Na2CO3 (850 mg , 8.02 mmol), H2O (5 mL) and dioxane (20 mL). The mixture was degassed and backfilled with nitrogen three times, then stirred at 80°C under nitrogen for 12 hours. The resulting mixture was quenched by adding water (30 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 20 g AgelaFlash® silica flash column, petroleum ether/EtOAc, where EtOAc was 0-40%, flow rate: 30 mL/min) to give 3- as a yellow solid Methyl-6-[6-(trifluoromethyl)-3-pyridinyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (720 mg, 80.3% yield). 1 H NMR (400 MHz, chloroform- d ) δ ppm 8.65 (d, J =1.5 Hz, 1 H), 7.73 (dd, J =8.1, 1.5 Hz, 1 H), 7.62 (d, J =8.1 Hz, 1 H), 5.44(t, J =3.7Hz, 1 H), 4.08(br dd, J =12.5, 2.8Hz, 1 H), 3.05(dd, J =12.5, 9.5Hz, 1 H), 2.38-2.54 (m,1H),1.98-2.17(m,1H),1.84-1.97(m,1H),1.12(br s, 9H ),1.05(d, J =6.6Hz,3H); F NMR (377 MHz, chloroform- d ) δ ppm -67.63.

步驟2：5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2-(三氟甲基)吡啶之合成Step 2: Synthesis of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-2-(trifluoromethyl)pyridine

向3-甲基-6-[6-(三氟甲基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(700mg，2.04mmol)於DCM(2mL)中之溶液中添加TFA(2mL，26.0mmol)。將混合物在20℃下攪拌12小時。藉由添加飽和NaHCO3 水溶液(30mL)淬滅所得混合物且用DCM(20mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色固體之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2-(三氟甲基)吡啶(480mg，96.9%產率)。LCMS(ESI)[M+H]+ m/z：計算值243.1，實測值243.1。To 3-methyl-6-[6-(trifluoromethyl)-3-pyridinyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (700 mg, 2.04 mmol) in DCM To the solution in (2 mL) was added TFA (2 mL, 26.0 mmol). The mixture was stirred at 20°C for 12 hours. The resulting mixture was quenched by addition of saturated aqueous NaHCO3 (30 mL) and extracted with DCM (20 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 5-(3-methyl-2,3,4,5-tetrahydropyridine-6- as a yellow solid yl)-2-(trifluoromethyl)pyridine (480 mg, 96.9% yield). LCMS (ESI) [M+H] + m/z: calcd 243.1, found 243.1.

步驟3：5-(5-甲基-2-哌啶基)-2-(三氟甲基)吡啶之合成Step 3: Synthesis of 5-(5-Methyl-2-piperidinyl)-2-(trifluoromethyl)pyridine

向5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2-(三氟甲基)吡啶(480mg，1.98mmol)於MeOH(20mL)中之溶液中添加NaBH4 (120mg，3.17mmol)。將混合物在20℃下攪拌1小時。藉由添加飽和NH4 Cl水溶液(20mL)淬滅所得混合物且用EtOAc(30mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色固體之5-(5-甲基-2-哌啶基)-2-(三氟甲基)吡啶(350mg，72.3%產率)。LCMS(ESI)[M+H]+ m/z：計算值245.1，實測值245.1。To a solution of 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-2-(trifluoromethyl)pyridine (480 mg, 1.98 mmol) in MeOH (20 mL) NaBH4 ( 120 mg, 3.17 mmol) was added. The mixture was stirred at 20°C for 1 hour. The resulting mixture was quenched by addition of saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 5-(5-methyl-2-piperidinyl)-2-(trifluoromethyl) as a yellow solid ) pyridine (350 mg, 72.3% yield). LCMS (ESI) [M+H] + m/z: calcd 245.1, found 245.1.

步驟4：N-[3-甲基-5-[[2-[5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[3-Methyl-5-[[2-[5-methyl-2-[6-(trifluoromethyl)-3-pyridyl]-1-piperidinyl]-2- Synthesis of pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester

向2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(150mg，0.508mmol)及5-(5-甲基-2-哌啶基)-2-(三氟甲基)吡啶(150mg，0.614mmol)於DCM(3mL)中之溶液中添加HATU(200mg，0.526mmol)及DIPEA(0.3mL，1.72mmol)。將混合物在20℃下攪拌1小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100 mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色油狀物之N-[3-甲基-5-[[2-[5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(250mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值522.2，實測值522.3。To 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (150 mg, 0.508 mmol) and 5-(5- Methyl-2-piperidinyl)-2-(trifluoromethyl)pyridine (150 mg, 0.614 mmol) in DCM (3 mL) was added HATU (200 mg, 0.526 mmol) and DIPEA (0.3 mL, 1.72 mmol) ). The mixture was stirred at 20°C for 1 hour. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL*2), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give N as a yellow oil -[3-Methyl-5-[[2-[5-methyl-2-[6-(trifluoromethyl)-3-pyridinyl]-1-piperidinyl]-2-side oxyethyl Acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (250 mg, crude). LCMS (ESI) [M+H] + m/z: calcd 522.2, found 522.3.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺之合成Step 5: N-(6-Amino-5-methyl-3-pyridyl)-2-[5-methyl-2-[6-(trifluoromethyl)-3-pyridyl]-1- Synthesis of Piperidinyl]-2-Pendant Oxyacetamide

向N-[3-甲基-5-[[2-[5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(250mg，0.479mmol)於DCM(1mL)中之溶液中添加TFA(1mL，13.0mmol)。將混合物在20℃下攪拌12小時。藉由添加飽和NaHCO3 水溶液(30mL)淬滅所得混合物且用DCM(30mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Waters Xbridge 150×50mm×10μm；流動相A：具有0.04%氫氧化銨之H2 O(v%)+10mmol NH4 HCO3 )；流動相B：MeCN；梯度：9.5min內29%至59% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化殘餘物，以得到呈白色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(50mg，24.8%產率)。LCMS(ESI)[M+H]+ m/z：計算值422.2，實測值422.2。to N-[3-methyl-5-[[2-[5-methyl-2-[6-(trifluoromethyl)-3-pyridyl]-1-piperidinyl]-2-oxygen To a solution of tert-butyl acetate (250 mg, 0.479 mmol) in DCM (1 mL) was added TFA (1 mL, 13.0 mmol). The mixture was stirred at 20°C for 12 hours. The resulting mixture was quenched by addition of saturated aqueous NaHCO 3 (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Waters Xbridge 150 x 50 mm x 10 μm; mobile phase A : H with 0.04% ammonium hydroxide O(v%)+10mmol NH4HCO3 ) ; Mobile Phase B: MeCN; Gradient: 29% to 59% B in 9.5min, hold 100% B for 2min; Flow Rate: 25mL/min; Column Temperature: 30°C ; wavelength: 220 nm, 254 nm) The residue was purified to give N-(6-amino-5-methyl-3-pyridyl)-2-[5-methyl-2-[6-( Trifluoromethyl)-3-pyridyl]-1-piperidinyl]-2-oxyacetamide (50 mg, 24.8% yield). LCMS (ESI) [M+H] + m/z: calcd 422.2, found 422.2.

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1012 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1015 )之合成Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(trifluoromethyl)-3- Pyridyl]-1-piperidinyl]-2-oxoacetamide ( Compound 1012 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R )-5-methyl-2-[6-(trifluoromethyl)-3-pyridyl]-1-piperidinyl]-2-side oxyacetamide ( compound 1015 ) synthesis

藉由掌性SFC(儀器：Thar80；管柱：Daicel Chiralcel OJ(250mm * 30mm，10μm)；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=55/45；流速： 80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離N-(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(60mg，0.142mmol)，以得到化合物1012 (峰2，保留時間：2.081min)及化合物1015 (峰3，保留時間：3.816min)。By chiral SFC (instrument: Thar80; column: Daicel Chiralcel OJ (250mm*30mm, 10μm); mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=55/45 ; Flow rate: 80 mL/min; Column temperature: 38 °C; Nozzle temperature: 100 bar; Nozzle temperature: 60 °C; Evaporator temperature: 20 °C; Amino-5-methyl-3-pyridyl)-2-[5-methyl-2-[6-(trifluoromethyl)-3-pyridyl]-1-piperidinyl]-2-side oxyacetamide (60 mg, 0.142 mmol) to give compound 1012 (peak 2, retention time: 2.081 min) and compound 1015 (peak 3, retention time: 3.816 min).

化合物1012 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(29mg，具有反式相對化學之單一未知鏡像異構物，峰2，保留時間=2.081min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.25(br s,1 H),8.75(s,1 H),8.02(br d,J =5.3Hz,2 H),7.87(d,J =8.0Hz,1 H),7.49(br s,1 H),5.55(br s,1 H),5.36(br s,2 H),3.18-3.95(m,2 H),2.19(br s,2 H),2.06(s,3 H),1.95(br s,1 H),1.68-1.80(m,1 H),1.31-1.42(m,1 H),1.06(d,J =7.0Hz,3 H)；19 F NMR(376MHz,DMSO-d 6 )δ ppm -66.25；LCMS(ESI)[M+H]+ m/z：計算值422.2；實測值422.1；HPLC：在254nm下為100%；100%ee。 Compound 1012 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(trifluoromethyl)-3- Pyridinyl]-1-piperidinyl]-2-oxoacetamide (29 mg, single unknown enantiomer with trans relative chemistry, peak 2, retention time = 2.081 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.25(br s, 1 H), 8.75(s, 1 H), 8.02(br d, J =5.3 Hz, 2 H), 7.87(d, J = 8.0Hz, 1 H), 7.49(br s, 1 H), 5.55(br s, 1 H), 5.36(br s, 2 H), 3.18-3.95(m, 2 H), 2.19(br s, 2 H), 2.06(s, 3 H), 1.95(br s, 1 H), 1.68-1.80(m, 1 H), 1.31-1.42(m, 1 H), 1.06(d, J =7.0Hz, 3 H); 19 F NMR (376 MHz, DMSO- d 6 ) δ ppm -66.25; LCMS (ESI) [M+H] + m/z: calculated 422.2; found 422.1; HPLC: 100% at 254 nm; 100%ee.

化合物1015 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(三氟甲基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(29mg，具有反式相對化學之單一未知鏡像異構物，峰3，保留時間=3.816min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.30(br s,1 H),8.75(s,1 H),7.99-8.10(m,2 H),7.87(d,J =8.3Hz,1 H),7.52(br s,1 H),5.55(br s,2 H),3.74(s,2 H),3.10-3.15(m,1 H),2.19(br s,2 H),2.07(s,3 H),1.95(br s,1 H),1.66-1.80(m,1 H),1.31-1.43(m,1 H),1.06(d,J =7.0Hz,3 H)；19 F NMR(376MHz,DMSO-d 6 )δ ppm -66.25；LCMS(ESI)[M+H]+ m/z：計算值422.2，實測值422.1；HPLC：在254nm下為100%；100%ee。 Compound 1015 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(trifluoromethyl)-3- Pyridinyl]-1-piperidinyl]-2-oxoacetamide (29 mg, single unknown enantiomer with trans relative chemistry, peak 3, retention time = 3.816 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.30(br s, 1 H), 8.75(s, 1 H), 7.99-8.10(m, 2 H), 7.87(d, J =8.3 Hz, 1 H), 7.52(br s, 1 H), 5.55(br s, 2 H), 3.74(s, 2 H), 3.10-3.15(m, 1 H), 2.19(br s, 2 H), 2.07( s, 3 H), 1.95 (br s, 1 H), 1.66-1.80 (m, 1 H), 1.31-1.43 (m, 1 H), 1.06 (d, J = 7.0 Hz, 3 H); 19 F NMR (376 MHz, DMSO - d6 ) δ ppm -66.25; LCMS (ESI) [M+H] + m/z: calcd 422.2, found 422.1; HPLC: 100% at 254 nm; 100% ee.

實例740. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1016)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物Example 740. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(6-ethyl-3-pyridyl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide (Compound 1016) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- (6-ethyl-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (compound 1013)之合成1013) synthesis

Figure 110128222-A0202-12-2372-608
Figure 110128222-A0202-12-2372-608

步驟1：2-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶之合成Step 1: Synthesis of 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridine

將5-溴-2-乙基吡啶(4.8g，25.8mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(7.2g，28.4mmol)、Pd(dppf)Cl2 -DCM(632mg，0.774mmol)、KOAc(7.6g，77.5mmol)於二噁烷(150mL)之混合物在氮氣下在100℃下攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；40g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~55%，40mL/min，254nm)進行純化，以得到呈棕色油狀物之2-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(5.2g，86.5%產率)。1 H NMR(400MHz,CDCl3 )δ ppm 8.86(s,1H),7.98(dd,J =7.7,1.6Hz,1H),7.16(d,J =7.8Hz,1H),2.84(d,J =7.6Hz,2H),1.35(s,12H),1.30(t,J =7.7Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值234.2，實測值234.1。5-Bromo-2-ethylpyridine (4.8 g, 25.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborol-2-yl)-1,3,2-dioxaborolane (7.2 g, 28.4 mmol), Pd(dppf)Cl2 - DCM (632 mg, 0.774 mmol) ), KOAc (7.6 g, 77.5 mmol) in dioxane (150 mL) was stirred at 100 °C for 12 h under nitrogen. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® ; 40 g AgelaFlash® silica) Purification by flash column, petroleum ether/EtOAc with 0-55% EtOAc, 40 mL/min, 254 nm) gave 2-ethyl-5-(4,4,5,5- as a brown oil) Tetramethyl-1,3,2-dioxaborol-2-yl)pyridine (5.2 g, 86.5% yield). 1 H NMR (400MHz, CDCl 3 ) δ ppm 8.86(s, 1H), 7.98(dd, J =7.7, 1.6Hz, 1H), 7.16(d, J =7.8Hz, 1H), 2.84(d, J = 7.6Hz, 2H), 1.35(s, 12H), 1.30(t, J =7.7Hz, 3H); LCMS(ESI)[M+H] + m/z: calculated 234.2, found 234.1.

步驟2：6-(6-乙基-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(6-ethyl-3-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁 酯(1g，2.90mmol)、2-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(1.5g，6.43mmol)、Pd(dppf)Cl2 (106mg，0.145mmol)、K2 CO3 (1.2g，8.68mmol)、二噁烷(20mL)及H2 O(5mL)之混合物在氮氣、100℃下攪拌12小時。所得混合物藉由添加水(30mL)來淬滅且用EtOAc(30mL * 3)萃取。將經合併之有機層用鹽水(100mL * 3)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；25g SepaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~15%，35mL/min，254nm)進行純化，以得到呈白色固體之6-(6-乙基-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(800mg，91.4%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1 g, 2.90 mmol), 2-ethyl- 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyridine (1.5 g, 6.43 mmol), Pd(dppf)Cl 2 ( A mixture of 106 mg, 0.145 mmol), K2CO3 ( 1.2 g, 8.68 mmol), dioxane (20 mL) and H2O (5 mL) was stirred under nitrogen at 100 °C for 12 h. The resulting mixture was quenched by adding water (30 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (100 mL*3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® ; 25 g SepaFlash® II Silica flash column, petroleum ether/EtOAc with 0-15% EtOAc, 35 mL/min, 254 nm) was purified to give 6-(6-ethyl-3-pyridyl)-3- as a white solid Methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (800 mg, 91.4% yield).

1 H NMR(400MHz,CDCl3 )δ ppm 8.45(d,J =1.8Hz,1H),7.48(dd,J =8.1,2.3Hz,1H),7.09(d,J =8.0Hz,1H),5.31(t,J =3.6Hz,1H),4.03-4.11(m,1H),3.00(dd,J =12.4,9.6Hz,1H),2.82(q,J =7.5Hz,2H),2.35-2.48(m,1H),1.80-1.99(m,2H),1.29(t,J =7.6Hz,3H),1.10(s,9H),1.02(d,J =6.6Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值303.2，實測值303.2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.45 (d, J = 1.8 Hz, 1 H), 7.48 (dd, J = 8.1, 2.3 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 5.31 (t, J =3.6Hz, 1H), 4.03-4.11(m, 1H), 3.00(dd, J =12.4, 9.6Hz, 1H), 2.82(q, J =7.5Hz, 2H), 2.35-2.48( m,1H),1.80-1.99(m,2H),1.29(t, J =7.6Hz,3H),1.10(s,9H),1.02(d, J =6.6Hz,3H); LCMS(ESI)[ M+H] + m/z: Calculated 303.2, Measured 303.2.

步驟3：2-乙基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶之合成Step 3: Synthesis of 2-ethyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine

將6-(6-乙基-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(800mg，2.65mmol)於TFA(3.3mL，42.8mmol)中之溶液在20℃下攪拌1小時。在真空中蒸發混合物。將碎冰(10g)添加到殘餘物中且將pH用10重量% NaOH水溶液調節至8。將所得混合物用EtOAc(20mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色固體之2-乙基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(530mg，99.0%產率)，其不經進一步純化即直接使用。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.75(d,J =2.0Hz,1H),8.06(dd,J =8.2,2.4Hz,1H),7.36(d,J =8.3Hz,1H),3.87-3.96(m,1H),3.22(dd,J =17.4,9.9Hz,1H),2.80-2.91(m,3H),1.96(d,J =12.5Hz,1H),1.69-1.83(m,1H),1.37-1.46(m,1H),1.27-1.33(m,4H),1.02(d,J =6.5Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值 203.1，實測值203.2。Dissolve 6-(6-ethyl-3-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (800 mg, 2.65 mmol) in TFA (3.3 mL, The solution in 42.8 mmol) was stirred at 20°C for 1 hour. The mixture was evaporated in vacuo. Crushed ice (10 g) was added to the residue and the pH was adjusted to 8 with 10 wt% aqueous NaOH. The resulting mixture was extracted with EtOAc (20 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 2-ethyl-5-(3-methyl-2,3,4,5-tetrakis as a yellow solid Hydropyridin-6-yl)pyridine (530 mg, 99.0% yield), which was used without further purification. 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.75 (d, J =2.0 Hz, 1H), 8.06 (dd, J =8.2, 2.4 Hz, 1H), 7.36 (d, J =8.3 Hz, 1H) ,3.87-3.96(m,1H),3.22(dd, J =17.4,9.9Hz,1H),2.80-2.91(m,3H),1.96(d, J =12.5Hz,1H),1.69-1.83(m ,1H),1.37-1.46(m,1H),1.27-1.33(m,4H),1.02(d, J =6.5Hz,3H); LCMS(ESI)[M+H] + m/z: Calculated 203.1, measured value 203.2.

步驟4：2-乙基-5-(5-甲基-2-哌啶基)吡啶之合成Step 4: Synthesis of 2-ethyl-5-(5-methyl-2-piperidinyl)pyridine

在0℃下，將NaBH4 (149mg，3.94mmol)一次性添加到2-乙基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(530mg，2.62mmol)於MeOH(10mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1小時。在真空中蒸發混合物。將殘餘物用水(50mL)稀釋且用DCM(30mL * 3)萃取。將經合併之有機層經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色油狀物之2-乙基-5-(5-甲基-2-哌啶基)吡啶(440mg，82.2%產率)，其不經進一步純化即直接使用。1 H NMR(400MHz,甲醇-d 4 )δ ppm 8.42(d,J =2.0Hz,1H),7.76(dd,J =8.0,2.3Hz,1H),7.29(d,J =8.0Hz,1H),3.59(dd,J =11.5,2.5Hz,1H),3.04-3.12(m,1H),2.79(q,J =7.5Hz,2H),2.39(t,J =11.5Hz,1H),1.88-1.96(m,1H),1.82(dq,J =13.2,3.1Hz,1H),1.54-1.72(m,2H),1.25-1.30(m,4H),0.92(d,J =6.5Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值205.2，實測值205.2。NaBH4 ( 149 mg, 3.94 mmol) was added in one portion to 2-ethyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine (530 mg at 0 °C) , 2.62 mmol) in a stirred solution of MeOH (10 mL). The resulting mixture was stirred at 0°C for 1 hour. The mixture was evaporated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (30 mL*3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 2-ethyl-5-(5-methyl-2-piperidinyl)pyridine as a yellow oil (440 mg, 82.2% yield), which was used directly without further purification. 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.42 (d, J = 2.0 Hz, 1 H), 7.76 (dd, J = 8.0, 2.3 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H) ,3.59(dd, J =11.5,2.5Hz,1H),3.04-3.12(m,1H),2.79(q, J =7.5Hz,2H),2.39(t, J =11.5Hz,1H),1.88- 1.96(m,1H),1.82(dq, J =13.2,3.1Hz,1H),1.54-1.72(m,2H),1.25-1.30(m,4H),0.92(d, J =6.5Hz,3H) ; LCMS (ESI) [M+H] + m/z: calculated 205.2, found 205.2.

步驟5：N-[5-[[2-[2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 5: N-[5-[[2-[2-(6-Ethyl-3-pyridinyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of tert-butyl ]-3-methyl-2-pyridyl]carbamate

在20℃下，向2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(100mg，0.339mmol)及2-乙基-5-(5-甲基-2-哌啶基)吡啶(83mg，0.406mmol)於DCM(5mL)中之經攪拌之溶液中添加HATU(129mg，0.339mmol)及TEA(0.14mL，1.00mmol)。將所得反應混合物在20℃下攪拌12小時。在LCMS上，反應物未完全轉化。添加HATU(129mg，0.339mmol)及TEA(0.14mL，1.00mmol)且將混合物在20℃下再攪拌12小時。在減壓下濃縮反應混合物且倒入到水(10mL)中。將水層用EtOAc(15mL * 2)萃取。將經合併之有機相用鹽水(50mL * 2)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；4g * 3 SepaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc 為0~85%，25mL/min，254nm)進行純化，以得到呈無色油狀物之N-[5-[[2-[2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(70mg，42.9%產率)。LCMS(ESI)[M+H]+ m/z：計算值482.3，實測值382.3(Boc裂解之質量)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (100 mg, 0.339 mmol) and To a stirred solution of 2-ethyl-5-(5-methyl-2-piperidinyl)pyridine (83 mg, 0.406 mmol) in DCM (5 mL) was added HATU (129 mg, 0.339 mmol) and TEA (0.14 mL, 1.00 mmol). The resulting reaction mixture was stirred at 20°C for 12 hours. On LCMS, the reaction was not completely converted. HATU (129 mg, 0.339 mmol) and TEA (0.14 mL, 1.00 mmol) were added and the mixture was stirred at 20 °C for an additional 12 h. The reaction mixture was concentrated under reduced pressure and poured into water (10 mL). The aqueous layer was extracted with EtOAc (15 mL*2). The combined organic phases were washed with brine (50 mL* 2 ), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give crude product, which was purified by flash chromatography ( ISCO® ; 4 g*3 SepaFlash ® silica flash column, petroleum ether/EtOAc with 0~85% EtOAc, 25 mL/min, 254 nm) was purified to give N-[5-[[[2-[2- as a colorless oil (6-ethyl-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid Tributyl ester (70 mg, 42.9% yield). LCMS (ESI) [M+H] + m/z: calcd 482.3, found 382.3 (mass of Boc cleavage).

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(6-ethyl-3-pyridyl)-5-methyl-1-piperidinyl] -2-Synthesis of Pendant Oxyacetamide

在20℃下，向N-[5-[[2-[2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(70mg，0.145mmol)於DCM(2mL)中之溶液中添加TFA(0.25mL，3.24mmol)。將所得反應混合物在20℃下攪拌1小時。將所得混合物用飽和NaHCO3 水溶液調節至pH=8，且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；4g * 2 SepaFlash® 二氧化矽急驟管柱，DCM/MeOH，其中MeOH為0~7%，25mL/min，254nm)進行純化，以得到呈無色油狀物之N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(40mg，72.1%產率)。LCMS(ESI)[M+H]+ m/z：計算值382.2,實測值382.2；外消旋物。At 20 °C, to N-[5-[[2-[2-(6-ethyl-3-pyridyl)-5-methyl-1-piperidinyl]-2-side oxyethanoyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (70 mg, 0.145 mmol) in DCM (2 mL) was added TFA (0.25 mL, 3.24 mmol). The resulting reaction mixture was stirred at 20°C for 1 hour. The resulting mixture was adjusted to pH= 8 with saturated aqueous NaHCO, and concentrated under reduced pressure to give crude product, which was purified by flash chromatography ( ISCO® ; 4g*2 SepaFlash® silica flash column, DCM/ MeOH, where MeOH was 0~7%, 25 mL/min, 254 nm) was purified to give N-(6-amino-5-methyl-3-pyridinyl)-2-[2 as a colorless oil -(6-ethyl-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (40 mg, 72.1% yield). LCMS (ESI) [M+H] + m/z: calcd 382.2, found 382.2; racemate.

步驟7：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1016 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1013 )之合成Step 7: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(6-ethyl-3-pyridyl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide ( Compound 1016 ) and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- Synthesis of (6-ethyl-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 1013 )

藉由掌性SFC(儀器：Sepiatec Prep SFC100；管柱：Daicel Chiralpak IC 250×30mm I.D.10μm；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=55/45；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)分離N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(40 mg，0.105mmol)，以得到化合物1016 及化合物1013 。By chiral SFC (instrument: Sepiatec Prep SFC100; column: Daicel Chiralpak IC 250×30 mm ID10 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=55/45; Flow rate: 80 mL/min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; dresser temperature: 25 °C; wavelength: 220 nm) separation of N-(6-amine) yl-5-methyl-3-pyridyl)-2-[2-(6-ethyl-3-pyridyl)-5-methyl-1-piperidinyl]-2-oxyacetamide (40 mg, 0.105 mmol) to give compound 1016 and compound 1013 .

化合物1016 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(30.9mg，具有反式相對立體化學之單一未知鏡像異構物，峰2，保留時間=2.802min，白色乾燥粉末)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.23(brs,1H),8.46(s,1H),8.02(s,1H),7.63(d,J =7.5Hz,1H),7.49(s,1H),7.25(d,J =8.3Hz,1H),5.24-5.61(m,3H),2.76(q,J =7.5Hz,2H),1.98-2.24(m,6H),1.93(s,1H),1.68-1.79(m,1H),1.31-1.39(m,1H),1.24(t,J =7.5Hz,4H),1.05(d,J =7.0Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值382.2，實測值382.2；HPLC：在254nm下為100%；100%ee；98.2%de。 Compound 1016 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-(6-ethyl-3-pyridyl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide (30.9 mg, single unknown enantiomer with trans relative stereochemistry, peak 2, retention time = 2.802 min, white dry powder). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.23(brs,1H), 8.46(s,1H), 8.02(s,1H), 7.63(d, J =7.5Hz,1H), 7.49(s, 1H), 7.25(d, J =8.3Hz, 1H), 5.24-5.61(m, 3H), 2.76(q, J =7.5Hz, 2H), 1.98-2.24(m, 6H), 1.93(s, 1H ), 1.68-1.79(m, 1H), 1.31-1.39(m, 1H), 1.24(t, J =7.5Hz, 4H), 1.05(d, J =7.0Hz, 3H); LCMS(ESI)[M +H] + m/z: calcd 382.2, found 382.2; HPLC: 100% at 254 nm; 100% ee; 98.2% de.

化合物1013 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(6-乙基-3-吡啶基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(30.8mg，具有反式相對立體化學之單一未知鏡像異構物，峰4，保留時間=3.896min，白色乾燥粉末)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.23(brs,1H),8.46(s,1H),8.02(s,1H),7.63(d,J =7.8Hz,1H),7.49(s,1H),7.25(d,J =8.3Hz,1H),5.30-5.54(m,3H),2.76(q,J =7.5Hz,2H),1.98-2.23(m,6H),1.88-1.97(m,1H),1.69-1.79(m,1H),1.31-1.39(m,1H),1.24(t,J =7.5Hz,4H),1.05(d,J =7.0Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值382.2，實測值382.2；HPLC：在254nm下為98.97%；100%ee；100%de。 Compound 1013 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(6-ethyl-3-pyridyl)-5-methyl- 1-Piperidinyl]-2-oxyacetamide (30.8 mg, single unknown enantiomer with trans relative stereochemistry, peak 4, retention time = 3.896 min, white dry powder). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.23(brs,1H), 8.46(s,1H), 8.02(s,1H), 7.63(d, J =7.8Hz,1H), 7.49(s, 1H), 7.25(d, J =8.3Hz, 1H), 5.30-5.54(m, 3H), 2.76(q, J =7.5Hz, 2H), 1.98-2.23(m, 6H), 1.88-1.97(m ,1H),1.69-1.79(m,1H),1.31-1.39(m,1H),1.24(t, J =7.5Hz,4H),1.05(d, J =7.0Hz,3H); LCMS(ESI) [M+H] + m/z: calcd 382.2, found 382.2; HPLC: 98.97% at 254 nm; 100% ee; 100% de.

實例741. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1018)及(化合物1011)之合成Example 741. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[6-(difluoromethyl)-3-pyridyl]-5 -Methyl-1-piperidinyl]-2-oxyacetamide and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- Synthesis of [6-(difluoromethyl)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxoacetamide (Compound 1018) and (Compound 1011)

Figure 110128222-A0202-12-2377-609
Figure 110128222-A0202-12-2377-609

步驟1：[6-(二氟甲基)-3-吡啶基]硼酸之合成Step 1: Synthesis of [6-(difluoromethyl)-3-pyridyl]boronic acid

向5-溴-2-(二氟甲基)吡啶(1g，4.81mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.55g，6.10mmol)、CH3 COOK(1.03g，10.5mmol)於二噁烷(10mL)中之溶液中添加Pd(dppf)Cl2 -DCM(200mg，0.245mmol)。在微波下將混合物在90℃下攪拌2小時。將所得混合物在減壓下濃縮，以得到呈黑色油狀物之[6-(二氟甲基)-3-吡啶基]硼酸(1.5g，粗品)。To 5-bromo-2-(difluoromethyl)pyridine (1 g, 4.81 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (1.55 g, 6.10 mmol), CH3COOK (1.03 g, 10.5 mmol) To a solution in dioxane (10 mL) was added Pd(dppf)Cl2 - DCM (200 mg, 0.245 mmol). The mixture was stirred at 90°C for 2 hours under microwave. The resulting mixture was concentrated under reduced pressure to give [6-(difluoromethyl)-3-pyridyl]boronic acid (1.5 g, crude) as a black oil.

步驟2：6-[6-(二氟甲基)-3-吡啶基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-[6-(difluoromethyl)-3-pyridinyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

在微波下，將[6-(二氟甲基)-3-吡啶基]硼酸(800mg，4.63mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.5g，4.34mmol)、Na2 CO3 (1.50g，14.2mmol)、Pd(dppf)Cl2 -DCM(200mg，0.245mmol)、二噁烷(10mL)及H2 O(2mL)之混合物在100℃下攪拌1小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL * 2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；12g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~13%，流速：30mL/min，254nm)純化殘餘物，以得到呈白色固體之6-[6-(二氟甲基)-3-吡啶基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(500mg，33.3%產率)。1 H NMR(400MHz，氯仿-d )δ ppm 8.58(d,J =1.51Hz,1 H),7.71(dd,J =8.03,2.01Hz,1 H),7.57(d,J =8.03Hz,1 H),6.45-6.83(m,1 H),5.41(t,J =3.76Hz,1 H),4.08(dd,J =12.42,2.89Hz,1 H),3.04(dd,J =12.42,9.41Hz,1 H),2.32-2.53(m,1 H),1.96-2.11(m,1 H),1.84-1.96(m,1 H),1.65(s,1 H),1.06-1.24(m,9 H),1.04(d,J =6.53Hz,3 H)；19 F NMR(376MHz，氯仿-d )δ ppm -115.056 ppm。[6-(difluoromethyl)-3-pyridinyl]boronic acid (800 mg, 4.63 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4 was combined under microwave - Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 4.34 mmol), Na2CO3 (1.50 g , 14.2 mmol), Pd(dppf)Cl2 - DCM (200 mg, 0.245 mmol), A mixture of dioxane (10 mL) and H2O ( 2 mL) was stirred at 100 °C for 1 hour. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (50 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash The residue was purified by analytical (ISCO®; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-13% EtOAc, flow rate: 30 mL/min, 254 nm) to give 6-[6 as a white solid -(Difluoromethyl)-3-pyridyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (500 mg, 33.3% yield). 1 H NMR (400 MHz, chloroform- d ) δ ppm 8.58 (d, J =1.51 Hz, 1 H), 7.71 (dd, J =8.03, 2.01 Hz, 1 H), 7.57 (d, J =8.03 Hz, 1 H), 6.45-6.83(m, 1 H), 5.41(t, J =3.76Hz, 1 H), 4.08(dd, J =12.42, 2.89Hz, 1 H), 3.04(dd, J =12.42, 9.41 Hz, 1 H), 2.32-2.53(m, 1 H), 1.96-2.11(m, 1 H), 1.84-1.96(m, 1 H), 1.65(s, 1 H), 1.06-1.24(m, 9 H), 1.04 (d, J = 6.53 Hz, 3 H); 19 F NMR (376 MHz, chloroform- d ) δ ppm - 115.056 ppm.

步驟3：2-(二氟甲基)-5-(5-甲基-2-哌啶基)吡啶之合成Step 3: Synthesis of 2-(difluoromethyl)-5-(5-methyl-2-piperidinyl)pyridine

將6-[6-(二氟甲基)-3-吡啶基]-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(400mg，1.23mmol)、TFA(2mL，26.0mmol)及DCM(5mL)之混合物在20℃下攪拌30分鐘。然後藉由添加水(10mL)來淬滅混合物且用EtOAc(10mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL * 2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。將殘餘物溶解於MeOH(5mL)中且在0℃下添加NaBH4 (200mg，5.29mmol)，然後將混合物在20℃下攪拌30分鐘。將所得混合物用Na2 CO3 溶液調節至pH=8~9且用DCM(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL * 2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色固體之2-(二氟甲基)-5-(5-甲基-2-哌啶基)吡啶(300mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值227.2，實測值227.2。6-[6-(Difluoromethyl)-3-pyridinyl]-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (400 mg, 1.23 mmol), TFA A mixture of (2 mL, 26.0 mmol) and DCM (5 mL) was stirred at 20 °C for 30 min. The mixture was then quenched by adding water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (10 mL*2), brine (10 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was dissolved in MeOH ( 5 mL) and NaBH4 (200 mg, 5.29 mmol) was added at 0 °C, then the mixture was stirred at 20 °C for 30 min. The resulting mixture was adjusted to pH=8~ 9 with Na2CO3 solution and extracted with DCM (50 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL*2), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 2-(di) as a yellow solid Fluoromethyl)-5-(5-methyl-2-piperidinyl)pyridine (300 mg, crude). LCMS (ESI) [M+H] + m/z: calcd 227.2, found 227.2.

步驟4：N-[5-[[2-[2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[5-[[2-[2-[6-(difluoromethyl)-3-pyridinyl]-5-methyl-1-piperidinyl]-2-pendoxoacetone Synthesis of tert-butyl]amino]-3-methyl-2-pyridyl]carbamate

向2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(100mg，0.339mmol)及2-(二氟甲基)-5-(5-甲基-2-哌啶基)吡啶(100mg，0.442mmol)於DCM(5mL)中之混合物中添加HATU(150mg，0.394mmol)及DIPEA(297mg，2.30mmol)且將混合物在20℃下攪拌12小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(10mL * 2)、鹽水(10mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉 由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~50%，流速：30mL/min)純化殘餘物，以得到呈黃色固體之N-[5-[[2-[2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(110mg，64.5%產率)。LCMS(ESI)[M+H]+ m/z：計算值504.2，實測值504.2。To 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (100 mg, 0.339 mmol) and 2-(difluoro Methyl)-5-(5-methyl-2-piperidinyl)pyridine (100 mg, 0.442 mmol) in DCM (5 mL) was added HATU (150 mg, 0.394 mmol) and DIPEA (297 mg, 2.30 mmol) And the mixture was stirred at 20°C for 12 hours. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (10 mL*2), brine (10 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc, where EtOAc was 0-50%, flow rate: 30 mL/min) to give N- as a yellow solid [5-[[2-[2-[6-(difluoromethyl)-3-pyridinyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] - 3-Methyl-2-pyridyl]carbamic acid tert-butyl ester (110 mg, 64.5% yield). LCMS (ESI) [M+H] + m/z: calcd 504.2, found 504.2.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺之合成Step 5: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-[6-(difluoromethyl)-3-pyridyl]-5-methyl-1- Synthesis of Piperidinyl]-2-Pendant Oxyacetamide

將N-[5-[[2-[2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(130mg，0.258mmol)、TFA(1.19g，10.4mmol)及DCM(3mL)之混合物在20℃下攪拌1小時。將所得混合物用NH3 -H2 O調節至pH=7~8且在減壓下濃縮，以得到粗產物，其藉由急驟層析(管柱：SepaFlash® Sphercial C18，25g，40-60μm,120Å；MeCN/水(0.5% NH3 -H2 O)，其中MeCN為0-45%，25mL/min，254nm)進行純化，以得到呈黃色固體之N-(6-胺基-5-甲基-3-吡啶基)-2-[2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(50mg，48.0%產率)。LCMS(ESI)[M+H]+ m/z：計算值404.3，實測值404.2。N-[5-[[2-[2-[6-(difluoromethyl)-3-pyridinyl]-5-methyl-1-piperidinyl]-2-oxyethanoyl] A mixture of amino]-3-methyl-2-pyridinyl]carbamic acid tert-butyl ester (130 mg, 0.258 mmol), TFA (1.19 g, 10.4 mmol) and DCM (3 mL) was stirred at 20°C for 1 hour. The resulting mixture was adjusted to pH=7-8 with NH3 - H2O and concentrated under reduced pressure to give crude product, which was purified by flash chromatography (column: SepaFlash® Sphercial C18, 25 g, 40-60 μm, 120Å; MeCN/water (0.5% NH 3 -H 2 O with 0-45% MeCN, 25 mL/min, 254 nm) was purified to give N-(6-amino-5-methyl) as a yellow solid ( 50 mg, 48.0% yield). LCMS (ESI) [M+H] + m/z: calcd 404.3, found 404.2.

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物1018 )及(化合物1011 )之合成Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[6-(difluoromethyl)-3-pyridyl]-5 -Methyl-1-piperidinyl]-2-oxyacetamide and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2- Synthesis of [6-(difluoromethyl)-3-pyridyl]-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 1018 ) and ( Compound 1011 )

藉由SFC(儀器：Berger，Multigr AM-II；管柱：Daicel Chiralpak AD(250mm * 30mm，10μm)；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=50/50；流速：60mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化N-(6-胺基-5-甲基-3-吡啶基)-2-[2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺 (49mg，0.121mmol)，以得到化合物1018 及化合物1011 。By SFC (instrument: Berger, Multigr AM-II; column: Daicel Chiralpak AD (250mm*30mm, 10μm); mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%) = 50/50; flow rate: 60mL/min; column temperature: 38°C; nozzle temperature: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; conditioner temperature: 25°C; wavelength: 220nm) to purify N- (6-Amino-5-methyl-3-pyridyl)-2-[2-[6-(difluoromethyl)-3-pyridyl]-5-methyl-1-piperidinyl]- 2-Pendant oxyacetamide (49 mg, 0.121 mmol) to give compound 1018 and compound 1011 .

化合物1018 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(20mg，具有反式相對化學之單一未知鏡像異構物，峰3，保留時間=2.434min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.26(br s,1 H),8.67(s,1 H),7.89-8.06(m,2 H),7.70(d,J =8.03Hz,1 H),7.49(br s,1 H),6.68-7.05(m,1 H),5.54(br s,1 H),5.36(br s,2 H),3.06(br s,1 H),2.19(br s,2 H),2.01-2.09(m,3 H),1.95(br s,1 H),1.64-1.78(m,1 H),1.37(br d,J =9.54Hz,1 H),1.06(d,J =7.03Hz,3 H)；19 F NMR(376MHz,DMSO-d 6 )δ ppm -115.086 ppm；LCMS(ESI)[M+H]+ m/z：計算值404.3，實測值404.3；HPLC在254nm下為100%；100%ee；98.3%de。 Compound 1018 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[6-(difluoromethyl)-3-pyridyl]-5 -Methyl-1-piperidinyl]-2-oxoacetamide (20 mg, single unknown enantiomer with trans relative chemistry, peak 3, retention time = 2.434 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.26 (br s, 1 H), 8.67 (s, 1 H), 7.89-8.06 (m, 2 H), 7.70 (d, J =8.03 Hz, 1 H), 7.49(br s, 1 H), 6.68-7.05(m, 1 H), 5.54(br s, 1 H), 5.36(br s, 2 H), 3.06(br s, 1 H), 2.19 (br s, 2 H), 2.01-2.09 (m, 3 H), 1.95 (br s, 1 H), 1.64-1.78 (m, 1 H), 1.37 (br d, J =9.54Hz, 1 H) , 1.06 (d, J =7.03 Hz, 3 H); 19 F NMR (376 MHz, DMSO- d 6 ) δ ppm -115.086 ppm; LCMS (ESI) [M+H] + m/z: calculated 404.3, found Value 404.3; HPLC 100% at 254 nm; 100% ee; 98.3% de.

化合物1011 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-[6-(二氟甲基)-3-吡啶基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(20mg，具有反式相對化學之單一未知鏡像異構物，峰4，保留時間=2.890min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.25(br s,1 H),8.67(s,1 H),8.03(br s,1 H),7.94(br d,J =6.78Hz,1 H),7.70(d,J =8.28Hz,1 H),7.50(br s,1 H),6.70-7.08(m,1 H),5.54(br s,1 H),5.36(br s,2 H),3.04(br d,J =5.52Hz,2 H),2.19(br s,2 H),2.07(s,3 H),1.95(br s,1 H),1.67-1.80(m,1 H),1.37(br d,J =8.53Hz,1 H),1.06(d,J =7.03Hz,3 H)；19 F NMR(376MHz,DMSO-d 6 )δ ppm -115.085 ppm；LCMS(ESI)[M+H]+ m/z：計算值404.3，實測值404.3；HPLC：在254nm下為100%；99.8%ee；99.6%de。 Compound 1011 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-[6-(difluoromethyl)-3-pyridyl]-5 -Methyl-1-piperidinyl]-2-oxyacetamide (20 mg, single unknown enantiomer with trans relative chemistry, peak 4, retention time = 2.890 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.25(br s, 1 H), 8.67(s, 1 H), 8.03(br s, 1 H), 7.94(br d, J =6.78Hz, 1 H), 7.70(d, J =8.28Hz, 1 H), 7.50(br s, 1 H), 6.70-7.08(m, 1 H), 5.54(br s, 1 H), 5.36(br s, 2 H), 3.04(br d, J =5.52Hz, 2 H), 2.19(br s, 2 H), 2.07(s, 3 H), 1.95(br s, 1 H), 1.67-1.80(m, 1 H), 1.37 (br d, J =8.53Hz, 1 H), 1.06 (d, J =7.03 Hz, 3 H); 19 F NMR (376 MHz, DMSO- d 6 ) δ ppm -115.085 ppm; LCMS (ESI ) [M+H] + m/z: calcd 404.3, found 404.3; HPLC: 100% at 254 nm; 99.8% ee; 99.6% de.

實例742. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1017)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1014)之合成Example 742. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(4-methylpiperazine-1 -yl)-3-pyridyl]-1-piperidinyl]-2-oxyacetamide (compound 1017) and N-(6-amino-5-methyl-3-pyridyl)-2 -[(2R,5S)-5-Methyl-2-[6-(4-Methylpiperazin-1-yl)-3-pyridyl]-1-piperidinyl]-2-side oxyethyl Synthesis of amide (compound 1014)

Figure 110128222-A0202-12-2381-610
Figure 110128222-A0202-12-2381-610

步驟1：[6-(4-甲基哌嗪-1-基)-3-吡啶基]硼酸之合成Step 1: Synthesis of [6-(4-Methylpiperazin-1-yl)-3-pyridyl]boronic acid

向2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(3g，0.013mol)、1-甲基哌嗪(2g，0.020mol)於DMSO(10mL)中之溶液中添加TEA(5.8mL，0.041mol)。將混合物在90℃下攪拌12小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL * 2)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈白色固體之[6-(4-甲基哌嗪-1-基)-3-吡啶基]硼酸(2.5g，粗品)。To 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridine (3 g, 0.013 mol), 1-methyl To a solution of piperazine (2 g, 0.020 mol) in DMSO (10 mL) was added TEA (5.8 mL, 0.041 mol). The mixture was stirred at 90°C for 12 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (50 mL*2), brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give [6-( 4-Methylpiperazin-1-yl)-3-pyridyl]boronic acid (2.5 g, crude).

步驟2：3-甲基-6-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: 3-Methyl-6-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester synthesis

在氮氣下，將[6-(4-甲基哌嗪-1-基)-3-吡啶基]硼酸(1g，4.52mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.2g，3.47mmol)、Pd(dppf)Cl2 -DCM(175mg，0.214mmol)、Na2 CO3 (1.47g，0.014mol)、二噁烷(3mL)及H2 O(1mL)之混合物在80℃下攪拌12小時。所得混合物藉由添加水(20mL)來淬滅且用EtOAc(20mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(20mL * 2)、鹽水(20mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；25g AgelaFlash® 二氧化矽急驟管柱DCM/MeOH，其中MeOH為0~10%，流速=30mL/min，254nm)純化殘餘物，以得到呈棕色油狀物之3-甲基-6-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯 (700mg，41.5%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.01(s,1 H),7.46(br d,J =8.5Hz,1 H),6.81(br d,J =8.8Hz,1 H),5.29(br s,1 H),3.94(br dd,J =12.4,2.4Hz,1 H),3.54(br s,4 H),3.08(br dd,J =12.2,9.2Hz,1 H),2.57(br d,J =4.3Hz,4 H),2.27-2.48(m,4 H),1.79-2.01(m,2 H),1.15(s,9 H),1.02(br d,J =6.5Hz,3 H)。[6-(4-Methylpiperazin-1-yl)-3-pyridyl]boronic acid (1 g, 4.52 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy) under nitrogen yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.2 g, 3.47 mmol), Pd(dppf)Cl2 - DCM (175 mg , 0.214 mmol), Na2CO3 (1.47 g, 0.014 mol), a mixture of dioxane (3 mL) and H2O (1 mL) was stirred at 80 °C for 12 h. The resulting mixture was quenched by adding water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (20 mL*2), brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 25g AgelaFlash® silica flash column DCM/MeOH with 0-10% MeOH, flow rate = 30 mL/min, 254 nm) to give as brown oil 3-Methyl-6-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (700 mg, 41.5% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.01(s,1H),7.46(br d, J =8.5Hz,1H),6.81(br d, J =8.8Hz,1H),5.29 (br s, 1 H), 3.94(br dd, J =12.4, 2.4Hz, 1 H), 3.54(br s, 4 H), 3.08(br dd, J =12.2, 9.2Hz, 1 H), 2.57 (br d, J =4.3Hz, 4 H), 2.27-2.48(m, 4 H), 1.79-2.01(m, 2 H), 1.15(s, 9 H), 1.02(br d, J =6.5Hz , 3H).

步驟3：1-甲基-4-[5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-2-吡啶基]哌嗪之合成Step 3: Synthesis of 1-methyl-4-[5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-2-pyridyl]piperazine

向3-甲基-6-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(700mg，1.88mmol)於DCM(2mL)中之溶液中添加TFA(2.0mL，0.026mol)。將混合物在20℃下攪拌12小時。將所得混合物用飽和NaHCO3 水溶液調節至pH=8且用DCM(50mL * 3)萃取。將經合併之有機層用鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈灰白色固體之1-甲基-4-[5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-2-吡啶基]哌嗪(400mg，78.2%產率)。To 3-methyl-6-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (700 mg , 1.88 mmol) in DCM (2 mL) was added TFA (2.0 mL, 0.026 mol). The mixture was stirred at 20°C for 12 hours. The resulting mixture was adjusted to pH=8 with saturated aqueous NaHCO 3 and extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 1-methyl-4-[5-(3-methyl) as an off-white solid -1,2,3,4-Tetrahydropyridin-6-yl)-2-pyridyl]piperazine (400 mg, 78.2% yield).

步驟4：1-甲基-4-[5-(5-甲基-2-哌啶基)-2-吡啶基]哌嗪之合成Step 4: Synthesis of 1-methyl-4-[5-(5-methyl-2-piperidinyl)-2-pyridyl]piperazine

向1-甲基-4-[5-(3-甲基-1,2,3,4-四氫吡啶-6-基)-2-吡啶基]哌嗪(400mg，1.47mmol)於MeOH(2mL)中之溶液中添加NaBH4 (120mg，3.17mmol)。將混合物在20℃下攪拌1小時。將所得混合物在減壓下濃縮以移除MeOH且藉由添加水(30mL)來淬滅，用EtOAc(30mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(30mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到呈黃色固體之1-甲基-4-[5-(5-甲基-2-哌啶基)-2-吡啶基]哌嗪(300mg，74.5%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.08(d,J =2.0Hz,1 H),7.60(dd,J =8.8,2.5Hz,1 H),6.81(d,J =8.8Hz,1 H),3.44-3.57(m,5 H),3.05(br dd,J =11.9,1.9Hz,1 H),2.55(t,J =5.1Hz,4 H),2.36-2.43(m,1 H),2.33(s,3 H),1.73-1.97(m,2 H),1.53-1.70(m,2 H),1.15-1.32(m,1 H),0.91(d,J =6.5Hz,3 H)。To 1-methyl-4-[5-(3-methyl-1,2,3,4-tetrahydropyridin-6-yl)-2-pyridyl]piperazine (400 mg, 1.47 mmol) in MeOH ( To the solution in 2 mL) was added NaBH4 (120 mg, 3.17 mmol). The mixture was stirred at 20°C for 1 hour. The resulting mixture was concentrated under reduced pressure to remove MeOH and quenched by adding water (30 mL), extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (30 mL*2), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 1-methyl as a yellow solid -4-[5-(5-Methyl-2-piperidinyl)-2-pyridyl]piperazine (300 mg, 74.5% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.08 (d, J =2.0 Hz, 1 H), 7.60 (dd, J =8.8, 2.5 Hz, 1 H), 6.81 (d, J =8.8 Hz, 1 H), 3.44-3.57 (m, 5 H), 3.05 (br dd, J = 11.9, 1.9 Hz, 1 H), 2.55 (t, J = 5.1 Hz, 4 H), 2.36-2.43 (m, 1 H), 2.33(s, 3 H), 1.73-1.97(m, 2 H), 1.53-1.70(m, 2 H), 1.15-1.32(m, 1 H), 0.91(d, J =6.5Hz, 3H).

步驟5：N-[3-甲基-5-[[2-[5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-Step 5: N-[3-Methyl-5-[[2-[5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-1-piperidine pyridyl]-2- 側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯)之合成Synthesis of pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester)

向2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(50mg，0.169mmol)、1-甲基-4-[5-(5-甲基-2-哌啶基)-2-吡啶基]哌嗪(50mg，0.182mmol)於DCM(4mL)中之溶液中添加HATU(100mg，0.263mmol)及DIEA(100μL,0.573mmol)。將混合物在20℃下攪拌2小時。所得混合物藉由添加水(20mL)來淬滅且用DCM(20mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，MeOH/EtOAc，其中EtOAc為0~60%，流速=30mL/min，254nm)純化殘餘物，以得到呈淡黃色油狀物之N-[3-甲基-5-[[2-[5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(50mg，49.7%產率)。To 2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (50 mg, 0.169 mmol), 1-methyl- To a solution of 4-[5-(5-methyl-2-piperidinyl)-2-pyridyl]piperazine (50 mg, 0.182 mmol) in DCM (4 mL) was added HATU (100 mg, 0.263 mmol) and DIEA (100 μL, 0.573 mmol). The mixture was stirred at 20°C for 2 hours. The resulting mixture was quenched by adding water (20 mL) and extracted with DCM (20 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL*2), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, MeOH/EtOAc with 0-60% EtOAc, flow = 30 mL/min, 254 nm) to give a pale yellow oil N-[3-methyl-5-[[2-[5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-1-piperidine yl]-2-pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (50 mg, 49.7% yield).

步驟6：N-[3-甲基-5-[[2-[5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸酯之合成Step 6: N-[3-Methyl-5-[[2-[5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-1-piperidine Synthesis of pyridyl]-2-side oxyacetyl]amino]-2-pyridyl]carbamate

向N-[3-甲基-5-[[2-[5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(50mg，0.091mmol)於DCM(2mL)中之溶液中添加TFA(160μL，2.12mmol)。將混合物在20℃下攪拌1小時。將所得混合物過濾且在減壓下濃縮，以得到呈白色固體之N-[3-甲基-5-[[2-[5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸酯(40mg)。to N-[3-methyl-5-[[2-[5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-1-piperidinyl ]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (50 mg, 0.091 mmol) in DCM (2 mL) was added TFA (160 μL, 2.12 mmol). The mixture was stirred at 20°C for 1 hour. The resulting mixture was filtered and concentrated under reduced pressure to give N-[3-methyl-5-[[2-[5-methyl-2-[6-(4-methylpiperazine- 1-yl)-3-pyridyl]-1-piperidinyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamate (40 mg).

步驟7：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1017 )及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(化合物1014 )之合成Step 7: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-[6-(4-methylpiperazine-1 -yl)-3-pyridyl]-1-piperidinyl]-2-oxyacetamide ( compound 1017 ) and N-(6-amino-5-methyl-3-pyridyl)-2 -[(2R,5S)-5-Methyl-2-[6-(4-Methylpiperazin-1-yl)-3-pyridyl]-1-piperidinyl]-2-side oxyethyl Synthesis of amide ( compound 1014 )

藉由掌性SFC 1 (儀器：Berger，Multigr AM-II；管柱：Chiralpak AD 250×30mm I.D.20μm；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=60/40；流速：80mL/min；管柱溫度：38℃；噴嘴溫度：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)純化N-[3-甲基-5-[[2-[5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸酯(40mg)，以得到化合物1017 (與一種非鏡像異構物混合，峰2，保留時間=5.910min)或化合物1014 (峰3，保留時間=6.357min)。By chiral SFC 1 (instrument: Berger, Multigr AM-II; column: Chiralpak AD 250×30 mm ID 20 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)=60 /40; flow rate: 80 mL/min; column temperature: 38 °C; nozzle temperature: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; 3-Methyl-5-[[2-[5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-1-piperidinyl]-2- Pendant oxyacetoxy]amino]-2-pyridyl]carbamate (40 mg) to give compound 1017 (mixed with a diastereomer, peak 2, retention time = 5.910 min) or compound 1014 (Peak 3, retention time = 6.357 min).

化合物1014 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(29mg，具有反式相對化學之單一未知鏡像異構物，峰3，保留時間=6.357min，白色固體)。1 H NMR(400MHz,DMSO-d 4 )δ ppm 10.19(br s,1 H),7.94-8.20(m,2 H),7.44-7.53(m,2 H),6.78(d,J =8.8Hz,1 H),5.34(br s,3 H),3.36-3.61(m,5 H),2.34-2.46(m,5 H),2.23(s,3 H),2.00-2.13(m,5 H),1.72-1.96(m,2 H),1.34(br d,J =12.5Hz,1 H),1.04(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值452.2，實測值452.3；HPLC：在254nm下為99.50%；97.9%ee。 Compound 1014 : N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[6-(4-methylpiperazine-1 -yl)-3-pyridyl]-1-piperidinyl]-2-oxoacetamide (29 mg, single unknown enantiomer with trans relative chemistry, peak 3, retention time = 6.357 min, white solid). 1 H NMR (400MHz, DMSO- d 4 ) δ ppm 10.19 (br s, 1 H), 7.94-8.20 (m, 2 H), 7.44-7.53 (m, 2 H), 6.78 (d, J =8.8 Hz ,1 H),5.34(br s,3 H),3.36-3.61(m,5 H),2.34-2.46(m,5 H),2.23(s,3 H),2.00-2.13(m,5 H) ), 1.72-1.96(m, 2 H), 1.34(br d, J =12.5Hz, 1 H), 1.04(d, J =7.0Hz, 3 H); LCMS(ESI)[M+H] + m /z: Calculated 452.2, found 452.3; HPLC: 99.50% at 254 nm; 97.9% ee.

化合物1017 ：藉由掌性SFC 2 (儀器：SFC-80Q；管柱：Daicel Chiralpak IC 250×30mm I.D.10μm；流動相：超臨界CO2 /EtOH(0.1% NH3 -H2 O，v%)=55/45；流速：80mL/min；管柱溫度：38℃；噴嘴壓力：100巴；噴嘴溫度：60℃；蒸發器溫度：20℃；修整器溫度：25℃；波長：220nm)進一步分離N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(與一種非鏡像異構物混合，峰2，保留時間=5.910min)，以得到化合物1017 ：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯胺(30mg，具有反式相對立體化學之單一未知鏡像異構物，峰2，保留時間=3.832min，白色固體)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 10.08(br s,1 H),7.92-8.26(m,2 H),7.49(br s,2 H),6.79(d,J = 8.8Hz,1 H),5.34(br s,3 H),3.34-3.63(m,5 H),2.35-2.45(m,5 H),2.23(s,3 H),2.01-2.13(m,5 H),1.71-1.96(m,2 H),1.34(br d,J =13.3Hz,1 H),1.04(d,J =7.0Hz,3 H)；LCMS(ESI)[M+H]+ m/z：計算值452.2，實測值452.3；HPLC：在254nm下為100%；100.0%ee。 Compound 1017 : by chiral SFC 2 (instrument: SFC-80Q; column: Daicel Chiralpak IC 250×30 mm ID 10 μm; mobile phase: supercritical CO 2 /EtOH (0.1% NH 3 -H 2 O, v%)= 55/45; flow rate: 80mL/min; column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; conditioner temperature: 25°C; wavelength: 220nm) to further separate N -(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(4-methylpiperazin-1-yl)- 3-Pyridinyl]-1-piperidinyl]-2-oxoacetamide (mixed with a diastereoisomer, peak 2, retention time = 5.910 min) to give compound 1017 : N-(6 -Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-[6-(4-methylpiperazin-1-yl)-3-pyridine yl]-1-piperidinyl]-2-oxoacetamide (30 mg, single unknown enantiomer with trans relative stereochemistry, peak 2, retention time = 3.832 min, white solid). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 10.08 (br s, 1 H), 7.92-8.26 (m, 2 H), 7.49 (br s, 2 H), 6.79 (d, J = 8.8 Hz, 1 H), 5.34(br s, 3 H), 3.34-3.63(m, 5 H), 2.35-2.45(m, 5 H), 2.23(s, 3 H), 2.01-2.13(m, 5 H) ,1.71-1.96(m,2 H),1.34(br d, J =13.3Hz,1 H),1.04(d, J =7.0Hz,3 H); LCMS(ESI)[M+H] + m/ z: Calculated 452.2, found 452.3; HPLC: 100% at 254 nm; 100.0% ee.

實例743. 5-[[2-[(2S,5R)-2-(4-羥基-3-異丙基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物552)之合成Example 743. 5-[[2-[(2S,5R)-2-(4-hydroxy-3-isopropylphenyl)-5-methyl-1-piperidinyl]-2-side oxyethyl Synthesis of Acyl]amino]pyridine-3-carbamoylamine (Compound 552)

Figure 110128222-A0202-12-2385-611
Figure 110128222-A0202-12-2385-611

步驟1：2-異丙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚之合成Step 1: Synthesis of 2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol

將4-溴-2-異丙基苯酚(10g，46.49mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(12.6g，49.62mmol)、乙酸鉀(18.25g，185.97mmol，11.63mL)及Pd(dppf)Cl2 DCM(1.54g，1.86mmol)混合於1,4-二噁烷(200mL)中且在惰性氣氛、80℃下攪拌16h。將反應混合物用水(500mL)稀釋且用DCM(3x200mL)萃取。將有機層合併，經Na2 SO4 乾燥且在真空中濃縮。將粗材料提交至管柱層析，以得到2-異丙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(7.5g，28.61mmol，61.54%產率)。4-Bromo-2-isopropylphenol (10 g, 46.49 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2 -dioxaborol-2-yl)-1,3,2-dioxaborolane (12.6 g, 49.62 mmol), potassium acetate (18.25 g, 185.97 mmol, 11.63 mL) and Pd(dppf) Cl2DCM (1.54 g, 1.86 mmol) was mixed in 1,4-dioxane (200 mL) and stirred at 80 °C for 16 h under an inert atmosphere. The reaction mixture was diluted with water (500 mL) and extracted with DCM (3 x 200 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude material was submitted to column chromatography to give 2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)phenol (7.5 g, 28.61 mmol, 61.54% yield).

LCMS(ESI)：[M+H]+ m/z：計算值262.2；實測值263.2；Rt=1.333min。LCMS (ESI): [M+H] + m/z: calculated 262.2; found 263.2; Rt=1.333 min.

步驟2：6-(4-羥基-3-異丙基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(4-hydroxy-3-isopropylphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將2-異丙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(3 g，11.44mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.16g，9.16mmol)、碳酸鈉(3.64g，34.33mmol，1.44mL)及Pd(dppf)Cl2 DCM(378.43mg，457.75μmol)溶解於1,4-二噁烷(25mL)及水(9mL)之混合物中。將反應混合物在氬氣氣氛、75℃下攪拌12h。冷卻之後，將反應混合物用水稀釋且用DCM(3x40mL)萃取。將經合併之萃取物經Na2 SO4 乾燥，在真空中濃縮且將殘餘物提交至管柱層析，以得到6-(4-羥基-3-異丙基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.8g，2.41mmol，21.09%產率)。2-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol (3 g, 11.44 mmol), 3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.16 g, 9.16 mmol), sodium carbonate (3.64 g , 34.33 mmol, 1.44 mL) and Pd(dppf)Cl 2 DCM (378.43 mg, 457.75 μmol) were dissolved in a mixture of 1,4-dioxane (25 mL) and water (9 mL). The reaction mixture was stirred under an argon atmosphere at 75 °C for 12 h. After cooling, the reaction mixture was diluted with water and extracted with DCM (3x40 mL). The combined extracts were dried over Na 2 SO 4 , concentrated in vacuo and the residue was submitted to column chromatography to give 6-(4-hydroxy-3-isopropylphenyl)-3-methyl - 3,4-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.8 g, 2.41 mmol, 21.09% yield).

1 H NMR(400MHz,CDCl3 )δ 0.93(d,3H),0.99(s,9H),1.05(m,6H),1.81(m,2H),2.13(m,1H),2.98(m,1H),3.81(m,1H),5.02(m,1H),6.34(d,1H),6.45(d,1H),6.98(s,1H),9.02(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.93(d,3H), 0.99(s,9H), 1.05(m,6H), 1.81(m,2H), 2.13(m,1H), 2.98(m,1H) ), 3.81(m, 1H), 5.02(m, 1H), 6.34(d, 1H), 6.45(d, 1H), 6.98(s, 1H), 9.02(s, 1H).

步驟3：2-異丙基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚之合成Step 3: Synthesis of 2-isopropyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol

將6-(4-羥基-3-異丙基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(0.3g，905.12μmol)添加到TFA(1.48g，12.98mmol，1mL)及DCM(1mL)之混合物中。將反應混合物攪拌0,5h且在真空中濃縮，以得到2-異丙基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(0.2g，粗品，TFA)，其不經純化即直接用於下一步驟中。6-(4-Hydroxy-3-isopropylphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.3 g, 905.12 μmol) was added to TFA (1.48 g, 12.98 mmol, 1 mL) and DCM (1 mL). The reaction mixture was stirred for 0,5 h and concentrated in vacuo to give 2-isopropyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (0.2 g, crude, TFA), which was used directly in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值231.2；實測值232.2；Rt=0.988min。LCMS (ESI): [M+H] + m/z: calculated 231.2; found 232.2; Rt=0.988 min.

步驟4：2-異丙基-4-[(2S,5R)-5-甲基-2-哌啶基]苯酚之合成Step 4: Synthesis of 2-isopropyl-4-[(2S,5R)-5-methyl-2-piperidinyl]phenol

將粗品2-異丙基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(0.2g，580.81μmol，TFA)溶解於甲醇(3mL)中且在攪拌之情況下一次性添加硼氫化鈉(26.37mg，696.97μmol，24.64μL)。當反應混合物之LCMS顯示反應完成時，添加過量HCl二噁烷溶液且在減壓下濃縮反應混合物，以得到2-異丙基-4-[(2S,5R)-5-甲基-2-哌啶基]苯酚(0.18g，粗品)，其不經純化即用於下一步驟中。Crude 2-isopropyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (0.2 g, 580.81 μmol, TFA) was dissolved in methanol (3 mL) and Sodium borohydride (26.37 mg, 696.97 μmol, 24.64 μL) was added in one portion with stirring. When LCMS of the reaction mixture showed that the reaction was complete, excess HCl in dioxane was added and the reaction mixture was concentrated under reduced pressure to give 2-isopropyl-4-[(2S,5R)-5-methyl-2- piperidinyl]phenol (0.18 g, crude), which was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值233.2；實測值234.2；Rt=0.791min。LCMS (ESI): [M+H] + m/z: calculated 233.2; found 234.2; Rt=0.791 min.

步驟step 5：5-[[2-[(2S,5R)-2-(4-羥基-3-異丙基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯5: 5-[[2-[(2S,5R)-2-(4-Hydroxy-3-isopropylphenyl)-5-methyl-1-piperidinyl]-2-side oxyacetyl 基]胺基]吡啶-3-甲醯胺(化合物552 )之合成Synthesis of yl]amino]pyridine-3-carboxamide ( compound 552 )

將粗品2-異丙基-4-[(2S,5R)-5-甲基-2-哌啶基]苯酚(0.18g，667.14μmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(167.45mg，800.57μmol)、HATU(304.40mg，800.57μmol)及DIPEA(742.00mg，5.74mmol，1mL)混合於DMSO(3mL)中且在25℃下攪拌15h。在反應完成之後，將反應混合物提交至HPLC，以得到5-[[2-[(2S,5R)-2-(4-羥基-3-異丙基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.166g，391.06μmol，58.62%產率)。The crude 2-isopropyl-4-[(2S,5R)-5-methyl-2-piperidinyl]phenol (0.18 g, 667.14 μmol, HCl), 2-[(5-aminocarbamoyl- 3-Pyridinyl)amino]-2-side oxyacetic acid (167.45 mg, 800.57 μmol), HATU (304.40 mg, 800.57 μmol) and DIPEA (742.00 mg, 5.74 mmol, 1 mL) were mixed in DMSO (3 mL) and Stir at 25°C for 15h. After the reaction was completed, the reaction mixture was submitted to HPLC to give 5-[[2-[(2S,5R)-2-(4-hydroxy-3-isopropylphenyl)-5-methyl-1- Piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (0.166 g, 391.06 μmol, 58.62% yield).

HPLC資料：2-10min 40-60%水+NH3 /MeOH+NH3 (裝載泵4ml MeOH+NH3 )管柱：TRIART 100* 20 5微米，注入體積1500.000HPLC profile: 2-10min 40-60% water+ NH3 /MeOH+ NH3 (loading pump 4ml MeOH+ NH3 ) Column: TRIART 100 * 20 5 microns, injection volume 1500.000

1 H NMR(600MHz,DMSO-d 6 )δ 0.98-1.03(m,3H),1.08-1.16(m,6H),1.26-1.36(m,1H),1.63-1.76(m,1H),1.80-1.92(m,1H),1.96-2.11(m,1H),2.11-2.20(m,1H),2.77-3.24(m,2H),3.39-4.02(m,1H),4.99-5.59(m,1H),6.70-6.81(m,1H),6.85-6.97(m,1H),6.98-7.05(m,1H),7.53-7.67(m,1H),8.06-8.19(m,1H),8.41-8.51(m,1H),8.69-8.78(m,1H),8.81-8.93(m,1H),9.21(s,1H),10.99-11.44(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.98-1.03(m,3H), 1.08-1.16(m,6H), 1.26-1.36(m,1H), 1.63-1.76(m,1H), 1.80- 1.92(m,1H),1.96-2.11(m,1H),2.11-2.20(m,1H),2.77-3.24(m,2H),3.39-4.02(m,1H),4.99-5.59(m,1H) ),6.70-6.81(m,1H),6.85-6.97(m,1H),6.98-7.05(m,1H),7.53-7.67(m,1H),8.06-8.19(m,1H),8.41-8.51 (m, 1H), 8.69-8.78 (m, 1H), 8.81-8.93 (m, 1H), 9.21 (s, 1H), 10.99-11.44 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值424.2；實測值425.2；Rt=2.662min。LCMS (ESI): [M+H] + m/z: calculated 424.2; found 425.2; Rt=2.662 min.

實例744. 5-[[2-[(2S ,5R )-2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R ,5S )-2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物335及化合物326)之合成Example 744. 5-[[2-[( 2S , 5R )-2-(4-hydroxy-3,5-dimethylphenyl)-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carbamide and 5-[[2-[( 2R , 5S )-2-(4-hydroxy-3,5-dimethylphenyl) Synthesis of -5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 335 and compound 326)

Figure 110128222-A0202-12-2388-612
Figure 110128222-A0202-12-2388-612

步驟1：2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚之合成Step 1: Synthesis of 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol

將4-溴-2,6-二甲基苯酚(18.7g，93.01mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(28.34g，111.61mmol)及KOAc(27.38g，279.02mmol，17.44mL)於1,4-二噁烷(400mL)中之正攪拌溶液用氬氣吹掃10分鐘。10分鐘之後，在氬氣下添加Pd(dppf)Cl2 ‧CH2 Cl2 (1.5g，1.84mmol)。將反應混合物在氬氣、100℃下攪拌16小時。然後將反應混合物冷卻至室溫，過濾且在減壓下濃縮濾液。藉由急驟層析(SiO2 ，溶析液：CHCl3 ：乙腈)純化所獲得之粗產物，以得到2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(10.4g，41.91mmol，45.07%產率)。4-Bromo-2,6-dimethylphenol (18.7 g, 93.01 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborol-2-yl)-1,3,2-dioxaborolane (28.34 g, 111.61 mmol) and KOAc (27.38 g, 279.02 mmol, 17.44 mL) ) in 1,4-dioxane (400 mL) was purged with argon for 10 minutes. After 10 minutes, Pd(dppf)Cl2 - CH2Cl2 ( 1.5 g, 1.84 mmol) was added under argon. The reaction mixture was stirred under argon at 100°C for 16 hours. The reaction mixture was then cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography ( SiO2 , eluent: CHCl3 :acetonitrile) to give 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)phenol (10.4 g, 41.91 mmol, 45.07% yield).

LCMS(ESI)：[M-H]- m/z：計算值248.2；實測值247.2；Rt=1.475minLCMS(ESI): [MH] - m/z: Calculated 248.2; Found 247.2; Rt=1.475min

步驟2：6-(4-羥基-3,5-二甲基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(4-hydroxy-3,5-dimethylphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.11g，3.22mmol)、2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(1g，4.03mmol)及碳酸鈉(1.03g，9.67mmol，405.21μL)於1,4-二噁烷(7.5mL)及水(2.5mL)中之正攪拌溶液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 ‧CH2 Cl2 (131.55mg，161.21μmol)。將反應混合物在氬氣、75℃下攪拌40小時。40小時之後，使反應混合物冷卻至室溫且過濾。將濾餅用1,4-二噁烷 (10mL)洗滌且丟棄。將濾液用水洗滌且用DCM萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下濃縮，以獲得6-(4-羥基-3,5-二甲基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.15g，粗品)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (1.11 g, 3.22 mmol), 2,6 -Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol (1 g, 4.03 mmol) and sodium carbonate ( A stirring solution of 1.03 g, 9.67 mmol, 405.21 μL) in 1,4-dioxane (7.5 mL) and water (2.5 mL) was purged with argon. Then, Pd(dppf)Cl 2 ·CH 2 Cl 2 (131.55 mg, 161.21 μmol) was added under argon. The reaction mixture was stirred under argon at 75°C for 40 hours. After 40 hours, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with 1,4-dioxane (10 mL) and discarded. The filtrate was washed with water and extracted with DCM. The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 6-(4-hydroxy-3,5-dimethylphenyl)-3-methyl-3,4-dihydro -2H-Pyridine-1-carboxylic acid tert -butyl ester (1.15 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值317.2；實測值318.2；Rt=1.594min。LCMS (ESI): [M+H] + m/z: calculated 317.2; found 318.2; Rt=1.594 min.

步驟3：2,6-二甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚之合成Step 3: Synthesis of 2,6-dimethyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol

將6-(4-羥基-3,5-二甲基苯基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.15g，粗品)溶解於三氟乙酸(4.44g，38.94mmol，3mL)中且在室溫下攪拌16小時。16小時之後，將反應混合物在減壓下濃縮，以得到深棕色油狀物。將所獲得之粗產物用NaOH水溶液處理，然後用NaHSO4 中和至pH=4-5。將所得懸浮液用DCM萃取。將有機層經Na2 SO4 乾燥且在真空下濃縮，以得到2,6-二甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(0.5g，粗品)。粗產物不經任何進一步純化即用於下一步反應。6-(4-Hydroxy-3,5-dimethylphenyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (1.15 g, crude) was dissolved Stir in trifluoroacetic acid (4.44 g, 38.94 mmol, 3 mL) at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated under reduced pressure to give a dark brown oil. The obtained crude product was treated with aqueous NaOH solution and then neutralized with NaHSO 4 to pH=4-5. The resulting suspension was extracted with DCM. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give 2,6-dimethyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (0.5 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值203.2；實測值204.2；Rt=0.680min。LCMS (ESI): [M+H] + m/z: calculated 203.2; found 204.2; Rt=0.680 min.

步驟4：2,6-二甲基-4-(5-甲基-2-哌啶基)苯酚之合成Step 4: Synthesis of 2,6-dimethyl-4-(5-methyl-2-piperidinyl)phenol

在0℃下，將硼氫化鈉(87.05mg，2.30mmol)分批添加到2,6-二甲基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(0.5g，2.30mmol)於甲醇(10mL)中之經攪拌之溶液中。將反應混合物在室溫下攪拌1小時。1小時之後，將反應混合物在減壓下濃縮，將殘餘物用水稀釋且用DCM(2 x 25mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在真空中蒸發，以獲得2,6-二甲基-4-(5-甲基-2-哌啶基)苯酚(0.4g，粗品)。Sodium borohydride (87.05 mg, 2.30 mmol) was added portionwise to 2,6-dimethyl-4-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0°C (0.5 g, 2.30 mmol) in a stirred solution of methanol (10 mL). The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water and extracted with DCM (2 x 25 mL). The combined organic phases were dried over Na 2 SO 4 and evaporated in vacuo to obtain 2,6-dimethyl-4-(5-methyl-2-piperidinyl)phenol (0.4 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值219.2；實測值220.2；Rt=0.780min。LCMS (ESI): [M+H] + m/z: calculated 219.2; found 220.2; Rt=0.780 min.

步驟5：5-[[2-[2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 5: 5-[[2-[2-(4-Hydroxy-3,5-dimethylphenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amine Synthesis of base]pyridine-3-carboxamide

向2,6-二甲基-4-(5-甲基-2-哌啶基)苯酚(0.4g，1.82mmol)、2-[(5-胺甲 醯基-3-吡啶基)胺基]-2-側氧基乙酸(283.31mg，912.88μmol，Et3 N鹽)及HATU(416.85mg，1.10mmol)於DMSO(4mL)中之經攪拌之溶液中添加DIPEA(120.39mg，931.48μmol，162.24μL)。將反應混合物在25℃下攪拌16小時。16小時之後，藉由反相HPLC(溶析液：2-10min,0-85%，MeOH/H2 O；流速：30mL/min；裝載泵：4mL，MeOH；管柱：SunFireC18 100 x 19mm，5um)純化反應混合物，以獲得5-[[2-[2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(60mg，146.18μmol，8.01%產率)。To 2,6-dimethyl-4-(5-methyl-2-piperidinyl)phenol (0.4 g, 1.82 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino ]-2-Pendoxacetic acid (283.31 mg, 912.88 μmol, Et3N salt) and HATU (416.85 mg, 1.10 mmol) in DMSO (4 mL) was added DIPEA (120.39 mg, 931.48 μmol, 162.24 μL). The reaction mixture was stirred at 25°C for 16 hours. After 16 hours, by reverse phase HPLC (eluent: 2-10 min, 0-85%, MeOH/ H2O ; flow rate: 30 mL/min; loading pump: 4 mL, MeOH; column: SunFire C18 100 x 19 mm, 5um) to purify the reaction mixture to obtain 5-[[2-[2-(4-hydroxy-3,5-dimethylphenyl)-5-methyl-1-piperidinyl]-2-side oxy Acetyl]amino]pyridine-3-carboxamide (60 mg, 146.18 μmol, 8.01% yield).

LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值411.2；Rt=2.913min。LCMS (ESI): [M+H] + m/z: calculated 410.2; found 411.2; Rt=2.913 min.

步驟6：5-[[2-[(2S,5R)-2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2R,5S)-2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物335 及化合物326 )之掌性分離Step 6: 5-[[2-[(2S,5R)-2-(4-hydroxy-3,5-dimethylphenyl)-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]pyridine-3-carbamide and 5-[[2-[(2R,5S)-2-(4-hydroxy-3,5-dimethylphenyl)-5-methyl Chiral isolation of yl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide ( compound 335 and compound 326 )

使5-[[2-[2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(60mg，146.18μmol)經歷掌性HPLC純化(管柱：Chiralpak IC(250 x 20mm，5um)；流動相：CO2 -MeOH，60-40；流速：40mL/min)，以得到呈淡棕色固體之5-[[2-[(2S ,5R )-2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物335 ，18.7mg)及5-[[2-[(2R ,5S)-2-(4-羥基-3,5-二甲基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物326 ，19.7mg)。make 5-[[2-[2-(4-Hydroxy-3,5-dimethylphenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] Pyridine-3-carboxamide (60 mg, 146.18 μmol) was purified by chiral HPLC (column: Chiralpak IC (250 x 20 mm, 5 um); mobile phase: CO2 -MeOH, 60-40; flow rate: 40 mL/min) , to give 5-[[2-[( 2S , 5R )-2-(4-hydroxy-3,5-dimethylphenyl)-5-methyl-1-piperidine as a light brown solid ( Compound 335 , 18.7 mg) and 5-[[2-[(2 R ,5S)-2-(4-hydroxyl) -3,5-Dimethylphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 326 , 19.7mg) .

化合物335：Compound 335:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.31(m,1H),1.70(m,1H),1.85(m,1H),1.95(m,1H),2.07(m,1H),2.15(m,6H),3.02(m,1H),3.68(m,1H),5.23(m,1H),6.84(m,2H),7.59(m,1H),8.16(m,2H),8.47(m,1H),8.75(m,1H),8.85(m,1H),11.21(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.31 (m, 1H), 1.70 (m, 1H), 1.85 (m, 1H), 1.95 (m, 1H) ,2.07(m,1H),2.15(m,6H),3.02(m,1H),3.68(m,1H),5.23(m,1H),6.84(m,2H),7.59(m,1H), 8.16 (m, 2H), 8.47 (m, 1H), 8.75 (m, 1H), 8.85 (m, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值411.2；Rt=4.399min。LCMS (ESI): [M+H] + m/z: calculated 410.2; found 411.2; Rt=4.399 min.

掌性HPLC：Rt=5.29min(管柱：IC；流動相：CO2 -MeOH，60-40；流速：0.6mL/min)。Chiral HPLC: Rt=5.29 min (column: IC; mobile phase: CO2 -MeOH, 60-40; flow rate: 0.6 mL/min).

化合物326：Compound 326:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00(m,3H),1.30(m,1H),1.72(m,1H),1.85(m,1H),2.00(m,1H),2.13(m,8H),2.92(m,1H),3.68(m,1H),5.23(m,1H),6.86(m,1H),7.59(m,1H),8.16(m,2H),8.47(m,1H),8.75(m,1H),8.85(m,1H),11.21(m,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 1.00 (m, 3H), 1.30 (m, 1H), 1.72 (m, 1H), 1.85 (m, 1H), 2.00 (m, 1H) ,2.13(m,8H),2.92(m,1H),3.68(m,1H),5.23(m,1H),6.86(m,1H),7.59(m,1H),8.16(m,2H), 8.47 (m, 1H), 8.75 (m, 1H), 8.85 (m, 1H), 11.21 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值411.2；Rt=4.398min。LCMS (ESI): [M+H] + m/z: calculated 410.2; found 411.2; Rt=4.398 min.

掌性HPLC：Rt=6.28min(管柱：IC；流動相：CO2 -MeOH，60-40；流速：0.6mL/min)。Chiral HPLC: Rt=6.28 min (column: IC; mobile phase: CO2 -MeOH, 60-40; flow rate: 0.6 mL/min).

實例745. 外消旋-5-[[2-[(2S,5R)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物212)、rel-5-[[2-[(2S,5R)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物570)及rel-5-[[2-[(2R,5S)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物569)之合成Example 745. Racemic-5-[[2-[(2S,5R)-2-(4-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]pyridine-3-carboxamide (Compound 212), rel-5-[[2-[(2S,5R)-2-(4-chlorophenyl)-5-methyl-1-piperidine yl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (Compound 570) and rel-5-[[2-[(2R,5S)-2-(4-chlorophenyl) )-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (compound 569) synthesis

Figure 110128222-A0202-12-2391-613
Figure 110128222-A0202-12-2391-613

步驟1：6-(4-氯苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(4-chlorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(6g，17.37mmol)、(4-氯苯基)硼酸(3.53g，22.59mmol)及碳酸鈉(5.52g，52.12mmol，2.18mL)添加到1,4-二噁烷(90mL)及水(30mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2．DCM(567.10mg，694.98μmol)。將反應混合物在氬氣、70℃下攪拌12h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析使用己烷/MTBE梯度(0-70% MTBE)純化殘餘物，以得到呈白色固體之6-(4-氯苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.2g，10.40mmol，59.83%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6 g, 17.37 mmol), (4-chlorobenzene yl)boronic acid (3.53 g, 22.59 mmol) and sodium carbonate (5.52 g, 52.12 mmol, 2.18 mL) were added to a mixture of 1,4-dioxane (90 mL) and water (30 mL). The resulting mixture was evacuated and backfilled with argon. This operation was repeated three times, and then Pd(dppf)Cl2 was added under argon. DCM (567.10 mg, 694.98 μmol). The reaction mixture was stirred under argon at 70 °C for 12 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a hexane/MTBE gradient (0-70% MTBE) to give 6-(4-chlorophenyl)-3-methan as a white solid tert-butyl-3,4-dihydro-2H-pyridine-1-carboxylate (3.2 g, 10.40 mmol, 59.83% yield).

1 H NMR(CDCl3 ,400MHz)：δ 0.98(d,3H),1.08(s,9H),1.78(m,1H),1.98(m,1H),2.38(m,1H),2.97(t,1H),4.02(d,1H),5.26(s,1H),7.24(m,4H)。 1 H NMR (CDCl 3 , 400MHz): δ 0.98 (d, 3H), 1.08 (s, 9H), 1.78 (m, 1H), 1.98 (m, 1H), 2.38 (m, 1H), 2.97 (t, 1H), 4.02 (d, 1H), 5.26 (s, 1H), 7.24 (m, 4H).

LCMS(ESI)：[M-tBu]+ m/z：計算值307.8；實測值252.0；Rt=1.829min。LCMS (ESI): [M-tBu] + m/z: calculated 307.8; found 252.0; Rt=1.829 min.

步驟2：6-(4-氯苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(4-Chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(4-氯苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.2g，10.40mmol)溶解於三氟乙酸(22.56g，197.87mmol，15.24mL)中。將所得溶液在25℃下攪拌1h，然後添加碎冰(20g)且將pH用氫氧化鈉珠粒(10.40g，259.90mmol，4.88mL)於水(50ml)中之溶液調節至10。將所得混濁溶液轉移至分液漏斗且用二氯甲烷(2*50ml)萃取。將經合併之有機萃取物用水(20ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色膠狀物之6-(4-氯苯基)-3-甲基-2,3,4,5-四氫吡啶(2.1g，10.11mmol，97.26%產率)。6-(4-Chlorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.2 g, 10.40 mmol) was dissolved in trifluoroacetic acid (22.56 g, 197.87 mmol, 15.24 mL). The resulting solution was stirred at 25°C for 1 h, then crushed ice (20 g) was added and the pH was adjusted to 10 with a solution of sodium hydroxide beads (10.40 g, 259.90 mmol, 4.88 mL) in water (50 ml). The resulting cloudy solution was transferred to a separatory funnel and extracted with dichloromethane (2*50ml). The combined organic extracts were washed with water (20 ml), dried over sodium sulfate and evaporated in vacuo to give 6-(4-chlorophenyl)-3-methyl-2,3 as a yellow gum 4,5-Tetrahydropyridine (2.1 g, 10.11 mmol, 97.26% yield).

1 H NMR(CDCl3 ,500MHz)：δ 1.0(d,3H),1.30(m,1H),1.70(m,1H),1.95(m,1H),2.50(m,1H),2.70(d,1H),3.20(m,1H),4.00(d,1H),7.33(d,2H),7.73(d,2H)。 1 H NMR (CDCl 3 , 500MHz): δ 1.0 (d, 3H), 1.30 (m, 1H), 1.70 (m, 1H), 1.95 (m, 1H), 2.50 (m, 1H), 2.70 (d, 1H), 3.20 (m, 1H), 4.00 (d, 1H), 7.33 (d, 2H), 7.73 (d, 2H).

LCMS(ESI)：[M+1]+ m/z：計算值207.0；實測值208.0；Rt=0.89min。LCMS (ESI): [M+1] + m/z: calculated 207.0; found 208.0; Rt=0.89 min.

步驟3：2-(4-氯苯基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(4-Chlorophenyl)-5-methylpiperidine

在0℃下，將硼氫化鈉(764.98mg，20.22mmol，714.94μL)一次性添加到6-(4-氯苯基)-3-甲基-2,3,4,5-四氫吡啶(2.1g，10.11mmol)於甲醇(20mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈無色油狀物之2-(4-氯苯基)-5-甲基哌啶(1.9g，9.06mmol，89.61%產率)，其直接用於下一步驟中。Sodium borohydride (764.98 mg, 20.22 mmol, 714.94 μL) was added in one portion to 6-(4-chlorophenyl)-3-methyl-2,3,4,5-tetrahydropyridine ( 2.1 g, 10.11 mmol) in a stirred solution of methanol (20 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-(4-chlorophenyl)-5-methylpiperidine (1.9 g, 9.06 mmol, 89.61%) as a colorless oil yield), which was used directly in the next step.

1 H NMR(CDCl3 ,400MHz)：δ 0.80(d,3H),1.15(m,1H),1.45(m,1H),1.60(brs,1H),1.75(m,1H),1.85(m,1H),2.38(t,1H),3.11(d,1H),3.50(d,1H),7.30(m,4H)。 1 H NMR (CDCl 3 , 400MHz): δ 0.80 (d, 3H), 1.15 (m, 1H), 1.45 (m, 1H), 1.60 (brs, 1H), 1.75 (m, 1H), 1.85 (m, 1H), 2.38 (t, 1H), 3.11 (d, 1H), 3.50 (d, 1H), 7.30 (m, 4H).

LCMS(ESI)：[M+1]+ m/z：計算值209.2；實測值210.2；Rt=0.861min。LCMS (ESI): [M+1] + m/z: calculated 209.2; found 210.2; Rt=0.861 min.

步驟4：5-[[2-[(2S,5R)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物212 )之合成Step 4: 5-[[2-[(2S,5R)-2-(4-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Synthesis of pyridine-3-carboxamide ( compound 212 )

將三乙胺(1.21g，11.92mmol，1.66mL)添加到2-(4-氯苯基)-5-甲基哌啶(250mg，1.19mmol)(來自前一步驟之粗品)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(369.96mg，1.19mmol，N(C2H5)3)及HATU(498.60mg，1.31mmol)於DMF(4mL)之混合物中。將反應混合物在25℃下攪拌12h，然後提交至反相HPLC(管柱：YMC-Triart C18 100x20mm 5um，流動相：35-75% 1-6min 0.1% NH3 -甲醇)，以得到呈白色固體之化合物212 5-[[2-[(2S,5R)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(173mg，431.57μmol，36.20%產率)。Triethylamine (1.21 g, 11.92 mmol, 1.66 mL) was added to 2-(4-chlorophenyl)-5-methylpiperidine (250 mg, 1.19 mmol) (crude from previous step), 2-[ (5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (369.96 mg, 1.19 mmol, N(C2H5)3) and HATU (498.60 mg, 1.31 mmol) in DMF (4 mL) in the mixture. The reaction mixture was stirred at 25°C for 12h, then submitted to reverse phase HPLC (column: YMC-Triart C18 100x20mm 5um, mobile phase: 35-75% 1-6 min 0.1% NH3 -methanol) to give a white solid Compound 212 5-[[2-[(2S,5R)-2-(4-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (173 mg, 431.57 μmol, 36.20% yield).

1 H NMR(DMSO-d6 ,500MHz)：δ(ppm)1.03(m,3H),1.34(m,1H),1.66(m,1H),1.91(d,1H),2.14(m,2H),3.01(m,1H),3.76(m,1H),5.38(d,1H),7.41(m,4H),7.61(m,1H),8.17(m,1H),8.48(m,1H),8.83(m,2H),11.25(m,1H)。 1 H NMR (DMSO-d 6 , 500MHz): δ (ppm) 1.03 (m, 3H), 1.34 (m, 1H), 1.66 (m, 1H), 1.91 (d, 1H), 2.14 (m, 2H) ,3.01(m,1H),3.76(m,1H),5.38(d,1H),7.41(m,4H),7.61(m,1H),8.17(m,1H),8.48(m,1H), 8.83 (m, 2H), 11.25 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值400.2；實測值401.2；Rt=3.189minLCMS(ESI): [M+1] + m/z: Calculated 400.2; Measured 401.2; Rt=3.189min

步驟5：rel-5-[[2-[(2S,5R)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物570 ))及rel-5-[[2-[(2R,5S)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物569 )之合成Step 5: rel-5-[[2-[(2S,5R)-2-(4-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine yl]pyridine-3-carboxamide ( compound 570 )) and rel-5-[[2-[(2R,5S)-2-(4-chlorophenyl)-5-methyl-1-piperidinyl Synthesis of ]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( compound 569 )

對5-[[2-[(2S,5R)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(150mg，374.20μmol)進行掌性分離(體系：管柱：IA-I(250*20，5mkm)，流動相：己烷-IPA-MeOH，50-25-25；流速：13ml/min。24℃，波長：205nm，215nm)p-5-[[2-[(2S,5R)-2-(4-chlorophenyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (150mg, 374.20μmol) for chiral separation (system: column: IA-I (250*20, 5mkm), mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 13ml/min. 24℃, wavelength: 205nm, 215nm)

Rt1=14.03-順式雜質Rt1=14.03-cis impurity

Rt2=20.5-化合物569 Rt2=20.5- Compound 569

Rt3=27.1-化合物570 )Rt3=27.1- Compound 570 )

以獲得呈米色固體之化合物570 5-[[2-[(2S,5R)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(59.69mg，148.91μmol，39.79%產率)(RT(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)=30.693min)及呈米色固體之化合物569 5-[[2-[(2R,5S)-2-(4-氯苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(65.53mg，163.47μmol，43.69%產率)(RT(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)=23.405min)。to obtain compound 570 as a beige solid yl]amino]pyridine-3-carboxamide (59.69 mg, 148.91 μmol, 39.79% yield) (RT(IA, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 30.693 min ) and compound 569 as beige solid yl]amino]pyridine-3-carboxamide (65.53 mg, 163.47 μmol, 43.69% yield) (RT(IA, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min) = 23.405 min ).

化合物569： 1H NMR(600MHz,DMSO-d 6 )δ 0.98-1.07(m,3H),1.26-1.40(m,1H),1.56-1.70(m,1H),1.82-1.97(m,1H),2.00-2.13(m,1H),2.14-2.25(m,1H),2.76-3.25(m,1H),3.43-4.06(m,1H),5.11-5.63(m,1H),7.30-7.40(m,2H),7.39-7.48(m,2H),7.54-7.65(m,1H),8.09-8.20(m,1H),8.43-8.52(m,1H),8.72-8.80(m,1H),8.81-8.93(m,1H),11.13-11.40(m,1H)。 Compound 569: 1H NMR (600 MHz, DMSO- d 6 ) δ 0.98-1.07 (m, 3H), 1.26-1.40 (m, 1H), 1.56-1.70 (m, 1H), 1.82-1.97 (m, 1H), 2.00-2.13(m, 1H), 2.14-2.25(m, 1H), 2.76-3.25(m, 1H), 3.43-4.06(m, 1H), 5.11-5.63(m, 1H), 7.30-7.40(m ,2H),7.39-7.48(m,2H),7.54-7.65(m,1H),8.09-8.20(m,1H),8.43-8.52(m,1H),8.72-8.80(m,1H),8.81 -8.93(m, 1H), 11.13-11.40(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值400.2；實測值401.2；Rt=2.845minLCMS(ESI): [M+1] + m/z: Calculated value 400.2; Measured value 401.2; Rt=2.845min

化合物570： 1H NMR(600MHz,DMSO-d 6 )δ 0.99-1.07(m,3H),1.27-1.36(m,1H),1.56-1.70(m,1H),1.82-1.95(m,1H),2.02-2.14(m,1H),2.14-2.23(m,1H), 2.73-3.24(m,1H),3.45-4.04(m,1H),5.10-5.66(m,1H),7.29-7.39(m,2H),7.40-7.49(m,2H),7.54-7.67(m,1H),8.08-8.22(m,1H),8.40-8.51(m,1H),8.68-8.80(m,1H),8.80-8.94(m,1H),11.13-11.34(m,1H)。 Compound 570: 1H NMR (600 MHz, DMSO- d 6 ) δ 0.99-1.07 (m, 3H), 1.27-1.36 (m, 1H), 1.56-1.70 (m, 1H), 1.82-1.95 (m, 1H), 2.02-2.14(m,1H), 2.14-2.23(m,1H), 2.73-3.24(m,1H), 3.45-4.04(m,1H), 5.10-5.66(m,1H), 7.29-7.39(m ,2H),7.40-7.49(m,2H),7.54-7.67(m,1H),8.08-8.22(m,1H),8.40-8.51(m,1H),8.68-8.80(m,1H),8.80 -8.94(m, 1H), 11.13-11.34(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值400.2；實測值401.2；Rt=2.845minLCMS(ESI): [M+1] + m/z: Calculated value 400.2; Measured value 401.2; Rt=2.845min

實例746.N -(6-胺基-5-甲基吡啶-3-基)-2-(4-異丁醯基-2-(2-側氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-基)-2-側氧基乙醯胺(化合物854及化合物853)之合成Example 746. N- (6-amino-5-methylpyridin-3-yl)-2-(4-isobutyryl-2-(2-oxy-1,2,3,4-tetrahydroquinoline) Synthesis of Lin-6-yl)piperidin-1-yl)-2-oxoacetamide (Compound 854 and Compound 853)

Figure 110128222-A0202-12-2395-614
Figure 110128222-A0202-12-2395-614

步驟1：1-(2-氯吡啶-4-基)-2-甲基丙-1-醇之合成Step 1: Synthesis of 1-(2-chloropyridin-4-yl)-2-methylpropan-1-ol

在0℃、氬氣氣氛下，向2-氯吡啶-4-甲酸(13.6g，96.08mmol)於THF(100mL)中之經攪拌之溶液中逐滴添加氯(異丙基 )鎂(104.50g，135.27mmol，110mL，LiCl)。將所得溶液在同一溫度下攪拌30分鐘。使反應混合物升溫至室溫且在20℃下攪拌12h。將反應混合物用飽和NH4 Cl水溶液淬滅且用MTBE萃取。將有機層經Na2 SO4 乾燥，過濾且在減壓下蒸發。藉由管柱層析(梯度氯仿-乙腈，流速：65ml/min)純化粗產物，以獲得1-(2-氯-4-吡啶基)-2-甲基丙-1-醇(4.6g，24.78mmol，25.79%產率)。To a stirred solution of 2-chloropyridine-4-carboxylic acid (13.6 g, 96.08 mmol) in THF (100 mL) was added dropwise chloro( isopropyl )magnesium (104.50 g at 0 °C under argon atmosphere) , 135.27 mmol, 110 mL, LiCl). The resulting solution was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature and stirred at 20 °C for 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with MTBE. The organic layer was dried over Na2SO4 , filtered and evaporated under reduced pressure. The crude product was purified by column chromatography (gradient chloroform-acetonitrile, flow rate: 65 ml/min) to obtain 1-(2-chloro-4-pyridyl)-2-methylpropan-1-ol (4.6 g, 24.78 mmol, 25.79% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.70(d,6H),1.68(m,1H),4.15(m,1H),5.18(m,1H),7.14(m,2H),8.12(s,1H)。LCMS(ESI)：[M]+ m/z：計算值185.2；實測值186.2；Rt=0.991min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.70(d, 6H), 1.68(m, 1H), 4.15(m, 1H), 5.18(m, 1H), 7.14(m, 2H), 8.12(s, 1H). LCMS (ESI): [M] + m/z: calculated 185.2; found 186.2; Rt=0.991 min.

步驟2：6-(4-(1-羥基-2-甲基丙基)吡啶-2-基)-3,4-二氫喹啉-2(1H)-酮之合成Step 2: Synthesis of 6-(4-(1-hydroxy-2-methylpropyl)pyridin-2-yl)-3,4-dihydroquinolin-2(1H)-one

在氬氣下，向6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二 氫-1H -喹啉-2-酮(6.62g，24.24mmol)、1-(2-氯-4-吡啶基)-2-甲基丙-1-醇(4.5g，24.24mmol)及碳酸鈉(7.71g，72.72mmol，3.05mL)於二噁烷(90mL)及水(90mL)之混合物中之經攪拌之溶液中添加Pd(dppf)Cl2 *DCM(1.19g，1.45mmol)。將反應混合物在80℃下加熱12h。然後將反應混合物用水稀釋且用DCM萃取，經Na2 SO4 乾燥且在減壓下濃縮。藉由管柱層析(梯度己烷：CHCl3 )純化所獲得之粗產物，以得到6-[4-(1-羥基-2-甲基丙基)-2-吡啶基]-3,4-二氫-1H -喹啉-2-酮(1.8g，6.07mmol，25.06%產率)。Under argon, add 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2- yl )-3,4-dihydro-1H- Quinolin-2-one (6.62 g, 24.24 mmol), 1-(2-chloro-4-pyridyl)-2-methylpropan-1-ol (4.5 g, 24.24 mmol) and sodium carbonate (7.71 g, To a stirred solution of 72.72 mmol, 3.05 mL) in a mixture of dioxane (90 mL) and water (90 mL) was added Pd(dppf)Cl2*DCM (1.19 g , 1.45 mmol). The reaction mixture was heated at 80 °C for 12 h. The reaction mixture was then diluted with water and extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (gradient hexane: CHCl3 ) to give 6-[4-(1-hydroxy-2-methylpropyl)-2-pyridinyl]-3,4 -Dihydro- 1H -quinolin-2-one (1.8 g, 6.07 mmol, 25.06% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.94(d,6H),1.98(m,1H),2.42(m,2H),3.06(m,2H),4.28(m,1H),5.24(m,1H),6.86(m,1H),7.18(m,1H),7.66(m,1H),7.91(m,2H),8.48(m,1H),10.22(m,1H)。LCMS(ESI)：[M]+ m/z：計算值296.2；實測值297.2；Rt=0.852min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.94(d, 6H), 1.98(m, 1H), 2.42(m, 2H), 3.06(m, 2H), 4.28(m, 1H), 5.24(m, 1H), 6.86(m, 1H), 7.18(m, 1H), 7.66(m, 1H), 7.91(m, 2H), 8.48(m, 1H), 10.22(m, 1H). LCMS (ESI): [M] + m/z: calculated 296.2; found 297.2; Rt=0.852 min.

步驟3：6-(4-(1-羥基-2-甲基丙基)哌啶-2-基)-3,4-二氫喹啉-2(1H)-酮之合成Step 3: Synthesis of 6-(4-(1-hydroxy-2-methylpropyl)piperidin-2-yl)-3,4-dihydroquinolin-2(1H)-one

將6-[4-(1-羥基-2-甲基丙基)-2-吡啶基]-3,4-二氫-1H -喹啉-2-酮(900mg，3.04mmol)溶解於CH3 COOH(25mL)中。在壓力H2 (3.04mmol)40atm、20℃下，將起始材料經Pt/C(200mg)氫化16h。然後添加200mg Evonik Pt/C催化劑且在同一壓力、20℃下將反應混合物再氫化24h。然後添加250mg Evonik Pt/C催化劑且在同一壓力、20℃下將反應混合物再氫化24h。將反應混合物過濾且在真空中濃縮，以獲得6-[4-(1-羥基-2-甲基丙基)-2-哌啶基]-3,4-二氫-1H -喹啉-2-酮(1.2g，粗品，CH3 COOH)。6-[4-(1-Hydroxy-2-methylpropyl)-2-pyridinyl]-3,4-dihydro- 1H -quinolin-2-one (900 mg, 3.04 mmol) was dissolved in CH3 in COOH (25 mL). The starting material was hydrogenated over Pt/C (200 mg) under pressure H2 (3.04 mmol) 40 atm, 20 °C for 16 h. Then 200 mg of Evonik Pt/C catalyst was added and the reaction mixture was hydrogenated for a further 24 h at the same pressure at 20°C. Then 250 mg of Evonik Pt/C catalyst were added and the reaction mixture was hydrogenated for a further 24 h at the same pressure at 20°C. The reaction mixture was filtered and concentrated in vacuo to obtain 6-[4-(1-hydroxy-2-methylpropyl)-2-piperidinyl]-3,4-dihydro- 1H -quinoline-2 - Ketone (1.2 g, crude, CH3COOH ).

LCMS(ESI)：[M]+ m/z：計算值302.2；實測值303.2；Rt=0.871min。LCMS (ESI): [M] + m/z: calculated 302.2; found 303.2; Rt=0.871 min.

步驟4：4-(1-羥基-2-甲基丙基)-2-(2-側氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-甲酸第三丁酯之合成Step 4: 4-(1-Hydroxy-2-methylpropyl)-2-(2-oxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylic acid Synthesis of tertiary butyl ester

將6-[4-(1-羥基-2-甲基丙基)-2-哌啶基]-3,4-二氫-1H -喹啉-2-酮(1.5g，4.96mmol，CH3 COOH)及TEA(1.51g，14.88mmol，2.07mL)混合於DCM(40 mL)中，用冰水浴冷卻且逐滴添加於5ml DCM中之Boc2 O(1.19g，5.46mmol，1.25mL)，然後攪拌隔夜。將反應混合物用水洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到4-(1-羥基-2-甲基丙基)-2-(2-側氧基-3,4-二氫-1H -喹啉-6-基)哌啶-1-甲酸第三丁 酯(2.2g，粗品)。6-[4-(1-Hydroxy-2-methylpropyl)-2-piperidinyl]-3,4-dihydro- 1H -quinolin-2-one (1.5 g, 4.96 mmol, CH 3 COOH) and TEA (1.51 g, 14.88 mmol, 2.07 mL) were mixed in DCM (40 mL), cooled with an ice-water bath and Boc2O (1.19 g , 5.46 mmol, 1.25 mL) in 5 mL of DCM was added dropwise, Then stir overnight. The reaction mixture was washed with water, dried over Na 2 SO 4 and concentrated in vacuo to give 4-(1-hydroxy-2-methylpropyl)-2-(2-oxy-3,4-dihydro - 1H -Quinolin-6-yl)piperidine-1-carboxylic acid tert- butyl ester (2.2 g, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.80(d,6H),1.21(s,9H),1.36(m,1H),1.64(m,4H),2.39(m,2H),2.81(m,2H),3.13(m,1H),3.81(m,1H),4.31(m,1H),4.58(m,1H),6.75(d,1H),6.95(d,1H),6.99(s,1H),9.98(s,1H)。LCMS(ESI)：[M-Boc]+ m/z：計算值302.2；實測值303.2；Rt=1.389min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.80(d, 6H), 1.21(s, 9H), 1.36(m, 1H), 1.64(m, 4H), 2.39(m, 2H), 2.81(m, 2H), 3.13(m, 1H), 3.81(m, 1H), 4.31(m, 1H), 4.58(m, 1H), 6.75(d, 1H), 6.95(d, 1H), 6.99 (s, 1H), 9.98 (s, 1H). LCMS (ESI): [M-Boc] + m/z: calculated 302.2; found 303.2; Rt=1.389 min.

步驟5：4-異丁醯基-2-(2-側氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of 4-isobutyryl-2-(2-oxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylic acid tert-butyl ester

將4-(1-羥基-2-甲基丙基)-2-(2-側氧基-3,4-二氫-1H-喹啉-6-基)哌啶-1-甲酸第三丁 酯(1g，2.48mmol)溶解於無水DCM(30mL)中。添加氯鉻酸吡啶(1.07g，4.97mmol)且將反應混合物在20℃下攪拌隔夜。將反應混合物用水洗滌然後蒸發至乾。獲得4-(2-甲基丙醯基)-2-(2-側氧基-3,4-二氫-1H -喹啉-6-基)哌啶-1-甲酸第三丁 酯(1.5g，粗品)。4-(1-Hydroxy-2-methylpropyl)-2-(2-oxy-3,4-dihydro-1H-quinolin-6-yl)piperidine-1-carboxylic acid tertiary butyl The ester (1 g, 2.48 mmol) was dissolved in dry DCM (30 mL). Pyridine chlorochromate (1.07 g, 4.97 mmol) was added and the reaction mixture was stirred at 20 °C overnight. The reaction mixture was washed with water and evaporated to dryness. 4-(2-Methylpropionyl)-2-(2-oxy-3,4-dihydro- 1H -quinolin-6-yl)piperidine-1-carboxylic acid tert- butyl ester (1.5 g, crude product).

LCMS(ESI)：[M-Boc]+ m/z：計算值300.2；實測值301.2；Rt=1.249min。LCMS (ESI): [M-Boc] + m/z: calculated 300.2; found 301.2; Rt=1.249 min.

步驟6：6-(4-異丁醯基哌啶-2-基)-3,4-二氫喹啉-2(1H)-酮之合成Step 6: Synthesis of 6-(4-isobutyrylpiperidin-2-yl)-3,4-dihydroquinolin-2(1H)-one

將4-(2-甲基丙醯基)-2-(2-側氧基-3,4-二氫-1H -喹啉-6-基)哌啶-1-甲酸第三丁 酯(1.5g，3.75mmol)溶解於TFA(10g，3.75mmol)中且攪拌隔夜。然後將反應混合物在真空中濃縮至乾。將粗產物用碳酸氫鈉水溶液處理且將所需產物用EA萃取，經Na2 SO4 乾燥且在真空中蒸發，以得到6-[4-(2-甲基丙醯基)-2-哌啶基]-3,4-二氫-1H -喹啉-2-酮(200mg，粗品)。4-(2-Methylpropionyl)-2-(2-oxy-3,4-dihydro- 1H -quinolin-6-yl)piperidine-1-carboxylic acid tert- butyl ester (1.5 g, 3.75 mmol) was dissolved in TFA (10 g, 3.75 mmol) and stirred overnight. The reaction mixture was then concentrated to dryness in vacuo. The crude product was treated with aqueous sodium bicarbonate solution and the desired product was extracted with EA, dried over Na 2 SO 4 and evaporated in vacuo to give 6-[4-(2-methylpropionyl)-2-piperidine Peridyl]-3,4-dihydro- 1H -quinolin-2-one (200 mg, crude).

LCMS(ESI)：[M]+ m/z：計算值300.2；實測值301.2；Rt=0.809min。LCMS (ESI): [M] + m/z: calculated 300.2; found 301.2; Rt=0.809 min.

步驟7：(5-(2-(4-異丁醯基-2-(2-側氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-基)-2-側氧Step 7: (5-(2-(4-Isobutyryl-2-(2-oxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1-yl)-2 - side oxygen 基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Synthesis of tert-butyl acetamido)-3-methylpyridin-2-yl)carbamate

將6-[4-(2-甲基丙醯基)-2-哌啶基]-3,4-二氫-1H -喹啉-2-酮(200mg，665.79μmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(196.60mg，665.79μmol)、HATU(303.78mg，798.95μmol)及TEA(134.74mg，1.33mmol，185.60μL)混合於DMSO(2mL)中且在20℃下攪拌隔夜。使DMSO中之溶液經歷HPLC(50-75% R1-2-10min流速：30ml/min；裝載泵4ml/min MeOH管柱Sun Fire 100 x 19mm，5mkm)。獲得N -[3-甲基-5-[[2-[4-(2-甲基丙醯基)-2-(2-側氧基-3,4-二氫-1H -喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(109mg，188.69μmol，28.34%產率)。6-[4-(2-Methylpropionyl)-2-piperidinyl]-3,4-dihydro- 1H -quinolin-2-one (200 mg, 665.79 μmol), 2-[[6 -( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (196.60 mg, 665.79 μmol), HATU (303.78 mg, 798.95 μmol) and TEA (134.74 mg, 1.33 mmol, 185.60 μL) were mixed in DMSO (2 mL) and stirred at 20 °C overnight. The solution in DMSO was subjected to HPLC (50-75% R1-2-10min flow rate: 30ml/min; loading pump 4ml/min MeOH column Sun Fire 100 x 19mm, 5mkm). Obtained N- [3-methyl-5-[[2-[4-(2-methylpropionyl)-2-(2-oxy-3,4-dihydro- 1H -quinoline-6 -yl)-1-piperidinyl]-2-oxoacetoxy]amino]-2-pyridyl]carbamic acid tert -butyl ester (109 mg, 188.69 μmol, 28.34% yield).

LCMS(ESI)：[M]+ m/z：計算值577.2；實測值578.2；Rt=2.935min。LCMS (ESI): [M] + m/z: calculated 577.2; found 578.2; Rt=2.935 min.

步驟8：N-(6-胺基-5-甲基吡啶-3-基)-2-(4-異丁醯基-2-(2-側氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-基)-2-側氧基乙醯胺(化合物854 及化合物853 )之合成Step 8: N-(6-Amino-5-methylpyridin-3-yl)-2-(4-isobutyryl-2-(2-oxy-1,2,3,4-tetrahydroquinoline) Synthesis of olin-6-yl)piperidin-1-yl)-2-oxoacetamide ( compound 854 and compound 853 )

將N -[3-甲基-5-[[2-[4-(2-甲基丙醯基)-2-(2-側氧基-3,4-二氫-1H -喹啉-6-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(109mg，188.69μmol)溶解於二噁烷(1.5mL)及水(0.5mL)之混合物且在100℃下攪拌隔夜達12h。使溶液經歷HPLC(2-10min 10-40% MeCN/H2 O 30ml/min(裝載泵4ml MeCN)管柱：SunFire C18，5微米)。獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S )-4-(2-甲基丙醯基)-2-(2-側氧基-3,4-二氫-1H -喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(25.8mg，54.03μmol，28.63%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,4R )-4-(2-甲基丙醯基)-2-(2-側氧基-3,4-二氫-1H -喹啉-6-基)-1-哌啶基]-2-側氧基乙醯胺(25.5mg，53.40μmol，28.30%產率)。 N- [3-Methyl-5-[[2-[4-(2-methylpropionyl)-2-(2-oxy-3,4-dihydro- 1H -quinoline-6 -yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (109 mg, 188.69 μmol) was dissolved in dioxane (1.5 mL) and water (0.5 mL) and stirred at 100 °C overnight for 12 h. The solution was subjected to HPLC (2-10 min 10-40% MeCN/ H2O 30 ml/min (loading pump 4 ml MeCN) Column: SunFire C18, 5 microns). Obtained N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S )-4-(2-methylpropionyl)-2-(2-side oxy-3, 4-Dihydro- 1H -quinolin-6-yl)-1-piperidinyl]-2-oxyacetamide (25.8 mg, 54.03 μmol, 28.63% yield) and N-(6-amino) -5-Methyl-3-pyridyl)-2-[( 2S,4R )-4-(2-methylpropionyl)-2-(2-oxy-3,4-dihydro- 1H -Quinolin-6-yl)-1-piperidinyl]-2-oxoacetamide (25.5 mg, 53.40 μmol, 28.30% yield).

化合物854： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.91-0.98(m,6H),1.71-1.76(m,1H),1.78-1.89(m,1H),1.98-2.04(m,3H),2.16-2.32(m,1H),2.39-2.44(m,2H),2.80-2.88(m,3H),2.93-3.06(m,1H),3.40-3.72(m,1H),3.76-4.35(m,1H), 5.05-5.58(m,1H),5.59-5.75(m,2H),6.64-6.86(m,1H),6.86-7.05(m,1H),7.04-7.18(m,2H),7.41-7.54(m,1H),7.91-8.17(m,1H),9.98-10.08(m,1H),10.37-10.58(m,1H)。 Compound 854: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.91-0.98 (m, 6H), 1.71-1.76 (m, 1H), 1.78-1.89 (m, 1H), 1.98-2.04 (m ,3H),2.16-2.32(m,1H),2.39-2.44(m,2H),2.80-2.88(m,3H),2.93-3.06(m,1H),3.40-3.72(m,1H),3.76 -4.35(m, 1H), 5.05-5.58(m, 1H), 5.59-5.75(m, 2H), 6.64-6.86(m, 1H), 6.86-7.05(m, 1H), 7.04-7.18(m, 2H), 7.41-7.54 (m, 1H), 7.91-8.17 (m, 1H), 9.98-10.08 (m, 1H), 10.37-10.58 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值477.2；實測值478.2；Rt=1.783min。LCMS (ESI): [M] + m/z: calculated 477.2; found 478.2; Rt=1.783 min.

化合物853： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.88-1.00(m,6H),1.69-1.77(m,1H),1.79-1.87(m,1H),1.87-1.98(m,2H),1.98-2.06(m,3H),2.14-2.35(m,2H),2.36-2.45(m,2H),2.81-2.87(m,2H),2.91-3.04(m,1H),3.43-3.90(m,1H),5.03-5.08(m,1H),5.49-5.65(m,2H),6.67-6.79(m,1H),6.93-7.12(m,2H),7.11-7.55(m,1H),7.58-8.14(m,1H),9.95-10.51(m,2H)。 Compound 853: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.88-1.00 (m, 6H), 1.69-1.77 (m, 1H), 1.79-1.87 (m, 1H), 1.87-1.98 (m ,2H),1.98-2.06(m,3H),2.14-2.35(m,2H),2.36-2.45(m,2H),2.81-2.87(m,2H),2.91-3.04(m,1H),3.43 -3.90(m, 1H), 5.03-5.08(m, 1H), 5.49-5.65(m, 2H), 6.67-6.79(m, 1H), 6.93-7.12(m, 2H), 7.11-7.55(m, 1H), 7.58-8.14 (m, 1H), 9.95-10.51 (m, 2H).

LCMS(ESI)：[M]+ m/z：計算值477.2；實測值478.2；Rt=1.775min。LCMS (ESI): [M] + m/z: calculated 477.2; found 478.2; Rt=1.775 min.

實例747. N-(5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-四氫萘-6-基-1-哌啶基]-2-側氧基乙醯胺(化合物80)之合成Example 747. N-(5-Methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-tetrahydronaphthalen-6-yl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 80)

Figure 110128222-A0202-12-2399-615
Figure 110128222-A0202-12-2399-615

步驟1：5-甲基-2-(萘-2-基)吡啶之合成Step 1: Synthesis of 5-methyl-2-(naphthalen-2-yl)pyridine

將2-溴-5-甲基吡啶(3g，17.44mmol)及萘-2-基硼酸(3.60g，20.93mmol)溶解於二噁烷(40mL)及水(4mL)之混合物中。將所得混合物攪拌5min，隨後添加碳酸銫(14.21g，43.60mmol)及肆(三苯基磷烷)鈀(0)(87.20μmol)。然後，將反應燒瓶快速抽真空且用氬氣再填充。將所得混合物在65℃下攪拌12h。此後，將其冷卻且蒸發。將殘餘物分配於EtOAc(100mL)與水(100mL)之間。收 集有機相，將其經Na2 SO4 乾燥且蒸發。使殘餘物經歷管柱層析，以獲得5-甲基-2-(萘-2-基)吡啶(0.7g，3.19mmol，18.30%產率)。2-Bromo-5-methylpyridine (3 g, 17.44 mmol) and naphth-2-ylboronic acid (3.60 g, 20.93 mmol) were dissolved in a mixture of dioxane (40 mL) and water (4 mL). The resulting mixture was stirred for 5 min, followed by the addition of cesium carbonate (14.21 g, 43.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (87.20 μmol). Then, the reaction flask was quickly evacuated and refilled with argon. The resulting mixture was stirred at 65 °C for 12 h. After that, it was cooled and evaporated. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic phase was collected, dried over Na2SO4 and evaporated. The residue was subjected to column chromatography to obtain 5-methyl-2-(naphthalen-2-yl)pyridine (0.7 g, 3.19 mmol, 18.30% yield).

1 H NMR(400MHz,CDCl3 )δ 2.388(s,3H),7.46(m,2H),7.59(d,1H),7.77(m,1H),7.84(m,1H),7.92(m,2H),8.11(m,1H),8.44(d,1H),8.56(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 2.388(s, 3H), 7.46(m, 2H), 7.59(d, 1H), 7.77(m, 1H), 7.84(m, 1H), 7.92(m, 2H) ), 8.11(m, 1H), 8.44(d, 1H), 8.56(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值219.1；實測值220.2；Rt=1.217min。LCMS (ESI): [M+H] + m/z: calculated 219.1; found 220.2; Rt=1.217 min.

步驟2：5-甲基-2-四氫萘-6-基哌啶之合成Step 2: Synthesis of 5-methyl-2-tetrahydronaphthalen-6-ylpiperidine

將乾燥的487型鈀(10%於碳上)(33.97mg，319.23μmol)添加到5-甲基-2-(2-萘基)吡啶(0.7g，3.19mmol)於MeOH(10mL)中之溶液中。將所得混合物在50atm壓力及80℃下氫化12h。在起始材料消耗(HNMR對照)之後，將所得混合物冷卻至室溫且過濾。將濾液蒸發至乾，以獲得5-甲基-2-四氫萘-6-基哌啶(0.35g，1.53mmol，47.80%產率)。Dry palladium Form 487 (10% on carbon) (33.97 mg, 319.23 μmol) was added to 5-methyl-2-(2-naphthyl)pyridine (0.7 g, 3.19 mmol) in MeOH (10 mL) in solution. The resulting mixture was hydrogenated at 50 atm pressure and 80 °C for 12 h. After consumption of starting material (HNMR control), the resulting mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness to obtain 5-methyl-2-tetrahydronaphthalen-6-ylpiperidine (0.35 g, 1.53 mmol, 47.80% yield).

1 H NMR(400MHz,DMSO-d6 )δ 0.82(m,3H),1.15(m,1H),1.34(m,1H),1.62(m,2H),1.76(m,6H),2.28(m,1H),2.61(m,4H),2.98(m,1H),3.48(m,1H),6.94(m,1H),7.10(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.82(m, 3H), 1.15(m, 1H), 1.34(m, 1H), 1.62(m, 2H), 1.76(m, 6H), 2.28(m , 1H), 2.61 (m, 4H), 2.98 (m, 1H), 3.48 (m, 1H), 6.94 (m, 1H), 7.10 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值229.1；實測值230.2；Rt=1.01min。LCMS (ESI): [M+H] + m/z: calculated 229.1; found 230.2; Rt=1.01 min.

步驟3：N-(5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-四氫萘-6-基-1-哌啶基]-2-側氧基乙醯胺(化合物80 )之合成Step 3: N-(5-Methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-tetrahydronaphthalen-6-yl-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 80 )

在-78℃下，將丁基鋰(195.50mg，3.05mmol)(2.5M於己烷中)逐滴添加到5-甲基-2-四氫萘-6-基哌啶(350.00mg，1.53mmol)於THF(30mL)中之溶液中。將所得混合物攪拌5min，隨後添加2-[(5-甲基-3-吡啶基)胺基]-2-側氧基乙酸2,2,2-三氟乙酯(400.09mg，1.53mmol)。將所得混合物升溫至室溫且在該溫度下攪拌12h。添加NH4 Cl(0.6g)水溶液。將所得混合物蒸發至乾。藉由HPLC(58% 0.5-6.5min；水-乙腈為流動相；流速30mL/min；(裝載泵4mL/min乙腈)；目標質量391；管柱SunFire 100* 19mm 5um)純化殘餘物(1g)，以獲得N-(5-甲基-3-吡 啶基)-2-[(2S,5R)-5-甲基-2-四氫萘-6-基-1-哌啶基]-2-側氧基乙醯胺(0.027g，68.96μmol，4.52%產率)。At -78°C, butyllithium (195.50 mg, 3.05 mmol) (2.5 M in hexanes) was added dropwise to 5-methyl-2-tetrahydronaphthalen-6-ylpiperidine (350.00 mg, 1.53 mmol) in THF (30 mL). The resulting mixture was stirred for 5 min, followed by the addition of 2-[(5-methyl-3-pyridinyl)amino]-2-oxoacetic acid 2,2,2-trifluoroethyl ester (400.09 mg, 1.53 mmol). The resulting mixture was warmed to room temperature and stirred at this temperature for 12 h. Aqueous NH4Cl (0.6 g) was added. The resulting mixture was evaporated to dryness. The residue (1 g) was purified by HPLC (58% 0.5-6.5 min; water-acetonitrile as mobile phase; flow rate 30 mL/min; (loading pump 4 mL/min acetonitrile); target mass 391; column SunFire 100 * 19mm 5um) , to obtain N-(5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-tetrahydronaphthalen-6-yl-1-piperidinyl]-2- Pendant oxyacetamide (0.027 g, 68.96 μmol, 4.52% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.03(m,3H),1.33(m,1H),1.72(m,5H),1.94(m,2H),2.19(m,1H),2.28(m,3H),2.70(m,4H),2.89(m,1H),3.43(m,1H),5.30(m,1H),7.03(m,3H),7.91(m,1H),8.17(m,1H),8.59(m,1H),11.03(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.03(m, 3H), 1.33(m, 1H), 1.72(m, 5H), 1.94(m, 2H), 2.19(m, 1H), 2.28(m ,3H),2.70(m,4H),2.89(m,1H),3.43(m,1H),5.30(m,1H),7.03(m,3H),7.91(m,1H),8.17(m, 1H), 8.59 (m, 1H), 11.03 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值391.2；實測值392.4；Rt=3.68min。LCMS (ESI): [M+H] + m/z: calculated 391.2; found 392.4; Rt=3.68 min.

實例748.外消旋 -N -(6-胺基-5-甲基吡啶-3-基)-2-((2R ,5S )-5-甲基-2-(2-甲基嘧啶-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物107)之合成Example 748. Racemic - N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R , 5S )-5-methyl-2-(2-methylpyrimidine-5 Synthesis of -yl)piperidin-1-yl)-2-oxoacetamide (Compound 107)

Figure 110128222-A0202-12-2401-456
Figure 110128222-A0202-12-2401-456

步驟1：3-甲基-6-(2-甲基嘧啶-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(2-methylpyrimidin-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(9g，26.06mmol)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶(7.17g，32.58mmol)及碳酸鈉(8.29g，78.19mmol，3.28mL)添加到1,4-二噁烷(75mL)及水(25mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(850.65mg，1.04mmol)。將反應混合物在氬氣、70℃下攪拌12h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析使用二氯甲烷/MTBE梯度(0-100% MTBE)純化殘餘物，以得到呈淡棕色固體之3-甲基-6-(2-甲基嘧啶-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(4.5g，15.55mmol，59.67%產 率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (9 g, 26.06 mmol), 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine (7.17g, 32.58mmol) and sodium carbonate (8.29g, 78.19g) mmol, 3.28 mL) was added to a mixture of 1,4-dioxane (75 mL) and water (25 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM ( 850.65 mg, 1.04 mmol) was added under argon. The reaction mixture was stirred under argon at 70 °C for 12 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo, and the residue was purified by silica gel column chromatography using a dichloromethane/MTBE gradient (0-100% MTBE) to give 3-methyl-6-(2-methylmethane as a light brown solid pyrimidin-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (4.5 g, 15.55 mmol, 59.67% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.98(d,3H),1.22(s,9H),1.98(m,1H),2.03(m,1H),2.42(m,1H),2.73(s,3H),3.06(m,1H),4.07(d,1H),5.36(m,1H),8.52(s,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.98(d, 3H), 1.22(s, 9H), 1.98(m, 1H), 2.03(m, 1H), 2.42(m, 1H), 2.73( s, 3H), 3.06 (m, 1H), 4.07 (d, 1H), 5.36 (m, 1H), 8.52 (s, 2H).

LCMS(ESI)：[M+1]m/z：計算值289.3；實測值290.2；Rt=1.389min。LCMS (ESI): [M+1] m/z: calculated 289.3; found 290.2; Rt=1.389 min.

步驟2：2-甲基-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)嘧啶之合成Step 2: Synthesis of 2-methyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)pyrimidine

將3-甲基-6-(2-甲基嘧啶-5-基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.6g，5.53mmol)溶解於三氟乙酸(12g，105.24mmol，8.11mL)中。將所得溶液在25℃下攪拌1h，然後添加碎冰(20g)且將pH用氫氧化鈉珠粒(6.63g，165.88mmol，3.11mL)於水(50ml)中之溶液調節至10。將所得混濁溶液轉移至分液漏斗且用二氯甲烷(2*50ml)萃取。將經合併之有機萃取物用水(20ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)嘧啶(0.9g，4.76mmol，86.01%產率)。3-Methyl-6-(2-methylpyrimidin-5-yl)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (1.6 g, 5.53 mmol) was dissolved in trifluoroacetic acid (12 g, 105.24 mmol, 8.11 mL). The resulting solution was stirred at 25°C for 1 h, then crushed ice (20 g) was added and the pH was adjusted to 10 with a solution of sodium hydroxide beads (6.63 g, 165.88 mmol, 3.11 mL) in water (50 ml). The resulting cloudy solution was transferred to a separatory funnel and extracted with dichloromethane (2*50ml). The combined organic extracts were washed with water (20ml), dried over sodium sulfate and evaporated in vacuo to give 2-methyl-5-(3-methyl-2,3,4,5- as a yellow solid Tetrahydropyridin-6-yl)pyrimidine (0.9 g, 4.76 mmol, 86.01% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.98(d,3H),1.42(m,1H),1.68(m,1H),1.95(m,1H),2.52(m,1H),2.68(m,1H),2.76(s,3H),3.27(m,1H),4.04(m,1H),8.98(s,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.98(d,3H), 1.42(m,1H), 1.68(m,1H), 1.95(m,1H), 2.52(m,1H), 2.68( m, 1H), 2.76 (s, 3H), 3.27 (m, 1H), 4.04 (m, 1H), 8.98 (s, 2H).

LCMS(ESI)：[M+1]m/z：計算值189.2；實測值190.2；Rt=0.682min。LCMS (ESI): [M+1] m/z: calculated 189.2; found 190.2; Rt=0.682 min.

步驟3：2-甲基-5-(5-甲基哌啶-2-基)嘧啶之合成Step 3: Synthesis of 2-methyl-5-(5-methylpiperidin-2-yl)pyrimidine

在0℃下，將硼氫化鈉(107.95mg，2.85mmol，100.88μL)一次性添加到2-甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)嘧啶(0.9g，4.76mmol)於甲醇(15mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之2-甲基-5-(5-甲基-2-哌啶基)嘧啶(0.82g，4.29mmol，90.15%產率)，其直接用於下一步驟中。Sodium borohydride (107.95 mg, 2.85 mmol, 100.88 μL) was added in one portion to 2-methyl-5-(3-methyl-2,3,4,5-tetrahydropyridine-6-) at 0 °C pyrimidine (0.9 g, 4.76 mmol) in a stirred solution of methanol (15 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 2-methyl-5-(5-methyl-2-piperidinyl)pyrimidine (0.82 g, 4.29 mmol, 2-methyl-5-(5-methyl-2-piperidinyl)pyrimidine) as a yellow solid 90.15% yield), which was used directly in the next step.

1 H NMR(400MHz,CDCl3 )δ(ppm)0.88(d,3H),1.21(m,1H),1.68(m,5H),2.39(m,1H),2.71(s,3H),3.15(m,1H),3.57(m,1H),8.65(s,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.88(d, 3H), 1.21(m, 1H), 1.68(m, 5H), 2.39(m, 1H), 2.71(s, 3H), 3.15( m, 1H), 3.57 (m, 1H), 8.65 (s, 2H).

LCMS(ESI)：[M+1]m/z：計算值191.2；實測值192.2；Rt=0.634min。LCMS (ESI): [M+1] m/z: calculated 191.2; found 192.2; Rt=0.634 min.

步驟4：外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(2-甲基嘧啶-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物107 )之合成Step 4: Racemic-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-methylpyrimidine-5 Synthesis of -yl)piperidin-1-yl)-2-side oxyacetamide ( compound 107 )

將TEA(1.16g，11.50mmol，1.60mL)添加到2-甲基-5-(5-甲基-2-哌啶基)嘧啶(220mg，1.15mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(339.64mg，1.15mmol)及HATU(481.07mg，1.27mmol)於DMF(15mL)之混合物中。將反應混合物在25℃下攪拌1h，然後在真空中蒸發。將殘餘物溶解於DCM(20mL)中且添加於二噁烷中之4.0M氯化氫溶液(15.09g，57.51mmol，18.86mL，13.9%純度)。將所得混合物在25℃下攪拌1h，然後再次在真空中蒸發。藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um)使用30-40% 0-5min 0.1% NH3 -甲醇作為流動相進行第一次HPLC且使用30-35% 0-6min 0.1% NH3 -MeCN進行第二次HPLC來純化殘餘物，以得到呈白色固體之化合物107 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-(2-甲基嘧啶-5-基)-1-哌啶基]-2-側氧基乙醯胺(20mg，54.28μmol，4.72%產率)。TEA (1.16 g, 11.50 mmol, 1.60 mL) was added to 2-methyl-5-(5-methyl-2-piperidinyl)pyrimidine (220 mg, 1.15 mmol), 2-[[6-( third Butoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (339.64 mg, 1.15 mmol) and HATU (481.07 mg, 1.27 mmol) in DMF (15 mL) in the mixture. The reaction mixture was stirred at 25°C for 1 h, then evaporated in vacuo. The residue was dissolved in DCM (20 mL) and a 4.0 M solution of hydrogen chloride in dioxane (15.09 g, 57.51 mmol, 18.86 mL, 13.9% pure) was added. The resulting mixture was stirred at 25°C for 1 h, then evaporated again in vacuo. The first HPLC was performed by reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um) using 30-40% 0-5 min 0.1% NH3 -methanol as mobile phase and 30-35% 0-6 min 0.1% NH 3 -MeCN was subjected to a second HPLC to purify the residue to give compound 107 as a white solid N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-5 - Methyl-2-(2-methylpyrimidin-5-yl)-1-piperidinyl]-2-oxyacetamide (20 mg, 54.28 μmol, 4.72% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.08(m,3H),1.42(m,1H),1.79(m,1H),1.99(m,1H),2.12(m,5H),2.69(s,3H),3.07(m,1H),4.63(m,3H),6.07(m,1H),7.67(s,1H),8.01(s,1H),8.55(m,2H),9.27(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.08(m, 3H), 1.42(m, 1H), 1.79(m, 1H), 1.99(m, 1H), 2.12(m, 5H), 2.69( s,3H),3.07(m,1H),4.63(m,3H),6.07(m,1H),7.67(s,1H),8.01(s,1H),8.55(m,2H),9.27(m , 1H).

LCMS(ESI)：[M+1]m/z：計算值368.4；實測值369.2；Rt=1.992min。LCMS (ESI): [M+1] m/z: calculated 368.4; found 369.2; Rt=1.992 min.

實例749.外消旋 -N -(6-胺基-5-甲基吡啶-3-基)-2-((2R ,5S )-5-甲基-2-(嘧啶-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物109)之合成Example 749. Racemic - N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R , 5S )-5-methyl-2-(pyrimidin-5-yl)piperidine Synthesis of pyridin-1-yl)-2-oxoacetamide (compound 109)

Figure 110128222-A0202-12-2404-457
Figure 110128222-A0202-12-2404-457

步驟1：3-甲基-6-(嘧啶-5-基)-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(pyrimidin-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(7g，20.27mmol)、嘧啶-5-基硼酸(3.27g，26.35mmol)及碳酸鈉(6.45g，60.81mmol，2.55mL)添加到1,4-二噁烷(90mL)及水(30mL)之混合物中。將所得混合物抽真空然後用氬氣回填，將此操作重複三次，然後在氬氣下添加Pd(dppf)Cl2 *DCM(827.02mg，1.01mmol)。將反應混合物在氬氣、75℃下攪拌12h，然後冷卻且過濾。將濾餅用1,4-二噁烷(2*20ml)洗滌且丟棄。在真空中蒸發濾液，且藉由矽膠管柱層析使用DCM/MTBE梯度(0-100% MTBE)純化殘餘物，以得到呈淡棕色固體之3-甲基-6-嘧啶-5-基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.3g，11.98mmol，59.13%產率)。Combine 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (7 g, 20.27 mmol), pyrimidin-5-yl Boric acid (3.27 g, 26.35 mmol) and sodium carbonate (6.45 g, 60.81 mmol, 2.55 mL) were added to a mixture of 1,4-dioxane (90 mL) and water (30 mL). The resulting mixture was evacuated and backfilled with argon, this was repeated three times, then Pd(dppf)Cl2*DCM ( 827.02 mg, 1.01 mmol) was added under argon. The reaction mixture was stirred under argon at 75 °C for 12 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2*20ml) and discarded. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using a DCM/MTBE gradient (0-100% MTBE) to give 3-methyl-6-pyrimidin-5-yl- 3,4-Dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (3.3 g, 11.98 mmol, 59.13% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.03(d,3H),1.21(s,9H),1.98(m,1H),2.04(m,1H),2.42(m,1H),3.07(m,1H),4.08(m,1H),5.41(d,1H),8.64(s,2H),9.09(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.03(d, 3H), 1.21(s, 9H), 1.98(m, 1H), 2.04(m, 1H), 2.42(m, 1H), 3.07( m, 1H), 4.08 (m, 1H), 5.41 (d, 1H), 8.64 (s, 2H), 9.09 (s, 1H).

LCMS(ESI)：[M+1]m/z：計算值275.3；實測值276.2；Rt=1.371min。LCMS (ESI): [M+1] m/z: calculated 275.3; found 276.2; Rt=1.371 min.

步驟2：5-(5-甲基-3,4,5,6-四氫吡啶-2-基)嘧啶之合成Step 2: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)pyrimidine

將3-甲基-6-嘧啶-5-基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.7g，6.17mmol)溶解於三氟乙酸(14.08g，123.48mmol，9.51mL)中。將所得溶液在25℃下攪拌1h，然後添加碎冰(20g)且將pH用氫氧化鈉珠粒(7.41g，185.22mmol，3.48mL)於水(50ml)中之溶液調節至10。將所得混濁溶液轉移至分液漏斗且用二氯甲烷(2*50ml)萃取。將經合併之有機萃取物用水(20ml)洗滌，經硫酸鈉乾燥 且在真空中蒸發，以得到呈黃色油狀物之5-(3-甲基-2,3,4,5-四氫吡啶-6-基)嘧啶(1g，5.71mmol，92.43%產率)，其直接用於下一步驟中。3-Methyl-6-pyrimidin-5-yl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (1.7 g, 6.17 mmol) was dissolved in trifluoroacetic acid (14.08 g, 123.48 mmol) , 9.51mL). The resulting solution was stirred at 25°C for 1 h, then crushed ice (20 g) was added and the pH was adjusted to 10 with a solution of sodium hydroxide beads (7.41 g, 185.22 mmol, 3.48 mL) in water (50 ml). The resulting cloudy solution was transferred to a separatory funnel and extracted with dichloromethane (2*50ml). The combined organic extracts were washed with water (20ml), dried over sodium sulfate and evaporated in vacuo to give 5-(3-methyl-2,3,4,5-tetrahydropyridine as a yellow oil -6-yl)pyrimidine (1 g, 5.71 mmol, 92.43% yield), which was used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.02(d,3H),1.46(m,1H),1.69(m,1H),1.95(m,1H),2.59(m,1H),2.75(m,1H),3.28(m,1H),4.05(m,1H),9.08(s,2H),9.21(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.02(d,3H), 1.46(m,1H), 1.69(m,1H), 1.95(m,1H), 2.59(m,1H), 2.75( m, 1H), 3.28 (m, 1H), 4.05 (m, 1H), 9.08 (s, 2H), 9.21 (s, 1H).

LCMS(ESI)：[M+1]m/z：計算值175.2；實測值176.2；Rt=0.555min。LCMS (ESI): [M+1] m/z: calculated 175.2; found 176.2; Rt=0.555 min.

步驟3：5-(5-甲基哌啶-2-基)嘧啶之合成Step 3: Synthesis of 5-(5-methylpiperidin-2-yl)pyrimidine

在0℃下，將硼氫化鈉(129.53mg，3.42mmol，121.06μL)一次性添加到5-(3-甲基-2,3,4,5-四氫吡啶-6-基)嘧啶(1g，5.71mmol)於甲醇(15mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌1h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用DCM(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到呈黃色固體之5-(5-甲基-2-哌啶基)嘧啶(0.8g，4.51mmol，79.09%產率)，其直接用於下一步驟中。Sodium borohydride (129.53 mg, 3.42 mmol, 121.06 μL) was added in one portion to 5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyrimidine (1 g at 0 °C) , 5.71 mmol) in a stirred solution of methanol (15 mL). The resulting mixture was stirred at 0 °C for 1 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with DCM (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl)pyrimidine (0.8 g, 4.51 mmol, 79.09% yield) as a yellow solid , which is used directly in the next step.

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.21(m,1H),1.68(m,5H),2.44(m,1H),3.17(m,1H),3.61(m,1H),8.75(s,2H),9.11(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d,3H), 1.21(m,1H), 1.68(m,5H), 2.44(m,1H), 3.17(m,1H), 3.61( m, 1H), 8.75 (s, 2H), 9.11 (s, 1H).

LCMS(ESI)：[M+1]m/z：計算值177.2；實測值178.2；Rt=0.573min。LCMS (ESI): [M+1] m/z: calculated 177.2; found 178.2; Rt=0.573 min.

步驟4：外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(嘧啶-5-基)哌啶-1-基)-2-側氧基乙醯胺(化合物109 )之合成Step 4: Racemic-N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(pyrimidin-5-yl)piperidine Synthesis of pyridin-1-yl)-2-oxoacetamide ( compound 109 )

將TEA(1.43g，14.10mmol，1.97mL)添加到5-(5-甲基-2-哌啶基)嘧啶(0.25g，1.41mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(458.15mg，1.55mmol)及HATU(589.93mg，1.55mmol)於DMF(15mL)之混合物中。將反應混合物在25℃下攪拌1h，然後在真空中蒸發。將殘餘物溶解於DCM(20mL)中且添加於二噁烷中之4.0M氯化氫溶液(18.50g，70.52mmol，23.12mL，13.9%純度)。將所得混合物在25℃下攪拌1h，然後再次在真空中蒸發。藉由反相HPLC(管柱：YMC Triart C18 100x20mm，5um)使用 30-30-50% 0-1-5min 0.1% NH3 -甲醇作為流動相純化殘餘物，以得到呈淡黃色泡沫之化合物109 N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-5-甲基-2-嘧啶-5-基-1-哌啶基]-2-側氧基乙醯胺(80mg，225.73μmol，16.00%產率)。TEA (1.43 g, 14.10 mmol, 1.97 mL) was added to 5-(5-methyl-2-piperidinyl)pyrimidine (0.25 g, 1.41 mmol), 2-[[6-( tert- butoxycarbonyl) amino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (458.15 mg, 1.55 mmol) and HATU (589.93 mg, 1.55 mmol) in DMF (15 mL). The reaction mixture was stirred at 25°C for 1 h, then evaporated in vacuo. The residue was dissolved in DCM (20 mL) and a 4.0 M solution of hydrogen chloride in dioxane (18.50 g, 70.52 mmol, 23.12 mL, 13.9% pure) was added. The resulting mixture was stirred at 25°C for 1 h, then evaporated again in vacuo. The residue was purified by reverse phase HPLC (column: YMC Triart C18 100x20mm, 5um) using 30-30-50% 0-1-5 min 0.1% NH3 -methanol as mobile phase to give compound 109 as a pale yellow foam N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S,5R )-5-methyl-2-pyrimidin-5-yl-1-piperidinyl]-2- Pendant oxyacetamide (80 mg, 225.73 μmol, 16.00% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.10(m,3H),1.44(m,1H),1.84(m,1H),2.01(m,1H),2.11(m,3H),2.24(m,2H),3.08(m,1H),4.69(m,3H),6.16(m,1H),7.69(s,1H),8.03(s,1H),8.69(m,2H),9.18(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.10(m, 3H), 1.44(m, 1H), 1.84(m, 1H), 2.01(m, 1H), 2.11(m, 3H), 2.24( m, 2H), 3.08(m, 1H), 4.69(m, 3H), 6.16(m, 1H), 7.69(s, 1H), 8.03(s, 1H), 8.69(m, 2H), 9.18(m , 2H).

LCMS(ESI)：[M+1]m/z：計算值354.4；實測值355.2；Rt=1.830min。LCMS (ESI): [M+1] m/z: calculated 354.4; found 355.2; Rt=1.830 min.

實例750. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(1-羥基-1-甲基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物672)之合成Example 750. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(1-hydroxy-1-methylethyl)phenyl ]-5-Methyl-1-piperidinyl]-2-oxoacetamide (Compound 672) Synthesis

Figure 110128222-A0202-12-2406-458
Figure 110128222-A0202-12-2406-458

步驟1：2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]丙-2-醇之合成Step 1: Synthesis of 2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]propan-2-ol

在氬氣氣氛、-80℃下，向(2R,5S)-2-(4-溴苯基)-5-甲基哌啶(300mg，1.18mmol)於四氫呋喃(10mL)中之經攪拌之溶液中逐滴添加第三丁基鋰(標稱1.5M於正戊烷中)(1.65g，3.78mmol，2.52mL，14.7%純度)。將所得溶液在同一溫度下攪拌40min分鐘。然後，將丙酮(274.21mg，4.72mmol，346.66μL)逐滴添加到溶液中。使所得反應混合物升溫至室溫且用20%NH4 Cl水溶液(15ml)淬滅。將所得混合物用乙酸乙酯(20ml)萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下蒸發，得到2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]丙-2-醇(290mg，粗品)。To a stirred solution of (2R,5S)-2-(4-bromophenyl)-5-methylpiperidine (300 mg, 1.18 mmol) in tetrahydrofuran (10 mL) under argon atmosphere at -80 °C To this was added tert-butyllithium (nominal 1.5M in n-pentane) (1.65 g, 3.78 mmol, 2.52 mL, 14.7% purity). The resulting solution was stirred at the same temperature for 40 min. Then, acetone (274.21 mg, 4.72 mmol, 346.66 μL) was added dropwise to the solution. The resulting reaction mixture was warmed to room temperature and quenched with 20% aqueous NH4Cl (15 ml). The resulting mixture was extracted with ethyl acetate (20 ml). The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 2-[ 4 -[(2R,5S)-5-methyl-2-piperidinyl]phenyl]propan-2-ol (290 mg, crude).

1 H NMR(CDCl3 ,400MHz)：0.85(d,3H),1.28(m,2H),1.23(s,3H),1.55(s,3H),1.88(m,1H),1.87(m,2H),2.39(t,1H),2.60(s,1H),3.10(m,1H),3.53(m,1H),7.34(m,2H),7.42(m,2H)，未觀測到NH。 1 H NMR (CDCl 3 , 400MHz): 0.85(d,3H), 1.28(m,2H), 1.23(s,3H), 1.55(s,3H), 1.88(m,1H), 1.87(m,2H) ), 2.39(t, 1H), 2.60(s, 1H), 3.10(m, 1H), 3.53(m, 1H), 7.34(m, 2H), 7.42(m, 2H), no NH was observed.

LCMS(ESI)：[M+H]+ m/z：計算值233.2；實測值234.2；Rt=0.843min。LCMS (ESI): [M+H] + m/z: calculated 233.2; found 234.2; Rt=0.843 min.

步驟2：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(1-羥基-1-甲基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物672 )之合成Step 2: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(1-hydroxy-1-methylethyl)phenyl Synthesis of ]-5-methyl-1-piperidinyl]-2-oxoacetamide ( Compound 672 )

向2-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]丙-2-醇(290mg，1.24mmol)、2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙酸(260mg，1.33mmol)及三乙胺(251.51mg，2.49mmol，346.44μL)於二甲基甲醯胺(3mL)中之經攪拌之混合物中添加HATU(519.80mg，1.37mmol)。將所得反應混合物在20℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC-Actus Triart C18 100*20mml.D.S-5um；0-5min 20-70%水-MeOH(NH3 0.1%)，流速30ml/min)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(1-羥基-1-甲基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(200mg，487.20μmol，39.20%產率)。To 2-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]propan-2-ol (290 mg, 1.24 mmol), 2-[(6-amino-5- Methyl-3-pyridyl)amino]-2-oxoacetic acid (260 mg, 1.33 mmol) and triethylamine (251.51 mg, 2.49 mmol, 346.44 μL) in dimethylformamide (3 mL) To the stirred mixture was added HATU (519.80 mg, 1.37 mmol). The resulting reaction mixture was stirred at 20 °C for 4 h. Then, it was subjected to HPLC (column: YMC-Actus Triart C18 100*20mml. DS-5um; 0-5min 20-70% water-MeOH ( NH3 0.1%), flow rate 30ml/min) to give N-( 6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(1-hydroxy-1-methylethyl)phenyl]-5-methyl -1-Piperidinyl]-2-oxyacetamide (200 mg, 487.20 μmol, 39.20% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)1.00(m,3H),1.39(m,8H),1.67(m,1H),1.85(m,1H),1.97(m,4H),2.21(m,1H),2.70(m,1H),3.61(m,1H),4.95(s,1H),5.57(m,3H),7.23(m,2H),7.46(m,3H),7.98(m,1H),10.47(m,1H) 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 1.00(m, 3H), 1.39(m, 8H), 1.67(m, 1H), 1.85(m, 1H), 1.97(m, 4H), 2.21(m, 1H), 2.70(m, 1H), 3.61(m, 1H), 4.95(s, 1H), 5.57(m, 3H), 7.23(m, 2H), 7.46(m, 3H), 7.98 (m,1H),10.47(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值410.3；實測值411.2；Rt=1.475min。LCMS (ESI): [M+H] + m/z: calculated 410.3; found 411.2; Rt=1.475 min.

實例751. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(1-羥基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物956)之合成Example 751. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(1-hydroxyethyl)phenyl]-5-methyl Synthesis of yl-1-piperidinyl]-2-oxoacetamide (compound 956)

Figure 110128222-A0202-12-2408-459
Figure 110128222-A0202-12-2408-459

步驟1：1-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]乙醇之合成Step 1: Synthesis of 1-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]ethanol

將(2R,5S)-2-(4-溴苯基)-5-甲基哌啶(0.5g，1.97mmol)溶解於THF(10mL)中且冷卻，隨後添加丁基鋰(2.5M,786.89μL)且攪拌10min。在短暫延遲後，一次性添加甲醛(173.32mg，3.93mmol)且將反應混合物緩慢升溫至0℃，傾倒在NH4 Cl水溶液上且用EtOAc(20mL)萃取。蒸發有機溶劑，得到粗品1-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]乙醇(0.5g，粗品)，其不經純化即用於下一步驟中。(2R,5S)-2-(4-bromophenyl)-5-methylpiperidine (0.5 g, 1.97 mmol) was dissolved in THF (10 mL) and cooled, followed by addition of butyllithium (2.5 M, 786.89 μL) and stirred for 10 min. After a short delay, formaldehyde (173.32 mg, 3.93 mmol) was added in one portion and the reaction mixture was slowly warmed to 0 °C, poured onto aq . NH4Cl and extracted with EtOAc (20 mL). The organic solvent was evaporated to give crude 1-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]ethanol (0.5 g, crude) which was used in the next step without purification middle.

LCMS(ESI)：[M+H]+ m/z：計算值219.2；實測值220.2；Rt=0.701min。LCMS (ESI): [M+H] + m/z: calculated 219.2; found 220.2; Rt=0.701 min.

步驟2：N-[5-[[2-[(2R,5S)-2-[4-(1-羥基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 2: N-[5-[[2-[(2R,5S)-2-[4-(1-hydroxyethyl)phenyl]-5-methyl-1-piperidinyl]-2-side Synthesis of tert-butyl oxyacetyl]amino]-3-methyl-2-pyridyl]carbamate

在輕微加熱下，將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(419.24mg，1.42mmol)、1-[4-[(2R,5S)-5-甲基-2-哌啶基]苯基]乙醇(311.39mg，1.42mmol，185.76μL)及DIPEA(550.47mg，4.26mmol，741.88μL)溶解於DMSO(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(647.81mg，1.70mmol)。在反應完成之後，藉由HPLC(34-40% 0.5-5.5min水-乙腈；流 速30ml/min(裝載泵4ml/min乙腈)；目標質量496；管柱SunFireC18 100x19mm 5um(R))純化混合物，以得到N-[5-[[2-[(2R,5S)-2-[4-(1-羥基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(90mg，181.23μmol，12.76%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (419.24 mg, 1.42 mmol) was added with gentle heating , 1-[4-[(2R,5S)-5-methyl-2-piperidinyl]phenyl]ethanol (311.39 mg, 1.42 mmol, 185.76 μL) and DIPEA (550.47 mg, 4.26 mmol, 741.88 μL) Dissolved in DMSO (6 mL). With vigorous stirring and occasional heating, HATU (647.81 mg, 1.70 mmol) was added in small batches. After the reaction was complete, it was analyzed by HPLC (34-40% 0.5-5.5 min water-acetonitrile; flow Speed 30ml/min (load pump 4ml/min acetonitrile); target mass 496; column SunFireC18 100x19mm 5um(R)) purify the mixture to give N-[5-[[2-[(2R,5S)-2-[ 4-(1-Hydroxyethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid Tertiary butyl ester (90 mg, 181.23 μmol, 12.76% yield).

LCMS(ESI)：[M+H]+ m/z：計算值496.3；實測值497.2；Rt=3.130min。LCMS (ESI): [M+H] + m/z: calculated 496.3; found 497.2; Rt=3.130 min.

步驟3：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(1-羥基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物956 )之合成Step 3: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(1-hydroxyethyl)phenyl]-5-methyl Synthesis of base-1-piperidinyl]-2-oxoacetamide ( compound 956 )

將N-[5-[[2-[(2R,5S)-2-[4-(1-羥基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(80mg，136.93μmol)溶解於二噁烷(3mL)及h2o(1mL)中。將所獲得之溶液在100℃下攪拌3hr；在反應完成之後，使混合物經歷HPLC(19% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min乙腈)；目標質量396；管柱SunFireC18 100x19mm 5um(R))，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-2-[4-(1-羥基乙基)苯基]-5-甲基-1-哌啶基]-2-側氧基乙醯胺(35mg，88.28μmol，64.47%產率)N-[5-[[2-[(2R,5S)-2-[4-(1-hydroxyethyl)phenyl]-5-methyl-1-piperidinyl]-2-oxygen Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (80 mg, 136.93 μmol) was dissolved in dioxane (3 mL) and h2o (1 mL). The obtained solution was stirred at 100 °C for 3 hr; after the reaction was complete, the mixture was subjected to HPLC (19% 0.5-6.5 min water-acetonitrile; flow rate 30 ml/min (loading pump 4 ml/min acetonitrile); target mass 396; tube Column SunFire C18 100x19mm 5um(R)) to give N-(6-amino-5-methyl-3-pyridyl)-2-[(2R,5S)-2-[4-(1-hydroxyethyl) )phenyl]-5-methyl-1-piperidinyl]-2-oxyacetamide (35 mg, 88.28 μmol, 64.47% yield)

1 H NMR(600MHz,DMSO-d6)δ 0.97-1.01(m,3H),1.27-1.33(m,4H),1.60-1.67(m,1H),1.80-1.90(m,1H),1.95-2.04(m,4H),2.15-2.25(m,1H),2.67-3.21(m,1H),3.39-4.03(m,1H),4.67-5.10(m,2H),5.55(s,1H),5.56-5.63(m,2H),7.19-7.28(m,2H),7.29-7.35(m,2H),7.41-7.50(m,1H),7.93-8.04(m,1H),10.47(s,1H)。 1 H NMR (600MHz, DMSO-d6)δ 0.97-1.01(m,3H), 1.27-1.33(m,4H), 1.60-1.67(m,1H), 1.80-1.90(m,1H), 1.95-2.04 (m,4H),2.15-2.25(m,1H),2.67-3.21(m,1H),3.39-4.03(m,1H),4.67-5.10(m,2H),5.55(s,1H),5.56 -5.63(m, 2H), 7.19-7.28(m, 2H), 7.29-7.35(m, 2H), 7.41-7.50(m, 1H), 7.93-8.04(m, 1H), 10.47(s, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值396.3；實測值397.2；Rt=1.997min。LCMS (ESI): [M+H] + m/z: calculated 396.3; found 397.2; Rt=1.997 min.

實例752.N -(6-胺基-5-甲基吡啶-3-基)-2-((2R ,5S )-5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物478)之合成Example 752. N- (6-amino-5-methylpyridin-3-yl)-2-(( 2R , 5S )-5-methyl-2-(3,4,5-trifluorophenyl) Synthesis of piperidin-1-yl)-2-oxoacetamide (compound 478)

Figure 110128222-A0202-12-2410-460
Figure 110128222-A0202-12-2410-460

步驟1：3,4,5-三氟苯甲醯氯之合成Step 1: Synthesis of 3,4,5-Trifluorobenzyl chloride

將3,4,5-三氟苯甲酸(25g，141.97mmol)分批添加到亞硫醯氯(50.67g，425.91mmol)於CHCl3 (100mL)中之經攪拌之溶液中。將所得混合物在68℃下攪拌15h，然後在真空中蒸發。將殘餘物倒入到己烷(200ml)中且過濾。將濾液乾燥且在真空中蒸發，以得到3,4,5-三氟苯甲醯氯(22.1g，113.60mmol，80.02%產率)。3,4,5-Trifluorobenzoic acid (25 g, 141.97 mmol) was added portionwise to a stirred solution of thionine chloride (50.67 g, 425.91 mmol) in CHCl3 (100 mL). The resulting mixture was stirred at 68 °C for 15 h, then evaporated in vacuo. The residue was poured into hexane (200 ml) and filtered. The filtrate was dried and evaporated in vacuo to give 3,4,5-trifluorobenzyl chloride (22.1 g, 113.60 mmol, 80.02% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)7.79(s,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.79 (s, 2H).

LCMS(ESI)：[M]+ m/z：計算值194.2；實測值195.2；Rt=1.205min。LCMS (ESI): [M] + m/z: calculated 194.2; found 195.2; Rt=1.205 min.

步驟2：(5S)-5-甲基-2-側氧基-3-(3,4,5-三氟苯甲醯基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of (5S)-5-methyl-2-oxo-3-(3,4,5-trifluorobenzyl)piperidine-1-carboxylic acid tert-butyl ester

在Ar氣氛、-78℃下，向(5S )-5-甲基-2-側氧基哌啶-1-甲酸第三丁 酯(4.1g，19.22mmol)於THF(100mL)中之溶液中逐滴添加98%雙(三甲基矽基)醯胺化鈉(7.76g，42.29mmol，27mL)。使所得混合物攪拌1h。將3,4,5-三氟苯甲醯氯(4.11g，21.15mmol)逐滴添加到t -boc -內醯胺中，使內部溫度維持低於-70℃。將溶液升溫至且逐滴添加於水(20mL)中之硫酸氫鈉(10.16g，84.59mmol)。將水層用EtOAc萃取3 x 50mL且將有機層合併，經Na2 SO4 乾燥，過濾且在真空中濃縮。獲得呈黃色油狀物之(5S )-5-甲基-2-側氧基-3-(3,4,5-三氟苯甲醯基)哌啶-1-甲酸第三丁 酯(10.2g，粗品)且其不經進一步純化即用於下一步驟中。To a solution of ( 5S )-5-methyl-2-oxypiperidine-1-carboxylic acid tert- butyl ester (4.1 g, 19.22 mmol) in THF (100 mL) under Ar atmosphere at -78 °C Sodium bis(trimethylsilyl)amide 98% (7.76 g, 42.29 mmol, 27 mL) was added dropwise. The resulting mixture was stirred for 1 h. 3,4,5-Trifluorobenzyl chloride (4.11 g, 21.15 mmol) was added dropwise to the t - boc -lactamide maintaining the internal temperature below -70°C. The solution was warmed to and sodium bisulfate (10.16 g, 84.59 mmol) in water (20 mL) was added dropwise. The aqueous layer was extracted with EtOAc 3 x 50 mL and the organic layers were combined, dried over Na2SO4 , filtered and concentrated in vacuo. ( 5S )-5-methyl-2-pendoxyloxy-3-(3,4,5-trifluorobenzyl)piperidine-1-carboxylic acid tert- butyl ester (10.2 g, crude) and it was used in the next step without further purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.02(d,3H),1.56(s,9H),2.24(m,3H),3.26(m,2H),3.96(m,1H),7.17(s,1H),7.72(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(d, 3H), 1.56(s, 9H), 2.24(m, 3H), 3.26(m, 2H), 3.96(m, 1H), 7.17( s, 1H), 7.72 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值271.2；實測值272.2；Rt=1.617min。LCMS (ESI): [M-Boc] + m/z: calculated 271.2; found 272.2; Rt=1.617 min.

步驟3：(S)-3-甲基-6-(3,4,5-三氟苯基)-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of (S)-3-methyl-6-(3,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyridine

將(5S )-5-甲基-2-側氧基-3-(3,4,5-三氟苯甲醯基)哌啶-1-甲酸第三丁 酯(10.2g，27.47mmol)溶解於氯化氫(40mL)中且分批添加CH3 COOH(30mL)。添加完成之後，將所得混合物在110℃下攪拌16h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(150ml)與DCM(30ml)之間。分離有機層且丟棄。將水層用10% NaHCO3 鹼化至ph

Figure 110128222-A0202-12-2411-544
9且用DCM(2x60ml)萃取。將DCM溶液分離，經K2 CO3 乾燥且在減壓下蒸發，得到(3S )-3-甲基-6-(3,4,5-三氟苯基)-2,3,4,5-四氫吡啶(4.2g，18.48mmol，67.29%產率)。Dissolve ( 5S )-5-methyl-2-oxo-3-(3,4,5-trifluorobenzyl)piperidine-1-carboxylic acid tert- butyl ester (10.2 g, 27.47 mmol) In hydrogen chloride (40 mL) and CH3COOH (30 mL) was added portionwise. After the addition was complete, the resulting mixture was stirred at 110 °C for 16 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between 1N HCl (150ml) and DCM (30ml). The organic layer was separated and discarded. The aqueous layer was basified to ph with 10 % NaHCO
Figure 110128222-A0202-12-2411-544
9 and extracted with DCM (2x60ml). The DCM solution was separated, dried over K2CO3 and evaporated under reduced pressure to give ( 3S )-3-methyl-6-(3,4,5-trifluorophenyl)-2,3,4,5 - Tetrahydropyridine (4.2 g, 18.48 mmol, 67.29% yield).

步驟4：(2R,5S)-5-甲基-2-(3,4,5-三氟苯基)哌啶之合成Step 4: Synthesis of (2R,5S)-5-methyl-2-(3,4,5-trifluorophenyl)piperidine

在0℃下，將硼氫化鈉(1.40g，36.97mmol，1.31mL)一次性添加到(3S )-3-甲基-6-(3,4,5-三氟苯基)-2,3,4,5-四氫吡啶(4.2g，18.48mmol)於MeOH(50mL)中之經攪拌之溶液中。將所得混合物在0℃下攪拌4h，然後在真空中蒸發。將殘餘物用水(20mL)稀釋且用DCM(2*50mL)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發，以得到(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)哌啶(4.1g，17.89mmol，96.76%產率)。Sodium borohydride (1.40 g, 36.97 mmol, 1.31 mL) was added in one portion to ( 3S )-3-methyl-6-(3,4,5-trifluorophenyl)-2,3 at 0 °C ,4,5-tetrahydropyridine (4.2 g, 18.48 mmol) in a stirred solution of MeOH (50 mL). The resulting mixture was stirred at 0 °C for 4 h, then evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with DCM (2*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give ( 2R,5S )-5-methyl-2-(3,4,5-trifluorophenyl)piperidine (4.1 g, 17.89 mmol, 96.76% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.88(d,3H),1.14(m,1H),1.48(m,1H),1.65(m,2H),1.87(m,2H),2.38(t,1H),3.13(d,1H),3.49(d,1H),7.02(s,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.88(d, 3H), 1.14(m, 1H), 1.48(m, 1H), 1.65(m, 2H), 1.87(m, 2H), 2.38( t, 1H), 3.13 (d, 1H), 3.49 (d, 1H), 7.02 (s, 2H).

LCMS(ESI)：[M]+ m/z：計算值229.2；實測值230.2；Rt=0.618min。LCMS (ESI): [M] + m/z: calculated 229.2; found 230.2; Rt=0.618 min.

步驟5：(3-甲基-5-(2-(5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 5: (3-Methyl-5-(2-(5-methyl-2-(3,4,5-trifluorophenyl)piperidin-1-yl)-2-oxyacetamide Synthesis of tert-butyl)pyridin-2-yl)carbamate

將2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(5.28g，17.89mmol)及5-甲基-2-(3,4,5-三氟苯基)哌啶(4.1g，17.89mmol)混合於DMF(100mL)中。將反應懸浮液冷卻至0℃且添加HATU(8.84g，23.25mmol)， 隨後添加TEA(5.43g，53.66mmol，7.48mL)，且在環境溫度下攪拌14h。將反應混合物在真空中蒸發且倒入到水(300ml)中且用EtOAc(2x100ml)萃取。將經合併之有機萃取物用水(2*50ml)洗滌，經硫酸鈉乾燥且在真空中蒸發，以留下8.2g粗產物，8.2g粗產物藉由矽膠管柱層析使用己烷/MTBE梯度(10-100% MTBE)進行純化，以得到產物N -[3-甲基-5-[[2-[5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(5.5g，10.86mmol，60.71%產率)。2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (5.28 g, 17.89 mmol) and 5-methyl -2-(3,4,5-Trifluorophenyl)piperidine (4.1 g, 17.89 mmol) was mixed in DMF (100 mL). The reaction suspension was cooled to 0 °C and HATU (8.84 g, 23.25 mmol) was added followed by TEA (5.43 g, 53.66 mmol, 7.48 mL) and stirred at ambient temperature for 14 h. The reaction mixture was evaporated in vacuo and poured into water (300ml) and extracted with EtOAc (2x100ml). The combined organic extracts were washed with water (2*50ml), dried over sodium sulfate and evaporated in vacuo to leave 8.2g of crude product which was subjected to silica gel column chromatography using a hexane/MTBE gradient (10-100% MTBE) to give the product N- [3-methyl-5-[[2-[5-methyl-2-(3,4,5-trifluorophenyl)-1- 3 -Butyl piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamate (5.5 g, 10.86 mmol, 60.71% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.12(d,3H),1.56(s,9H),1.98(m,1H),2.24(s,3H),2.36(m,5H),3.12(m,1H),4.68(m,1H),6.20(m,1H),6.98(m,2H),8.32(m,2H),9.48(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.12(d, 3H), 1.56(s, 9H), 1.98(m, 1H), 2.24(s, 3H), 2.36(m, 5H), 3.12( m, 1H), 4.68 (m, 1H), 6.20 (m, 1H), 6.98 (m, 2H), 8.32 (m, 2H), 9.48 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=1.477min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=1.477 min.

步驟6：掌性分離Step 6: Palm Separation

使N -[3-甲基-5-[[2-[5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(10.5g，20.73mmol)(具有約10%順式異構物)經歷掌性HPLC純化(管柱：AD-H III(250*30mm，20um)，溶析液：CO2 -MeOH，60-40，90ml/min補充流速-30ml/min)，以獲得呈白色固體之純產物N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(6.1g，12.04mmol，58.10%產率)。make N- [3-methyl-5-[[2-[5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxoacetyl tert-butyl]amino]-2-pyridyl] carbamate (10.5 g, 20.73 mmol) (with about 10% cis isomer) was purified by chiral HPLC (column: AD-H III (250 *30mm, 20um), eluent: CO2 -MeOH, 60-40, 90ml/min supplemental flow rate-30ml/min) to obtain pure product N- [3-methyl-5-[[ as a white solid 2-[( 2R,5S )-5-methyl-2-(3,4,5-trifluorophenyl)-1-piperidinyl]-2-oxyethanoyl]amino]-2 - tert -butyl pyridyl]carbamate (6.1 g, 12.04 mmol, 58.10% yield).

保留時間：5.59minRetention time: 5.59min

1 H NMR(500MHz,CDCl3 )δ(ppm)1.09(d,3H),1.41(m,1H),1.56(s,9H),1.86(m,1H),2.04(m,2H),2.28(m,1H),2.31(s,3H),3.26(m,1H),4.68(m,1H),6.20(m,1H),6.71(m,1H),6.90(m,2H),8.03(m,1H),8.38(m,1H),9.32(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.09(d,3H), 1.41(m,1H), 1.56(s,9H), 1.86(m,1H), 2.04(m,2H), 2.28( m, 1H), 2.31(s, 3H), 3.26(m, 1H), 4.68(m, 1H), 6.20(m, 1H), 6.71(m, 1H), 6.90(m, 2H), 8.03(m , 1H), 8.38 (m, 1H), 9.32 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值506.2；實測值507.2；Rt=1.354min。LCMS (ESI): [M] + m/z: calculated 506.2; found 507.2; Rt=1.354 min.

步驟7：N-(6-胺基-5-甲基吡啶-3-基)-2-((2R,5S)-5-甲基-2-(3,4,5-三氟苯基)哌啶-1-基)-2-側氧基乙醯胺(化合物478 )之合成Step 7: N-(6-Amino-5-methylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(3,4,5-trifluorophenyl) Synthesis of piperidin-1-yl)-2-oxoacetamide ( compound 478 )

在室溫下將水(50mL)添加到N -[3-甲基-5-[[2-[(2R,5S )-5-甲基-2-(3,4,5-三氟苯基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(6.1g，12.04mmol)於二噁烷(100mL)中之經攪拌之溶液中。將所得混合物在95℃下攪拌15h，然後在真空中蒸發，留下4.75g粗產物，4.75g粗產物藉由矽膠管柱層析使用MTBE/MeOH梯度(10-100% MeOH)純化，以得到4.3g純產物，將其用MeOH稀釋，在旋轉蒸發器中在30℃下蒸發，然後在油泵(0.5mm Hg)下在35℃下乾燥12h，以獲得呈白色固體之純產物5-[[2-[(2R,5S )-2-(4-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(23.4g，60.87mmol，66.29%產率)化合物478 。a21D=+103.2(EtOH,0.25M)Water (50 mL) was added to N- [3-methyl-5-[[2-[( 2R,5S )-5-methyl-2-(3,4,5-trifluorophenyl at room temperature )-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (6.1 g, 12.04 mmol) in dioxane (100 mL) in the stirred solution. The resulting mixture was stirred at 95 °C for 15 h, then evaporated in vacuo, leaving 4.75 g of crude product, which was purified by silica gel column chromatography using a MTBE/MeOH gradient (10-100% MeOH) to give 4.3 g of pure product, which was diluted with MeOH, evaporated in a rotary evaporator at 30 °C, and then dried at 35 °C for 12 h under an oil pump (0.5 mm Hg) to obtain pure product 5-[[ as a white solid 2-[( 2R,5S )-2-(4-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (23.4 g, 60.87 mmol, 66.29% yield) Compound 478 . a21D=+103.2(EtOH,0.25M)

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.96-1.01(m,3H),1.25-1.36(m,1H),1.56-1.69(m,1H),1.81-1.93(m,1H),1.97-2.09(m,4H),2.11-2.23(m,1H),2.72-3.24(m,1H),3.38-4.02(m,1H),5.05-5.49(m,1H),5.57-5.66(m,2H),7.20-7.32(m,2H),7.42-7.50(m,1H),7.93-8.02(m,1H),10.42-10.60(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.96-1.01(m,3H), 1.25-1.36(m,1H), 1.56-1.69(m,1H), 1.81-1.93(m,1H) ,1.97-2.09(m,4H),2.11-2.23(m,1H),2.72-3.24(m,1H),3.38-4.02(m,1H),5.05-5.49(m,1H),5.57-5.66( m, 2H), 7.20-7.32 (m, 2H), 7.42-7.50 (m, 1H), 7.93-8.02 (m, 1H), 10.42-10.60 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值406.2；實測值407.2；Rt=1.752min。LCMS (ESI): [M] + m/z: calculated 406.2; found 407.2; Rt=1.752 min.

實例753. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1-甲基苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物132)之合成Example 753. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(1-methylbenzimidazol-4-yl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 132)

Figure 110128222-A0202-12-2413-461
Figure 110128222-A0202-12-2413-461

步驟1：1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并咪唑之合成Step 1: Synthesis of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzimidazole

將乙酸鉀(3.72g，37.90mmol，2.37mL)添加到4-溴-1-甲基苯并咪唑(4g，18.95mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2- 基)-1,3,2-二氧雜硼雜環戊烷(5.78g，22.74mmol)於二噁烷(50mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2 DPPF* CH2 Cl2 (773.85mg，947.61μmol)。在惰性氣氛下將所得混合物在100℃下攪拌48h。然後，將其冷卻，用MTBE(80ml)稀釋且過濾。將濾液在減壓下濃縮，得到1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并咪唑(6.49g，粗品)。Potassium acetate (3.72 g, 37.90 mmol, 2.37 mL) was added to 4-bromo-1-methylbenzimidazole (4 g, 18.95 mmol) and 4,4,5,5-tetramethyl-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (5.78 g, 22.74 mmol ) in dioxane (50 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl 2 DPPF * CH 2 Cl 2 (773.85 mg, 947.61 μmol) was added under argon flow. The resulting mixture was stirred at 100 °C for 48 h under an inert atmosphere. It was then cooled, diluted with MTBE (80ml) and filtered. The filtrate was concentrated under reduced pressure to give 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzone Imidazole (6.49 g, crude).

1 H NMR(500MHz,DMSO-d6 )δ 1.18(m,12H),3.82(s,3H),7.23(dd,1H),7.52(d,1H),7.64(d,1H),8.15(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.18(m, 12H), 3.82(s, 3H), 7.23(dd, 1H), 7.52(d, 1H), 7.64(d, 1H), 8.15(s , 1H).

LCMS(ESI)：[M-C6H12]+ m/z：計算值176.1；實測值177.2；Rt=0.481min。LCMS (ESI): [M-C6H12] + m/z: calculated 176.1; found 177.2; Rt=0.481 min.

步驟2：6-(1-甲基苯并咪唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(1-methylbenzimidazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鉀(6.46g，46.77mmol，2.82mL)添加到1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并咪唑(6.49g，15.59mmol)及6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(6.18g，17.15mmol)於二噁烷(50mL)及水(15mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2 DPPF* CH2 Cl2 (636.51mg，779.43μmol)。在惰性氣氛下將所得混合物在60℃下攪拌18h。然後，在減壓下移除溶劑且藉由管柱層析(RediSep管柱：330g；22-38%氯仿-MeCN；流速：90ml/min)純化殘餘物，得到6-(1-甲基苯并咪唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.1g，13.08mmol，83.92%產率)。Potassium carbonate (6.46 g, 46.77 mmol, 2.82 mL) was added to 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzimidazole (6.49g, 15.59mmol) and 6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.18g , 17.15 mmol) in dioxane (50 mL) and water (15 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl 2 DPPF * CH 2 Cl 2 (636.51 mg, 779.43 μmol) was added under argon flow. The resulting mixture was stirred at 60 °C for 18 h under an inert atmosphere. Then, the solvent was removed under reduced pressure and the residue was purified by column chromatography (RediSep column: 330 g; 22-38% chloroform-MeCN; flow rate: 90 ml/min) to give 6-(1-methylbenzene) Zimidazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.1 g, 13.08 mmol, 83.92% yield).

1 H NMR(500MHz,DMSO-d6 )δ 1.02(s,9H),1.24(m,1H),1.40(m,1H),1.66(m,2H),1.95(s,3H),2.37(m,1H),3.83(m,1H),5.75(m,1H),7.26(m,3H),7.84(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.02(s, 9H), 1.24(m, 1H), 1.40(m, 1H), 1.66(m, 2H), 1.95(s, 3H), 2.37(m , 1H), 3.83 (m, 1H), 5.75 (m, 1H), 7.26 (m, 3H), 7.84 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值313.2；實測值314.2；Rt=0.986min。LCMS (ESI): [M+H] + m/z: calculated 313.2; found 314.2; Rt=0.986 min.

步驟3：1-甲基-4-(2,3,4,5-四氫吡啶-6-基)苯并咪唑之合成Step 3: Synthesis of 1-methyl-4-(2,3,4,5-tetrahydropyridin-6-yl)benzimidazole

將6-(1-甲基苯并咪唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.1 g，13.08mmol)溶解於三氟乙酸(22.38g，196.24mmol，15.12mL)中。將所得溶液在25℃下攪拌1h。然後，將其倒入到氫氧化鈉(10.47g，261.65mmol，4.91mL)於水(150ml)中之冰冷溶液中。將所得混合物用DCM(4* 30ml)萃取。在經Na2 SO4 乾燥之後，在減壓下移除溶劑，得到1-甲基-4-(2,3,4,5-四氫吡啶-6-基)苯并咪唑(2.1g，9.85mmol，75.26%產率)。6-(1-Methylbenzimidazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.1 g, 13.08 mmol) was dissolved in trifluoroacetic acid (22.38 g) , 196.24 mmol, 15.12 mL). The resulting solution was stirred at 25 °C for 1 h. It was then poured into an ice-cold solution of sodium hydroxide (10.47 g, 261.65 mmol, 4.91 mL) in water (150 mL). The resulting mixture was extracted with DCM (4 * 30ml). After drying over Na 2 SO 4 , the solvent was removed under reduced pressure to give 1-methyl-4-(2,3,4,5-tetrahydropyridin-6-yl)benzimidazole (2.1 g, 9.85 g mmol, 75.26% yield).

1 H NMR(400MHz,CDCl3 )δ 1.21(m,1H),1.74(m,2H),1.88(m,2H),2.30(m,1H),3.09(m,1H),3.88(s,3H),5.27(m,1H),7.31(m,2H),7.57(d,1H),7.87(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.21 (m, 1H), 1.74 (m, 2H), 1.88 (m, 2H), 2.30 (m, 1H), 3.09 (m, 1H), 3.88 (s, 3H) ), 5.27(m, 1H), 7.31(m, 2H), 7.57(d, 1H), 7.87(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值213.1；實測值214.2；Rt=0.818min。LCMS (ESI): [M+H] + m/z: calculated 213.1; found 214.2; Rt=0.818 min.

步驟4：1-甲基-4-(2-哌啶基)苯并咪唑之合成Step 4: Synthesis of 1-methyl-4-(2-piperidinyl)benzimidazole

將1-甲基-4-(2,3,4,5-四氫吡啶-6-基)苯并咪唑(2.1g，9.85mmol)溶解於甲醇(40mL)中，且在20min期間分批添加硼氫化鈉(744.97mg，19.69mmol，696.23μL)。在添加完成之後，將所得混合物在25℃下攪拌1h。然後，將其在減壓下濃縮且將殘餘物分配於水(20ml)與EtOAc(40ml)之間。將有機層分離，經Na2 SO4 乾燥且用4M二噁烷/HCl酸化。將所得沉澱過濾且乾燥，得到1-甲基-4-(2-哌啶基)苯并咪唑(2.18g，7.56mmol，76.82%產率，2HCl)。1-Methyl-4-(2,3,4,5-tetrahydropyridin-6-yl)benzimidazole (2.1 g, 9.85 mmol) was dissolved in methanol (40 mL) and added portionwise over 20 min Sodium borohydride (744.97 mg, 19.69 mmol, 696.23 μL). After the addition was complete, the resulting mixture was stirred at 25 °C for 1 h. It was then concentrated under reduced pressure and the residue was partitioned between water (20ml) and EtOAc (40ml). The organic layer was separated, dried over Na2SO4 and acidified with 4M dioxane/HCl. The resulting precipitate was filtered and dried to give 1-methyl-4-(2-piperidinyl)benzimidazole (2.18 g, 7.56 mmol, 76.82% yield, 2HCl).

1 H NMR(400MHz,DMSO-d6 )δ 1.04(m,1H),1.85(m,6H),3.10(m,1H),3.42(m,1H),4.05(s,3H),5.12(m,1H),7.66(dd,1H),7.95(m,2H),9.57(s,1H),10.01(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.04(m, 1H), 1.85(m, 6H), 3.10(m, 1H), 3.42(m, 1H), 4.05(s, 3H), 5.12(m , 1H), 7.66 (dd, 1H), 7.95 (m, 2H), 9.57 (s, 1H), 10.01 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值215.1；實測值216.1；Rt=0.748min。LCMS (ESI): [M+H] + m/z: calculated 215.1; found 216.1; Rt=0.748 min.

步驟5：N-[3-甲基-5-[[2-[2-(1-甲基苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 5: N-[3-Methyl-5-[[2-[2-(1-methylbenzimidazol-4-yl)-1-piperidinyl]-2-oxyethanoyl] Synthesis of tertiary butyl amino]-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(205.74mg，696.72μmol)、HATU(291.41mg，766.39μmol)及三乙胺(352.51mg，3.48mmol，485.55μL)一起混合於二甲基甲醯胺(1.5mL)中且添加1-甲基-4-(2-哌 啶基)苯并咪唑(150mg，696.72μmol，2HCl)。將所得混合物在25℃下攪拌15h。然後，將其用水(10ml)稀釋且用乙酸乙酯(2* 15ml)萃取。將有機層用水(3* 10ml)及鹽水(20ml)洗滌，經Na2 SO4 乾燥且在真空中濃縮，得到N-[3-甲基-5-[[2-[2-(1-甲基苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(170mg，345.13μmol，49.54%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (205.74 mg, 696.72 μmol), HATU (291.41 mg , 766.39 μmol) and triethylamine (352.51 mg, 3.48 mmol, 485.55 μL) were mixed together in dimethylformamide (1.5 mL) and 1-methyl-4-(2-piperidinyl)benzone was added Imidazole (150 mg, 696.72 μmol, 2HCl). The resulting mixture was stirred at 25 °C for 15 h. It was then diluted with water (10ml) and extracted with ethyl acetate (2 * 15ml). The organic layer was washed with water (3 * 10ml) and brine (20ml), dried over Na2SO4 and concentrated in vacuo to give N-[3-methyl-5-[[2-[2-(1-methylmethane tert-butyl benzimidazol-4-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamate (170 mg, 345.13 μmol, 49.54% yield Rate).

LCMS(ESI)：[M+2H]+ m/z：計算值492.2；實測值494.2；Rt=1.048min。LCMS (ESI): [M+2H] + m/z: calculated 492.2; found 494.2; Rt=1.048 min.

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1-甲基苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物132 )之合成Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(1-methylbenzimidazol-4-yl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 132 )

將於二噁烷中之4.0M氯化氫溶液(1.52g，4.16mmol，1.5mL，10%純度)添加到N-[3-甲基-5-[[2-[2-(1-甲基苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(170mg，345.13μmol)於二氯甲烷(2mL)中之溶液中。將所得混合物在25℃下攪拌15h。然後，將其在減壓下濃縮且使殘餘物經歷HPLC(管柱：YMC-Actus Triart C18 100* 20mm，5um；0-5min 20-70%水-甲醇(NH3 0.1%)，流速30ml/min)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1-甲基苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(26mg，66.25μmol，19.20%產率)。A 4.0 M solution of hydrogen chloride in dioxane (1.52 g, 4.16 mmol, 1.5 mL, 10% purity) was added to N-[3-methyl-5-[[2-[2-(1-methylbenzene Ziimidazol-4-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (170 mg, 345.13 μmol) in dichloromethane ( 2mL) in the solution. The resulting mixture was stirred at 25 °C for 15 h. It was then concentrated under reduced pressure and the residue was subjected to HPLC (column: YMC-Actus Triart C18 100 * 20mm, 5um; 0-5min 20-70% water-methanol ( NH3 0.1%), flow rate 30ml/ min) to give N-(6-amino-5-methyl-3-pyridyl)-2-[2-(1-methylbenzimidazol-4-yl)-1-piperidinyl]-2 - Pendant oxyacetamide (26 mg, 66.25 μmol, 19.20% yield).

1 H NMR(400MHz,DMSO-d 6 )δ 1.30(m,2H),1.61(m,2H),1.91(m,1H),2.01(m,3H),2.91(m,1H),3.47(m,1H),3.85(m,3H),4.15(m,1H),5.76(m,3H),7.10(m,1H),7.28(m,1H),7.50(m,2H),7.98(m,1H),8.24(m,1H),10.70(d,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ 1.30(m, 2H), 1.61(m, 2H), 1.91(m, 1H), 2.01(m, 3H), 2.91(m, 1H), 3.47(m ,1H),3.85(m,3H),4.15(m,1H),5.76(m,3H),7.10(m,1H),7.28(m,1H),7.50(m,2H),7.98(m, 1H), 8.24 (m, 1H), 10.70 (d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值392.2；實測值393.2；Rt=1.766min。LCMS (ESI): [M+H] + m/z: calculated 392.2; found 393.2; Rt=1.766 min.

實例754. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1H-苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物142)之合成Example 754. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(1H-benzimidazol-4-yl)-1-piperidinyl]-2-oxygen Synthesis of Ethylacetamide (Compound 142)

Figure 110128222-A0202-12-2417-462
Figure 110128222-A0202-12-2417-462

步驟1：4-溴-1-四氫哌喃-2-基苯并咪唑之合成Step 1: Synthesis of 4-bromo-1-tetrahydropyran-2-ylbenzimidazole

將二氫哌喃(3.84g，45.68mmol，4.15mL)及對甲苯磺酸單水合物(144.81mg，761.30μmol，116.78μL)添加到4-溴-1H-苯并咪唑(3g，15.23mmol)於氯仿(50mL)中之懸浮液中。將所得混合物在60℃下攪拌20h。然後，將其冷卻至室溫且在劇烈攪拌之情況下添加過量固體NaHCO3 ，隨後添加1ml水。當CO2 逸出停止時，透過矽膠墊過濾混合物。將濾液在減壓下濃縮且將殘餘物用冷己烷(30ml)研磨。將所得固體過濾且乾燥，得到4-溴-1-四氫哌喃-2-基苯并咪唑(3.76g，13.37mmol，87.84%產率)。Dihydropyran (3.84 g, 45.68 mmol, 4.15 mL) and p-toluenesulfonic acid monohydrate (144.81 mg, 761.30 μmol, 116.78 μL) were added to 4-bromo-1H-benzimidazole (3 g, 15.23 mmol) In suspension in chloroform (50 mL). The resulting mixture was stirred at 60 °C for 20 h. It was then cooled to room temperature and excess solid NaHCO3 was added with vigorous stirring, followed by 1 ml of water. When CO evolution ceased, the mixture was filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure and the residue was triturated with cold hexanes (30 ml). The resulting solid was filtered and dried to give 4-bromo-1-tetrahydropyran-2-ylbenzimidazole (3.76 g, 13.37 mmol, 87.84% yield).

1 H NMR(500MHz,CDCl3 )δ 1.76(m,4H),2.13(m,3H),3.75(m,1H),4.12(m,1H),5.48(m,1H),7.17(dd,1H),7.48(m,2H),8.12(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.76 (m, 4H), 2.13 (m, 3H), 3.75 (m, 1H), 4.12 (m, 1H), 5.48 (m, 1H), 7.17 (dd, 1H) ), 7.48(m, 2H), 8.12(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值280.0；實測值281.2；Rt=1.127min。LCMS (ESI): [M+H] + m/z: calculated 280.0; found 281.2; Rt=1.127 min.

步驟2：1-四氫哌喃-2-基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并咪唑之合成Step 2: 1-Tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzo Synthesis of imidazole

將乙酸鉀(2.63g，26.75mmol，1.67mL)添加到4-溴-1-四氫哌喃-2-基苯并咪唑(3.76g，13.37mmol)及4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(4.08g，16.05mmol)於二噁烷(30mL) 中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2 DPPF* CH2 Cl2 (436.86mg，534.95μmol)。在惰性氣氛下將所得混合物在100℃下攪拌48h。然後，將其冷卻，用MTBE(50ml)稀釋且過濾。將濾液在減壓下濃縮，得到1-四氫哌喃-2-基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并咪唑(6.09g，粗品)。Potassium acetate (2.63 g, 26.75 mmol, 1.67 mL) was added to 4-bromo-1-tetrahydropyran-2-ylbenzimidazole (3.76 g, 13.37 mmol) and 4,4,5,5-tetramethyl yl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane alkane (4.08 g, 16.05 mmol) in dioxane (30 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl 2 DPPF * CH 2 Cl 2 (436.86 mg, 534.95 μmol) was added under argon flow. The resulting mixture was stirred at 100 °C for 48 h under an inert atmosphere. It was then cooled, diluted with MTBE (50ml) and filtered. The filtrate was concentrated under reduced pressure to give 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzimidazole (6.09 g, crude).

LCMS(ESI)：[M-THP]+ m/z：計算值244.2；實測值247.2；Rt=0.827min。LCMS (ESI): [M-THP] + m/z: calculated 244.2; found 247.2; Rt=0.827 min.

步驟3：6-(1-四氫哌喃-2-基苯并咪唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 6-(1-tetrahydropyran-2-ylbenzimidazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鉀(3.19g，23.06mmol，1.39mL)添加到1-四氫哌喃-2-基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯并咪唑(5.74g，11.53mmol)及6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.98g，13.84mmol)於二噁烷(50mL)及水(10mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加PdCl2 DPPF* CH2 Cl2 (376.71mg，461.30μmol)。在惰性氣氛下將所得混合物在60℃下攪拌18h。然後，在減壓下移除溶劑且藉由管柱層析(RediSep管柱：220g；0-20%氯仿-MeCN；流速：85ml/min)純化殘餘物，得到6-(1-四氫哌喃-2-基苯并咪唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.4g，8.87mmol，76.88%產率)。Potassium carbonate (3.19 g, 23.06 mmol, 1.39 mL) was added to 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boron-2-yl)benzimidazole (5.74 g, 11.53 mmol) and 6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid A solution of tributyl ester (4.98 g, 13.84 mmol) in dioxane (50 mL) and water (10 mL). The reaction flask was evacuated and refilled with argon 3 times. Then, PdCl 2 DPPF * CH 2 Cl 2 (376.71 mg, 461.30 μmol) was added under argon flow. The resulting mixture was stirred at 60 °C for 18 h under an inert atmosphere. Then, the solvent was removed under reduced pressure and the residue was purified by column chromatography (RediSep column: 220 g; 0-20% chloroform-MeCN; flow rate: 85 ml/min) to give 6-(1-tetrahydropiperidine) Pyran-2-ylbenzimidazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.4 g, 8.87 mmol, 76.88% yield).

1 H NMR(400MHz,CDCl3 )δ 0.81(s,9H),1.21(m,2H),1.66(m,4H),1.92(m,2H),2.06(m,2H),2.33(m,1H),3.72(m,1H),3.82(m,1H),4.10(m,1H),5.47(m,1H),5.66(s,1H),7.19(m,2H),7.36(d,1H),8.01(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ 0.81(s, 9H), 1.21(m, 2H), 1.66(m, 4H), 1.92(m, 2H), 2.06(m, 2H), 2.33(m, 1H) ), 3.72(m, 1H), 3.82(m, 1H), 4.10(m, 1H), 5.47(m, 1H), 5.66(s, 1H), 7.19(m, 2H), 7.36(d, 1H) , 8.01(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.2；Rt=1.205min。LCMS (ESI): [M+H] + m/z: calculated 383.2; found 384.2; Rt=1.205 min.

步驟4：1-四氫哌喃-2-基-4-(2,3,4,5-四氫吡啶-6-基)苯并咪唑之合成Step 4: Synthesis of 1-tetrahydropyran-2-yl-4-(2,3,4,5-tetrahydropyridin-6-yl)benzimidazole

將6-(1-四氫哌喃-2-基苯并咪唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.4g，8.87mmol)溶解於三氟乙酸(15.16g，132.99mmol，10.25mL)中。將 所得溶液在25℃下攪拌1h。然後，將其倒入到氫氧化鈉(7.09g，177.32mmol，3.33mL)於水(150ml)中之冰冷溶液中。將所得混合物用DCM(4* 30ml)萃取。在經Na2 SO4 乾燥之後，在減壓下移除溶劑，得到1-四氫哌喃-2-基-4-(2,3,4,5-四氫吡啶-6-基)苯并咪唑(2g，7.06mmol，79.61%產率)。6-(1-Tetrahydropyran-2-ylbenzimidazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.4 g, 8.87 mmol) was dissolved in in trifluoroacetic acid (15.16 g, 132.99 mmol, 10.25 mL). The resulting solution was stirred at 25 °C for 1 h. It was then poured into an ice-cold solution of sodium hydroxide (7.09 g, 177.32 mmol, 3.33 mL) in water (150 mL). The resulting mixture was extracted with DCM (4 * 30ml). After drying over Na 2 SO 4 , the solvent was removed under reduced pressure to give 1-tetrahydropyran-2-yl-4-(2,3,4,5-tetrahydropyridin-6-yl)benzo Imidazole (2 g, 7.06 mmol, 79.61% yield).

LCMS(ESI)：[M+H]+ m/z：計算值283.2；實測值284.2；Rt=0.906min。LCMS (ESI): [M+H] + m/z: calculated 283.2; found 284.2; Rt=0.906 min.

步驟5：4-(2-哌啶基)-1-四氫哌喃-2-基苯并咪唑)之合成Step 5: Synthesis of 4-(2-piperidinyl)-1-tetrahydropyran-2-ylbenzimidazole)

將1-四氫哌喃-2-基-4-(2,3,4,5-四氫吡啶-6-基)苯并咪唑(2g，7.06mmol)溶解於甲醇(40mL)中，且在20min期間分批添加硼氫化鈉(534.04mg，14.12mmol，499.11μL)。在添加完成之後，將所得混合物在25℃下攪拌1h。然後，將其在減壓下濃縮且將殘餘物分配於水(20ml)與EtOAc(40ml)之間。將有機層分離，經Na2 SO4 乾燥且用4M二噁烷/HCl酸化。將所得沉澱過濾且乾燥，得到4-(2-哌啶基)-1-四氫哌喃-2-基苯并咪唑(2.3g，6.42mmol，90.95%產率，2HCl)。1-Tetrahydropyran-2-yl-4-(2,3,4,5-tetrahydropyridin-6-yl)benzimidazole (2 g, 7.06 mmol) was dissolved in methanol (40 mL) and in Sodium borohydride (534.04 mg, 14.12 mmol, 499.11 μL) was added portionwise during 20 min. After the addition was complete, the resulting mixture was stirred at 25 °C for 1 h. It was then concentrated under reduced pressure and the residue was partitioned between water (20ml) and EtOAc (40ml). The organic layer was separated, dried over Na2SO4 and acidified with 4M dioxane/HCl. The resulting precipitate was filtered and dried to give 4-(2-piperidinyl)-1-tetrahydropyran-2-ylbenzimidazole (2.3 g, 6.42 mmol, 90.95% yield, 2HCl).

1 H NMR(500MHz,DMSO-d6 )δ 1.15(m,1H),1.82(m,2H),1.98(m,5H),3.09(m,2H),3.39(m,2H),3.79(m,1H),3.99(m,1H),5.02(m,1H),5.17(m,1H),5.89(m,1H),7.66(m,2H),7.92(m,2H),9.55(m,2H),9.74(s,1H),10.04(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.15(m, 1H), 1.82(m, 2H), 1.98(m, 5H), 3.09(m, 2H), 3.39(m, 2H), 3.79(m ,1H),3.99(m,1H),5.02(m,1H),5.17(m,1H),5.89(m,1H),7.66(m,2H),7.92(m,2H),9.55(m, 2H), 9.74 (s, 1H), 10.04 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值285.2；實測值286.2；Rt=0.883min。LCMS (ESI): [M+H] + m/z: calculated 285.2; found 286.2; Rt=0.883 min.

步驟6：4-(2-哌啶基)-1H-苯并咪唑之合成Step 6: Synthesis of 4-(2-Piperidinyl)-1H-benzimidazole

將於二噁烷中之4.0M氯化氫溶液(3.03g，8.31mmol，3mL，10%純度)添加到4-(2-哌啶基)-1-四氫哌喃-2-基苯并咪唑(2.3g，6.42mmol，2HCl)於甲醇(30mL)中之溶液中。將所得溶液在60℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物用乙酸乙酯(20ml)研磨。將所得沉澱過濾且乾燥，得到4-(2-哌啶基)-1H-苯并咪唑(1.6g，5.84mmol，90.91%產率，2HCl)。A 4.0M solution of hydrogen chloride in dioxane (3.03 g, 8.31 mmol, 3 mL, 10% purity) was added to 4-(2-piperidinyl)-1-tetrahydropyran-2-ylbenzimidazole ( 2.3 g, 6.42 mmol, 2HCl) in methanol (30 mL). The resulting solution was stirred at 60 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was triturated with ethyl acetate (20 ml). The resulting precipitate was filtered and dried to give 4-(2-piperidinyl)-lH-benzimidazole (1.6 g, 5.84 mmol, 90.91% yield, 2HCl).

1 H NMR(400MHz,DMSO-d6 )δ 1.85(m,6H),(m,2H),3.40(m,2H),5.14(m,1H),7.63(dd,1H),7.85(d,1H),7.95(d,1H),9.56(m,1H),9.67(s,1H),9.95(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.85(m, 6H), (m, 2H), 3.40(m, 2H), 5.14(m, 1H), 7.63(dd, 1H), 7.85(d, 1H), 7.95 (d, 1H), 9.56 (m, 1H), 9.67 (s, 1H), 9.95 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值201.1；實測值202.2；Rt=0.623min。LCMS (ESI): [M+H] + m/z: calculated 201.1; found 202.2; Rt=0.623 min.

步驟7：N-[5-[[2-[2-(1H-苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 7: N-[5-[[2-[2-(1H-benzimidazol-4-yl)-1-piperidinyl]-2-oxyacetyl]amino]-3-methyl Synthesis of tert-butyl-2-pyridyl]carbamate

將2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(269.24mg，911.78μmol)、HATU(381.35mg，1.00mmol)及三乙胺(461.32mg，4.56mmol，635.42μL)一起混合於二甲基甲醯胺(2mL)中且添加4-(2-哌啶基)-1H-苯并咪唑(250mg，911.78μmol，2HCl)。將所得混合物在25℃下攪拌4h。然後，使其經歷HPLC(管柱：YMC Triart C18 100* 20mm，5um；40-40-90% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min)，得到N-[5-[[2-[2-(1H-苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(128mg，267.48μmol，29.34%產率)。2-[[6-(Third-butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (269.24 mg, 911.78 μmol), HATU (381.35 mg , 1.00 mmol) and triethylamine (461.32 mg, 4.56 mmol, 635.42 μL) were mixed together in dimethylformamide (2 mL) and 4-(2-piperidinyl)-1H-benzimidazole (250 mg) was added , 911.78 μmol, 2HCl). The resulting mixture was stirred at 25 °C for 4 h. Then, it was subjected to HPLC (column: YMC Triart C18 100 * 20mm, 5um; 40-40-90% 0-1-6min 0.1% NH3 -methanol, flow rate: 30ml/min) to give N-[5- [[2-[2-(1H-benzimidazol-4-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]amine 3-Butyl formate (128 mg, 267.48 μmol, 29.34% yield).

LCMS(ESI)：[M+2H]+ m/z：計算值478.2；實測值480.2；Rt=2.824min。LCMS (ESI): [M+2H] + m/z: calculated 478.2; found 480.2; Rt=2.824 min.

步驟8：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1H-苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物142)之合成Step 8: N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(1H-benzimidazol-4-yl)-1-piperidinyl]-2-oxygen Synthesis of Acetamide (Compound 142)

將於二噁烷中之4.0M氯化氫溶液(1.46g，4.01mmol，1.45mL，10%純度)添加到N-[5-[[2-[2-(1H-苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(128mg，267.48μmol)於二氯甲烷(2mL)中之溶液中。將所得混合物在25℃下攪拌16h。然後，將其在減壓下濃縮且使殘餘物經歷HPLC(管柱：YMC-Actus Triart C18 100* 20mm，5um；0-5min 20-45%水-乙腈(NH3 0.1%)，流速30ml/min)，得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1H-苯并咪唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(51mg，134.77μmol，50.38%產率)。A 4.0M solution of hydrogen chloride in dioxane (1.46 g, 4.01 mmol, 1.45 mL, 10% purity) was added to N-[5-[[2-[2-(1H-benzimidazol-4-yl) -1-Piperidinyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (128 mg, 267.48 μmol) in dichloromethane (2 mL) in the solution. The resulting mixture was stirred at 25 °C for 16 h. It was then concentrated under reduced pressure and the residue was subjected to HPLC (column: YMC-Actus Triart C18 100 * 20mm, 5um; 0-5min 20-45% water-acetonitrile ( NH3 0.1%), flow rate 30ml/ min) to give N-(6-amino-5-methyl-3-pyridyl)-2-[2-(1H-benzimidazol-4-yl)-1-piperidinyl]-2-side Oxyacetamide (51 mg, 134.77 μmol, 50.38% yield).

1 H NMR(600MHz,DMSO-d 6 )δ 1.25(m,1H),1.47(m,1H),1.56(m,1H),1.64(m,1H),1.90(m,1H),1.98(m,3H),3.03(m,1H),3.44(m,1H),4.04(m,1H),5.58(m,3H),7.07(m,1H),7.19(m,1H),7.46(m,2H),7.94(m,1H),8.24(m,1H),10.54(m, 1H),12.38(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 1.25(m,1H), 1.47(m,1H), 1.56(m,1H), 1.64(m,1H), 1.90(m,1H), 1.98(m ,3H),3.03(m,1H),3.44(m,1H),4.04(m,1H),5.58(m,3H),7.07(m,1H),7.19(m,1H),7.46(m, 2H), 7.94 (m, 1H), 8.24 (m, 1H), 10.54 (m, 1H), 12.38 (m, 1H).

LCMS(ESI)：[M+2H]+ m/z：計算值378.2；實測值380.2；Rt=0.734min。LCMS (ESI): [M+2H] + m/z: calculated 378.2; found 380.2; Rt=0.734 min.

實例755. N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(2-側氧基吲哚啉-4-基)-1-哌啶基]乙醯胺(化合物116)之合成Example 755. N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[2-(2-oxyindolin-4-yl)-1- Synthesis of piperidinyl]acetamide (compound 116)

Figure 110128222-A0202-12-2421-463
Figure 110128222-A0202-12-2421-463

步驟1：6-(2-側氧基吲哚啉-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(2-oxyindolin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8g，24.15mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲哚啉-2-酮(5.96g，23.00mmol)及碳酸鈉(7.31g，68.99mmol，2.89mL)於二噁烷(100mL)及水(20mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加Pd(dppf)Cl2* DCM(939.00mg，1.15mmol)。將所得混合物除氣，用Ar再填充且在65℃下攪拌12h。過濾出沉澱，將其用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於150ml水中且用EtOAc(2* 100ml)萃取。將經合併之有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(9g)。藉由梯度層析(SiO2 ；己烷-EtOAc)純化粗產物，以獲得6-(2-側氧基吲哚啉-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.2g，13.36mmol，58.09%產率)。6-(Trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8 g, 24.15 mmol), 4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborol-2-yl)indolin-2-one (5.96g, 23.00mmol) and sodium carbonate (7.31g, 68.99mmol, 2.89mL) ) in dioxane (100 mL) and water (20 mL) was degassed and refilled three times with Ar. To this solution was added Pd(dppf)Cl2 * DCM (939.00 mg, 1.15 mmol). The resulting mixture was degassed, refilled with Ar and stirred at 65 °C for 12 h. The precipitate was filtered off and washed with dioxane (50ml). The solvent was evaporated in vacuo and the residue was dissolved in 150 ml of water and extracted with EtOAc (2 * 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (9 g). The crude product was purified by gradient chromatography ( SiO2 ; hexane-EtOAc) to obtain 6-(2-oxyindolin-4-yl)-3,4-dihydro-2H-pyridine-1- 3-Butyl formate (4.2 g, 13.36 mmol, 58.09% yield).

1 H NMR(500MHz,DMSO-d6 )δ 1.00(s,9H),1.21(m,2H),1.84(m,2H),2.25(m,2H),3.62(m,2H),5.24(s,1H),6.68(d,1H),6.76(d,1H),7.07(dd,1H),10.27(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.00(s, 9H), 1.21(m, 2H), 1.84(m, 2H), 2.25(m, 2H), 3.62(m, 2H), 5.24(s , 1H), 6.68 (d, 1H), 6.76 (d, 1H), 7.07 (dd, 1H), 10.27 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值214.2；實測值215.2；Rt=1.330min。LCMS (ESI): [M-Boc] + m/z: calculated 214.2; found 215.2; Rt=1.330 min.

步驟2：4-(2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮之合成Step 2: Synthesis of 4-(2,3,4,5-tetrahydropyridin-6-yl)indolin-2-one

將6-(2-側氧基吲哚啉-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.2g，13.36mmol)溶解於三氟乙酸(1.52g，13.36mmol，1.03mL)中。將所得混合物在25℃下攪拌2h(直至氣體逸出結束)。將溶液之pH用10% NaOH溶液調節至8且用DCM(3*70ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得4-(2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮(2.5g，11.67mmol，87.34%產率)。6-(2-Oxyindolin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.2 g, 13.36 mmol) was dissolved in trifluoroacetic acid (1.52 mmol) g, 13.36 mmol, 1.03 mL). The resulting mixture was stirred at 25°C for 2 h (until gas evolution was complete). The pH of the solution was adjusted to 8 with 10% NaOH solution and extracted with DCM (3*70ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated in vacuo to give 4-(2,3,4,5-tetrahydropyridin-6-yl)indoline- 2-keto (2.5 g, 11.67 mmol, 87.34% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.56(m,2H),1.72(m,2H),2.53(m,2H),3.58(s,2H),3.73(m,2H),6.83(dd,1H),7.21(m,2H),10.37(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.56(m, 2H), 1.72(m, 2H), 2.53(m, 2H), 3.58(s, 2H), 3.73(m, 2H), 6.83(dd , 1H), 7.21 (m, 2H), 10.37 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值214.2；實測值215.2；Rt=0.513min。LCMS (ESI): [M+H] + m/z: calculated 214.2; found 215.2; Rt=0.513 min.

步驟3：4-(2-哌啶基)吲哚啉-2-酮之合成Step 3: Synthesis of 4-(2-Piperidinyl)indolin-2-one

在0℃下，向4-(2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮(2.5g，11.67mmol)於甲醇(50mL)中之溶液中分批添加硼氫化鈉(441.43mg，11.67mmol，412.55μL)。將所得混合物在環境溫度下攪拌2h且蒸發。將殘餘物溶解於水(50ml)中且用DCM(3* 50ml)萃取。將經合併之有機層用鹽水(2* 40ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得4-(2-哌啶基)吲哚啉-2-酮(1.9g，8.78mmol，75.29%產率)。To a solution of 4-(2,3,4,5-tetrahydropyridin-6-yl)indolin-2-one (2.5 g, 11.67 mmol) in methanol (50 mL) portionwise at 0 °C Sodium borohydride (441.43 mg, 11.67 mmol, 412.55 μL) was added. The resulting mixture was stirred at ambient temperature for 2 h and evaporated. The residue was dissolved in water (50ml) and extracted with DCM (3 * 50ml). The combined organic layers were washed with brine (2 * 40 ml), dried over Na2SO4 and evaporated in vacuo to give 4- (2-piperidinyl)indolin-2-one (1.9 g, 8.78 g mmol, 75.29% yield).

LCMS(ESI)：[M+H]+ m/z：計算值216.2；實測值217.2；Rt=0.599min。LCMS (ESI): [M+H] + m/z: calculated 216.2; found 217.2; Rt=0.599 min.

步驟4：N-[3-甲基-5-[[2-側氧基-2-[2-(2-側氧基吲哚啉-4-基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[3-Methyl-5-[[2-oxy-2-[2-(2-oxyindolin-4-yl)-1-piperidinyl]acetyl Synthesis of tert-butyl ]amino]-2-pyridyl]carbamate

向4-(2-哌啶基)吲哚啉-2-酮(0.3g，1.39mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(409.60mg，1.39mmol)及HATU(527.42mg，1.39mmol)於DMF(3mL)中之懸浮液中添加三乙胺(701.80mg，6.94 mmol，966.67μL)。將所得混合物在環境溫度下攪拌12h，溶解於水(40ml)中且用EtOAc(3* 20ml)萃取。將經合併之有機層用鹽水(3* 20ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得N-[3-甲基-5-[[2-側氧基-2-[2-(2-側氧基吲哚啉-4-基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.6g，粗品)。此化合物不經純化即用於下一步驟。To 4-(2-piperidinyl)indolin-2-one (0.3 g, 1.39 mmol), 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridine Triethylamine (701.80 mg, 6.94 mmol, 966.67 g) to a suspension of HATU (527.42 mg, 1.39 mmol) in DMF (3 mL) was added triethylamine (701.80 mg, 6.94 mmol, 966.67 μL). The resulting mixture was stirred at ambient temperature for 12h, dissolved in water (40ml) and extracted with EtOAc (3 * 20ml). The combined organic layers were washed with brine (3 * 20ml), dried over Na2SO4 and evaporated to obtain N-[3-methyl-5-[[2-oxy-2-[2-( 2-Oxyindolin-4-yl)-1-piperidinyl]acetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (0.6 g, crude). This compound was used in the next step without purification.

1 H NMR(500MHz,DMSO-d6 )δ 1.43(s,9H),1.65(m,4H),2.18(s,3H),2.29(m,2H),2.68(m,2H),3.50(m,2H),5.54(m,1H),6.76(dd,1H),7.01(d,1H),7.21(d,1H),7.95(s,1H),8.45(s,1H),9.05(s,1H),10.42(s,1H),11.00(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.43(s, 9H), 1.65(m, 4H), 2.18(s, 3H), 2.29(m, 2H), 2.68(m, 2H), 3.50(m ,2H),5.54(m,1H),6.76(dd,1H),7.01(d,1H),7.21(d,1H),7.95(s,1H),8.45(s,1H),9.05(s, 1H), 10.42 (s, 1H), 11.00 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值393.2；實測值394.2；Rt=1.191min。LCMS (ESI): [M-Boc] + m/z: calculated 393.2; found 394.2; Rt=1.191 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(2-側氧基吲哚啉-4-基)-1-哌啶基]乙醯胺(化合物116 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[2-(2-oxyindolin-4-yl)-1- Synthesis of piperidinyl]acetamide ( compound 116 )

向N-[3-甲基-5-[[2-側氧基-2-[2-(2-側氧基吲哚啉-4-基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(0.6g，1.22mmol)於DCM(20mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌12h且在真空中蒸發，以獲得粗產物(0.8g)。藉由HPLC(40-40-80% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量393，管柱：YMC Triart C18 100* 20mm，5um)純化粗產物，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-(2-側氧基吲哚啉-4-基)-1-哌啶基]乙醯胺(115mg，292.30μmol，24.04%產率)。To N-[3-methyl-5-[[2-oxy-2-[2-(2-oxy-indolin-4-yl)-1-piperidinyl]acetyl]amine tert-butyl]-2-pyridyl]carbamate (0.6 g, 1.22 mmol) in DCM (20 mL) was added to a 4.0 M solution of hydrogen chloride in dioxane (8.00 g, 219.41 mmol, 10 mL) . The resulting mixture was stirred at 25 °C for 12 h and evaporated in vacuo to obtain crude product (0.8 g). By HPLC (40-40-80% 0-1-6min 0.1% NH3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 393, column: YMC Triart C18 100 * 20mm, 5um) to purify the crude product to give N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-[2-(2-oxy-indoline-4- yl)-1-piperidinyl]acetamide (115 mg, 292.30 μmol, 24.04% yield).

1 H NMR(500MHz,DMSO+CCl4)δ 1.54(m,1H),1.65(m,3H),1.83(m,1H),2.02(m,3H),2.31(m,1H),3.06(m,1H),3.46(m,2H),3.99(m,1H),5.54(m,1H),5.62(m,2H),6.77(m,1H),6.96(m,1H),7.21(m,1H),7.46(m,1H),7.99(m,1H),10.41(m,1H),10.48(m,1H)。 1 H NMR(500MHz, DMSO+CCl4)δ 1.54(m,1H), 1.65(m,3H), 1.83(m,1H), 2.02(m,3H), 2.31(m,1H), 3.06(m, 1H), 3.46(m, 2H), 3.99(m, 1H), 5.54(m, 1H), 5.62(m, 2H), 6.77(m, 1H), 6.96(m, 1H), 7.21(m, 1H) ), 7.46 (m, 1H), 7.99 (m, 1H), 10.41 (m, 1H), 10.48 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值393.2；實測值394.2；Rt=1.995min。LCMS (ESI): [M+H] + m/z: calculated 393.2; found 394.2; Rt=1.995 min.

實例756. N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物714)之合成Example 756. N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-5-methyl-2-(2-oxyindoline-4- yl)-1-piperidinyl]-2-oxoacetamide (compound 714)

Figure 110128222-A0202-12-2424-464
Figure 110128222-A0202-12-2424-464

步驟1：3-甲基-6-(2-側氧基吲哚啉-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-methyl-6-(2-oxyindolin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將碳酸鈉(4.91g，46.31mmol，1.94mL)添加到3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(8.80g，25.47mmol)及4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲哚啉-2-酮(6g，23.16mmol)於二噁烷(90mL)及水(30mL)中之溶液中。將反應燒瓶抽真空且用氬氣再填充3次。然後，在氬氣流下添加Pd(dppf)Cl2* DCM(945.52mg，1.16mmol)，在惰性氣氛下將所得混合物在90℃下攪拌14h。然後，將混合物蒸發，以得到粗產物(21g)，其藉由梯度管柱層析(SiO2 ；己烷-MeOH)進行純化，以得到3-甲基-6-(2-側氧基吲哚啉-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5.2g，15.83mmol，68.38%產率)。Sodium carbonate (4.91 g, 46.31 mmol, 1.94 mL) was added to 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid third Butyl ester (8.80 g, 25.47 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indoline-2- A solution of ketone (6 g, 23.16 mmol) in dioxane (90 mL) and water (30 mL). The reaction flask was evacuated and refilled 3 times with argon. Then, Pd(dppf)Cl 2 * DCM (945.52 mg, 1.16 mmol) was added under argon flow and the resulting mixture was stirred at 90 °C for 14 h under an inert atmosphere. Then, the mixture was evaporated to give the crude product (21 g), which was purified by gradient column chromatography ( SiO2 ; hexane-MeOH) to give 3-methyl-6-(2-pentoxyindium) Indol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.2 g, 15.83 mmol, 68.38% yield).

1 H NMR(500MHz,CDCl3 )δ 1.04(s,9H),1.28(m,2H),1.33(d,3H),1.46(m,1H),1.86(m,1H),2.04(m,1H),3.47(m,2H),5.25(s,1H),6.77(d,1H),6.95(d,1H),7.16(dd,1H),8.30(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.04(s, 9H), 1.28(m, 2H), 1.33(d, 3H), 1.46(m, 1H), 1.86(m, 1H), 2.04(m, 1H) ), 3.47(m, 2H), 5.25(s, 1H), 6.77(d, 1H), 6.95(d, 1H), 7.16(dd, 1H), 8.30(s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值228.2；實測值229.2；Rt=1.376minLCMS(ESI): [M-Boc] + m/z: Calculated 228.2; Measured 229.2; Rt=1.376min

步驟2：4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮之合成Step 2: Synthesis of 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)indolin-2-one

向3-甲基-6-(2-側氧基吲哚啉-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁 酯(2g，6.09mmol)中添加三氟乙酸(6.94g，60.90mmol，4.69mL)且將反應混合物在25℃下攪拌1h。蒸發TFA。將殘餘物用氯仿稀釋且蒸發至乾，以得到4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮(1.1g，粗品)。To 3-methyl-6-(2-oxyindolin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl To the ester (2 g, 6.09 mmol) was added trifluoroacetic acid (6.94 g, 60.90 mmol, 4.69 mL) and the reaction mixture was stirred at 25 °C for 1 h. Evaporate TFA. The residue was diluted with chloroform and evaporated to dryness to give 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)indolin-2-one (1.1 g, crude) .

1 H NMR(400MHz,CDCl3 )δ 1.05(m,2H),1.43(m,3H),2.12(m,1H),3.19(m,1H),3.41(m,2H),3.82(m,2H),4.05(m,1H),7.24(m,2H),7.41(dd,1H),9.43(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 1.05 (m, 2H), 1.43 (m, 3H), 2.12 (m, 1H), 3.19 (m, 1H), 3.41 (m, 2H), 3.82 (m, 2H) ), 4.05 (m, 1H), 7.24 (m, 2H), 7.41 (dd, 1H), 9.43 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值228.1；實測值229.2；Rt=0.683min。LCMS (ESI): [M+H] + m/z: calculated 228.1; found 229.2; Rt=0.683 min.

步驟3：4-[(2S,5R)-5-甲基-2-哌啶基]吲哚啉-2-酮之合成Step 3: Synthesis of 4-[(2S,5R)-5-methyl-2-piperidinyl]indolin-2-one

向4-(3-甲基-2,3,4,5-四氫吡啶-6-基)吲哚啉-2-酮(1.1g，4.82mmol)於MeOH(15mL)中之預冷卻(0℃)溶液中分批添加硼氫化鈉(218.75mg，5.78mmol，204.44μL)。然後將反應混合物在25℃下攪拌1h。將MeOH蒸發，將殘餘物再溶解於MeOH(5ml)中且添加HCl(於二噁烷中之4.0M溶液，5ml)。將混合物攪拌15min且將溶劑蒸發，以得到粗品固體。將產物用THF(2* 10ml)洗滌，在真空中乾燥，以得到4-[(2S,5R)-5-甲基-2-哌啶基]吲哚啉-2-酮(2.1g，粗品，HCl)。產物含有約17% NaCl。To a precooling (0 °C) solution was added portionwise sodium borohydride (218.75 mg, 5.78 mmol, 204.44 μL). The reaction mixture was then stirred at 25°C for 1 h. The MeOH was evaporated, the residue was redissolved in MeOH (5ml) and HCl (4.0M in dioxane, 5ml) was added. The mixture was stirred for 15 min and the solvent was evaporated to give crude solid. The product was washed with THF (2 * 10ml) and dried in vacuo to give 4-[(2S,5R)-5-methyl-2-piperidinyl]indolin-2-one (2.1g, crude , HCl). The product contained about 17% NaCl.

1 H NMR(500MHz,DMSO-d6 )δ 0.93(m,2H),1.03(m,2H),1.28(m,2H),1.86(m,2H),3.58(m,1H),3.78(m,3H),4.01(m,2H),6.84(d,1H),7.24(dd,1H),7.37(d,1H),9.58(m,1H),10.56(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.93(m, 2H), 1.03(m, 2H), 1.28(m, 2H), 1.86(m, 2H), 3.58(m, 1H), 3.78(m , 3H), 4.01 (m, 2H), 6.84 (d, 1H), 7.24 (dd, 1H), 7.37 (d, 1H), 9.58 (m, 1H), 10.56 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值230.1；實測值231.2；Rt=0.611min。LCMS (ESI): [M+H] + m/z: calculated 230.1; found 231.2; Rt=0.611 min.

步驟4：N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[3-Methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-oxyindolin-4-yl)-1-piperidine Synthesis of tert-butyl]-2-oxyacetoxy]amino]-2-pyridyl]carbamate

向4-[(2S,5R)-5-甲基-2-哌啶基]吲哚啉-2-酮(330mg，1.24mmol，HCl)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(365.29mg，1.24mmol)及三乙胺(876.23mg，8.66mmol，1.21mL)於DMF(4mL)中之溶液中分批添加HATU(517.40mg，1.36mmol)。將混合物在25℃下攪拌2h。將反 應混合物用水(50ml)稀釋且將產物用EtOAc(3*25ml)萃取。將經合併之有機層用水、鹽水洗滌且經Na2 SO4 乾燥。將溶劑蒸發，以得到N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(260mg，512.23μmol，41.41%產率)。To 4-[(2S,5R)-5-methyl-2-piperidinyl]indolin-2-one (330 mg, 1.24 mmol, HCl), 2-[[6-(tert-butoxycarbonyl Amino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (365.29 mg, 1.24 mmol) and triethylamine (876.23 mg, 8.66 mmol, 1.21 mL) in DMF (4 mL) To the solution was added HATU (517.40 mg, 1.36 mmol) in portions. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50ml) and the product was extracted with EtOAc (3*25ml). The combined organic layers were washed with water, brine and dried over Na2SO4 . The solvent was evaporated to give N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-oxyindolin-4-yl)-1 -Piperidinyl]-2-Pendant oxyacetyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (260 mg, 512.23 μmol, 41.41% yield).

1 H NMR(400MHz,DMSO-d6 )δ 0.96(m,3H),1.13(m,1H),1.40(s,9H),1.95(m,2H),2.14(m,3H),2.65(m,5H),2.85(m,1H),3.98(m,1H),5.31(m,1H),6.71(d,1H),6.94(d,1H),7.16(dd,1H),7.91(m,1H),8.40(m,1H),9.02(s,1H),10.38(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.96(m, 3H), 1.13(m, 1H), 1.40(s, 9H), 1.95(m, 2H), 2.14(m, 3H), 2.65(m ,5H),2.85(m,1H),3.98(m,1H),5.31(m,1H),6.71(d,1H),6.94(d,1H),7.16(dd,1H),7.91(m, 1H), 8.40 (m, 1H), 9.02 (s, 1H), 10.38 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值507.2；實測值508.2；Rt=1.242min。LCMS (ESI): [M+H] + m/z: calculated 507.2; found 508.2; Rt=1.242 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物714 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2S,5R)-5-methyl-2-(2-oxyindoline-4- Synthesis of yl)-1-piperidinyl]-2-oxoacetamide ( Compound 714 )

向N-[3-甲基-5-[[2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(260mg，512.23μmol)於DCM(10mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(186.77mg，5.12mmol，233.46μL)。將反應混合物在25℃下攪拌4h。在真空中蒸發溶劑，以得到粗產物(250mg)，其藉由反相HPLC(0-5min 15-65%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，目標質量407.48管柱：YMC-Actus Triart C18 100*20mml.D.S-5um)進行純化，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-5-甲基-2-(2-側氧基吲哚啉-4-基)-1-哌啶基]-2-側氧基乙醯胺(44mg，107.98μmol，21.08%產率)。to N-[3-methyl-5-[[2-[(2S,5R)-5-methyl-2-(2-oxyindolin-4-yl)-1-piperidinyl] tert-butyl-2-oxyacetoxy]amino]-2-pyridyl]carbamate (260 mg, 512.23 μmol) in dioxane was added to a stirred solution of DCM (10 mL) 4.0 M hydrogen chloride solution (186.77 mg, 5.12 mmol, 233.46 [mu]L). The reaction mixture was stirred at 25 °C for 4 h. The solvent was evaporated in vacuo to give the crude product (250 mg) which was purified by reverse phase HPLC (0-5 min 15-65% water-methanol (NH 3 0.1%), flow rate 30 ml/min (load pump 4 ml/min methanol ( NH3 0.1%)), target mass 407.48 column: YMC-Actus Triart C18 100*20mml.DS-5um) was purified to give N-(6-amino-5-methyl-3-pyridyl)- 2-[(2S,5R)-5-methyl-2-(2-oxyindolin-4-yl)-1-piperidinyl]-2-oxyacetamide (44 mg, 107.98 μmol, 21.08% yield).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.98(m,3H),1.24(m,1H),1.98(m,7H),3.45(m,3H),5.46(m,3H),6.69(m,1H),6.94(m,1H),7.17(m,1H),7.35(m,1H),7.89(m,1H),10.43(m,2H)。 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 0.98 (m, 3H), 1.24 (m, 1H), 1.98 (m, 7H), 3.45 (m, 3H), 5.46 (m, 3H), 6.69 (m, 1H), 6.94 (m, 1H), 7.17 (m, 1H), 7.35 (m, 1H), 7.89 (m, 1H), 10.43 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值407.2；實測值408.2；Rt=1.816min。LCMS (ESI): [M+H] + m/z: calculated 407.2; found 408.2; Rt=1.816 min.

實例757. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噻唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物129)之合成Example 757. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(1,3-benzothiazol-4-yl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide (Compound 129)

Figure 110128222-A0202-12-2427-465
Figure 110128222-A0202-12-2427-465

步驟1：6-(1,3-苯并噻唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(1,3-benzothiazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.5g，28.67mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(7.13g，27.31mmol)及碳酸鈉(8.68g，81.93mmol，3.43mL)於二噁烷(100mL)及水(25mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加Pd(dppf)Cl2* DCM(1.12g，1.37mmol)。將所得混合物除氣，用Ar再填充且在60℃下攪拌12h。過濾出沉澱，將其用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於150ml水中且用EtOAc(2* 100ml)萃取。將經合併之有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(9g)。藉由梯度層析純化粗產物(SiO2 ，己烷-EtOAc)，以獲得6-(1,3-苯并噻唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.5g，11.06mmol，40.50%產率)。6-(Trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.5 g, 28.67 mmol), 4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (7.13 g, 27.31 mmol) and sodium carbonate (8.68 g, 81.93 mmol, A suspension of 3.43 mL) in dioxane (100 mL) and water (25 mL) was degassed and refilled three times with Ar. To this solution was added Pd(dppf)Cl2 * DCM (1.12 g, 1.37 mmol). The resulting mixture was degassed, refilled with Ar and stirred at 60 °C for 12 h. The precipitate was filtered off and washed with dioxane (50ml). The solvent was evaporated in vacuo and the residue was dissolved in 150 ml of water and extracted with EtOAc (2 * 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (9 g). The crude product was purified by gradient chromatography ( SiO2 , hexane-EtOAc) to obtain 6-(1,3-benzothiazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid Tertiary butyl ester (3.5 g, 11.06 mmol, 40.50% yield).

1 H NMR(500MHz,DMSO-d6 )δ 0.89(s,9H),1.92(m,2H),2.33(m,2H),3.74(m,2H),5.36(m,1H),7.36(m,2H),7.94(d,1H),9.21(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.89(s, 9H), 1.92(m, 2H), 2.33(m, 2H), 3.74(m, 2H), 5.36(m, 1H), 7.36(m , 2H), 7.94 (d, 1H), 9.21 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值216.2；實測值217.2；Rt=1.540min。LCMS (ESI): [M-Boc] + m/z: calculated 216.2; found 217.2; Rt=1.540 min.

步驟2：4-(2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑之合成Step 2: Synthesis of 4-(2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole

將6-(1,3-苯并噻唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.5g，11.06mmol)溶解於三氟乙酸(12.61g，110.61mmol，8.52mL)中。將所得混合物 在25℃下攪拌2h(直至氣體逸出結束)。將溶液之pH用10% NaOH溶液調節至8且用DCM(3* 70ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得4-(2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(2.3g，10.63mmol，96.13%產率)。6-(1,3-Benzothiazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.5 g, 11.06 mmol) was dissolved in trifluoroacetic acid (12.61 g) , 110.61 mmol, 8.52 mL). The resulting mixture was stirred at 25°C for 2 h (until gas evolution was complete). The pH of the solution was adjusted to 8 with 10% NaOH solution and extracted with DCM (3 * 70ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated in vacuo to give 4-(2,3,4,5-tetrahydropyridin-6-yl)-1,3 - benzothiazole (2.3 g, 10.63 mmol, 96.13% yield).

1 H NMR(500MHz,DMSO-d6 )δ 1.64(m,2H),1.76(m,2H),2.91(m,2H),3.73(m,2H),7.47(dd,1H),7.59(d,1H),8.17(d,1H),9.41(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.64(m, 2H), 1.76(m, 2H), 2.91(m, 2H), 3.73(m, 2H), 7.47(dd, 1H), 7.59(d , 1H), 8.17(d, 1H), 9.41(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值216.2；實測值217.2；Rt=0.727min。LCMS (ESI): [M+H] + m/z: calculated 216.2; found 217.2; Rt=0.727 min.

步驟3：4-(2-哌啶基)-1,3-苯并噻唑之合成Step 3: Synthesis of 4-(2-piperidinyl)-1,3-benzothiazole

在0℃下，向4-(2,3,4,5-四氫吡啶-6-基)-1,3-苯并噻唑(2.3g，10.63mmol)於MeOH(50mL)中之溶液中分批添加硼氫化鈉(402.29mg，10.63mmol，375.97μL)。將所得混合物在環境溫度下攪拌2h且蒸發。將殘餘物溶解於水(50ml)中且用DCM(3* 50ml)萃取。將經合併之有機層用鹽水(2* 40ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得4-(2-哌啶基)-1,3-苯并噻唑(1.75g，8.02mmol，75.38%產率)。To a solution of 4-(2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzothiazole (2.3 g, 10.63 mmol) in MeOH (50 mL) at 0 °C Sodium borohydride (402.29 mg, 10.63 mmol, 375.97 μL) was added in batches. The resulting mixture was stirred at ambient temperature for 2 h and evaporated. The residue was dissolved in water (50ml) and extracted with DCM (3 * 50ml). The combined organic layers were washed with brine (2 * 40ml), dried over Na2SO4 and evaporated in vacuo to give 4- (2-piperidinyl)-1,3-benzothiazole (1.75g, 8.02 mmol, 75.38% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.48(m,4H),1.88(m,2H),2.74(m,1H),3.11(m,1H),4.46(m,1H),7.44(dd,1H),7.50(d,1H),8.00(d,1H),9.37(s,1H)，未觀測到NH。 1 H NMR (400MHz, DMSO-d 6 )δ 1.48(m, 4H), 1.88(m, 2H), 2.74(m, 1H), 3.11(m, 1H), 4.46(m, 1H), 7.44(dd , 1H), 7.50 (d, 1H), 8.00 (d, 1H), 9.37 (s, 1H), no NH was observed.

LCMS(ESI)：[M+H]+ m/z：計算值218.1；實測值219.0；Rt=0.877min。LCMS (ESI): [M+H] + m/z: calculated 218.1; found 219.0; Rt=0.877 min.

步驟4：N-[5-[[2-[2-(1,3-苯并噻唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[5-[[2-[2-(1,3-benzothiazol-4-yl)-1-piperidinyl]-2-oxyacetoxy]amino]-3 -Synthesis of tert-butyl methyl-2-pyridyl]carbamate

向4-(2-哌啶基)-1,3-苯并噻唑(0.4g，1.83mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(541.03mg，1.83mmol)及HATU(696.66mg，1.83mmol)於DMF(3mL)中之懸浮液中添加三乙胺(927.00mg，9.16mmol，1.28mL)。將所得混合物在環境溫度下攪拌12h，溶解於水(40ml)中且用 EtOAc(3* 20ml)萃取。將經合併之有機層用鹽水(3* 20ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得N-[5-[[2-[2-(1,3-苯并噻唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.9g，粗品)。此化合物不經純化即用於下一步驟。To 4-(2-piperidinyl)-1,3-benzothiazole (0.4 g, 1.83 mmol), 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3- Pyridyl]amino]-2-oxoacetic acid (541.03 mg, 1.83 mmol) and HATU (696.66 mg, 1.83 mmol) in DMF (3 mL) was added triethylamine (927.00 mg, 9.16 mmol, 1.28mL). The resulting mixture was stirred at ambient temperature for 12h, dissolved in water (40ml) and extracted with EtOAc (3 * 20ml). The combined organic layers were washed with brine (3 * 20ml), dried over Na2SO4 and evaporated to obtain N-[5-[[2-[2-(1,3-benzothiazol-4-yl )-1-piperidinyl]-2-oxoacetoxy]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (0.9 g, crude). This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.43(s,9H),1.59(m,2H),1.74(m,2H),1.98(m,2H),2.19(s,3H),2.68(m,2H),3.67(m,1H),3.93(m,1H),7.41(m,2H),8.12(m,1H),8.46(m,1H),9.07(m,1H),9.44(m,1H),11.02(m,1H) 1 H NMR (400MHz, DMSO-d 6 )δ 1.43(s, 9H), 1.59(m, 2H), 1.74(m, 2H), 1.98(m, 2H), 2.19(s, 3H), 2.68(m ,2H),3.67(m,1H),3.93(m,1H),7.41(m,2H),8.12(m,1H),8.46(m,1H),9.07(m,1H),9.44(m, 1H),11.02(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值495.2；實測值496.2；Rt=1.316min。LCMS (ESI): [M+H] + m/z: calculated 495.2; found 496.2; Rt=1.316 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噻唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物129 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridinyl)-2-[2-(1,3-benzothiazol-4-yl)-1-piperidinyl]-2- Synthesis of Pendant Oxyacetamide ( Compound 129 )

向N-[5-[[2-[2-(1,3-苯并噻唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.9g，1.82mmol)於DCM(20mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌12h且在真空中蒸發，以獲得粗產物(0.8g)。藉由HPLC(40/60% 0-4min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量395，管柱：YMC Triart C18 100* 20mm，5um)純化粗產物，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噻唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(311mg，786.39μmol，43.30%產率)。To N-[5-[[2-[2-(1,3-benzothiazol-4-yl)-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl To a solution of tert-butyl-2-pyridyl]carbamate (0.9 g, 1.82 mmol) in DCM (20 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (8.00 g, 219.41 mmol, 10 mL). The resulting mixture was stirred at 25 °C for 12 h and evaporated in vacuo to obtain crude product (0.8 g). The crude was purified by HPLC (40/60% 0-4min 0.1% NH3 -methanol, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 395, column: YMC Triart C18 100 * 20mm, 5um) product to give N-(6-amino-5-methyl-3-pyridinyl)-2-[2-(1,3-benzothiazol-4-yl)-1-piperidinyl]-2 - Pendant oxyacetamide (311 mg, 786.39 μmol, 43.30% yield).

1 H NMR(500MHz,DMSO+CCl4)δ 1.31(m,1H),1.63(m,2H),1.75(m,1H),2.06(m,3H),2.65(m,1H),3.10(m,1H),3.66(m,1H),4.20(m,1H),5.69(m,2H),6.09(m,1H),7.34(m,1H),7.51(m,2H),7.98(m,1H),8.10(m,1H),9.40(m,1H),10.40(m,1H)。 1 H NMR(500MHz, DMSO+CCl4)δ 1.31(m,1H), 1.63(m,2H), 1.75(m,1H), 2.06(m,3H), 2.65(m,1H), 3.10(m, 1H), 3.66(m, 1H), 4.20(m, 1H), 5.69(m, 2H), 6.09(m, 1H), 7.34(m, 1H), 7.51(m, 2H), 7.98(m, 1H) ), 8.10(m, 1H), 9.40(m, 1H), 10.40(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值395.1；實測值396.2；Rt=2.325min。LCMS (ESI): [M+H] + m/z: calculated 395.1; found 396.2; Rt=2.325 min.

實例758. N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噁唑-4-基)-1-哌啶基]-2-Example 758. N-(6-Amino-5-methyl-3-pyridyl)-2-[2-(1,3-benzoxazol-4-yl)-1-piperidinyl]-2 - 側氧基乙醯胺(化合物140)之合成Synthesis of Pendant Oxyacetamide (Compound 140)

Figure 110128222-A0202-12-2430-466
Figure 110128222-A0202-12-2430-466

步驟1：6-(1,3-苯并噁唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(1,3-benzoxazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(9.5g，28.67mmol)、4-(4,4,5,5-四甲基-1,3-二氧環戊烷-2-基)-1,3-苯并噁唑(6.95g，28.11mmol)及碳酸鈉(8.94g，84.34mmol，3.53mL)於二噁烷(100mL)及水(25mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加Pd(dppf)Cl2* DCM(918.29mg，1.12mmol)。將所得混合物除氣，用Ar再填充且在65℃下攪拌12h。過濾出沉澱，將其用二噁烷(50ml)洗滌。在真空中蒸發溶劑且將殘餘物溶解於150ml水中且用EtOAc(2* 100ml)萃取。將經合併之有機層用鹽水(100ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得粗產物(9g)。藉由梯度層析(SiO2 ，己烷-EtOAc)純化粗產物，以獲得6-(1,3-苯并噁唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.5g，11.65mmol，41.45%產率)。6-(Trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.5 g, 28.67 mmol), 4-(4,4,5, 5-Tetramethyl-1,3-dioxolan-2-yl)-1,3-benzoxazole (6.95 g, 28.11 mmol) and sodium carbonate (8.94 g, 84.34 mmol, 3.53 mL) were dissolved in A suspension in dioxane (100 mL) and water (25 mL) was degassed and refilled three times with Ar. To this solution was added Pd(dppf)Cl2 * DCM (918.29 mg, 1.12 mmol). The resulting mixture was degassed, refilled with Ar and stirred at 65 °C for 12 h. The precipitate was filtered off and washed with dioxane (50ml). The solvent was evaporated in vacuo and the residue was dissolved in 150 ml of water and extracted with EtOAc (2 * 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and evaporated to obtain crude product (9 g). The crude product was purified by gradient chromatography ( SiO2 , hexane-EtOAc) to obtain 6-(1,3-benzoxazol-4-yl)-3,4-dihydro-2H-pyridine-1- 3-Butyl formate (3.5 g, 11.65 mmol, 41.45% yield).

1 H NMR(500MHz,DMSO-d6 )δ 0.85(s,9H),1.89(m,2H),2.35(m,2H),3.71(m,2H),5.59(m,1H),7.20(d,1H),7.30(dd,1H),7.49(d,1H),8.50(s,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.85(s, 9H), 1.89(m, 2H), 2.35(m, 2H), 3.71(m, 2H), 5.59(m, 1H), 7.20(d , 1H), 7.30 (dd, 1H), 7.49 (d, 1H), 8.50 (s, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值200.1；實測值201.2；Rt=1.482min。LCMS (ESI): [M-Boc] + m/z: calculated 200.1; found 201.2; Rt=1.482 min.

步驟2：4-(2,3,4,5-四氫吡啶-6-基)-1,3-苯并噁唑之合成Step 2: Synthesis of 4-(2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzoxazole

將6-(1,3-苯并噁唑-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(3.5g，11.65mmol)溶解於三氟乙酸(14.80g，129.80mmol，10mL)中。將所得混合物在 25℃下攪拌2h(直至氣體逸出結束)。將溶液之pH用10% NaOH溶液調節至8且用DCM(3* 70ml)萃取。將經合併之有機層用鹽水(50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得4-(2,3,4,5-四氫吡啶-6-基)-1,3-苯并噁唑(2.05g，10.24mmol，87.86%產率)。6-(1,3-Benzoxazol-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.5 g, 11.65 mmol) was dissolved in trifluoroacetic acid (14.80 g, 129.80 mmol, 10 mL). The resulting mixture was stirred at 25°C for 2 h (until gas evolution was complete). The pH of the solution was adjusted to 8 with 10% NaOH solution and extracted with DCM (3 * 70ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and evaporated in vacuo to give 4-(2,3,4,5-tetrahydropyridin-6-yl)-1,3 - Benzoxazole (2.05 g, 10.24 mmol, 87.86% yield).

1 H NMR(500MHz,CDCl3 )δ 1.73(m,2H),1.88(m,2H),3.00(m,2H),3.89(m,2H),7.39(dd,1H),7.58(d,1H),7.69(d,1H),8.09(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.73 (m, 2H), 1.88 (m, 2H), 3.00 (m, 2H), 3.89 (m, 2H), 7.39 (dd, 1H), 7.58 (d, 1H) ), 7.69(d, 1H), 8.09(s, 1H).

步驟3：4-(2-哌啶基)-1,3-苯并噁唑之合成Step 3: Synthesis of 4-(2-piperidinyl)-1,3-benzoxazole

在0℃下，向4-(2,3,4,5-四氫吡啶-6-基)-1,3-苯并噁唑(2.05g，10.24mmol)於MeOH中之溶液中分批添加硼氫化鈉(387.33mg，10.24mmol，361.99μL)。將所得混合物在環境溫度下攪拌2h且蒸發。將殘餘物溶解於水(50ml)中且用DCM(3* 50ml)萃取。將經合併之有機層用鹽水(2* 40ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得4-(2-哌啶基)-1,3-苯并噁唑(1.45g，粗品)。To a solution of 4-(2,3,4,5-tetrahydropyridin-6-yl)-1,3-benzoxazole (2.05 g, 10.24 mmol) in MeOH was added portionwise at 0 °C Sodium borohydride (387.33 mg, 10.24 mmol, 361.99 [mu]L). The resulting mixture was stirred at ambient temperature for 2 h and evaporated. The residue was dissolved in water (50ml) and extracted with DCM (3 * 50ml). The combined organic layers were washed with brine (2 * 40ml), dried over Na2SO4 and evaporated in vacuo to give 4- (2-piperidinyl)-1,3-benzoxazole (1.45g) ,Crude).

1 H NMR(500MHz,DMSO-d6 )δ 1.44(m,4H),1.85(m,2H),2.70(m,1H),3.10(m,1H),4.15(m,1H),7.39(m,2H),7.59(d,1H),8.69(s,1H)，未觀測到NH。 1 H NMR (500MHz, DMSO-d 6 )δ 1.44(m, 4H), 1.85(m, 2H), 2.70(m, 1H), 3.10(m, 1H), 4.15(m, 1H), 7.39(m , 2H), 7.59(d, 1H), 8.69(s, 1H), no NH was observed.

LCMS(ESI)：[M+H]+ m/z：計算值202.1；實測值203.2；Rt=0.666min。LCMS (ESI): [M+H] + m/z: calculated 202.1; found 203.2; Rt=0.666 min.

步驟4：N-[5-[[2-[2-(1,3-苯并噁唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[5-[[2-[2-(1,3-benzoxazol-4-yl)-1-piperidinyl]-2-oxyacetyl]amino]- Synthesis of 3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向4-(2-哌啶基)-1,3-苯并噁唑(0.4g，1.98mmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(584.01mg，1.98mmol)及HATU(751.99mg，1.98mmol)於DMF(3mL)中之懸浮液中添加三乙胺(1.00g，9.89mmol，1.38mL)。將所得混合物在環境溫度下攪拌12h，溶解於水(40ml)中且用EtOAc(3* 20ml)萃取。將經合併之有機層用鹽水(3* 20ml)洗滌，經Na2 SO4 乾燥且蒸發，以獲得N-[5-[[2-[2-(1,3-苯并噁唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.8g，粗品)。此化合物不經純化即用於下一步 驟。To 4-(2-piperidinyl)-1,3-benzoxazole (0.4 g, 1.98 mmol), 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3 -Pyridinyl]amino]-2-oxoacetic acid (584.01 mg, 1.98 mmol) and HATU (751.99 mg, 1.98 mmol) in DMF (3 mL) was added triethylamine (1.00 g, 9.89 mmol) , 1.38mL). The resulting mixture was stirred at ambient temperature for 12h, dissolved in water (40ml) and extracted with EtOAc (3 * 20ml). The combined organic layers were washed with brine (3 * 20ml), dried over Na2SO4 and evaporated to obtain N-[5-[[2-[2-(1,3-benzoxazole-4- (0.8 g, crude). This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.45(s,9H),1.64(m,4H),2.19(s,3H),2.95(m,2H),3.89(m,1H),5.69(m,1H),5.98(m,1H),6.99(d,1H),7.25(dd,1H),7.48(d,1H),8.19(s,1H),8.31(s,1H),8.79(s,1H),9.07(s,1H),11.02(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.45(s, 9H), 1.64(m, 4H), 2.19(s, 3H), 2.95(m, 2H), 3.89(m, 1H), 5.69(m ,1H),5.98(m,1H),6.99(d,1H),7.25(dd,1H),7.48(d,1H),8.19(s,1H),8.31(s,1H),8.79(s, 1H), 9.07 (s, 1H), 11.02 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值479.2；實測值480.2；Rt=1.21min。LCMS (ESI): [M+H] + m/z: calculated 479.2; found 480.2; Rt=1.21 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噁唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(化合物140 )之合成Step 5: N-(6-Amino-5-methyl-3-pyridinyl)-2-[2-(1,3-benzoxazol-4-yl)-1-piperidinyl]-2 - Synthesis of Pendant Oxyacetamide ( Compound 140 )

向N-[5-[[2-[2-(1,3-苯并噁唑-4-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(0.8g，1.67mmol)於DCM(20mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌12h且在真空中蒸發，以獲得粗產物(0.8g)。藉由HPLC(0-5min 30-80%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))管柱：YMC-Actus Triart C18 100* 20mml.D.S-5um)純化粗產物，以得到N-(6-胺基-5-甲基-3-吡啶基)-2-[2-(1,3-苯并噁唑-4-基)-1-哌啶基]-2-側氧基乙醯胺(250mg，658.92μmol，39.50%產率)。To N-[5-[[2-[2-(1,3-benzoxazol-4-yl)-1-piperidinyl]-2-oxyacetoxy]amino]-3- To a solution of tert-butyl methyl-2-pyridyl]carbamate (0.8 g, 1.67 mmol) in DCM (20 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (8.00 g, 219.41 mmol, 10 mL) . The resulting mixture was stirred at 25 °C for 12 h and evaporated in vacuo to obtain crude product (0.8 g). By HPLC (0-5min 30-80% water-methanol ( NH3 0.1%), flow rate 30ml/min (load pump 4ml/min methanol ( NH3 0.1%)) Column: YMC-Actus Triart C18 100 * 20mml .DS-5um) to purify the crude product to give N-(6-amino-5-methyl-3-pyridyl)-2-[2-(1,3-benzoxazol-4-yl)- 1-Piperidinyl]-2-oxoacetamide (250 mg, 658.92 μmol, 39.50% yield).

1 H NMR(400MHz,DMSO-d6 )δ 1.29(m,1H),1.62(m,3H),2.01(m,4H),2.99(m,1H),3.41(m,1H),4.02(m,1H),5.62(m,3H),7.26(m,1H),7.49(m,2H),7.71(m,1H),8.07(m,1H),8.79(m,1H),10.52(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.29(m,1H), 1.62(m,3H), 2.01(m,4H), 2.99(m,1H), 3.41(m,1H), 4.02(m ,1H),5.62(m,3H),7.26(m,1H),7.49(m,2H),7.71(m,1H),8.07(m,1H),8.79(m,1H),10.52(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值397.2；實測值；Rt=0.939min。LCMS (ESI): [M+H] + m/z: calculated 397.2; found; Rt=0.939 min.

實例759.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5R )-2-(3,3-二甲基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物150)之合成Example 759. N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5R )-2-(3,3-dimethylcyclohexyl)-5-methyl Synthesis of yl-1-piperidinyl]-2-oxoacetamide (Compound 150)

Figure 110128222-A0202-12-2433-467
Figure 110128222-A0202-12-2433-467

步驟1：6-(5,5-二甲基環己烯-1-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(5,5-Dimethylcyclohexen-1-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

向3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(8.04g，23.29mmol)及2-(5,5-二甲基環己烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(5g，21.17mmol)於二噁烷(90mL)中之經攪拌之溶液中添加碳酸鈉(6.73g，63.52mmol，2.66mL)於水(30mL)中之溶液。將所得混合物用氬氣吹掃。然後，添加Pd(dppf)Cl2 (864.50mg，1.06mmol)且將所得反應混合物在80℃下攪拌14小時。14小時之後，在減壓下濃縮反應混合物且藉由管柱層析純化殘餘物，以獲得呈無色油狀物之產物6-(5,5-二甲基環己烯-1-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.70g，5.57mmol，26.29%)。To 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (8.04 g, 23.29 mmol) and 2-( 5,5-Dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 21.17 mmol) in two To the stirred solution in oxane (90 mL) was added a solution of sodium carbonate (6.73 g, 63.52 mmol, 2.66 mL) in water (30 mL). The resulting mixture was purged with argon. Then, Pd(dppf)Cl2 ( 864.50 mg, 1.06 mmol) was added and the resulting reaction mixture was stirred at 80°C for 14 hours. After 14 hours, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the product 6-(5,5-dimethylcyclohexen-1-yl)- as a colorless oil 3-Methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (1.70 g, 5.57 mmol, 26.29%).

LCMS(ESI)：[M+Boc]+ m/z：計算值305.3；實測值250.2(t -Bu裂解之產物質量)；Rt=1.954min。LCMS (ESI): [M+Boc] + m/z: calculated 305.3; found 250.2 ( t -Bu cleavage product mass); Rt=1.954 min.

步驟2：6-(5,5-二甲基環己烯-1-基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 2: Synthesis of 6-(5,5-Dimethylcyclohexen-1-yl)-3-methyl-2,3,4,5-tetrahydropyridine

將6-(5,5-二甲基環己烯-1-基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.7g，5.57mmol)及三氟乙酸(20g，175.41mmol，13.51mL)之混合物在25℃下攪拌3小時。3小時之後，逐滴添加20% NaOH水溶液(15g)。將所得懸浮液用DCM(2 x 100mL)萃取。將經合併之有機層用水(100mL)、鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以得到呈無色油狀物之產物6-(5,5-二甲基環己烯-1-基)-3-甲基-2,3,4,5-四氫吡啶(1.2g，粗品)。粗產物不經任何進一步純化即用於下一步 反應。6-(5,5-Dimethylcyclohexen-1-yl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (1.7 g, 5.57 mmol ) and trifluoroacetic acid (20 g, 175.41 mmol, 13.51 mL) were stirred at 25°C for 3 hours. After 3 hours, 20% aqueous NaOH (15 g) was added dropwise. The resulting suspension was extracted with DCM (2 x 100 mL). The combined organic layers were washed with water (100 mL), brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the product 6-(5,5-dimethylcyclohexene- as a colorless oil) 1-yl)-3-methyl-2,3,4,5-tetrahydropyridine (1.2 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值205.2；實測值206.2；Rt=1.018min。LCMS (ESI): [M+H] + m/z: calculated 205.2; found 206.2; Rt=1.018 min.

步驟3：2-(5,5-二甲基環己烯-1-基)-5-甲基哌啶之合成Step 3: Synthesis of 2-(5,5-Dimethylcyclohexen-1-yl)-5-methylpiperidine

向6-(5,5-二甲基環己烯-1-基)-3-甲基-2,3,4,5-四氫吡啶(1.2g，5.84mmol)於MeOH(25mL)中之經攪拌之溶液中添加硼氫化鈉(221.09mg，5.84mmol)。將所得反應混合物在25℃下攪拌4小時。4小時之後，在減壓下濃縮反應混合物。將所獲得之殘餘物用水(70mL)稀釋且用DCM(2 x 100mL)萃取。將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈淡黃色油狀物之2-(5,5-二甲基環己烯-1-基)-5-甲基哌啶(0.9g，4.34mmol，74.27%產率)。粗產物不經任何進一步純化即用於下一步反應。To 6-(5,5-dimethylcyclohexen-1-yl)-3-methyl-2,3,4,5-tetrahydropyridine (1.2 g, 5.84 mmol) in MeOH (25 mL) To the stirred solution was added sodium borohydride (221.09 mg, 5.84 mmol). The resulting reaction mixture was stirred at 25°C for 4 hours. After 4 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (70 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 2-(5,5-dimethylcyclohexen-1-yl) as a pale yellow oil -5-Methylpiperidine (0.9 g, 4.34 mmol, 74.27% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值207.3；實測值208.2；Rt=1.058minLCMS(ESI): [M+H] + m/z: Calculated 207.3; Measured 208.2; Rt=1.058min

步驟4：2-(3,3-二甲基環己基)-5-甲基哌啶之合成Step 4: Synthesis of 2-(3,3-Dimethylcyclohexyl)-5-methylpiperidine

在25℃、氫氣氣氛下，將2-(5,5-二甲基環己烯-1-基)-5-甲基哌啶(0.9g，4.34mmol)於MeOH(25mL)中之溶液經乾燥的487型鈀(10%於碳上)(0.1g，939.67μmol)氫化72小時。72小時之後，將反應混合物過濾，將濾餅用MeOH洗滌且蒸發濾液，以得到呈黃色油狀物之2-(3,3-二甲基環己基)-5-甲基哌啶(0.6g，2.87mmol，66.02%產率)。粗產物不經任何進一步純化即用於下一步反應。A solution of 2-(5,5-dimethylcyclohexen-1-yl)-5-methylpiperidine (0.9 g, 4.34 mmol) in MeOH (25 mL) was added to Dry palladium type 487 (10% on carbon) (0.1 g, 939.67 μmol) was hydrogenated for 72 hours. After 72 hours, the reaction mixture was filtered, the filter cake was washed with MeOH and the filtrate was evaporated to give 2-(3,3-dimethylcyclohexyl)-5-methylpiperidine (0.6 g) as a yellow oil , 2.87 mmol, 66.02% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值209.3；實測值210.2；Rt=1.016min。LCMS (ESI): [M+H] + m/z: calculated 209.3; found 210.2; Rt=1.016 min.

步驟5：N-[5-[[2-[2-(3,3-二甲基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 5: N-[5-[[2-[2-(3,3-Dimethylcyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino Synthesis of tert-butyl ]-3-methyl-2-pyridyl]carbamate

向2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(423.11mg，1.43mmol)、2-(3,3-二甲基環己基)-5-甲基哌啶(0.3g，1.43mmol)及HATU(599.30mg，1.58mmol)於DMF(1mL)中之經攪拌之溶液中添加三乙胺(579.97mg，5.73mmol，798.86μL)。將所得反應混合物在25℃下攪拌4小時。4 小時之後，藉由反相HPLC(溶析液：50-100%，0-6min，水-乙腈；流速：30mL/min；裝載泵：4mL/min，乙腈；管柱：SunFireC18 100x19mm 5um)純化反應混合物，以得到N -[5-[[2-[2-(3,3-二甲基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.19g，390.43μmol，27.25%產率)。To 2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (423.11 mg, 1.43 mmol), 2-(3 ,3-dimethylcyclohexyl)-5-methylpiperidine (0.3 g, 1.43 mmol) and HATU (599.30 mg, 1.58 mmol) in DMF (1 mL) was added triethylamine (579.97 mmol) to a stirred solution of mg, 5.73 mmol, 798.86 μL). The resulting reaction mixture was stirred at 25°C for 4 hours. After 4 hours, purified by reverse phase HPLC (eluent: 50-100%, 0-6 min, water-acetonitrile; flow rate: 30 mL/min; loading pump: 4 mL/min, acetonitrile; column: SunFire C18 100x19mm 5um) Reaction mixture to give N- [5-[[2-[2-(3,3-dimethylcyclohexyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl] Amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.19 g, 390.43 [mu]mol, 27.25% yield).

LCMS(ESI)：[M+H]+ m/z：計算值486.4；實測值487.4；Rt=4.673min。LCMS (ESI): [M+H] + m/z: calculated 486.4; found 487.4; Rt=4.673 min.

步驟6：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3,3-二甲基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物150 )之合成Step 6: N-(6-Amino-5-methyl-3-pyridyl)-2-[(2S,5R)-2-(3,3-dimethylcyclohexyl)-5-methyl- Synthesis of 1-Piperidinyl]-2-Oxyacetamide ( Compound 150 )

將N -[5-[[2-[2-(3,3-二甲基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.14g，287.68μmol)及於二噁烷中之4M氯化氫溶液(104.89mg，2.88mmol，131.12μL)之混合物在25℃下攪拌2小時。2小時之後，藉由反相HPLC(溶析液：0-1-6min，65-65-70%，水-0.1% NH3 -甲醇；流速：30mL/min；裝載泵：4mL/min；管柱：YMC-Triart C18 100 x 20mm，5um)純化反應混合物，以得到呈灰白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R)-2-(3,3-二甲基環己基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(化合物150 ，25mg，64.68μmol，22.48%產率)。 N- [5-[[2-[2-(3,3-Dimethylcyclohexyl)-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]- A mixture of tert-butyl 3-methyl-2-pyridyl] carbamate (0.14 g, 287.68 μmol) and a 4M solution of hydrogen chloride in dioxane (104.89 mg, 2.88 mmol, 131.12 μL) was stirred at 25 °C 2 hours. After 2 hours, by reverse phase HPLC (eluent: 0-1-6 min, 65-65-70%, water-0.1% NH3 -methanol; flow rate: 30 mL/min; loading pump: 4 mL/min; tube Column: YMC-Triart C18 100 x 20mm, 5um) The reaction mixture was purified to give N- (6-amino-5-methyl-3-pyridyl)-2-[(2S,5R)- as an off-white solid 2-(3,3-Dimethylcyclohexyl)-5-methyl-1-piperidinyl]-2-oxyacetamide ( Compound 150 , 25 mg, 64.68 μmol, 22.48% yield).

1 H NMR(CDCl3 ,400MHz)：δ(ppm)0.87(m,8H),1.01(m,3H),1.35(m,4H),1.61(m,3H),1.82(m,2H),1.99(m,3H),2.12(s,3H),3.08(m,1H),4.23(m,1H),4.50(m,2H),4.73(m,1H),7.71(m,1H),8.04(m,1H),9.06(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 0.87 (m, 8H), 1.01 (m, 3H), 1.35 (m, 4H), 1.61 (m, 3H), 1.82 (m, 2H), 1.99 (m, 3H), 2.12(s, 3H), 3.08(m, 1H), 4.23(m, 1H), 4.50(m, 2H), 4.73(m, 1H), 7.71(m, 1H), 8.04( m, 1H), 9.06 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值386.3；實測值387.2；Rt=3.476min。LCMS (ESI): [M+H] + m/z: calculated 386.3; found 387.2; Rt=3.476 min.

實例760.N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-1-哌啶基]乙醯胺及N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-二級丁基-1-哌啶基)乙醯胺(化合物217及化合物232)之合成Example 760. N- (6-Amino-5-methyl-3-pyridyl)-2-oxy-2-[2-[3-(trifluoromethyl)-1-bicyclo[1.1.1 ]pentyl]-1-piperidinyl]acetamide and N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-(2-secondarybutyl- Synthesis of 1-Piperidinyl)acetamide (Compound 217 and Compound 232)

Figure 110128222-A0202-12-2436-468
Figure 110128222-A0202-12-2436-468

步驟1：6-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-碘-1-(三氟甲基)雙環[1.1.1]戊烷(2g，7.63mmol)溶解於乙醚(20mL)中且在氬氣氣氛下冷卻至-78℃。經由注射器逐滴添加第三丁基 鋰(18%於戊烷中)(5.70g，16.03mmol，8.44mL)，同時保持溫度低於-70℃。將所得溶液在-70℃下攪拌1小時。1小時之後，逐滴添加氯化鋅(無水)(1.14g，8.40mmol)於四氫呋喃(10mL)中之溶液。使所得反應混合物升溫至室溫且在同一溫度下攪拌1小時。此後，添加6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(2.53g，7.63mmol)且將所得混合物加熱至50℃，直到大部分乙醚被蒸發。將所獲得之殘餘物用四氫呋喃(20mL)稀釋且分成2個相等部分。向第一部分中添加Pd(dppf)Cl2 ˙CH2 Cl2 (62.34mg，76.33μmol)且向第二部分中添加肆(三苯基磷烷)鈀(0)(99.8%(基於金屬)，Pd 9% min)(88.21mg，76.33μmol)。將兩種所得混合物在60℃下攪拌15小時。GCMS及NMR指示在Pd(dppf)Cl2 ˙CH2 Cl2 之情況下之更好轉化。將反應(第1部分)混合物用飽和K2 CO3 溶液(4mL)淬滅且攪拌5分鐘。5分鐘之後，將有機層分離，經K2 CO3 乾燥且在減壓下濃縮，以獲得呈棕色油狀物之6-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.1g，3.47mmol，90.82%產率)。3-Iodo-1-(trifluoromethyl)bicyclo[1.1.1]pentane (2 g, 7.63 mmol) was dissolved in diethyl ether (20 mL) and cooled to -78 °C under argon atmosphere. Tertiary- butyllithium (18% in pentane) (5.70 g, 16.03 mmol, 8.44 mL) was added dropwise via syringe while keeping the temperature below -70 °C. The resulting solution was stirred at -70°C for 1 hour. After 1 hour, a solution of zinc chloride (anhydrous) (1.14 g, 8.40 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting reaction mixture was warmed to room temperature and stirred at the same temperature for 1 hour. After this time, tert- butyl 6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylate (2.53 g, 7.63 mmol) was added and the resulting mixture was heated to 50 °C until most of the ether has evaporated. The obtained residue was diluted with tetrahydrofuran (20 mL) and divided into 2 equal portions. To the first part was added Pd(dppf) Cl2˙CH2Cl2 (62.34 mg , 76.33 μmol) and to the second part tetra(triphenylphosphine)palladium(0) (99.8% (metal based), Pd 9% min) (88.21 mg, 76.33 μmol). The two resulting mixtures were stirred at 60°C for 15 hours. GCMS and NMR indicated better conversion in the case of Pd( dppf ) Cl2˙CH2Cl2 . The reaction (Part 1 ) mixture was quenched with saturated K2CO3 solution ( 4 mL) and stirred for 5 minutes. After 5 minutes, the organic layer was separated, dried over K2CO3 and concentrated under reduced pressure to give 6-[ 3- (trifluoromethyl)-1-bicyclo[1.1.1] as a brown oil Amyl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (1.1 g, 3.47 mmol, 90.82% yield).

GCMS：m/z：計算值317.2；實測值317.2；Rt=8.316min。GCMS: m/z: calculated 317.2; found 317.2; Rt=8.316 min.

步驟2：2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]哌啶之合成Step 2: Synthesis of 2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]piperidine

將三氟乙酸(13.20g，115.80mmol，8.92mL)添加到6-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.05g，3.31mmol)且將所得溶液在室溫下攪拌30分鐘。30分鐘之後，在減壓下濃縮反應混合物且將所獲得之殘餘物溶解於甲醇(20mL)中。在10分鐘期間分批添加硼氫化鈉(1.00g，26.47mmol，935.90μL)。將所得反應混合物在20℃下攪拌1小時，然後在減壓下濃縮。將所獲得之殘餘物分配於2N HCl(30mL)與MTBE(20mL)之間。將水層用K2 CO3 鹼化至pH=10且用DCM(3 x 15mL)萃取。將經合併之有機層經K2 CO3 乾燥且在真空中蒸發，以獲得呈黃色油狀物之2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]哌啶(200mg，912.22μmol，27.57%產率)。粗產物不經任何進一步純化即用於下一步反應。Trifluoroacetic acid (13.20 g, 115.80 mmol, 8.92 mL) was added to 6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]-3,4-dihydro- 2H- 3-butyl pyridine-1-carboxylate (1.05 g, 3.31 mmol) and the resulting solution was stirred at room temperature for 30 minutes. After 30 minutes, the reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in methanol (20 mL). Sodium borohydride (1.00 g, 26.47 mmol, 935.90 μL) was added portionwise over 10 minutes. The resulting reaction mixture was stirred at 20°C for 1 hour and then concentrated under reduced pressure. The obtained residue was partitioned between 2N HCl (30 mL) and MTBE (20 mL). The aqueous layer was basified with K2CO3 to pH= 10 and extracted with DCM ( 3 x 15 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 2- [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]piperidine as a yellow oil pyridine (200 mg, 912.22 μmol, 27.57% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值219.2；實測值220.2；Rt=0.957min。LCMS (ESI): [M+H] + m/z: calculated 219.2; found 220.2; Rt=0.957 min.

步驟3：N-[3-甲基-5-[[2-側氧基-2-[2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 3: N-[3-Methyl-5-[[2-oxy-2-[2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]-1- Synthesis of tert-butyl piperidinyl]acetyl]amino]-2-pyridyl]carbamate

向2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(296.31mg，1.00mmol)、HATU(398.88mg，1.05mmol)及三乙胺(184.61mg，1.82mmol，254.29μL)於二甲基甲醯胺(3mL)中之經攪拌之溶液中添加2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]哌啶(200mg，912.22μmol)。將所得混合物在20℃下攪拌15小時。15小時之後，將反應混合物用水(15mL)稀釋且用乙酸乙酯(2 x15mL)萃取。將經合併之有機層用水(3 x10mL)及鹽水(20mL)洗滌，經Na2 SO4 乾燥且在真空中濃縮，以得到呈棕色膠狀物之N -[3-甲基-5-[[2-側氧基-2-[2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(390mg，785.47μmol，86.11%產率)。粗產物不經任何進一步純化即用於下一步反應。To 2-[[6-( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (296.31 mg, 1.00 mmol), HATU (398.88 mg , 1.05 mmol) and triethylamine (184.61 mg, 1.82 mmol, 254.29 μL) in dimethylformamide (3 mL) was added 2-[3-(trifluoromethyl)-1- Bicyclo[1.1.1]pentyl]piperidine (200 mg, 912.22 μmol). The resulting mixture was stirred at 20°C for 15 hours. After 15 hours, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with water (3 x 10 mL) and brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo to give N- [3-methyl-5-[[ as a brown gum 2-Pendant oxy-2-[2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]-1-piperidinyl]acetyl]amino]-2-pyridine tert -butyl ]carbamate (390 mg, 785.47 [mu]mol, 86.11% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+Boc]+ m/z：計算值496.3；實測值497.2；Rt=1.388min。LCMS (ESI): [M+Boc] + m/z: calculated 496.3; found 497.2; Rt=1.388 min.

步驟4：N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-[3-(三氟甲基)-1-雙環[1.1.1]Step 4: N-(6-Amino-5-methyl-3-pyridyl)-2-oxo-2-[2-[3-(trifluoromethyl)-1-bicyclo[1.1.1 ] 戊基]-1-哌啶基]乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-二級丁基-1-哌啶基)乙醯胺(化合物217 及化合物232 )之合成Amyl]-1-piperidinyl]acetamide and N-(6-amino-5-methyl-3-pyridyl)-2-oxy-2-(2-secondarybutyl-1 Synthesis of -Piperidinyl)acetamide ( Compound 217 and Compound 232 )

將於二噁烷中之4.0M氯化氫溶液(2.86g，7.85mmol，3.58mL)添加到N -[3-甲基-5-[[2-側氧基-2-[2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(390mg，785.46μmol)於二氯甲烷(5mL)中之經攪拌之溶液中。將所得反應混合物在20℃下攪拌4小時。4小時之後，將反應混合物用DCM(30mL)及10%K2 CO3 水溶液(20mL)稀釋。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。使所獲得之殘餘物經歷HPLC純化(溶析液：0-50-75%,0-1-6min，0.1% NH3 -甲醇；流速30mL/min；管柱：YMC Triart C18 100 x 20mm，5um)，以得到呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-[2-[3-(三氟甲基)-1-雙環[1.1.1]戊基]-1-哌啶基]乙醯胺(化合物217 ，111mg，280.02μmol，35.65%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基-2-(2-二級丁基-1-哌啶基)乙醯胺(化合物232 ，52mg，163.31μmol，20.79%產率)。A 4.0M solution of hydrogen chloride in dioxane (2.86 g, 7.85 mmol, 3.58 mL) was added to N- [3-methyl-5-[[2-oxy-2-[2-[3-( Trifluoromethyl)-1-bicyclo[1.1.1]pentyl]-1-piperidinyl]acetoxy]amino]-2-pyridyl]carbamic acid tert- butyl ester (390 mg, 785.46 μmol) in A stirred solution in dichloromethane (5 mL). The resulting reaction mixture was stirred at 20°C for 4 hours. After 4 hours, the reaction mixture was diluted with DCM (30 mL) and 10 % aqueous K2CO3 ( 20 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was subjected to HPLC purification (eluent: 0-50-75%, 0-1-6 min, 0.1% NH3 -methanol; flow rate 30 mL/min; column: YMC Triart C18 100 x 20 mm, 5 um ) to give N- (6-amino-5-methyl-3-pyridyl)-2-oxy-2-[2-[3-(trifluoromethyl)-1- as a white solid Bicyclo[1.1.1]pentyl]-1-piperidinyl]acetamide ( compound 217 , 111 mg, 280.02 μmol, 35.65% yield) and N-(6-amino-5-methyl-3-pyridine) yl)-2-oxy-2-(2-secondarybutyl-1-piperidinyl)acetamide ( Compound 232 , 52 mg, 163.31 μmol, 20.79% yield).

化合物217 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)1.35(m,1H),1.65(m,5H),2.01(m,9H),2.96(m,1H),4.02(m,2H),5.62(s,2H),7.48(s,1H),8.00(m,1H),10.33(m,1H)。 Compound 217 1 H NMR (DMSO- d 6 , 500MHz): δ (ppm) 1.35 (m, 1H), 1.65 (m, 5H), 2.01 (m, 9H), 2.96 (m, 1H), 4.02 (m, 2H), 5.62 (s, 2H), 7.48 (s, 1H), 8.00 (m, 1H), 10.33 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=2.654min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=2.654 min.

化合物232 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.80(d,3H),0.91(t,3H),1.26-1.51(m,3H),1.51-1.75(m,6H),1.95-2.06(m,3H),2.75-3.21(m,1H),3.50-3.98(m,1H),4.14-4.69(m,1H),5.52-5.82(m,2H),6.95-7.51(m,1H),7.56-8.09(m,1H),9.65-10.45(m,1H)。 Compound 232 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.80 (d, 3H), 0.91 (t, 3H), 1.26-1.51 (m, 3H), 1.51-1.75 (m, 6H), 1.95-2.06(m, 3H), 2.75-3.21(m, 1H), 3.50-3.98(m, 1H), 4.14-4.69(m, 1H), 5.52-5.82(m, 2H), 6.95-7.51(m , 1H), 7.56-8.09 (m, 1H), 9.65-10.45 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值318.2；實測值319.2；Rt=2.463min。LCMS (ESI): [M+H] + m/z: calculated 318.2; found 319.2; Rt=2.463 min.

實例761.N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-5-甲基-2-(2-側氧基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯胺及N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5S )-5-甲基Example 761. N- (6-amino-5-methyl-3-pyridyl)-2-[( 2R , 5S )-5-methyl-2-(2-oxy-4-piperidine Peridyl )-1-piperidinyl]-2-oxyacetamide and N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S ,5S)- 5-methyl -2-(2-側氧基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物156及化合物159)之合成- Synthesis of 2-(2-oxo-4-piperidinyl)-1-piperidinyl]-2-oxoacetamide (Compound 156 and Compound 159)

Figure 110128222-A0202-12-2439-469
Figure 110128222-A0202-12-2439-469

步驟1：4-(1-第三丁氧基羰基-3-甲基-3,4-二氫-2H-吡啶-6-基)-6-側氧基-2,3-二氫吡啶-1-甲酸第三丁酯之合成Step 1: 4-(1-Third-butoxycarbonyl-3-methyl-3,4-dihydro-2H-pyridin-6-yl)-6-side oxy-2,3-dihydropyridine- Synthesis of 3-butyl 1-formate

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(4.00g，11.58mmol)、6-側氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2,3-二氫吡啶-1-甲酸第三丁 酯(3.74g，11.58mmol)及碳酸鈉(3.68g，34.75mmol)於1,4-二噁烷(75mL)及水(25mL)中之正攪拌溶液用氬氣吹掃。然後，在氬氣下添加Pd(dppf)Cl2 (378.07mg，463.32μmol)。將反應混合物在氬氣、65℃下攪拌12小時。12小時之後，將反應混合物冷卻且過濾。將濾餅用1.4-二噁烷(2 x 20mL)洗滌且丟棄。在真空中蒸發濾液且藉由管柱層析(SiO2 ，溶析液：己烷中之0-100% MTBE)純化殘餘物，以得到呈淡棕色油狀物之4-(1-第三丁氧基 羰基-3-甲基-3,4-二氫-2H -吡啶-6-基)-6-側氧基-2,3-二氫吡啶-1-甲酸第三丁 酯(3.00g，7.64mmol，65.99%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (4.00 g, 11.58 mmol), 6-side Oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-2,3-dihydropyridine- 1 -carboxylic acid A stirring solution of tributyl ester (3.74 g, 11.58 mmol) and sodium carbonate (3.68 g, 34.75 mmol) in 1,4-dioxane (75 mL) and water (25 mL) was purged with argon. Then, Pd(dppf)Cl 2 (378.07 mg, 463.32 μmol) was added under argon. The reaction mixture was stirred under argon at 65°C for 12 hours. After 12 hours, the reaction mixture was cooled and filtered. The filter cake was washed with 1.4-dioxane (2 x 20 mL) and discarded. The filtrate was evaporated in vacuo and the residue was purified by column chromatography ( SiO2 , eluent: 0-100% MTBE in hexanes) to give 4-(l- tertiary as a light brown oil Butoxycarbonyl -3-methyl-3,4-dihydro- 2H -pyridin-6-yl)-6-oxy-2,3-dihydropyridine-1-carboxylic acid tert- butyl ester (3.00 g, 7.64 mmol, 65.99% yield).

LCMS(ESI)：[M+Boc]+ m/z：計算值392.2；實測值338.2(t -Bu裂解之產物質量)；Rt=1.591min。LCMS (ESI): [M+Boc] + m/z: calculated 392.2; found 338.2 ( t -Bu cleavage product mass); Rt=1.591 min.

步驟2：4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2,3-二氫-1H-吡啶-6-酮之合成Step 2: Synthesis of 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-2,3-dihydro-1H-pyridin-6-one

將4-(1-第三丁氧基 羰基-3-甲基-3,4-二氫-2H -吡啶-6-基)-6-側氧基 -2,3-二氫吡啶-1-甲酸第三丁 酯(1g，2.55mmol)溶解於三氟乙酸(11.62g，101.91mmol，7.85mL)中。將所得反應混合物在25℃下攪拌1小時。1小時之後，添加碎冰(20g)且將pH用氫氧化鈉珠粒(4.59g，114.65mmol，2.15mL)於水(35mL)中之溶液調節至10。將所得懸浮液用二氯甲烷(2 x 50mL)萃取。將經合併之有機相經Na2 SO4 乾燥且在減壓下蒸發，以得到呈白色固體之4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2,3-二氫-1H -吡啶-6-酮(0.35g，1.82mmol，71.45%產率)。4-(1- Third- butoxycarbonyl-3-methyl-3,4-dihydro- 2H -pyridin-6-yl)-6-oxy-2,3-dihydropyridine-1 - tert -butyl formate (1 g, 2.55 mmol) was dissolved in trifluoroacetic acid (11.62 g, 101.91 mmol, 7.85 mL). The resulting reaction mixture was stirred at 25°C for 1 hour. After 1 hour, crushed ice (20 g) was added and the pH was adjusted to 10 with a solution of sodium hydroxide beads (4.59 g, 114.65 mmol, 2.15 mL) in water (35 mL). The resulting suspension was extracted with dichloromethane (2 x 50 mL). The combined organic phases were dried over Na 2 SO 4 and evaporated under reduced pressure to give 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)- as a white solid 2,3-Dihydro-1 H -pyridin-6-one (0.35 g, 1.82 mmol, 71.45% yield).

LCMS(ESI)：[M+H]+ m/z：計算值192.2；實測值193.2；Rt=0.325min。LCMS (ESI): [M+H] + m/z: calculated 192.2; found 193.2; Rt=0.325 min.

步驟3：4-(5-甲基-2-哌啶基)-2,3-二氫-1H-吡啶-6-酮之合成Step 3: Synthesis of 4-(5-Methyl-2-piperidinyl)-2,3-dihydro-1H-pyridin-6-one

在0℃下，將硼氫化鈉(344.34mg，9.10mmol)分批添加到4-(3-甲基-2,3,4,5-四氫吡啶-6-基)-2,3-二氫-1H -吡啶-6-酮(0.35g，1.82mmol)於甲醇(10mL)中之經攪拌之溶液中。將反應混合物在0℃下攪拌1小時。1小時之後，移除冷卻浴且使反應混合物升溫至25℃。將反應混合物在同一溫度下攪拌12小時。12小時之後，在減壓下濃縮反應混合物，將殘餘物用氯仿(50mL)稀釋，攪拌30min且過濾。在真空中蒸發濾液，以得到呈淡黃色膠狀物之4-(5-甲基-2-哌啶基)-2,3-二氫-1H -吡啶-6-酮(0.27g，1.39mmol，76.34%產率)，其直接用於下一步驟中LCMS(ESI)：[M+H]+ m/z：計算值194.2；實測值195.2；Rt=0.581min。Sodium borohydride (344.34 mg, 9.10 mmol) was added portionwise to 4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)-2,3-di at 0 °C Hydrogen- 1H -pyridin-6-one (0.35 g, 1.82 mmol) in a stirred solution of methanol (10 mL). The reaction mixture was stirred at 0°C for 1 hour. After 1 hour, the cooling bath was removed and the reaction mixture was allowed to warm to 25°C. The reaction mixture was stirred at the same temperature for 12 hours. After 12 hours, the reaction mixture was concentrated under reduced pressure, the residue was diluted with chloroform (50 mL), stirred for 30 min and filtered. The filtrate was evaporated in vacuo to give 4-(5-methyl-2-piperidinyl)-2,3-dihydro-1 H -pyridin-6-one (0.27 g, 1.39 g) as a pale yellow gum mmol, 76.34% yield), which was used directly in the next step LCMS (ESI): [M+H] + m/z: calcd 194.2; found 195.2; Rt=0.581 min.

步驟4：4-(5-甲基-2-哌啶基)哌啶-2-酮之合成Step 4: Synthesis of 4-(5-methyl-2-piperidinyl)piperidin-2-one

在氫氣氣氛、25℃下，將4-(5-甲基-2-哌啶基)-2,3-二氫-1H -吡啶-6-酮(0.27g，1.39mmol)於甲醇(20mL)中之溶液經鈀(10%於碳上)(0.5g)氫化12小時。完成之後，過濾反應混合物，將濾餅用甲醇(10mL)洗滌且在減壓下濃縮濾液，以得到呈淡黃色膠狀物之4-(5-甲基-2-哌啶基)哌啶-2-酮(0.23g，1.17mmol，84.31%產率)，其直接用於下一步驟中4-(5-Methyl-2-piperidinyl)-2,3-dihydro-1 H -pyridin-6-one (0.27 g, 1.39 mmol) was dissolved in methanol (20 mL) under a hydrogen atmosphere at 25 °C ) was hydrogenated over palladium (10% on carbon) (0.5 g) for 12 hours. After completion, the reaction mixture was filtered, the filter cake was washed with methanol (10 mL) and the filtrate was concentrated under reduced pressure to give 4-(5-methyl-2-piperidinyl)piperidine- 2-keto (0.23 g, 1.17 mmol, 84.31% yield), which was used directly in the next step

LCMS(ESI)：[M+H]+ m/z：計算值196.2；實測值197.4；Rt=0.628min。LCMS (ESI): [M+H] + m/z: calculated 196.2; found 197.4; Rt=0.628 min.

步驟5：N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-(2-側氧基-4-哌啶基)-1-Step 5: N-(6-Amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-5-methyl-2-(2-oxo-4-piperidinyl )-1- 哌啶基]-2-側氧基乙醯胺及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5S)-5-甲基-2-(2-側氧基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物156 及化合物159 )之合成Piperidinyl]-2-oxyacetamide and N-(6-amino-5-methyl-3-pyridyl)-2-[(2S,5S)-5-methyl-2-( Synthesis of 2-oxo-4-piperidinyl)-1-piperidinyl]-2-oxoacetamide ( Compound 156 and Compound 159 )

向4-(5-甲基-2-哌啶基)哌啶-2-酮(230mg，1.17mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(346.01mg，1.17mmol)及HATU(445.53mg，1.17mmol)於DMF(5mL)中之經攪拌之溶液中添加三乙胺(1.19g，11.72mmol，1.63mL)。將反應混合物在25℃下攪拌1小時。1小時之後，將反應混合物在減壓下濃縮，且藉由反相HPLC純化(溶析液：30-65%，0-6min，水-甲醇；管柱：SunFireC18 100 x 19mm，5um)純化殘餘物，以得到兩種級分。To 4-(5-methyl-2-piperidinyl)piperidin-2-one (230 mg, 1.17 mmol), 2-[[6-( tert- butoxycarbonylamino)-5-methyl- To a stirred solution of 3-pyridyl]amino]-2-oxoacetic acid (346.01 mg, 1.17 mmol) and HATU (445.53 mg, 1.17 mmol) in DMF (5 mL) was added triethylamine (1.19 g) , 11.72 mmol, 1.63 mL). The reaction mixture was stirred at 25°C for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (eluent: 30-65%, 0-6 min, water-methanol; column: SunFire C18 100 x 19 mm, 5 um) to obtain two fractions.

將HPLC後之第1級分(34mg)溶解於二氯甲烷(2mL)中且添加於二噁烷中之4.0M氯化氫(2.10g，8.01mmol，2mL，13.9%純度)。將所得反應混合物在25℃下攪拌1小時。1小時之後，在真空中濃縮反應混合物且藉由反相HPLC(溶析液：5-35%，0-5min，0.1% NH3 -乙腈；管柱：YMC Triart C18 100 x 20mm，5um)純化殘餘物，以獲得呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S ,5S )-5-甲基-2-(2-側氧基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物159 ，20mg，53.55μmol，4.57%產率)。Fraction 1 after HPLC (34 mg) was dissolved in dichloromethane (2 mL) and 4.0 M hydrogen chloride in dioxane (2.10 g, 8.01 mmol, 2 mL, 13.9% purity) was added. The resulting reaction mixture was stirred at 25°C for 1 hour. After 1 hour, the reaction mixture was concentrated in vacuo and purified by reverse phase HPLC (eluent: 5-35%, 0-5 min, 0.1% NH3 -acetonitrile; column: YMC Triart C18 100 x 20 mm, 5 um) residue to obtain N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S , 5S )-5-methyl-2-(2-side as a white solid Oxy-4-piperidinyl)-1-piperidinyl]-2-oxoacetamide ( Compound 159 , 20 mg, 53.55 μmol, 4.57% yield).

將HPLC後之第2級分(94mg)溶解於二氯甲烷(2mL)中且添加於二噁烷中之4.0M氯化氫(2.10g，8.01mmol，2mL，13.9%純度)。將所得反應混合物在25℃下攪拌1小時。1小時之後，在真空中濃縮反應混合物且藉由反相HPLC(溶析液：5-40%，0-5min，0.1% NH3 -乙腈；管柱：YMC Triart C18 100 x 20mm，5um)純化殘餘物，以獲得呈白色固體之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R ,5S )-5-甲基-2-(2-側氧基-4-哌啶基)-1-哌啶基]-2-側氧基乙醯胺(化合物156 ，59mg，157.99μmol，13.48%產率)。Fraction 2 after HPLC (94 mg) was dissolved in dichloromethane (2 mL) and 4.0 M hydrogen chloride in dioxane (2.10 g, 8.01 mmol, 2 mL, 13.9% purity) was added. The resulting reaction mixture was stirred at 25°C for 1 hour. After 1 hour, the reaction mixture was concentrated in vacuo and purified by reverse phase HPLC (eluent: 5-40%, 0-5 min, 0.1% NH3 -acetonitrile; column: YMC Triart C18 100 x 20 mm, 5 um) residue to obtain N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2R , 5S )-5-methyl-2-(2-side as a white solid Oxy-4-piperidinyl)-1-piperidinyl]-2-oxoacetamide ( Compound 156 , 59 mg, 157.99 μmol, 13.48% yield).

化合物156： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.96(m,3H),1.26(m,2H),1.77 (m,5H),2.06(m,5H),2.40(m,1H),2.79(m,1H),3.15(m,2H),4.11(m,1H),5.61(m,2H),7.48(m,2H),7.96(m,1H),10.38(m,1H)。 Compound 156: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.96 (m, 3H), 1.26 (m, 2H), 1.77 (m, 5H), 2.06 (m, 5H), 2.40 (m ,1H),2.79(m,1H),3.15(m,2H),4.11(m,1H),5.61(m,2H),7.48(m,2H),7.96(m,1H),10.38(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值373.2；實測值374.2；Rt=2.091min。LCMS (ESI): [M+H] + m/z: calculated 373.2; found 374.2; Rt=2.091 min.

化合物159： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.96(m,3H),1.21(m,2H),1.78(m,7H),2.03(s,3H),2.29(m,3H),3.13(m,3H),4.10(m,1H),5.61(s,2H),7.48(m,2H),8.00(s,1H),10.32(m,1H)。 Compound 159: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.96 (m, 3H), 1.21 (m, 2H), 1.78 (m, 7H), 2.03 (s, 3H), 2.29 (m , 3H), 3.13(m, 3H), 4.10(m, 1H), 5.61(s, 2H), 7.48(m, 2H), 8.00(s, 1H), 10.32(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值373.2；實測值374.2；Rt=1.918min。LCMS (ESI): [M+H] + m/z: calculated 373.2; found 374.2; Rt=1.918 min.

實例762.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(5-側氧基吡咯啶-3-基)哌啶-1-基)-2-側氧基乙醯胺(化合物210)之合成Example 762. N- (6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(5-oxypyrrolidin-3-yl)piperidine-1- Synthesis of yl)-2-oxoacetamide (Compound 210)

Figure 110128222-A0202-12-2442-470
Figure 110128222-A0202-12-2442-470

步驟1：3-(5-甲基吡啶-2-基)丙烯酸乙酯之合成Step 1: Synthesis of ethyl 3-(5-methylpyridin-2-yl)acrylate

將膦醯基乙酸三乙酯(10.18g，45.40mmol，9.01mL)逐滴添加到於礦物油中之氫化鈉(油分散物)60%分散物(1.73g，43.34mmol)於THF(100mL)中之懸浮液中。在環境溫度下攪拌1h之後，逐滴添加於THF(10mL)中之5-甲基吡啶-2-甲醛(5g，41.28mmol)。將所得溶液攪拌隔夜。蒸發THF且將混合物用DCM(100ml)稀釋且用水(2x50ml)洗滌。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得3-(5-甲基-2-吡啶基)丙-2-烯酸乙酯(7.7g，40.27mmol，97.56%產率)。Triethyl phosphonoacetate (10.18 g, 45.40 mmol, 9.01 mL) was added dropwise to a 60% dispersion of sodium hydride (oil dispersion) in mineral oil (1.73 g, 43.34 mmol) in THF (100 mL) in suspension. After stirring for 1 h at ambient temperature, 5-picoline-2-carbaldehyde (5 g, 41.28 mmol) in THF (10 mL) was added dropwise. The resulting solution was stirred overnight. THF was evaporated and the mixture was diluted with DCM (100ml) and washed with water (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain ethyl 3-(5-methyl-2-pyridyl)prop-2-enoate (7.7 g, 40.27 mmol, 97.56% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.31(t,3H),2.34(s,3H),4.24(m,2H),6.82(d,1H),7.32(d,1H),7.48(d,1H),7.63(d,1H),8.45(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.31(t, 3H), 2.34(s, 3H), 4.24(m, 2H), 6.82(d, 1H), 7.32(d, 1H), 7.48( d, 1H), 7.63 (d, 1H), 8.45 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值191.2；實測值192.2；Rt=1.083min。LCMS (ESI): [M] + m/z: calculated 191.2; found 192.2; Rt=1.083 min.

步驟2：3-(5-甲基吡啶-2-基)-4-硝基丁酸乙酯之合成Step 2: Synthesis of 3-(5-methylpyridin-2-yl)-4-nitrobutyric acid ethyl ester

將3-(5-甲基-2-吡啶基)丙-2-烯酸乙酯(7.7g，40.27mmol)、硝基甲烷(7.37g，120.80mmol，6.53mL)及於THF中之1M四丁基氟化銨(2.11g，8.05mmol，2.33mL)於THF(77mL)中之溶液回流12h。在減壓下蒸發溶劑。將所得材料用MTBE(200ml)稀釋且用鹽水(2x50ml)洗滌。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得3-(5-甲基-2-吡啶基)-4-硝基丁酸乙酯(10g，39.64mmol，98.45%產率)。Combine 3-(5-methyl-2-pyridyl)prop-2-enoic acid ethyl ester (7.7 g, 40.27 mmol), nitromethane (7.37 g, 120.80 mmol, 6.53 mL) and 1M tetramine in THF A solution of butylammonium fluoride (2.11 g, 8.05 mmol, 2.33 mL) in THF (77 mL) was refluxed for 12 h. The solvent was evaporated under reduced pressure. The resulting material was diluted with MTBE (200ml) and washed with brine (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain ethyl 3-(5-methyl-2-pyridyl)-4-nitrobutyrate (10 g, 39.64 mmol, 98.45% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.16(t,3H),2.27(s,3H),2.75(m,2H),4.04(m,2H),4.79(m,2H),7.11(d,1H),7.40(d,1H),8.32(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.16(t, 3H), 2.27(s, 3H), 2.75(m, 2H), 4.04(m, 2H), 4.79(m, 2H), 7.11( d, 1H), 7.40 (d, 1H), 8.32 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值252.2；實測值253.2；Rt=1.172min。LCMS (ESI): [M] + m/z: calculated 252.2; found 253.2; Rt=1.172 min.

步驟3：4-(5-甲基吡啶-2-基)吡咯啶-2-酮之合成Step 3: Synthesis of 4-(5-methylpyridin-2-yl)pyrrolidin-2-one

將3-(5-甲基-2-吡啶基)-4-硝基丁酸乙酯(9.5g，37.66mmol)及5%氫氧化鈀/碳(464.82mg，3.77mmol)混合於甲醇(100mL)中。在高壓釜中，在70℃、H2 (50atm)氣氛下，將混合物攪拌24h。將反應混合物冷卻至室溫，過濾且在真空中蒸發溶劑。藉由管柱層析(80g SiO2 ，MTBE/MeOH 0~95%，流速=60mL/min，Rt=16min)純化所得粗材料，以獲得4-(5-甲基-2-吡啶基)吡咯啶-2-酮(0.5g，2.84mmol，7.53%產率)。Ethyl 3-(5-methyl-2-pyridyl)-4-nitrobutyrate (9.5 g, 37.66 mmol) and 5% palladium hydroxide on carbon (464.82 mg, 3.77 mmol) were mixed in methanol (100 mL) )middle. In the autoclave, the mixture was stirred for 24 h at 70 °C under H2 (50 atm) atmosphere. The reaction mixture was cooled to room temperature, filtered and the solvent was evaporated in vacuo. The resulting crude material was purified by column chromatography (80 g SiO 2 , MTBE/MeOH 0~95%, flow rate=60 mL/min, Rt=16 min) to obtain 4-(5-methyl-2-pyridyl)pyrrole Iridin-2-one (0.5 g, 2.84 mmol, 7.53% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)2.29(s,3H),2.67(m,1H),3.59(m,1H),3.78(m,2H),6.21(m,2H),7.06(d,1H),7.42(d,1H),8.37(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 2.29(s, 3H), 2.67(m, 1H), 3.59(m, 1H), 3.78(m, 2H), 6.21(m, 2H), 7.06( d, 1H), 7.42 (d, 1H), 8.37 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值176.2；實測值177.2；Rt=0.477min。LCMS (ESI): [M] + m/z: calculated 176.2; found 177.2; Rt=0.477 min.

步驟4：4-(5-甲基哌啶-2-基)吡咯啶-2-酮之合成Step 4: Synthesis of 4-(5-methylpiperidin-2-yl)pyrrolidin-2-one

將4-(5-甲基-2-吡啶基)吡咯啶-2-酮(0.4g，2.27mmol)及乾燥的487型鈀(10%於碳上)(24.16mg，227.00μmol)JM催化劑(A402028-10)混合於甲醇(4mL)中。在高壓釜中，在70℃、H2 (50atm)氣氛下，將混合物攪拌100h。將反應 混合物冷卻至室溫，過濾且在真空中蒸發溶劑，以獲得4-(5-甲基-2-哌啶基)吡咯啶-2-酮(450mg，粗品)。4-(5-Methyl-2-pyridyl)pyrrolidin-2-one (0.4 g, 2.27 mmol) and dry palladium type 487 (10% on carbon) (24.16 mg, 227.00 μmol) JM catalyst ( A402028-10) in methanol (4 mL). In the autoclave, the mixture was stirred for 100 h at 70 °C under H2 (50 atm) atmosphere. The reaction mixture was cooled to room temperature, filtered and the solvent was evaporated in vacuo to give 4-(5-methyl-2-piperidinyl)pyrrolidin-2-one (450 mg, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.86(d,3H),1.70(m,9H),2.45(m,2H),3.05(m,1H),3.20(m,1H),3.43(m,1H),5.75(bds,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.86(d, 3H), 1.70(m, 9H), 2.45(m, 2H), 3.05(m, 1H), 3.20(m, 1H), 3.43( m, 1H), 5.75 (bds, 1H).

LCMS(ESI)：[M]+ m/z：計算值182.2；實測值183.2；Rt=0.261min。LCMS (ESI): [M] + m/z: calculated 182.2; found 183.2; Rt=0.261 min.

步驟5：(3-甲基-5-(2-(5-甲基-2-(5-側氧基吡咯啶-3-基)哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 5: (3-Methyl-5-(2-(5-methyl-2-(5-oxopyrrolidin-3-yl)piperidin-1-yl)-2-oxoacetone Synthesis of tertiary butyl amino)pyridin-2-yl)carbamate

將4-(5-甲基-2-哌啶基)吡咯啶-2-酮(200mg，1.10mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(324.03mg，1.10mmol)、TEA(555.19mg，5.49mmol，764.72μL)混合於DMF(5mL)中，然後添加HATU(625.85mg，1.65mmol)。將所得混合物在25℃下攪拌12h。將混合物在減壓下蒸發且藉由HPLC(2-10min 10-50% MeOH，30ml/min)純化，以獲得N -[3-甲基-5-[[2-[5-甲基-2-(5-側氧基吡咯啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(77.1mg，粗品)。4-(5-Methyl-2-piperidinyl)pyrrolidin-2-one (200 mg, 1.10 mmol), 2-[[6-( 3- butoxycarbonylamino)-5-methyl- 3-Pyridinyl]amino]-2-side oxyacetic acid (324.03 mg, 1.10 mmol), TEA (555.19 mg, 5.49 mmol, 764.72 μL) were mixed in DMF (5 mL), then HATU (625.85 mg, 1.65 μL) was added mmol). The resulting mixture was stirred at 25 °C for 12 h. The mixture was evaporated under reduced pressure and purified by HPLC (2-10 min 10-50% MeOH, 30 ml/min) to obtain N- [3-methyl-5-[[2-[5-methyl-2 tert- butyl -(5-oxypyrrolidin-3-yl)-1-piperidinyl]-2-oxyacetyl]amino]-2-pyridyl]carbamic acid (77.1 mg, Crude).

LCMS(ESI)：[M]+ m/z：計算值459.5；實測值460.2；Rt=1.065min。LCMS (ESI): [M] + m/z: calculated 459.5; found 460.2; Rt=1.065 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(5-側氧基吡咯啶-3-基)哌啶-1-基)-2-側氧基乙醯胺(化合物210 )之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(5-oxypyrrolidin-3-yl)piperidine-1- Synthesis of yl)-2-oxoacetamide ( Compound 210 )

將N -[3-甲基-5-[[2-[5-甲基-2-(5-側氧基吡咯啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(77.1mg，167.78μmol)於二噁烷(2mL)及水(2mL)中之溶液在100℃下加熱12h。將混合物在減壓下蒸發且藉由HPLC(2-10min 10-50%水-MeOH+NH3 )純化，以獲得N -(6-胺基-5-甲基-3-吡啶基)-2-[5-甲基-2-(5-側氧基吡咯啶-3-基)-1-哌啶基]-2-側氧基乙醯胺(18.2mg，50.64μmol，30.18%產率)。 N- [3-methyl-5-[[2-[5-methyl-2-(5-oxypyrrolidin-3-yl)-1-piperidinyl]-2-oxyethyl A solution of acyl]amino]-2-pyridyl]carbamic acid tert-butyl ester (77.1 mg, 167.78 μmol) in dioxane (2 mL) and water (2 mL) was heated at 100 °C for 12 h. The mixture was evaporated under reduced pressure and purified by HPLC (2-10 min 10-50% water-MeOH+ NH3 ) to obtain N- (6-amino-5-methyl-3-pyridinyl)-2 -[5-Methyl-2-(5-oxypyrrolidin-3-yl)-1-piperidinyl]-2-oxyacetamide (18.2 mg, 50.64 μmol, 30.18% yield) .

1 H NMR(400MHz,CDCl3 )δ(ppm)1.02(m,3H),1.40(m,2H),1.90(m,2H),2.10 (m,5H),2.28(m,2H),3.10(m,3H),4.43(m,3H),4.90(m,1H),6.47(m,1H),7.68(m,1H),8.00(m,1H),9.50(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(m, 3H), 1.40(m, 2H), 1.90(m, 2H), 2.10(m, 5H), 2.28(m, 2H), 3.10( m, 3H), 4.43 (m, 3H), 4.90 (m, 1H), 6.47 (m, 1H), 7.68 (m, 1H), 8.00 (m, 1H), 9.50 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值359.4；實測值360.2；Rt=0.790min。LCMS (ESI): [M] + m/z: calculated 359.4; found 360.2; Rt=0.790 min.

實例763. 外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基-2-((2R,5S)-2-苯基-5-(三氟甲基)哌啶-1-基)乙醯胺(化合物177)之合成Example 763. Racemic-N-(6-amino-5-methylpyridin-3-yl)-2-oxy-2-((2R,5S)-2-phenyl-5-(tris Synthesis of Fluoromethyl)piperidin-1-yl)acetamide (Compound 177)

Figure 110128222-A0202-12-2445-471
Figure 110128222-A0202-12-2445-471

步驟1：2-側氧基-5-(三氟甲基)哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 2-oxy-5-(trifluoromethyl)piperidine-1-carboxylate

將二碳酸二-第三丁酯(11.06g，50.68mmol，11.63mL)逐滴添加到5-(三氟甲基)哌啶-2-酮(7.7g，46.07mmol)及4-二甲胺基吡啶(281.43mg，2.30mmol，4.89mL)於乙腈(140mL)中之溶液中。將所得溶液在25℃下攪拌12h。然後蒸發溶劑且將所得粗材料用EtOAc(100ml)稀釋且用飽和碳酸氫鈉溶液(2x100ml)洗滌。將有機相經硫酸鈉乾燥且在減壓下蒸發，以獲得2-側氧基-5-(三氟甲基)哌啶-1-甲酸第三丁酯(11.18g，41.83mmol，90.80%產率)Di-tert-butyl dicarbonate (11.06 g, 50.68 mmol, 11.63 mL) was added dropwise to 5-(trifluoromethyl)piperidin-2-one (7.7 g, 46.07 mmol) and 4-dimethylamine pyridine (281.43 mg, 2.30 mmol, 4.89 mL) in acetonitrile (140 mL). The resulting solution was stirred at 25 °C for 12 h. The solvent was then evaporated and the resulting crude material was diluted with EtOAc (100ml) and washed with saturated sodium bicarbonate solution (2x100ml). The organic phase was dried over sodium sulfate and evaporated under reduced pressure to give tert-butyl 2-oxy-5-(trifluoromethyl)piperidine-1-carboxylate (11.18 g, 41.83 mmol, 90.80% yield). Rate)

1 H NMR(CDCl3 ,400MHz)：δ 1.53(s,9H),1.93(m,1H),2.13(m,1H),2.50(m,1H),2.65(m,1H),3.75(m,1H),4.02(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ 1.53 (s, 9H), 1.93 (m, 1H), 2.13 (m, 1H), 2.50 (m, 1H), 2.65 (m, 1H), 3.75 (m, 1H), 4.02 (m, 1H).

LCMS(ESI)：[M-tBu+1]+ m/z：計算值267.2；實測值212.0；Rt=1.277min。LCMS (ESI): [M-tBu+1] + m/z: calculated 267.2; found 212.0; Rt=1.277 min.

步驟2：N-[5-側氧基-5-苯基-2-(三氟甲基)戊基]胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-[5-oxy-5-phenyl-2-(trifluoromethyl)pentyl]carbamate

在-78℃、惰性氣氛下，將苯基溴化鎂(9.10g，50.20mmol)(62.75ml，於THF中之0.8M溶液)添加到2-側氧基-5-(三氟甲基)哌啶-1-甲酸第三丁酯(11.18g，41.83mmol)於THF(200mL)中之溶液中。將所得溶液在-78℃下攪拌1h，之 後升溫至室溫且攪拌12h。將反應物用MTBE(500ml)稀釋且用100mL飽和氯化鈉水溶液緩慢萃取。將有機相用飽和碳酸氫鈉水溶液(2x200ml)洗滌。將經合併之水性級分用MTBE反萃取兩次。將經合併之有機級分經硫酸鈉乾燥，且藉由旋轉蒸發來濃縮，以獲得粗材料，其藉由管柱層析(120g SiO2，己烷/MTBE，其中MTBE為0~15%，流速=80mL/min，RC 9CV)進行純化，以獲得N-[5-側氧基-5-苯基-2-(三氟甲基)戊基]胺甲酸第三丁酯(5.5g，15.93mmol，38.07%產率)Phenylmagnesium bromide (9.10 g, 50.20 mmol) (62.75 ml, 0.8M solution in THF) was added to 2-pentoxy-5-(trifluoromethyl) at -78°C under inert atmosphere A solution of tert-butyl piperidine-1-carboxylate (11.18 g, 41.83 mmol) in THF (200 mL). The resulting solution was stirred at -78 °C for 1 h. It was then warmed to room temperature and stirred for 12 h. The reaction was diluted with MTBE (500 ml) and slowly extracted with 100 mL of saturated aqueous sodium chloride. The organic phase was washed with saturated aqueous sodium bicarbonate solution (2x200ml). The combined aqueous fractions were back extracted twice with MTBE. The combined organic fractions were dried over sodium sulfate and concentrated by rotary evaporation to obtain crude material, which was chromatographed by column (120 g SiO, hexane/MTBE, where MTBE was 0-15%, flow rate = 80 mL/min, RC 9CV) for purification to obtain tert-butyl N-[5-oxy-5-phenyl-2-(trifluoromethyl)pentyl]carbamate (5.5 g, 15.93 mmol) , 38.07% yield)

1 H NMR(CDCl3 ,400MHz)：δ 1.41(s,9H),1.92(m,1H),2.05(m,1H),2.42(m,1H),3.16(m,2H),3.30(m,1H),3.41(m,1H),4.86(brs,1H),7.44(t,2H),7.55(t,1H),7.95(d,2H)。 1 H NMR (CDCl 3 , 400MHz): δ 1.41 (s, 9H), 1.92 (m, 1H), 2.05 (m, 1H), 2.42 (m, 1H), 3.16 (m, 2H), 3.30 (m, 1H), 3.41 (m, 1H), 4.86 (brs, 1H), 7.44 (t, 2H), 7.55 (t, 1H), 7.95 (d, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值345.3；實測值246.2；Rt=1,502min。LCMS (ESI): [M-Boc] + m/z: calculated 345.3; found 246.2; Rt=1,502 min.

步驟3：6-苯基-3-(三氟甲基)-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-phenyl-3-(trifluoromethyl)-2,3,4,5-tetrahydropyridine

將N-[5-側氧基-5-苯基-2-(三氟甲基)戊基]胺甲酸第三丁酯(5.5g，15.93mmol)於TFA(25mL)及DCM(25mL)中之溶液在25℃下攪拌2h。將硫酸鈉飽和水溶液添加到溶液(50ml)中，然後用DCM(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得6-苯基-3-(三氟甲基)-2,3,4,5-四氫吡啶(3.5g，15.40mmol，96.72%產率)3-butyl N-[5-oxy-5-phenyl-2-(trifluoromethyl)pentyl]carbamate (5.5 g, 15.93 mmol) in TFA (25 mL) and DCM (25 mL) The resulting solution was stirred at 25 °C for 2 h. Saturated aqueous sodium sulfate was added to the solution (50ml), then extracted with DCM (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 6-phenyl-3-(trifluoromethyl)-2,3,4,5-tetrahydropyridine (3.5 g, 15.40 mmol, 96.72% yield )

1 H NMR(CDCl3 ,500MHz)：δ 1.83(m,1H),2.19(m,1H),2.40(m,1H),2.64(m,1H),2.91(m,1H),3.75(m,1H),4.23(d,1H),7.42(m,3H),7.77(d,2H) 1 H NMR (CDCl 3 , 500MHz): δ 1.83 (m, 1H), 2.19 (m, 1H), 2.40 (m, 1H), 2.64 (m, 1H), 2.91 (m, 1H), 3.75 (m, 1H), 4.23(d, 1H), 7.42(m, 3H), 7.77(d, 2H)

步驟4：2-苯基-5-(三氟甲基)哌啶之合成Step 4: Synthesis of 2-phenyl-5-(trifluoromethyl)piperidine

將硼氫化鈉(1.17g，30.81mmol，1.09mL)分批添加到6-苯基-3-(三氟甲基)-2,3,4,5-四氫吡啶(3.5g，15.40mmol)於甲醇(70mL)中之溶液中。將混合物在室溫下攪拌12h。添加水(50ml)且將所得混合物用EtOAc(2x50ml)萃取。將有機相經硫酸鈉乾燥，過濾且蒸發，以獲得2-苯基-5-(三氟甲基)哌啶(3.3g，14.40mmol，93.46%產率)。Sodium borohydride (1.17 g, 30.81 mmol, 1.09 mL) was added portionwise to 6-phenyl-3-(trifluoromethyl)-2,3,4,5-tetrahydropyridine (3.5 g, 15.40 mmol) in methanol (70 mL). The mixture was stirred at room temperature for 12 h. Water (50ml) was added and the resulting mixture was extracted with EtOAc (2x50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give 2-phenyl-5-(trifluoromethyl)piperidine (3.3 g, 14.40 mmol, 93.46% yield).

1H NMR(400MHz,CDCl3 )δ 1.59(m,2H),1.73(brs,1H),1.92(m,1H),2.15(m,1H),2.35(m,1H),2.82(t,1H),3.39(d,1H),3.61(d,1H),7.34(m,5H)。1H NMR (400MHz, CDCl 3 )δ 1.59(m, 2H), 1.73(brs, 1H), 1.92(m, 1H), 2.15(m, 1H), 2.35(m, 1H), 2.82(t, 1H) , 3.39 (d, 1H), 3.61 (d, 1H), 7.34 (m, 5H).

GCMS[M]+ m/z：計算值229.2；實測值229.1；Rt=6.295minGCMS[M] + m/z: Calculated 229.2; Measured 229.1; Rt=6.295min

步驟5：N-[3-甲基-5-[[2-側氧基-2-[2-苯基-5-(三氟甲基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯之合成Step 5: N-[3-Methyl-5-[[2-oxy-2-[2-phenyl-5-(trifluoromethyl)-1-piperidinyl]acetyl]amino Synthesis of 3-butyl ]-2-pyridyl]carbamate

將2-苯基-5-(三氟甲基)哌啶(200mg，872.44μmol)、2-[[6-(第三丁氧基羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(257.63mg，872.44μmol)、三乙胺(441.41mg，4.36mmol，608.01μL)混合於DMF(5mL)中，然後添加HATU(497.59mg，1.31mmol)。將所得混合物在25℃下攪拌12h。將混合物在減壓下蒸發且藉由HPLC(2-10min 10-50% R1，30ml/min)純化，以獲得N-[3-甲基-5-[[2-側氧基-2-[2-苯基-5-(三氟甲基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(94.6mg，186.77μmol，21.41%產率)2-Phenyl-5-(trifluoromethyl)piperidine (200 mg, 872.44 μmol), 2-[[6-(tert-butoxycarbonylamino)-5-methyl-3-pyridyl] Amino]-2-oxoacetic acid (257.63 mg, 872.44 μmol), triethylamine (441.41 mg, 4.36 mmol, 608.01 μL) were mixed in DMF (5 mL), then HATU (497.59 mg, 1.31 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The mixture was evaporated under reduced pressure and purified by HPLC (2-10 min 10-50% R1, 30 ml/min) to obtain N-[3-methyl-5-[[2-pendoxyl-2-[ 2-Phenyl-5-(trifluoromethyl)-1-piperidinyl]acetoxy]amino]-2-pyridyl]carbamic acid tert-butyl ester (94.6 mg, 186.77 μmol, 21.41% yield )

1 H NMR(400MHz,CDCl3 )δ 1.48(s,9H),1.50-2.10(m,4H),2.22(m,4H),2.34(m,1H),3.57(m,0.5H),4.79(m,0.5H),5.66(m,1H),6.66(m,1H),7.26(m,5H),7.98(s,1H),8.33(s,1H),9.20(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.48(s, 9H), 1.50-2.10(m, 4H), 2.22(m, 4H), 2.34(m, 1H), 3.57(m, 0.5H), 4.79( m, 0.5H), 5.66 (m, 1H), 6.66 (m, 1H), 7.26 (m, 5H), 7.98 (s, 1H), 8.33 (s, 1H), 9.20 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值506.2；實測值507.2；Rt=1,436min。LCMS (ESI): [M+1] + m/z: calculated 506.2; found 507.2; Rt=1,436 min.

步驟6：外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基-2-((2R,5S)-2-苯基-5-(三氟甲基)哌啶-1-基)乙醯胺(化合物177 )之合成Step 6: Racemic-N-(6-amino-5-methylpyridin-3-yl)-2-oxy-2-((2R,5S)-2-phenyl-5-(tris Synthesis of Fluoromethyl)piperidin-1-yl)acetamide ( Compound 177 )

將N-[3-甲基-5-[[2-側氧基-2-[2-苯基-5-(三氟甲基)-1-哌啶基]乙醯基]胺基]-2-吡啶基]胺甲酸第三丁酯(94.6mg，186.77μmol)於二噁烷(2mL)及水(2mL)中之溶液在100℃下加熱12h。將溶劑蒸發至乾。。藉由HPLC(30-40%水-乙腈，10min，流速30ml/min)純化粗材料，以得到外消旋-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基-2-((2R,5S)-2-苯基-5-(三氟甲基)哌啶-1-基)乙醯胺(54.2mg，133.37μmol，71.41%產率)N-[3-Methyl-5-[[2-oxy-2-[2-phenyl-5-(trifluoromethyl)-1-piperidinyl]acetyl]amino]- A solution of tert-butyl 2-pyridyl]carbamate (94.6 mg, 186.77 μmol) in dioxane (2 mL) and water (2 mL) was heated at 100° C. for 12 h. The solvent was evaporated to dryness. . The crude material was purified by HPLC (30-40% water-acetonitrile, 10 min, flow rate 30 ml/min) to give rac-N-(6-amino-5-methylpyridin-3-yl)-2- Pendant oxy-2-((2R,5S)-2-phenyl-5-(trifluoromethyl)piperidin-1-yl)acetamide (54.2 mg, 133.37 μmol, 71.41% yield)

1 H NMR(DMSO-d6,500MHz)：δ(ppm)1.76(m,2H),2.00(m,3H),2.18(m,2H),2.81(m,1H),3.56(m,1H),4.50(m,1H),5.39(m,1H),5.61(m,2H),7.36(m,6H),7.96(m,1H),10.40(m,1H)。 1 H NMR (DMSO-d6, 500MHz): δ(ppm) 1.76(m, 2H), 2.00(m, 3H), 2.18(m, 2H), 2.81(m, 1H), 3.56(m, 1H), 4.50(m, 1H), 5.39(m, 1H), 5.61(m, 2H), 7.36(m, 6H), 7.96(m, 1H), 10.40(m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值406.2；實測值407.0；Rt=1.001min。LCMS (ESI): [M+1] + m/z: calculated 406.2; found 407.0; Rt=1.001 min.

實例764. 1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-6-苯基哌啶-3-甲醯胺(化合物315、化合物328)之合成Example 764. 1-(2-((6-amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-6-phenylpiperidine-3-carboxylate Synthesis of Amines (Compound 315, Compound 328)

Figure 110128222-A0202-12-2448-472
Figure 110128222-A0202-12-2448-472

步驟1：2-氰基-5-側氧基-5-苯基戊酸乙酯之合成Step 1: Synthesis of ethyl 2-cyano-5-oxy-5-phenylvalerate

將KOH(9.98g，177.92mmol，4.89mL)添加到EtOH(200mL)中。在均質化之後，添加2-氰基乙酸乙酯(80.50g，711.66mmol，75.94mL)，且在5min之後添加3-氯-1-苯基丙-1-酮(20g，118.61mmol)。將反應混合物在25℃下攪拌2h。蒸發溶劑且藉由管柱層析純化殘餘物(60g)，以得到產物與2-氰基乙酸乙酯之混合物。藉由在真空中蒸餾移除2-氰基乙酸乙酯，以得到2-氰基-5-側氧基-5-苯基戊酸乙酯(18g，73.39mmol，61.87%產率)。KOH (9.98 g, 177.92 mmol, 4.89 mL) was added to EtOH (200 mL). After homogenization, ethyl 2-cyanoacetate (80.50 g, 711.66 mmol, 75.94 mL) was added, and after 5 min 3-chloro-1-phenylpropan-1-one (20 g, 118.61 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. The solvent was evaporated and the residue was purified by column chromatography (60 g) to give a mixture of product and ethyl 2-cyanoacetate. Ethyl 2-cyanoacetate was removed by distillation in vacuo to give ethyl 2-cyano-5-oxy-5-phenylvalerate (18 g, 73.39 mmol, 61.87% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.32(t,3H),2.32(m,1H),2.48(m,1H),3.26(t,2H),3.81(t,1H),4.29(m,2H),7.48(t,2H),7.59(t,1H),7.96(d,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.32(t, 3H), 2.32(m, 1H), 2.48(m, 1H), 3.26(t, 2H), 3.81(t, 1H), 4.29( m, 2H), 7.48 (t, 2H), 7.59 (t, 1H), 7.96 (d, 2H).

LCMS(ESI)：[M+1]m/z：計算值245.2；實測值246.2；Rt=1.306min。LCMS (ESI): [M+1] m/z: calculated 245.2; found 246.2; Rt=1.306 min.

步驟2：6-苯基哌啶-3-甲酸乙酯之合成Step 2: Synthesis of 6-phenylpiperidine-3-carboxylic acid ethyl ester

將2-氰基-5-側氧基-5-苯基戊酸乙酯(2g，8.15mmol)溶解於EtOH(80mL)中且添加於水中之雷氏鎳(300mg，3.50mmol)。將反應混合物在70℃下在高壓容器中在50atm H2 壓力下加熱48h。過濾出催化劑，用MeOH洗滌且蒸發溶 劑，將殘餘物乾燥，以得到6-苯基哌啶-3-甲酸乙酯(1.5g，粗品)。Ethyl 2-cyano-5-pendoxo-5-phenylvalerate (2 g, 8.15 mmol) was dissolved in EtOH (80 mL) and Raney's nickel (300 mg, 3.50 mmol) in water was added. The reaction mixture was heated at 70 °C in a high pressure vessel under 50 atm H2 pressure for 48 h. The catalyst was filtered off, washed with MeOH and the solvent was evaporated, the residue was dried to give ethyl 6-phenylpiperidine-3-carboxylate (1.5 g, crude).

LCMS(ESI)：[M+1]m/z：計算值233.2；實測值234.2；Rt=0.947min。LCMS (ESI): [M+1] m/z: calculated 233.2; found 234.2; Rt=0.947 min.

步驟3：6-苯基哌啶-1,3-二甲酸1-第三丁酯3-乙酯之合成Step 3: Synthesis of 6-phenylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester

向6-苯基哌啶-3-甲酸乙酯(1.5g，6.43mmol)於THF(30mL)中之懸浮液中添加TEA(1.63g，16.07mmol，2.24mL)及二碳酸二-第三丁酯(1.54g，7.07mmol，1.62mL)。將反應混合物在25℃下攪拌12h且蒸發。將殘餘物溶解於水且用DCM萃取。將有機萃取物經Na2 SO4 乾燥且蒸發，以得到呈略黃色油狀物之6-苯基哌啶-1,3-二甲酸O1-第三丁 酯O3-乙酯(1.9g，粗品)。To a suspension of ethyl 6-phenylpiperidine-3-carboxylate (1.5 g, 6.43 mmol) in THF (30 mL) was added TEA (1.63 g, 16.07 mmol, 2.24 mL) and di-tert-butyl dicarbonate Ester (1.54 g, 7.07 mmol, 1.62 mL). The reaction mixture was stirred at 25 °C for 12 h and evaporated. The residue was dissolved in water and extracted with DCM. The organic extracts were dried over Na2SO4 and evaporated to give 6-phenylpiperidine-1,3-dicarboxylic acid O1-tert- butyl ester O3-ethyl ester (1.9 g, crude) as a slightly yellow oil ).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.25(t,3H),1.43(s,9H),1.92(m,2H),2.49(m,1H),2.78(t,1H),3.03(m,1H),4.15(m,2H),4.28(m,1H),4.48(m,1H),5.33(m,1H),7.23(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.25(t, 3H), 1.43(s, 9H), 1.92(m, 2H), 2.49(m, 1H), 2.78(t, 1H), 3.03( m, 1H), 4.15 (m, 2H), 4.28 (m, 1H), 4.48 (m, 1H), 5.33 (m, 1H), 7.23 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值233.4；實測值234.2；Rt=0.846min。LCMS (ESI): [M-Boc] + m/z: calculated 233.4; found 234.2; Rt=0.846 min.

步驟4：1-(第三丁氧基羰基)-6-苯基哌啶-3-甲酸之合成Step 4: Synthesis of 1-(3-butoxycarbonyl)-6-phenylpiperidine-3-carboxylic acid

向6-苯基哌啶-1,3-二甲酸O1-第三丁 酯O3-乙酯(1.9g，5.70mmol)於MeOH(25mL)/H2 O(10mL)中之溶液中添加氫氧化鉀(639.44mg，11.40mmol，313.45μL)且將反應混合物在25℃下攪拌13h。將混合物蒸發至乾。將殘餘物(水溶液)用硫酸氫鈉酸化至稍微酸性pH。將產物用EtOAc(3*30ml)萃取，經Na2 SO4 乾燥。蒸發EtOAc，以得到1-第三丁氧基 羰基-6-苯基哌啶-3-甲酸(1g，粗品)。To a solution of 6-phenylpiperidine-1,3-dicarboxylic acid O1-tert -butyl ester O3-ethyl ester (1.9 g, 5.70 mmol) in MeOH (25 mL)/ H2O (10 mL) was added hydroxide Potassium (639.44 mg, 11.40 mmol, 313.45 μL) and the reaction mixture was stirred at 25 °C for 13 h. The mixture was evaporated to dryness. The residue (aqueous) was acidified with sodium bisulfate to a slightly acidic pH. The product was extracted with EtOAc (3*30ml), dried over Na2SO4 . The EtOAc was evaporated to give 1 -tert -butoxycarbonyl-6-phenylpiperidine-3-carboxylic acid (1 g, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.45(s,9H),1.97(m,2H),2.48(m,1H),2.92(t,1H),2.96(m,1H),4.28(m,1H),4.45(m,1H),5.30(m,1H),7.25(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.45(s, 9H), 1.97(m, 2H), 2.48(m, 1H), 2.92(t, 1H), 2.96(m, 1H), 4.28( m, 1H), 4.45 (m, 1H), 5.30 (m, 1H), 7.25 (m, 5H).

LCMS(ESI)：LCMS (ESI):

[M-Boc]+ m/z：計算值205.4；實測值206.2；Rt=1.384min。[M-Boc] + m/z: calculated 205.4; found 206.2; Rt=1.384 min.

步驟5：5-胺甲醯基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of tert-butyl 5-aminocarbamoyl-2-phenylpiperidine-1-carboxylate

向1-第三丁氧基 羰基-6-苯基哌啶-3-甲酸(1g，3.27mmol)於THF(30 mL)中之經攪拌之溶液中添加羰基二咪唑(690.29mg，4.26mmol)且將反應混合物在50℃下攪拌1.5h。使氨鼓泡穿過反應混合物30min。將反應混合物在25℃下攪拌30min。蒸發THF。將殘餘物用水(40ml)稀釋，將產物用EtOAc(50ml)萃取。將有機層經Na2 SO4 乾燥。蒸發EtOAc，以得到5-胺甲醯基-2-苯基哌啶-1-甲酸第三丁 酯(1.2g，粗品)。To a stirred solution of 1 -tert -butoxycarbonyl-6-phenylpiperidine-3-carboxylic acid (1 g, 3.27 mmol) in THF (30 mL) was added carbonyldiimidazole (690.29 mg, 4.26 mmol) And the reaction mixture was stirred at 50 °C for 1.5 h. Ammonia was bubbled through the reaction mixture for 30 min. The reaction mixture was stirred at 25 °C for 30 min. Evaporate THF. The residue was diluted with water (40ml) and the product was extracted with EtOAc (50ml). The organic layer was dried over Na2SO4 . The EtOAc was evaporated to give tert -butyl 5-aminocarboxy-2-phenylpiperidine-1-carboxylate (1.2 g, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.45(s,9H),1.73(m,2H),2.48(m,1H),2.87(t,1H),3.03(m,1H),4.34(m,1H),5.42(m,1H),5.65(m,1H),7.25(m,5H),9.55(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.45(s, 9H), 1.73(m, 2H), 2.48(m, 1H), 2.87(t, 1H), 3.03(m, 1H), 4.34( m, 1H), 5.42 (m, 1H), 5.65 (m, 1H), 7.25 (m, 5H), 9.55 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值204.2；實測值205.2；Rt=1.333min。LCMS (ESI): [M-Boc] + m/z: calculated 204.2; found 205.2; Rt=1.333 min.

步驟6：6-苯基哌啶-3-甲醯胺之合成Step 6: Synthesis of 6-phenylpiperidine-3-carboxamide

向5-胺甲醯基-2-苯基哌啶-1-甲酸第三丁 酯(0.7g，2.30mmol)於DCM(7mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(838.50mg，23.00mmol，1.05mL)且將所得混合物在25℃下攪拌1.5h。蒸發溶劑，以得到6-苯基哌啶-3-甲醯胺(0.5g，粗品，HCl)。To a solution of tert- butyl 5-aminocarbamoyl-2-phenylpiperidine-1-carboxylate (0.7 g, 2.30 mmol) in DCM (7 mL) was added a 4.0 M solution of hydrogen chloride in dioxane ( 838.50 mg, 23.00 mmol, 1.05 mL) and the resulting mixture was stirred at 25 °C for 1.5 h. The solvent was evaporated to give 6-phenylpiperidine-3-carboxamide (0.5 g, crude, HCl).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.95(m,3H),3.25(m,4H),4.28(m,1H),7.48(m,5H),7.63(m,2H),9.17(m,1H)。 1 H NMR (500MHz, DMSO- d 6 ) δ(ppm) 1.95(m, 3H), 3.25(m, 4H), 4.28(m, 1H), 7.48(m, 5H), 7.63(m, 2H), 9.17(m, 1H).

LCMS(ESI)：[M+1]m/z：計算值204.2；實測值205.2；Rt=0.619min。LCMS (ESI): [M+1] m/z: calculated 204.2; found 205.2; Rt=0.619 min.

步驟7：(5-(2-(5-胺甲醯基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 7: (5-(2-(5-Aminocarbamoyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)-3-methylpyridin-2-yl) Synthesis of tertiary butyl carbamate

向6-苯基哌啶-3-甲醯胺(0.5g，2.08mmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(613.33mg，2.08mmol)及HATU(868.72mg，2.28mmol)於DMF(8mL)中之溶液中添加三乙胺(840.70mg，8.31mmol，1.16mL)。將混合物在25℃下攪拌2h。將混合物用水(30ml)稀釋且用EtOAc(3*50ml)萃取。將經合併之有機層用水(3*50ml)及鹽水洗滌，然後經Na2 SO4 乾 燥且蒸發，以得到N -[5-[[2-(5-胺甲醯基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.5g，粗品)。To 6-phenylpiperidine-3-carboxamide (0.5 g, 2.08 mmol, HCl), 2-[[6-( 3- butoxycarbonylamino)-5-methyl-3-pyridyl] Amino]-2-pendoxoacetic acid (613.33 mg, 2.08 mmol) and HATU (868.72 mg, 2.28 mmol) in DMF (8 mL) was added triethylamine (840.70 mg, 8.31 mmol, 1.16 mL). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (30ml) and extracted with EtOAc (3*50ml). The combined organic layers were washed with water (3*50ml) and brine, then dried over Na2SO4 and evaporated to give N- [ 5 -[[2-(5-aminocarbamoyl-2-phenyl- 1-Piperidinyl)-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.5 g, crude).

LCMS(ESI)[M+1]m/z：計算值481.5；實測值482.2；Rt=1.138min。LCMS(ESI)[M+1]m/z: Calculated 481.5; Found 482.2; Rt=1.138min.

步驟8：1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-6-苯基哌啶-3-甲醯胺(化合物315 及化合物328 )之合成Step 8: 1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-6-phenylpiperidine-3-carboxylate Synthesis of Amines ( Compound 315 and Compound 328 )

向N -[5-[[2-(5-胺甲醯基-2-苯基-1-哌啶基)-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.5g，1.04mmol)於DCM(5mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(378.58mg，10.38mmol，473.23μL)且將所得混合物在25℃下攪拌2h。蒸發溶劑。藉由反相HPLC(30-30-40% 0-1-6min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量381，管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以得到(3R,6R )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-6-苯基哌啶-3-甲醯胺(78mg，204.50μmol，19.69%產率)及(3R,6S )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-6-苯基哌啶-3-甲醯胺(21mg，55.06μmol，5.30%產率)。To N- [5-[[2-(5-aminocarbamoyl-2-phenyl-1-piperidinyl)-2-oxyethanoyl]amino]-3-methyl-2- To a solution of tert-butyl pyridyl] carbamate (0.5 g, 1.04 mmol) in DCM (5 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (378.58 mg, 10.38 mmol, 473.23 μL) and the resulting mixture was combined Stir at 25°C for 2h. Evaporate the solvent. By reverse phase HPLC (30-30-40% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 381, column: YMC Triart C18 100x20mm, 5um) to purify the residue to give ( 3R,6R )-1-[2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxyethanoyl]- 6-Phenylpiperidine-3-carboxamide (78 mg, 204.50 μmol, 19.69% yield) and ( 3R,6S )-1-[2-[(6-amino-5-methyl-3-pyridine (21 mg, 55.06 μmol, 5.30% yield).

化合物315： 1 H NMR(400MHz,CDCl3 )δ(ppm)2.08(m,3H),2.18(m,1H),2.33(m,1H),2.52(m,1H),3.19(m,1H),4.45(m,2H),4.91(m,1H),5.85(m,1H),6.16(m,1H),7.31(m,8H),7.69(m,1H),8.07(m,1H),9.47(m,1H)。 Compound 315: 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 2.08 (m, 3H), 2.18 (m, 1H), 2.33 (m, 1H), 2.52 (m, 1H), 3.19 (m, 1H) ,4.45(m,2H),4.91(m,1H),5.85(m,1H),6.16(m,1H),7.31(m,8H),7.69(m,1H),8.07(m,1H), 9.47 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值381.4；實測值382.2；Rt=1.751min。LCMS (ESI): [M+1]m/z: calculated 381.4; found 382.2; Rt=1.751 min.

化合物328： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.47(m,1H),1.84(m,2H),2.00(m,3H),2.96(m,2H),3.99(m,1H),5.50(m,3H),6.87(m,1H),7.29(m,3H),7.34(m,1H),7.39(m,3H),7.48(m,1H),8.00(d,1H),10.57(s,1H)。 Compound 328: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 1.47 (m, 1H), 1.84 (m, 2H), 2.00 (m, 3H), 2.96 (m, 2H), 3.99 (m, 1H), 5.50(m, 3H), 6.87(m, 1H), 7.29(m, 3H), 7.34(m, 1H), 7.39(m, 3H), 7.48(m, 1H), 8.00(d, 1H) ), 10.57(s, 1H).

LCMS(ESI)：[M+1]m/z：計算值381.4；實測值382.2；Rt=1.678min。LCMS (ESI): [M+1] m/z: calculated 381.4; found 382.2; Rt=1.678 min.

實例765. 1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-N -甲基-6-苯基哌啶-3-甲醯胺(化合物249、化合物253)之合成Example 765. 1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl) -N -methyl-6-phenylpiperidine -Synthesis of 3-formamide (compound 249, compound 253)

Figure 110128222-A0202-12-2452-473
Figure 110128222-A0202-12-2452-473

步驟1：5-(甲基胺甲醯基)-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 5-(methylaminocarboxy)-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

向1-第三丁氧基 羰基-6-苯基哌啶-3-甲酸(如上文所述製備)(3g，9.82mmol)於THF(100mL)中之經攪拌之溶液中添加羰基二咪唑(2.07g，12.77mmol)且將反應混合物在50℃下攪拌1.5h。使甲胺鼓泡穿過反應混合物達30min。將反應混合物在25℃下攪拌30min。蒸發THF。將殘餘物用水(150ml)稀釋，將產物用EtOAc(2*100ml)萃取。將有機層經Na2 SO4 乾燥。蒸發EtOAc，以得到5-(甲基胺甲醯基)-2-苯基哌啶-1-甲酸第三丁 酯(2g，粗品)。To a stirred solution of 1 -tert -butoxycarbonyl-6-phenylpiperidine-3-carboxylic acid (prepared as above) (3 g, 9.82 mmol) in THF (100 mL) was added carbonyldiimidazole ( 2.07 g, 12.77 mmol) and the reaction mixture was stirred at 50 °C for 1.5 h. Methylamine was bubbled through the reaction mixture for 30 min. The reaction mixture was stirred at 25 °C for 30 min. Evaporate THF. The residue was diluted with water (150ml) and the product was extracted with EtOAc (2*100ml). The organic layer was dried over Na2SO4 . The EtOAc was evaporated to give 3 -butyl 5-(methylaminocarboxy)-2-phenylpiperidine-1-carboxylate (2 g, crude).

LCMS(ESI)：[M-Boc]+ m/z：計算值218.2；實測值219.2；Rt=1.360min。LCMS (ESI): [M-Boc] + m/z: calculated 218.2; found 219.2; Rt=1.360 min.

步驟2：N-甲基-6-苯基哌啶-3-甲醯胺之合成Step 2: Synthesis of N-methyl-6-phenylpiperidine-3-carboxamide

向5-(甲基胺甲醯基)-2-苯基哌啶-1-甲酸第三丁 酯(0.7g，2.20mmol)於DCM(7mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(801.57mg，21.98mmol，1.00mL)且將所得混合物在25℃下攪拌2h。蒸發溶劑，以得到N -甲基 -6-苯基哌啶-3-甲醯胺(0.5g，粗品，HCl)。To a solution of tert- butyl 5-(methylaminocarboxy)-2-phenylpiperidine-1-carboxylate (0.7 g, 2.20 mmol) in DCM (7 mL) was added 4.0 mol in dioxane M hydrogen chloride solution (801.57 mg, 21.98 mmol, 1.00 mL) and the resulting mixture was stirred at 25 °C for 2 h. The solvent was evaporated to give N - methyl -6-phenylpiperidine-3-carboxamide (0.5 g, crude, HCl).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.28(m,1H),1.55(m,2H),1.97(m,2H),2.83(m,2H),3.55(d,3H),4.29(m,1H),7.44(m,5H),8.15(m,1H),8.43(m,1H)。 1 H NMR (500MHz, DMSO- d 6 ) δ(ppm) 1.28(m, 1H), 1.55(m, 2H), 1.97(m, 2H), 2.83(m, 2H), 3.55(d, 3H), 4.29 (m, 1H), 7.44 (m, 5H), 8.15 (m, 1H), 8.43 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值218.2；實測值219.2；Rt=0.656min。LCMS (ESI): [M+1] m/z: calculated 218.2; found 219.2; Rt=0.656 min.

步驟3：(3-甲基-5-(2-(5-(甲基胺甲醯基)-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)吡啶-2-基)胺甲酸第三丁酯之合成Step 3: (3-Methyl-5-(2-(5-(methylaminocarbamoyl)-2-phenylpiperidin-1-yl)-2-oxyacetamido)pyridine- Synthesis of 3-butyl 2-yl)carbamate

向N -甲基 -6-苯基哌啶-3-甲醯胺(0.5g，2.29mmol)、2-[[6-(第三丁氧 基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(676.36mg，2.29mmol)及HATU(870.91mg，2.29mmol)於DMF(2mL)中之溶液中添加三乙胺(231.77mg，2.29mmol，319.25μL)。將混合物在25℃下攪拌2h。將混合物用水(30ml)稀釋且用EtOAc(3*50ml)萃取。將經合併之有機層用水(3*50ml)及鹽水洗滌，然後經Na2 SO4 乾燥且蒸發，以得到N -[3-甲基-5-[[2-[5-(甲基胺甲醯基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.8g，粗品)。To N - methyl -6-phenylpiperidine-3-carboxamide (0.5 g, 2.29 mmol), 2-[[6-( tert - butoxycarbonylamino)-5-methyl-3- Pyridyl]amino]-2-oxoacetic acid (676.36 mg, 2.29 mmol) and HATU (870.91 mg, 2.29 mmol) in DMF (2 mL) was added triethylamine (231.77 mg, 2.29 mmol, 319.25 mmol) μL). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (30ml) and extracted with EtOAc (3*50ml). The combined organic layers were washed with water (3*50ml) and brine, then dried over Na2SO4 and evaporated to give N- [3-methyl-5-[[2-[5-(methylamine methyl Acrylo)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.8 g, crude).

LCMS(ESI)：[M+1]m/z：計算值495.5；實測值496.2；Rt=1.183min。LCMS (ESI): [M+1]m/z: calculated 495.5; found 496.2; Rt=1.183 min.

步驟4：1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-N-甲基-6-苯基哌啶-3-甲醯胺(化合物249 及化合物253 )之合成Step 4: 1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-N-methyl-6-phenylpiperidine -Synthesis of 3-formamide ( compound 249 and compound 253 )

向N -[3-甲基-5-[[2-[5-(甲基胺甲醯基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.8g，1.61mmol)於DCM(15mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(58.86mg，1.61mmol，73.57μL)且將所得混合物在25℃下攪拌1.5h。蒸發溶劑且將殘餘物提交用於反相HPLC(30-30-50% 0-1-6min 0.1%NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇))，以得到2種級分：第1級分：100mg(100% LCMS)；(2D-NMR：順式異構物)及第2級分：71mg(98.5% LCMS)；(2D-NMR：反式異構物)。to N- [3-methyl-5-[[2-[5-(methylaminocarboxy)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino ]-2-Pyridinyl]carbamic acid tert- butyl ester (0.8 g, 1.61 mmol) in DCM (15 mL) was added to a 4.0 M solution of hydrogen chloride in dioxane (58.86 mg, 1.61 mmol, 73.57 μL) And the resulting mixture was stirred at 25 °C for 1.5 h. The solvent was evaporated and the residue was submitted for reverse phase HPLC (30-30-50% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol)) to give 2 species Fractions: Fraction 1: 100 mg (100% LCMS); (2D-NMR: cis isomer) and Fraction 2: 71 mg (98.5% LCMS); (2D-NMR: trans isomer) .

化合物249： LCMS(ESI)：[M]+ m/z：計算值395.4；實測值396.2；Rt=1.916min。 Compound 249: LCMS (ESI): [M] + m/z: calcd. 395.4; found 396.2; Rt=1.916 min.

化合物253： LCMS(ESI)：[M]+ m/z：計算值395.4；實測值396.2；Rt=1.916min。 Compound 253: LCMS (ESI): [M] + m/z: calcd. 395.4; found 396.2; Rt=1.916 min.

實例766.外消旋 -5-(2-側氧基-2-((2R,5S )-2-苯基-5-(1H -吡唑-5-基)哌啶-1-基)乙醯胺基)菸鹼醯胺(化合物669)之合成Example 766. Racemic -5-(2-oxo-2-(( 2R,5S )-2-phenyl-5-( 1H -pyrazol-5-yl)piperidin-1-yl)ethane Synthesis of amido)nicotinamide (compound 669)

Figure 110128222-A0202-12-2454-474
Figure 110128222-A0202-12-2454-474

步驟1：5-(甲氧基(甲基)胺甲醯基)-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 5-(Methoxy(methyl)aminocarboxy)-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

向1-第三丁氧基 羰基-6-苯基哌啶-3-甲酸(13.5g，44.21mmol)(如上文所述製備)於THF(200mL)中之經攪拌之溶液中添加CDI(9.32g，57.47mmol)且將反應混合物在25℃下攪拌2h。添加N,O -二甲基羥基胺鹽酸鹽(6.04g，61.89mmol)，隨後添加三乙胺(6.26g，61.89mmol，8.63mL)。將反應混合物在25℃下攪拌15h。蒸發四氫呋喃。將殘餘物用DCM(200ml)稀釋且用水(3*100ml)洗滌。將有機層經Na2 SO4 乾燥。蒸發DCM，以得到5-[甲氧基(甲基)胺甲醯基]-2-苯基哌啶-1-甲酸第三丁 酯(20g，粗品)，其不經進一步純化即用於下一步驟中。To a stirred solution of 1 -tert -butoxycarbonyl-6-phenylpiperidine-3-carboxylic acid (13.5 g, 44.21 mmol) (prepared as above) in THF (200 mL) was added CDI (9.32 mmol) g, 57.47 mmol) and the reaction mixture was stirred at 25 °C for 2 h. N,O -Dimethylhydroxylamine hydrochloride (6.04 g, 61.89 mmol) was added followed by triethylamine (6.26 g, 61.89 mmol, 8.63 mL). The reaction mixture was stirred at 25 °C for 15 h. The tetrahydrofuran was evaporated. The residue was diluted with DCM (200ml) and washed with water (3*100ml). The organic layer was dried over Na2SO4 . DCM was evaporated to give tert -butyl 5-[methoxy(methyl)aminocarbamoyl]-2-phenylpiperidine-1-carboxylate (20 g, crude) which was used in the next step without further purification in one step.

1 H NMR(500MHz,CDCl3 )δ(ppm)1.48(s,9H),1.75(m,2H),1.84(m,2H),2.48(m,1H),2.88(m,1H),3.68(s,3H),3.72(s,3H),4.72(m,1H),5.41(m,1H),7.24(m,5H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.48(s, 9H), 1.75(m, 2H), 1.84(m, 2H), 2.48(m, 1H), 2.88(m, 1H), 3.68( s, 3H), 3.72 (s, 3H), 4.72 (m, 1H), 5.41 (m, 1H), 7.24 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值248.2；實測值249.2；Rt=1.366min。LCMS (ESI): [M-Boc] + m/z: calculated 248.2; found 249.2; Rt=1.366 min.

步驟2：2-苯基-5-丙炔醯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-butyl 2-phenyl-5-propynylpiperidine-1-carboxylate

在-30℃下，向於THF中之0.5M經攪拌乙炔基溴化鎂溶液(9.27g，71.75mmol，143mL)中逐滴添加5-[甲氧基(甲基)胺甲醯基]-2-苯基哌啶-1-甲酸第三丁 酯(5g，14.35mmol)於THF(70mL)中之溶液。將反應混合物緩慢加熱至室溫且攪拌12h。將反應混合物添加到經劇烈攪拌(先前製備)之NaHSO4 溶液(17.2g於170ml水中)中且在25℃下攪拌4h。蒸發有機相。將水相用DCM(2*60ml)萃 取。將經合併之有機相用水、鹽水洗滌且經Na2 SO4 乾燥。在真空中蒸發溶劑，以得到2-苯基-5-丙-2-炔醯基哌啶-1-甲酸第三丁 酯(3.5g，11.17mmol，77.83%產率)。To a stirred solution of 0.5M ethynylmagnesium bromide in THF (9.27 g, 71.75 mmol, 143 mL) at -30°C was added dropwise 5-[methoxy(methyl)aminocarbamoyl]- A solution of tert -butyl 2-phenylpiperidine-1-carboxylate (5 g, 14.35 mmol) in THF (70 mL). The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was added to a vigorously stirred (previously prepared) solution of NaHSO 4 (17.2 g in 170 ml water) and stirred at 25° C. for 4 h. The organic phase was evaporated. The aqueous phase was extracted with DCM (2*60ml). The combined organic phases were washed with water, brine and dried over Na2SO4 . The solvent was evaporated in vacuo to give tert-butyl 2-phenyl-5-prop-2- ynylpiperidine -1-carboxylate (3.5 g, 11.17 mmol, 77.83% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.46(s,9H),1.82(m,2H),2.02(m,1H),2.45(m,1H),2.66(m,1H),2.77(m,1H),3.21(m,1H),4.39(m,1H),5.43(m,1H),7.28(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.46(s, 9H), 1.82(m, 2H), 2.02(m, 1H), 2.45(m, 1H), 2.66(m, 1H), 2.77( m, 1H), 3.21 (m, 1H), 4.39 (m, 1H), 5.43 (m, 1H), 7.28 (m, 5H).

LCMS(ESI)：[M-Boc]m/z：計算值213.2；實測值214.2；Rt=1.507min。LCMS (ESI): [M-Boc] m/z: calculated 213.2; found 214.2; Rt=1.507 min.

步驟3：5-(3-(二乙基胺基)丙烯醯基)-2-苯基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of tert-butyl 5-(3-(diethylamino)acryloyl)-2-phenylpiperidine-1-carboxylate

向2-苯基-5-丙-2-炔醯基哌啶-1-甲酸第三丁 酯(3.5g，11.17mmol)於乙醇(100mL)中之溶液中添加二乙胺(1.23g，16.75mmol，1.74mL)且將反應混合物在25℃下攪拌1.5h。在真空中蒸發乙醇，以得到5-[(E )-3-(二乙基胺基)丙-2-烯醯基]-2-苯基哌啶-1-甲酸第三丁 酯(3.5g，粗品)。To a solution of tert-butyl 2-phenyl-5-prop-2- ynylpiperidine -1-carboxylate (3.5 g, 11.17 mmol) in ethanol (100 mL) was added diethylamine (1.23 g, 16.75 g mmol, 1.74 mL) and the reaction mixture was stirred at 25 °C for 1.5 h. The ethanol was evaporated in vacuo to give tert- butyl 5-[( E )-3-(diethylamino)prop-2-enyl]-2-phenylpiperidine-1-carboxylate (3.5 g ,Crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.18(m,6H),1.42(s,9H),1.67(m,2H),1.88(m,3H),2.44(m,2H),2.79(m,1H),3.18(m,4H),5.05(m,1H),7.27(m,5H),7.50(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.18(m, 6H), 1.42(s, 9H), 1.67(m, 2H), 1.88(m, 3H), 2.44(m, 2H), 2.79( m, 1H), 3.18 (m, 4H), 5.05 (m, 1H), 7.27 (m, 5H), 7.50 (m, 1H).

LCMS(ESI)：[M-Boc]m/z：計算值286.2；實測值287.2；Rt=1.520min。LCMS (ESI): [M-Boc] m/z: calculated 286.2; found 287.2; Rt=1.520 min.

步驟4：2-苯基-5-(1H-吡唑-5-基)哌啶-1-甲酸第三丁酯之合成 向5-[(E )-3-(二乙基胺基)丙-2-烯醯基]-2-苯基哌啶-1-甲酸第三丁 酯(1g，2.59mmol)於乙醇(30mL)中之經攪拌之溶液中添加於水中之55%水合肼溶液(35%肼)(518.05mg，5.17mmol，502.97μL，50%純度)且將所得混合物在78℃下攪拌24h。蒸發乙醇。將殘餘物用水(100ml)稀釋且用乙酸乙酯(2*50ml)萃取。將經合併之有機層經Na2 SO4 乾燥。蒸發EtOAc，以得到2-苯基-5-(1H -吡唑-5-基)哌啶-1-甲酸第三丁 酯(700mg，粗品)。 Step 4: Synthesis of 3-butyl 2-phenyl-5-(1H-pyrazol-5-yl)piperidine-1-carboxylate to 5-[( E )-3-(diethylamino)propane A 55% solution of hydrazine hydrate in water ( 35% hydrazine) (518.05 mg, 5.17 mmol, 502.97 μL, 50% purity) and the resulting mixture was stirred at 78 °C for 24 h. Evaporate the ethanol. The residue was diluted with water (100ml) and extracted with ethyl acetate (2*50ml). The combined organic layers were dried over Na2SO4 . The EtOAc was evaporated to give 3 -butyl 2-phenyl-5-( lH -pyrazol-5-yl)piperidine-l-carboxylate (700 mg, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.49(s,9H),1.74(m,2H),2.08(m,2H),2.48(m, 1H),2.79(m,1H),2.98(m,1H),4.34(m,1H),5.52(m,1H),6.04(m,1H),7.35(m,5H),7.43(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.49(s, 9H), 1.74(m, 2H), 2.08(m, 2H), 2.48(m, 1H), 2.79(m, 1H), 2.98( m, 1H), 4.34 (m, 1H), 5.52 (m, 1H), 6.04 (m, 1H), 7.35 (m, 5H), 7.43 (m, 1H).

LCMS(ESI)：[M-Boc]m/z：計算值227.2；實測值228.2；Rt=1.406min。LCMS (ESI): [M-Boc] m/z: calculated 227.2; found 228.2; Rt=1.406 min.

步驟5：2-苯基-5-(1H-吡唑-5-基)哌啶之合成Step 5: Synthesis of 2-phenyl-5-(1H-pyrazol-5-yl)piperidine

向2-苯基-5-(1H -吡唑-5-基)哌啶-1-甲酸第三丁 酯(700mg，2.14mmol)於DCM(5mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(779.51mg，21.38mmol，974.39μL)。將反應混合物在25℃下攪拌3h。在真空中蒸發溶劑，以得到2-苯基-5-(1H -吡唑-5-基)哌啶(700mg，粗品，2HCl)。To a stirred solution of 2-phenyl-5-( 1H -pyrazol-5-yl)piperidine-1- carboxylate (700 mg, 2.14 mmol) in DCM (5 mL) was added in dioxane 4.0 M hydrogen chloride solution in alkane (779.51 mg, 21.38 mmol, 974.39 [mu]L). The reaction mixture was stirred at 25 °C for 3 h. The solvent was evaporated in vacuo to give 2-phenyl-5-( lH -pyrazol-5-yl)piperidine (700 mg, crude, 2HCl).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.68(m,1H),1.87(m,1H),2.09(m,3H),3.39(m,2H),4.42(m,1H),6.33(m,1H),7.46(m,5H),7.76(m,1H),8.49(m,1H),10.03(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.68(m,1H), 1.87(m,1H), 2.09(m,3H), 3.39(m,2H), 4.42(m,1H), 6.33 (m, 1H), 7.46 (m, 5H), 7.76 (m, 1H), 8.49 (m, 1H), 10.03 (m, 1H).

LCMS(ESI)：[M+1]m/z：計算值227.2；實測值228.2；Rt=0.860min。LCMS (ESI): [M+1] m/z: calculated 227.2; found 228.2; Rt=0.860 min.

步驟6：外消旋-5-(2-側氧基-2-((2R,5S)-2-苯基-5-(1H-吡唑-5-基)哌啶-1-基)乙醯胺基)菸鹼醯胺(化合物669 )之合成Step 6: Racemic-5-(2-oxo-2-((2R,5S)-2-phenyl-5-(1H-pyrazol-5-yl)piperidin-1-yl)ethane Synthesis of amido)nicotinamide ( compound 669 )

向2-苯基-5-(1H -吡唑-5-基)哌啶(300mg，999.25μmol，2HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(209.00mg，673.44μmol，Et3 N)及三乙胺(707.80mg，6.99mmol，974.93μL)於DMF(3mL)中之溶液中分批添加HATU(417.94mg，1.10mmol)。將混合物在25℃下攪拌2h。藉由反相HPLC(20-70% 0-5min水/MeOH+FA，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量419，管柱：Chromatorex 18 SMB100-5T 100x19mm 5u)純化反應混合物，以得到5-[[2-側氧基-2-[(2S,5R )-2-苯基-5-(1H -吡唑-5-基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(97mg，231.81μmol，23.20%產率)。To 2-phenyl-5-( 1H -pyrazol-5-yl)piperidine (300 mg, 999.25 μmol, 2HCl), 2-[(5-aminocarboxy-3-pyridinyl)amino]-2 - To a solution of oxyacetic acid (209.00 mg, 673.44 μmol, Et3N ) and triethylamine (707.80 mg, 6.99 mmol, 974.93 μL) in DMF (3 mL) was added HATU (417.94 mg, 1.10 mmol) portionwise . The mixture was stirred at 25 °C for 2 h. The reaction was purified by reverse phase HPLC (20-70% 0-5min water/MeOH+FA, flow rate: 30ml/min (load pump 4ml/min methanol), target mass 419, column: Chromatorex 18 SMB100-5T 100x19mm 5u) mixture to give 5-[[2-oxy-2-[( 2S,5R )-2-phenyl-5-( 1H -pyrazol-5-yl)-1-piperidinyl]acetinyl ]amino]pyridine-3-carboxamide (97 mg, 231.81 μmol, 23.20% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.52(m,1H),1.96(m,1H),2.59(m,1H),2.86(m,1H),3.00(m,1H),4.23(m,2H),5.52(m,1H),6.00(m,1H),7.28(m,3H), 7.40(m,3H),7.48(m,1H),7.62(m,1H),8.15(m,1H),8.51(m,1H),8.75(m,1H),8.91(m,1H),11.3(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.52(m,1H), 1.96(m,1H), 2.59(m,1H), 2.86(m,1H), 3.00(m,1H), 4.23(m, 2H), 5.52(m, 1H), 6.00(m, 1H), 7.28(m, 3H), 7.40(m, 3H), 7.48(m, 1H), 7.62(m, 1H), 8.15 (m, 1H), 8.51 (m, 1H), 8.75 (m, 1H), 8.91 (m, 1H), 11.3 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值418.4；實測值419.2；Rt=2.052min。LCMS (ESI): [M] + m/z: calculated 418.4; found 419.2; Rt=2.052 min.

實例767. 5-(2-(5-(羥基甲基)-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物266、化合物285)之合成Example 767. 5-(2-(5-(Hydroxymethyl)-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 266, Compound 285) synthesis

Figure 110128222-A0202-12-2457-475
Figure 110128222-A0202-12-2457-475

步驟1：(6-苯基哌啶-3-基)甲醇之合成Step 1: Synthesis of (6-phenylpiperidin-3-yl)methanol

向6-苯基哌啶-3-甲酸乙酯(2g，8.57mmol)(如上文所述製備)於THF(50mL)中之經預冷卻(-10℃)之經攪拌之溶液中分批添加氫化鋰鋁(325.36mg，8.57mmol)。將反應混合物在25℃下攪拌1.5h。將反應混合物用於THF中之20%水溶液淬滅。過濾所獲得之沉澱且將殘餘物用熱THF洗滌。將經合併之濾液在減壓下蒸發，以得到(6-苯基-3-哌啶基)甲醇(1.7g，粗品)。To a precooled (-10°C) stirred solution of ethyl 6-phenylpiperidine-3-carboxylate (2 g, 8.57 mmol) (prepared as described above) in THF (50 mL) was added portionwise Lithium aluminum hydride (325.36 mg, 8.57 mmol). The reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with a 20% aqueous solution in THF. The precipitate obtained was filtered and the residue was washed with hot THF. The combined filtrates were evaporated under reduced pressure to give (6-phenyl-3-piperidinyl)methanol (1.7 g, crude).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.95(m,4H),2.32(m,1H),2.82(m,1H),3.48(m,1H),3.63(m,2H),3.95(m,1H),4.04(m,1H),7.32(m,5H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.95(m, 4H), 2.32(m, 1H), 2.82(m, 1H), 3.48(m, 1H), 3.63(m, 2H), 3.95 (m, 1H), 4.04 (m, 1H), 7.32 (m, 5H).

LCMS(ESI)：[M]+ m/z：計算值191.2；實測值192.2；Rt=0.724min。LCMS (ESI): [M] + m/z: calculated 191.2; found 192.2; Rt=0.724 min.

步驟2：5-(2-(5-(羥基甲基)-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物266 及化合物285 )之合成Step 2: 5-(2-(5-(Hydroxymethyl)-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide ( Compound 266 and Compound 285 ) synthesis

向(6-苯基-3-哌啶基)甲醇(0.4g，2.09mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(513.66mg，2.09mmol，HCl)及HATU(874.69mg，2.30mmol)於DMF(4.5mL)中之溶液中添加三乙胺(1.06g，10.46mmol，1.46mL)。將混合物在25℃下攪拌2h。將混合物提交用於反相HPLC(0-5min 0-40%水-甲醇(NH3 0.1%)，流速30ml/min(裝載泵4ml/min甲醇(NH3 0.1%))，以得到3種級 分：第1級分：97mg(96% LCMS)-(2D研究：順式異構物)，第2級分：68mg(96% LCMS)-(2D研究：反式異構物)，第3級分：40mg(非鏡像異構物之混合物)。To (6-phenyl-3-piperidinyl)methanol (0.4 g, 2.09 mmol), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (513.66 g mg, 2.09 mmol, HCl) and HATU (874.69 mg, 2.30 mmol) in DMF (4.5 mL) was added triethylamine (1.06 g, 10.46 mmol, 1.46 mL). The mixture was stirred at 25 °C for 2 h. The mixture was submitted for reverse phase HPLC (0-5 min 0-40% water-methanol ( NH3 0.1%), flow rate 30 ml/min (load pump 4 ml/min methanol ( NH3 0.1%)) to give 3 grades Fractions: Fraction 1: 97 mg (96% LCMS) - (2D study: cis isomer), Fraction 2: 68 mg (96% LCMS) - (2D study: trans isomer), 3rd Fractions: 40 mg (mixture of diastereomers).

化合物266： LCMS(ESI)：[M]+ m/z：計算值382.4；實測值383.2；Rt=2.569min。 Compound 266: LCMS (ESI): [M] + m/z: calcd 382.4; found 383.2; Rt=2.569 min.

化合物285： LCMS(ESI)：[M]+ m/z：計算值382.4；實測值383.2；Rt=2.525min。 Compound 285: LCMS (ESI): [M] + m/z: calcd 382.4; found 383.2; Rt=2.525 min.

實例768. 5-[[2-[(2R ,5S )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S ,5R )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、5-[[2-[(2R ,5R )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S ,5S )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物350、化合物351、化合物401及化合物402)之合成Example 768. 5-[[2-[( 2R , 5S )-5-methyl-2-(6-oxy- 1H -pyridin-3-yl)-1-piperidinyl]-2 -Pendant oxyacetyl]amino]pyridine-3-carboxamide and 5-[[2-[( 2S , 5R )-5-methyl-2-(6-sideoxy- 1H -Pyridin-3-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide, 5-[[2-[(2 R ,5 R )- 5-Methyl-2-(6-oxo- 1H -pyridin-3-yl)-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide and 5-[[2-[( 2S , 5S )-5-methyl-2-(6-side oxy- 1H -pyridin-3-yl)-1-piperidinyl]-2-side Synthesis of Oxyacetyl]amino]pyridine-3-carboxamide (Compound 350, Compound 351, Compound 401 and Compound 402)

Figure 110128222-A0202-12-2458-476
Figure 110128222-A0202-12-2458-476

步驟1：6-(6-甲氧基-3-吡啶基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(6-methoxy-3-pyridyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(10g，26.06mmol)、(6-甲氧基-3-吡啶基)硼酸(3.99g，26.06mmol)及碳酸鈉(8.29g，78.19mmol，3.28mL)於1,4-二噁烷(120mL)及水(40mL)中之正攪拌懸浮液用氬氣吹掃10分鐘。10分鐘之後，在氬氣下添加Pd(dppf)Cl2 ˙CH2 Cl2 (956.99mg，1.17mmol)。將反應混合物在氬氣、90℃下攪拌18小時。18小時之後，將反應混合物冷卻至室溫且過濾。將濾餅用乙酸乙酯(4 x 50mL)洗滌且丟棄。在減壓下蒸發濾液，且藉由管柱層析(SiO2 ，己烷中之0-100% MTBE)純化粗殘餘物，以獲得呈淡黃色固體之6-(6-甲氧基-3-吡啶基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三 丁 酯(3.60g，11.83mmol，45.38%產率)。3-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (10 g, 26.06 mmol), (6-methyl) Positive stirring suspension of oxy-3-pyridyl)boronic acid (3.99 g, 26.06 mmol) and sodium carbonate (8.29 g, 78.19 mmol, 3.28 mL) in 1,4-dioxane (120 mL) and water (40 mL) The liquid was purged with argon for 10 minutes. After 10 minutes, Pd(dppf)Cl 2 ˙CH 2 Cl 2 (956.99 mg, 1.17 mmol) was added under argon. The reaction mixture was stirred under argon at 90°C for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (4 x 50 mL) and discarded. The filtrate was evaporated under reduced pressure, and the crude residue was purified by column chromatography ( SiO2 , 0-100% MTBE in hexanes) to obtain 6-(6-methoxy-3 as a pale yellow solid) -pyridyl)-3-methyl-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert -butyl ester (3.60 g, 11.83 mmol, 45.38% yield).

LCMS(ESI)：[M+H]+ m/z：計算值304.2；實測值305.2；Rt=1.528minLCMS(ESI): [M+H] + m/z: Calculated 304.2; Measured 305.2; Rt=1.528min

步驟2：2-甲氧基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶之合成Step 2: Synthesis of 2-methoxy-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine

將三氟乙酸(11.99g，105.13mmol，8.10mL)添加到6-(6-甲氧基-3-吡啶基)-3-甲基-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(1.60g，5.26mmol)中且將所得反應混合物在25℃下攪拌1小時。1小時之後，在減壓下濃縮反應混合物，以獲得淡黃色液體殘餘物。將所獲得之殘餘物溶解於20mL冰冷水中且逐滴添加10% NaOH溶液，直到pH=9-10。將所得懸浮液用二氯甲烷(3 x 20mL)萃取。將經合併之有機相用水(10mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈淡黃色固體之2-甲氧基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(1.30g，粗品)。粗產物不經任何進一步純化即用於下一步反應。Trifluoroacetic acid (11.99 g, 105.13 mmol, 8.10 mL) was added to 6-(6-methoxy-3-pyridyl)-3-methyl-3,4-dihydro- 2H -pyridine-1- tert -butyl formate (1.60 g, 5.26 mmol) and the resulting reaction mixture was stirred at 25[deg.]C for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure to obtain a pale yellow liquid residue. The obtained residue was dissolved in 20 mL of ice-cold water and 10% NaOH solution was added dropwise until pH=9-10. The resulting suspension was extracted with dichloromethane (3 x 20 mL). The combined organic phases were washed with water (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give 2-methoxy-5-(3-methyl-2,3,3,3,3,3 as a pale yellow solid) 4,5-Tetrahydropyridin-6-yl)pyridine (1.30 g, crude). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值204.2；實測值205.2；Rt=0.728min。LCMS (ESI): [M+H] + m/z: calculated 204.2; found 205.2; Rt=0.728 min.

步驟3：2-甲氧基-5-(5-甲基-2-哌啶基)吡啶之合成Step 3: Synthesis of 2-methoxy-5-(5-methyl-2-piperidinyl)pyridine

在0℃下，將硼氫化鈉(325.15mg，8.59mmol)分批添加到2-甲氧基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)吡啶(1.30g，5.73mmol)於甲醇(15mL)中之經攪拌之溶液中。將反應混合物在室溫下攪拌2小時。2小時之後，在減壓下濃縮反應混合物，以獲得淡黃色液體殘餘物。將所獲得之殘餘物溶解於水(20mL)中且用二氯甲烷(3 x 25mL)萃取。將經合併之有機相用水(2 x 10mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，以獲得呈黃色液體之粗產物2-甲氧基-5-(5-甲基-2-哌啶基)吡啶(1.00g，4.85mmol，84.61%產率)。粗產物不經任何進一步純化即用於下一步反應。Sodium borohydride (325.15 mg, 8.59 mmol) was added portionwise to 2-methoxy-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl) at 0 °C Pyridine (1.30 g, 5.73 mmol) in a stirred solution of methanol (15 mL). The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure to obtain a pale yellow liquid residue. The obtained residue was dissolved in water (20 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic phases were washed with water (2 x 10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain crude 2-methoxy-5-(5-methyl-2 as a yellow liquid) -Piperidinyl)pyridine (1.00 g, 4.85 mmol, 84.61% yield). The crude product was used in the next reaction without any further purification.

LCMS(ESI)：[M+H]+ m/z：計算值206.2；實測值207.2；Rt=0.668min。LCMS (ESI): [M+H] + m/z: calculated 206.2; found 207.2; Rt=0.668 min.

步驟4：5-(5-甲基-2-哌啶基)-1H-吡啶-2-酮之合成Step 4: Synthesis of 5-(5-methyl-2-piperidinyl)-1H-pyridin-2-one

將2-甲氧基-5-(5-甲基-2-哌啶基)吡啶(0.3g，1.45mmol)於6N鹽酸水 溶液(10mL)中之溶液在95℃下攪拌48小時。48小時之後，使反應混合物冷卻至室溫且在真空中蒸發，以得到呈黃色固體之5-(5-甲基-2-哌啶基)-1H -吡啶-2-酮(320mg，1.40mmol，96.20%產率，鹽酸鹽)。粗產物直接用於下一步反應中。A solution of 2-methoxy-5-(5-methyl-2-piperidinyl)pyridine (0.3 g, 1.45 mmol) in 6N aqueous hydrochloric acid (10 mL) was stirred at 95°C for 48 hours. After 48 hours, the reaction mixture was cooled to room temperature and evaporated in vacuo to give 5-(5-methyl-2-piperidinyl) -1H -pyridin-2-one (320 mg, 1.40 g) as a yellow solid mmol, 96.20% yield, hydrochloride). The crude product was used directly in the next reaction.

LCMS(ESI)：[M+H]+ m/z：計算值192.2；實測值193.2；Rt=0.591min。LCMS (ESI): [M+H] + m/z: calculated 192.2; found 193.2; Rt=0.591 min.

步驟5：5-[[2-[5-甲基-2-(6-側氧基-1H-吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 5: 5-[[2-[5-Methyl-2-(6-pendoxyl-1H-pyridin-3-yl)-1-piperidinyl]-2-pendoxetyl]amine Synthesis of base]pyridine-3-carboxamide

在25℃下，向5-(5-甲基-2-哌啶基)-1H -吡啶-2-酮(300mg，1.31mmol，鹽酸鹽)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(407.07mg，1.31mmol，Et3 N鹽)及N ,N -二異丙基乙胺(847.61mg，6.56mmol，1.14mL)於DMF(10mL)中之經攪拌之溶液中分批添加HATU(598.48mg，1.57mmol)。將所得反應混合物在25℃下攪拌72小時。72小時之後，將樣品提交用於LCMS分析。LCMS指示約20%所要產物質量。在減壓下濃縮反應混合物，以獲得粗產物，其藉由反相HPLC(溶析液：0-5min，10-25%水-甲醇+甲酸；管柱：SunFireC18 100 x 19mm，5um；流速：30mL/min；裝載泵：4mL/min，甲醇)進行純化，以得到呈黃色膠狀物之產物5-[[2-[5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(120mg，312.99μmol，23.86%產率)。To 5-(5-methyl-2-piperidinyl) -1H -pyridin-2-one (300 mg, 1.31 mmol, hydrochloride), 2-[(5-aminocarbamoyl at 25°C -3-Pyridinyl)amino]-2-oxoacetic acid (407.07 mg, 1.31 mmol, Et 3 N salt) and N , N -diisopropylethylamine (847.61 mg, 6.56 mmol, 1.14 mL) in To a stirred solution in DMF (10 mL) was added HATU (598.48 mg, 1.57 mmol) portionwise. The resulting reaction mixture was stirred at 25°C for 72 hours. After 72 hours, samples were submitted for LCMS analysis. LCMS indicated about 20% mass of the desired product. The reaction mixture was concentrated under reduced pressure to obtain crude product by reverse phase HPLC (eluent: 0-5 min, 10-25% water-methanol + formic acid; column: SunFire C18 100 x 19 mm, 5 um; flow rate: 30 mL/min; loading pump: 4 mL/min, methanol) was purified to give the product 5-[[2-[5-methyl-2-(6-oxy- 1H -pyridine as a yellow gum -3-yl)-1-piperidinyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide (120 mg, 312.99 μmol, 23.86% yield).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.2；Rt=2.035min。LCMS (ESI): [M+H] + m/z: calculated 383.2; found 384.2; Rt=2.035 min.

步驟6：5-[[2-[(2R,5S)-5-甲基-2-(6-側氧基-1H-吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S,5R)-5-甲基-2-(6-側氧基-1H-吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺、5-[[2-[(2R,5R)-5-甲基-2-(6-側氧基-1H-吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺及5-[[2-[(2S,5S)-5-甲基-2-(6-側氧基-1H-吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物350 、化合物351 、化合物401 及化合物402 )之掌性分離Step 6: 5-[[2-[(2R,5S)-5-methyl-2-(6-oxo-1H-pyridin-3-yl)-1-piperidinyl]-2-oxo Acetyl]amino]pyridine-3-carboxamide and 5-[[2-[(2S,5R)-5-methyl-2-(6-oxy-1H-pyridin-3-yl )-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide, 5-[[2-[(2R,5R)-5-methyl-2-( 6-oxy-1H-pyridin-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide and 5-[[2-[( 2S,5S)-5-Methyl-2-(6-oxy-1H-pyridin-3-yl)-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 - Chiral separation of carboxamide ( compound 350 , compound 351 , compound 401 and compound 402 )

使5-[[2-[5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(120mg，312.99μmol)經歷掌性HPLC純化(管柱：Chiralpak AD-H-III(250 x 20mm，5um)；流動相：己烷-IPA-MeOH，60-20-20；流速：14mL/min)，以得到呈灰白色固體之5-[[2-[(2S ,5S )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物402 ，5.6mg，14.61μmol，4.67%產率)、5-[[2-[(2R ,5R )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物401 ，5.6mg，14.61μmol，4.67%產率)、5-[[2-[(2S ,5R )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物351 ，44mg，114.76μmol，36.67%產率)及5-[[2-[(2R ,5S )-5-甲基-2-(6-側氧基-1H -吡啶-3-基)-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物350 ，62mg，161.71μmol，51.67%產率)。make 5-[[2-[5-methyl-2-(6-oxo- 1H -pyridin-3-yl)-1-piperidinyl]-2-oxoacetyl]amino ] Pyridine-3-carboxamide (120 mg, 312.99 μmol) was purified by chiral HPLC (column: Chiralpak AD-H-III (250 x 20 mm, 5 um); mobile phase: Hexane-IPA-MeOH, 60-20 -20; flow rate: 14 mL/min) to give 5-[[2-[( 2S , 5S )-5-methyl-2-(6-oxy- 1H -pyridine- 3-yl)-1-piperidinyl]-2-side oxyacetyl]amino]pyridine-3-carboxamide ( Compound 402 , 5.6 mg, 14.61 μmol, 4.67% yield), 5-[ [2-[(2 R ,5 R )-5-methyl-2-(6-oxy- 1H -pyridin-3-yl)-1-piperidinyl]-2-oxyacetyl yl]amino]pyridine-3-carboxamide ( compound 401 , 5.6 mg, 14.61 μmol, 4.67% yield), 5-[[2-[( 2S , 5R )-5-methyl-2- (6-oxy- 1H -pyridin-3-yl)-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( compound 351 , 44 mg, 114.76 μmol, 36.67% yield) and 5-[[2-[( 2R , 5S )-5-methyl-2-(6-oxy- 1H -pyridin-3-yl)-1-piperidine Peridyl]-2-pendant oxyacetyl]amino]pyridine-3-carboxamide ( compound 350 , 62 mg, 161.71 μmol, 51.67% yield).

化合物350： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)1.00-1.03(m,3H),1.26-1.35(m,1H),1.69-1.76(m,1H),1.84-1.91(m,1H),1.93-2.06(m,2H),2.81-3.23(m,1H),3.39-3.93(m,1H),4.88-5.38(m,1H),6.29-6.40(m,1H),7.17-7.24(m,1H),7.33-7.48(m,1H),7.56-7.64(m,1H),8.11-8.18(m,1H),8.42-8.50(m,1H),8.73-8.79(m,1H),8.83-8.90(m,1H),11.12-11.26(m,1H),11.60(s,1H)。 Compound 350: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 1.00-1.03 (m, 3H), 1.26-1.35 (m, 1H), 1.69-1.76 (m, 1H), 1.84-1.91 ( m,1H),1.93-2.06(m,2H),2.81-3.23(m,1H),3.39-3.93(m,1H),4.88-5.38(m,1H),6.29-6.40(m,1H), 7.17-7.24(m, 1H), 7.33-7.48(m, 1H), 7.56-7.64(m, 1H), 8.11-8.18(m, 1H), 8.42-8.50(m, 1H), 8.73-8.79(m , 1H), 8.83-8.90 (m, 1H), 11.12-11.26 (m, 1H), 11.60 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.0；Rt=3.340min。LCMS (ESI): [M+H] + m/z: calculated 383.2; found 384.0; Rt=3.340 min.

掌性HPLC：Rt=20.45min(管柱：AD-H；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=20.45 min (column: AD-H; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

化合物351： 1 H NMR(DMSO-d 6 ,500MHz)：δ(ppm)0.97-1.02(m,3H),1.25-1.38(m,1H),1.68-1.76(m,1H),1.79-1.91(m,1H),1.91-1.98(m,1H),1.99-2.03(m,1H),2.79-3.23(m,1H),3.36-3.96(m,1H),4.86-5.38(m,1H),6.29-6.40(m,1H),7.20(s,1H),7.31-7.46(m,1H),7.54-7.64(m,1H),8.08-8.21(m,1H),8.43-8.50(m,1H),8.71-8.81(m,1H),8.82-8.91(m,1H),11.15-11.34(m,1H),11.60(s,1H)。 Compound 351: 1 H NMR (DMSO- d 6 , 500 MHz): δ (ppm) 0.97-1.02 (m, 3H), 1.25-1.38 (m, 1H), 1.68-1.76 (m, 1H), 1.79-1.91 ( m,1H),1.91-1.98(m,1H),1.99-2.03(m,1H),2.79-3.23(m,1H),3.36-3.96(m,1H),4.86-5.38(m,1H), 6.29-6.40(m, 1H), 7.20(s, 1H), 7.31-7.46(m, 1H), 7.54-7.64(m, 1H), 8.08-8.21(m, 1H), 8.43-8.50(m, 1H) ), 8.71-8.81(m, 1H), 8.82-8.91(m, 1H), 11.15-11.34(m, 1H), 11.60(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.0；Rt=3.338min。LCMS (ESI): [M+H] + m/z: calculated 383.2; found 384.0; Rt=3.338 min.

掌性HPLC：Rt=15.45min(管柱：AD-H；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=15.45 min (column: AD-H; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

化合物401： 1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.75-0.84(m,3H),1.11-1.18(m,1H),1.57-1.69(m,2H),1.71-1.87(m,1H),2.26-2.29(m,1H),2.51-2.58(m,1H),3.54-4.18(m,1H),4.88-5.45(m,1H),6.34-6.42(m,1H),7.16-7.21(m,1H),7.30-7.43(m,1H),7.57-7.65(m,1H),8.11-8.22(m,1H),8.44-8.50(m,1H),8.74-8.79(m,1H),8.82-8.90(m,1H),11.07-11.39(m,1H),11.62(s,1H)。 Compound 401: 1 H NMR (DMSO- d 6 , 600 MHz): δ (ppm) 0.75-0.84 (m, 3H), 1.11-1.18 (m, 1H), 1.57-1.69 (m, 2H), 1.71-1.87 ( m,1H), 2.26-2.29(m,1H), 2.51-2.58(m,1H), 3.54-4.18(m,1H), 4.88-5.45(m,1H), 6.34-6.42(m,1H), 7.16-7.21(m, 1H), 7.30-7.43(m, 1H), 7.57-7.65(m, 1H), 8.11-8.22(m, 1H), 8.44-8.50(m, 1H), 8.74-8.79(m , 1H), 8.82-8.90 (m, 1H), 11.07-11.39 (m, 1H), 11.62 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.0；Rt=3.311min。LCMS (ESI): [M+H] + m/z: calculated 383.2; found 384.0; Rt=3.311 min.

掌性HPLC：Rt=12.57min(管柱：AD-H；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=12.57 min (column: AD-H; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

化合物402：Compound 402:

1 H NMR(DMSO-d 6 ,600MHz)：δ(ppm)0.73-0.84(m,3H),1.10-1.17(m,1H),1.57-1.70(m,2H),1.73-1.85(m,1H),2.13-2.19(m,0.6H),2.25-2.30(m,1H),2.54-2.58(m,0.4H),3.42-4.19(m,1H),4.87-5.48(m,1H),6.32-6.42(m,1H),7.14-7.24(m,1H),7.32-7.46(m,1H),7.56-7.65(m,1H),8.10-8.22(m,1H),8.44-8.54(m,1H),8.71-8.80(m,1H),8.82-8.91(m,1H),11.20-11.33(m,1H),11.62(br s,1H)。 1 H NMR (DMSO- d 6 , 600MHz): δ (ppm) 0.73-0.84 (m, 3H), 1.10-1.17 (m, 1H), 1.57-1.70 (m, 2H), 1.73-1.85 (m, 1H) ), 2.13-2.19(m, 0.6H), 2.25-2.30(m, 1H), 2.54-2.58(m, 0.4H), 3.42-4.19(m, 1H), 4.87-5.48(m, 1H), 6.32 -6.42(m,1H),7.14-7.24(m,1H),7.32-7.46(m,1H),7.56-7.65(m,1H),8.10-8.22(m,1H),8.44-8.54(m, 1H), 8.71-8.80 (m, 1H), 8.82-8.91 (m, 1H), 11.20-11.33 (m, 1H), 11.62 (br s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值383.2；實測值384.0；Rt=3.313min。LCMS (ESI): [M+H] + m/z: calculated 383.2; found 384.0; Rt=3.313 min.

掌性HPLC：Rt=9.96min(管柱：AD-H；流動相：己烷-IPA-MeOH，50-25-25；流速：0.6mL/min)。Chiral HPLC: Rt=9.96 min (column: AD-H; mobile phase: hexane-IPA-MeOH, 50-25-25; flow rate: 0.6 mL/min).

實例769. 5-[[2-[(2S,5R)-2-(3-羥基環戊基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物517)之合成Example 769. 5-[[2-[(2S,5R)-2-(3-hydroxycyclopentyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide (Compound 517)

Figure 110128222-A0202-12-2463-477
Figure 110128222-A0202-12-2463-477

步驟1：3-溴環戊-2-烯-1-酮之合成Step 1: Synthesis of 3-bromocyclopent-2-en-1-one

在0℃下，向三苯基膦(6.42g，24.46mmol)於DCM(50mL)中之經攪拌之溶液中添加溴(3.26g，20.39mmol，2.19mL)。將反應混合物在同一溫度下攪拌45min。然後，添加環戊烷-1,3-二酮(2g，20.39mmol)及三乙胺(2.48g，24.46mmol，3.41mL)於DCM(50mL)中之溶液。將反應混合物在25℃下攪拌15h。蒸發DCM，以得到粗產物，其藉由急驟層析使用己烷(兩次)進行純化。蒸發己烷，以得到3-溴環戊-2-烯-1-酮(0.5g，3.11mmol，15.23%產率)。To a stirred solution of triphenylphosphine (6.42 g, 24.46 mmol) in DCM (50 mL) at 0 °C was added bromine (3.26 g, 20.39 mmol, 2.19 mL). The reaction mixture was stirred at the same temperature for 45 min. Then, a solution of cyclopentane-1,3-dione (2 g, 20.39 mmol) and triethylamine (2.48 g, 24.46 mmol, 3.41 mL) in DCM (50 mL) was added. The reaction mixture was stirred at 25 °C for 15 h. The DCM was evaporated to give the crude product which was purified by flash chromatography using hexanes (twice). Hexane was evaporated to give 3-bromocyclopent-2-en-1-one (0.5 g, 3.11 mmol, 15.23% yield).

1 H NMR(500MHz,CDCl3 )δ 2.54(m,2H),2.98(m,2H),8.41(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 2.54 (m, 2H), 2.98 (m, 2H), 8.41 (s, 1H).

GCMS(EI)：[M+H]+ m/z：計算值161.0；實測值160.0；Rt=4.321min。GCMS (EI): [M+H] + m/z: calculated 161.0; found 160.0; Rt=4.321 min.

步驟2：3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環戊-2-烯-1-酮之合成Step 2: Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclopent-2-en-1-one

向3-溴環戊-2-烯-1-酮(0.5g，3.11mmol)於二噁烷(15mL)中之溶液中添加4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(1.58g，6.21mmol)、Pd(dppf)Cl2(126.81mg，155.28μmol)及乙酸鉀(914.39mg，9.32mmol，582.41μL)。將所得混合物在80℃下攪拌15h。將溶液冷卻至室溫，用水(40ml)稀釋且用二氯甲烷(2* 50ml)萃取。將所收集之有機層經Na2 SO4 乾燥，過濾。蒸發DCM，以得到3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環戊-2-烯-1-酮(0.8g，粗品)。To a solution of 3-bromocyclopent-2-en-1-one (0.5 g, 3.11 mmol) in dioxane (15 mL) was added 4,4,5,5-tetramethyl-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.58 g, 6.21 mmol ), Pd(dppf)Cl2 (126.81 mg, 155.28 μmol) and potassium acetate (914.39 mg, 9.32 mmol, 582.41 μL). The resulting mixture was stirred at 80 °C for 15 h. The solution was cooled to room temperature, diluted with water (40ml) and extracted with dichloromethane (2 * 50ml). The collected organic layers were dried over Na2SO4 and filtered. DCM was evaporated to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclopent-2-en-1-one ( 0.8g, crude).

1 H NMR(500MHz,CDCl3 )δ 1.31(m,8H),2.34(m,2H),2.75(m,2H),3.69(s,4H), 6.62(s,1H)。 1 H NMR (500 MHz, CDCl 3 ) δ 1.31 (m, 8H), 2.34 (m, 2H), 2.75 (m, 2H), 3.69 (s, 4H), 6.62 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值208.1；實測值209.2；Rt=0.269min。LCMS (ESI): [M+H] + m/z: calculated 208.1; found 209.2; Rt=0.269 min.

步驟3：3-甲基-6-(3-側氧基環戊烯-1-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 3-methyl-6-(3-oxycyclopenten-1-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

向3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環戊-2-烯-1-酮(7g，33.64mmol)及3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(11.62g，33.64mmol)於二噁烷(150mL)中之經攪拌之溶液中添加碳酸鈉(10.70g，100.93mmol，4.23mL)於水(50mL)中之溶液。將所得混合物抽真空，然後用氬氣回填，將此操作重複三次。添加Pd(dppf)Cl2 (1.37g，1.68mmol)且將反應混合物在80℃下攪拌14h。過濾反應混合物，蒸發溶劑。藉由梯度層析純化殘餘物，以得到3-甲基-6-(3-側氧基環戊烯-1-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.5g，9.01mmol，26.79%產率)。To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclopent-2-en-1-one (7 g, 33.64 mmol ) and 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.62 g, 33.64 mmol) in dioxane To the stirred solution in (150 mL) was added a solution of sodium carbonate (10.70 g, 100.93 mmol, 4.23 mL) in water (50 mL). The resulting mixture was evacuated and backfilled with argon, which was repeated three times. Pd(dppf)Cl2 (1.37 g , 1.68 mmol) was added and the reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was filtered and the solvent was evaporated. The residue was purified by gradient chromatography to give 3-methyl-6-(3-oxycyclopenten-1-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl Ester (2.5 g, 9.01 mmol, 26.79% yield).

1 H NMR(500MHz,CDCl3 )δ 1.01(d,3H),1.40(s,9H),.97(m,1H),1.99(m,1H),2.49(m,3H),2.89(m,1H),2.77(m,1H),2.92(m,1H),3.92(m,1H),5.76(s,1H),6.04(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ 1.01(d, 3H), 1.40(s, 9H), .97(m, 1H), 1.99(m, 1H), 2.49(m, 3H), 2.89(m, 1H), 2.77 (m, 1H), 2.92 (m, 1H), 3.92 (m, 1H), 5.76 (s, 1H), 6.04 (s, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值221.2；實測值222.2；Rt=1.258min。LCMS (ESI): [M-tBu] + m/z: calculated 221.2; found 222.2; Rt=1.258 min.

步驟4：3-(5-甲基-2-哌啶基)環戊-2-烯-1-醇之合成Step 4: Synthesis of 3-(5-methyl-2-piperidinyl)cyclopent-2-en-1-ol

向3-甲基-6-(3-側氧基環戊烯-1-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(1.9g，6.85mmol)中添加三氟乙酸(7.81g，68.50mmol，5.28mL)且將反應混合物在25℃下攪拌1.5h。蒸發TFA。將殘餘物用DME(40mL)稀釋且在0℃下分批添加硼氫化鈉(1.30g，34.25mmol，1.21mL)。將反應混合物在25℃下攪拌1.5h，然後用甲醇(5ml)淬滅。蒸發溶劑。將殘餘物用10% NaOH溶液洗滌且用DCM(2* 50ml)萃取。將有機層合併，經Na2 SO4 乾燥。蒸發DCM，以得到3-(5-甲基-2-哌啶基)環戊-2-烯-1-醇(0.85g，粗品)。To 3-methyl-6-(3-oxycyclopenten-1-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.9 g, 6.85 mmol) was added Trifluoroacetic acid (7.81 g, 68.50 mmol, 5.28 mL) and the reaction mixture was stirred at 25 °C for 1.5 h. Evaporate TFA. The residue was diluted with DME (40 mL) and sodium borohydride (1.30 g, 34.25 mmol, 1.21 mL) was added portionwise at 0 °C. The reaction mixture was stirred at 25°C for 1.5h and then quenched with methanol (5ml). Evaporate the solvent. The residue was washed with 10% NaOH solution and extracted with DCM (2 * 50ml). The organic layers were combined and dried over Na2SO4 . The DCM was evaporated to give 3-(5-methyl-2-piperidinyl)cyclopent-2-en-1-ol (0.85 g, crude).

LCMS(ESI)：[M+H]+ m/z：計算值181.2；實測值182.2；Rt=0.698min。LCMS (ESI): [M+H] + m/z: calculated 181.2; found 182.2; Rt=0.698 min.

步驟5：3-(5-甲基-2-哌啶基)環戊醇之合成Step 5: Synthesis of 3-(5-methyl-2-piperidinyl)cyclopentanol

向3-(5-甲基-2-哌啶基)環戊-2-烯-1-醇(0.85g，4.69mmol)於MeOH(40mL)中之經攪拌之溶液中添加乾燥的487型鈀(10%於碳上)(0.6g，5.64mmol)。將反應燒瓶抽真空且藉由氫氣再填充。在氫氣氣氛下將反應混合物在54℃下攪拌14h。透過SiO2 過濾反應混合物。蒸發甲醇，以得到3-(5-甲基-2-哌啶基)環戊醇(0.45g，2.46mmol，52.36%產率)，其不經進一步純化即用於下一步驟中。To a stirred solution of 3-(5-methyl-2-piperidinyl)cyclopent-2-en-1-ol (0.85 g, 4.69 mmol) in MeOH (40 mL) was added dry palladium type 487 (10% on carbon) (0.6 g, 5.64 mmol). The reaction flask was evacuated and refilled with hydrogen. The reaction mixture was stirred at 54 °C for 14 h under a hydrogen atmosphere. The reaction mixture was filtered through SiO2 . The methanol was evaporated to give 3-(5-methyl-2-piperidinyl)cyclopentanol (0.45 g, 2.46 mmol, 52.36% yield) which was used in the next step without further purification.

1 H NMR(500MHz,CDCl3 )δ 0.81(d,3H),1.22(m,6H),2.17(m,8H),2.28(m,2H),3.01(m,1H),4.33(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.81(d,3H), 1.22(m,6H), 2.17(m,8H), 2.28(m,2H), 3.01(m,1H), 4.33(m,1H) ).

LCMS(ESI)：[M+H]+ m/z：計算值183.2；實測值184.2；Rt=0.524min。LCMS (ESI): [M+H] + m/z: calculated 183.2; found 184.2; Rt=0.524 min.

步驟6：5-[[2-[(2S,5R)-2-(3-羥基環戊基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物517 )之合成Step 6: 5-[[2-[(2S,5R)-2-(3-hydroxycyclopentyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide ( Compound 517 )

向3-[(2R,5S)-5-甲基-2-哌啶基]環戊醇(0.35g，1.91mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(592.62mg，1.91mmol，Et3N)及三乙胺(1.35g，13.37mmol，1.86mL)於DMF(4mL)中之溶液中分批添加HATU(798.67mg，2.10mmol)。將混合物在25℃下攪拌2h。反應混合物之LCMS分析顯示45%產物。將反應混合物提交用於反相HPLC(10-10-60% 0-1-5min 0.1% NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量374，管柱：YMC Triart C18 100* 20mm，5um)，以得到呈圍繞C-OH之非鏡像異構物之混合物的5-[[2-[(2S,5R)-2-(3-羥基環戊基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(66mg，176.27μmol，9.23%產率)。To 3-[(2R,5S)-5-methyl-2-piperidinyl]cyclopentanol (0.35 g, 1.91 mmol), 2-[(5-aminocarboxy-3-pyridinyl)amino ]-2-Pendoxacetic acid (592.62 mg, 1.91 mmol, Et3N) and triethylamine (1.35 g, 13.37 mmol, 1.86 mL) in DMF (4 mL) was added HATU (798.67 mg, 2.10 mmol) portionwise ). The mixture was stirred at 25 °C for 2 h. LCMS analysis of the reaction mixture showed 45% product. The reaction mixture was submitted for reverse phase HPLC (10-10-60% 0-1-5 min 0.1% NH3 -methanol, flow rate: 30 ml/min (load pump 4 ml/min methanol), target mass 374, column: YMC Triart C18 100 * 20mm, 5um) to give 5-[[2-[(2S,5R)-2-(3-hydroxycyclopentyl)-5 as a mixture of diastereoisomers around C-OH -Methyl-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (66 mg, 176.27 μmol, 9.23% yield).

LCMS(ESI)：[M+H]+ m/z：計算值374.2；實測值375.2；Rt=1.846min。LCMS (ESI): [M+H] + m/z: calculated 374.2; found 375.2; Rt=1.846 min.

實例770. 5-[[2-側氧基-2-[2-苯基-5-(三氟甲氧基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物411)之合成Example 770. 5-[[2-Oxy-2-[2-phenyl-5-(trifluoromethoxy)-1-piperidinyl]acetyl]amino]pyridine-3-carboxylate Synthesis of Amine (Compound 411)

Figure 110128222-A0202-12-2466-478
Figure 110128222-A0202-12-2466-478

步驟1：6-苯基哌啶-3-醇之合成Step 1: Synthesis of 6-Phenylpiperidin-3-ol

將6-苯基吡啶-3-醇(8.00g，46.73mmol)溶解於MeOH(250mL)中且添加乾燥的487型鈀(10%於碳上)(2.49g，2.34mmol，10%純度)。將反應混合物在50℃下、在高壓容器中、在100巴H2 壓力下加熱120h。過濾出催化劑，用MeOH洗滌且蒸發溶劑，以得到6-苯基哌啶-3-醇(8.1g，45.70mmol，97.80%產率)。此化合物不經純化即用於下一步驟。6-Phenylpyridin-3-ol (8.00 g, 46.73 mmol) was dissolved in MeOH (250 mL) and dry palladium Form 487 (10% on carbon) (2.49 g, 2.34 mmol, 10% pure) was added. The reaction mixture was heated at 50 °C in a high pressure vessel under 100 bar H2 pressure for 120 h. The catalyst was filtered off, washed with MeOH and the solvent was evaporated to give 6-phenylpiperidin-3-ol (8.1 g, 45.70 mmol, 97.80% yield). This compound was used in the next step without purification.

1 H NMR(500MHz,DMSO-d6 )δ 1.33(m,2H),1.69(m,2H),1.94(m,1H),2.35(m,1H),3.98(m,1H),3.44(m,2H),7.27(m,5H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.33(m, 2H), 1.69(m, 2H), 1.94(m, 1H), 2.35(m, 1H), 3.98(m, 1H), 3.44(m , 2H), 7.27 (m, 5H).

LCMS(ESI)：[M+H]+ m/z：計算值177.2；實測值178.2；Rt=0.656min。LCMS (ESI): [M+H] + m/z: calculated 177.2; found 178.2; Rt=0.656 min.

步驟2：5-羥基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl 5-hydroxy-2-phenylpiperidine-1-carboxylate

向6-苯基哌啶-3-醇(8.1g，45.70mmol)於THF(150mL)中之溶液中添加二碳酸二-第三丁酯(10.47g，47.99mmol，11.01mL)。將所得混合物在25℃下攪拌12h，蒸發，溶解於水(30ml)中，用DCM(3* 50ml)萃取，經Na2 SO4 乾燥且在真空中蒸發，以獲得粗產物，藉由梯度層析(己烷-MTBE)純化該粗產物，以獲得5-羥基-2-苯基哌啶-1-甲酸第三丁酯(2g，7.21mmol，15.78%產率)及藉由GCMS為純度87%之級分(4g)。純級分之結構使用2D NMR證實為反式。To a solution of 6-phenylpiperidin-3-ol (8.1 g, 45.70 mmol) in THF (150 mL) was added di-tert-butyl dicarbonate (10.47 g, 47.99 mmol, 11.01 mL). The resulting mixture was stirred at 25°C for 12h, evaporated, dissolved in water (30ml), extracted with DCM (3 * 50ml), dried over Na2SO4 and evaporated in vacuo to obtain crude product by gradient layer The crude product was purified by analytical (hexane-MTBE) to obtain tert-butyl 5-hydroxy-2-phenylpiperidine-1-carboxylate (2 g, 7.21 mmol, 15.78% yield) with purity 87 by GCMS % fraction (4g). The structure of the pure fraction was confirmed in trans using 2D NMR.

1 H NMR(400MHz,CDCl3 )δ 1 H NMR (400MHz, CDCl 3 )δ

LCMS(ESI)：[M+H]+ m/z：計算值227.2；實測值228.0；Rt=1.342min。LCMS (ESI): [M+H] + m/z: calculated 227.2; found 228.0; Rt=1.342 min.

步驟3：2-苯基-5-(三氟甲氧基)哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 2-phenyl-5-(trifluoromethoxy)piperidine-1-carboxylic acid tert-butyl ester

在Ar氣氛下，向裝備有攪拌棒且用鋁箔覆蓋之反應燒瓶中添加5-羥基-2-苯基哌啶-1-甲酸第三丁酯(0.55g，1.98mmol)、三氟甲基磺酸銀(1.53g，5.95mmol)、氟化鉀(460.82mg，7.93mmol)及1-氯甲基-4-氟-1,4-二氮雜雙環[2.2.2]辛烷雙(四氟硼酸酯)(1.05g，2.97mmol)。然後依次逐滴添加EtOAc(10mL)、2-氟-吡啶(577.59mg，5.95mmol，511.14μL)及三氟甲基三甲基矽烷(845.91mg，5.95mmol，945.16μL)，同時使用水浴保持內部溫度低於30℃。將反應混合物在25℃下攪拌12h。透過矽膠塞過濾所得混合物且將濾液(80ml)用鹽水(3* 50ml)洗滌，經Na2 SO4 乾燥且在真空中蒸發，以獲得粗品2-苯基-5-(三氟甲氧基)哌啶-1-甲酸第三丁酯(0.7g，粗品)。此化合物不經純化即用於下一步驟。Under Ar atmosphere, to a reaction flask equipped with a stir bar and covered with aluminum foil was added tert-butyl 5-hydroxy-2-phenylpiperidine-1-carboxylate (0.55 g, 1.98 mmol), trifluoromethanesulfonic acid Silver acid (1.53 g, 5.95 mmol), potassium fluoride (460.82 mg, 7.93 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoro boronate) (1.05 g, 2.97 mmol). Then EtOAc (10 mL), 2-fluoro-pyridine (577.59 mg, 5.95 mmol, 511.14 μL) and trifluoromethyltrimethylsilane (845.91 mg, 5.95 mmol, 945.16 μL) were added dropwise sequentially while using a water bath to keep the interior The temperature is below 30°C. The reaction mixture was stirred at 25 °C for 12 h. The resulting mixture was filtered through a plug of silica gel and the filtrate (80ml) was washed with brine (3 * 50ml), dried over Na2SO4 and evaporated in vacuo to give crude 2-phenyl-5-(trifluoromethoxy) 3-Butyl piperidine-1-carboxylate (0.7 g, crude). This compound was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ 1.43(m,9H),1.69(m,2H),1.91(m,2H),2.90(m,1H),4.28(m,1H),5.45(m,1H),7.20(m,3H),7.35(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 1.43 (m, 9H), 1.69 (m, 2H), 1.91 (m, 2H), 2.90 (m, 1H), 4.28 (m, 1H), 5.45 (m, 1H) ), 7.20 (m, 3H), 7.35 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值245.2；實測值246.2；Rt=1.446min。LCMS (ESI): [M-Boc] + m/z: calculated 245.2; found 246.2; Rt=1.446 min.

步驟4：2-苯基-5-(三氟甲氧基)哌啶之合成Step 4: Synthesis of 2-phenyl-5-(trifluoromethoxy)piperidine

向2-苯基-5-(三氟甲氧基)哌啶-1-甲酸第三丁酯(0.7g，2.03mmol)於DCM(15mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(6.40g，175.53mmol，8mL)。將所得混合物在25℃下攪拌12h且在真空中蒸發，以得到2-苯基-5-(三氟甲氧基)哌啶(0.7g，粗品，HCl)。此化合物不經純化即用於下一步驟。To a solution of tert-butyl 2-phenyl-5-(trifluoromethoxy)piperidine-1-carboxylate (0.7 g, 2.03 mmol) in DCM (15 mL) was added 4.0 M in dioxane Hydrogen chloride solution (6.40 g, 175.53 mmol, 8 mL). The resulting mixture was stirred at 25 °C for 12 h and evaporated in vacuo to give 2-phenyl-5-(trifluoromethoxy)piperidine (0.7 g, crude, HCl). This compound was used in the next step without purification.

1 H NMR(400MHz,DMSO-d6 )δ 1.72(m,2H),3.67(m,2H),3.90(m,3H),4.28(m,1H),4.98(m,1H),7.16(m,1H),7.38(m,2H),7.58(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.72(m, 2H), 3.67(m, 2H), 3.90(m, 3H), 4.28(m, 1H), 4.98(m, 1H), 7.16(m , 1H), 7.38 (m, 2H), 7.58 (m, 2H).

LCMS(ESI)：[M+H]+ m/z：計算值245.2；實測值246.0；Rt=0.897min。LCMS (ESI): [M+H] + m/z: calculated 245.2; found 246.0; Rt=0.897 min.

步驟5：5-[[2-側氧基-2-[2-苯基-5-(三氟甲氧基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物411 )之合成Step 5: 5-[[2-Pendoxo-2-[2-phenyl-5-(trifluoromethoxy)-1-piperidinyl]acetyl]amino]pyridine-3-carboxylate Synthesis of Amine ( Compound 411 )

向2-苯基-5-(三氟甲氧基)哌啶(0.7g，2.00mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(490.76mg，2.00mmol，HCl)及三乙胺(1.01g，9.99mmol，1.39mL)之溶液中添加HATU(835.69mg，2.20mmol)。將所得混合物在25℃下攪拌3h且使其經歷HPLC：20-45% 0-5min水-乙腈+0.1% FA流速30ml/min(裝載泵4ml/min乙腈+0.1%FA)，目標質量436.39，管柱：XBridge C18 100x19mm 5um)，以得到5-[[2-側氧基-2-[2-苯基-5-(三氟甲氧基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(10mg，22.92μmol，1.15%產率)。To 2-phenyl-5-(trifluoromethoxy)piperidine (0.7 g, 2.00 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-side oxy To a solution of acetic acid (490.76 mg, 2.00 mmol, HCl) and triethylamine (1.01 g, 9.99 mmol, 1.39 mL) was added HATU (835.69 mg, 2.20 mmol). The resulting mixture was stirred at 25°C for 3 h and subjected to HPLC: 20-45% 0-5 min water-acetonitrile + 0.1% FA flow rate 30 ml/min (loading pump 4 ml/min acetonitrile + 0.1% FA), target mass 436.39, Column: XBridge C18 100x19mm 5um) to give 5-[[2-Pendoxyloxy-2-[2-phenyl-5-(trifluoromethoxy)-1-piperidinyl]acetyl]amine yl]pyridine-3-carboxamide (10 mg, 22.92 μmol, 1.15% yield).

1 H NMR(500MHz,DMSO)δ 1.72-1.93(m,2H),2.08-2.27(m,1H),2.38-2.42(m,1H),2.88-3.28(m,1H),4.06-4.15(m,0.6H),4.54-4.59(m,0.4H),4.61-4.76(m,1H),5.37-5.87(m,1H),7.31-7.47(m,5H),7.56-7.73(m,1H),8.11-8.22(m,1H),8.44-8.59(m,1H),8.69-8.84(m,1H),8.84-8.98(m,1H),11.23-11.42(m,1H)。 1 H NMR(500MHz, DMSO)δ 1.72-1.93(m, 2H), 2.08-2.27(m, 1H), 2.38-2.42(m, 1H), 2.88-3.28(m, 1H), 4.06-4.15(m ,0.6H),4.54-4.59(m,0.4H),4.61-4.76(m,1H),5.37-5.87(m,1H),7.31-7.47(m,5H),7.56-7.73(m,1H) , 8.11-8.22(m, 1H), 8.44-8.59(m, 1H), 8.69-8.84(m, 1H), 8.84-8.98(m, 1H), 11.23-11.42(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值436.2；實測值437.2；Rt=3.108min。LCMS (ESI): [M+H] + m/z: calculated 436.2; found 437.2; Rt=3.108 min.

實例771. 5-[[2-[(2S,5R)-5-(二氟甲氧基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物379)及5-[[2-[(2R,5R)-5-(二氟甲氧基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物400)之合成Example 771. 5-[[2-[(2S,5R)-5-(difluoromethoxy)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide (Compound 379) and 5-[[2-[(2R,5R)-5-(difluoromethoxy)-2-phenyl-1-piperidinyl]-2-side Synthesis of oxyacetyl]amino]pyridine-3-carboxamide (compound 400)

Figure 110128222-A0202-12-2468-479
Figure 110128222-A0202-12-2468-479

步驟1：5-(二氟甲氧基)-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 5-(difluoromethoxy)-2-phenylpiperidine-1-carboxylate

將5-羥基-2-苯基哌啶-1-甲酸第三丁酯(0.6g，2.16mmol)(如上文所述製備)及碘化銅(I)(82.40mg，432.65μmol，14.66μL)溶解於ACN(30mL)中且在氬氣氣氛下加熱至45℃。在10min內向此溶液中逐滴添加2,2-二氟-2-氟磺醯基乙酸(770.50mg，4.33mmol，447.97μL)於ACN(3ml)中之溶液。將所得混合物在45℃下攪拌1.5h且在10min內逐滴添加額外2,2-二氟-2-氟磺醯基乙酸(770.50mg，4.33mmol，447.97μL)於ACN(3ml)中之溶液。將所得混合物在45℃下攪拌12小時且在真空中蒸發。將殘餘物用DCM(75ml)及飽和碳酸氫鈉水溶液(75ml)稀釋。將有機層分離，用鹽水(50ml)洗滌，經Na2 SO4 乾燥且蒸發，以得到5-(二氟甲氧基)-2-苯基哌啶-1-甲酸第三丁酯(0.7g，粗品)。此化合物不經純化即用於下一步驟。Combine tert-butyl 5-hydroxy-2-phenylpiperidine-1-carboxylate (0.6 g, 2.16 mmol) (prepared as described above) and copper (I) iodide (82.40 mg, 432.65 μmol, 14.66 μL) Dissolved in ACN (30 mL) and heated to 45 °C under argon atmosphere. To this solution was added dropwise a solution of 2,2-difluoro-2-fluorosulfonylacetic acid (770.50 mg, 4.33 mmol, 447.97 μL) in ACN (3 ml) over 10 min. The resulting mixture was stirred at 45 °C for 1.5 h and an additional solution of 2,2-difluoro-2-fluorosulfonylacetic acid (770.50 mg, 4.33 mmol, 447.97 μL) in ACN (3 ml) was added dropwise over 10 min . The resulting mixture was stirred at 45°C for 12 hours and evaporated in vacuo. The residue was diluted with DCM (75ml) and saturated aqueous sodium bicarbonate (75ml). The organic layer was separated, washed with brine (50 ml), dried over Na 2 SO 4 and evaporated to give tert-butyl 5-(difluoromethoxy)-2-phenylpiperidine-1-carboxylate (0.7 g ,Crude). This compound was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ 1.45(s,9H),1.65(m,2H),2.14(m,1H),2.29(m,2H),2.60(m,1H),2.88(m,1H),4.22(m,2H),7.24(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ 1.45(s, 9H), 1.65(m, 2H), 2.14(m, 1H), 2.29(m, 2H), 2.60(m, 1H), 2.88(m, 1H) ), 4.22 (m, 2H), 7.24 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值227.2；實測值228.2；Rt=0.847min。LCMS (ESI): [M-Boc] + m/z: calculated 227.2; found 228.2; Rt=0.847 min.

步驟2：5-(二氟甲氧基)-2-苯基哌啶之合成Step 2: Synthesis of 5-(difluoromethoxy)-2-phenylpiperidine

向5-(二氟甲氧基)-2-苯基哌啶-1-甲酸第三丁酯(0.7g，2.14mmol)於DCM(15mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.00g，219.41mmol，10mL)。將所得混合物在25℃下攪拌3h且在真空中蒸發，以得到5-(二氟甲氧基)-2-苯基哌啶(0.5g，粗品，HCl)。此化合物不經純化即用於下一步驟。To a solution of tert-butyl 5-(difluoromethoxy)-2-phenylpiperidine-1-carboxylate (0.7 g, 2.14 mmol) in DCM (15 mL) was added 4.0 M in dioxane Hydrogen chloride solution (8.00 g, 219.41 mmol, 10 mL). The resulting mixture was stirred at 25 °C for 3 h and evaporated in vacuo to give 5-(difluoromethoxy)-2-phenylpiperidine (0.5 g, crude, HCl). This compound was used in the next step without purification.

1 H NMR(500MHz,CDCl3 )δ 1.67(m,2H),1.82(m,2H),2.16(m,2H),2.90(2,1H),4.24(m,2H),7.25(m,5H)。 1 H NMR (500MHz, CDCl 3 ) δ 1.67 (m, 2H), 1.82 (m, 2H), 2.16 (m, 2H), 2.90 (2, 1H), 4.24 (m, 2H), 7.25 (m, 5H) ).

LCMS(ESI)：[M+H]+ m/z：計算值227.1；實測值228.2；Rt=0.740min。LCMS (ESI): [M+H] + m/z: calculated 227.1; found 228.2; Rt=0.740 min.

步驟3：5-[[2-[(2S,5R)-5-(二氟甲氧基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物379 )及5-[[2-[(2R,5R)-5-(二氟甲氧基)-2-苯基-1-哌啶基]-2-Step 3: 5-[[2-[(2S,5R)-5-(difluoromethoxy)-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino] Pyridine-3-carboxamide ( Compound 379 ) and 5-[[2-[(2R,5R)-5-(difluoromethoxy)-2-phenyl-1-piperidinyl]-2- 側氧基乙醯基]胺基]吡啶-3-甲醯胺Pendant oxyacetyl]amino]pyridine-3-carboxamide

(化合物400 )之合成Synthesis of ( Compound 400 )

向5-(二氟甲氧基)-2-苯基哌啶(0.5g，1.90mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(465.70mg，1.90mmol，HCl)及三乙胺(959.29mg，9.48mmol，1.32mL)之溶液中添加HATU(793.01mg，2.09mmol)。將所得混合物在25℃下攪拌3h且使其經歷HPLC：0-5min 15-40%水-乙腈+0.1% TFA，流速30ml/min(裝載泵4ml/min乙腈+0.1%TFA)，目標質量418.40，管柱：SunFireC18 100* 19mm 5um)，以得到5-[[2-[(2S,5R)-5-(二氟甲氧基)-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(34mg，81.26μmol，5.36%產率)。To 5-(difluoromethoxy)-2-phenylpiperidine (0.5 g, 1.90 mmol, HCl), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-side To a solution of oxyacetic acid (465.70 mg, 1.90 mmol, HCl) and triethylamine (959.29 mg, 9.48 mmol, 1.32 mL) was added HATU (793.01 mg, 2.09 mmol). The resulting mixture was stirred at 25°C for 3 h and subjected to HPLC: 0-5 min 15-40% water-acetonitrile + 0.1% TFA, flow rate 30 ml/min (loading pump 4 ml/min acetonitrile + 0.1% TFA), target mass 418.40 , column: SunFireC18 100 * 19mm 5um) to give 5-[[2-[(2S,5R)-5-(difluoromethoxy)-2-phenyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]pyridine-3-carboxamide (34 mg, 81.26 μmol, 5.36% yield).

化合物379： 1 H NMR(600MHz,DMSO-d 6 )δ 1.62-1.71(m,1H),1.71-1.81(m,1H),2.07-2.24(m,1H),2.29-2.35(m,1H),2.82-3.21(m,1H),3.97-4.52(m,2H),5.26-5.77(m,1H),6.50-6.92(m,1H),7.23-7.31(m,1H),7.31-7.33(m,1H),7.33-7.36(m,1H),7.37-7.45(m,2H),7.52-7.66(m,1H),8.09-8.18(m,1H),8.43-8.53(m,1H),8.71-8.80(m,1H),8.83-8.92(m,1H),11.15-11.39(m,1H)。 Compound 379: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.62-1.71 (m, 1H), 1.71-1.81 (m, 1H), 2.07-2.24 (m, 1H), 2.29-2.35 (m, 1H) ,2.82-3.21(m,1H),3.97-4.52(m,2H),5.26-5.77(m,1H),6.50-6.92(m,1H),7.23-7.31(m,1H),7.31-7.33( m,1H),7.33-7.36(m,1H),7.37-7.45(m,2H),7.52-7.66(m,1H),8.09-8.18(m,1H),8.43-8.53(m,1H), 8.71-8.80 (m, 1H), 8.83-8.92 (m, 1H), 11.15-11.39 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=2.811min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=2.811 min.

化合物400： 1 H NMR(600MHz,DMSO-d 6 )δ 1.41-1.49(m,1H),1.90-2.06(m,2H),2.40-2.45(m,1H),2.54-2.56(m,0.4H),2.81-2.86(m,0.6H),3.98-4.20(m,1H),4.31-4.51(m,1H),5.17-5.66(m,1H),6.48-6.91(m,1H),7.15-7.30(m,1H),7.31-7.34(m,1H),7.35-7.38(m,1H),7.39-7.43(m,2H),7.55-7.67(m,1H),8.10-8.22(m,1H),8.42-8.54(m,1H),8.72-8.81(m,1H),8.81-8.95(m,1H),11.29-11.33(m,1H)。 Compound 400: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.41-1.49 (m, 1H), 1.90-2.06 (m, 2H), 2.40-2.45 (m, 1H), 2.54-2.56 (m, 0.4H) ), 2.81-2.86(m, 0.6H), 3.98-4.20(m, 1H), 4.31-4.51(m, 1H), 5.17-5.66(m, 1H), 6.48-6.91(m, 1H), 7.15- 7.30(m,1H),7.31-7.34(m,1H),7.35-7.38(m,1H),7.39-7.43(m,2H),7.55-7.67(m,1H),8.10-8.22(m,1H) ), 8.42-8.54(m, 1H), 8.72-8.81(m, 1H), 8.81-8.95(m, 1H), 11.29-11.33(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值418.2；實測值419.2；Rt=3.015min。LCMS (ESI): [M+H] + m/z: calculated 418.2; found 419.2; Rt=3.015 min.

實例772. 5-[[2-[(2R,5S)-5-羥基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物349)之合成Example 772. 5-[[2-[(2R,5S)-5-Hydroxy-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3-carboxylate Synthesis of Amine (Compound 349)

Figure 110128222-A0202-12-2471-480
Figure 110128222-A0202-12-2471-480

步驟1：(3S,6R)-6-苯基哌啶-3-醇之合成Step 1: Synthesis of (3S,6R)-6-phenylpiperidin-3-ol

來自先前實例之經boc保護之胺的結構經證實為反式。The structure of the boc-protected amine from the previous example was confirmed to be trans.

將(2R,5S)-5-羥基-2-苯基哌啶-1-甲酸第三丁酯(500.00mg，1.80mmol)於於二噁烷中之4.0M氯化氫溶液(6.40g，175.53mmol，8mL)中之溶液在25℃下攪拌3h且在真空中蒸發，以獲得(3S,6R)-6-苯基哌啶-3-醇(0.3g，1.40mmol，77.87%產率，HCl)。A solution of (2R,5S)-tert-butyl 5-hydroxy-2-phenylpiperidine-1-carboxylate (500.00 mg, 1.80 mmol) in 4.0 M hydrogen chloride in dioxane (6.40 g, 175.53 mmol, The solution in 8 mL) was stirred at 25 °C for 3 h and evaporated in vacuo to give (3S,6R)-6-phenylpiperidin-3-ol (0.3 g, 1.40 mmol, 77.87% yield, HCl).

1 H NMR(400MHz,DMSO-d6 )δ 1.55(m,1H),1.95(m,3H),2.74(m,1H),3.23(m,1H),4.02(m,1H),4.19(m,1H),7.41(m,3H),7.59(m,2H),9.46(m,1H),9.85(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.55(m,1H), 1.95(m,3H), 2.74(m,1H), 3.23(m,1H), 4.02(m,1H), 4.19(m , 1H), 7.41 (m, 3H), 7.59 (m, 2H), 9.46 (m, 1H), 9.85 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值177.1；實測值178.2；Rt=0.662min。LCMS (ESI): [M+H] + m/z: calculated 177.1; found 178.2; Rt=0.662 min.

步驟2：5-[[2-[(2R,5S)-5-羥基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物349 )之合成Step 2: 5-[[2-[(2R,5S)-5-Hydroxy-2-phenyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Synthesis of Amine ( Compound 349 )

向(3S,6R)-6-苯基哌啶-3-醇(290.28mg，1.64mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(402.27mg，1.64mmol，HCl)及三乙胺(828.64mg，8.19mmol，1.14mL)之溶液中添加HATU(685.01mg，1.80mmol)。將所得混合物在25℃下攪拌3h且使其經歷HPLC：20-20-65% 0-1-6min 0.2%TFA-甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量368，管柱：YMC Triart C18 100* 20mm，5um)，以得到5-[[2-[(2R,5S)-5-羥基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(250mg，678.64μmol，41.44%產率)。經boc保護之胺的結構經證實為反式。To (3S,6R)-6-phenylpiperidin-3-ol (290.28 mg, 1.64 mmol, HCl), 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-side To a solution of oxyacetic acid (402.27 mg, 1.64 mmol, HCl) and triethylamine (828.64 mg, 8.19 mmol, 1.14 mL) was added HATU (685.01 mg, 1.80 mmol). The resulting mixture was stirred at 25°C for 3 h and subjected to HPLC: 20-20-65% 0-1-6 min 0.2% TFA-methanol, flow rate: 30 ml/min (loading pump 4 ml/min methanol), target mass 368, Column: YMC Triart C18 100 * 20mm, 5um) to give 5-[[2-[(2R,5S)-5-hydroxy-2-phenyl-1-piperidinyl]-2-side oxyethyl Acyl]amino]pyridine-3-carboxamide (250 mg, 678.64 μmol, 41.44% yield). The structure of the boc protected amine was confirmed to be trans.

1 H NMR(600MHz,DMSO-d 6 )δ 1.44-1.64(m,2H),2.09-2.27(m,2H),2.65-3.13(m,1H),3.67-4.33(m,2H),4.73-4.95(m,1H),5.19-5.73(m,1H),7.24-7.29(m,1H),7.29-7.34(m,2H),7.35-7.42(m,2H),7.54-7.63(m,1H),8.08-8.21(m,1H),8.44-8.57(m,1H),8.69-8.78(m,1H),8.81-8.95(m,1H),11.01-11.33(m,1H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.44-1.64 (m, 2H), 2.09-2.27 (m, 2H), 2.65-3.13 (m, 1H), 3.67-4.33 (m, 2H), 4.73- 4.95(m,1H),5.19-5.73(m,1H),7.24-7.29(m,1H),7.29-7.34(m,2H),7.35-7.42(m,2H),7.54-7.63(m,1H) ), 8.08-8.21(m, 1H), 8.44-8.57(m, 1H), 8.69-8.78(m, 1H), 8.81-8.95(m, 1H), 11.01-11.33(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值368.2；實測值369.2；Rt=2.375min。LCMS (ESI): [M+H] + m/z: calculated 368.2; found 369.2; Rt=2.375 min.

實例773. 5-[[2-側氧基-2-[(2S,5S)-2-苯基-5-(2,2,2-三氟乙基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物342)及5-[[2-側氧基-2-[(2R,5S)-2-苯基-5-(2,2,2-三氟乙基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物318)之合成Example 773. 5-[[2-Oxy-2-[(2S,5S)-2-phenyl-5-(2,2,2-trifluoroethyl)-1-piperidinyl]acetone yl]amino]pyridine-3-carboxamide (compound 342) and 5-[[2-oxy-2-[(2R,5S)-2-phenyl-5-(2,2,2- Synthesis of trifluoroethyl)-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide (compound 318)

Figure 110128222-A0202-12-2472-481
Figure 110128222-A0202-12-2472-481

步驟1：2-側氧基-5-(2,2,2-三氟乙基)哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-butyl 2-oxy-5-(2,2,2-trifluoroethyl)piperidine-1-carboxylate

將碳酸第三丁氧基羰基酯第三丁酯(15.06g，69.00mmol，15.84mL)於DCM(25.00mL)中之溶液緩慢(達5h)添加到5-(2,2,2-三氟乙基)哌啶-2-酮(5g，27.60mmol)及DMAP(33.72mg，276.01μmol)於DCM(25.00mL)中之經回流之溶液中。等分試樣顯示約50%轉化成所要產物；以類似方式添加另外1當量碳酸第三丁氧基羰基酯第三丁酯(15.06g，69.00mmol，15.84mL)。在反應完成之後，將有機溶劑蒸發，以得到2-側氧基-5-(2,2,2-三氟乙基)哌啶-1-甲酸第三丁酯(8.2g，粗品)，其不經純化即用於下一步驟中。A solution of tert-butyl tert-butoxycarbonyl carbonate (15.06 g, 69.00 mmol, 15.84 mL) in DCM (25.00 mL) was added slowly (over 5 h) to 5-(2,2,2-trifluoro) Ethyl)piperidin-2-one (5 g, 27.60 mmol) and DMAP (33.72 mg, 276.01 [mu]mol) in a refluxed solution in DCM (25.00 mL). An aliquot showed approximately 50% conversion to the desired product; an additional 1 equivalent of tert-butyl tert-butoxycarbonyl carbonate (15.06 g, 69.00 mmol, 15.84 mL) was added in a similar fashion. After completion of the reaction, the organic solvent was evaporated to give tert-butyl 2-oxy-5-(2,2,2-trifluoroethyl)piperidine-1-carboxylate (8.2 g, crude), which Used in the next step without purification.

1 H NMR(500MHz,DMSO-d6 )δ 1.38(s,9H),1.55(m,1H),1.82(m,1H),2.18(m,1H),2.39(m,4H),3.41(m,1H),3.62(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.38(s, 9H), 1.55(m, 1H), 1.82(m, 1H), 2.18(m, 1H), 2.39(m, 4H), 3.41(m , 1H), 3.62 (m, 1H).

步驟2：N-[5-側氧基-5-苯基-2-(2,2,2-三氟乙基)戊基]胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-[5-oxy-5-phenyl-2-(2,2,2-trifluoroethyl)pentyl]carbamate

將2-側氧基-5-(2,2,2-三氟乙基)哌啶-1-甲酸第三丁酯(1g，3.56mmol)溶解於THF(5.00mL)中且在Ar下冷卻至-78℃。逐滴添加溴(苯基)鎂(644.62mg，3.56mmol，1.4mL)之溶液且將反應混合物升溫至室溫。30min之後，將反應物用過量飽和NH4 Cl水溶液淬滅，且用EtOAc(15mL)萃取。蒸發溶劑，得到N-[5-側氧基-5-苯基-2-(2,2,2-三氟乙基)戊基]胺甲酸第三丁酯(0.8g，粗品)。2-Pendoxo-5-(2,2,2-trifluoroethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.56 mmol) was dissolved in THF (5.00 mL) and cooled under Ar to -78°C. A solution of bromo(phenyl)magnesium (644.62 mg, 3.56 mmol, 1.4 mL) was added dropwise and the reaction mixture was warmed to room temperature. After 30 min, the reaction was quenched with excess saturated aqueous NH4Cl and extracted with EtOAc (15 mL). The solvent was evaporated to give tert-butyl N-[5-oxy-5-phenyl-2-(2,2,2-trifluoroethyl)pentyl]carbamate (0.8 g, crude).

1 H NMR(400MHz,CDCl3 )δ 1.46(m,9H),1.83(m,7H),3.05(m,4H),4.77(m,1H),7.45(m,3H),7.95(s,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (m, 9H), 1.83 (m, 7H), 3.05 (m, 4H), 4.77 (m, 1H), 7.45 (m, 3H), 7.95 (s, 2H) ).

LCMS(ESI)：[M-Boc]+ m/z：計算值259.2；實測值260.2；Rt=1.406min。LCMS (ESI): [M-Boc] + m/z: calculated 259.2; found 260.2; Rt=1.406 min.

步驟3：6-苯基-3-(2,2,2-三氟乙基)-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-phenyl-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyridine

將N-[5-側氧基-5-苯基-2-(2,2,2-三氟乙基)戊基]胺甲酸第三丁酯(3g，8.35mmol)溶解於DCM(20mL)中，隨後添加TFA(2.86g，25.04mmol，1.93mL)。在反應完成(藉由HNMR推測)之後，將反應混合物用50% KOH水溶液(4.68g，83.48mmol，2.30mL)中和。將混合物用DCM(50mL)萃取，將有機溶劑經Na2 SO4 乾燥且蒸發，以得到6-苯基-3-(2,2,2-三氟乙基)-2,3,4,5-四氫吡啶(1.3g，5.39mmol，64.55%產率)。3-butyl N-[5-oxy-5-phenyl-2-(2,2,2-trifluoroethyl)pentyl]carbamate (3 g, 8.35 mmol) was dissolved in DCM (20 mL) , followed by the addition of TFA (2.86 g, 25.04 mmol, 1.93 mL). After completion of the reaction (presumed by HNMR), the reaction mixture was neutralized with 50% aqueous KOH (4.68 g, 83.48 mmol, 2.30 mL). The mixture was extracted with DCM (50 mL), the organic solvent was dried over Na 2 SO 4 and evaporated to give 6-phenyl-3-(2,2,2-trifluoroethyl)-2,3,4,5 - Tetrahydropyridine (1.3 g, 5.39 mmol, 64.55% yield).

1 H NMR(500MHz,CDCl3 )δ 1.55(m,1H),2.11(m,4H),2.64(m,1H),2.84(m,1H),3.45(m,1H),4.11(m,1H),7.40(m,3H),7.78(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ 1.55(m,1H), 2.11(m,4H), 2.64(m,1H), 2.84(m,1H), 3.45(m,1H), 4.11(m,1H) ), 7.40 (m, 3H), 7.78 (m, 2H).

步驟4：2-苯基-5-(2,2,2-三氟乙基)哌啶之合成Step 4: Synthesis of 2-phenyl-5-(2,2,2-trifluoroethyl)piperidine

將6-苯基-3-(2,2,2-三氟乙基)-2,3,4,5-四氫吡啶(1.3g，5.39mmol)、6-苯基-3-(2,2,2-三氟乙基)-2,3,4,5-四氫吡啶(1.3g，5.39mmol)溶解於MeOH(20mL)及H2 O(5mL)中且冷卻至25℃。將硼氫化鈉(407.73mg，10.78mmol，381.05μL)分批添加到所獲得之混合物中且再攪拌隔夜。反應完成之後，將反應混合物用10% HCl水溶液酸化至pH 2，用MTBE(2* 10mL)洗滌，用10% NaOH水溶液鹼化 至pH 10且用DCm(30mL)萃取。蒸發溶劑，得到呈順式異構物及反式異構物(20：80)之混合物之純的2-苯基-5-(2,2,2-三氟乙基)哌啶(1g，4.11mmol，76.29%產率)。6-Phenyl-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyridine (1.3 g, 5.39 mmol), 6-phenyl-3-(2, 2,2-Trifluoroethyl)-2,3,4,5-tetrahydropyridine (1.3 g, 5.39 mmol) was dissolved in MeOH (20 mL) and H2O (5 mL) and cooled to 25 °C. Sodium borohydride (407.73 mg, 10.78 mmol, 381.05 μL) was added portionwise to the obtained mixture and stirred overnight. After completion of the reaction, the reaction mixture was acidified to pH 2 with 10% aqueous HCl, washed with MTBE (2 * 10 mL), basified to pH 10 with 10% aqueous NaOH and extracted with DCm (30 mL). Evaporation of the solvent gave pure 2-phenyl-5-(2,2,2-trifluoroethyl)piperidine (1 g, 4.11 mmol, 76.29% yield).

1 H NMR(400MHz,CDCl3 )δ 1.31(m,1H),1.44(m,1H),1.71(m,1H),1.94(m,4H),2.51(m,1H),3.01(m,1H),3.22(m,1H),3.48(m,1H),7.28(m,5H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.31 (m, 1H), 1.44 (m, 1H), 1.71 (m, 1H), 1.94 (m, 4H), 2.51 (m, 1H), 3.01 (m, 1H) ), 3.22(m, 1H), 3.48(m, 1H), 7.28(m, 5H).

步驟5：5-[[2-側氧基-2-[(2S,5S)-2-苯基-5-(2,2,2-三氟乙基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物342)及5-[[2-側氧基-2-[(2R,5S)-2-苯基-5-(2,2,2-三氟乙基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物318 )之合成Step 5: 5-[[2-Oxy-2-[(2S,5S)-2-phenyl-5-(2,2,2-trifluoroethyl)-1-piperidinyl]acetone yl]amino]pyridine-3-carboxamide (compound 342) and 5-[[2-oxy-2-[(2R,5S)-2-phenyl-5-(2,2,2- Synthesis of trifluoroethyl)-1-piperidinyl]acetyl]amino]pyridine-3-carboxamide ( compound 318 )

將DIPEA(368.33mg，2.85mmol，496.41μL)添加到相應2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(0.2g，814.27μmol，HCl)及2-苯基-5-(2,2,2-三氟乙基)哌啶(198.08mg，814.27μmol)於DMF(10mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(340.57mg，895.69μmol)於DMF(2mL)中之溶液。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 19* 100 5mkm管柱且以H2 O-MeCN為流動相)，以得到純的反式5-[[2-側氧基-2-[(2S,5S)-2-苯基-5-(2,2,2-三氟乙基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(0.18g，414.35μmol，50.89%產率)及順式5-[[2-側氧基-2-[(2R,5S)-2-苯基-5-(2,2,2-三氟乙基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(30.2mg，69.52μmol，8.54%產率)非鏡像異構物。DIPEA (368.33 mg, 2.85 mmol, 496.41 μL) was added to the corresponding 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (0.2 g, 814.27 μmol, HCl) and 2-phenyl-5-(2,2,2-trifluoroethyl)piperidine (198.08 mg, 814.27 μmol) in DMF (10 mL). The resulting mixture was stirred for 5 min, then a solution of HATU (340.57 mg, 895.69 μmol) in DMF (2 mL) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (Waters Sunfire C18 19 * 100 5mkm column with H2O -MeCN as mobile phase) to give pure trans 5-[[2-oxy-2-[(2S ,5S)-2-phenyl-5-(2,2,2-trifluoroethyl)-1-piperidinyl]acetoxy]amino]pyridine-3-carboxamide (0.18 g, 414.35 μmol , 50.89% yield) and cis-5-[[2-oxy-2-[(2R,5S)-2-phenyl-5-(2,2,2-trifluoroethyl)-1- Piperidinyl]acetoxy]amino]pyridine-3-carboxamide (30.2 mg, 69.52 μmol, 8.54% yield) diastereoisomer.

化合物342： 1 H NMR(600MHz,DMSO-d 6 )δ 1.54(m,1H),1.67(m,1H),1.97(m,1H),2.09(m,1H),2.27(m,1H),2.43(m,1H),2.79(m,1H),4.01(m,1H),5.39(m,1H),7.27(m,1H),7.31(m,2H),7.36(m,1H),7.40(m,2H),7.60(m,1H),8.15(m,1H),8.45(m,1H),8.76(m,1H),8.86(m,1H),11.25(m,1H)。 Compound 342: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.54 (m, 1H), 1.67 (m, 1H), 1.97 (m, 1H), 2.09 (m, 1H), 2.27 (m, 1H), 2.43(m, 1H), 2.79(m, 1H), 4.01(m, 1H), 5.39(m, 1H), 7.27(m, 1H), 7.31(m, 2H), 7.36(m, 1H), 7.40 (m, 2H), 7.60 (m, 1H), 8.15 (m, 1H), 8.45 (m, 1H), 8.76 (m, 1H), 8.86 (m, 1H), 11.25 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值434.2；實測值435.2；Rt=3.262min。LCMS (ESI): [M+H] + m/z: calculated 434.2; found 435.2; Rt=3.262 min.

化合物318： 1 H NMR(600MHz,DMSO-d 6 )δ 1.25(m,1H),1.77(m,1H),1.88(m,1H),1.98(m,1H),2.08(m,2H),2.70(m,2H),4.07(m,1H),5.50(m,1H),7.28(m,1H),7.30(m,1H),7.35(m,1H),7.40(m,2H),7.60(m,1H),8.15(m,1H),8.46(m,1H),8.77(m,1H),8.86(m,1H),11.29(m,1H)。 Compound 318: 1 H NMR (600 MHz, DMSO- d 6 ) δ 1.25 (m, 1H), 1.77 (m, 1H), 1.88 (m, 1H), 1.98 (m, 1H), 2.08 (m, 2H), 2.70(m, 2H), 4.07(m, 1H), 5.50(m, 1H), 7.28(m, 1H), 7.30(m, 1H), 7.35(m, 1H), 7.40(m, 2H), 7.60 (m, 1H), 8.15 (m, 1H), 8.46 (m, 1H), 8.77 (m, 1H), 8.86 (m, 1H), 11.29 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值434.2；實測值435.2；Rt=3.217min。LCMS (ESI): [M+H] + m/z: calculated 434.2; found 435.2; Rt=3.217 min.

實例774.外消旋 -5-[[2-[(2R,5S)-2-(3-羥基環丁基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物413)及外消旋 -5-[[2-[(2R,5S)-2-(3-羥基環丁基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物407)之合成Example 774. Racemic -5-[[2-[(2R,5S)-2-(3-hydroxycyclobutyl)-5-methyl-1-piperidinyl]-2-oxoacetyl yl]amino]pyridine-3-carboxamide (compound 413) and rac -5-[[2-[(2R,5S)-2-(3-hydroxycyclobutyl)-5-methyl- Synthesis of 1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (compound 407)

Figure 110128222-A0202-12-2475-482
Figure 110128222-A0202-12-2475-482

步驟1：3-(3-苯甲基氧基環丁烷羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 3-(3-benzyloxycyclobutanecarbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

向5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(3.6g，16.88mmol)於THF(100mL)中之經預冷卻之(-78℃)溶液中逐滴添加LiHMDS(35.45mmol，33.5mL)。將所得混合物在-78℃下攪拌1h。一次性添加3-苯甲基氧基環丁烷羰基氯(3.79g，16.88mmol)之溶液。使反應混合物升溫至室溫且在該溫度下攪拌4h。將反應混合物用NaHSO4 (10g；10%溶液)淬滅且用DCM(2*100ml)萃取。將有機層用水洗滌，經Na2 SO4 乾燥。蒸發DCM，以得到3-(3-苯甲基氧基環丁烷羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(8g，粗品)To a pre-cooled (-78°C) solution of 5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (3.6 g, 16.88 mmol) in THF (100 mL) was added LiHMDS dropwise (35.45 mmol, 33.5 mL). The resulting mixture was stirred at -78 °C for 1 h. A solution of 3-benzyloxycyclobutanecarbonyl chloride (3.79 g, 16.88 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred at this temperature for 4 h. The reaction mixture was quenched with NaHSO4 (10 g; 10% solution) and extracted with DCM (2*100 ml). The organic layer was washed with water, dried over Na2SO4 . Evaporation of DCM to give 3-(3-benzyloxycyclobutanecarbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (8 g, crude)

1 H NMR(CDCl3 ,400MHz)：δ 0.95(s,3H),1.20(m,2H),1.45(m,9H),1.90(m,2H),2.10-2.25(m,4H),3.00(m,2H),3.75(m,1H),3.95(m,1H),4.42(m,2H),7.31(m,5H)。 1 H NMR (CDCl 3 , 400MHz): δ 0.95 (s, 3H), 1.20 (m, 2H), 1.45 (m, 9H), 1.90 (m, 2H), 2.10-2.25 (m, 4H), 3.00 ( m, 2H), 3.75 (m, 1H), 3.95 (m, 1H), 4.42 (m, 2H), 7.31 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值401.2；實測值302.2；Rt=1.447min。LCMS (ESI): [M-Boc] + m/z: calculated 401.2; found 302.2; Rt=1.447 min.

步驟2：3-(5-甲基-2-哌啶基)環丁醇之合成Step 2: Synthesis of 3-(5-methyl-2-piperidinyl)cyclobutanol

將3-(3-苯甲基氧基環丁烷羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(2g，4.98mmol)溶解於AcOH(25mL)中且分批添加氯化氫水溶液(1.82g，4.98mmol，25mL，10%純度)。添加完成之後，將所得混合物在100℃下攪拌14h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(5ml)與DCM(20ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至ph

Figure 110128222-A0202-12-2476-545
10且用EtOAc(2x30ml)萃取。分離EtOAc溶液，經Na2 SO4 乾燥且在減壓下蒸發，得到3-(3-甲基-2,3,4,5-四氫吡啶-6-基)環丁醇(300mg，1.79mmol，36.01%產率)。粗產物不經進一步純化即用於下一步驟中。3-(3-Benzyloxycyclobutanecarbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (2 g, 4.98 mmol) was dissolved in AcOH (25 mL) And aqueous hydrogen chloride solution (1.82 g, 4.98 mmol, 25 mL, 10% purity) was added portionwise. After the addition was complete, the resulting mixture was stirred at 100 °C for 14 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (5ml) and DCM (20ml). The organic layer was separated and discarded. The aqueous layer was basified to pH with 10% NaOH
Figure 110128222-A0202-12-2476-545
10 and extracted with EtOAc (2x30ml). The EtOAc solution was separated, dried over Na2SO4 and evaporated under reduced pressure to give 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)cyclobutanol (300 mg, 1.79 mmol , 36.01% yield). The crude product was used in the next step without further purification.

1 H NMR(CDCl3 ,400MHz)：δ 0.90(m,3H),1.10-1.20(m,1H),1.50(m,1H),1.70(m,1H),1.85-2.20(m,4H),2.30-2.50(m,3H),2.95(m,1H),3.25-3.40(brs,1H),3.68(d,1H),4.13(m,1H)。 1 H NMR (CDCl 3 , 400MHz): δ 0.90 (m, 3H), 1.10-1.20 (m, 1H), 1.50 (m, 1H), 1.70 (m, 1H), 1.85-2.20 (m, 4H), 2.30-2.50 (m, 3H), 2.95 (m, 1H), 3.25-3.40 (brs, 1H), 3.68 (d, 1H), 4.13 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值257.2；實測值258.2；Rt=0.803min。LCMS (ESI): [M+1] + m/z: calculated 257.2; found 258.2; Rt=0.803 min.

步驟3：3-(5-甲基-2-哌啶基)環丁醇之合成Step 3: Synthesis of 3-(5-methyl-2-piperidinyl)cyclobutanol

在25℃下，向3-(3-甲基-2,3,4,5-四氫吡啶-6-基)環丁醇(0.45g，2.69mmol)於MeOH(10mL)中之溶液中分批添加硼氫化鈉(101.79mg，2.69mmol，95.13μL)。將所得混合物在25℃下攪拌2h且在真空中蒸發。將殘餘物用氯化氫二噁烷溶液處理。然後蒸發二噁烷。將沉澱用THF洗滌，在真空中乾燥，以得到3-(5-甲基-2-哌啶基)環丁醇(300mg，粗品，HCl)To a solution of 3-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)cyclobutanol (0.45 g, 2.69 mmol) in MeOH (10 mL) was partitioned at 25 °C Sodium borohydride (101.79 mg, 2.69 mmol, 95.13 μL) was added in batches. The resulting mixture was stirred at 25 °C for 2 h and evaporated in vacuo. The residue was treated with a solution of hydrogen chloride in dioxane. Dioxane was then evaporated. The precipitate was washed with THF and dried in vacuo to give 3-(5-methyl-2-piperidinyl)cyclobutanol (300 mg, crude, HCl)

1 H NMR(CDCl3 ,400MHz)：δ 0.90(d,3H),1.00-1.10(m,1H),1.20-1.30(m,1H),1.40-1.50(m,1H),1.60-2.00(m,5H),2.10-2.40(m,3H),2.80(m,1H),3.00(m,1H),3.50(brs,1H),3.83(m,1H),9.00(brs,1H),9.40(brs,1H)。 1 H NMR (CDCl 3 , 400MHz): δ 0.90 (d, 3H), 1.00-1.10 (m, 1H), 1.20-1.30 (m, 1H), 1.40-1.50 (m, 1H), 1.60-2.00 (m ,5H),2.10-2.40(m,3H),2.80(m,1H),3.00(m,1H),3.50(brs,1H),3.83(m,1H),9.00(brs,1H),9.40( brs, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值169.2；實測值170.2；Rt=0.645min。LCMS (ESI): [M+1] + m/z: calculated 169.2; found 170.2; Rt=0.645 min.

步驟4：外消旋-5-[[2-[(2R,5S)-2-(3-羥基環丁基)-5-甲基-1-哌啶基]-2-側氧基乙醯Step 4: Racemic-5-[[2-[(2R,5S)-2-(3-hydroxycyclobutyl)-5-methyl-1-piperidinyl]-2-oxoacetyl 基]胺基]吡啶-3-甲醯胺(化合物413 )及外消旋-5-[[2-[(2R,5S)-2-(3-羥基環丁基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物407 )之合成yl]amino]pyridine-3-carboxamide ( compound 413 ) and rac-5-[[2-[(2R,5S)-2-(3-hydroxycyclobutyl)-5-methyl- Synthesis of 1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide ( compound 407 )

向3-(5-甲基-2-哌啶基)環丁醇(0.3g，1.46mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(358.18mg，1.46mmol，HCl)及三乙胺(1.48g，14.58mmol，2.03mL)於DMF(3mL)中之溶液中分批添加HATU(609.92mg，1.60mmol)。將混合物在25℃下攪拌2h。將反應混合物提交用於HPLC(10-10-40% 0-1-6min 0.1%NH3 -甲醇，流速：30ml/min(裝載泵4ml/min甲醇)，目標質量360，管柱：YMC Triart C18 100x20mm，5um)，以得到5-[[2-[(2R,5S)-2-(3-羥基環丁基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(12mg，33.30μmol，2.28%產率)及5-[[2-[(2R,5S)-2-(3-羥基環丁基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(100mg，277.46μmol，19.03%產率)。5-[[2-[(2R,5S)-2-(3-羥基環丁基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(12mg，33.30μmol，2.28%產率)To 3-(5-methyl-2-piperidinyl)cyclobutanol (0.3 g, 1.46 mmol, HCl), 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2- To a solution of oxyacetic acid (358.18 mg, 1.46 mmol, HCl) and triethylamine (1.48 g, 14.58 mmol, 2.03 mL) in DMF (3 mL) was added HATU (609.92 mg, 1.60 mmol) portionwise. The mixture was stirred at 25 °C for 2 h. The reaction mixture was submitted for HPLC (10-10-40% 0-1-6 min 0.1% NH3 -methanol, flow rate: 30 ml/min (load pump 4 ml/min methanol), target mass 360, column: YMC Triart C18 100x20mm, 5um) to give 5-[[2-[(2R,5S)-2-(3-hydroxycyclobutyl)-5-methyl-1-piperidinyl]-2-side oxyacetyl yl]amino]pyridine-3-carboxamide (12 mg, 33.30 μmol, 2.28% yield) and 5-[[2-[(2R,5S)-2-(3-hydroxycyclobutyl)-5- Methyl-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (100 mg, 277.46 μmol, 19.03% yield). 5-[[2-[(2R,5S)-2-(3-hydroxycyclobutyl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine- 3-Carboxamide (12 mg, 33.30 μmol, 2.28% yield)

化合物413：Compound 413:

1 H NMR(500MHz,DMSO)δ 0.89-1.00(m,3H),1.21-1.33(m,1H),1.35-1.48(m,1H),1.64-1.80(m,1H),1.80-1.89(m,3H),1.91-2.15(m,3H),2.71-2.81(m,1H),2.85-3.25(m,1H),3.41-3.47(m,1H),3.78-4.01(m,1H),4.22-4.44(m,1H),4.94-5.05(m,1H),7.57-7.65(m,1H),8.14-8.21(m,1H),8.45-8.57(m,1H),8.72-8.83(m,1H),8.86-8.94(m,1H),11.10(br s,1H)。 1 H NMR (500MHz, DMSO)δ 0.89-1.00(m, 3H), 1.21-1.33(m, 1H), 1.35-1.48(m, 1H), 1.64-1.80(m, 1H), 1.80-1.89(m ,3H),1.91-2.15(m,3H),2.71-2.81(m,1H),2.85-3.25(m,1H),3.41-3.47(m,1H),3.78-4.01(m,1H),4.22 -4.44(m, 1H), 4.94-5.05(m, 1H), 7.57-7.65(m, 1H), 8.14-8.21(m, 1H), 8.45-8.57(m, 1H), 8.72-8.83(m, 1H), 8.86-8.94 (m, 1H), 11.10 (br s, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值360.2；實測值361.2；Rt=2.180min。LCMS (ESI): [M+1] + m/z: calculated 360.2; found 361.2; Rt=2.180 min.

化合物407：Compound 407:

1 H NMR(500MHz,DMSO)δ 0.90-1.01(m,3H),1.24-1.45(m,3H),1.47-1.68(m,2H),1.68-2.04(m,3H),2.19-2.23(m,1H),2.28-2.33(m,1H),2.93-3.25(m,1H),3.41-3.78(m,1H),3.82-3.93(m,1H),3.97-4.45(m,1H),4.88-5.03(m,1H),7.54 -7.70(m,1H),8.11-8.24(m,1H),8.44-8.57(m,1H),8.72-8.85(m,1H),8.87-8.97(m,1H),11.00-11.17(m,1H)。 1 H NMR(500MHz, DMSO)δ 0.90-1.01(m,3H), 1.24-1.45(m,3H), 1.47-1.68(m,2H), 1.68-2.04(m,3H), 2.19-2.23(m ,1H),2.28-2.33(m,1H),2.93-3.25(m,1H),3.41-3.78(m,1H),3.82-3.93(m,1H),3.97-4.45(m,1H),4.88 -5.03(m, 1H), 7.54 -7.70(m, 1H), 8.11-8.24(m, 1H), 8.44-8.57(m, 1H), 8.72-8.85(m, 1H), 8.87-8.97(m, 1H), 11.00-11.17 (m, 1H).

LCMS(ESI)：[M+1]+ m/z：計算值360.2；實測值361.2；Rt=2.336min。LCMS (ESI): [M+1] + m/z: calculated 360.2; found 361.2; Rt=2.336 min.

實例775. 5-(2-(5-甲基八氫異喹啉-2(1H )-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物515、化合物536)之合成Example 775. Synthesis of 5-(2-(5-methyloctahydroisoquinolin-2( 1H )-yl)-2-oxyacetamido)nicotinamide (Compound 515, Compound 536)

Figure 110128222-A0202-12-2478-483
Figure 110128222-A0202-12-2478-483

步驟1：5-甲基十氫異喹啉之合成Step 1: Synthesis of 5-methyldecahydroisoquinoline

將5-甲基-1,2,3,4-四氫異喹啉(0.5g，2.72mmol，HCl)溶解於MeOH中且在高壓力下氫化48h。在反應完成之後，過濾出催化劑且蒸發有機溶劑，得到5-甲基-1,2,3,4,4a,5,6,7,8,8a-十氫異喹啉(0.3g，1.58mmol，58.09%產率，HCl)，其不經純化即用於下一步驟中。5-Methyl-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2.72 mmol, HCl) was dissolved in MeOH and hydrogenated under high pressure for 48 h. After the reaction was completed, the catalyst was filtered off and the organic solvent was evaporated to give 5-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline (0.3 g, 1.58 mmol) , 58.09% yield, HCl), which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.86(d,3H),1.52(m,7H),2.92(m,4H),3.28(m,2H),4.16(m,2H),8.45(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.86(d, 3H), 1.52(m, 7H), 2.92(m, 4H), 3.28(m, 2H), 4.16(m, 2H), 8.45 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值153.2；實測值154.2；Rt=0.723min。LCMS (ESI): [M] + m/z: calculated 153.2; found 154.2; Rt=0.723 min.

步驟2：5-(2-(5-甲基八氫異喹啉-2(1H)-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物515 及化合物536 )之合成Step 2: Synthesis of 5-(2-(5-methyloctahydroisoquinolin-2(1H)-yl)-2-oxyacetamido)nicotinamide ( Compound 515 and Compound 536 )

在輕微加熱下，將5-甲基-1,2,3,4,4a,5,6,7,8,8a-十氫異喹啉(0.35g，1.84mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(385.85mg，1.84mmol，TEA)及DIPEA(715.27mg，5.53mmol，963.98μL)溶解於DMF(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(841.73mg，2.21mmol)。在反應完成之後，藉由HPLC(21% 0.5-6.5min；水-MeCN；30ml/min；裝載泵4ml/minMeCN；目標質量344；管柱SunFire 19*100mm)純化混合物且再純化(11-18% 0.5-5min；水-MeCN+NH3 30ml/min；裝載泵MeCN 4ml/min；目標質量 344，管柱Triart 19*100mm)，以得到呈4種級分之5-[[2-[(4aS,5R,8aR )-5-甲基-3,4,4a,5,6,7,8,8a-八氫-1H -異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(5mg，14.52μmol，7.87-1%產率)。胺核心之結構未得到驗證；由於1D H-NMR而分配相對組態。5-Methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline (0.35 g, 1.84 mmol, HCl), 2-[( 5-Aminocarbamoyl-3-pyridyl)amino]-2-oxoacetic acid (385.85 mg, 1.84 mmol, TEA) and DIPEA (715.27 mg, 5.53 mmol, 963.98 μL) were dissolved in DMF (6 mL) . With vigorous stirring and occasional heating, HATU (841.73 mg, 2.21 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC (21% 0.5-6.5min; water-MeCN; 30ml/min; loading pump 4ml/minMeCN; target mass 344; column SunFire 19*100mm) and repurified (11-18 % 0.5-5min; water-MeCN+NH 3 30ml/min; loading pump MeCN 4ml/min; target mass 344, column Triart 19*100mm) to obtain 5-[[2-[( 4aS,5R,8aR )-5-methyl-3,4,4a,5,6,7,8,8a-octahydro- 1H -isoquinolin-2-yl]-2-side oxyacetyl ]amino]pyridine-3-carboxamide (5 mg, 14.52 μmol, 7.87-1% yield). The structure of the amine core was not verified; the relative configuration was assigned due to 1D H-NMR.

化合物515： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.83-0.92(m,4H),0.95-1.07(m,2H),1.06-1.32(m,3H),1.32-1.42(m,1H),1.52-1.77(m,3H),1.83-1.98(m,1H),2.25-2.32(m,0.5H),2.58-2.66(m,0.5H),2.66-2.74(m,0.5H),3.02-3.08(m,0.5H),3.74-4.07(m,1H),4.21-4.54(m,1H),7.29(s,1H),7.96(s,1H),8.41-8.48(m,1H),8.70(s,1H),8.86(s,1H),10.87(s,1H)。 Compound 515: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.83-0.92 (m, 4H), 0.95-1.07 (m, 2H), 1.06-1.32 (m, 3H), 1.32-1.42 (m) ,1H),1.52-1.77(m,3H),1.83-1.98(m,1H),2.25-2.32(m,0.5H),2.58-2.66(m,0.5H),2.66-2.74(m,0.5H ), 3.02-3.08(m, 0.5H), 3.74-4.07(m, 1H), 4.21-4.54(m, 1H), 7.29(s, 1H), 7.96(s, 1H), 8.41-8.48(m, 1H), 8.70(s, 1H), 8.86(s, 1H), 10.87(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=2.642min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=2.642 min.

化合物536： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.79-0.86(m,3H),0.97-1.05(m,1H),1.17-1.31(m,3H),1.35-1.52(m,3H),1.54-1.65(m,2H),1.68-1.86(m,2H),2.63-2.85(m,1H),2.97-3.24(m,1H),3.56-3.90(m,1H),4.10-4.45(m,1H),7.59(s,1H),8.14(s,1H),8.43-8.50(m,1H),8.74-8.77(m,1H),8.82-8.88(m,1H),11.05(s,1H)。 Compound 536: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.79-0.86 (m, 3H), 0.97-1.05 (m, 1H), 1.17-1.31 (m, 3H), 1.35-1.52 (m) ,3H),1.54-1.65(m,2H),1.68-1.86(m,2H),2.63-2.85(m,1H),2.97-3.24(m,1H),3.56-3.90(m,1H),4.10 -4.45(m, 1H), 7.59(s, 1H), 8.14(s, 1H), 8.43-8.50(m, 1H), 8.74-8.77(m, 1H), 8.82-8.88(m, 1H), 11.05 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值344.2；實測值345.2；Rt=2.445min。LCMS (ESI): [M] + m/z: calculated 344.2; found 345.2; Rt=2.445 min.

實例776. 5-(2-(2,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物521)之合成Example 776. Synthesis of 5-(2-(2,5-Dimethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide (Compound 521)

Figure 110128222-A0202-12-2479-484
Figure 110128222-A0202-12-2479-484

步驟1：5-甲基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of tert-butyl 5-methyl-2-phenylpiperidine-1-carboxylate

將5-甲基-2-苯基哌啶(1g，5.71mmol)溶解於THF(20mL)中，隨後以逐滴方式添加boc2 O(1.25g，5.71mmol，1.31mL)。1h之後，蒸發溶劑且藉由CC(Companion combiflash；40g SiO2 ；氯仿/MeCN，其中MeCN為0至10%，流速=40 ml/min，Rv=3-8 cv.)純化，得到5-甲基-2-苯基哌啶-1-甲酸第三丁 酯(1.1g，3.99mmol，70.01%產率)。5-Methyl-2-phenylpiperidine (1 g, 5.71 mmol) was dissolved in THF (20 mL) followed by the addition of boc 2 O (1.25 g, 5.71 mmol, 1.31 mL) dropwise. After 1 h, the solvent was evaporated and purified by CC (Companion combiflash; 40 g SiO 2 ; chloroform/MeCN with 0 to 10% MeCN, flow rate=40 ml/min, Rv=3-8 cv.) to give 5-methanone tert -butyl-2-phenylpiperidine-1-carboxylate (1.1 g, 3.99 mmol, 70.01% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.06(d,3H),1.21(m,1H),1.46(s,9H),1.86(m,2H),2.08(m,2H),2.98(d,1H),3.86(d,1H),5.24(m,1H),7.28(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.06(d, 3H), 1.21(m, 1H), 1.46(s, 9H), 1.86(m, 2H), 2.08(m, 2H), 2.98( d, 1H), 3.86 (d, 1H), 5.24 (m, 1H), 7.28 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值175.4；實測值176.2；Rt=1.617min。LCMS (ESI): [M-Boc] + m/z: calculated 175.4; found 176.2; Rt=1.617 min.

步驟2：2,5-二甲基-2-苯基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 2,5-dimethyl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

將5-甲基-2-苯基哌啶-1-甲酸第三丁 酯(0.4g，1.45mmol)溶解於THF(5mL)中且在Ar下冷卻至-40℃。以逐滴方式添加丁基鋰(2.5M，697.21μL)，同時保持溫度低於-35℃，且在同一溫度下再攪拌30min。中間物等分試樣(用氘化甲醇CD3 OD淬滅)顯示約80%轉化成鋰化產物。將反應混合物冷卻至-78℃且一次性添加碘甲烷(618.50mg，4.36mmol，271.27μL)且將反應混合物升溫至室溫，隨後再攪拌2h。將反應混合物用過量飽和NH4 Cl水溶液淬滅且用EtOAc萃取兩次。將經合併之有機層經Na2 SO4 乾燥且在減壓下蒸發，以得到2,5-二甲基-2-苯基哌啶-1-甲酸第三丁 酯(0.33g，粗品)，其不經純化即用於下一步驟中。5-Methyl-2-phenylpiperidine-1-carboxylic acid tert- butyl ester (0.4 g, 1.45 mmol) was dissolved in THF (5 mL) and cooled to -40&lt;0&gt;C under Ar. Butyllithium (2.5M, 697.21 μL) was added dropwise while keeping the temperature below -35°C and stirring at the same temperature for an additional 30 min. An aliquot of the intermediate (quenched with deuterated methanol CD3OD ) showed about 80% conversion to the lithiated product. The reaction mixture was cooled to -78°C and iodomethane (618.50 mg, 4.36 mmol, 271.27 μL) was added in one portion and the reaction mixture was warmed to room temperature, then stirred for an additional 2 h. The reaction mixture was quenched with excess saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic layers were dried over Na 2 SO 4 and evaporated under reduced pressure to give tert- butyl 2,5-dimethyl-2-phenylpiperidine-1-carboxylate (0.33 g, crude), It was used in the next step without purification.

1 H NMR(400MHz,CDCl3 )δ(ppm)1.06(d,3H),1.21(s,3H),1.46(s,9H),1.58(m,2H),2.98(m,1H),3.12(m,1H),3.86(m,1H),4.12(m,1H),5.24(m,1H),7.28(m,5H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.06(d,3H), 1.21(s,3H), 1.46(s,9H), 1.58(m,2H), 2.98(m,1H), 3.12( m, 1H), 3.86 (m, 1H), 4.12 (m, 1H), 5.24 (m, 1H), 7.28 (m, 5H).

LCMS(ESI)：[M-Boc]+ m/z：計算值189.4；實測值190.2；Rt=1.758min。LCMS (ESI): [M-Boc] + m/z: calculated 189.4; found 190.2; Rt=1.758 min.

步驟3：2,5-二甲基-2-苯基哌啶之合成Step 3: Synthesis of 2,5-Dimethyl-2-phenylpiperidine

將2,5-二甲基-2-苯基哌啶-1-甲酸第三丁 酯(0.3g，1.04mmol)溶解於二噁烷(5mL)中，隨後添加HCl(377.95mg，10.37mmol，472.44μL)於二噁烷(5mL)中之溶液。在反應完成之後，將有機溶劑蒸發，且將粗產物與MeOH(10mL)及甲苯(10mL)一起再蒸發，以得到2,5-二甲基-2-苯基哌啶(0.2g，885.91μmol，85.46%產率，HCl)，其不經純化即用於下一步驟中。2,5-Dimethyl-2-phenylpiperidine-1-carboxylic acid tert- butyl ester (0.3 g, 1.04 mmol) was dissolved in dioxane (5 mL) followed by addition of HCl (377.95 mg, 10.37 mmol, 472.44 μL) in dioxane (5 mL). After completion of the reaction, the organic solvent was evaporated and the crude product was re-evaporated with MeOH (10 mL) and toluene (10 mL) to give 2,5-dimethyl-2-phenylpiperidine (0.2 g, 885.91 μmol , 85.46% yield, HCl), which was used in the next step without purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.42(s,3H),1.92(m,4H),2.12(m,1H),2.56(m,3H),7.58(m,5H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.98(d,3H), 1.42(s,3H), 1.92(m,4H), 2.12(m,1H), 2.56(m,3H), 7.58 (m, 5H).

步驟4：5-(2-(2,5-二甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺(化合物521 )之合成Step 4: Synthesis of 5-(2-(2,5-Dimethyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide ( Compound 521 )

在輕微加熱下，將2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(185.30mg，885.91μmol，TEA)、2,5-二甲基-2-苯基哌啶(0.2g，885.91μmol，HCl)及DIPEA(343.48mg，2.66mmol，462.92μL)溶解於DMF(6mL)中。在劇烈攪拌及偶爾加熱下，小批量添加HATU(404.22mg，1.06mmol)。反應完成之後，藉由HPLC(23% 0.5-6.5min水-MeCN；流速：30ml/min；(裝載泵4ml/min MeCN)；目標質量380；管柱：SunFireC18 100x19mm 5um(L))純化混合物，以得到5-[[2-[(2R,5S )-2,5-二甲基-2-苯基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(27mg，70.97μmol，8.01%產率)。藉由2D-NMR光譜法證實胺核心之結構。2-[(5-Aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (185.30 mg, 885.91 μmol, TEA), 2,5-dimethyl- 2-Phenylpiperidine (0.2 g, 885.91 μmol, HCl) and DIPEA (343.48 mg, 2.66 mmol, 462.92 μL) were dissolved in DMF (6 mL). With vigorous stirring and occasional heating, HATU (404.22 mg, 1.06 mmol) was added in small batches. After completion of the reaction, the mixture was purified by HPLC (23% 0.5-6.5min water-MeCN; flow rate: 30ml/min; (loading pump 4ml/min MeCN); target mass 380; column: SunFire C18 100x19mm 5um (L)), to give 5-[[2-[( 2R,5S )-2,5-dimethyl-2-phenyl-1-piperidinyl]-2-oxyacetyl]amino]pyridine-3 - Formamide (27 mg, 70.97 μmol, 8.01% yield). The structure of the amine core was confirmed by 2D-NMR spectroscopy.

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.93(d,3H),1.11-1.19(m,1H),1.48-1.59(m,1H),1.66-1.74(m,1H),1.81(s,3H),1.86-1.99(m,2H),3.08-3.19(m,1H),3.54-3.63(m,1H),7.12-7.20(m,1H),7.25-7.34(m,4H),7.60(s,1H),8.15(s,1H),8.49(s,1H),8.76(s,1H),8.89(d,1H),10.97(s,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.93(d,3H), 1.11-1.19(m,1H), 1.48-1.59(m,1H), 1.66-1.74(m,1H), 1.81 (s,3H),1.86-1.99(m,2H),3.08-3.19(m,1H),3.54-3.63(m,1H),7.12-7.20(m,1H),7.25-7.34(m,4H) , 7.60(s, 1H), 8.15(s, 1H), 8.49(s, 1H), 8.76(s, 1H), 8.89(d, 1H), 10.97(s, 1H).

LCMS(ESI)：[M]+ m/z：計算值380.4；實測值381.2；Rt=2.619min。LCMS (ESI): [M] + m/z: calculated 380.4; found 381.2; Rt=2.619 min.

實例777. 5-[[2-[(2R,5S)-2-(3-第三丁基-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物610)之合成Example 777. 5-[[2-[(2R,5S)-2-(3-tert-butyl-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-side oxy Synthesis of Acetyl]amino]pyridine-3-carbamoylamine (Compound 610)

Figure 110128222-A0202-12-2482-485
Figure 110128222-A0202-12-2482-485

步驟1：2-第三丁基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚之合成Step 1: Synthesis of 2-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol

在氬氣氣氛下，將4-溴-2-第三丁基苯酚(15g，65.47mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(17.79g，70.05mmol)、無水乙酸鉀(25.70g，261.88mmol，16.37mL)、Pd(dppf)Cl2* DCM(2.71g，3.27mmol)及1,4-二噁烷(200mL)置於3頸圓底燒瓶中且在80℃下攪拌15h。冷卻之後，將反應混合物用水(500mL)稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。將所得殘餘物提交至急驟管柱層析，以得到2-第三丁基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(12g，43.45mmol，66.37%產率)。Under argon atmosphere, 4-bromo-2-tert-butylphenol (15 g, 65.47 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl) yl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane (17.79 g, 70.05 mmol), anhydrous potassium acetate (25.70 g) , 261.88 mmol, 16.37 mL), Pd(dppf)Cl2 * DCM (2.71 g, 3.27 mmol) and 1,4-dioxane (200 mL) were placed in a 3-neck round bottom flask and stirred at 80 °C for 15 h. After cooling, the reaction mixture was diluted with water (500 mL) and extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was submitted to flash column chromatography to give 2-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenol (12 g, 43.45 mmol, 66.37% yield).

層析資料：RediSep管柱：330g，運行長度：18.7CV，流速：100ml/minChromatography data: RediSep column: 330g, run length: 18.7CV, flow rate: 100ml/min

溶劑A：CHCl3 ；溶劑B：乙腈Solvent A: CHCl3 ; Solvent B: Acetonitrile

1 H NMR(400MHz,DMSO-d6 )δ 1.19(s,12H),1.27(s,9H),6.63(d,1H),7.22(d,1H),7.38(s,1H),9.35(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.19(s, 12H), 1.27(s, 9H), 6.63(d, 1H), 7.22(d, 1H), 7.38(s, 1H), 9.35(s , 1H).

步驟2：6-(3-第三丁基-4-羥基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 6-(3-tert-butyl-4-hydroxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將2-第三丁基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(6.8g，24.62mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(6.80g，19.70mmol)、碳酸鈉(7.83g，73.87mmol，3.09mL)及Pd(dppf)Cl2* DCM(814.21 mg，984.87μmol)添加到1,4-二噁烷(50mL)及水(20mL)之混合物中。將反應混合物在85℃、氬氣氣氛下攪拌85℃。冷卻之後，將反應混合物用水(100mL)稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮，以得到6-(3-第三丁基-4-羥基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(5g，粗品)，其不經純化即用於下一步驟中。2-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol (6.8 g, 24.62 mmol) , 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.80 g, 19.70 mmol), sodium carbonate (7.83 g, 73.87 mmol, 3.09 mL) and Pd(dppf)Cl2 * DCM (814.21 mg, 984.87 μmol) were added to a mixture of 1,4-dioxane (50 mL) and water (20 mL). The reaction mixture was stirred at 85°C under an argon atmosphere at 85°C. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with DCM. The organic layer was separated, dried over Na 2 SO 4 and concentrated under reduced pressure to give 6-(3-tert-butyl-4-hydroxyphenyl)-3-methyl-3,4-dihydro-2H - tert-butyl pyridine-1-carboxylate (5 g, crude), which was used in the next step without purification.

LCMS(ESI)：[M-tBu]+ m/z：計算值289.2；實測值290.2；Rt=1.532min。LCMS (ESI): [M-tBu] + m/z: calculated 289.2; found 290.2; Rt=1.532 min.

步驟3：2-第三丁基-4-[(2R,5S)-5-甲基-2-哌啶基]苯酚之合成Step 3: Synthesis of 2-tert-butyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenol

將6-(3-第三丁基-4-羥基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.3g，4.39mmol)溶解於TFA(7.40g，64.90mmol，5mL)及DCM(5mL)之混合物中且在室溫下攪拌0.5h。在旋轉蒸發器上濃縮反應混合物(浴溫45C)，以得到粗品甲亞胺，其直接用於下一步驟中。將來自前一步驟之粗材料溶解於甲醇(50mL)中，隨後一次性添加硼氫化鈉(216.11mg，5.71mmol，201.97μL)。將反應混合物在室溫下攪拌隔夜且用HCl/二噁烷溶液酸化。將所得溶液在減壓下濃縮，以得到2-第三丁基-4-[(2R,5S)-5-甲基-2-哌啶基]苯酚，其不經純化即用於下一步驟中。Dissolve 6-(3-tert-butyl-4-hydroxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.3 g, 4.39 mmol) in in a mixture of TFA (7.40 g, 64.90 mmol, 5 mL) and DCM (5 mL) and stirred at room temperature for 0.5 h. The reaction mixture was concentrated on a rotary evaporator (bath temperature 45C) to give crude formimine, which was used directly in the next step. The crude material from the previous step was dissolved in methanol (50 mL) followed by the addition of sodium borohydride (216.11 mg, 5.71 mmol, 201.97 μL) in one portion. The reaction mixture was stirred at room temperature overnight and acidified with HCl/dioxane solution. The resulting solution was concentrated under reduced pressure to give 2-tert-butyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenol, which was used in the next step without purification middle.

LCMS(ESI)：[M+H]+ m/z：計算值247.2；實測值248.2；Rt=0.783min。LCMS (ESI): [M+H] + m/z: calculated 247.2; found 248.2; Rt=0.783 min.

步驟4：5-[[2-[(2R,5S)-2-(3-第三丁基-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物610 )之合成Step 4: 5-[[2-[(2R,5S)-2-(3-tert-butyl-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Synthesis of Acetyl]amino]pyridine-3-carbamoylamine ( Compound 610 )

將2-第三丁基-4-[(2R,5S)-5-甲基-2-哌啶基]苯酚(500.00mg，1.03mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(237.17mg，1.13mmol，TEA)及DIPEA(742.00mg，5.74mmol，1mL)溶解於DMSO(5mL)中，隨後添加HATU(509.54mg，1.34mmol)。將反應混合物在室溫下攪拌15h，然後提交至HPLC，以得到5-[[2-[(2R,5S)-2-(3-第三丁基-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.07g，159.63μmol，15.49%產率)。2-tert-butyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenol (500.00 mg, 1.03 mmol), 2-[(5-aminocarboxy-3- Pyridyl)amino]-2-oxoacetic acid (237.17 mg, 1.13 mmol, TEA) and DIPEA (742.00 mg, 5.74 mmol, 1 mL) were dissolved in DMSO (5 mL) followed by the addition of HATU (509.54 mg, 1.34 mmol) ). The reaction mixture was stirred at room temperature for 15 h, then submitted to HPLC to give 5-[[2-[(2R,5S)-2-(3-tert-butyl-4-hydroxyphenyl)-5-methan (0.07 g, 159.63 μmol, 15.49% yield).

HPLC資料：2-10min 50-60% MeCN/H2 O 30ml/min(裝載泵4ml MeCN)管柱：SunFire 100*19mm，5微米；樣品資訊：2-10min 50-60%水/MeCN+NH3 (裝載泵4ml MeCN+NH3 )，管柱：TRIART 100*20 5微米HPLC data: 2-10min 50-60% MeCN/H 2 O 30ml/min (loading pump 4ml MeCN) Column: SunFire 100*19mm, 5 microns; Sample information: 2-10min 50-60% water/MeCN+NH 3 (loading pump 4ml MeCN+ NH3 ), column: TRIART 100*20 5 microns

1 H NMR(600MHz,DMSO-d 6 )δ 0.95-1.07(m,3H),1.25-1.36(m,10H),1.63-1.79(m,1H),1.79-1.94(m,1H),1.96-2.09(m,1H),2.09-2.18(m,1H),2.74-3.26(m,1H),3.37-3.98(m,1H),5.01-5.58(m,1H),6.69-6.81(m,1H),6.90-7.01(m,1H),7.01-7.12(m,1H),7.50-7.65(m,1H),8.08-8.21(m,1H),8.40-8.55(m,1H),8.67-8.79(m,1H),8.79-8.92(m,1H),9.28(s,1H),11.02-11.32(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.95-1.07(m,3H), 1.25-1.36(m,10H), 1.63-1.79(m,1H), 1.79-1.94(m,1H), 1.96- 2.09(m, 1H), 2.09-2.18(m, 1H), 2.74-3.26(m, 1H), 3.37-3.98(m, 1H), 5.01-5.58(m, 1H), 6.69-6.81(m, 1H ),6.90-7.01(m,1H),7.01-7.12(m,1H),7.50-7.65(m,1H),8.08-8.21(m,1H),8.40-8.55(m,1H),8.67-8.79 (m, 1H), 8.79-8.92 (m, 1H), 9.28 (s, 1H), 11.02-11.32 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值438.2；實測值439.2；Rt=3.087min。LCMS (ESI): [M+H] + m/z: calculated 438.2; found 439.2; Rt=3.087 min.

實例778. 5-[[2-[(2R,5S)-2-(3-乙基-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物642)之合成Example 778. 5-[[2-[(2R,5S)-2-(3-ethyl-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone Synthesis of yl]amino]pyridine-3-carboxamide (compound 642)

Figure 110128222-A0202-12-2484-486
Figure 110128222-A0202-12-2484-486

步驟1：4-溴-2-乙基苯酚之合成Step 1: Synthesis of 4-bromo-2-ethylphenol

將2-乙基苯酚(14g，114.60mmol，13.73mL)及硫酸(224.80mg，2.29mmol)溶解於THF(500mL)中且將混合物冷卻至-25℃。在-25℃下，在攪拌之情況下，分批添加NBS(21.21g，119.18mmol)且在此溫度下將反應混合物攪拌1h，然後使其升溫至室溫達2h。在減壓下濃縮反應混合物且將其溶解於乙酸乙酯中。將有機層用NaHCO3 溶液、NaHSO3 溶液、水洗滌，經Na2 SO4 乾燥且在旋轉蒸發器上濃縮，以得到4-溴-2-乙基苯酚(18g，粗品)，其不經純化即用於下一步驟中。2-Ethylphenol (14 g, 114.60 mmol, 13.73 mL) and sulfuric acid (224.80 mg, 2.29 mmol) were dissolved in THF (500 mL) and the mixture was cooled to -25 °C. At -25°C, with stirring, NBS (21.21 g, 119.18 mmol) was added in portions and the reaction mixture was stirred at this temperature for 1 h, then allowed to warm to room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The organic layer was washed with NaHCO 3 solution, NaHSO 3 solution, water, dried over Na 2 SO 4 and concentrated on rotary evaporator to give 4-bromo-2-ethylphenol (18 g, crude) without purification that is used in the next step.

1 H NMR(400MHz,DMSO-d6 )δ 1.10(t,3H),2.49(q,2H),6.72(d,1H),7.12(d,1H),7.19(s,1H),9.55(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.10(t, 3H), 2.49(q, 2H), 6.72(d, 1H), 7.12(d, 1H), 7.19(s, 1H), 9.55(s , 1H).

步驟2：2-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚之合成Step 2: Synthesis of 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol

將4-溴-2-乙基苯酚(18g，80.57mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(22.51g，88.63mmol)、乙酸鉀(31.63g，322.29mmol，20.15mL)及Pd(dppf)Cl2 DCM(3.33g，4.03mmol)混合於1,4-二噁烷(400mL)中且將反應混合物在氬氣氣氛、80℃下攪拌16h。在反應完成之後，將反應混合物冷卻，用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且在減壓下濃縮。將所得殘餘物提交至急驟管柱層析，以得到2-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(10g，40.30mmol，50.02%產率)。層析資料：RediSep管柱：330g，運行長度：25.0CV，流速：100ml/min，溶劑A：CHCl3 ，溶劑B：乙腈。4-Bromo-2-ethylphenol (18 g, 80.57 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)-1,3,2-dioxaborolane (22.51 g, 88.63 mmol), potassium acetate (31.63 g, 322.29 mmol, 20.15 mL) and Pd (dppf)Cl 2 DCM (3.33 g, 4.03 mmol) was mixed in 1,4-dioxane (400 mL) and the reaction mixture was stirred under argon atmosphere at 80 °C for 16 h. After completion of the reaction, the reaction mixture was cooled, diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was submitted to flash column chromatography to give 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenol (10 g, 40.30 mmol, 50.02% yield). Chromatographic data: RediSep column: 330 g, run length: 25.0 CV, flow rate: 100 ml/min, solvent A: CHCl3 , solvent B: acetonitrile.

1 H NMR(400MHz,DMSO-d6 )δ 1.10(t,3H),1.14(s,12H),2.49(q,2H),6.67(d,1H),7.26(d,1H),7.33(s,1H),9.39(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 1.10(t, 3H), 1.14(s, 12H), 2.49(q, 2H), 6.67(d, 1H), 7.26(d, 1H), 7.33(s , 1H), 9.39(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值247.2；實測值248.2；Rt=1.447min。LCMS (ESI): [M+H] + m/z: calculated 247.2; found 248.2; Rt=1.447 min.

步驟3：6-(3-乙基-4-羥基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: Synthesis of 6-(3-ethyl-4-hydroxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將2-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(2.5g，10.08mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.78g，8.06mmol)、碳酸鈉(3.20g，30.23mmol，1.27mL)及Pd(dppf)Cl2 DCM(333.19mg，403.02μmol)添加到1,4-二噁烷(20mL)及水(10mL)之混合物中且將反應混合物在氬氣氣氛、80℃下攪拌18h。冷卻之後，將反應混合物用水稀釋且用DCM萃取。將有機層分離，經Na2 SO4 乾燥且透過小矽膠墊過濾。在減壓下濃縮濾液，以得到6-(3-乙基-4-羥基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2g，粗品)，其不經純化即用於下一步驟中。2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenol (2.5 g, 10.08 mmol), 3 - methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.78g, 8.06mmol), sodium carbonate (3.20g, 30.23 mmol, 1.27 mL) and Pd(dppf)Cl 2 DCM (333.19 mg, 403.02 μmol) were added to a mixture of 1,4-dioxane (20 mL) and water (10 mL) and the reaction mixture was placed under argon atmosphere, Stir at 80°C for 18h. After cooling, the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4 and filtered through a small pad of silica gel. The filtrate was concentrated under reduced pressure to give tert-butyl 6-(3-ethyl-4-hydroxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid (2 g, crude product), which was used in the next step without purification.

LCMS(ESI)：[M-tBu]+ m/z：計算值261.2；實測值262.2；Rt=1.585min。LCMS (ESI): [M-tBu] + m/z: calculated 261.2; found 262.2; Rt=1.585min.

步驟4：2-乙基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚之合成Step 4: Synthesis of 2-ethyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol

將6-(3-乙基-4-羥基苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2g，2.90mmol)溶解於TFA(7.40g，64.90mmol，5mL)及DCM(5mL)之混合物中且將反應混合物在室溫下攪拌0.5h且在減壓下濃縮，以得到2-乙基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(1.36g，粗品)，其不經純化即用於下一步驟中。6-(3-Ethyl-4-hydroxyphenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2 g, 2.90 mmol) was dissolved in TFA (7.40 g, 64.90 mmol, 5 mL) and DCM (5 mL) and the reaction mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure to give 2-ethyl-4-(3-methyl-2, 3,4,5-Tetrahydropyridin-6-yl)phenol (1.36 g, crude) was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值217.2；實測值218.4；Rt=0.919min。LCMS (ESI): [M+H] + m/z: calculated 217.2; found 218.4; Rt=0.919 min.

步驟5：2-乙基-4-[(2R,5S)-5-甲基-2-哌啶基]苯酚之合成Step 5: Synthesis of 2-ethyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenol

將粗品2-乙基-4-(3-甲基-2,3,4,5-四氫吡啶-6-基)苯酚(1.36g，2.38mmol)溶解於甲醇(30mL)中且一次性添加硼氫化鈉(0.2g，5.29mmol，186.92μL)。將反應混合物在室溫下攪拌12h，然後用HCl-二噁烷溶液酸化。將所得溶液在減壓下濃縮，以得到2-乙基-4-[(2R,5S)-5-甲基-2-哌啶基]苯酚(1.3g，粗品，HCl)，其不經純化即用於下一步驟中。Crude 2-ethyl-4-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl)phenol (1.36 g, 2.38 mmol) was dissolved in methanol (30 mL) and added in one portion Sodium borohydride (0.2 g, 5.29 mmol, 186.92 [mu]L). The reaction mixture was stirred at room temperature for 12 h, then acidified with HCl-dioxane solution. The resulting solution was concentrated under reduced pressure to give 2-ethyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenol (1.3 g, crude, HCl) without purification that is used in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值219.2；實測值220.2；Rt=0.901min。LCMS (ESI): [M+H] + m/z: calculated 219.2; found 220.2; Rt=0.901 min.

步驟6：5-[[2-[(2R,5S)-2-(3-乙基-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物642 )之合成Step 6: 5-[[2-[(2R,5S)-2-(3-ethyl-4-hydroxyphenyl)-5-methyl-1-piperidinyl]-2-pendoxetylacetone Synthesis of yl]amino]pyridine-3-carboxamide ( compound 642 )

將2-乙基-4-[(2R,5S)-5-甲基-2-哌啶基]苯酚(0.2g，265.85μmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(78.36mg，319.02μmol，HCl)及DIPEA(742.00mg，5.74mmol，1mL)添加到DMSO(1.5mL)中，隨後添加HATU(141.52mg，372.19μmol)。將反應混合物在20℃下攪拌15h。在反應完成(LCMS對照)之後，將反應混合物提交至HPLC，以得到呈兩種級分之5-[[2-[(2R,5S)-2-(3-乙基-4-羥基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.021g，51.16μmol，19.24%產率)：級分_1(8mg，藉由LCMS為100%)及級分(14mg，藉由LCMS為98%)。2-Ethyl-4-[(2R,5S)-5-methyl-2-piperidinyl]phenol (0.2 g, 265.85 μmol, HCl), 2-[(5-aminocarboxy-3- Pyridyl)amino]-2-oxoacetic acid (78.36 mg, 319.02 μmol, HCl) and DIPEA (742.00 mg, 5.74 mmol, 1 mL) were added to DMSO (1.5 mL) followed by HATU (141.52 mg, 372.19 μmol). The reaction mixture was stirred at 20 °C for 15 h. After completion of the reaction (LCMS control), the reaction mixture was submitted to HPLC to give 5-[[2-[(2R,5S)-2-(3-ethyl-4-hydroxyphenyl as two fractions )-5-methyl-1-piperidinyl]-2-oxoacetyl]amino]pyridine-3-carboxamide (0.021 g, 51.16 μmol, 19.24% yield): Fraction_1 (8 mg, 100% by LCMS) and fractions (14 mg, 98% by LCMS).

HPLC資料：HPLC data:

樣品資訊：2-10min 60-85%水/MeOH+NH3 (裝載泵4ml MeOH+NH3 )，管柱：TRIART 100* 20mm 5微米Sample information: 2-10min 60-85% water/MeOH+NH 3 (loading pump 4ml MeOH+NH 3 ), column: TRIART 100 * 20mm 5 microns

1 H NMR(DMSO-d6 ,600MHz)：δ(ppm)1.05(m,6H),1.31(m,1H),1.72(m,1H),1.84(m,1H),2.01(m,1H),2.14(m,1H),2.52(m,2H),2.92(m,1H),3.58(m,1H),5.27(m,1H),6.74(m,1H),6.98(m,2H),7.57(m,1H),8.13(m,1H),8.46(m,1H),8.73(m,1H),8.96(m,2H),11.20(s,1H) 1 H NMR (DMSO-d 6 , 600MHz): δ (ppm) 1.05 (m, 6H), 1.31 (m, 1H), 1.72 (m, 1H), 1.84 (m, 1H), 2.01 (m, 1H) ,2.14(m,1H),2.52(m,2H),2.92(m,1H),3.58(m,1H),5.27(m,1H),6.74(m,1H),6.98(m,2H), 7.57(m, 1H), 8.13(m, 1H), 8.46(m, 1H), 8.73(m, 1H), 8.96(m, 2H), 11.20(s, 1H)

LCMS(ESI)：[M+H]+ m/z：計算值410.2；實測值411.4；Rt=2.425min。LCMS (ESI): [M+H] + m/z: calculated 410.2; found 411.4; Rt=2.425 min.

實例779. 2-(2-(1H -吲唑-6-基)-5-甲基哌啶-1-基)-N -(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物613及化合物636)之合成Example 779. 2-(2-( 1H - Indazol -6-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridin-3-yl)- Synthesis of 2-Pendant Oxyacetamide (Compound 613 and Compound 636)

Figure 110128222-A0202-12-2487-487
Figure 110128222-A0202-12-2487-487

步驟1：6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吲唑-1-甲酸第三丁酯之合成Step 1: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-indazole-1-carboxylic acid tert-butyl ester synthesis

在環境溫度下，向6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H -吲唑(2.00g，8.19mmol)、TEA(1.04g，10.24mmol，1.43mL)於MeCN(20mL)中之經攪拌之混合物中添加二碳酸二-第三丁酯(1.97g，9.01mmol，2.07mL)，隨後添加DMAP(100.10mg，819.35μmol)，然後將反應混合物在70℃下攪拌12h。將反應混合物在真空中濃縮且將所獲得之殘餘物溶解於DCM中，用NaHSO4 (水溶液)、NaHCO3 (水溶液)、鹽水洗滌，然後經Na2 SO4 乾燥，過濾且在真空中濃縮，以得到6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁 酯(1g，2.91mmol，35.46%產率)，其不經進一步純化即用於下一步驟中。To 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2- yl )-1H-indazole (2.00 g, 8.19 g) at ambient temperature mmol), TEA (1.04 g, 10.24 mmol, 1.43 mL) in MeCN (20 mL) was added di-tert-butyl dicarbonate (1.97 g, 9.01 mmol, 2.07 mL) followed by DMAP ( 100.10 mg, 819.35 μmol), then the reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated in vacuo and the obtained residue was dissolved in DCM, washed with NaHSO 4 (aq), NaHCO 3 (aq), brine, then dried over Na 2 SO 4 , filtered and concentrated in vacuo, to give 3 -butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylate (1 g, 2.91 mmol, 35.46% yield), which was used in the next step without further purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)1.29(s,12H),1.62(s,9H),7.59(m,1H),7.83(m,1H),8.40(m,1H),8.48(m,1H)。步驟2：6-(1H-吲唑-6-基)-3-甲基-3,4-二氫吡啶-1(2H)-甲酸第三丁酯之合成 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 1.29(s, 12H), 1.62(s, 9H), 7.59(m, 1H), 7.83(m, 1H), 8.40(m, 1H), 8.48 (m, 1H). Step 2: Synthesis of 6-(1H-Indazol-6-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吲唑-1-甲酸第三丁 酯(1.87g，5.43mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(2.06g，5.98mmol)及碳酸鈉(1.15g，10.87mmol，455.19μL)一起混合於二噁烷(30mL)及水(10mL)之混合物中。將燒瓶抽真空且用氬氣回填三次，且向其中添加二氯(1,1'-雙( 二苯基磷烷基)二茂鐵)鈀(II)*DCM(221.75mg，271.63μmol)。將反應混合物在85℃下加熱12h。將反應混合物用EtOAc/水稀釋，將有機相分離，將水相用額外EtOAc洗滌，將經合併之有機相經Na2 SO4 乾燥，過濾且在真空中濃縮，以得到6-(1-第三丁氧基 羰基-3-甲基-3,4-二氫-2H -吡啶-6-基)吲唑-1-甲酸第三丁 酯(2.2g，5.32mmol，97.93%產率)，其不經進一步純化即用於下一步驟中。6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)indazole-1-carboxylic acid tert- butyl ester (1.87 g, 5.43 g mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (2.06 g, 5.98 mmol) and sodium carbonate (1.15 g, 10.87 mmol, 455.19 μL) were mixed together in a mixture of dioxane (30 mL) and water (10 mL). The flask was evacuated and backfilled with argon three times, and to it was added dichloro(1,1'- bis( diphenylphosphonyl)ferrocene)palladium(II)*DCM (221.75 mg, 271.63 μmol). The reaction mixture was heated at 85 °C for 12 h. The reaction mixture was diluted with EtOAc/water, the organic phase was separated, the aqueous phase was washed with additional EtOAc, the combined organic phases were dried over Na2SO4 , filtered and concentrated in vacuo to give 6-(1- th Tributoxycarbonyl -3-methyl-3,4-dihydro- 2H -pyridin-6-yl)indazole-1-carboxylic acid tert- butyl ester (2.2 g, 5.32 mmol, 97.93% yield), It was used in the next step without further purification.

LCMS(ESI)：[M-Boc]+ m/z：計算值313.2；實測值314.2；Rt=1.464min。LCMS (ESI): [M-Boc] + m/z: calculated 313.2; found 314.2; Rt=1.464 min.

步驟3：6-(5-甲基-3,4,5,6-四氫吡啶-2-基)-1H-吲唑之合成Step 3: Synthesis of 6-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-1H-indazole

將6-(1-第三丁氧基 羰基-3-甲基-3,4-二氫-2H -吡啶-6-基)吲唑-1-甲酸第三丁 酯(3.4g，8.22mmol)溶解於DCM(12mL)及TFA(12mL)之混合物，然後在室溫下攪拌1h。將反應混合物用20% NaOH水溶液中和，將所獲得之溶液用DCM稀釋，將有機相分離且將水層用額外DCM洗滌。將有機相經Na2 SO4 乾燥，過濾且在真空中濃縮，以得到6-(3-甲基-2,3,4,5-四氫吡啶-6-基)-1H -吲唑(1.15g，5.39mmol，65.58%產率)，其不經進一步純化即用於下一步驟中。6-(1- Third- butoxycarbonyl-3-methyl-3,4-dihydro- 2H -pyridin-6-yl)indazole-1-carboxylic acid tert- butyl ester (3.4 g, 8.22 mmol) Dissolved in a mixture of DCM (12 mL) and TFA (12 mL), then stirred at room temperature for 1 h. The reaction mixture was neutralized with 20% aqueous NaOH, the resulting solution was diluted with DCM, the organic phase was separated and the aqueous layer was washed with additional DCM. The organic phase was dried over Na2SO4 , filtered and concentrated in vacuo to give 6-(3-methyl-2,3,4,5-tetrahydropyridin-6- yl )-1H-indazole (1.15 g, 5.39 mmol, 65.58% yield), which was used in the next step without further purification.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.91(d,3H),1.27(m,1H),1.61(m,1H),1.83(m,1H),2.59(m,1H),2.78(m,1H),3.12(m,1H),3.83(m,1H),7.43(d,1H),7.50(d,1H),7.84(s,1H),7.89(s,1H)。LCMS(ESI)：[M]+ m/z：計算值213.2；實測值214.2； Rt=0.878min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.91(d,3H), 1.27(m,1H), 1.61(m,1H), 1.83(m,1H), 2.59(m,1H), 2.78(m,1H), 3.12(m,1H), 3.83(m,1H), 7.43(d,1H), 7.50(d,1H), 7.84(s,1H), 7.89(s,1H). LCMS (ESI): [M] + m/z: calculated 213.2; found 214.2; Rt=0.878 min.

步驟4：外消旋-6-((2R,5S)-5-甲基哌啶-2-基)-1H-吲唑之合成Step 4: Synthesis of Racemic-6-((2R,5S)-5-methylpiperidin-2-yl)-1H-indazole

將6-(5-甲基-3,4,5,6-四氫吡啶-2-基)-1H -吲唑(1.15g，5.39mmol)溶解於MeOH(15mL)中且在用冰水冷卻下分批添加硼氫化鈉(1.02g，26.96mmol，953.24μL)。將反應混合物加熱至室溫且攪拌12h。添加NH4 Cl(水溶液)且蒸發MeOH，將水層用DCM(3*30ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且在真空中在45℃下蒸發，以得到外消旋 -6-((2R,5S )-5-甲基哌啶-2-基)-1H -吲唑(0.36g，1.67mmol，31.01%產率)，其不經純化即用於下一步驟中。6-(5-Methyl-3,4,5,6-tetrahydropyridin-2- yl )-1H-indazole (1.15 g, 5.39 mmol) was dissolved in MeOH (15 mL) and cooled with ice water Sodium borohydride (1.02 g, 26.96 mmol, 953.24 μL) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 12 h. NH 4 Cl (aq) was added and MeOH was evaporated, the aqueous layer was extracted with DCM (3*30 ml) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated in vacuo at 45°C to give external Racemic -6-(( 2R,5S )-5-methylpiperidin-2- yl )-1H-indazole (0.36 g, 1.67 mmol, 31.01% yield), which was used in the next step without purification in steps.

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.80(d,3H),1.07(m,1H),1.34(m,1H),1.49(m,1H),1.73(m,2H),2.25(m,1H),2.35(m,1H),2.97(m,1H),3.54(m,2H),7.05(d,1H),7.43(s,1H),7.58(d,1H),7.93(s,1H)。LCMS(ESI)：[M]+ m/z：計算值215.2；實測值216.2；Rt=1.035min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.80(d,3H), 1.07(m,1H), 1.34(m,1H), 1.49(m,1H), 1.73(m,2H), 2.25(m, 1H), 2.35(m, 1H), 2.97(m, 1H), 3.54(m, 2H), 7.05(d, 1H), 7.43(s, 1H), 7.58(d, 1H), 7.93 (s, 1H). LCMS (ESI): [M] + m/z: calculated 215.2; found 216.2; Rt=1.035 min.

步驟5：外消旋-(5-(2-((2R,5S)-2-(1H-吲唑-6-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 5: Racemic-(5-(2-((2R,5S)-2-(1H-indazol-6-yl)-5-methylpiperidin-1-yl)-2-pendoxyl Synthesis of acetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

將N -[3-甲基-5-(醯胺草醯基胺基)-2-吡啶基]胺甲酸第三丁 酯(492.12mg，1.67mmol)及TEA(1.69g，16.72mmol，2.33mL)溶解於DMF(10mL)中且冷卻至0℃，添加HATU(953.69mg，2.51mmol)且在0℃下將混合物攪拌15min。添加6-[(2S,5R )-5-甲基-2-哌啶基]-1H -吲唑(0.36g，1.67mmol)且將混合物升溫至室溫且攪拌3h。添加10ml乙酸乙酯且將有機相用鹽水洗滌三次。將有機相經Na2 SO4 乾燥，過濾且在45℃下在真空中濃縮，以得到粗產物，其藉由HPLC(40-60%水/MeOH，2-10min，(裝載泵4ml MeOH)，管柱：TRIART 100*20)進行純化，以得到N -[5-[[2-[(2S,5R )-2-(1H -吲唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.07g，142.11μmol，8.50%產率)。Combine N- [3-methyl-5-(amidopyramido)-2-pyridyl]carbamic acid tert- butyl ester (492.12 mg, 1.67 mmol) and TEA (1.69 g, 16.72 mmol, 2.33 mL) ) was dissolved in DMF (10 mL) and cooled to 0 °C, HATU (953.69 mg, 2.51 mmol) was added and the mixture was stirred at 0 °C for 15 min. 6-[( 2S,5R )-5-methyl-2-piperidinyl] -1H -indazole (0.36 g, 1.67 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h. 10 ml of ethyl acetate were added and the organic phase was washed three times with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo at 45° C. to give the crude product by HPLC (40-60% water/MeOH, 2-10 min, (loading pump 4 ml MeOH), Column: TRIART 100*20) for purification to give N- [5-[[2-[( 2S,5R )-2-( 1H -indazol-6-yl)-5-methyl-1-piperidine Peridyl]-2-pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.07 g, 142.11 [mu]mol, 8.50% yield).

LCMS(ESI)：[M]+ m/z：計算值492.2；實測值493.2；Rt=1.120min。LCMS (ESI): [M] + m/z: calculated 492.2; found 493.2; Rt=1.120 min.

步驟6：掌性分離Step 6: Palm Separation

使用(管柱：Chiralpak OD-H(250 * 30mm，5mkm)；流動相：己烷-IPA-MeOH 50-25-25；流速：20mL/min)進行掌性分離，以得到呈順式異構物及反式異構物之混合物之第1鏡像異構物及呈純的鏡像異構物之(5-(2-(2-(1H -吲唑-6-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁 酯(0.02g，40.60μmol，28.57%產率)。Chiral separation was performed using (column: Chiralpak OD-H (250*30mm, 5mkm); mobile phase: Hexane-IPA-MeOH 50-25-25; flow rate: 20mL/min) to give cis-isomers The 1st enantiomer as a mixture of compound and trans isomer and (5-(2-(2-( 1H -indazol-6-yl)-5-methylpiperin as pure enantiomer pyridin-1-yl)-2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert -butyl ester (0.02 g, 40.60 [mu]mol, 28.57% yield).

使用(Chiralpak IB(250 * 20mm，5mkm)；流動相：己烷-EtOH 90-10，流速：14mL/min)分離順式異構物及反式異構物之混合物，以得到呈純的鏡像異構物(反式 )之(5-(2-(2-(1H -吲唑-6-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁 酯(0.014g，28.42μmol，20.00%產率)。The mixture of cis and trans isomers was separated using (Chiralpak IB (250*20mm, 5mkm); mobile phase: Hexane-EtOH 90-10, flow rate: 14 mL/min) to give the mirror image as pure Isomer ( trans ) of (5-(2-(2-( 1H -indazol-6-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido) - 3-Methylpyridin-2-yl)carbamic acid tert -butyl ester (0.014 g, 28.42 [mu]mol, 20.00% yield).

E1於分析條件下(管柱：OD-H，以己烷-IPA-MeOH，50-25-25，0.6ml/min為流動相)之保留時間為29.09min且E2之保留時間為15.60min。The retention time of E1 under analytical conditions (column: OD-H, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min as mobile phase) was 29.09 min and that of E2 was 15.60 min.

E1： LCMS(ESI)：[M]+ m/z：計算值492.2；實測值493.2；Rt=4.930min。 E1: LCMS (ESI): [M] + m/z: calculated 492.2; found 493.2; Rt=4.930 min.

E2： LCMS(ESI)：[M]+ m/z：計算值492.2；實測值493.2；Rt=4.941min。 E2: LCMS (ESI): [M] + m/z: calculated 492.2; found 493.2; Rt=4.941 min.

步驟7：2-(2-(1H-吲唑-6-基)-5-甲基哌啶-1-基)-N-(6-胺基-5-甲基吡啶-3-基)-2-側氧基乙醯胺(化合物613 及化合物636 )之合成Step 7: 2-(2-(1H-Indazol-6-yl)-5-methylpiperidin-1-yl)-N-(6-amino-5-methylpyridin-3-yl)- Synthesis of 2-Pendant Oxyacetamide ( Compound 613 and Compound 636 )

將N -[5-[[2-[(2S,5R )-2-(1H -吲唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.014g，28.42μmol)及N -[5-[[2-[(2R,5S )-2-(1H -吲唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.02g，40.60μmol)溶解於二噁烷(2mL)及水(2mL)之混合物中，然後在100℃下攪拌12h。在真空中在55℃下濃縮反應混合物，以得到粗產物，其藉由HPLC(0.1% FA/MeCN，5-95% MeCN，6min，管柱：Zorbax Eclips-plus C18 4.6*100mm，3.5mkm)進行純化，以得到N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(1H -吲唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.001g， 2.55μmol，8.97%產率)及N-(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-2-(1H -吲唑-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(0.001g，2.55μmol，6.28%產率)。 N- [5-[[2-[( 2S,5R )-2-( 1H -indazol-6-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl ]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.014 g, 28.42 μmol) and N- [5-[[2-[( 2R,5S )-2-( 1H- Indazol-6-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester ( 0.02 g, 40.60 μmol) was dissolved in a mixture of dioxane (2 mL) and water (2 mL), then stirred at 100° C. for 12 h. The reaction mixture was concentrated in vacuo at 55°C to give crude product by HPLC (0.1% FA/MeCN, 5-95% MeCN, 6 min, column: Zorbax Eclips-plus C18 4.6*100 mm, 3.5 mkm) Purification to give N- (6-amino-5-methyl-3-pyridinyl)-2-[( 2S,5R )-2-( 1H -indazol-6-yl)-5-methyl -1-Piperidinyl]-2-oxyacetamide (0.001 g, 2.55 μmol, 8.97% yield) and N-(6-amino-5-methyl-3-pyridyl)-2- [( 2R,5S )-2-( 1H -indazol-6-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (0.001 g, 2.55 μmol, 6.28% yield Rate).

化合物613： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.07(m,1H),1.36(m,2H),1.86(m,2H),2.24(s,3H),2.28(m,2H),4.18(m,1H),5.68(m,2H),7.16(m,1H),7.48(m,2H),7.78(m,1H),8.03(m,2H),10.56(m,1H),13.02(m,1H)。 Compound 613: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98 (d, 3H), 1.07 (m, 1H), 1.36 (m, 2H), 1.86 (m, 2H), 2.24 (s, 3H), 2.28(m, 2H), 4.18(m, 1H), 5.68(m, 2H), 7.16(m, 1H), 7.48(m, 2H), 7.78(m, 1H), 8.03(m, 2H) ), 10.56 (m, 1H), 13.02 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值392.2；實測值393.2；Rt=3.623min。LCMS (ESI): [M] + m/z: calculated 392.2; found 393.2; Rt=3.623 min.

化合物636： 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.98(d,3H),1.07(m,1H),1.36(m,2H),1.86(m,2H),2.24(s,3H),2.28(m,2H),4.18(m,1H),5.68(m,2H),7.16(m,1H),7.48(m,2H),7.78(m,1H),8.03(m,2H),10.56(m,1H),13.02(m,1H)。 Compound 636: 1 H NMR (600 MHz, DMSO- d 6 ) δ (ppm) 0.98 (d, 3H), 1.07 (m, 1H), 1.36 (m, 2H), 1.86 (m, 2H), 2.24 (s, 3H), 2.28(m, 2H), 4.18(m, 1H), 5.68(m, 2H), 7.16(m, 1H), 7.48(m, 2H), 7.78(m, 1H), 8.03(m, 2H) ), 10.56 (m, 1H), 13.02 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值392.2；實測值393.2；Rt=3.599min。LCMS (ESI): [M] + m/z: calculated 392.2; found 393.2; Rt=3.599 min.

實例780. 5-[[2-[(2R,5S)-2-(2-氰基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物664)之合成Example 780. 5-[[2-[(2R,5S)-2-(2-cyanophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide (Compound 664)

Figure 110128222-A0202-12-2491-489
Figure 110128222-A0202-12-2491-489

步驟1：2-溴苯甲醯氯之合成Step 1: Synthesis of 2-bromobenzyl chloride

將2-溴苯甲酸(5g，24.87mmol)及草醯氯(4.74g，37.31mmol，3.24mL)懸浮於DCM(50mL)中。向其中分3批添加DMF(1.82g，24.87mmol，1.93mL)。將所得混合物在25℃下攪拌2h。當氣體逸出停止時，在減壓下濃縮所得澄清溶 液。將殘餘物再溶解於己烷(150ml)中，過濾且在真空中蒸發，得到2-溴苯甲醯氯(5g，22.78mmol，91.60%產率)。2-Bromobenzoic acid (5 g, 24.87 mmol) and oxalic chloride (4.74 g, 37.31 mmol, 3.24 mL) were suspended in DCM (50 mL). To this was added DMF (1.82 g, 24.87 mmol, 1.93 mL) in 3 portions. The resulting mixture was stirred at 25 °C for 2 h. When gas evolution ceased, the resulting clear solution was concentrated under reduced pressure liquid. The residue was redissolved in hexanes (150 ml), filtered and evaporated in vacuo to give 2-bromobenzyl chloride (5 g, 22.78 mmol, 91.60% yield).

1 H NMR(500MHz,DMSO-d6 )δ 7.44(m,2H),7.71(m,2H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.44 (m, 2H), 7.71 (m, 2H).

GCMS：m/z：計算值217.0；實測值214.0；Rt=7.52min。GCMS: m/z: calculated 217.0; found 214.0; Rt=7.52 min.

步驟2：3-(2-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-(2-Bromobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester

在-78℃下，將雙(三甲基矽基)醯胺化鋰(3.20g，19.14mmol)逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(1.94g，9.11mmol)於THF(50mL)中之經預冷卻之溶液中。在添加完成之後，將其在同一溫度下攪拌1h。此後，一次性添加2-溴苯甲醯氯(2g，9.11mmol)且移除冷卻浴。將所得混合物緩慢升高至20℃且在此溫度下攪拌1h。然後，將其用15%NaHSO4 水溶液(50ml)淬滅且用乙酸乙酯(100ml)萃取。將有機層用20%NaCl(2x50ml)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以得到3-(2-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(3.5g，8.83mmol，96.92%產率)。Lithium bis(trimethylsilyl)amide (3.20 g, 19.14 mmol) was added dropwise to tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate at -78°C (1.94 g, 9.11 mmol) in a precooled solution in THF (50 mL). After the addition was complete, it was stirred at the same temperature for 1 h. After this time, 2-bromobenzyl chloride (2 g, 9.11 mmol) was added in one portion and the cooling bath was removed. The resulting mixture was slowly raised to 20 °C and stirred at this temperature for 1 h. It was then quenched with 15% aqueous NaHSO 4 (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with 20% NaCl (2 x 50 ml), dried over Na 2 SO 4 and evaporated under reduced pressure to give 3-(2-bromobenzyl)-5-methyl-2-pentoxypiperidine 3-butyl pyridine-1-carboxylate (3.5 g, 8.83 mmol, 96.92% yield).

1 H NMR(500MHz,DMSO-d6 )δ 0.85(d,3H),1.47(m,8H),1.80(m,1H),1.91(m,2H),3.13(m,1H),3.29(m,2H),3.72(m,1H),7.18(m,1H),7.25(m,1H),7.49(d,1H),7.72(d,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 0.85(d, 3H), 1.47(m, 8H), 1.80(m, 1H), 1.91(m, 2H), 3.13(m, 1H), 3.29(m , 2H), 3.72 (m, 1H), 7.18 (m, 1H), 7.25 (m, 1H), 7.49 (d, 1H), 7.72 (d, 1H).

LCMS(ESI)：[M-tBu]+ m/z：計算值339.1；實測值340.2；Rt=1.519min。LCMS (ESI): [M-tBu] + m/z: calculated 339.1; found 340.2; Rt=1.519 min.

步驟3：6-(2-溴苯基)-3-甲基-2,3,4,5-四氫吡啶之合成Step 3: Synthesis of 6-(2-Bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine

將3-(2-溴苯甲醯基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(3.5g，8.83mmol)溶解於AcOH(26mL)中且分批添加36% w/w鹽酸水溶液(20.93g，574.10mmol，26.17mL)(產生大量泡沫)。添加完成之後，將所得混合物在100℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(100ml)與DCM(200ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至pH 10且用DCM(2x100ml)萃取。蒸發DCM溶液，將其經Na2 SO4 乾燥且在減壓下蒸發，以 得到6-(2-溴苯基)-3-甲基-2,3,4,5-四氫吡啶(1.2g，4.76mmol，53.88%產率)。3-(2-Bromobenzyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert-butyl ester (3.5 g, 8.83 mmol) was dissolved in AcOH (26 mL) and portioned Aqueous 36% w/w hydrochloric acid (20.93 g, 574.10 mmol, 26.17 mL) was added (profuse foaming occurred). After the addition was complete, the resulting mixture was stirred at 100 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (100ml) and DCM (200ml). The organic layer was separated and discarded. The aqueous layer was basified to pH 10 with 10% NaOH and extracted with DCM (2x100ml). The DCM solution was evaporated, dried over Na2SO4 and evaporated under reduced pressure to give 6-(2-bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine (1.2 g , 4.76 mmol, 53.88% yield).

1 H NMR(400MHz,DMSO-d6 )δ 0.91(d,3H),1.32(m,1H),1.65(m,1H),1.77(m,1H),2.39(m,2H),3.08(m,1H),3.75(m,1H),7.23(m,2H),7.35(m,1H),7.57(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.91(d,3H), 1.32(m,1H), 1.65(m,1H), 1.77(m,1H), 2.39(m,2H), 3.08(m , 1H), 3.75 (m, 1H), 7.23 (m, 2H), 7.35 (m, 1H), 7.57 (d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值251.0；實測值252.2；Rt=0.812min。LCMS (ESI): [M+H] + m/z: calculated 251.0; found 252.2; Rt=0.812 min.

步驟4：2-(2-溴苯基)-5-甲基哌啶之合成Step 4: Synthesis of 2-(2-Bromophenyl)-5-methylpiperidine

在0℃下，將硼氫化鈉(360.10mg，9.52mmol，336.54μL)一次性添加到6-(2-溴苯基)-3-甲基-2,3,4,5-四氫吡啶(1.2g，4.76mmol)於MeOH(10mL)中之經攪拌之溶液中。將所得混合物攪拌10h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2* 40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷，以得到2-(2-溴苯基)-5-甲基哌啶(0.8g，3.15mmol，66.14%產率)。Sodium borohydride (360.10 mg, 9.52 mmol, 336.54 μL) was added in one portion to 6-(2-bromophenyl)-3-methyl-2,3,4,5-tetrahydropyridine ( 1.2 g, 4.76 mmol) in a stirred solution of MeOH (10 mL). The resulting mixture was stirred for 10 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2 * 40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The obtained oil was subjected to 2-(2-bromophenyl)-5-methylpiperidine (0.8 g, 3.15 mmol, 66.14% yield).

1 H NMR(400MHz,DMSO-d6 )δ 0.80(d,3H),1.09(m,2H),1.51(m,1H),1.76(m,2H),2.23(m,1H),2.96(m,1H),3.28(m,1H),3.74(m,1H),7.12(dd,1H),7.33(dd,1H),7.50(d,1H),7.56(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ 0.80(d, 3H), 1.09(m, 2H), 1.51(m, 1H), 1.76(m, 2H), 2.23(m, 1H), 2.96(m , 1H), 3.28 (m, 1H), 3.74 (m, 1H), 7.12 (dd, 1H), 7.33 (dd, 1H), 7.50 (d, 1H), 7.56 (d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值253.0；實測值254.0；Rt=0.800min。LCMS (ESI): [M+H] + m/z: calculated 253.0; found 254.0; Rt=0.800 min.

步驟5：5-[[2-[2-(2-溴苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺之合成Step 5: 5-[[2-[2-(2-Bromophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Synthesis of Amines

將DIPEA(610.20mg，4.72mmol，822.37μL)添加到相應2-(2-溴苯基)-5-甲基哌啶(0.3g，1.18mmol)及2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(246.88mg，1.01mmol，HCl)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(493.68mg，1.30mmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 19* 100 5mkm管柱且以 H2 O-MeOH+NH3 為溶析液混合物)，以得到純的5-[[2-[2-(2-溴苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.4g，898.25μmol，76.10%產率)。DIPEA (610.20 mg, 4.72 mmol, 822.37 μL) was added to the corresponding 2-(2-bromophenyl)-5-methylpiperidine (0.3 g, 1.18 mmol) and 2-[(5-aminocarbamoyl- 3-Pyridinyl)amino]-2-pendoxoacetic acid (246.88 mg, 1.01 mmol, HCl) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (493.68 mg, 1.30 mmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (Waters Sunfire C18 19 * 100 5mkm column with H2O -MeOH+ NH3 as eluent mixture) to give pure 5-[[2-[2-(2- Bromophenyl)-5-methyl-1-piperidinyl]-2-pendoxetyl]amino]pyridine-3-carboxamide (0.4 g, 898.25 μmol, 76.10% yield).

LCMS(ESI)：[M+3H]+ m/z：計算值444.1；實測值447.0；Rt=1.261min。LCMS (ESI): [M+3H] + m/z: calculated 444.1; found 447.0; Rt=1.261 min.

步驟6：5-[[2-[(2R,5S)-2-(2-氰基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物664 )之合成Step 6: 5-[[2-[(2R,5S)-2-(2-cyanophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino ] Synthesis of pyridine-3-carboxamide ( Compound 664 )

將5-[[2-[2-(2-溴苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(40mg，89.83μmol)及氰化鋅(21.10mg，179.65μmol，11.40μL)於DMF(5mL)中之懸浮液除氣且用Ar再填充三次。向此溶液中添加肆(三苯基磷烷)鈀(0)(10.38mg，8.98μmol)。將所得混合物除氣，用Ar再填充且在100℃下攪拌16h。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 19*100 5mkm管柱且以H2 O-MeCN為溶析液混合物)，以得到純的5-[[2-[(2R,5S)-2-(2-氰基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(3.5mg，8.94μmol，9.95%產率)。5-[[2-[2-(2-Bromophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide ( A suspension of 40 mg, 89.83 μmol) and zinc cyanide (21.10 mg, 179.65 μmol, 11.40 μL) in DMF (5 mL) was degassed and refilled three times with Ar. To this solution was added tetra(triphenylphosphine)palladium(0) (10.38 mg, 8.98 μmol). The resulting mixture was degassed, refilled with Ar and stirred at 100 °C for 16 h. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (Waters Sunfire C18 19*100 5mkm column with H2O -MeCN as eluent mixture) to give pure 5-[[2-[(2R,5S)-2- (2-Cyanophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (3.5 mg, 8.94 μmol, 9.95% yield Rate).

1 H NMR(DMSO-d6,600MHz)：δ(ppm)0.93(m,4H),1.10(m,1H),1.86(m,2H),2.07(m,1H),3.77(m,2H),5.34(m,1H),7.46(m,1H),7.56(m,1H),7.61(m,1H),7.70(m,1H),7.84(m,1H),8.16(m,1H),8.49(m,1H),8.76(m,1H),8.86(m,1H),11.19(m,1H)。 1 H NMR (DMSO-d6, 600MHz): δ(ppm) 0.93(m, 4H), 1.10(m, 1H), 1.86(m, 2H), 2.07(m, 1H), 3.77(m, 2H), 5.34(m, 1H), 7.46(m, 1H), 7.56(m, 1H), 7.61(m, 1H), 7.70(m, 1H), 7.84(m, 1H), 8.16(m, 1H), 8.49 (m, 1H), 8.76 (m, 1H), 8.86 (m, 1H), 11.19 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值391.4；實測值392.4；Rt=2.286min。LCMS (ESI): [M+H] + m/z: calculated 391.4; found 392.4; Rt=2.286 min.

實例781. 5-[[2-[(2S,5R)-2-(2-甲氧基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物558)之合成Example 781. 5-[[2-[(2S,5R)-2-(2-methoxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of yl]pyridine-3-carboxamide (Compound 558)

Figure 110128222-A0202-12-2495-490
Figure 110128222-A0202-12-2495-490

步驟1：N-[5-(2-甲氧基苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯之合成Step 1: Synthesis of N-[5-(2-methoxyphenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester

在氬氣氣氛下，將1-溴-2-甲氧基苯(5g，26.73mmol，3.33mL)添加到THF(30mL)及鎂(649.75mg，26.73mmol，373.42μL)之混合物中。向其中添加碘(67.85mg，267.33μmol)且將所得混合物加熱至回流達1h。在-78℃下，將所得混合物冷卻至室溫且逐滴添加到5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(5.70g，26.73mmol)於THF(30mL)中之溶液中。使所得混合物升溫至室溫然後倒入NH4 Cl水溶液中。將所得混合物用EtOAc(2x40ml)萃取。將經合併之有機萃取物用鹽水洗滌，經Na2 SO4 乾燥且蒸發，以獲得N-[5-(2-甲氧基苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(7g，21.78mmol，81.47%產率)，其不經純化即用於下一步驟中。1-Bromo-2-methoxybenzene (5 g, 26.73 mmol, 3.33 mL) was added to a mixture of THF (30 mL) and magnesium (649.75 mg, 26.73 mmol, 373.42 μL) under argon atmosphere. To this was added iodine (67.85 mg, 267.33 μmol) and the resulting mixture was heated to reflux for 1 h. The resulting mixture was cooled to room temperature and added dropwise to tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (5.70 g, 26.73 mmol) in THF (30 mL) at -78 °C in the solution. The resulting mixture was allowed to warm to room temperature and poured into aqueous NH4Cl . The resulting mixture was extracted with EtOAc (2x40ml). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated to give N-[5-(2-methoxyphenyl)-2-methyl-5-pentoxypentyl] 3-Butyl carbamate (7 g, 21.78 mmol, 81.47% yield) was used in the next step without purification.

LCMS(ESI)：[M+H]+ m/z：計算值221.2；實測值222.2；Rt=1.364min。LCMS (ESI): [M+H] + m/z: calculated 221.2; found 222.2; Rt=1.364 min.

步驟2：2-(2-甲氧基苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(2-Methoxyphenyl)-5-methylpiperidine

將N-[5-(2-甲氧基苯基)-2-甲基-5-側氧基戊基]胺甲酸第三丁酯(7g，21.78mmol)溶解於三氟乙酸(24.83g，217.79mmol，16.78mL)中且將所得混合物攪拌1h。向其中添加50%NaOH水溶液，直到pH 11-12。將所得混合物用 CH2Cl2(4x40l)萃取，將經合併之有機層蒸發至乾。將殘餘物再溶解於MeOH(50mL)中且添加硼氫化鈉(823.96mg，21.78mmol，770.05μL)。將所得混合物在20℃下攪拌12h且蒸發。將50%NaOH水溶液添加到殘餘物中。將所得混合物用CH2 Cl2 (4x40ml)萃取，將經合併之有機層蒸發至乾，以獲得2-(2-甲氧基苯基)-5-甲基哌啶(3g，14.61mmol，67.10%產率)，其不經純化即用於下一步驟中。N-[5-(2-Methoxyphenyl)-2-methyl-5-oxypentyl]carbamic acid tert-butyl ester (7 g, 21.78 mmol) was dissolved in trifluoroacetic acid (24.83 g, 217.79 mmol, 16.78 mL) and the resulting mixture was stirred for 1 h. To this was added 50% aqueous NaOH until pH 11-12. The resulting mixture was extracted with CH2Cl2 (4x40l) and the combined organic layers were evaporated to dryness. The residue was redissolved in MeOH (50 mL) and sodium borohydride (823.96 mg, 21.78 mmol, 770.05 μL) was added. The resulting mixture was stirred at 20 °C for 12 h and evaporated. Aqueous 50% NaOH was added to the residue. The resulting mixture was extracted with CH 2 Cl 2 (4×40 ml) and the combined organic layers were evaporated to dryness to give 2-(2-methoxyphenyl)-5-methylpiperidine (3 g, 14.61 mmol, 67.10 % yield), which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d6 )δ 1.10(d,3H),1.22(m,1H),1.48(m,2H),1.52(m,2H),1.76(m,2H),2.98(m,1H)3.75(s,3H),3.77(m,1H),6.88(m,2H),7.15(dd,1H),7.40(d,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ 1.10(d, 3H), 1.22(m, 1H), 1.48(m, 2H), 1.52(m, 2H), 1.76(m, 2H), 2.98(m , 1H) 3.75(s, 3H), 3.77(m, 1H), 6.88(m, 2H), 7.15(dd, 1H), 7.40(d, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值205.2；實測值206.2；Rt=0.762min。LCMS (ESI): [M+H] + m/z: calculated 205.2; found 206.2; Rt=0.762 min.

步驟3：5-[[2-[(2S,5R)-2-(2-甲氧基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物558 )之合成Step 3: 5-[[2-[(2S,5R)-2-(2-methoxyphenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amine Synthesis of base]pyridine-3-carboxamide ( compound 558 )

將2-(2-甲氧基苯基)-5-甲基哌啶(0.2g，974.21μmol)與HATU(407.46mg，1.07mmol)混合於DMF(4mL)中且將所得混合物在20℃下攪拌10min，隨後添加2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(239.28mg，974.21μmol，HCl)。將所得混合物在20℃下攪拌12h。使所得溶液經歷HPLC，以獲得5-[[2-[(2S,5R)-2-(2-甲氧基苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0874g，220.46μmol，22.63%產率)2-(2-Methoxyphenyl)-5-methylpiperidine (0.2 g, 974.21 μmol) was mixed with HATU (407.46 mg, 1.07 mmol) in DMF (4 mL) and the resulting mixture was heated at 20 °C Stir for 10 min, then add 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-pendoxoacetic acid (239.28 mg, 974.21 μmol, HCl). The resulting mixture was stirred at 20 °C for 12 h. The resulting solution was subjected to HPLC to obtain 5-[[2-[(2S,5R)-2-(2-methoxyphenyl)-5-methyl-1-piperidinyl]-2-pendoxyl Acetyl]amino]pyridine-3-carboxamide (0.0874 g, 220.46 μmol, 22.63% yield)

HPLC條件：23% 0.5-6.5min水-乙腈；流速：30ml/min；(裝載泵4ml/min乙腈)；目標質量396；管柱：SunFireC18 100x19mm 5um(L)HPLC conditions: 23% 0.5-6.5min water-acetonitrile; flow rate: 30ml/min; (loading pump 4ml/min acetonitrile); target mass 396; column: SunFireC18 100x19mm 5um (L)

1 H NMR(600MHz,DMSO-d 6 )δ 0.95-1.00(m,3H),1.07-1.38(m,1H),1.67-1.97(m,2H),1.98-2.04(m,1H),2.05-2.21(m,1H),3.14-3.20(m,0.4H),3.55-3.59(m,0.6H),3.60-3.92(m,4H),5.37-5.56(m,1H),6.83-7.03(m,2H),7.12-7.32(m,2H),7.52-7.64(m,1H),8.09-8.20(m,1H),8.36-8.51(m,1H),8.71-8.93(m,2H),10.70-11.33(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ 0.95-1.00(m,3H), 1.07-1.38(m,1H), 1.67-1.97(m,2H), 1.98-2.04(m,1H), 2.05- 2.21(m, 1H), 3.14-3.20(m, 0.4H), 3.55-3.59(m, 0.6H), 3.60-3.92(m, 4H), 5.37-5.56(m, 1H), 6.83-7.03(m ,2H),7.12-7.32(m,2H),7.52-7.64(m,1H),8.09-8.20(m,1H),8.36-8.51(m,1H),8.71-8.93(m,2H),10.70 -11.33 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值396.2；實測值397.2；Rt=2.608min。LCMS (ESI): [M+H] + m/z: calculated 396.2; found 397.2; Rt=2.608 min.

實例782. 5-[[2-[(2R,5S)-2-(2-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物595)之合成Example 782. 5-[[2-[(2R,5S)-2-(2-fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Synthesis of pyridine-3-carboxamide (compound 595)

Figure 110128222-A0202-12-2497-491
Figure 110128222-A0202-12-2497-491

步驟1：6-(2-氟苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(2-fluorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

在氬氣氣氛下，將(2-氟苯基)硼酸(1g，7.15mmol)、3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.71g，7.86mmol)及碳酸銫(6.99g，21.44mmol)混合於二噁烷(30mL)中。添加肆(三苯基磷烷)鈀(0)(99.8%(基於金屬)，Pd 9% min)(247.76mg，214.41μmol)且將所得混合物加熱至100℃達12h。將所得混合物冷卻至室溫且在真空中蒸發。將殘餘物分配於EtOAc(50ml)與水(50ml)之間。收集有機相，將其用鹽水洗滌，經硫酸鈉乾燥且蒸發，以獲得6-(2-氟苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.5g，粗品)，其不經純化即用於下一步驟中。Under argon atmosphere, (2-fluorophenyl)boronic acid (1 g, 7.15 mmol), 3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H- 3-butyl pyridine-1-carboxylate (2.71 g, 7.86 mmol) and cesium carbonate (6.99 g, 21.44 mmol) were mixed in dioxane (30 mL). Four(triphenylphosphine)palladium(0) (99.8% (metal based), Pd 9% min) (247.76 mg, 214.41 μmol) was added and the resulting mixture was heated to 100 °C for 12 h. The resulting mixture was cooled to room temperature and evaporated in vacuo. The residue was partitioned between EtOAc (50ml) and water (50ml). The organic phase was collected, washed with brine, dried over sodium sulfate and evaporated to give 6-(2-fluorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid third Butyl ester (2.5 g, crude) was used in the next step without purification.

LCMS(ESI)：[M-tBu]+ m/z：計算值235.0；實測值236.0；Rt=1.359min。LCMS (ESI): [M-tBu] + m/z: calculated 235.0; found 236.0; Rt=1.359 min.

步驟2：2-(2-氟苯基)-5-甲基哌啶之合成Step 2: Synthesis of 2-(2-Fluorophenyl)-5-methylpiperidine

將6-(2-氟苯基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(2.5g，8.58mmol)溶解於三氟乙酸(9.78g，85.80mmol，6.61mL)中且將所得混合物攪拌1h。向其中添加50%NaOH水溶液，直到pH 11-12。將所得混合物用CH2Cl2(4x40l) 萃取，將經合併之有機層蒸發至乾。將殘餘物再溶解於MeOH(20mL)中且添加硼氫化鈉(324.62mg，8.58mmol，303.38μL)。將所得混合物在20℃下攪拌12h且蒸發。將50%NaOH水溶液添加到殘餘物中。將所得混合物用CH2 Cl2 (4x40ml)萃取，將經合併之有機層蒸發至乾，以獲得2-(2-氟苯基)-5-甲基哌啶(1g，粗品)，其不經純化即用於下一步驟中。6-(2-Fluorophenyl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.5 g, 8.58 mmol) was dissolved in trifluoroacetic acid (9.78 g, 85.80 mmol, 6.61 mL) and the resulting mixture was stirred for 1 h. To this was added 50% aqueous NaOH until pH 11-12. The resulting mixture was extracted with CH2Cl2 (4x40l) and the combined organic layers were evaporated to dryness. The residue was redissolved in MeOH (20 mL) and sodium borohydride (324.62 mg, 8.58 mmol, 303.38 μL) was added. The resulting mixture was stirred at 20 °C for 12 h and evaporated. Aqueous 50% NaOH was added to the residue. The resulting mixture was extracted with CH2Cl2 ( 4x40ml) and the combined organic layers were evaporated to dryness to give 2-(2-fluorophenyl)-5-methylpiperidine (1 g, crude) Purification was used in the next step.

LCMS(ESI)：[M+H]+ m/z：計算值193.2；實測值194.0；Rt=0.698min。LCMS (ESI): [M+H] + m/z: calculated 193.2; found 194.0; Rt=0.698 min.

步驟3：5-[[2-[(2R,5S)-2-(2-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物595 )之合成Step 3: 5-[[2-[(2R,5S)-2-(2-Fluorophenyl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino] Synthesis of pyridine-3-carboxamide ( compound 595 )

將2-(2-氟苯基)-5-甲基哌啶(0.2g，1.03mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(254.19mg，1.03mmol，HCl)及三乙胺(261.80mg，2.59mmol，360.60μL)混合於DMF(5mL)中。在劇烈攪拌之情況下，向其中小批量添加HATU(432.84mg，1.14mmol)且將所得混合物在20℃下攪拌12h。使所得混合物經歷HPLC，以獲得5-[[2-[(2R,5S)-2-(2-氟苯基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0709g，184.44μmol，17.82%產率)。2-(2-Fluorophenyl)-5-methylpiperidine (0.2 g, 1.03 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-side oxy Acetic acid (254.19 mg, 1.03 mmol, HCl) and triethylamine (261.80 mg, 2.59 mmol, 360.60 [mu]L) were mixed in DMF (5 mL). To this was added HATU (432.84 mg, 1.14 mmol) in small batches with vigorous stirring and the resulting mixture was stirred at 20 °C for 12 h. The resulting mixture was subjected to HPLC to obtain 5-[[2-[(2R,5S)-2-(2-fluorophenyl)-5-methyl-1-piperidinyl]-2-pendoxoacetone yl]amino]pyridine-3-carboxamide (0.0709 g, 184.44 μmol, 17.82% yield).

HPLC條件：HPLC conditions:

23% 0.5-6.5min水-乙腈；流速30ml/min(裝載泵4ml/min；乙腈)；目標質量384；管柱SunFireC18 100x19mm 5um(R)23% 0.5-6.5min water-acetonitrile; flow rate 30ml/min (loading pump 4ml/min; acetonitrile); target mass 384; column SunFireC18 100x19mm 5um(R)

1 H NMR(400MHz,DMSO-d 6 )δ 0.89-1.10(m,3H),1.14-1.46(m,1H),1.73-1.98(m,2H),1.99-2.24(m,1.7H),3.19-3.29(m,0.3H),3.57-4.06(m,2H),5.43-5.52(m,1H),7.03-7.25(m,2H),7.26-7.43(m,2H),7.54-7.69(m,1H),8.09-8.29(m,1H),8.33-8.59(m,1H),8.73-9.00(m,2H),10.71-11.46(m,1H)。 1 H NMR (400 MHz, DMSO- d 6 ) δ 0.89-1.10 (m, 3H), 1.14-1.46 (m, 1H), 1.73-1.98 (m, 2H), 1.99-2.24 (m, 1.7H), 3.19 -3.29(m, 0.3H), 3.57-4.06(m, 2H), 5.43-5.52(m, 1H), 7.03-7.25(m, 2H), 7.26-7.43(m, 2H), 7.54-7.69(m , 1H), 8.09-8.29 (m, 1H), 8.33-8.59 (m, 1H), 8.73-9.00 (m, 2H), 10.71-11.46 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值384.2；實測值385.2；Rt=2.588min。LCMS (ESI): [M+H] + m/z: calculated 384.2; found 385.2; Rt=2.588 min.

實例783. 5-[[2-[(4S,4aR,8aR)-4-甲基-3,4,4a,5,6,7,8,8a-八氫-1H-異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物541)、5-[[2-[(4S,4aR,8aS)-4-甲Example 783. 5-[[2-[(4S,4aR,8aR)-4-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2- (Compound 541), 5-[[2-[(4S,4aR,8aS)-4-methyl 基-3,4,4a,5,6,7,8,8a-八氫-1H-異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物543)及5-[[2-[(4S,4aS,8aS)-4-甲基-3,4,4a,5,6,7,8,8a-八氫-1H-異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物542)之合成yl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-2-oxyethanoyl]amino]pyridine-3-carboxylate Amine (Compound 543) and 5-[[2-[(4S,4aS,8aS)-4-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline Synthesis of -2-yl]-2-side oxyacetyl]amino]pyridine-3-carboxamide (compound 542)

Figure 110128222-A0202-12-2499-492
Figure 110128222-A0202-12-2499-492

步驟1：4-甲基-1,2,3,4,4a,5,6,7,8,8a-十氫異喹啉之合成Step 1: Synthesis of 4-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline

將4-甲基-1,2,3,4-四氫異喹啉(1g，5.44mmol，HCl)溶解於MeOH(20mL)中且在高壓力下氫化18h。在反應完成之後，過濾出催化劑。在減壓下蒸發濾液，以得到4-甲基-1,2,3,4,4a,5,6,7,8,8a-十氫異喹啉(1.1g，粗品，HCl)，其不經純化即用於下一步驟中。4-Methyl-1,2,3,4-tetrahydroisoquinoline (1 g, 5.44 mmol, HCl) was dissolved in MeOH (20 mL) and hydrogenated under high pressure for 18 h. After the reaction was complete, the catalyst was filtered off. The filtrate was evaporated under reduced pressure to give 4-methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline (1.1 g, crude, HCl) which was not Purified and used in the next step.

1 H NMR(400MHz,DMSO-d6 )δ 0.89(d,3H),1.65(m,11H),2.92(m,4H),9.03(m,1H) 1 H NMR (400MHz, DMSO-d 6 )δ 0.89(d,3H), 1.65(m,11H), 2.92(m,4H), 9.03(m,1H)

LCMS(ESI)：[M+H]+ m/z：計算值153.2；實測值154.2；Rt=0.674min。LCMS (ESI): [M+H] + m/z: calculated 153.2; found 154.2; Rt=0.674 min.

步驟2：5-[[2-[(4S,4aR,8aR)-4-甲基-3,4,4a,5,6,7,8,8a-八氫-1H-異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物541 )、5-[[2-[(4S,4aR,8aS)-4-甲基-3,4,4a,5,6,7,8,8a-八氫-1H-異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物543 )及5-[[2-[(4S,4aS,8aS)-4-甲基-3,4,4a,5,6,7,8,8a-八氫-1H-異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物542 )之合成Step 2: 5-[[2-[(4S,4aR,8aR)-4-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2- ( Compound 541 ), 5-[[2-[(4S,4aR,8aS)-4-methyl-3,4 ,4a,5,6,7,8,8a-Octahydro-1H-isoquinolin-2-yl]-2-oxyacetyl]amino]pyridine-3-carboxamide ( Compound 543 ) and 5-[[2-[(4S,4aS,8aS)-4-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl] Synthesis of -2-oxyacetoxy]amino]pyridine-3-carboxamide ( compound 542 )

在輕微加熱下，將4-甲基-1,2,3,4,4a,5,6,7,8,8a-十氫異喹啉(0.2g，1.05mmol，HCl)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(220.49mg，1.05mmol)及HATU(521.07mg，1.37mmol)溶解於DMF(7mL)中。在劇烈攪拌及偶爾加熱下，小批量添加DIPEA(408.73mg，3.16mmol，550.85μL)。在反應完成之後，藉由HPLC(0.5-6.5min；水-乙腈；30ml/min；裝載泵4ml/min乙腈；目標質量344；管柱SunFire 19*100mm)純化混合物，以得到呈4種級分之5-[[2-[(4S,4aR,8aR)-4-甲基-3,4,4a,5,6,7,8,8a-八氫-1H-異喹啉-2-基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(50mg，145.18μmol，13.77%產率)。4-Methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline (0.2 g, 1.05 mmol, HCl), 2-[( 5-Aminocarboxy-3-pyridyl)amino]-2-pendoxoacetic acid (220.49 mg, 1.05 mmol) and HATU (521.07 mg, 1.37 mmol) were dissolved in DMF (7 mL). With vigorous stirring and occasional heating, DIPEA (408.73 mg, 3.16 mmol, 550.85 μL) was added in small batches. After completion of the reaction, the mixture was purified by HPLC (0.5-6.5 min; water-acetonitrile; 30 ml/min; loading pump 4 ml/min acetonitrile; target mass 344; column SunFire 19*100 mm) to give 4 fractions 5-[[2-[(4S,4aR,8aR)-4-methyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl] -2-Pendant oxyacetyl]amino]pyridine-3-carboxamide (50 mg, 145.18 μmol, 13.77% yield).

化合物541： 1 H NMR(600MHz,DMSO-d 6 )δ 0.76-0.88(m,3H),1.10-1.35(m,3H),1.36-1.44(m,3H),1.44-1.62(m,2H),1.65-1.91(m,4H),2.82-3.00(m,1H),3.39-3.67(m,1H),3.94-4.27(m,1H),7.59(s,1H),8.15(s,1H),8.43-8.53(m,1H),8.75(s,1H),8.80-8.89(m,1H),11.08(s,1H)。 Compound 541: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.76-0.88 (m, 3H), 1.10-1.35 (m, 3H), 1.36-1.44 (m, 3H), 1.44-1.62 (m, 2H) ,1.65-1.91(m,4H),2.82-3.00(m,1H),3.39-3.67(m,1H),3.94-4.27(m,1H),7.59(s,1H),8.15(s,1H) , 8.43-8.53(m, 1H), 8.75(s, 1H), 8.80-8.89(m, 1H), 11.08(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=2.938min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.2; Rt=2.938 min.

化合物543： 1 H NMR(600MHz,DMSO-d 6 )δ 0.77-0.88(m,3H),1.19-1.36(m,5H),1.43-1.50(m,2H),1.59-1.72(m,2H),1.74-1.92(m,3H),2.72-3.06(m,1H),3.56-3.69(m,1H),3.96-4.10(m,1H),7.59(s,1H),8.14(s,1H),8.45-8.51(m,1H),8.74-8.78(m,1H),8.83-8.89(m,1H),11.05(s,1H)。 Compound 543: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.77-0.88 (m, 3H), 1.19-1.36 (m, 5H), 1.43-1.50 (m, 2H), 1.59-1.72 (m, 2H) ,1.74-1.92(m,3H),2.72-3.06(m,1H),3.56-3.69(m,1H),3.96-4.10(m,1H),7.59(s,1H),8.14(s,1H) , 8.45-8.51(m, 1H), 8.74-8.78(m, 1H), 8.83-8.89(m, 1H), 11.05(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=2.901min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.2; Rt=2.901 min.

化合物542： 1 H NMR(600MHz,DMSO-d 6 )δ 0.74-0.99(m,6H),1.11-1.24(m,3H),1.23-1.46(m,1H),1.46-1.62(m,1H),1.62-1.81(m,2H),1.88(t,1H),2.34-2.40(m,1H),2.78(t,1H),3.58-3.73(m,1H),4.15-4.31(m,1H),7.59(s,1H),8.15(s,1H),8.47(s,1H),8.75(s,1H),8.84(s,1H),11.08(s,1H)。 Compound 542: 1 H NMR (600 MHz, DMSO- d 6 ) δ 0.74-0.99 (m, 6H), 1.11-1.24 (m, 3H), 1.23-1.46 (m, 1H), 1.46-1.62 (m, 1H) ,1.62-1.81(m,2H),1.88(t,1H),2.34-2.40(m,1H),2.78(t,1H),3.58-3.73(m,1H),4.15-4.31(m,1H) , 7.59(s, 1H), 8.15(s, 1H), 8.47(s, 1H), 8.75(s, 1H), 8.84(s, 1H), 11.08(s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值344.2；實測值345.2；Rt=3.014min。LCMS (ESI): [M+H] + m/z: calculated 344.2; found 345.2; Rt=3.014 min.

實例784. 2-[(2S,5S)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基Example 784. 2-[(2S,5S)-2-(3-acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl -3-吡啶基)-2-側氧基乙醯胺(化合物562)之合成、2-[(2R,5R)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物564)之合成及2-[(2R,5S)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物563)之合成Synthesis of -3-pyridyl)-2-oxoacetamide (compound 562), 2-[(2R,5R)-2-(3-acetamidocyclobutyl)-5-methyl- Synthesis and 2-[(2R,5S)- 2-(3-Acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3-pyridyl)-2-oxygen Synthesis of Acetamide (Compound 563)

Figure 110128222-A0202-12-2501-493
Figure 110128222-A0202-12-2501-493

步驟1：N-[3-(5-甲基-2-吡啶基)環丁基]胺甲酸第三丁酯及N-[3-(5-甲基-2-吡啶基)環丁基]胺甲酸第三丁酯之合成Step 1: tert-butyl N-[3-(5-methyl-2-pyridyl)cyclobutyl]carbamate and N-[3-(5-methyl-2-pyridyl)cyclobutyl] Synthesis of tertiary butyl carbamate

向裝備有鐵氟龍塗佈之磁性攪拌棒之玻璃小瓶中添加4,4'-二-第三丁基-2,2'-二吡啶基(232.43mg，866.01μmol)及NiCl2 ˙DME(190.28mg，866.01μmol)及THF(10mL)。將小瓶加蓋且用加熱槍簡單加熱所得懸浮液，直到鎳及配體完全溶解，得到淺綠色溶液。在真空下移除溶劑，以得到經連接之鎳錯合物之微細塗層(顏色為淡綠色)。一旦乾燥，即接連添加2-溴-5-甲基吡啶(2.98g，17.32mmol)(與溶劑一起添加液體芳基溴化物)、[3-(第三丁氧基羰基胺基)環丁基]-三氟硼氫化鉀(4.8g，17.32mmol)、[Ir{dF(CF3 )ppy}2 (dtbpy)]PF6 (485.79mg，433.01μmol)及碳酸銫(8.46g，25.98mmol)。將小瓶加蓋，吹掃且抽真空四次。在惰性氣氛下，引入二噁烷(80mL)。將含有所有試劑之小瓶用石蠟膜進一步密封且在距離兩個26W螢光燈泡約4cm處攪拌5h。然後，透過約2cm* 2cm圓柱形矽藻土塞過濾粗反應混合物，用EtOAc(10-20mL)洗滌。將所得溶液濃縮且藉由管柱層析(Companion combiflash，220g SiO2 ，石油醚/MtBE，其中MtBE為10~50%，流速=100mL/min,Rv=11CV)純化殘餘物。在SFC上(管柱：Chiralpak IC(250 * 20mm，5mkm)；流動相：CO2 -MeOH,90-10.流速：40mL/min；管柱溫度：40℃；波長：215nm。保留時間(順式)=6.84min；保留時間(反式)=8.89min)分離非鏡像異構物。獲得呈白色固體之N-[3-(5-甲基-2-吡啶基)環丁基]胺甲酸第三丁酯(414.64mg，1.58mmol，9.13%產率)及N-[3-(5-甲基-2-吡啶基)環丁基]胺甲酸第三丁酯(622.9mg，2.37mmol，13.71%產率)。To a glass vial equipped with a Teflon-coated magnetic stir bar was added 4,4'-di-tert-butyl-2,2'-dipyridyl (232.43 mg, 866.01 μmol) and NiCl2˙DME ( 190.28 mg, 866.01 μmol) and THF (10 mL). The vial was capped and the resulting suspension was briefly heated with a heat gun until the nickel and ligand were completely dissolved, resulting in a light green solution. The solvent was removed under vacuum to give a fine coating of attached nickel complexes (light green in color). Once dry, 2-bromo-5-methylpyridine (2.98 g, 17.32 mmol) (liquid aryl bromide was added with solvent), [3-(tert-butoxycarbonylamino)cyclobutyl ), were added successively ]-Potassium trifluoroborohydride (4.8 g, 17.32 mmol), [Ir{dF(CF 3 )ppy} 2 (dtbpy)]PF 6 (485.79 mg, 433.01 μmol) and cesium carbonate (8.46 g, 25.98 mmol). The vial was capped, purged and evacuated four times. Under an inert atmosphere, dioxane (80 mL) was introduced. The vials containing all reagents were further sealed with parafilm and stirred for 5 h at approximately 4 cm from two 26W fluorescent bulbs. The crude reaction mixture was then filtered through a plug of approximately 2cm * 2cm cylindrical celite, washed with EtOAc (10-20 mL). The resulting solution was concentrated and the residue was purified by column chromatography (Companion combiflash, 220 g SiO2 , petroleum ether/MtBE, where MtBE was 10-50%, flow rate=100 mL/min, Rv=11 CV). On SFC (column: Chiralpak IC (250*20mm, 5mkm); mobile phase: CO2 -MeOH, 90-10. flow rate: 40mL/min; column temperature: 40°C; wavelength: 215nm. formula) = 6.84 min; retention time (trans) = 8.89 min) to separate the non-spiroisomers. 3-Butyl N-[3-(5-methyl-2-pyridyl)cyclobutyl]carbamate (414.64 mg, 1.58 mmol, 9.13% yield) and N-[3-( 3-butyl 5-methyl-2-pyridyl)cyclobutyl]carbamate (622.9 mg, 2.37 mmol, 13.71% yield).

順式：1 H NMR(400MHz,CDCl3 )δ 1.39(s,9H),2.11(m,2H),2.24(s,3H),2.70(m,2H),3.16(m,1H),4.13(m,1H),4.96(m,1H),6.97(d,1H),7.33(d,1H),8.34(s,1H)。cis: 1 H NMR (400 MHz, CDCl 3 ) δ 1.39 (s, 9H), 2.11 (m, 2H), 2.24 (s, 3H), 2.70 (m, 2H), 3.16 (m, 1H), 4.13 ( m, 1H), 4.96 (m, 1H), 6.97 (d, 1H), 7.33 (d, 1H), 8.34 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值262.2；實測值263.2；Rt=3.491min。LCMS (ESI): [M+H] + m/z: calculated 262.2; found 263.2; Rt=3.491 min.

反式：1 H NMR(400MHz,CDCl3 )δ 1.39(s,9H),2.26(m,5H),2.61(m,2H),3.54(m,1H),4.29(m,1H),4.85(m,1H),7.05(d,1H),7.37(d,1H),8.34(s,1H)。Trans: 1 H NMR (400 MHz, CDCl 3 ) δ 1.39 (s, 9H), 2.26 (m, 5H), 2.61 (m, 2H), 3.54 (m, 1H), 4.29 (m, 1H), 4.85 ( m, 1H), 7.05 (d, 1H), 7.37 (d, 1H), 8.34 (s, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值262.2；實測值263.2；Rt=3.482min。LCMS (ESI): [M+H] + m/z: calculated 262.2; found 263.2; Rt=3.482 min.

步驟2：N-[3-(5-甲基-2-哌啶基)環丁基]胺甲酸第三丁酯之合成Step 2: Synthesis of tert-butyl N-[3-(5-methyl-2-piperidinyl)cyclobutyl]carbamate

在三頸圓底燒瓶中向N-[3-(5-甲基-2-吡啶基)環丁基]胺甲酸第三丁酯(622.9mg，2.37mmol)於MeOH(25mL)中之溶液中添加5R39型Pd(5%於C上)(0.05g)。將反應燒瓶抽真空且用分子氫(239.31mg，118.72mmol)回填且使混合物攪拌隔夜。藉由LCMS及HNMR監測反應進展。透過薄矽膠墊過濾，隨後濃縮且在真空下乾燥，得到呈黃色油狀物之N-[3-(5-甲基-2-哌啶基)環丁基]胺甲酸第三丁酯(0.54g，2.01mmol，84.74%產率)(非鏡像異構物之混合物)。To a solution of tert-butyl N-[3-(5-methyl-2-pyridinyl)cyclobutyl]carbamate (622.9 mg, 2.37 mmol) in MeOH (25 mL) in a three-necked round bottom flask Pd type 5R39 (5% on C) (0.05 g) was added. The reaction flask was evacuated and backfilled with molecular hydrogen (239.31 mg, 118.72 mmol) and the mixture was allowed to stir overnight. The progress of the reaction was monitored by LCMS and HNMR. Filtration through a thin pad of silica gel followed by concentration and drying in vacuo gave tert-butyl N-[3-(5-methyl-2-piperidinyl)cyclobutyl]carbamate (0.54 g) as a yellow oil g, 2.01 mmol, 84.74% yield) (mixture of diastereoisomers).

1 H NMR(500MHz,CDCl3 )δ 0.93(m,4H),1.44(s,9H),1.57(m,2H),1.79(m,2H),1.96(m,2H),2.17(m,4H),2.75(m,2H),3.08(m,1H),4.13(m,1H),4.79(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ 0.93(m, 4H), 1.44(s, 9H), 1.57(m, 2H), 1.79(m, 2H), 1.96(m, 2H), 2.17(m, 4H) ), 2.75(m, 2H), 3.08(m, 1H), 4.13(m, 1H), 4.79(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值268.2；實測值269.4；Rt=1.995min。LCMS (ESI): [M+H] + m/z: calculated 268.2; found 269.4; Rt=1.995 min.

步驟3：2-[2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯之合成Step 3: Synthesis of methyl 2-[2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2-oxoacetate

在0℃下，向N-[3-(5-甲基-2-哌啶基)環丁基]胺甲酸第三丁酯(0.54g，2.01mmol)及三乙胺(244.31mg，2.41mmol，336.51μL)於DCM(25mL)中之溶液中添加2-氯-2-側氧基乙酸甲酯(271.13mg，2.21mmol)。在室溫下攪拌1h之後，將所得混合物過濾且蒸發至乾，以得到呈黃色固體之2-[2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.64g，粗品)，其不經進一步純化即用於下一步驟中。To 3-butyl N-[3-(5-methyl-2-piperidinyl)cyclobutyl]carbamate (0.54 g, 2.01 mmol) and triethylamine (244.31 mg, 2.41 mmol) at 0°C , 336.51 μL) in DCM (25 mL) was added methyl 2-chloro-2-oxoacetate (271.13 mg, 2.21 mmol). After stirring at room temperature for 1 h, the resulting mixture was filtered and evaporated to dryness to give 2-[2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl as a yellow solid Methyl-l-piperidinyl]-2-oxoacetate (0.64 g, crude) was used in the next step without further purification.

LCMS(ESI)：[M-tBu]+ m/z：計算值298.2；實測值299.0；Rt=1.256min。LCMS (ESI): [M-tBu] + m/z: calculated 298.2; found 299.0; Rt=1.256 min.

步驟4：N-[5-[[2-[2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之合成Step 4: N-[5-[[2-[2-[3-(Third-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2-pendantoxy Synthesis of Acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

向2-[2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙酸甲酯(0.64g，1.81mmol)於MeOH(25mL)中之溶液中添加氫氧化鈉珠粒(79.44mg，1.99mmol，37.30μL)。攪拌所得混合物1h。然後，蒸發溶劑且將殘 餘物與EtOH一起再蒸發。此後，將固體溶解於DMF(15mL)中且添加HATU(686.57mg，1.81mmol)，隨後添加N-(5-胺基-3-甲基-2-吡啶基)胺甲酸第三丁酯(403.15mg，1.81mmol)且將所得混合物攪拌12h。將所得混合物倒入到水中，用EtOAc萃取3次，將經合併之有機物用水、鹽水洗滌且蒸發。使殘餘物經歷HPLC(40-65% 2-7min；水-乙腈30ml/min；裝載泵：乙腈；4ml/min；管柱SunFire 19* 100mm)。獲得呈非鏡像異構物之混合物之N-[5-[[2-[2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(490.7mg，899.26μmol，49.80%產率)。白色固體。To methyl 2-[2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2-oxoacetate (0.64 g, 1.81 mmol ) in MeOH (25 mL) was added sodium hydroxide beads (79.44 mg, 1.99 mmol, 37.30 μL). The resulting mixture was stirred for 1 h. Then, the solvent was evaporated and the residue was re-evaporated with EtOH. After this time, the solid was dissolved in DMF (15 mL) and HATU (686.57 mg, 1.81 mmol) was added followed by tert-butyl N-(5-amino-3-methyl-2-pyridyl)carbamate (403.15 mmol) mg, 1.81 mmol) and the resulting mixture was stirred for 12 h. The resulting mixture was poured into water, extracted 3 times with EtOAc, the combined organics were washed with water, brine and evaporated. The residue was subjected to HPLC (40-65% 2-7min; water-acetonitrile 30ml/min; loading pump: acetonitrile; 4ml/min; column SunFire 19 * 100mm). N-[5-[[2-[2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl was obtained as a mixture of diastereoisomers ]-2-Oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (490.7 mg, 899.26 μmol, 49.80% yield). White solid.

1 H NMR(400MHz,CDCl3 )δ 1.00(d,3H),1.41(s,9H),1.49(s,9H),1.85(m,7H),2.29(s,3H),2.95(m,2H),4.18(m,1H),4.71(m,2H),5.27(m,1H),6.78(m,1H),8.10(s,1H),8.36(s,1H),9.39(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 1.00(d,3H), 1.41(s,9H), 1.49(s,9H), 1.85(m,7H), 2.29(s,3H), 2.95(m,2H) ), 4.18(m, 1H), 4.71(m, 2H), 5.27(m, 1H), 6.78(m, 1H), 8.10(s, 1H), 8.36(s, 1H), 9.39(m, 1H) .

LCMS(ESI)：[M+H]+ m/z：計算值545.3；實測值546.4；Rt=3.718min。LCMS (ESI): [M+H] + m/z: calculated 545.3; found 546.4; Rt=3.718 min.

步驟5：N-[5-[[2-[2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯之掌性分離Step 5: N-[5-[[2-[2-[3-(Third-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2-pendoxyl Chiral separation of acetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester

進行兩次連續純化： 第1次SFC。自P2之混合物中分離P1且獲得P4。在此步驟中失去P3。IC(250* 20，5mkm)，CO2 -MeOH，70-30,40ml/min；流速=15ml/min；第2次HPLC。自P4分離P2。IA-II(250* 20，5mkm)，己烷-IPA-MeOH，50-25-25，12ml/min Two consecutive purifications were performed: 1st SFC. P1 was isolated from the mixture of P2 and P4 was obtained. Lose P3 in this step. IC (250 * 20, 5mkm), CO2 -MeOH, 70-30, 40ml/min; flow rate=15ml/min; 2nd HPLC. P2 is isolated from P4. IA-II (250 * 20, 5mkm), Hexane-IPA-MeOH, 50-25-25, 12ml/min

N-[5-[[2-[(2S,5S)-2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(138.86mg，254.48μmol，28.30%產率)之RT=12.854min(IC,CO2-MeOH，70-30，2.0ml/min)N-[5-[[2-[(2S,5S)-2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2- RT=12.854 min (IC, CO2-MeOH) , 70-30, 2.0ml/min)

LCMS(ESI)：[M+H]+ m/z：計算值545.3；實測值546.2；Rt=5.646min。LCMS (ESI): [M+H] + m/z: calculated 545.3; found 546.2; Rt=5.646 min.

N-[5-[[2-[(2R,5R)-2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(97.02mg，177.80μmol， 19.77%產率)之RT=32.773min(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)N-[5-[[2-[(2R,5R)-2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2- Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (97.02 mg, 177.80 μmol, 19.77% yield) RT = 32.773 min (IA, hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)

LCMS(ESI)：[M+H]+ m/z：計算值545.3；實測值546.2；Rt=5.631min。LCMS (ESI): [M+H] + m/z: calculated 545.3; found 546.2; Rt=5.631 min.

N-[5-[[2-[(2R,5S)-2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(25.36mg，46.48μmol，5.17%產率)之RT=9.201min(IA，己烷-IPA-MeOH，50-25-25，0.6ml/min)N-[5-[[2-[(2R,5S)-2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2- RT=9.201 min (IA, hexane- IPA-MeOH, 50-25-25, 0.6ml/min)

LCMS(ESI)：[M+H]+ m/z：計算值545.3；實測值546.2；Rt 5.696=min。LCMS (ESI): [M+H] + m/z: calcd 545.3; found 546.2; Rt 5.696=min.

2-[(2S,5S)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物562 )之合成2-[(2S,5S)-2-(3-acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3- Synthesis of Pyridyl)-2-Pendant Oxyacetamide ( Compound 562 )

向N-[5-[[2-[(2S,5S)-2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(138.86mg，254.48μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(46.39mg，1.27mmol，57.99μL)。攪拌所得混合物2小時。將反應混合物蒸發至乾且懸浮於DCM(10mL)中且添加三乙胺(257.50mg，2.54mmol，354.69μL)。使反應混合物攪拌隔夜。將所得混合物蒸發且使其經歷HPLC(5-30 2-7min水-乙腈；流速：30ml/min；(裝載泵4ml/min；乙腈)；管柱：SunFireC18 100* 19mm 5um(L))，以得到呈白色固體之2-[(2S,5S)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(63.6mg，164.14μmol，64.50%產率)。To N-[5-[[2-[(2S,5S)-2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (138.86 mg, 254.48 μmol) in dioxane (2 mL) was added to dioxane 4.0 M hydrogen chloride solution in alkane (46.39 mg, 1.27 mmol, 57.99 [mu]L). The resulting mixture was stirred for 2 hours. The reaction mixture was evaporated to dryness and suspended in DCM (10 mL) and triethylamine (257.50 mg, 2.54 mmol, 354.69 μL) was added. The reaction mixture was allowed to stir overnight. The resulting mixture was evaporated and subjected to HPLC (5-30 2-7 min water-acetonitrile; flow rate: 30 ml/min; (loading pump 4 ml/min; acetonitrile); column: SunFire C18 100 * 19mm 5um(L)) to give 2-[(2S,5S)-2-(3-acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5- Methyl-3-pyridyl)-2-oxyacetamide (63.6 mg, 164.14 μmol, 64.50% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.88-0.96(m,3H),1.21-1.29(m,1H),1.33-1.42(m,1H),1.61-1.73(m,1H),1.73-1.78(m,3H),1.78-2.00(m,6H),2.00-2.05(m,3H),2.72-3.24(m,2H),3.33-3.87(m,1H),3.91-4.53(m,2H),5.54-5.65(m,2H),7.41-7.49(m,1H),7.93-8.01(m,1H),8.03-8.13(m,1H),10.20-10.36(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.88-0.96(m,3H), 1.21-1.29(m,1H), 1.33-1.42(m,1H), 1.61-1.73(m,1H), 1.73- 1.78(m,3H),1.78-2.00(m,6H),2.00-2.05(m,3H),2.72-3.24(m,2H),3.33-3.87(m,1H),3.91-4.53(m,2H) ), 5.54-5.65(m, 2H), 7.41-7.49(m, 1H), 7.93-8.01(m, 1H), 8.03-8.13(m, 1H), 10.20-10.36(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值387.2；實測值388.4；Rt=1.334min。LCMS (ESI): [M+H] + m/z: calculated 387.2; found 388.4; Rt=1.334 min.

2-[(2R,5R)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶2-[(2R,5R)-2-(3-acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3- Pyridine 基)-2-側氧基乙醯胺(化合物564 )之合成Synthesis of yl)-2-oxoacetamide ( Compound 564 )

向N-[5-[[2-[(2R,5R)-2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(97.02mg，177.80μmol)於二噁烷(2mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(32.41mg，889.00μmol，40.52μL)且將所得混合物攪拌2h。將反應混合物蒸發至乾且懸浮於DCM(10mL)中且添加三乙胺(179.92mg，1.78mmol，247.82μL)。使反應混合物攪拌隔夜。將所得混合物蒸發且使其經歷HPLC(5-30 2-7min水-乙腈；流速：30ml/min；(裝載泵4ml/min；乙腈)；管柱：SunFireC18 100* 19mm 5um(L))，以得到呈白色固體之2-[(2R,5R)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(42.6mg，109.94μmol，61.83%產率)。To N-[5-[[2-[(2R,5R)-2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (97.02 mg, 177.80 μmol) in dioxane (2 mL) was added to dioxane 4.0 M hydrogen chloride solution in alkane (32.41 mg, 889.00 μmol, 40.52 μL) and the resulting mixture was stirred for 2 h. The reaction mixture was evaporated to dryness and suspended in DCM (10 mL) and triethylamine (179.92 mg, 1.78 mmol, 247.82 μL) was added. The reaction mixture was allowed to stir overnight. The resulting mixture was evaporated and subjected to HPLC (5-30 2-7 min water-acetonitrile; flow rate: 30 ml/min; (loading pump 4 ml/min; acetonitrile); column: SunFire C18 100 * 19mm 5um(L)) to give 2-[(2R,5R)-2-(3-acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5- Methyl-3-pyridyl)-2-oxyacetamide (42.6 mg, 109.94 μmol, 61.83% yield).

1 H NMR(600MHz,DMSO-d6 )δ 0.88-0.95(m,3H),1.20-1.27(m,1H),1.32-1.40(m,1H),1.61-1.72(m,1H),1.73-1.77(m,3H),1.78-1.98(m,6H),2.00-2.05(m,3H),2.70-3.20(m,2H),3.33-3.85(m,1H),3.91-4.53(m,2H),5.55-5.63(m,2H),7.41-7.49(m,1H),7.95-8.01(m,1H),8.05-8.11(m,1H),10.24-10.38(m,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ 0.88-0.95(m,3H), 1.20-1.27(m,1H), 1.32-1.40(m,1H), 1.61-1.72(m,1H), 1.73- 1.77(m, 3H), 1.78-1.98(m, 6H), 2.00-2.05(m, 3H), 2.70-3.20(m, 2H), 3.33-3.85(m, 1H), 3.91-4.53(m, 2H ), 5.55-5.63(m, 2H), 7.41-7.49(m, 1H), 7.95-8.01(m, 1H), 8.05-8.11(m, 1H), 10.24-10.38(m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值387.2；實測值388.4；Rt=1.339min。LCMS (ESI): [M+H] + m/z: calculated 387.2; found 388.4; Rt=1.339 min.

2-[(2R,5S)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(化合物563 )之合成2-[(2R,5S)-2-(3-acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5-methyl-3- Synthesis of Pyridyl)-2-Pendant Oxyacetamide ( Compound 563 )

向N-[5-[[2-[(2R,5S)-2-[3-(第三丁氧基羰基胺基)環丁基]-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁酯(25.36mg，46.48μmol)於二噁烷(1mL)中之溶液中添加於二噁烷中之4.0M氯化氫溶液(8.47mg，232.38μmol，10.59μL)。攪拌所得混合物2小時。將反應混合物蒸發至乾且懸浮於DCM(5mL)中且添加三乙胺(47.03mg，464.75μmol，64.78μL)。使反應混合物攪拌隔夜。將所得混合物蒸發且使其經歷HPLC(5-30 2-7min水-乙腈；流速： 30ml/min；(裝載泵4ml/min；乙腈)；管柱：SunFireC18 100* 19mm 5um(L))，以獲得呈白色固體之2-[(2R,5S)-2-(3-乙醯胺基環丁基)-5-甲基-1-哌啶基]-N-(6-胺基-5-甲基-3-吡啶基)-2-側氧基乙醯胺(10mg，25.81μmol，55.53%產率)。To N-[5-[[2-[(2R,5S)-2-[3-(tert-butoxycarbonylamino)cyclobutyl]-5-methyl-1-piperidinyl]-2 - Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert-butyl ester (25.36 mg, 46.48 μmol) in dioxane (1 mL) was added to dioxane 4.0 M hydrogen chloride solution in alkane (8.47 mg, 232.38 μmol, 10.59 μL). The resulting mixture was stirred for 2 hours. The reaction mixture was evaporated to dryness and suspended in DCM (5 mL) and triethylamine (47.03 mg, 464.75 μmol, 64.78 μL) was added. The reaction mixture was allowed to stir overnight. The resulting mixture was evaporated and subjected to HPLC (5-30 2-7min water-acetonitrile; flow rate: 30ml/min; (loading pump 4ml/min; acetonitrile); column: SunFireC18 100 * 19mm 5um(L)) to give 2-[(2R,5S)-2-(3-acetamidocyclobutyl)-5-methyl-1-piperidinyl]-N-(6-amino-5- Methyl-3-pyridyl)-2-oxyacetamide (10 mg, 25.81 μmol, 55.53% yield).

1 H NMR(500MHz,DMSO-d6 +CCl4 )δ 0.80-0.93(m,3H),1.22-1.31(m,1H),1.45-1.64(m,4H),1.72-1.79(m,3H),1.83-2.02(m,4H),2.03-2.06(m,3H),2.08-2.30(m,1H),2.68-2.85(m,1H),3.40-3.87(m,1H),3.98-4.16(m,1H),4.24-4.59(m,1H),5.56-5.69(m,2H),7.42-7.60(m,1H),7.98-8.05(m,1H),8.06-8.15(m,1H),10.28-10.49(m,1H)。 1 H NMR (500MHz, DMSO-d 6 +CCl 4 )δ 0.80-0.93 (m, 3H), 1.22-1.31 (m, 1H), 1.45-1.64 (m, 4H), 1.72-1.79 (m, 3H) ,1.83-2.02(m,4H),2.03-2.06(m,3H),2.08-2.30(m,1H),2.68-2.85(m,1H),3.40-3.87(m,1H),3.98-4.16( m,1H),4.24-4.59(m,1H),5.56-5.69(m,2H),7.42-7.60(m,1H),7.98-8.05(m,1H),8.06-8.15(m,1H), 10.28-10.49 (m, 1H).

LCMS(ESI)：[M+H]+ m/z：計算值387.2；實測值388.4；Rt=1.621min。LCMS (ESI): [M+H] + m/z: calculated 387.2; found 388.4; Rt=1.621 min.

實例785.N -(6-胺基-5-甲基吡啶-3-基)-2-(2-(6-胺基螺[3 .3 ]庚-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物773)之合成Example 785. N- (6-Amino-5-methylpyridin- 3 -yl)-2-(2-(6-aminospiro[ 3.3 ]hept-2-yl)-5-methylpiperin Synthesis of pyridin-1-yl)-2-oxoacetamide (compound 773)

Figure 110128222-A0202-12-2507-494
Figure 110128222-A0202-12-2507-494

步驟1：外消旋-(2R,5S)-2-(6-羥基螺[3.3]庚-2-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of racemic-(2R,5S)-2-(6-hydroxyspiro[3.3]hept-2-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向6-[(2R,5S )-5-甲基-2-哌啶基]螺[3 .3 ]庚-2-醇(3.5g，16.72mmol)於THF(100mL)中之溶液中添加TEA(3.38g，33.44mmol，4.66mL)，隨後添加二碳酸二-第三丁酯(3.65g，16.72mmol，3.84mL)。將反應混合物在25℃下攪拌13h且蒸發。將殘餘物溶解於水(150ml)中且用DCM(3*70ml)萃取。將有機萃取物用水及鹽水洗滌，然後經Na2 SO4 乾燥且蒸發，以得到呈黃色油狀物之 (2R,5S )-2-(2-羥基螺[3 .3 ]庚-6-基)-5-甲基哌啶-1-甲酸第三丁 酯(4.8g，粗品)。To a solution of 6-[( 2R,5S )-5-methyl-2-piperidinyl]spiro[ 3.3 ]heptan- 2 -ol (3.5 g, 16.72 mmol) in THF (100 mL) was added TEA (3.38 g, 33.44 mmol, 4.66 mL) followed by the addition of di-tert-butyl dicarbonate (3.65 g, 16.72 mmol, 3.84 mL). The reaction mixture was stirred at 25 °C for 13 h and evaporated. The residue was dissolved in water (150ml) and extracted with DCM (3*70ml). The organic extracts were washed with water and brine, then dried over Na2SO4 and evaporated to give ( 2R,5S )-2-( 2 -hydroxyspiro[ 3.3 ]hept-6-yl as a yellow oil )-3- butyl 5-methylpiperidine-1- carboxylate (4.8 g, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.86(d,3H),1.43(m,3H),1.51(s,9H),1.88(m,9H),2.26(m,1H),2.42(m,1H),2.62(m,1H),2.89(m,1H),3.65(m,1H),4.14(m,2H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.86(d,3H), 1.43(m,3H), 1.51(s,9H), 1.88(m,9H), 2.26(m,1H), 2.42( m, 1H), 2.62 (m, 1H), 2.89 (m, 1H), 3.65 (m, 1H), 4.14 (m, 2H).

LCMS(ESI)：[M-Boc]+ m/z：計算值209.4；實測值210.2；Rt=1.494min。LCMS (ESI): [M-Boc] + m/z: calculated 209.4; found 210.2; Rt=1.494 min.

步驟2：外消旋-(2R,5S)-5-甲基-2-(6-((甲基磺醯基)氧基)螺[3.3]庚-2-基)哌啶-1-甲酸第三丁酯之合成Step 2: Racemic-(2R,5S)-5-methyl-2-(6-((methylsulfonyl)oxy)spiro[3.3]hept-2-yl)piperidine-1-carboxylic acid Synthesis of tertiary butyl ester

向(2R,5S )-2-(2-羥基螺[3 .3 ]庚-6-基)-5-甲基哌啶-1-甲酸第三丁 酯(4.8g，15.51mmol)於DCM(150mL)中之溶液中添加TEA(2.35g，23.27mmol，3.24mL)，隨後添加甲磺醯氯(1.25g，10.91mmol，844.59μL)。將反應混合物在25℃下攪拌12h。將反應混合物用水(3*100ml)洗滌。將有機萃取物用鹽水洗滌，然後經Na2 SO4 乾燥且蒸發，以得到呈黃色油狀物之(2R,5S )-5-甲基-2-(2-甲基磺醯基氧基螺[3 .3 ]庚-6-基)哌啶-1-甲酸第三丁 酯(5.6g，粗品)。To ( 2R,5S )-2-( 2 -hydroxyspiro[ 3.3 ]hept-6-yl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (4.8 g, 15.51 mmol) in DCM ( To a solution in 150 mL) was added TEA (2.35 g, 23.27 mmol, 3.24 mL) followed by mesylate chloride (1.25 g, 10.91 mmol, 844.59 μL). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was washed with water (3*100ml). The organic extracts were washed with brine, then dried over Na2SO4 and evaporated to give ( 2R,5S )-5-methyl-2-(2-methylsulfonyloxyspiro as a yellow oil [ 3.3 ]Hept- 6 -yl)piperidine-1-carboxylic acid tert- butyl ester (5.6 g, crude).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.93(d,3H),1.24(m,2H),1.43(s,9H),1.69(m,3H),1.93(m,2H),2.12(m,1H),2.26(m,2H),2.46(m,2H),2.54(m,2H),2.88(m,1H),2.94(s,3H),3.65(m,1H),4.05(m,1H),4.86(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.93(d, 3H), 1.24(m, 2H), 1.43(s, 9H), 1.69(m, 3H), 1.93(m, 2H), 2.12( m, 1H), 2.26(m, 2H), 2.46(m, 2H), 2.54(m, 2H), 2.88(m, 1H), 2.94(s, 3H), 3.65(m, 1H), 4.05(m , 1H), 4.86 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值287.4；實測值288.2；Rt=1.658min。LCMS (ESI): [M-Boc] + m/z: calculated 287.4; found 288.2; Rt=1.658 min.

步驟3：外消旋-(2R,5S)-2-(6-疊氮基螺[3.3]庚-2-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 3: Synthesis of rac-(2R,5S)-2-(6-azidospiro[3.3]hept-2-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(2R,5S )-5-甲基-2-(2-甲基磺醯基氧基螺[3 .3 ]庚-6-基)哌啶-1-甲酸第三丁 酯(3g，7.74mmol)於DMF(10mL)中之溶液中添加疊氮化鈉(1.51g，23.22mmol，816.10μL)。將反應混合物在90℃下攪拌48h。將反應混合物用水(80ml)稀釋且將產物用EtOAc(2*100ml)萃取。將經合併之有機層用水(3*50ml)及鹽水洗滌，經Na2 SO4 乾燥。蒸發EtOAc，以得到粗品(2R,5S )-2-(2-疊氮基螺[3 .3 ]庚-6- 基)-5-甲基哌啶-1-甲酸第三丁 酯(2g，5.98mmol，77.25%產率)。To ( 2R,5S )-5-methyl-2-(2-methylsulfonyloxyspiro[ 3.3 ]hept-6-yl)piperidine-1-carboxylic acid tert- butyl ester ( 3 g, 7.74 g mmol) in DMF (10 mL) was added sodium azide (1.51 g, 23.22 mmol, 816.10 [mu]L). The reaction mixture was stirred at 90 °C for 48 h. The reaction mixture was diluted with water (80ml) and the product was extracted with EtOAc (2*100ml). The combined organic layers were washed with water (3*50ml) and brine, dried over Na2SO4 . Evaporation of EtOAc to give crude ( 2R,5S )-2-( 2 -azidospiro[ 3.3 ]hept-6-yl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (2 g, 5.98 mmol, 77.25% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.92(d,3H),1.25(m,2H),1.43(s,9H),1.75(m,5H),2.03(m,3H),2.22(m,1H),2.38(m,1H),2.65(m,1H),2.93(m,2H),3.68(m,2H),4.04(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.92(d,3H), 1.25(m,2H), 1.43(s,9H), 1.75(m,5H), 2.03(m,3H), 2.22( m, 1H), 2.38 (m, 1H), 2.65 (m, 1H), 2.93 (m, 2H), 3.68 (m, 2H), 4.04 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值234.4；實測值235.2；Rt=1.510min。LCMS (ESI): [M-Boc] + m/z: calculated 234.4; found 235.2; Rt=1.510 min.

步驟4：外消旋-(2R,5S)-2-(6-疊氮基螺[3.3]庚-2-基)-5-甲基哌啶之合成Step 4: Synthesis of Racemic-(2R,5S)-2-(6-azidospiro[3.3]hept-2-yl)-5-methylpiperidine

向(2S,5R )-2-(2-疊氮基螺[3 .3 ]庚-6-基)-5-甲基哌啶-1-甲酸第三丁 酯(1.8g，5.38mmol)於DCM(15mL)中之溶液中分批添加於二噁烷中之4.0M氯化氫溶液(1.96g，53.82mmol，2.45mL)。將混合物在25℃下攪拌12h。將反應混合物蒸發，以得到(2S,5R )-2-(2-疊氮基螺[3 .3 ]庚-6-基)-5-甲基哌啶(0.8g，2.95mmol，54.89%產率，HCl)。To ( 2S,5R )-2-( 2 -azidospiro[ 3.3 ]hept-6-yl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (1.8 g, 5.38 mmol) was added A solution of 4.0 M hydrogen chloride in dioxane (1.96 g, 53.82 mmol, 2.45 mL) was added portionwise to a solution in DCM (15 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was evaporated to give ( 2S,5R )-2-( 2 -azidospiro[ 3.3 ]hept-6-yl)-5-methylpiperidine (0.8 g, 2.95 mmol, 54.89% yield rate, HCl).

LCMS(ESI)：[M]+ m/z：計算值234.4；實測值235.2；Rt=1.085min。LCMS (ESI): [M] + m/z: calculated 234.4; found 235.2; Rt=1.085min.

步驟5：外消旋-(5-(2-((2R,5S)-2-(6-疊氮基螺[3.3]庚-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 5: Racemic-(5-(2-((2R,5S)-2-(6-azidospiro[3.3]hept-2-yl)-5-methylpiperidin-1-yl) Synthesis of -2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

向(2S,5R )-2-(2-疊氮基螺[3 .3 ]庚-6-基)-5-甲基哌啶(0.80.g，2.95mmol，HCl)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(872.35mg，2.95mmol)及TEA(2.09g，20.68mmol，2.88mL)於DMF(3mL)中之溶液中分批添加HATU(1.24g，3.25mmol)。將混合物在25℃下攪拌2h。將反應混合物用水(50ml)稀釋且將產物用EtOAc(3*25ml)萃取。將經合併之有機層用水、鹽水洗滌且經Na2 SO4 乾燥。蒸發溶劑，以得到N -[5-[[2-[(2S,5R )-2-(2-疊氮基螺[3 .3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1.5g，粗品)。To ( 2S,5R )-2-( 2 -azidospiro[ 3.3 ]hept-6-yl)-5-methylpiperidine (0.80.g, 2.95 mmol, HCl), 2-[[6 -( Third- butoxycarbonylamino)-5-methyl-3-pyridyl]amino]-2-oxoacetic acid (872.35 mg, 2.95 mmol) and TEA (2.09 g, 20.68 mmol, 2.88 mL) ) in DMF (3 mL) was added portionwise HATU (1.24 g, 3.25 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50ml) and the product was extracted with EtOAc (3*25ml). The combined organic layers were washed with water, brine and dried over Na2SO4 . The solvent was evaporated to give N- [5-[[2-[( 2S,5R )-2-( 2 -azidospiro[ 3.3 ]hept-6-yl)-5-methyl-1-piperidine Peridyl]-2-oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (1.5 g, crude).

LCMS(ESI)：[M]+ m/z：計算值511.4；實測值512.2；Rt=0.849min。LCMS (ESI): [M] + m/z: calculated 511.4; found 512.2; Rt=0.849 min.

步驟6：外消旋-(5-(2-((2R,5S)-2-(6-胺基螺[3.3]庚-2-基)-5-甲基哌啶-1-基)-2-側氧Step 6: Racemic-(5-(2-((2R,5S)-2-(6-aminospiro[3.3]hept-2-yl)-5-methylpiperidin-1-yl)- 2-side oxygen 基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Synthesis of tert-butyl acetamido)-3-methylpyridin-2-yl)carbamate

將N -[5-[[2-[(2S,5R )-2-(2-疊氮基螺[3 .3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1.5g，2.93mmol)及乾燥的487型鈀(10%於碳上)(312.01mg，2.93mmol)於MeOH(50mL)中之混合物在氫氣氣氛、25℃下攪拌15h。過濾出催化劑，在真空中蒸發濾液。將殘餘物溶解於水(50ml)中且用DCM(2*50ml)萃取。將有機層用鹽水(40ml)洗滌，經Na2 SO4 乾燥，以得到N -[5-[[2-[(2S,5R )-2-(2-胺基螺[3 .3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1g，粗品)。 N- [5-[[2-[( 2S,5R )-2-( 2 -azidospiro[ 3.3 ]hept-6-yl)-5-methyl-1-piperidinyl]- 2-Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (1.5 g, 2.93 mmol) and dry palladium type 487 (10% on carbon) ( A mixture of 312.01 mg, 2.93 mmol) in MeOH (50 mL) was stirred under a hydrogen atmosphere at 25 °C for 15 h. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in water (50ml) and extracted with DCM (2*50ml). The organic layer was washed with brine (40ml), dried over Na2SO4 to give N- [ 5 -[[2-[( 2S,5R )-2-( 2 -aminospiro[ 3.3 ]heptane- 6-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (1 g, crude ).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.99(d,3H),2.26(m,2H),1.49(s,9H),1.85(m,18H),2.86(s,3H),4.54(m,1H),7.26(m,1H),8.02(m,1H),8.35(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.99(d,3H), 2.26(m,2H), 1.49(s,9H), 1.85(m,18H), 2.86(s,3H), 4.54( m, 1H), 7.26 (m, 1H), 8.02 (m, 1H), 8.35 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值485.4；實測值486.2；Rt=1.084min。LCMS (ESI): [M] + m/z: calculated 485.4; found 486.2; Rt=1.084 min.

步驟7：N-(6-胺基-5-甲基吡啶-3-基)-2-(2-(6-胺基螺[3.3]庚-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺(化合物773 )之合成Step 7: N-(6-Amino-5-methylpyridin-3-yl)-2-(2-(6-aminospiro[3.3]hept-2-yl)-5-methylpiperidine- Synthesis of 1-yl)-2-oxyacetamide ( compound 773 )

向N -[5-[[2-[(2S,5R )-2-(2-胺基螺[3 .3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(0.6g，1.24mmol)於DCM(10mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(450.49mg，12.36mmol，563.11μL)。將反應混合物在25℃下攪拌12h。將溶劑蒸發。藉由反相HPLC(30-65% 0-5min H2 O/MeOH 0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以得到呈非鏡像異構物之混合物之N -(6-胺基-5-甲基-3-吡啶基)-2-[(2S,5R )-2-(2-胺基螺[3 .3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯胺(28mg，72.63μmol，5.88%產率)。To N- [5-[[2-[( 2S,5R )-2-( 2 -aminospiro[ 3.3 ]hept-6-yl)-5-methyl-1-piperidinyl]-2 -Pendant oxyacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (0.6 g, 1.24 mmol) in DCM (10 mL) was added to two 4.0 M hydrogen chloride solution in oxane (450.49 mg, 12.36 mmol, 563.11 [mu]L). The reaction mixture was stirred at 25 °C for 12 h. The solvent was evaporated. The residue was purified by reverse phase HPLC (30-65% 0-5min H2O /MeOH 0.1% NH4OH , flow rate: 30ml/min (loading pump 4ml/min MeOH) Column: YMC Triart C18 100x20mm, 5um) , to give N- (6-amino-5-methyl-3-pyridyl)-2-[( 2S,5R )-2-(2-aminospiro[ 3 ] as a mixture of diastereoisomers .3 ]Hept-6-yl)-5-methyl-1-piperidinyl]-2-oxyacetamide (28 mg, 72.63 μmol, 5.88% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.85-0.93(m,3H),1.19-1.32(m,2H),1.39-1.51(m,1H),1.51-1.60(m,2H),1.61-1.72(m,2H),1.73-1.84(m,3H),1.86-1.98(m,2H),1.98-2.01(m,3H),2.01-2.16(m,2H),2.20-2.30(m,1H),2.65-2.86(m, 2H),2.97-3.13(m,1H),3.23-3.26(m,0.6H),3.67-3.73(m,0.4H),3.90-4.40(m,1H),5.56-5.62(m,2H),7.40-7.49(m,1H),7.94-8.04(m,1H),10.18-10.44(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.85-0.93(m,3H), 1.19-1.32(m,2H), 1.39-1.51(m,1H), 1.51-1.60(m,2H) ,1.61-1.72(m,2H),1.73-1.84(m,3H),1.86-1.98(m,2H),1.98-2.01(m,3H),2.01-2.16(m,2H),2.20-2.30( m,1H),2.65-2.86(m,2H),2.97-3.13(m,1H),3.23-3.26(m,0.6H),3.67-3.73(m,0.4H),3.90-4.40(m,1H ), 5.56-5.62 (m, 2H), 7.40-7.49 (m, 1H), 7.94-8.04 (m, 1H), 10.18-10.44 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值385.4；實測值386.2；Rt=1.211min。LCMS (ESI): [M] + m/z: calculated 385.4; found 386.2; Rt=1.211 min.

實例786. 6-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)螺[3.3]庚-2-甲醯胺(化合物812)之合成Example 786. 6-(1-(2-((6-amino-5-methylpyridin-3-yl)amino)-2-oxyethanoyl)-5-methylpiperidine-2 -Synthesis of spiro[3.3]hept-2-carboxamide (compound 812)

Figure 110128222-A0202-12-2511-495
Figure 110128222-A0202-12-2511-495

步驟1：外消旋-(2R,5S)-2-(6-氰基螺[3.3]庚-2-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 1: Synthesis of rac-(2R,5S)-2-(6-cyanospiro[3.3]hept-2-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(2R,5S )-5-甲基-2-(2-甲基磺醯基氧基螺[3 .3 ]庚-6-基)哌啶-1-甲酸第三丁 酯(1.5g，3.87mmol)於DMSO(7mL)中之溶液中添加氰化鉀(756.17mg，11.61mmol)。將反應混合物在85℃下攪拌36h。將反應混合物用水(70ml)稀釋且將產物用EtOAc(2*40ml)萃取。將經合併之有機層用水(3*30ml)及鹽水洗滌，經Na2 SO4 乾燥。蒸發EtOAc，以得到粗品(2R,5S )-2-(6-氰基螺[3 .3 ]庚-2-基)-5-甲基哌啶-1-甲酸第三丁 酯(1g，3.14mmol，81.13%產率)。To ( 2R,5S )-5-methyl-2-( 2 -methylsulfonyloxyspiro[ 3.3 ]hept-6-yl)piperidine-1-carboxylic acid tert- butyl ester (1.5 g, 3.87 mmol) in DMSO (7 mL) was added potassium cyanide (756.17 mg, 11.61 mmol). The reaction mixture was stirred at 85 °C for 36 h. The reaction mixture was diluted with water (70ml) and the product was extracted with EtOAc (2*40ml). The combined organic layers were washed with water (3*30ml) and brine, dried over Na2SO4 . Evaporation of EtOAc to give crude ( 2R,5S )-2-(6-cyanospiro[ 3.3 ]hept- 2 -yl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (1 g, 3.14 mmol, 81.13% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.91(d,3H),1.31(m,3H),1.42(s,9H),1.67(m,5H),1.96(m,1H),2.05(m,1H),2.30(m,4H),2.59(m,1H),2.86(m,1H),3.65(m,1H),4.08(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.91(d,3H), 1.31(m,3H), 1.42(s,9H), 1.67(m,5H), 1.96(m,1H), 2.05( m, 1H), 2.30 (m, 4H), 2.59 (m, 1H), 2.86 (m, 1H), 3.65 (m, 1H), 4.08 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值218.4；實測值219.2；Rt=1.606min。LCMS (ESI): [M-Boc] + m/z: calculated 218.4; found 219.2; Rt=1.606 min.

步驟2：外消旋-(2R,5S)-2-(6-胺甲醯基螺[3.3]庚-2-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of racemic-(2R,5S)-2-(6-aminocarboxyspiro[3.3]hept-2-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

在60℃下，向(2R,5S )-2-(6-氰基螺[3 .3 ]庚-2-基)-5-甲基哌啶-1-甲酸第三丁 酯(900mg，2.83mmol)及99%無水碳酸鉀(781.19mg，5.65mmol，341.13μL)於DMSO(6mL)中之經攪拌之溶液中逐滴添加35%過氧化氫(2.97g，87.32mmol，2.70mL)。將反應混合物在80℃下攪拌24h。將反應混合物用水(25ml)稀釋且用EtOAc(3*25ml)萃取。將經合併之有機層經Na2 SO4 乾燥。在真空中蒸發溶劑，以得到(2R,5S )-2-(2-胺甲醯基螺[3 .3 ]庚-6-基)-5-甲基哌啶-1-甲酸第三丁 酯(1g，粗品)。To ( 2R,5S )-2-(6-cyanospiro[ 3.3 ]hept- 2 -yl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (900 mg, 2.83 mmol) and 99% anhydrous potassium carbonate (781.19 mg, 5.65 mmol, 341.13 μL) in DMSO (6 mL) was added dropwise 35% hydrogen peroxide (2.97 g, 87.32 mmol, 2.70 mL). The reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was diluted with water (25ml) and extracted with EtOAc (3*25ml). The combined organic layers were dried over Na2SO4 . The solvent was evaporated in vacuo to give ( 2R,5S )-2-( 2 -aminocarboxyspiro[ 3.3 ]hept-6-yl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (1 g, crude).

LCMS(ESI)：[M-Boc]+ m/z：計算值236.4；實測值237.2；Rt=1.407min。LCMS (ESI): [M-Boc] + m/z: calculated 236.4; found 237.2; Rt=1.407 min.

步驟3：外消旋-6-((2R,5S)-5-甲基哌啶-2-基)螺[3.3]庚-2-甲醯胺之合成Step 3: Synthesis of racemic-6-((2R,5S)-5-methylpiperidin-2-yl)spiro[3.3]hept-2-carboxamide

向(2R,5S )-2-(2-胺甲醯基螺[3 .3 ]庚-6-基)-5-甲基哌啶-1-甲酸第三丁 酯(1g，2.97mmol)於DCM(10mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(1.08g，29.72mmol，1.35mL)。將反應混合物在25℃下攪拌12h。將溶劑蒸發至乾，以得到6-[(2R,5S )-5-甲基-2-哌啶基]螺[3 .3 ]庚-2-甲醯胺(0.7g，粗品，HCl)。To ( 2R,5S )-2-( 2 -aminocarboxyspiro[ 3.3 ]hept-6-yl)-5-methylpiperidine-1-carboxylic acid tert- butyl ester (1 g, 2.97 mmol) was added To the stirred solution in DCM (10 mL) was added a 4.0 M solution of hydrogen chloride in dioxane (1.08 g, 29.72 mmol, 1.35 mL). The reaction mixture was stirred at 25 °C for 12 h. The solvent was evaporated to dryness to give 6-[( 2R,5S )-5-methyl-2-piperidinyl]spiro[ 3.3 ]hept- 2 -carboxamide (0.7 g, crude, HCl).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.83(d,3H),1.23(m,2H),1.87(m,8H),2.14(m,2H),2.46(m,3H),2.73(m,2H),2.95(m,1H),5.45(m,2H),9.04(m,1H)。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.83(d,3H), 1.23(m,2H), 1.87(m,8H), 2.14(m,2H), 2.46(m,3H), 2.73 (m, 2H), 2.95 (m, 1H), 5.45 (m, 2H), 9.04 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值236.4；實測值237.2；Rt=0.545min。LCMS (ESI): [M] + m/z: calculated 236.4; found 237.2; Rt=0.545 min.

步驟4：外消旋-(5-(2-((2R,5S)-2-(6-胺甲醯基螺[3.3]庚-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 4: Racemic-(5-(2-((2R,5S)-2-(6-aminocarboxyspiro[3.3]hept-2-yl)-5-methylpiperidin-1-yl )-2-oxyacetamido)-3-methylpyridin-2-yl)carbamic acid tert-butyl ester

向6-[(2R,5S )-5-甲基-2-哌啶基]螺[3 .3 ]庚-2-甲醯胺(0.7g，2.96mmol)、2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(874.56 mg，2.96mmol)及TEA(2.10g，20.73mmol，2.89mL)於DMF(3mL)中之溶液中分批添加HATU(1.24g，3.26mmol)。將混合物在25℃下攪拌2h。將反應混合物用水(50ml)稀釋且將產物用EtOAc(3*25ml)萃取。將經合併之有機層用水、鹽水洗滌且經Na2 SO4 乾燥。蒸發溶劑，以得到N -[5-[[2-[(2R,5S )-2-(2-胺甲醯基螺[3 .3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1g，粗品)。To 6-[( 2R,5S )-5-methyl-2-piperidinyl]spiro[ 3.3 ]hept- 2 -carboxamide (0.7 g, 2.96 mmol), 2-[[6-( th Tributoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-side oxyacetic acid (874.56 mg, 2.96 mmol) and TEA (2.10 g, 20.73 mmol, 2.89 mL) in DMF To the solution in (3 mL) was added HATU (1.24 g, 3.26 mmol) portionwise. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50ml) and the product was extracted with EtOAc (3*25ml). The combined organic layers were washed with water, brine and dried over Na2SO4 . The solvent was evaporated to give N- [5-[[2-[( 2R,5S )-2-( 2 -aminocarboxyspiro[ 3.3 ]heptan-6-yl)-5-methyl-1- Piperidinyl]-2-oxoacetyl]amino]-3-methyl-2-pyridyl]carbamic acid tert- butyl ester (1 g, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.98(d,3H),1.23(m,4H),1.47(s,9H),1.86(m,6H),2.02(m,2H),2.27(s,3H),2.85(m,4H),2.98(m,2H),3.27(m,1H),4.57(m,1H),6.73(m,1H),8.01(m,1H),8.32(m,1H),9.45(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.98(d, 3H), 1.23(m, 4H), 1.47(s, 9H), 1.86(m, 6H), 2.02(m, 2H), 2.27( s, 3H), 2.85(m, 4H), 2.98(m, 2H), 3.27(m, 1H), 4.57(m, 1H), 6.73(m, 1H), 8.01(m, 1H), 8.32(m , 1H), 9.45 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值513.4；實測值514.2；Rt=1.244min。LCMS (ESI): [M] + m/z: calculated 513.4; found 514.2; Rt=1.244 min.

步驟5：6-(1-(2-((6-胺基-5-甲基吡啶-3-基)胺基)-2-側氧基乙醯基)-5-甲基哌啶-2-基)螺[3.3]庚-2-甲醯胺(化合物812 )之合成Step 5: 6-(1-(2-((6-Amino-5-methylpyridin-3-yl)amino)-2-oxyacetyl)-5-methylpiperidine-2 -Synthesis of spiro[3.3]hept-2-carboxamide ( compound 812 )

向N -[5-[[2-[(2R,5S )-2-(2-胺甲醯基螺[3 .3 ]庚-6-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]-3-甲基-2-吡啶基]胺甲酸第三丁 酯(1g，1.95mmol)於DCM(10mL)中之經攪拌之溶液中添加於二噁烷中之4.0M氯化氫溶液(709.87mg，19.47mmol，887.34μL)。將反應混合物在25℃下攪拌2h。將溶劑蒸發。藉由反相HPLC(15-15-40% 0-1-6min H2 O/ACN/0.1% NH4 OH，流速：30ml/min(裝載泵4ml/min MeOH)目標質量413.52管柱：YMC Triart C18 100x20mm，5um)純化殘餘物，以得到6-[(2R,5S )-1-[2-[(6-胺基-5-甲基-3-吡啶基)胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]螺[3.3]庚-2-甲醯胺(40mg，96.73μmol，4.97%產率)。亦在HPLC上收集2種級分：第1級分：58mg(95% LCMS)；第2級分：36mg(99% LCMS)。to N- [5-[[2-[( 2R,5S )-2-( 2 -aminocarboxyspiro[ 3.3 ]hept-6-yl)-5-methyl-1-piperidinyl] To a stirred solution of tert-butyl-2-oxyacetyl]amino]-3-methyl-2-pyridyl] carbamate (1 g, 1.95 mmol) in DCM (10 mL) was added to A 4.0M solution of hydrogen chloride in dioxane (709.87 mg, 19.47 mmol, 887.34 [mu]L). The reaction mixture was stirred at 25 °C for 2 h. The solvent was evaporated. By reverse phase HPLC (15-15-40% 0-1-6 min H2O /ACN/0.1% NH4OH , flow rate: 30 ml/min (loading pump 4 ml/min MeOH) target mass 413.52 Column: YMC Triart C18 100x20mm, 5um), the residue was purified to give 6-[( 2R,5S )-1-[2-[(6-amino-5-methyl-3-pyridyl)amino]-2-oxygen Acetyl]-5-methyl-2-piperidinyl]spiro[3.3]hept-2-carboxamide (40 mg, 96.73 μmol, 4.97% yield). Two fractions were also collected on HPLC: Fraction 1: 58 mg (95% LCMS); Fraction 2: 36 mg (99% LCMS).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.86-0.94(m,3H),1.20-1.32(m,2H),1.40-1.66(m,2H),1.68-1.84(m,4H),1.89-1.93(m,1H),1.94-2.00(m,2H),2.00-2.02 (m,3H),2.03-2.13(m,2H),2.64-3.01(m,4H),3.63-3.98(m,1H),4.32-5.06(m,1H),5.55-5.66(m,2H),6.60-7.08(m,1H),7.39-7.50(m,1H),7.91-8.07(m,1H),10.24-10.43(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.86-0.94(m,3H), 1.20-1.32(m,2H), 1.40-1.66(m,2H), 1.68-1.84(m,4H) ,1.89-1.93(m,1H),1.94-2.00(m,2H),2.00-2.02(m,3H),2.03-2.13(m,2H),2.64-3.01(m,4H),3.63-3.98( m,1H),4.32-5.06(m,1H),5.55-5.66(m,2H),6.60-7.08(m,1H),7.39-7.50(m,1H),7.91-8.07(m,1H), 10.24-10.43 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值413.4；實測值414.2；Rt=1.746min。LCMS (ESI): [M] + m/z: calculated 413.4; found 414.2; Rt=1.746 min.

實例787.N -(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(螺[3 .3 ]庚-2-基)哌啶-1-基)-2-側氧基乙醯胺(化合物692)之合成Example 787. N- (6-Amino-5-methylpyridin- 3 -yl)-2-(5-methyl-2-(spiro[ 3.3 ]hept-2-yl)piperidin-1- Synthesis of yl)-2-oxoacetamide (Compound 692)

Figure 110128222-A0202-12-2514-496
Figure 110128222-A0202-12-2514-496

步驟1：螺[3.3]庚烷-2-羰基氯之合成Step 1: Synthesis of spiro[3.3]heptane-2-carbonyl chloride

將於亞硫醯氯(8.49g，71.34mmol)中之螺[3 .3 ]庚烷-2-甲酸(1g，7.13mmol)在回流下攪拌12h。然後在真空中蒸發反應混合物，以得到螺[3 .3 ]庚烷-2-羰基氯(0.9g，5.67mmol，79.53%產率)，其不經純化即用於下一步驟中。Spiro[ 3.3 ]heptane- 2 -carboxylic acid (1 g, 7.13 mmol) in thionium chloride (8.49 g, 71.34 mmol) was stirred at reflux for 12 h. The reaction mixture was then evaporated in vacuo to give spiro[ 3.3 ]heptane- 2 -carbonyl chloride (0.9 g, 5.67 mmol, 79.53% yield) which was used in the next step without purification.

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.73(m,2H),1.85(m,2H),1.97(m,2H),2.11(m,4H),2.86(m,1H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ (ppm) 1.73 (m, 2H), 1.85 (m, 2H), 1.97 (m, 2H), 2.11 (m, 4H), 2.86 (m, 1H).

GCMS：計算值158.4；實測值158.2；Rt=4.384min。GCMS: Calculated 158.4; Found 158.2; Rt=4.384 min.

步驟2：5-甲基-2-側氧基-3-(螺[3.3]庚烷-2-羰基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-(spiro[3.3]heptane-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

在-78℃下，將雙(三甲基矽基)醯胺化鋰(2.09g，12.48mmol)逐滴添加5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(1.21g，5.67mmol)於THF(20mL)中之經預冷卻之溶液中。在添加完成之後，將其在同一溫度下攪拌1h。此後，一次性添加螺[3 .3 ]庚烷-2-羰基氯(0.9g，5.67mmol)且移除冷卻浴。將所得混合物緩慢升高至25℃且在此溫度下攪拌1h。然後，將其用15%NaHSO4 水溶液(50ml)淬 滅且用乙酸乙酯(100ml)萃取。將有機層用20%NaCl水溶液(2x50ml)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，以得到5-甲基-2-側氧基-3-(螺[3 .3 ]庚-2-羰基)哌啶-1-甲酸第三丁 酯(1.6g，4.77mmol，84.07%產率)。Lithium bis(trimethylsilyl)amide (2.09 g, 12.48 mmol) was added dropwise at -78 °C tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate ( 1.21 g, 5.67 mmol) in a precooled solution in THF (20 mL). After the addition was complete, it was stirred at the same temperature for 1 h. After this time, spiro[ 3.3 ]heptane- 2 -carbonyl chloride (0.9 g, 5.67 mmol) was added in one portion and the cooling bath was removed. The resulting mixture was slowly raised to 25°C and stirred at this temperature for 1 h. It was then quenched with 15% aqueous NaHSO 4 (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with 20% aqueous NaCl (2×50 ml), dried over Na 2 SO 4 and evaporated under reduced pressure to give 5-methyl-2-pentoxy- 3- (spiro[ 3.3 ]heptane- 2-Carbonyl)piperidine-1-carboxylic acid tert -butyl ester (1.6 g, 4.77 mmol, 84.07% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.91(d,3H),1.40(s,9H),1.53(m,1H),1.76(m,6H),1.95(m,4H),2.07(m,4H),3.04(m,1H),3.62(m,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.91(d,3H), 1.40(s,9H), 1.53(m,1H), 1.76(m,6H), 1.95(m,4H), 2.07 (m, 4H), 3.04 (m, 1H), 3.62 (m, 1H).

LCMS(ESI)：[M-Boc]+ m/z：計算值235.4；實測值236.2；Rt=1.570min。LCMS (ESI): [M-Boc] + m/z: calculated 235.4; found 236.2; Rt=1.570 min.

步驟3：6-(5-甲基-3,4,5,6-四氫吡啶-2-基)螺[3.3]庚-2-胺之合成Step 3: Synthesis of 6-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)spiro[3.3]hept-2-amine

將5-甲基-2-側氧基-3-(螺[3 .3 ]庚-2-羰基)哌啶-1-甲酸第三丁 酯(1.6g，4.77mmol)溶解於AcOH(16mL)中且分批添加36% w/w鹽酸水溶液(12.87g，352.97mmol，16.09mL)(產生大量泡沫)。添加完成之後，將所得混合物在100℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物分配於1N HCl(100ml)與DCM(200ml)之間。分離有機層且丟棄。將水層用10% NaOH鹼化至pH 10且用DCM(2x100ml)萃取。分離DCM溶液，經Na2 SO4 乾燥且在減壓下蒸發，得到3-甲基-6-螺[3 .3 ]庚-2-基-2,3,4,5-四氫吡啶(0.2g，1.05mmol，21.92%產率)。5-Methyl-2-oxy- 3- (spiro[ 3.3 ]hept-2-carbonyl)piperidine-1-carboxylic acid tert- butyl ester (1.6 g, 4.77 mmol) was dissolved in AcOH (16 mL) Aqueous 36% w/w hydrochloric acid (12.87 g, 352.97 mmol, 16.09 mL) was added in and portionwise (a lot of foaming occurred). After the addition was complete, the resulting mixture was stirred at 100 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between IN HCl (100ml) and DCM (200ml). The organic layer was separated and discarded. The aqueous layer was basified to pH 10 with 10% NaOH and extracted with DCM (2x100ml). The DCM solution was separated, dried over Na2SO4 and evaporated under reduced pressure to give 3 -methyl-6-spiro[ 3.3 ]hept-2-yl-2,3,4,5-tetrahydropyridine (0.2 g, 1.05 mmol, 21.92% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.84(d,3H),1.10(m,1H),1.45(m,1H),1.64(m,1H),1.76(m,4H),1.98(m,8H),2.73(m,1H),2.84(m,1H),3.56(d,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.84(d,3H), 1.10(m,1H), 1.45(m,1H), 1.64(m,1H), 1.76(m,4H), 1.98(m, 8H), 2.73(m, 1H), 2.84(m, 1H), 3.56(d, 1H).

LCMS(ESI)：[M]+ m/z：計算值191.4；實測值192.2；Rt=0.872min。LCMS (ESI): [M] + m/z: calculated 191.4; found 192.2; Rt=0.872 min.

步驟4：6-(5-甲基哌啶-2-基)螺[3.3]庚-2-胺之合成Step 4: Synthesis of 6-(5-methylpiperidin-2-yl)spiro[3.3]hept-2-amine

在0℃下，將硼氫化鈉(79.10mg，2.09mmol，73.93μL)一次性添加到3-甲基-6-螺[3 .3 ]庚-2-基-2,3,4,5-四氫吡啶(0.2g，1.05mmol)於MeOH(5mL)中之經攪拌之溶液中。將所得混合物攪拌15h，然後在真空中蒸發。將殘餘物用水(20ml)稀釋且用二氯甲烷(2*40ml)萃取。將經合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。使所獲得之油狀物經歷，以得到5-甲基-2-螺[3 .3 ]庚-2-基哌啶(0.16g，827.61μmol，79.17%產率)。Sodium borohydride (79.10 mg, 2.09 mmol, 73.93 μL) was added in one portion to 3 -methyl-6-spiro[ 3.3 ]hept-2-yl-2,3,4,5- at 0 °C In a stirred solution of tetrahydropyridine (0.2 g, 1.05 mmol) in MeOH (5 mL). The resulting mixture was stirred for 15 h, then evaporated in vacuo. The residue was diluted with water (20ml) and extracted with dichloromethane (2*40ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The obtained oil was subjected to 5-methyl-2-spiro[ 3.3 ]hept- 2 -ylpiperidine (0.16 g, 827.61 μmol, 79.17% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)0.75(d,3H),0.88(m,2H),1.33(m,1H),1.49(m,1H),1.65(m,3H),1.75(m,4H),1.94(m,6H),2.03(m,1H),2.11(m,1H),2.84(d,1H)。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 0.75(d, 3H), 0.88(m, 2H), 1.33(m, 1H), 1.49(m, 1H), 1.65(m, 3H), 1.75(m, 4H), 1.94(m, 6H), 2.03(m, 1H), 2.11(m, 1H), 2.84(d, 1H).

LCMS(ESI)：[M]+ m/z：計算值193.4；實測值194.2；Rt=0.827min。LCMS (ESI): [M] + m/z: calculated 193.4; found 194.2; Rt=0.827 min.

步驟5：(5-(2-(2-(6-胺基螺[3.3]庚-2-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)-3-甲基吡啶-2-基)胺甲酸第三丁酯之合成Step 5: (5-(2-(2-(6-Aminospiro[3.3]hept-2-yl)-5-methylpiperidin-1-yl)-2-oxyacetamido) Synthesis of -3-methylpyridin-2-yl)carbamic acid tert-butyl ester

將DIPEA(320.89mg，2.48mmol，432.46μL)添加到相應5-甲基-2-螺[3.3]庚-2-基哌啶(0.16g，827.61μmol)及2-[[6-(第三丁氧基 羰基胺基)-5-甲基-3-吡啶基]胺基]-2-側氧基乙酸(244.39mg，827.61μmol)於DMF(5mL)中之溶液中。將所得混合物攪拌5min，隨後添加HATU(346.15mg，910.37μmol)。然後，將反應混合物在室溫下攪拌隔夜。在藉由LCMS監測到反應完成之後，將所得懸浮液在減壓下濃縮。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeCN為溶析液混合物)，以得到純的N -[3-甲基-5-[[2-(5-甲基-2-螺[3 .3 ]庚-2-基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.22g，467.49μmol，56.49%產率)。DIPEA (320.89 mg, 2.48 mmol, 432.46 μL) was added to the corresponding 5-methyl-2-spiro[3.3]hept-2-ylpiperidine (0.16 g, 827.61 μmol) and 2-[[6-( third Butoxycarbonylamino )-5-methyl-3-pyridyl]amino]-2-pendoxoacetic acid (244.39 mg, 827.61 [mu]mol) in DMF (5 mL). The resulting mixture was stirred for 5 min before HATU (346.15 mg, 910.37 μmol) was added. Then, the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, the resulting suspension was concentrated under reduced pressure. The obtained solid was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeCN as eluent mixture) to give pure N- [3-methyl-5-[[2-( 5-Methyl-2-spiro[ 3.3 ]hept- 2 -yl-1-piperidinyl)-2-oxyacetoxy]amino]-2-pyridyl]carbamic acid tert- butyl ester (0.22 g, 467.49 μmol, 56.49% yield).

LCMS(ESI)：[M]+ m/z：計算值470.4；實測值471.2；Rt=4.127min。LCMS (ESI): [M] + m/z: calculated 470.4; found 471.2; Rt=4.127 min.

步驟6：N-(6-胺基-5-甲基吡啶-3-基)-2-(5-甲基-2-(螺[3.3]庚-2-基)哌啶-1-基)-2-側氧基乙醯胺(化合物692 )之合成Step 6: N-(6-Amino-5-methylpyridin-3-yl)-2-(5-methyl-2-(spiro[3.3]hept-2-yl)piperidin-1-yl) Synthesis of -2-oxoacetamide ( Compound 692 )

將N -[3-甲基-5-[[2-(5-甲基-2-螺[3.3]庚-2-基-1-哌啶基)-2-側氧基乙醯基]胺基]-2-吡啶基]胺甲酸第三丁 酯(0.22g，467.49μmol)溶解於二噁烷(2mL)及水(5mL)之混合物中。然後，將反應混合物在100℃下攪拌16h。在反應完成(藉由LCMS監測)之後，在減壓下濃縮所得懸浮液。使所獲得之固體經歷HPLC(Waters Sunfire C18 20*100 5mkm管柱且以H2 O-MeCN(45-60%)+FA為溶析液混合物)，以得到純的N -(6-胺基-5-甲基-3-吡啶基)-2-[(2R,5S )-5-甲基-2-螺[3 .3 ]庚-2- 基-1-哌啶基]-2-側氧基乙醯胺(101.7mg，274.50μmol，58.72%產率)。 N- [3-Methyl-5-[[2-(5-methyl-2-spiro[3.3]hept-2-yl-1-piperidinyl)-2-oxyethanoyl]amine tert -butyl ]-2-pyridyl]carbamate (0.22 g, 467.49 [mu]mol) was dissolved in a mixture of dioxane (2 mL) and water (5 mL). Then, the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by LCMS), the resulting suspension was concentrated under reduced pressure. The solid obtained was subjected to HPLC (Waters Sunfire C18 20*100 5mkm column with H2O -MeCN (45-60%)+FA as eluent mixture) to give pure N- (6-amino -5-Methyl- 3 -pyridyl)-2-[( 2R,5S )-5-methyl-2-spiro[ 3.3 ]hept-2-yl-1-piperidinyl]-2-side Oxyacetamide (101.7 mg, 274.50 μmol, 58.72% yield).

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)0.90(d,3H),1.27(m,2H),1.78(m,13H),2.00(s,4H),2.69(m,1H),3.69(m,1H),4.09(m,1H),5.58(m,2H),7.44(d,1H),7.98(d,1H),10.29(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 0.90(d, 3H), 1.27(m, 2H), 1.78(m, 13H), 2.00(s, 4H), 2.69(m, 1H), 3.69(m, 1H), 4.09(m, 1H), 5.58(m, 2H), 7.44(d, 1H), 7.98(d, 1H), 10.29(m, 1H).

LCMS(ESI)：[M]+ m/z：計算值370.4；實測值371.2；Rt=2.890min。LCMS (ESI): [M] + m/z: calculated 370.4; found 371.2; Rt=2.890 min.

實例788. 5-[[2-[(2S,6S )-2-甲基-6-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物561)之合成Example 788. 5-[[2-[( 2S,6S )-2-methyl-6-[6-(methylamino)-3-pyridyl]-1-piperidinyl]-2-pendantoxy Synthesis of Acetyl]amino]pyridine-3-carbamoylamine (Compound 561)

Figure 110128222-A0202-12-2517-497
Figure 110128222-A0202-12-2517-497

步驟1：6-甲基-6'-(甲胺基)-5,6-二氫-[2,3'-聯吡啶]-1(4H)-甲酸第三丁酯之合成Step 1: Synthesis of 6-methyl-6'-(methylamino)-5,6-dihydro-[2,3'-bipyridine]-1(4H)-carboxylic acid tert-butyl ester

將2-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(7g，20.27mmol)、[6-(甲胺基)-3-吡啶基]硼酸(4.20g，22.30mmol，HCl)及碳酸鈉(6.45g，60.81mmol，2.55mL)一起混合於二噁烷(75mL)及水(25mL)之混合物中。將混合物抽真空且用氬氣回填三次，且向其中添加[1,1'-雙 (聯苯基膦基)二茂鐵]二氯鈀(II)與DCM之複合物(1.66g，2.03mmol)。將反應混合物在90℃下加熱18h。將反應混合物冷卻至室溫且用水(50ml)稀釋。將所得混合物用EtOAc(3*100ml)萃取且將經合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且蒸發。藉由管柱層析純化殘餘物，以獲得2-甲基-6-[6-(甲胺基)-3-吡啶基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.98g，13.12mmol，64.72%產率)。2-Methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (7 g, 20.27 mmol), [6-(methyl) Amino)-3-pyridyl]boronic acid (4.20 g, 22.30 mmol, HCl) and sodium carbonate (6.45 g, 60.81 mmol, 2.55 mL) were mixed together in a mixture of dioxane (75 mL) and water (25 mL). The mixture was evacuated and backfilled with argon three times, and to it was added a complex of [1,1'- bis (biphenylphosphino)ferrocene]dichloropalladium(II) and DCM (1.66 g, 2.03 mmol ). The reaction mixture was heated at 90 °C for 18 h. The reaction mixture was cooled to room temperature and diluted with water (50 ml). The resulting mixture was extracted with EtOAc (3*100 ml) and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography to obtain 2-methyl-6-[6-(methylamino)-3-pyridyl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid third Butyl ester (3.98 g, 13.12 mmol, 64.72% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.17(s,9H),1.21(d,3H),1.67(m,1H),1.92(m, 1H),2.22(m,2H),2.93(d,3H),4.61(bds,1H),4.72(m,1H),5.24(m,1H),6.36(d,1H),7.33(d,1H),8.03(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.17(s, 9H), 1.21(d, 3H), 1.67(m, 1H), 1.92(m, 1H), 2.22(m, 2H), 2.93( d, 3H), 4.61 (bds, 1H), 4.72 (m, 1H), 5.24 (m, 1H), 6.36 (d, 1H), 7.33 (d, 1H), 8.03 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值303.2；實測值304.2；Rt=1.071min。LCMS (ESI): [M] + m/z: calculated 303.2; found 304.2; Rt=1.071 min.

步驟2：N,6-二甲基-3,4,5,6-四氫-[2,3'-聯吡啶]-6'-胺之合成Step 2: Synthesis of N,6-dimethyl-3,4,5,6-tetrahydro-[2,3'-bipyridyl]-6'-amine

將2-甲基-6-[6-(甲胺基)-3-吡啶基]-3,4-二氫-2H -吡啶-1-甲酸第三丁 酯(3.98g，13.12mmol)溶解於DCM(16mL)中且向其中添加TFA(16mL)。將所得混合物攪拌1h。將反應混合物小心倒入到K2 CO3 (35g)之溶液中且將所得混合物用DCM(2*100ml)萃取。將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得N -甲基-5-(2-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-2-胺(2.1g，10.33mmol，78.75%產率)。2-Methyl-6-[6-(methylamino)-3-pyridyl]-3,4-dihydro- 2H -pyridine-1-carboxylic acid tert- butyl ester (3.98 g, 13.12 mmol) was dissolved in DCM (16 mL) and to this was added TFA (16 mL). The resulting mixture was stirred for 1 h. The reaction mixture was poured carefully into a solution of K2CO3 (35 g ) and the resulting mixture was extracted with DCM (2*100 ml). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated to obtain N -methyl-5-(2-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridine- 2-amine (2.1 g, 10.33 mmol, 78.75% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.22(m,1H),1.30(d,3H),1.70(m,1H),1.87(m,2H),2.46(m,1H),2.57(m,1H),2.93(d,3H),3.64(m,1H),4.73(m,1H),6.38(d,1H),8.05(d,1H),8.43(s,1H)。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.22(m,1H), 1.30(d,3H), 1.70(m,1H), 1.87(m,2H), 2.46(m,1H), 2.57( m, 1H), 2.93 (d, 3H), 3.64 (m, 1H), 4.73 (m, 1H), 6.38 (d, 1H), 8.05 (d, 1H), 8.43 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值203.2；實測值204.2；Rt=0.557min。LCMS (ESI): [M] + m/z: calculated 203.2; found 204.2; Rt=0.557 min.

步驟3：N-甲基-5-(6-甲基哌啶-2-基)吡啶-2-胺之合成Step 3: Synthesis of N-methyl-5-(6-methylpiperidin-2-yl)pyridin-2-amine

將N -甲基-5-(2-甲基-2,3,4,5-四氫吡啶-6-基)吡啶-2-胺(2.1g，10.33mmol)溶解於MeOH(30mL)中且分批添加硼氫化鈉(1.17g，30.99mmol，1.10mL)。將所得混合物攪拌18h。將反應混合物在真空中濃縮且將水(30ml)添加到殘餘物中。將所得混合物用DCM(2*50ml)萃取且將經合併之有機層經Na2 SO4 乾燥，過濾且蒸發，以獲得N -甲基-5-(6-甲基-2-哌啶基)吡啶-2-胺(2.07g，10.09mmol，97.70%產率)。 N -methyl-5-(2-methyl-2,3,4,5-tetrahydropyridin-6-yl)pyridin-2-amine (2.1 g, 10.33 mmol) was dissolved in MeOH (30 mL) and Sodium borohydride (1.17 g, 30.99 mmol, 1.10 mL) was added portionwise. The resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and water (30 ml) was added to the residue. The resulting mixture was extracted with DCM (2*50ml) and the combined organic layers were dried over Na2SO4 , filtered and evaporated to obtain N -methyl-5-(6-methyl-2-piperidinyl) Pyridin-2-amine (2.07 g, 10.09 mmol, 97.70% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.08(d,3H),1.16(m,1H),1.42(m,2H),1.63(m,3H),1.82(m,1H),2.76(m,1H),2.89(d,3H),3.51(m,1H),4.44(m,1H),6.35(d,1H),7.51(d,1H),8.01(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.08(d,3H), 1.16(m,1H), 1.42(m,2H), 1.63(m,3H), 1.82(m,1H), 2.76( m, 1H), 2.89 (d, 3H), 3.51 (m, 1H), 4.44 (m, 1H), 6.35 (d, 1H), 7.51 (d, 1H), 8.01 (s, 1H).

LCMS(ESI)：[M]+ m/z：計算值205.2；實測值206.2；Rt=0.265min。LCMS (ESI): [M] + m/z: calculated 205.2; found 206.2; Rt=0.265 min.

步驟4：5-[[2-[(2S,6S)-2-甲基-6-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(化合物561 )之合成Step 4: 5-[[2-[(2S,6S)-2-methyl-6-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-pendoxyl Synthesis of Acetyl]amino]pyridine-3-carbamoylamine ( Compound 561 )

將N -甲基 -5-(6-甲基-2-哌啶基)吡啶-2-胺(0.25g，1.22mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(299.10mg，1.22mmol，HCl)及TEA(1.23g，12.18mmol，1.70mL)一起混合於DMF(6mL)中且向其中添加HATU(694.53mg，1.83mmol)。將所得混合物攪拌18h。將反應混合物在真空中濃縮且藉由HPLC(2-10min 40-60%水/MeCN(裝載泵4ml MeCN)，管柱：TRIART 100*20 5微米)純化殘餘物，以獲得5-[[2-[(2S,6S )-2-甲基-6-[6-(甲胺基)-3-吡啶基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(0.0114g，28.76μmol，2.36%產率)及N-(5-胺甲醯基-3-吡啶基)-N' -甲基-N' -[5-(6-甲基-2-哌啶基)-2-吡啶基]草醯胺(23.60mg，59.53μmol，4.89%產率)。 N - methyl -5-(6-methyl-2-piperidinyl)pyridin-2-amine (0.25 g, 1.22 mmol), 2-[(5-aminocarbamoyl-3-pyridinyl)amine [methyl]-2-oxoacetic acid (299.10 mg, 1.22 mmol, HCl) and TEA (1.23 g, 12.18 mmol, 1.70 mL) were mixed together in DMF (6 mL) and to this was added HATU (694.53 mg, 1.83 mmol) . The resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (2-10 min 40-60% water/MeCN (loading pump 4 ml MeCN), column: TRIART 100*20 5 microns) to obtain 5-[[2 -[( 2S,6S )-2-methyl-6-[6-(methylamino)-3-pyridinyl]-1-piperidinyl]-2-oxyethanoyl]amino]pyridine -3-Carboxamide (0.0114 g, 28.76 μmol, 2.36% yield) and N-(5-aminocarbamoyl-3-pyridyl)-N'-methyl- N ' -[5-(6- Methyl-2-piperidinyl)-2-pyridyl]oxamide (23.60 mg, 59.53 μmol, 4.89% yield).

化合物561：Compound 561:

1 H NMR(600MHz,DMSO-d 6 )δ(ppm)1.31-1.36(m,3H),1.43-1.60(m,2H),1.62-1.75(m,2H),1.87-2.20(m,2H),2.55-2.75(m,3H),4.11-4.29(m,1H),4.82-5.19(m,1H),6.19-6.43(m,2H),7.22-7.34(m,1H),7.48-7.62(m,1H),7.80-7.94(m,1H),8.03-8.17(m,1H),8.20-8.52(m,1H),8.61-8.91(m,2H),10.42-11.31(m,1H)。 1 H NMR (600MHz, DMSO- d 6 )δ(ppm) 1.31-1.36(m,3H), 1.43-1.60(m,2H), 1.62-1.75(m,2H), 1.87-2.20(m,2H) ,2.55-2.75(m,3H),4.11-4.29(m,1H),4.82-5.19(m,1H),6.19-6.43(m,2H),7.22-7.34(m,1H),7.48-7.62( m, 1H), 7.80-7.94 (m, 1H), 8.03-8.17 (m, 1H), 8.20-8.52 (m, 1H), 8.61-8.91 (m, 2H), 10.42-11.31 (m, 1H).

LCMS(ESI)：[M]+ m/z：計算值396.2；實測值397.2；Rt=1.248min。LCMS (ESI): [M] + m/z: calculated 396.2; found 397.2; Rt=1.248 min.

實例789. 5-(2-(5-甲基-2-(4,5,6,7-四氫-1H -吲唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)哌啶-3-甲醯胺(化合物755)之合成Example 789. 5-(2-(5-Methyl-2-(4,5,6,7-tetrahydro- 1H -indazol-5-yl)piperidin-1-yl)-2-side oxy Synthesis of Acetamido)Piperidin-3-Carboxamide (Compound 755)

Figure 110128222-A0202-12-2520-498
Figure 110128222-A0202-12-2520-498

步驟1：1-苯甲基-4,5,6,7-四氫-1H-吲唑-5-甲酸甲酯之合成Step 1: Synthesis of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester

將4,5,6,7-四氫-1H -吲唑-5-甲酸甲酯(2g，11.10mmol)溶解於MeCN(30mL)中。向其中添加氯甲基苯(1.48g，11.65mmol，1.34mL)、碘化鈉(166.36mg，1.11mmol，45.33μL)及碳酸鉀(2.30g，16.65mmol，1.00mL)。將所得混合物在80℃下攪拌15h。然後，在減壓下移除溶劑且將殘餘物用MTBE(50ml)稀釋。過濾出不溶性固體且在真空中濃縮殘餘物，得到呈位置異構物之混合物之1-苯甲基-4,5,6,7-四氫吲唑-5-甲酸甲酯(2.95g，10.91mmol，98.33%產率)。Methyl 4,5,6,7-tetrahydro- 1H -indazole-5-carboxylate (2 g, 11.10 mmol) was dissolved in MeCN (30 mL). To this were added chloromethylbenzene (1.48 g, 11.65 mmol, 1.34 mL), sodium iodide (166.36 mg, 1.11 mmol, 45.33 μL) and potassium carbonate (2.30 g, 16.65 mmol, 1.00 mL). The resulting mixture was stirred at 80 °C for 15 h. Then, the solvent was removed under reduced pressure and the residue was diluted with MTBE (50 ml). The insoluble solids were filtered off and the residue was concentrated in vacuo to give methyl 1-benzyl-4,5,6,7-tetrahydroindazole-5-carboxylate (2.95 g, 10.91 g) as a mixture of positional isomers mmol, 98.33% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)1.89(m,1H),2.22(m,1H),2.72(m,3H),2.84(m,2H),3.71(s,3H),5.29(s,2H),7.09(s,1H),7.32(m,5H)。LCMS(ESI)：[M]+ m/z：計算值270.2；實測值271.2；Rt=1.150min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 1.89(m,1H), 2.22(m,1H), 2.72(m,3H), 2.84(m,2H), 3.71(s,3H), 5.29( s, 2H), 7.09 (s, 1H), 7.32 (m, 5H). LCMS (ESI): [M] + m/z: calculated 270.2; found 271.2; Rt=1.150 min.

步驟2：1-苯甲基-4,5,6,7-四氫-1H-吲唑-5-甲酸之合成Step 2: Synthesis of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid

將氫氧化鈉(654.72mg，16.37mmol，307.38μL)添加到1-苯甲基-4,5,6,7-四氫吲唑-5-甲酸甲酯(2.95g，10.91mmol)於MeOH(50mL)及水(5mL)中之溶液中。將所得混合物在50℃下攪拌5h。然後，在減壓下蒸發甲醇且將殘餘物用水(40ml)稀釋。透過棉花墊過濾所得混濁溶液。將濾液用溶解於水(10ml)中之硫酸氫鈉單水合物(2.34g，16.91mmol)酸化。過濾所獲得之沉澱，用水洗滌且乾燥，得到1-苯甲基-4,5,6,7-四氫吲唑-5-甲酸(2.31g，9.01mmol，82.59%產率)。Sodium hydroxide (654.72 mg, 16.37 mmol, 307.38 μL) was added to methyl 1-benzyl-4,5,6,7-tetrahydroindazole-5-carboxylate (2.95 g, 10.91 mmol) in MeOH ( 50 mL) and water (5 mL). The resulting mixture was stirred at 50 °C for 5 h. Then, methanol was evaporated under reduced pressure and the residue was diluted with water (40 ml). The resulting cloudy solution was filtered through a cotton pad. The filtrate was acidified with sodium bisulfate monohydrate (2.34 g, 16.91 mmol) dissolved in water (10 ml). The obtained precipitate was filtered, washed with water and dried to give 1-benzyl-4,5,6,7-tetrahydroindazole-5-carboxylic acid (2.31 g, 9.01 mmol, 82.59% yield).

1 H NMR(500MHz,DMSO-d 6 )δ(ppm)1.71(m,1H),2.07(m,1H),2.62(m,5H), 5.17(s,2H),7.08(s,1H),7.29(m,5H),12.18(bds,1H)。LCMS(ESI)：[M]+ m/z：計算值256.2；實測值257.2；Rt=1.106min。 1 H NMR (500MHz, DMSO- d 6 )δ(ppm) 1.71(m,1H), 2.07(m,1H), 2.62(m,5H), 5.17(s,2H), 7.08(s,1H), 7.29 (m, 5H), 12.18 (bds, 1H). LCMS (ESI): [M] + m/z: calculated 256.2; found 257.2; Rt=1.106 min.

步驟3：1-苯甲基-4,5,6,7-四氫-1H-吲唑-5-羰基氯之合成Step 3: Synthesis of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-5-carbonyl chloride

將1-苯甲基-4,5,6,7-四氫吲唑-5-甲酸(2.31g，9.01mmol)溶解於亞硫醯氯(16.40g，137.85mmol，10mL)中。將所得混合物在74℃下攪拌2h。然後，將其在減壓下濃縮且將殘餘物與苯(15ml)一起共同蒸發3次，得到1-苯甲基-4,5,6,7-四氫吲唑-5-羰基氯(3.1g，粗品，HCl)。1-Benzyl-4,5,6,7-tetrahydroindazole-5-carboxylic acid (2.31 g, 9.01 mmol) was dissolved in thionine chloride (16.40 g, 137.85 mmol, 10 mL). The resulting mixture was stirred at 74 °C for 2 h. It was then concentrated under reduced pressure and the residue was co-evaporated 3 times with benzene (15 ml) to give 1-benzyl-4,5,6,7-tetrahydroindazole-5-carbonyl chloride (3.1 g, crude, HCl).

1 H NMR(500MHz,CDCl3 )δ(ppm)2.12(m,1H),2.40(m,1H),3.18(m,5H),5.77(s,2H),7.43(m,6H)。LCMS(ESI)：[M]+ m/z：計算值274.2；實測值275.2；Rt=1.100min。 1 H NMR (500 MHz, CDCl 3 ) δ (ppm) 2.12 (m, 1H), 2.40 (m, 1H), 3.18 (m, 5H), 5.77 (s, 2H), 7.43 (m, 6H). LCMS (ESI): [M] + m/z: calculated 274.2; found 275.2; Rt=1.100 min.

步驟4：3-(1-苯甲基-3a,4,5,6,7,7a-六氫-1H-吲唑-5-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯之合成Step 4: 3-(1-Benzyl-3a,4,5,6,7,7a-hexahydro-1H-indazole-5-carbonyl)-5-methyl-2-oxypiperidine- Synthesis of 3-butyl 1-formate

將5-甲基-2-側氧基哌啶-1-甲酸第三丁 酯(1.03g，4.82mmol)溶解於THF(15mL)中且在氬氣流下冷卻至-70℃。向其中逐滴添加雙(三甲基矽基)醯胺化鋰(20%於THF/乙基苯))(16.13g，19.28mmol，18.12mL，20%純度)。將所得溶液在此溫度下攪拌40分鐘，之後逐滴添加1-苯甲基-4,5,6,7-四氫吲唑-5-羰基氯(1.5g，4.82mmol，HCl)於THF(10mL)中之溶液。然後，移除冷卻浴且將所得混合物在20℃下攪拌15h。此後，將其用5% NaHSO4 水溶液酸化至pH

Figure 110128222-A0202-12-2521-548
2-3且用乙酸乙酯(50ml)萃取。將有機層依次用水(40ml)及鹽水(40ml)洗滌，經Na2 SO4 乾燥且在減壓下蒸發，得到3-(1-苯甲基-4,5,6,7-四氫吲唑-5-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁 酯(2.2g，粗品)。 3 -Butyl 5-methyl-2-oxypiperidine-1-carboxylate (1.03 g, 4.82 mmol) was dissolved in THF (15 mL) and cooled to -70 &lt;0&gt;C under a stream of argon. To this was added lithium bis(trimethylsilyl)amide (20% in THF/ethylbenzene) (16.13 g, 19.28 mmol, 18.12 mL, 20% purity) dropwise. The resulting solution was stirred at this temperature for 40 minutes, after which 1-benzyl-4,5,6,7-tetrahydroindazole-5-carbonyl chloride (1.5 g, 4.82 mmol, HCl) in THF ( 10 mL) of the solution. Then, the cooling bath was removed and the resulting mixture was stirred at 20 °C for 15 h. After this, it was acidified to pH with 5% aqueous NaHSO4
Figure 110128222-A0202-12-2521-548
2-3 and extracted with ethyl acetate (50 ml). The organic layer was washed sequentially with water (40ml) and brine (40ml), dried over Na2SO4 and evaporated under reduced pressure to give 3-(1-benzyl-4,5,6,7-tetrahydroindazole -5-Carbonyl)-5-methyl-2-oxypiperidine-1-carboxylic acid tert- butyl ester (2.2 g, crude).

1 H NMR(400MHz,CDCl3 )δ(ppm)1.02(d,3H),1.23(m,1H),1.52(s,9H),2.02(m,3H),2.17(m,1H),2.64(m,5H),3.05(m,2H),3.78(m,1H),5.21(s,2H),7.24(m,6H)。LCMS(ESI)：[M]+ m/z：計算值451.2；實測值452.2；Rt=1.732min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 1.02(d, 3H), 1.23(m, 1H), 1.52(s, 9H), 2.02(m, 3H), 2.17(m, 1H), 2.64( m, 5H), 3.05 (m, 2H), 3.78 (m, 1H), 5.21 (s, 2H), 7.24 (m, 6H). LCMS (ESI): [M] + m/z: calculated 451.2; found 452.2; Rt=1.732 min.

步驟5：1-苯甲基-5-(5-甲基-3,4,5,6-四氫吡啶-2-基)-3a,4,5,6,7,7a-六氫-1H-吲唑之合成Step 5: 1-Benzyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)-3a,4,5,6,7,7a-hexahydro-1H -Synthesis of indazole

將36% w/w鹽酸水溶液(11.80g，116.51mmol，10.00mL，36%純度)添加到3-(1-苯甲基-4,5,6,7-四氫吲唑-5-羰基)-5-甲基-2-側氧基哌啶-1-甲酸第三丁 酯(2.2g，4.87mmol)於乙酸(15mL)中之溶液中且將所得混合物在100℃下攪拌15h。然後，在減壓下移除揮發物且將殘餘物溶解於水(60ml)中。透過棉花墊過濾出一些不溶性焦油。將濾液用DCM(2x10ml)萃取且丟棄有機層。然後，將水層用固體K2 CO3 鹼化至pH

Figure 110128222-A0202-12-2522-549
10且用DCM(2x20ml)萃取。將有機層分離，經K2 CO3 乾燥且在減壓下濃縮，得到1-苯甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-4,5,6,7-四氫吲唑(760mg，2.47mmol，50.74%產率)。36% w/w aqueous hydrochloric acid (11.80 g, 116.51 mmol, 10.00 mL, 36% purity) was added to 3-(1-benzyl-4,5,6,7-tetrahydroindazole-5-carbonyl) - A solution of tert -butyl 5-methyl-2-oxypiperidine-1-carboxylate (2.2 g, 4.87 mmol) in acetic acid (15 mL) and the resulting mixture was stirred at 100 &lt;0&gt;C for 15 h. Then, the volatiles were removed under reduced pressure and the residue was dissolved in water (60 ml). Filter out some insoluble tar through a cotton pad. The filtrate was extracted with DCM (2x10ml) and the organic layer was discarded. Then, the aqueous layer was basified to pH with solid K2CO3
Figure 110128222-A0202-12-2522-549
10 and extracted with DCM (2x20ml). The organic layer was separated, dried over K2CO3 and concentrated under reduced pressure to give 1-benzyl-5-( 3 -methyl-2,3,4,5-tetrahydropyridin-6-yl)- 4,5,6,7-Tetrahydroindazole (760 mg, 2.47 mmol, 50.74% yield).

1 H NMR(400MHz,CDCl3 )δ(ppm)0.92(d,3H),1.23(m,1H),1.57(m,1H),1.73(m,2H),2.23(m,4H),2.67(m,3H),2.86(m,1H),3.01(m,1H),3.74(d,1H),5.18(s,2H),7.04(s,1H),7.29(m,5H)。LCMS(ESI)：[M]+ m/z：計算值307.2；實測值308.2；Rt=1.016min。 1 H NMR (400MHz, CDCl 3 )δ(ppm) 0.92(d,3H), 1.23(m,1H), 1.57(m,1H), 1.73(m,2H), 2.23(m,4H), 2.67( m, 3H), 2.86 (m, 1H), 3.01 (m, 1H), 3.74 (d, 1H), 5.18 (s, 2H), 7.04 (s, 1H), 7.29 (m, 5H). LCMS (ESI): [M] + m/z: calculated 307.2; found 308.2; Rt=1.016 min.

步驟6：1-苯甲基-5-(5-甲基哌啶-2-基)-3a,4,5,6,7,7a-六氫-1H-吲唑之合成Step 6: Synthesis of 1-benzyl-5-(5-methylpiperidin-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-indazole

在15分鐘期間將硼氫化鈉(187.05mg，4.94mmol，174.81μL)分批添加1-苯甲基-5-(3-甲基-2,3,4,5-四氫吡啶-6-基)-4,5,6,7-四氫吲唑(760mg，2.47mmol)於MeOH(20mL)中之溶液中。將所得溶液在20℃下攪拌2h。然後，在減壓下移除溶劑且將殘餘物分配於水(20ml)與DCM(30ml)之間。將有機層分離，經Na2 SO4 乾燥且在真空中蒸發，得到1-苯甲基-5-(5-甲基-2-哌啶基)-4,5,6,7-四氫吲唑(750mg，2.42mmol，98.04%產率)。Sodium borohydride (187.05 mg, 4.94 mmol, 174.81 μL) was added portionwise over 15 minutes to 1-benzyl-5-(3-methyl-2,3,4,5-tetrahydropyridin-6-yl )-4,5,6,7-tetrahydroindazole (760 mg, 2.47 mmol) in MeOH (20 mL). The resulting solution was stirred at 20 °C for 2 h. Then, the solvent was removed under reduced pressure and the residue was partitioned between water (20ml) and DCM (30ml). The organic layer was separated, dried over Na 2 SO 4 and evaporated in vacuo to give 1-benzyl-5-(5-methyl-2-piperidinyl)-4,5,6,7-tetrahydroindoline azole (750 mg, 2.42 mmol, 98.04% yield).

1 H NMR(500MHz,CDCl3 )δ(ppm)0.83(d,3H),1.00(m,1H),1.22(m,2H),1.71(m,4H),1.83(m,2H),2.03(m,1H),2.37(m,3H),2.64(m,2H),3.06(d,1H),5.20(s,2H),7.08(s,1H),7.31(m,5H)。LCMS(ESI)：[M]+ m/z：計算值309.2；實測值310.2； Rt=0.895min。 1 H NMR (500MHz, CDCl 3 )δ(ppm) 0.83(d,3H), 1.00(m,1H), 1.22(m,2H), 1.71(m,4H), 1.83(m,2H), 2.03( m, 1H), 2.37 (m, 3H), 2.64 (m, 2H), 3.06 (d, 1H), 5.20 (s, 2H), 7.08 (s, 1H), 7.31 (m, 5H). LCMS (ESI): [M] + m/z: calculated 309.2; found 310.2; Rt=0.895min.

步驟7：5-(2-(2-(1-苯甲基-3a,4,5,6,7,7a-六氫-1H-吲唑-5-基)-5-甲基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺之合成Step 7: 5-(2-(2-(1-Benzyl-3a,4,5,6,7,7a-hexahydro-1H-indazol-5-yl)-5-methylpiperidine- Synthesis of 1-yl)-2-oxyacetamido)nicotinamide

將1-苯甲基-5-(5-甲基-2-哌啶基)-4,5,6,7-四氫吲唑(750mg，2.42mmol)、2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(595.30mg，2.42mmol，HCl)及TEA(735.76mg，7.27mmol，1.01mL)一起混合於DMF(10mL)中。將所獲得之混合物簡單加熱至60-70℃，直到形成澄清溶液。在冷卻至5-10℃之後，在5min期間分批添加HATU(1.01g，2.67mmol)。將所得溶液在20℃下攪拌15h。然後，將其用水(40ml)稀釋且用乙酸乙酯(80ml)萃取。將有機層用水(2x30ml)及鹽水(30ml)洗滌，經Na2 SO4 乾燥且在減壓下蒸發。使殘餘物經歷HPLC(管柱：YMC Triart C18 100x20mm，5um；60-60-80% 0-1-6min 0.1% NH3 -MeOH，流速：30ml/min)，得到5-[[2-[2-(1-苯甲基-4,5,6,7-四氫吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(443mg，884.95μmol，36.51%產率)。1-Benzyl-5-(5-methyl-2-piperidinyl)-4,5,6,7-tetrahydroindazole (750 mg, 2.42 mmol), 2-[(5-aminocarboxylate (595.30 mg, 2.42 mmol, HCl) and TEA (735.76 mg, 7.27 mmol, 1.01 mL) were mixed together in DMF (10 mL). The obtained mixture was heated briefly to 60-70°C until a clear solution formed. After cooling to 5-10 °C, HATU (1.01 g, 2.67 mmol) was added portionwise during 5 min. The resulting solution was stirred at 20 °C for 15 h. It was then diluted with water (40ml) and extracted with ethyl acetate (80ml). The organic layer was washed with water (2x30ml) and brine (30ml), dried over Na2SO4 and evaporated under reduced pressure. The residue was subjected to HPLC (column: YMC Triart C18 100x20mm, 5um; 60-60-80% 0-1-6 min 0.1% NH3 -MeOH, flow rate: 30 ml/min) to give 5-[[2-[2 -(1-Benzyl-4,5,6,7-tetrahydroindazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyacetyl]amino] Pyridine-3-carboxamide (443 mg, 884.95 μmol, 36.51% yield).

1 H NMR(400MHz,DMSO-d 6 )δ(ppm)0.75(m,1H),0.93(d,3H),1.13(m,1H),1.26(m,2H),1.66(m,2H),1.84(m,1H),1.94(m,3H),2.22(m,1H),2.64(m,2H),2.93(m,1H),3.61(m,1H),5.14(s,2H),7.18(m,5H),7.46(m,1H),7.61(m,1H),8.16(m,1H),8.45(m,1H),8.74(m,1H),8.87(m,1H),11.11(m,1H)。LCMS(ESI)：[M]+ m/z：計算值500.2；實測值501.2；Rt=2.371min。 1 H NMR (400MHz, DMSO- d 6 )δ(ppm) 0.75(m, 1H), 0.93(d, 3H), 1.13(m, 1H), 1.26(m, 2H), 1.66(m, 2H), 1.84(m, 1H), 1.94(m, 3H), 2.22(m, 1H), 2.64(m, 2H), 2.93(m, 1H), 3.61(m, 1H), 5.14(s, 2H), 7.18 (m,5H),7.46(m,1H),7.61(m,1H),8.16(m,1H),8.45(m,1H),8.74(m,1H),8.87(m,1H),11.11( m, 1H). LCMS (ESI): [M] + m/z: calculated 500.2; found 501.2; Rt=2.371 min.

步驟8：5-(2-(5-甲基-2-(4,5,6,7-四氫-1H-吲唑-5-基)哌啶-1-基)-2-側氧基乙醯胺基)哌啶-3-甲醯胺(化合物755 )之合成Step 8: 5-(2-(5-Methyl-2-(4,5,6,7-tetrahydro-1H-indazol-5-yl)piperidin-1-yl)-2-pendoxyl Synthesis of Acetamido)Piperidin-3-Carboxamide ( Compound 755 )

將鈀(5%於活性碳上)noblyst p1090(400mg，187.93μmol，5%純度)添加到5-[[2-[2-(1-苯甲基-4,5,6,7-四氫吲唑-5-基)-5-甲基-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(443mg，884.95μmol)於MeOH(20mL)中之溶液中。將所得混合物在氫氣氣氛、40℃下攪拌6天(氣球壓力)且在10巴下攪拌48小時。然 後，過濾出催化劑且將濾液在減壓下濃縮。藉由HPLC(管柱：SunFireC18 100*19mm 5um；15-65% 0-5min水-MeOH，流速30ml/min)純化殘餘物，得到5-[[2-[(2S,5R )-2,5-二甲基-2-[(5R )-5-甲基-1,4,6,7-四氫吲唑-5-基]-1-哌啶基]-2-側氧基乙醯基]胺基]吡啶-3-甲醯胺(16mg，36.49μmol，4.12%產率)及5-[[2-[5-甲基-2-(4,5,6,7-四氫-1H -吲唑-5-基)-1-哌啶基]-2-側氧基乙醯基]胺基]哌啶-3-甲醯胺(49mg，117.64μmol，13.29%產率)。Palladium (5% on activated carbon) noblyst p1090 (400 mg, 187.93 μmol, 5% purity) was added to 5-[[2-[2-(1-benzyl-4,5,6,7-tetrahydro Indazol-5-yl)-5-methyl-1-piperidinyl]-2-oxyethanoyl]amino]pyridine-3-carboxamide (443 mg, 884.95 μmol) in MeOH (20 mL) in the solution. The resulting mixture was stirred under a hydrogen atmosphere at 40° C. for 6 days (balloon pressure) and at 10 bar for 48 hours. Then, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: SunFire C18 100*19mm 5um; 15-65% 0-5min water-MeOH, flow rate 30ml/min) to give 5-[[2-[( 2S,5R )-2,5 -Dimethyl-2-[( 5R )-5-methyl-1,4,6,7-tetrahydroindazol-5-yl]-1-piperidinyl]-2-side oxyacetyl ]amino]pyridine-3-carboxamide (16 mg, 36.49 μmol, 4.12% yield) and 5-[[2-[5-methyl-2-(4,5,6,7-tetrahydro- 1H -Indazol-5-yl)-1-piperidinyl]-2-oxoacetoxy]amino]piperidine-3-carbamide (49 mg, 117.64 μmol, 13.29% yield).

化合物755：Compound 755:

LCMS(ESI)：[M]+ m/z：計算值416.2；實測值417.2；Rt=1.747min。LCMS (ESI): [M] + m/z: calculated 416.2; found 417.2; Rt=1.747 min.

實例790. 5-[[2-側氧基-2-[2-(2-側氧基-1H-吡啶-4-基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物262)之合成Example 790. 5-[[2-Oxy-2-[2-(2-Oxy-1H-pyridin-4-yl)-1-piperidinyl]acetyl]amino]pyridine-3 -Synthesis of carboxamide (compound 262)

Figure 110128222-A0202-12-2524-499
Figure 110128222-A0202-12-2524-499

步驟1：6-(2-側氧基-1H-吡啶-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of 6-(2-oxy-1H-pyridin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

向4-溴-1H-吡啶-2-酮(180mg，1.03mmol)於二噁烷(35mL)/H2 O(6mL)中之溶液中添加Pd(PPh3 )4 (35mg，30.3μmol)、K2 CO3 (402mg，2.91mmol)及6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(300mg，0.970mmol)。將懸浮液除氣且用氮氣吹掃3次。將混合物在氮氣、90℃下攪拌12小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(15mL * 3)萃取。將經合併之有機層用鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~100%，然後EtOAc/MeOH，其中MeOH為0~20%，流速： 30mL/min)純化殘餘物，以得到呈黃色固體之6-(2-側氧基-1H-吡啶-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(60mg，粗品)。LCMS(ESI)[M+H]+ m/z計算值277.2，實測值277.1。To a solution of 4-bromo-1H-pyridin-2-one (180 mg, 1.03 mmol) in dioxane (35 mL)/H 2 O (6 mL) was added Pd(PPh 3 ) 4 (35 mg, 30.3 μmol), K 2 CO 3 (402 mg, 2.91 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4- Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (300 mg, 0.970 mmol). The suspension was degassed and purged with nitrogen 3 times. The mixture was stirred under nitrogen at 90°C for 12 hours. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (15 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-100% EtOAc, then EtOAc/MeOH with 0-20% MeOH, flow rate: 30 mL/min ) purification of the residue to give tert-butyl 6-(2-oxy-1H-pyridin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid as a yellow solid (60 mg, Crude). LCMS (ESI) [M+H] + m/z calcd 277.2, found 277.1.

步驟2：2-(2-側氧基-1H-吡啶-4-基)哌啶-1-甲酸第三丁酯之合成Step 2: Synthesis of 3-butyl 2-(2-oxy-1H-pyridin-4-yl)piperidine-1-carboxylate

在氮氣下，向6-(2-側氧基-1H-吡啶-4-基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(50mg，0.181mmol)於MeOH(5mL)中之溶液中添加Pd/C(10mg，具有50重量%水之10重量% Pd)。將混合物除氣且用氮氣吹掃3次。將混合物在氫氣(在氣球中，約15psi)、20℃下攪拌12小時。將所得混合物過濾且在減壓下濃縮，以得到呈黃色固體之2-(2-側氧基-1H-吡啶-4-基)哌啶-1-甲酸第三丁酯(50mg，粗品)，其不經進一步純化即直接用於下一步驟中。To 6-(2-oxy-1H-pyridin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.181 mmol) in MeOH ( Pd/C (10 mg, 10 wt % Pd with 50 wt % water) was added to the solution in 5 mL). The mixture was degassed and purged with nitrogen three times. The mixture was stirred under hydrogen (in a balloon, about 15 psi) at 20°C for 12 hours. The resulting mixture was filtered and concentrated under reduced pressure to give tert-butyl 2-(2-oxy-lH-pyridin-4-yl)piperidine-l-carboxylate (50 mg, crude) as a yellow solid, It was used directly in the next step without further purification.

步驟3：4-(2-哌啶基)-1H-吡啶-2-酮之合成Step 3: Synthesis of 4-(2-piperidinyl)-1H-pyridin-2-one

向2-(2-側氧基-1H-吡啶-4-基)哌啶-1-甲酸第三丁酯(50mg，0.180mmol)於DCM(5mL)中之溶液中添加TFA(0.5mL)。將混合物在20℃下攪拌2小時。將所得混合物在減壓下濃縮，以得到呈黃色油狀物之4-(2-哌啶基)-1H-吡啶-2-酮(50mg，粗品，TFA)，其不經進一步純化即用於下一步驟中。To a solution of tert-butyl 2-(2-oxy-lH-pyridin-4-yl)piperidine-l-carboxylate (50 mg, 0.180 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at 20°C for 2 hours. The resulting mixture was concentrated under reduced pressure to give 4-(2-piperidinyl)-1H-pyridin-2-one (50 mg, crude, TFA) as a yellow oil, which was used without further purification in the next step.

步驟4：2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸乙酯之合成Step 4: Synthesis of ethyl 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-oxoacetate

向5-胺基吡啶-3-甲醯胺(200mg，1.46mmol)、DIPEA(800μL，4.59mmol)於DCM(8mL)中之溶液中添加2-氯-2-側氧基乙酸乙酯(300mg，2.20mmol)且將反應混合物在20℃下攪拌12小時。所得混合物藉由添加水(10mL)來淬滅且用EtOAc(20mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(20mL)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由製備型TLC(二氧化矽，DCM/MeOH=10：1，254nm)純化殘餘物，以得到呈黃色固體之2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸乙酯(70mg，20.2%產率)。1 H NMR(400MHz,甲醇-d 4 )δ ppm 9.04(d,J =2.5Hz,1 H),8.82(d,J =2.0Hz,1 H),8.67(t,J =2.3Hz, 1 H),4.43(q,J =7.3Hz,1 H),1.43(t,J =7.2Hz,2 H)；LCMS(ESI)[M+H]+ m/z計算值238.1，實測值238.2。To a solution of 5-aminopyridine-3-carboxamide (200 mg, 1.46 mmol), DIPEA (800 μL, 4.59 mmol) in DCM (8 mL) was added ethyl 2-chloro-2-oxoacetate (300 mg) , 2.20 mmol) and the reaction mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by adding water (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (20 mL), brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica, DCM/MeOH=10:1, 254 nm) to give 2-[(5-aminocarbamoyl-3-pyridinyl)amino]- as a yellow solid Ethyl 2-Pendoxoacetate (70 mg, 20.2% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 9.04 (d, J =2.5 Hz, 1 H), 8.82 (d, J =2.0 Hz, 1 H), 8.67 (t, J =2.3 Hz, 1 H) ), 4.43(q, J =7.3Hz, 1 H), 1.43(t, J =7.2Hz, 2 H); LCMS(ESI)[M+H] + m/z calculated 238.1, found 238.2.

步驟5：2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸之合成Step 5: Synthesis of 2-[(5-aminocarbamoyl-3-pyridyl)amino]-2-pendoxoacetic acid

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸乙酯(60mg，0.253mmol)於THF(5mL)/H2 O(1mL)中之溶液中添加LiOH-H2 O(11mg，0.262mmol)。將混合物在20℃下攪拌30分鐘。將所得混合物過濾，以得到黃色固體，將其溶解於4M HCl/EtOAc(15mL，60mmol)中，且將混合物在20℃下攪拌3小時。將所得混合物過濾，以得到呈黃色固體之2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(50mg，80.5%產率，HCl)。1 H NMR(400MHz,DMSO-d 6 )δ ppm 11.25(s,1 H),9.08(d,J =2.5Hz,1 H),8.87(d,J =1.8Hz,1 H),8.74(d,J =2.0Hz,1 H),8.27(br s,1 H),7.73(br s,1 H)。To a solution of ethyl 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetate (60 mg, 0.253 mmol) in THF (5 mL)/H 2 O (1 mL) To this was added LiOH- H2O (11 mg, 0.262 mmol). The mixture was stirred at 20°C for 30 minutes. The resulting mixture was filtered to give a yellow solid, which was dissolved in 4M HCl/EtOAc (15 mL, 60 mmol), and the mixture was stirred at 20°C for 3 hours. The resulting mixture was filtered to give 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (50 mg, 80.5% yield, HCl) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 11.25(s,1H), 9.08(d, J =2.5Hz,1H), 8.87(d, J =1.8Hz,1H), 8.74(d , J = 2.0Hz, 1 H), 8.27(br s, 1 H), 7.73(br s, 1 H).

步驟6：5-[[2-側氧基-2-[2-(2-側氧基-1H-吡啶-4-基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(化合物262 )之合成Step 6: 5-[[2-Oxy-2-[2-(2-Oxy-1H-pyridin-4-yl)-1-piperidinyl]acetyl]amino]pyridine-3 -Synthesis of carboxamide ( compound 262 )

向2-[(5-胺甲醯基-3-吡啶基)胺基]-2-側氧基乙酸(38mg，0.155mmol，HCl)於DMF(2mL)中之混合物中添加HATU(80mg，0.210mmol)及DIPEA(300μL，1.72mmol)。將混合物在20℃下攪拌1小時。藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：3_Phenomenex Luna C18 75 * 30mm * 3μm；流動相A：水(0.225%FA)；流動相B：MeCN；梯度：在8.5min內0%至25% B，保持100% B達1min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)純化所得混合物，以得到呈白色固體之5-[[2-側氧基-2-[2-(2-側氧基-1H-吡啶-4-基)-1-哌啶基]乙醯基]胺基]吡啶-3-甲醯胺(6.8mg，13.1%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.93-9.06(m,1 H),8.79-8.85(m,1 H),8.67(s,1 H),8.62(s,1 H),7.46-7.52(m,1 H),6.54(s,1 H),6.43-6.51(m,1 H),5.66(br s,1 H),5.45(br s,1 H),4.49(br d,J =11.3Hz,1 H),4.02(br d,J =14.6Hz,1 H),3.17(br d,J =14.6Hz,1 H),2.43(br d,J =13.3Hz,1 H),1.94-2.09(m,1 H),1.75(br d,J =11.5Hz,3 H),1.59(br s,1 H)；LCMS(ESI)[M+H]+ m/z計算值370.1，實測值370.3；HPLC：在254nm下為100%；外消旋物。To a mixture of 2-[(5-aminocarbamoyl-3-pyridinyl)amino]-2-oxoacetic acid (38 mg, 0.155 mmol, HCl) in DMF (2 mL) was added HATU (80 mg, 0.210 mmol) and DIPEA (300 μL, 1.72 mmol). The mixture was stirred at 20°C for 1 hour. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase A: water (0.225% FA); mobile phase A: water (0.225% FA) Phase B: MeCN; Gradient: 0% to 25% B in 8.5 min, hold 100% B for 1 min; Flow rate: 25 mL/min; Column temperature: 30°C; Wavelength: 220 nm, 254 nm) The resulting mixture was purified to give 5-[[2-Oxy-2-[2-(2-Oxy-1H-pyridin-4-yl)-1-piperidinyl]acetyl]amino]pyridine- as a white solid 3-Carboxamide (6.8 mg, 13.1% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 8.93-9.06(m,1H), 8.79-8.85(m,1H), 8.67(s,1H), 8.62(s,1H), 7.46 -7.52(m, 1 H), 6.54(s, 1 H), 6.43-6.51(m, 1 H), 5.66(br s, 1 H), 5.45(br s, 1 H), 4.49(br d, J = 11.3Hz, 1 H), 4.02(br d, J =14.6Hz, 1 H), 3.17(br d, J =14.6Hz, 1 H), 2.43(br d, J =13.3Hz, 1 H) ,1.94-2.09(m,1 H),1.75(br d, J =11.5Hz,3 H),1.59(br s,1 H); LCMS(ESI)[M+H] + m/z calcd 370.1 , found 370.3; HPLC: 100% at 254 nm; racemate.

實例791. N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1240)之合成Example 791. N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[2-(4-piperidinyl)-1 Synthesis of ,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1240)

Figure 110128222-A0202-12-2527-500
Figure 110128222-A0202-12-2527-500

步驟1：(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 1: Synthesis of (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將(5S)-5-甲基-2-側氧基哌啶-1-甲酸第三丁酯(5g，23.4mmol)於THF(60mL)中之混合物密封且在真空下除氣且用N2 吹掃三次，然後在-78℃下逐滴添加1M LiHMDS/THF(42.0mL，42.0mmol)，將混合物在-78℃下攪拌1.5小時，然後添加PhNTf2 (13.0g，36.4mmol)於THF(20mL)中之溶液。將溶液在25℃下攪拌12小時。藉由添加飽和NH4 Cl水溶液(100mL)淬滅所得混合物且用EtOAc(200mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL)、鹽水(100mL) 洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO®；80g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~1%，流速=60mL/min，I2 )純化殘餘物，以得到呈無色油狀物之(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.3g，90.2%產率)。LCMS(ESI)[M+H]+ m/z：計算值346.1，實測值290.0(Boc及t-Bu裂解質量)。A mixture of (5S)-tert-butyl 5-methyl-2-oxypiperidine-1-carboxylate (5 g, 23.4 mmol) in THF (60 mL) was sealed and degassed under vacuum and filled with N 2 After purging three times, 1M LiHMDS/THF (42.0 mL, 42.0 mmol) was added dropwise at -78 °C, the mixture was stirred at -78 °C for 1.5 h, then PhNTf 2 (13.0 g, 36.4 mmol) in THF ( 20mL) solution. The solution was stirred at 25°C for 12 hours. The resulting mixture was quenched by addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (200 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL), brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-1% EtOAc, flow = 60 mL/min, I 2 ) to give a colorless oil (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.3 g, 90.2%) Yield). LCMS (ESI) [M+H] + m/z: calculated 346.1, found 290.0 (Boc and t-Bu fragmentation mass).

步驟2：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑之合成Step 2: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole

將5-溴-1,3-苯并噻唑(5g，23.4mmol)、KOAc(1.3g，46.7mmol)、環戊基(二苯基)磷烷；二氯鈀；鐵(2g，2.73mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(13.5g，53.2mmol)及二噁烷(50mL)之混合物在100℃、N2 下攪拌60h。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；80g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~10%，流速：30mL/min，254nm)進行純化，以得到呈白色固體之5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(4.5g，73.8%產率)。LCMS(ESI)[M+H]+ m/z：計算值262.1，實測值261.7。5-Bromo-1,3-benzothiazole (5 g, 23.4 mmol), KOAc (1.3 g, 46.7 mmol), cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (2 g, 2.73 mmol) , 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1, A mixture of 3,2-dioxaborolane (13.5 g, 53.2 mmol) and dioxane (50 mL) was stirred at 100 °C under N 2 for 60 h. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (100 mL*2), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash (ISCO®; 80 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-10% EtOAc, flow rate: 30 mL/min, 254 nm) was purified to give 5-(4,1 as a white solid). 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (4.5 g, 73.8% yield). LCMS (ESI) [M+H] + m/z: calcd 262.1, found 261.7.

步驟3：(3S)-6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯之合成Step 3: Synthesis of (3S)-6-(1,3-benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

將5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-苯并噻唑(4.5g，17.2mmol)、(3S)-3-甲基-6-(三氟甲基磺醯基氧基)-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(7.14g，20.7mmol)、Na2 CO3 (5.94g，56.0mmol)、環戊基(二苯基)磷烷；二氯甲烷；二氯鈀；鐵(1.44g，1.76mmol)、二噁烷(50mL)及H2 O(20mL)之混合物在85℃下攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL * 2)、鹽水(100mL) 洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~10%，流速：30mL/min，254nm)進行純化，以得到呈黃色固體之(3S)-6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.2g，73.8%產率)。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-benzothiazole (4.5 g, 17.2 mmol) , (3S)-3-methyl-6-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.14 g, 20.7 mmol), Na2CO3 (5.94 g , 56.0 mmol), cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; iron (1.44 g, 1.76 mmol), dioxane (50 mL) and H2O (20 mL) of the mixture was stirred at 85°C for 12 hours. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (100 mL*2), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash (ISCO®; 24g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-10% EtOAc, flow rate: 30 mL/min, 254 nm) was purified to give (3S)-6 as a yellow solid -(1,3-Benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.2 g, 73.8% yield).

LCMS(ESI)[M+H]+ m/z：計算值331.1，實測值331.2。LCMS (ESI) [M+H] + m/z: calcd 331.1, found 331.2.

步驟4：(5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成 將(3S)-6-(1,3-苯并噻唑-5-基)-3-甲基-3,4-二氫-2H-吡啶-1-甲酸第三丁酯(4.2g，12.7mmol)、TFA(10mL，0.130mol)於DCM(10mL)之混合物在20℃下攪拌2小時。在減壓下濃縮混合物。將殘餘物用MeOH(20mL)溶解，然後在0℃下添加K2 CO3 (5.3g，38.4mmol)及NaBH4 (420mg，11.1mmol)。將所得混合物在0℃下攪拌0.5小時。添加碳酸第三丁氧基羰基酯第三丁酯(7g，32.1mmol)及H2 O(10mL)。將混合物在20℃下攪拌12小時。所得混合物藉由添加水(100mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(100mL * 2)、鹽水(100mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；24g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~15%，流速：30mL/min，254nm)純化殘餘物，以得到呈白色固體之(5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(4g，94.7%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 9.25(s,1H),8.06(d,J =8.3Hz,1H),7.94(s,1H),7.42(dd,J =8.4,1.4Hz,1H),5.40(s,1H),3.77(br d,J =13.6Hz,1H),3.13(dd,J =13.6,3.8Hz,1H),2.10-2.29(m,2H),1.86-1.93(m,1H),1.75-1.84(m,1H),1.45(s,9H),1.32-1.42(m,1H),1.08(d,J =6.8Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值333.2，實測值333.1。 Step 4: Synthesis of (5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (3S)-6-(1,3 -Benzothiazol-5-yl)-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.2 g, 12.7 mmol), TFA (10 mL, 0.130 mol) in DCM (10 mL) of the mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL), then K2CO3 ( 5.3 g , 38.4 mmol) and NaBH4 ( 420 mg, 11.1 mmol) were added at 0 °C. The resulting mixture was stirred at 0°C for 0.5 hours. 3-Butoxycarbonyl carbonate 3-butyl ester (7 g, 32.1 mmol) and H2O (10 mL) were added. The mixture was stirred at 20°C for 12 hours. The resulting mixture was quenched by adding water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (100 mL*2), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash The residue was purified by analytical (ISCO®; 24 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-15% EtOAc, flow rate: 30 mL/min, 254 nm) to give (5S)- as a white solid - 2-(1,3-Benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (4 g, 94.7% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 9.25 (s, 1H), 8.06 (d, J =8.3 Hz, 1H), 7.94 (s, 1H), 7.42 (dd, J =8.4, 1.4 Hz, 1H), 5.40(s, 1H), 3.77(br d, J =13.6Hz, 1H), 3.13(dd, J =13.6, 3.8Hz, 1H), 2.10-2.29(m, 2H), 1.86-1.93( m,1H),1.75-1.84(m,1H),1.45(s,9H),1.32-1.42(m,1H),1.08(d, J =6.8Hz,3H); LCMS(ESI)[M+H ] + m/z: Calculated 333.2, Measured 333.1.

步驟5：(5S)-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯之合成Step 5: Synthesis of (5S)-2-(2-bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester

向(5S)-2-(1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(4g，12.0 mmol)、t-BuONa(3.47g，36.1mmol)及DMF(30mL)之混合物中緩慢添加CBr4 (4.42g，13.3mmol)。將混合物在20℃下攪拌1小時。所得混合物藉由添加水(30mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(30mL * 2)、鹽水(30mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，以得到殘餘物，其藉由急驟層析(ISCO®；40g AgelaFlash®二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~20%，流速：30mL/min，254nm)進行純化，以得到呈黃色固體之(5S)-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(2.4g，48.5%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 7.93(d,J =8.5Hz,1H),7.81(s,1 H),7.39(dd,J =8.5,1.0Hz,1 H),5.36(t,J =4.8Hz,1 H),3.76(br d,J =13.6Hz,1 H),3.11(dd,J =13.6,3.8Hz,1 H),2.06-2.27(m,2 H),1.87(br dd,J =6.4,2.9Hz,1 H),1.70-1.84(m,1 H),1.48(br d,J =5.5Hz,1 H),1.44(s,9 H),1.07(d,J =6.8Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值413.1，實測值413.0。To (5S)-3-butyl 2-(1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylate (4 g, 12.0 mmol), t-BuONa (3.47 g, 36.1 mmol) and DMF (30 mL) was slowly added CBr4 (4.42 g, 13.3 mmol). The mixture was stirred at 20°C for 1 hour. The resulting mixture was quenched by adding water (30 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH 4 Cl (30 mL*2), brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was washed by flash (ISCO®; 40 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-20% EtOAc, flow rate: 30 mL/min, 254 nm) for purification to give (5S)-2 as a yellow solid -(2-Bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (2.4 g, 48.5% yield). 1 H NMR (400 MHz, methanol- d 4 ) δ ppm 7.93 (d, J =8.5 Hz, 1 H), 7.81 (s, 1 H), 7.39 (dd, J =8.5, 1.0 Hz, 1 H), 5.36 ( t, J =4.8Hz,1H),3.76(br d, J =13.6Hz,1H),3.11(dd, J =13.6,3.8Hz,1H),2.06-2.27(m,2H), 1.87(br dd, J =6.4,2.9Hz,1 H),1.70-1.84(m,1 H),1.48(br d, J =5.5Hz,1 H),1.44(s,9 H),1.07( d, J =6.8Hz,3H); LCMS(ESI)[M+H] + m/z: calculated 413.1, found 413.0.

步驟6：4-[5-[(5S)-1-第三丁氧基羰基-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯之合成Step 6: 4-[5-[(5S)-1-tert-butoxycarbonyl-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6 - Synthesis of benzyl dihydro-2H-pyridine-1-carboxylate

向(5S)-2-(2-溴-1,3-苯并噻唑-5-基)-5-甲基哌啶-1-甲酸第三丁酯(300mg，0.729mmol)及4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H-吡啶-1-甲酸苯甲酯(375mg，1.09mmol)於EtOH(4mL)及H2 O(1mL)中之混合物中添加Pd(PPh3 )4 (90mg，0.0779mmol)及K2 CO3 (300mg，2.17mmol)。將所得混合物在微波、95℃下攪拌1.5小時。所得混合物藉由添加水(50mL)來淬滅且用EtOAc(100mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~30%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色固體之4-[5-[(5S)-1-第三丁氧基羰基-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯(340 mg，85.1%產率)。LCMS(ESI)[M+H]+ m/z：計算值548.3，實測值548.3。To (5S)-3-butyl 2-(2-bromo-1,3-benzothiazol-5-yl)-5-methylpiperidine-1-carboxylate (300 mg, 0.729 mmol) and 4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl (375mg , 1.09 mmol) in EtOH (4 mL) and H2O (1 mL) was added Pd( PPh3 ) 4 (90 mg, 0.0779 mmol) and K2CO3 ( 300 mg , 2.17 mmol). The resulting mixture was stirred in the microwave at 95°C for 1.5 hours. The resulting mixture was quenched by adding water (50 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL), brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-30% EtOAc, flow rate = 30 mL/min, 254 nm) to give a yellow solid 4-[5-[(5S)-1-Third-butoxycarbonyl-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6-dihydro -2H-Pyridine-1-carboxylic acid benzyl (340 mg, 85.1% yield). LCMS (ESI) [M+H] + m/z: calcd 548.3, found 548.3.

步驟7：4-[5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯之合成Step 7: 4-[5-[(5S)-5-Methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1 -Synthesis of benzyl formate

將4-[5-[(5S)-1-第三丁氧基羰基-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯(290mg，0.529mmol)、MeOH(3mL)及4M HCl/MeOH(3mL，12.0mmol)之混合物在20℃下攪拌12小時。將所得混合物在減壓下濃縮，以得到呈白色固體之4-[5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯(250mg，粗品，HCl)。4-[5-[(5S)-1-tert-butoxycarbonyl-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6-di A mixture of benzyl hydrogen-2H-pyridine-1-carboxylate (290 mg, 0.529 mmol), MeOH (3 mL) and 4M HCl/MeOH (3 mL, 12.0 mmol) was stirred at 20 °C for 12 h. The resulting mixture was concentrated under reduced pressure to give 4-[5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]- 3,6-Dihydro-2H-pyridine-1-carboxylic acid benzyl ester (250 mg, crude, HCl).

步驟8：4-[5-[(5S)-1-[2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯之合成Step 8: 4-[5-[(5S)-1-[2-[[6-[bis(tert-butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]- 2-Oxyacetyl]-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzene Synthesis of methyl esters

將4-[5-[(5S)-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯(250mg，0.516mmol，HCl)、2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙酸(230mg，0.562mmol)、HATU(240mg，0.631mmol)及DIPEA(0.45mL，2.58mmol)於DCM(6mL)中之混合物在20℃下攪拌2小時。所得混合物藉由添加水(50mL)來淬滅且用DCM(50mL * 3)萃取。將經合併之有機層用飽和NH4 Cl水溶液(50mL)、鹽水(50mL)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~70%，流速=30mL/min，254nm)純化殘餘物，以得到呈黃色油狀物之4-[5-[(5S)-1-[2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯(300mg，69.2%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.43-8.75(m,1H),8.22(br s,1H),7.95(br s,2H),7.34-7.52(m,6H),5.85(br s,1H),5.49(s,2H),5.20(br d,J =14.3Hz,2H),3.66-3.86(m,3H),2.50-2.70(m,3H),2.35 (br s,4H),1.96(br s,2H),1.51(br s,2H),1.36-1.41(m,18H),1.29(br s,3H),1.16(br d,J =6.8Hz,3H)。4-[5-[(5S)-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid Benzyl methyl ester (250 mg, 0.516 mmol, HCl), 2-[[6-[bis(tert-butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2-oxygen A mixture of acetic acid (230 mg, 0.562 mmol), HATU (240 mg, 0.631 mmol) and DIPEA (0.45 mL, 2.58 mmol) in DCM (6 mL) was stirred at 20 °C for 2 h. The resulting mixture was quenched by adding water (50 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with saturated aqueous NH4Cl (50 mL), brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( ISCO® ; 12g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-70% EtOAc, flow = 30 mL/min, 254 nm) to give a yellow oil 4-[5-[(5S)-1-[2-[[6-[bis(tertiary butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2 -Pendant oxyacetyl]-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (300 mg, 69.2% yield). 1 H NMR (400MHz, methanol- d 4 ) δ ppm 8.43-8.75(m,1H), 8.22(br s,1H), 7.95(br s,2H), 7.34-7.52(m,6H), 5.85(br s,1H),5.49(s,2H),5.20(br d, J =14.3Hz,2H),3.66-3.86(m,3H),2.50-2.70(m,3H),2.35(br s,4H) , 1.96(br s, 2H), 1.51(br s, 2H), 1.36-1.41(m, 18H), 1.29(br s, 3H), 1.16(br d, J = 6.8Hz, 3H).

步驟9：4-[5-[(5S)-1-[2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]哌啶-1-甲酸苯甲酯之合成Step 9: 4-[5-[(5S)-1-[2-[[6-[bis(tert-butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]- Synthesis of benzyl 2-oxyacetyl]-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]piperidine-1-carboxylate

將4-[5-[(5S)-1-[2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]-3,6-二氫-2H-吡啶-1-甲酸苯甲酯(200mg，0.238mmol)及Pd/C(50mg，具有50重量%水之10重量% Pd/C)於t-BuOH(6mL)中之混合物在50℃下在H2 下(在氣球中)攪拌12小時。將所得混合物過濾且在減壓下濃縮，以得到粗產物，其藉由急驟層析(ISCO® ；12g AgelaFlash® 二氧化矽急驟管柱，石油醚/EtOAc，其中EtOAc為0~70%，流速=30mL/min，254nm)進行純化，以得到呈黃色固體之4-[5-[(5S)-1-[2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]哌啶-1-甲酸苯甲酯(140mg，粗品)。LCMS(ESI)[M+H]+ m/z：計算值841.4，實測值841.4。4-[5-[(5S)-1-[2-[[6-[bis(tertiary butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2- Pendant oxyacetyl]-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester A mixture of (200 mg, 0.238 mmol) and Pd/C (50 mg, 10 wt % Pd/C with 50 wt % water) in t-BuOH ( 6 mL) was stirred at 50 °C under H (in a balloon) 12 hours. The resulting mixture was filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography ( ISCO® ; 12 g AgelaFlash® silica flash column, petroleum ether/EtOAc with 0-70% EtOAc, flow rate = 30 mL/min, 254 nm) to obtain 4-[5-[(5S)-1-[2-[[6-[bis(tert-butoxycarbonyl)amino]-5 as a yellow solid -Ethyl-3-pyridyl]amino]-2-oxyacetyl]-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]piperidine- Benzyl 1-carboxylate (140 mg, crude). LCMS (ESI) [M+H] + m/z: calculated 841.4, found 841.4.

步驟10：N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基Step 10: N-(6-Amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl -- 2-[2-(4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(化合物1240)之合成Synthesis of 2-[2-(4-Piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxoacetamide (Compound 1240)

將4-[5-[(5S)-1-[2-[[6-[雙(第三丁氧基羰基)胺基]-5-乙基-3-吡啶基]胺基]-2-側氧基乙醯基]-5-甲基-2-哌啶基]-1,3-苯并噻唑-2-基]哌啶-1-甲酸苯甲酯(140mg，0.166mmol)及TFA(5mL，64.9mmol)之混合物在20℃下攪拌12小時。在減壓下濃縮混合物，以得到粗產物，其藉由製備型HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Welch Xtimate C18 150 * 25mm * 5um；流動相A：具有0.225% FA(v%)之H2 O；流動相B：MeCN；梯度：在9.5min內10%至40% B，保持100% B達2min；流速：25mL/min；管柱溫度：30℃；波長：220nm，254nm)進行純化，以得到白色固體。藉由製備型 HPLC(儀器：Gilson GX-281 Liquid Handler，Gilson 322泵，Gilson 156 UV偵測器；管柱：Phenomenex Gemini-NX 80 * 40mm * 3um；流動相A：具有10mmol NH4 HCO3 之H2 O(v%)；流動相B：MeCN；梯度：在7.8min內22%至57% B，保持100% B達1min；流速：25mL/min；管柱溫度：30℃；波長：220nm、，254nm)進一步純化固體，以得到呈白色固體之N-(6-胺基-5-乙基-3-吡啶基)-2-[(2R,5S)-5-甲基-2-[2-(4-哌啶基)-1,3-苯并噻唑-5-基]-1-哌啶基]-2-側氧基乙醯胺(8mg，9.5%產率)。1 H NMR(400MHz，甲醇-d 4 )δ ppm 8.11(br s,1H),7.93-8.02(m,2H),7.65(br s,1H),7.47(br s,1H),5.52-5.90(m,1H),3.74(br s,1H),3.42(br d,J =13.1Hz,3H),3.10(br d,J =12.8Hz,2H),2.51(br s,2H),2.33(br s,4H),1.87-2.10(m,5H),1.48(br s,1H),1.25-1.34(m,3H),1.15(br d,J =7.0Hz,3H)；LCMS(ESI)[M+H]+ m/z：計算值507.2，實測值507.3；HPLC：在254nm下為99.18%，在254nm下為100%；82.4%de。4-[5-[(5S)-1-[2-[[6-[bis(tertiary butoxycarbonyl)amino]-5-ethyl-3-pyridyl]amino]-2- Pendant oxyacetyl]-5-methyl-2-piperidinyl]-1,3-benzothiazol-2-yl]piperidine-1-carboxylic acid benzyl ester (140 mg, 0.166 mmol) and TFA ( 5 mL, 64.9 mmol) of the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give crude product, which was purified by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; column: Welch Xtimate C18 150*25mm*5um ; Mobile phase A: H2O with 0.225% FA (v%); Mobile phase B: MeCN; Gradient: 10% to 40% B in 9.5 min, hold 100% B for 2 min; Flow rate: 25 mL/min; Column temperature: 30°C; wavelength: 220nm, 254nm) for purification to give a white solid. By preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV detector; Column: Phenomenex Gemini-NX 80*40mm*3um; Mobile phase A: with 10 mmol NH4HCO3 H 2 O (v%); mobile phase B: MeCN; gradient: 22% to 57% B in 7.8 min, hold 100% B for 1 min; flow rate: 25 mL/min; column temperature: 30 °C; wavelength: 220 nm ,, 254 nm) the solid was further purified to give N-(6-amino-5-ethyl-3-pyridyl)-2-[(2R,5S)-5-methyl-2-[ as a white solid 2-(4-Piperidinyl)-1,3-benzothiazol-5-yl]-1-piperidinyl]-2-oxyacetamide (8 mg, 9.5% yield). 1 H NMR (400MHz, methanol- d 4 ) δ ppm 8.11(br s,1H),7.93-8.02(m,2H),7.65(br s,1H),7.47(br s,1H),5.52-5.90( m,1H),3.74(br s,1H),3.42(br d, J =13.1Hz,3H),3.10(br d, J =12.8Hz,2H),2.51(br s,2H),2.33(br s, 4H), 1.87-2.10 (m, 5H), 1.48 (br s, 1H), 1.25-1.34 (m, 3H), 1.15 (br d, J = 7.0Hz, 3H); LCMS (ESI) [M +H] + m/z: calcd 507.2, found 507.3; HPLC: 99.18% at 254 nm, 100% at 254 nm; 82.4% de.

實例792. PRMT5協同檢定Example 792. PRMT5 synergy assay

藉由利用螢光異向性作為訊號來量測固定濃度之C末端5'-TAMRA標記之肽自Prmt5之劑量依賴性位移，來平衡地評定在輔因子SAM或MTA不存在及存在下之PRMT5抑制劑功效及協同性。將兩種肽用於此等研究：Equilibrium assessment of PRMT5 in the absence and presence of cofactors SAM or MTA by measuring the dose-dependent shift from Prmt5 of a fixed concentration of C-terminal 5'-TAMRA-labeled peptide using fluorescence anisotropy as a signal Inhibitor efficacy and synergy. Two peptides were used in these studies:

Me0：Ac-SGRGKGGKGLGKGGAKRHRKV--K(5-TAMRA)--NH2。Me0: Ac-SGRGKGGKGLGKGGAKRHRKV--K(5-TAMRA)--NH2.

Me2：Ac-SGR(Sym Me2)GKGGKGLGKGGAKRHRKV--K(5-TAMRA)--NH2Me2: Ac-SGR(Sym Me2)GKGGKGLGKGGAKRHRKV--K(5-TAMRA)--NH2

使用肽Me0確定在輔因子不存在下及在作為輔因子之MTA存在下化合物之親和力。使用肽Me2確定在作為輔因子之SAM存在下化合物之親和力。The affinity of the compounds in the absence of cofactor and in the presence of MTA as cofactor was determined using peptide Me0. The affinity of the compounds in the presence of SAM as a cofactor was determined using the peptide Me2.

研究化合物及參考化合物：Study compounds and reference compounds:

●以10mM儲備濃度開始，將研究化合物溶解於DMSO中• Starting with a 10 mM stock concentration, the study compound was dissolved in DMSO

●參考化合物1：EPZ015666(GSK3235025)(SelleckChem，目錄號S7748-5mg，10mM於DMSO中)- Reference compound 1: EPZ015666 (GSK3235025) (SelleckChem, cat. no. S7748-5 mg, 10 mM in DMSO)

●參考化合物2：(S)-2-(環丁基胺基)-N-(3-(8,9-二氫-[1,3]二氧雜環戊烯并[4,5-f]異喹啉-7(6H)-基)-2-羥基丙基)異菸鹼醯胺(PRMT5抑制劑，10mM於DMSO中)● Reference compound 2: (S)-2-(cyclobutylamino)-N-(3-(8,9-dihydro-[1,3]dioxolo[4,5-f] ]Isoquinolin-7(6H)-yl)-2-hydroxypropyl)isonicotinamide (PRMT5 inhibitor, 10 mM in DMSO)

檢定條件：Test conditions:

●研究化合物及參考化合物濃度：自125μM之3倍連續稀釋● Study compound and reference compound concentration: 3-fold serial dilution from 125 μM

●各檢定盤含有以上兩種參考化合物●Each assay plate contains the above two reference compounds

●各孔中之DMSO濃度：1.25% DMSO●DMSO concentration in each well: 1.25% DMSO

●在3個檢定條件下確定化合物IC50 ：• Determine compound IC50 under 3 assay conditions:

1.50μM輔因子SAM+25nM Me2+100nM PRMT51.50μM cofactor SAM+25nM Me2+100nM PRMT5

2.50μM輔因子MTA+25nM Me0+25nM PRMT52.50μM cofactor MTA+25nM Me0+25nM PRMT5

3.無輔因子+25nM Me0+100nM PRMT53. No cofactor + 25nM Me0+100nM PRMT5

材料：Material:

Figure 110128222-A0202-12-2534-501
Figure 110128222-A0202-12-2534-501

輔因子溶液之製備Preparation of cofactor solutions

˙將SAM溶解於去離子蒸餾水中，製成32mM溶液，將其儲存在-20℃下且在一個冷凍-解凍循環後丟棄。˙ SAM was dissolved in deionized distilled water to make a 32 mM solution, stored at -20°C and discarded after one freeze-thaw cycle.

˙將MTA-溶解於去離子蒸餾水中，製成2.5mM儲備溶液。在必要時使用輕微加熱37℃達1分鐘，以充分溶解。將溶液儲存在-20℃下且在多個冷凍-解凍循環中使用。˙ MTA- was dissolved in deionized distilled water to make a 2.5 mM stock solution. Use gentle heating to 37°C for 1 minute if necessary to fully dissolve. Solutions were stored at -20°C and used in multiple freeze-thaw cycles.

盤：plate:

Figure 110128222-A0202-12-2535-502
Figure 110128222-A0202-12-2535-502

儀器配置：Instrument configuration:

Figure 110128222-A0202-12-2535-503
Figure 110128222-A0202-12-2535-503

試劑製備：Reagent preparation:

在檢定盤中製備化合物稀釋液：To prepare compound dilutions in assay dishes:

˙製備9μL於DMSO中之10mM化合物˙ Prepare 9 μL of 10 mM compound in DMSO

˙如表2詳述，製備10點3倍稀釋液，最高工作濃度為125μM。˙ As detailed in Table 2, prepare a 10-point 3-fold dilution with a maximum working concentration of 125 μM.

˙針對四個檢定條件生成了4個化合物盤副本以˙For the four test conditions, 4 copies of compound disks were generated to

Figure 110128222-A0202-12-2535-504
Figure 110128222-A0202-12-2535-504

˙來源盤1之化合物濃度為10mM˙The compound concentration of source plate 1 is 10mM

˙中間盤1之化合物濃度為1.534mM，其藉由將1.2μL 10mM化合物轉移到6.576μL DMSO中來製備˙ The compound concentration of middle plate 1 was 1.534 mM, which was prepared by transferring 1.2 μL of 10 mM compound into 6.576 μL DMSO

˙中間盤2之化合物濃度為0.01905mM，其藉由將15nL 0.1mM化合物轉移到7.858μL DMSO中來製備˙ The compound concentration of middle plate 2 was 0.01905 mM, which was prepared by transferring 15 nL of 0.1 mM compound into 7.858 μL of DMSO

˙將187.5nL DMSO分配在表3所示之檢定盤之第1、12、13及24列中以用於對照反應，將187.5nL化合物稀釋液分配在第3至22列中。˙ 187.5nL DMSO was dispensed in columns 1, 12, 13 and 24 of the assay plate shown in Table 3 for control reactions and 187.5nL compound dilution was dispensed in columns 3-22.

Figure 110128222-A0202-12-2536-505
Figure 110128222-A0202-12-2536-505

˙新鮮製備檢定緩衝液：30mM二羥乙甘胺酸pH 8、0.003% Tween 20、1.5mM DTT及150mM NaCl˙Freshly prepared assay buffer: 30mM Diglycine pH 8, 0.003% Tween 20, 1.5mM DTT and 150mM NaCl

˙製備四個檢定樣品：˙ Prepare four test samples:

˙在冰上解凍PRMT5；在室溫下解凍Me2、Me0、SAM及MTA。將肽儲備液稀釋至7μM於ddH2 O中。˙ Thaw PRMT5 on ice; Thaw Me2, Me0, SAM and MTA at room temperature. Peptide stocks were diluted to 7 [mu]M in ddH2O.

○SAM Me2檢定樣品：○SAM Me2 test sample:

- 3 X SAM(輔因子)：製備檢定緩衝液中之150μM SAM(Cayman)。- 3 X SAM (cofactor): 150 μM SAM (Cayman) in assay buffer was prepared.

- 1.5 X PRMT5/Me2(最大對照)：製備於檢定緩衝液中之150nM PRMT5及37.5nM Me2。- 1.5 X PRMT5/Me2 (maximum control): 150 nM PRMT5 and 37.5 nM Me2 in assay buffer.

- 1.5 X Me2(最小對照)：製備於檢定緩衝液中之37.5nM Me2。- 1.5 X Me2 (minimum control): 37.5 nM Me2 in assay buffer.

○Apo-Me0檢定樣品：○Apo-Me0 test sample:

- 3 X無輔因子：僅製備檢定緩衝液- 3 X no cofactor: prepare assay buffer only

- 1.5 X PRMT5/Me0(最大對照)：製備於檢定緩衝液中之150nM PRMT5及37.5nM Me2。- 1.5 X PRMT5/Me0 (maximum control): 150 nM PRMT5 and 37.5 nM Me2 in assay buffer.

- 1.5 X Me0(最小對照)：製備於檢定緩衝液中之37.5nM Me2- 1.5 X Me0 (minimum control): 37.5nM Me2 in assay buffer

○MTA-Me0檢定樣品：○MTA-Me0 test sample:

- 3 X MTA(輔因子)：製備於檢定緩衝液中之150μM MTA。- 3 X MTA (cofactor): 150 μM MTA prepared in assay buffer.

- 1.5 X PRMT5/Me0(最大對照)：製備於檢定緩衝液中之37.5nM PRMT5及37.5nM Me0。- 1.5 X PRMT5/Me0 (maximum control): 37.5 nM PRMT5 and 37.5 nM Me0 in assay buffer.

- 1.5 X Me0(最小對照)：製備於檢定緩衝液中之37.5nM Me0。- 1.5 X Me0 (minimum control): 37.5 nM Me0 prepared in assay buffer.

檢定程序：Verification procedure:

˙製備以上試劑˙Prepare the above reagents

˙藉由16道電動移液器將5μL 3X輔因子溶液分配到所有列中之孔中˙ Dispense 5 μL of 3X cofactor solution into wells in all columns by means of a 16-channel electronic pipette

˙將含有化合物之檢定盤在1000rpm下旋轉60s。˙ Spin the assay disc containing the compound at 1000rpm for 60s.

˙藉由16道電動移液器將10μL最小對照(肽)溶液分配到各孔(第1及13列)˙ Dispense 10 μL of the minimal control (peptide) solution into each well (columns 1 and 13) by means of a 16-channel electric pipette

˙藉由16道電動移液器將10μL酶(1.5 X酶/肽)溶液分配到各孔(第2-12及14-24列)中˙ Dispense 10 μL of enzyme (1.5 X enzyme/peptide) solution into each well (columns 2-12 and 14-24) via a 16-channel electric pipette

˙將含有化合物之檢定盤在1000rpm下旋轉60s，且在23℃下孵育30min˙ Spin the assay plate containing the compound at 1000rpm for 60s and incubate at 23°C for 30min

˙針對其他三個檢定條件重複程序且將所有盤孵育30min˙ Repeat procedure for the other three assay conditions and incubate all plates for 30 min

˙在Envision儀器上讀取檢定盤˙ Read the calibration plate on the Envision instrument

資料分析date analyzing

˙將螢光偏振正規化以計算%抑制。˙ Normalize the fluorescence polarization to calculate the % suppression.

Figure 110128222-A0202-12-2537-506
Figure 110128222-A0202-12-2537-506

其中：in:

%抑制為在給定抑制劑濃度下之抑制百分比% inhibition is the percent inhibition at a given inhibitor concentration

i為在給定抑制劑濃度下之螢光異向性i is the fluorescence anisotropy at a given inhibitor concentration

P為由單獨肽給出之異向性訊號且表示最小訊號P is the anisotropic signal given by the individual peptides and represents the minimum signal

Prmt5_P為在DMSO存在下由Prmt5及肽複合物給出之異向性訊號，表示最大螢光異向性訊號Prmt5_P is the anisotropic signal given by Prmt5 and the peptide complex in the presence of DMSO, representing the maximum fluorescent anisotropic signal

˙%抑制資料使用4參數邏輯模型擬合。將最小值及最大值分別固定至0%及100%。報告IC50 值。˙% inhibition data were fitted using a 4-parameter logistic model. Fix the minimum and maximum values to 0% and 100%, respectively. IC50 values are reported.

˙Ki可使用Cheng-Prussof方程由IC50 計算：˙Ki can be calculated from IC 50 using the Cheng-Prussof equation:

Figure 110128222-A0202-12-2538-507
Figure 110128222-A0202-12-2538-507

˙對於在SAM存在下進行之檢定，在SAM存在下Me2肽對PRMT5之結合親和力經確定為50nm，且肽濃度為25nm，因此IC 50 =Ki ×1.5˙ For assays performed in the presence of SAM, the binding affinity of the Me2 peptide to PRMT5 in the presence of SAM was determined to be 50 nm and the peptide concentration was 25 nm, thus IC50 = Ki x 1.5

˙對於在MTA存在下進行之檢定，在MTA存在下Me0肽對PRMT5之結合親和力經確定為2nm，且肽濃度為25nm，因此IC 50 =Ki ×13.5˙ For assays performed in the presence of MTA, the binding affinity of the Me0 peptide to PRMT5 in the presence of MTA was determined to be 2 nm and the peptide concentration was 25 nm, thus IC50 = Ki x 13.5

Envision ®設定： Envision® settings:

˙鏡(條碼682)˙Mirror (Barcode 682)

˙濾波器(條碼245)˙Filter (Barcode 245)

˙濾波器(條碼246)˙Filter (Barcode 246)

˙濾波器(條碼132)˙Filter (Barcode 132)

此實例之資料展示於表1第4-6列。The data for this example are shown in Table 1, columns 4-6.

實例793. 細胞檢定-SDMA細胞內西方方案Example 793. Cell Assay - SDMA Intracellular Western Protocol

自Horizon Discovery(HZGHC004894c005)獲得HAP1MTAP -同基因型細胞株對且將其保持在於經加濕之10% CO2組織培養孵育器中之DMEM(ThermoFisher 11965)+10% FBS(Gemini 100-500)中。SAM協同PRMT5抑制劑GSK3326595來源於SelleckChem且作為10mM DMSO儲備液保持。將所有測試化合物作為10mM DMSO儲備液保持。HAP1 MTAP -isogenic cell line pairs were obtained from Horizon Discovery (HZGHC004894c005) and maintained in DMEM (ThermoFisher 11965) + 10% FBS (Gemini 100-500) in a humidified 10% CO2 tissue culture incubator . The SAM synergistic PRMT5 inhibitor GSK3326595 was derived from SelleckChem and maintained as a 10 mM DMSO stock. All test compounds were maintained as 10 mM DMSO stocks.

在第0天，將MTAP 完整或MTAP 缺失細胞接種於384孔盤中，且在經加濕之5% CO2組織培養孵育器中孵育16-24小時。在第1天，使用Tecan D300e數字分配器將測試化合物以限定濃度分配到各孔中(n=4)，且將DMSO之體積正規化至最高類別體積。各盤包括投配限定濃度GSK33226595作為盤對照之孔。將 化合物與細胞一起在經加濕之5% CO2組織培養孵育器中孵育24小時。On day 0, MTAP- intact or MTAP-depleted cells were seeded in 384-well dishes and incubated in a humidified 5% CO2 tissue culture incubator for 16-24 hours. On day 1, test compounds were dispensed at defined concentrations into each well (n=4) using a Tecan D300e digital dispenser, and the volume of DMSO was normalized to the highest class volume. Each plate included wells dosed with a defined concentration of GSK33226595 as a plate control. Compounds were incubated with cells for 24 hours in a humidified 5% CO2 tissue culture incubator.

在第2天，將經化合物處理之細胞用最終濃度4%甲醛固定。然後將細胞用1X PBS+0.1% Triton X-100洗滌/透化，然後用5%山羊血清/1X TBS封閉。然後將經固定之細胞與一級SDMA抗體混合物(Cell Signaling 13222)一起在4℃下孵育隔夜。On day 2, compound-treated cells were fixed with a final concentration of 4% formaldehyde. Cells were then washed/permeabilized with 1X PBS + 0.1% Triton X-100 and then blocked with 5% goat serum/1X TBS. The fixed cells were then incubated with a primary SDMA antibody cocktail (Cell Signaling 13222) at 4°C overnight.

在第3天，將細胞用1X PBS+0.1% Triton X-100洗滌，然後在室溫下與亦含有DRAQ5之NIR螢光二級抗體混合物(LiCor 926-32211及VWR 10761-508)一起孵育1小時。將細胞用1X PBS+0.1% Triton X-100洗滌，然後再次用ddH20洗滌。然後使用NIR螢光成像器(LiCor Odyssey)對盤進行成像。On day 3, cells were washed with 1X PBS + 0.1% Triton X-100 and then incubated with NIR fluorescent secondary antibody cocktail (LiCor 926-32211 and VWR 10761-508) also containing DRAQ5 for 1 hour at room temperature . Cells were washed with 1X PBS + 0.1% Triton X-100 and then again with ddH20. The discs were then imaged using a NIR fluorescence imager (LiCor Odyssey).

對於資料分析，將SDMA訊號正規化至DRAQ5訊號。藉由自用1μM GSK3326595處理之孔之訊號確定檢定背景，且將其自每個孔減去。將資料獨立地呈MTAP 完整及MTAP 缺失細胞株之DMSO對照孔之%進行作圖，且擬合至4參數邏輯(4-PL)希爾(Hill)方程，其中最大效應限制於0。使用GraphPad Prism或Dotmatics Studies 5.4中之預設IC50擬合程序作為定製資料分析方案之部分來進行擬合。For data analysis, normalize the SDMA signal to the DRAQ5 signal. Assay background was determined by the signal from wells treated with 1 μM GSK3326595 and subtracted from each well. Data were independently plotted as % of DMSO control wells for MTAP- intact and MTAP-depleted cell lines and fitted to a 4-parameter logistic (4-PL) Hill equation with the maximum effect limited to zero. Fits were performed using the preset IC50 fitting programs in GraphPad Prism or Dotmatics Studies 5.4 as part of a custom data analysis protocol.

在此實驗中獲得之資料呈現於表1第7-9列。The data obtained in this experiment are presented in Table 1, columns 7-9.

實例794. 活力檢定方案Example 794. Vitality testing scheme

自Horizon Discovery(HZGHC004894c005)獲得HAP1MTAP -同基因型細胞株對且將其保持在於經加濕之5或10% CO2組織培養孵育器中之DMEM(ThermoFisher 11965)+10% FBS(Gemini 100-500)中。將所有測試化合物作為10mM DMSO儲備液保持。HAP1 MTAP -isogenic cell line pairs were obtained from Horizon Discovery (HZGHC004894c005) and maintained in DMEM (ThermoFisher 11965) + 10% FBS (Gemini 100-500) in a humidified 5 or 10% CO2 tissue culture incubator )middle. All test compounds were maintained as 10 mM DMSO stocks.

在第0天，將MTAP 完整及MTAP 缺失細胞接種於96孔盤中，且在經加濕之5或10% CO2組織培養孵育器中孵育16-24小時。在第1天，使用Tecan D300e數字分配器將測試化合物以限定濃度分配到各孔中(n=3)，且將DMSO之體積正 規化至最高類別體積(0.2%)。將經化合物處理之盤在經加濕之5%或10% CO2組織培養孵育器中孵育7天。On day 0, MTAP- intact and MTAP- deficient cells were seeded in 96-well dishes and incubated for 16-24 hours in a humidified 5 or 10% CO2 tissue culture incubator. On day 1, test compounds were dispensed into wells at defined concentrations (n=3) using a Tecan D300e digital dispenser, and the volume of DMSO was normalized to the highest class volume (0.2%). Compound-treated dishes were incubated for 7 days in a humidified 5% or 10% CO2 tissue culture incubator.

在第7天，自組織培養孵育器移出各盤且使其平衡至室溫。然後將½體積CellTiter-Glo發光細胞活力檢定(Luminescent Cell Viability Assay)試劑(Promega G7572)添加到各孔中，或自各孔移出培養基且添加CellTiter-Glo 2.0細胞活力檢定試劑(Promega G9241)於1X PBS中之1：3稀釋液。在添加後十分鐘，藉由Envision盤讀取器偵測發光訊號。將資料獨立地呈MTAP 完整及MTAP 缺失細胞株之DMSO對照孔之%進行作圖，且擬合至4參數邏輯(4-PL)希爾方程，其中最大效應限制於0。使用GraphPad Prism或Dotmatics Studies 5.4中之預設IC50擬合程序作為定製資料分析方案之部分來進行擬合。On day 7, plates were removed from the tissue culture incubator and allowed to equilibrate to room temperature. ½ volume of CellTiter-Glo Luminescent Cell Viability Assay (Promega G7572) was then added to each well, or the medium was removed from each well and CellTiter-Glo 2.0 Cell Viability Assay (Promega G9241) was added in 1X PBS 1:3 dilution of the medium. Ten minutes after addition, the luminescent signal was detected by the Envision disc reader. Data were independently plotted as % of DMSO control wells for MTAP- intact and MTAP-depleted cell lines and fit to a 4-parameter logistic (4-PL) Hill equation with the maximum effect limited to zero. Fits were performed using the preset IC50 fitting programs in GraphPad Prism or Dotmatics Studies 5.4 as part of a custom data analysis protocol.

在此實驗中獲得之資料呈現於表1第10列中。The data obtained in this experiment are presented in column 10 of Table 1.

實例795. 組合活力檢定方案Example 795. Combination Vitality Assay Scheme

在MTAP缺失SW1573親本細胞株中，藉由重構MTAP基因表現或藉由引入空白對照載體來生成SW1573MTAP 同基因型細胞株對。將細胞株在經加濕之5% CO2組織培養孵育器中保持在DMEM+10% FBS中。將所有測試化合物作為10mM DMSO儲備液保持。SW1573 MTAP isogenic cell line pairs were generated by reconstituting MTAP gene expression in the MTAP-deficient SW1573 parental cell line or by introducing a blank control vector. Cell lines were maintained in DMEM+10% FBS in a humidified 5% CO2 tissue culture incubator. All test compounds were maintained as 10 mM DMSO stocks.

在第0天，將MTAP 完整及MTAP 缺失細胞接種於384孔盤中，且在經加濕之5% CO2組織培養孵育器中孵育16-24小時。在第1天，將測試化合物以限定濃度分配到各孔中(n=2)，且將DMSO之體積正規化至最高類別體積。將經化合物處理之盤在經加濕之5% CO2組織培養孵育器中孵育7天。On day 0, MTAP- intact and MTAP- deficient cells were seeded in 384-well dishes and incubated in a humidified 5% CO2 tissue culture incubator for 16-24 hours. On day 1, test compounds were dispensed into wells at defined concentrations (n=2), and the volume of DMSO was normalized to the highest class volume. Compound-treated dishes were incubated for 7 days in a humidified 5% CO2 tissue culture incubator.

在第7天，自組織培養孵育器移出各盤且使其平衡至室溫。藉由添加CellTiter-Glo試劑來評定相對活力，且使用4參數擬合非線性迴歸模型(GraphPad Prism)將資料呈各細胞株中各化合物之DMSO對照之%進行作圖。根據HSA模型，藉由Combenefit軟體包(版本2.021)確定協同作用。On day 7, plates were removed from the tissue culture incubator and allowed to equilibrate to room temperature. Relative viability was assessed by addition of CellTiter-Glo reagent and data were plotted as % of DMSO control for each compound in each cell line using a 4-parameter fitted nonlinear regression model (GraphPad Prism). Synergy was determined by the Combenefit software package (version 2.021) according to the HSA model.

PRMT5抑制劑及MAT2A抑制劑表示MTAP缺失腫瘤中之潛在臨床組合。PRMT5 inhibitors and MAT2A inhibitors represent potential clinical combinations in MTAP-deficient tumors.

Marjon等人(Cell Reports 2016)及Kalev等人(Cancer Cell 2021)將MAT2A識別為MTAP缺失腫瘤中之治療靶標。評定了MAT2A抑制劑與選擇性靶向MTAP無效細胞中之PRMT5之抑制劑的組合是否將呈現合理的治療策略。在MTAP無效Sw1573癌細胞株中之7日活力檢定中MAT2A抑制劑AG-270與範例MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強(圖2)。Marjon et al. (Cell Reports 2016) and Kalev et al. (Cancer Cell 2021) identified MAT2A as a therapeutic target in MTAP-deficient tumors. It was assessed whether the combination of a MAT2A inhibitor with an inhibitor that selectively targets PRMT5 in MTAP null cells would represent a reasonable therapeutic strategy. The combination of the MAT2A inhibitor AG-270 with the exemplary MTAP- null selective PRMT5 inhibitor demonstrated a lack of enhanced cell viability in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line (Figure 2).

根據HSA模型，此組合作用為協同的，其中協同得分定量了過量的最高單一化合物反應(圖3)。This combined effect was synergistic according to the HSA model, with the synergy score quantifying the highest excess single compound response (Figure 3).

PRMT5抑制劑及MAPK或KRASG12C抑制劑表示MTAP缺失KRAS突變腫瘤中之潛在臨床組合。PRMT5 inhibitors and MAPK or KRASG12C inhibitors represent a potential clinical combination in MTAP-deficient KRAS mutant tumors.

MTAP缺失可與KRAS基因中之突變(例如KRASG12C)共同出現。存在靶向KRAS或MAPK途徑之其他成員(例如MAPK3、MAPK1、MEK1及MEK2)之療法。評定了此等抑制劑與選擇性靶向MTAP無效細胞中之PRMT5之抑制劑的組合是否將呈現治療策略。MTAP deletion can co-occur with mutations in the KRAS gene (eg, KRASG12C). Therapies exist that target KRAS or other members of the MAPK pathway, such as MAPK3, MAPK1, MEK1 and MEK2. It was assessed whether the combination of these inhibitors with inhibitors that selectively target PRMT5 in MTAP null cells would present a therapeutic strategy.

在MTAP無效Sw1573癌細胞株中之7日活力檢定中KRASG12C抑制劑AMG-510與範例MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強(圖4)。The combination of the KRASG12C inhibitor AMG-510 and the exemplary MTAP- null selective PRMT5 inhibitor demonstrated a lack of enhanced cell viability in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line (Figure 4).

在MTAP無效Sw1573癌細胞株中之在7日活力檢定中MAPK1/MAPK3抑制劑(由烏裡替尼及SCH772984例示)與示範性MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強(圖5)。The combination of a MAPK1/MAPK3 inhibitor (exemplified by Uritinib and SCH772984) with an exemplary MTAP- null selective PRMT5 inhibitor demonstrated a lack of enhanced cell viability in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line (Figure 5 ).

在MTAP-無效Sw1573癌細胞株中之7日活力檢定中MEK抑制劑(由曲美替尼例示)與示範性MTAP無效 選擇性PRMT5抑制劑之組合證明細胞活力缺乏增強(圖6)。The combination of a MEK inhibitor (exemplified by trametinib) with an exemplary MTAP- null selective PRMT5 inhibitor demonstrated a lack of enhanced cell viability in a 7-day viability assay in the MTAP-null Sw1573 cancer cell line (Figure 6).

其他實施例other embodiments

除非相反指示或另外由上下文清楚，否則在申請專利範圍中，冠詞諸如「一個」、「一種」及「該」可意謂一者或多於一者。除非相反指示或另外由上下文清楚，否則在一組之一或多個成員之間包括「或」之申請專利範圍或說明書認為滿足組成員之一者、多於一者、或全部存在於給定產物或方法中、用於該產品或方法中或另外與該產物或方法相關。本發明包括精確該組之一成員存在於給定產物或方法中、用於該產物或方法中或在其他方面與該產物或方法相關之實施例。本發明包括多於一或全部組成員存在於給定產物或方法中、用於該產物或方法中或在其他方面與該產物或方法相關之實施例。In the scope of the claims, articles such as "a," "an," and "the" can mean one or more than one unless indicated to the contrary or otherwise clear from context. Unless indicated to the contrary or otherwise clear from context, claims or the specification that include "or" between one or more members of a group are considered to satisfy that one, more than one, or all of the group members are present in a given group. In, use in, or otherwise relate to a product or process. The invention includes embodiments in which precisely one member of this group is present in, used in, or otherwise related to a given product or method. The invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or method.

此外，本發明涵蓋將一或多項所列之請求項之一或多個限制、要素、條款及描述性術語併入至另一請求項的所有變化、組合及排列。例如，任一附屬於另一請求項的請求項可修改成包括一或多個任一附屬於相同基礎請求項的其他請求項中存在的限制。在要素如清單例如在Markush組形式中呈現時，亦揭示該等要素之各子組，且可自該組移除任何要素。應理解，一般而言，在本發明或本發明之樣態被稱為包含具體要素及/或特徵之情況下，本發明之某些實施例或本發明之態樣由此類要素及/或特徵組成或基本上由此類要素及/或特徵組成。出於簡化目的，該等實施例未在本文中明文(in haec verba)確切描述。亦應注意，術語「包含(comprising)」及「含有(containing)」意欲為開放的且允許包含額外要素或步驟。在給出範圍之情況下，包括端點。此外，除非相反指示或另外由上下文及一般熟習此項技術者之理解清楚，否則表述為範圍的值可假定為本發明之不同實施例中在所說明之範圍內的任何特定值或子範圍，除非上下文另有明確說明，否則至該範圍之下限之十分之一單位。Furthermore, the invention covers all variations, combinations and permutations of one or more of the limitations, elements, clauses and descriptive terms listed in one or more of the listed claims into another claim. For example, any claim that is dependent on another claim may be modified to include restrictions that exist in one or more of the other claims that are dependent on the same underlying claim. When elements such as lists are presented, for example, in Markush group form, subgroups of those elements are also disclosed, and any element may be removed from the group. It is to be understood that, in general, where the invention or aspects of the invention are referred to as comprising specific elements and/or features, certain embodiments of the invention or aspects of the invention consist of such elements and/or Features consist of or consist essentially of such elements and/or features. For the sake of simplicity, these embodiments are not precisely described herein in haec verba. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless indicated to the contrary or otherwise clear from the context and understanding of one of ordinary skill in the art, values stated as ranges may be assumed to be any particular value or sub-range within the stated range in different embodiments of the invention, Unless the context clearly dictates otherwise, to the lower tenth of the range.

本申請案係指各種經頒布之專利、經公佈之專利申請案、雜誌文章及其他出版物，其全部以引用之方式併入本文。若任何所併入之參考文獻與本說明書之間存在衝突，則以本說明書為準。另外，本發明之屬於先前技術之任 何具體實施例可明確自任一或多個請求項中排除。因為此類實施例似乎為熟悉此項技術者熟知的，所以即使本文未明確陳述排除亦可排除它們。出於任何原因，無論是否與先前技術之存在相關，可自任一請求項排除本發明之任何具體實施例。This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, the present specification controls. In addition, any aspect of the present invention pertaining to the prior art Any specific embodiment may be expressly excluded from any one or more of the claims. Because such embodiments appear to be well known to those skilled in the art, they may be excluded even though they are not expressly stated herein. Any specific embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

熟習此項技術者將認識到或僅僅使用常規實驗即能夠探悉本文中描述之特定實施例之若干等價物。本文所述之本發明實施例之範圍不旨在局限於上述說明書，而是如所附申請專利範圍所陳述。熟悉此項技術者將瞭解，可對此說明書作出各種改變及修改而不背離本發明之如以下申請專利範圍所限定之精神或範圍。Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, several equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein are not intended to be limited by the foregoing description, but are instead set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications of this specification can be made without departing from the spirit or scope of the invention as defined in the following claims.

Figure 110128222-A0202-11-0002-1099
Figure 110128222-A0202-11-0002-1099

Claims (114)

一種種式(I)化合物或其醫藥學上可接受之鹽； A compound of formula (I) or a pharmaceutically acceptable salt thereof; 其中： in:
Figure 110128222-A0202-13-0001-508
Figure 110128222-A0202-13-0001-508
 各R1 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa1 、-N(Ra1 )2 、-C(=O)Ra1 、-C(=O)ORa1 、-NRa1 C(=O)Ra1 、-NRa1 C(=O)ORa1 、-C(=O)N(Ra1 )2 、-OC(=O)N(Ra1 )2 、-S(=O)Ra1 、-S(=O)2 Ra1 、-SRa1 、-S(=O)(=NRa1 )Ra1 、-NRa1 S(=O)2 Ra1 及-S(=O)2 N(Ra1 )2 ；Each R 1 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O)OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 , -OC(=O)N(R a1 ) 2 , -S(=O)R a1 , -S(=O) 2 R a1 , -SR a1 , -S(=O)(=NR a1 ) R a1 , -NR a1 S(=O) 2 R a1 and -S(=O) 2 N(R a1 ) 2 ; 各R2 獨立地選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)ORa2 、-NRa2 C(=O)Ra2 、-NRa2 C(=O)ORa2 、-C(=O)N(Ra2 )2 、-C(=O)N(ORa2 )(Ra2 )、-OC(=O)N(Ra2 )2 、-S(=O)Ra2 、-S(=O)2 Ra2 、-SRa2 、-S(=O)(=NRa2 )Ra2 、-NRa2 S(=O)2 Ra2 及-S(=O)2 N(Ra2 )2 ；Each R 2 is independently selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkane Oxy group, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a2 , -N (R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(= O)N(R a2 ) 2 , -C(=O)N(OR a2 )(R a2 ), -OC(=O)N(R a2 ) 2 , -S(=O)R a2 , -S( =O) 2 R a2 , -SR a2 , -S(=O)(=NR a2 )R a2 , -NR a2 S(=O) 2 R a2 and -S(=O) 2 N(R a2 ) 2 ; 各R3 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa3 、-N(Ra3 )2 、-C(=O)Ra3 、-C(=O)ORa3 、-NRa3 C(=O)Ra3 、-NRa3 C(=O)ORa3 、-C(=O)N(Ra3 )2 、-OC(=O)N(Ra3 )2 、-S(=O)Ra3 、-S(=O)2 Ra3 、-SRa3 、-S(=O)(=NRa3 )Ra3 、-NRa3 S(=O)2 Ra3 及-S(=O)2 N(Ra3 )2 ；Each R 3 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O)OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 , -OC(=O)N(R a3 ) 2 , -S(=O)R a3 , -S(=O) 2 R a3 , -SR a3 , -S(=O)(=NR a3 ) R a3 , -NR a3 S(=O) 2 R a3 and -S(=O) 2 N(R a3 ) 2 ; 各R4 獨立地選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷 基、環烷基烷基、-ORa4 、-N(Ra4 )2 、-C(=O)Ra4 、-C(=O)ORa4 、-NRa4 C(=O)Ra4 、-NRa4 C(=O)ORa4 、-C(=O)N(Ra4 )2 、-OC(=O)N(Ra4 )2 、-S(=O)Ra4 、-S(=O)2 Ra4 、-SRa4 、-S(=O)(=NRa4 )Ra4 、-NRa4 S(=O)2 Ra4 及-S(=O)2 N(Ra4 )2 ；Each R 4 is independently selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O)OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 , -OC(=O)N(R a4 ) 2 , -S(=O)R a4 , -S(=O) 2 R a4 , -SR a4 , -S(=O)(=NR a4 ) R a4 , -NR a4 S(=O) 2 R a4 and -S(=O) 2 N(R a4 ) 2 ; 各R6 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代；Each R 6 is independently absent or selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl , cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each Alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl are optionally substituted at any available position; 各R7 獨立地不存在或選自H、-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 羥基烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、5-6員單環雜芳基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa7 、-N(Ra7 )2 、-C(=O)Ra7 、-C(=O)ORa7 、-NRa7 C(=O)Ra7 、-NRa7 C(=O)ORa7 、-C(=O)N(Ra7 )2 、-OC(=O)N(Ra7 )2 、-S(=O)Ra7 、-S(=O)2 Ra7 、-SRa7 、-S(=O)(=NRa7 )Ra7 、-NRa7 S(=O)2 Ra7 及-S(=O)2 N(Ra7 )2 ；Each R 7 is independently absent or selected from H, -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 hydroxyalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, 5-6 membered monocyclic heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl , -OR a7 , -N(R a7 ) 2 , -C(=O)R a7 , -C(=O)OR a7 , -NR a7 C(=O)R a7 , -NR a7 C(=O) OR a7 , -C(=O)N(R a7 ) 2 , -OC(=O)N(R a7 ) 2 , -S(=O)R a7 , -S(=O) 2 R a7 , -SR a7 , -S(=O)(=NR a7 )R a7 , -NR a7 S(=O) 2 R a7 and -S(=O) 2 N(R a7 ) 2 ; 各R8 獨立地選自H、-D、=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa8 、-N(Ra8 )2 、-C(=O)Ra8 、-C(=O)ORa8 、-NRa8 C(=O)Ra8 、-NRa8 C(=O)ORa8 、-CH2 C(=O)N(Ra8 )2 、-C(=O)N(Ra8 )2 、-OC(=O)N(Ra8 )2 、-CH2 C(=O)N(Ra8 )2 、-S(=O)Ra8 、-S(=O)2 Ra8 、-SRa8 、-S(=O)(=NRa8 )Ra8 、-NRa8 S(=O)2 Ra8 及-S(=O)2 N(Ra8 )2 ，其中R8 之兩個實例連同其所連接之一或多個原子可一起形成3-10員環烷基或雜環基環(例如，連 同結構I之哌啶環可以形成橋聯、稠合或螺雙環雜環的環)Each R 8 is independently selected from H, -D, =O, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O)OR a8 , -NR a8 C(=O)R a8 , -NR a8 C(=O)OR a8 , -CH 2 C(=O )N(R a8 ) 2 , -C(=O)N(R a8 ) 2 , -OC(=O)N(R a8 ) 2 , -CH 2 C(=O)N(R a8 ) 2 , - S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S(=O)(=NR a8 )R a8 , -NR a8 S(=O) 2 R a8 and -S (=O) 2 N(R a8 ) 2 , wherein two instances of R 8 together with one or more atoms to which they are attached can be taken together to form a 3-10 membered cycloalkyl or heterocyclyl ring (eg, together with Structure I The piperidine ring can form a bridged, fused or spirobicyclic heterocyclic ring) 各Ra1 、Ra2 、Ra3 、Ra4 、Ra6 、Ra7 及Ra8 獨立地選自H、C1 -C6 烷基、-C1 -C6 雜烷基、C3 -C9 環烷基、3-7員雜環基、環烷基烷基、雜環基烷基、芳基、5-6員雜芳基、芳基烷基及雜芳基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代(例如， 經R9 之0、1、2或3個實例取代，其中各R9 獨立地選自=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、-ORb 、-N(Rb )2 、-C(=O)Rb 、-C(=O)ORb 、-NRb C(=O)Rb 、-NRb C(=O)ORb 、-C(=O)N(Rb )2 、-OC(=O)N(Rb )2 、-S(=O)Rb 、-S(=O)2 Rb 、-SRb 、-S(=O)(=NRb )Rb 、-NRb S(=O)2 Rb 及-S(=O)2 N(Rb )2 ，其中各Rb 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)；且Each of R a1 , R a2 , R a3 , R a4 , R a6 , R a7 and R a8 is independently selected from H, C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, C 3 -C 9 Cycloalkyl, 3-7 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl, wherein each alkyl , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl are optionally substituted at any available position ( eg, by 0, 1, 2 or 3 instances of R 9 are substituted, wherein each R 9 is independently selected from =0, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, Heterocyclylalkyl, arylalkyl, heteroarylalkyl, -ORb , -N( Rb ) 2 , -C(=O) Rb , -C(=O) ORb , -NRb C(=O)R b , -NR b C(=O)OR b , -C(=O)N(R b ) 2 , -OC(=O)N(R b ) 2 , -S(=O )R b , -S(=O) 2 R b , -SR b , -S(=O)(=NR b )R b , -NR b S(=O) 2 R b and -S(=O) 2 N(R b ) 2 , wherein each R b is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr , -iPr , -nBu, -tBu, - sec -Bu, -iso -Bu) and C3 - C9 cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); and 1、2或31, 2 or 3 前提條件為： The prerequisites are: (i)當R1 為H時，R2 不為鹵基、-OPr、-N(CH3 )2 或-CF3 ；(i) when R 1 is H, R 2 is not halo, -OPr, -N(CH 3 ) 2 or -CF 3 ; (ii)當R1 為ORa1 時，R2 不為-ORa2 ；(ii) when R 1 is OR a1 , R 2 is not -OR a2 ; (iii)當R1 為H且R2 為-CH3 時，R8 基團不可一起形成環且R6 並非不存在或為H，且不為噻唑基、呋喃基或吡咯基；(iii ) when R1 is H and R2 is -CH3 , the R8 groups may not together form a ring and R6 is not absent or H, and not thiazolyl, furanyl or pyrrolyl ; (iv)當R2 為Me時，R1 不為視情況經取代之哌啶(iv) when R 2 is Me, R 1 is not optionally substituted piperidine (v)該化合物不為： (v) the compound is not: A.5-(2-(5-甲基-2-(對甲苯基)哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺或其任何鏡像異構物或非鏡像異構物； A. 5-(2-(5-Methyl-2-(p-tolyl)piperidin-1-yl)-2-oxyacetamido)nicotinamide or any of its enantiomers or non-spiroisomers; B.2-(2-(4-(2H-四唑-5-基)苯基)-5-甲基哌啶-1-基)-N-(5,6-二甲基吡 啶-3-基)-2-側氧基乙醯胺或其任何鏡像異構物或非鏡像異構物； B. 2-(2-(4-(2H-Tetrazol-5-yl)phenyl)-5-methylpiperidin-1-yl)-N-(5,6-dimethylpyridine pyridin-3-yl)-2-oxyacetamide or any of its enantiomers or diastereomers; C.2-氰基-5-(2-(5-甲基-2-苯基哌啶-1-基)-2-側氧基乙醯胺基)菸鹼醯胺或其任何鏡像異構物或非鏡像異構物。 C. 2-cyano-5-(2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxyacetamido)nicotinamide or any of its mirror isomers isomers or non-spiroisomers. 如請求項1之化合物，其中R6 及R7 不為H且呈反式相對組態。The compound of claim 1, wherein R 6 and R 7 are not H and are in a trans relative configuration. 如請求項1之化合物，其中R6 及R7 不為H且呈順式相對組態。The compound of claim 1, wherein R 6 and R 7 are not H and are in a cis relative configuration. 如請求項1至3中任一項之化合物，其中表示為
Figure 110128222-A0202-13-0004-510
之部分選自：The compound of any one of claims 1 to 3, wherein it is expressed as
Figure 110128222-A0202-13-0004-510
part from:
Figure 110128222-A0202-13-0004-509
Figure 110128222-A0202-13-0004-509
 2及4中任一項之化合物，其中表示為
Figure 110128222-A0202-13-0004-512
之部分選自：The compound of any one of 2 and 4, which is represented by
Figure 110128222-A0202-13-0004-512
part from:
Figure 110128222-A0202-13-0004-513
Figure 110128222-A0202-13-0004-513
 3及4中任一項之化合物，其中表示為
Figure 110128222-A0202-13-0004-514
之部分選自：The compound of any one of 3 and 4, which is represented as
Figure 110128222-A0202-13-0004-514
part from:
Figure 110128222-A0202-13-0004-515
Figure 110128222-A0202-13-0004-515
 如請求項5之化合物，其中該化合物為式(Ia)化合物 The compound of claim 5, wherein the compound is a compound of formula (Ia)
Figure 110128222-A0202-13-0005-516
Figure 110128222-A0202-13-0005-516
 如請求項5之化合物，其中該化合物為式(Ib)化合物 The compound of claim 5, wherein the compound is a compound of formula (Ib)
Figure 110128222-A0202-13-0005-517
Figure 110128222-A0202-13-0005-517
 如請求項6之化合物，其中該化合物為式(Ic)化合物 The compound of claim 6, wherein the compound is a compound of formula (Ic)
Figure 110128222-A0202-13-0005-518
Figure 110128222-A0202-13-0005-518
 如請求項6之化合物，其中該化合物為式(Id)化合物 The compound of claim 6, wherein the compound is a compound of formula (Id)
Figure 110128222-A0202-13-0005-519
Figure 110128222-A0202-13-0005-519
 如請求項1至10中任一項之化合物，其中各R8 獨立地選自H、-D、=O、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、雜環基烷基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa8 、-N(Ra8 )2 、-C(=O)Ra8 、-C(=O)ORa8 、-NRa8 C(=O)Ra8 、-NRa8 C(=O)ORa8 、-CH2 C(=O)N(Ra8 )2 -C(=O)N(Ra8 )2 、-OC(=O)N(Ra8 )2 、-CH2 C(=O)N(Ra8 )2 、-S(=O)Ra8 、-S(=O)2 Ra8 、-SRa8 、-S(=O)(=NRa8 )Ra8 、-NRa8 S(=O)2 Ra8 及-S(=O)2 N(Ra8 )2 。The compound of any one of claims 1 to 10, wherein each R 8 is independently selected from H, -D, =O, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 Heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, ring Alkylalkyl, -OR a8 , -N(R a8 ) 2 , -C(=O)R a8 , -C(=O)OR a8 , -NR a8 C(=O)R a8 , -NR a8 C (=O)OR a8 , -CH 2 C(=O)N(R a8 ) 2 -C(=O)N(R a8 ) 2 , -OC(=O)N(R a8 ) 2 , -CH 2 C(=O)N(R a8 ) 2 , -S(=O)R a8 , -S(=O) 2 R a8 , -SR a8 , -S(=O)(=NR a8 )R a8 , - NR a8 S(=O) 2 R a8 and -S(=O) 2 N(R a8 ) 2 . 如請求項1至11中任一項之化合物，其中R1 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環 基、-ORa1 、-N(Ra1 )2 、-C(=O)Ra1 、-C(=O)ORa1 、-NRa1 C(=O)Ra1 、-NRa1 C(=O)ORa1 、-C(=O)N(Ra1 )2 及-OC(=O)N(Ra1 )2 。The compound of any one of claims 1 to 11, wherein R 1 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a1 , -N(R a1 ) 2 , -C(=O)R a1 , -C(=O) OR a1 , -NR a1 C(=O)R a1 , -NR a1 C(=O)OR a1 , -C(=O)N(R a1 ) 2 and -OC(=O)N(R a1 ) 2 . 如請求項1至12中任一項之化合物，其中R1 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基、-ORa1 及-N(Ra1 )2 。The compound of any one of claims 1 to 12, wherein R 1 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -OR a1 and - N(R a1 ) 2 . 如請求項1至13中任一項之化合物，其中R1 選自H、-C1 -C6 烷基、-C1 -C6 鹵烷基、-ORa1 及-N(Ra1 )2 。The compound of any one of claims 1 to 13, wherein R 1 is selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -OR a1 and -N(R a1 ) 2 . 如請求項1至14中任一項之化合物，其中各Ra1 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)及-C1 -C6 鹵烷基(例如， -CHF2 、-CF3 )。The compound of any one of claims 1 to 14, wherein each R a1 is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr, -i Pr, -n Bu , -tBu , -sec -Bu, -iso -Bu), and -C1 - C6 haloalkyl ( eg, -CHF2, -CF3 ). 如請求項1至15中任一項之化合物，其中R1 選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-C1 -C6 鹵烷基(例如， -CF3 、-CHF2 )、-OH、-O-(C1 -C6 烷基)(例如， -OMe、-OEt)、-O-(C1 -C6 鹵烷基)(例如， -OCF3 、-OCHF2 )、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。The compound of any one of claims 1 to 15, wherein R 1 is selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu, -t Bu, -sec-Bu, -iso -Bu), -C 1 -C 6 haloalkyl ( eg, -CF 3 , -CHF 2 ), -OH, -O-(C 1 -C 6 alkyl) ( For example, -OMe, -OEt), -O-(C 1 -C 6 haloalkyl) ( eg, -OCF 3 , -OCHF 2 ), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg, -NHMe) and -N-(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). 如請求項1至16中任一項之化合物，其中R1 選自H、-Me、-Et、-CHF2 、-OMe、-OEt、-OCHF2 、-OCF3、 -OH及-NH2 。The compound of any one of claims 1 to 16, wherein R 1 is selected from H, -Me, -Et, -CHF 2 , -OMe, -OEt, -OCHF 2 , -OCF 3 , -OH and -NH 2 . 如請求項1至16中任一項之化合物，其中R1 選自H、-Et、-OMe、-OEt、-OCHF2 、-OCF3 及-OH。The compound of any one of claims 1 to 16, wherein R 1 is selected from H, -Et, -OMe, -OEt, -OCHF 2 , -OCF 3 and -OH. 如請求項1至16中任一項之化合物，其中R1 選自H及-OMe。The compound of any one of claims 1 to 16, wherein R 1 is selected from H and -OMe. 如請求項1至16中任一項之化合物，其中R1 為H。The compound of any one of claims 1 to 16, wherein R 1 is H. 如請求項1至16中任一項之化合物，其中R1 為-OMe。The compound of any one of claims 1 to 16, wherein R 1 is -OMe. 如請求項1至16中任一項之化合物，其中R1 選自H、-Me、-CHF2 及-NH2 。The compound of any one of claims 1 to 16, wherein R 1 is selected from H, -Me, -CHF 2 and -NH 2 . 如請求項1至16中任一項之化合物，其中R1 選自-Me及-NH2 。The compound of any one of claims 1 to 16, wherein R 1 is selected from -Me and -NH 2 . 如請求項1至16中任一項之化合物，其中R1 為-Me。The compound of any one of claims 1 to 16, wherein R 1 is -Me. 如請求項1至16中任一項之化合物，其中R1 為-NH2 。The compound of any one of claims 1 to 16, wherein R 1 is -NH 2 . 如請求項1至25中任一項之化合物，其中R2 選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)ORa2 、-NRa2 C(=O)Ra2 、-NRa2 C(=O)ORa2 、-C(=O)N(Ra2 )2 、-OC(=O)N(Ra2 )2 。The compound of any one of claims 1 to 25, wherein R 2 is selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 halo Alkyl, -C 1 -C 6 haloalkoxy, -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxanyl, tetrahydrofuranyl), - OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)OR a2 , -NR a2 C(=O)R a2 , -NR a2 C(=O)OR a2 , -C(=O)N(R a2 ) 2 , -OC(=O)N(R a2 ) 2 . 如請求項1至26中任一項之化合物，其中R2 選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-N(Ra2 )2 、-C(=O)Ra2 、-C(=O)N(ORa2 )(Ra2 )及-C(=O)N(Ra2 )2 。The compound of any one of claims 1 to 26, wherein R 2 is selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 halo Alkoxy, -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxo group, tetrahydrofuranyl), -OR a2 , -N(R a2 ) 2 , -C(=O)R a2 , -C(=O)N(OR a2 )(R a2 ) and -C(=O)N(R a2 ) 2 . 如請求項1至27中任一項之化合物，其中R2 選自鹵基、-C1 -C6 烷基、-C1 -C6 鹵烷基、-C1 -C6 鹵烷氧基、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-ORa2 、-C(=O)N(ORa2 )(Ra2 )、-C(=O)Ra2 及-C(=O)N(Ra2 )2 。The compound of any one of claims 1 to 27, wherein R 2 is selected from halo, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy , -C 3 -C 9 cycloalkyl ( for example, cyclopropyl), 3-6 membered heterocyclyl ( for example, oxo group, tetrahydrofuranyl), -OR a2 , -C(=O)N(OR a2 )(R a2 ), -C(=O)R a2 and -C(=O)N(R a2 ) 2 . 如請求項1至28中任一項之化合物，其中R2 選自鹵基、-C1 -C6 烷基、-C3 -C9 環烷基(例如， 環丙基)、-C1 -C6 鹵烷氧基、3-6員雜環基(例如， 氧呾基、四氫呋喃基)、-C1 -C6 鹵烷基、-ORa2 及-C(=O)N(Ra2 )2 。The compound of any one of claims 1 to 28, wherein R 2 is selected from halo, -C 1 -C 6 alkyl, -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), -C 1 -C 6 haloalkoxy, 3-6 membered heterocyclyl ( eg, oxo group, tetrahydrofuranyl), -C 1 -C 6 haloalkyl, -OR a2 and -C(=O)N(R a2 ) 2 . 如請求項1至29中任一項之化合物，其中各Ra2 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr,- n Bu、- t Bu、-sec -Bu、-iso -Bu)。The compound of any one of claims 1 to 29, wherein each R a2 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr, -i Pr, -n Bu , -t Bu, -sec -Bu, -iso -Bu). 如請求項1至30中任一項之化合物，其中R2 選自鹵基(例如， -Cl)、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-C1 -C6 鹵烷基(例如， -CF3 、CHF2 )、-C1 -C6 鹵烷氧基(例如， -OCH2 F、-OCF3 )、-C3 -C9 環烷基(例如， 環丙基)、3-6員雜環基(例如， 氧呾 基、四氫呋喃基)、-C1 -C6 鹵烷氧基(例如， -OCF3 、-OCHF2 )、-OMe、-C(=O)H、-C(=O)NHOH及-C(=O)NH2 。The compound of any one of claims 1 to 30, wherein R 2 is selected from halo ( eg, -Cl), -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr, -i Pr) , -n Bu, -t Bu, -sec -Bu, -iso -Bu), -C 1 -C 6 haloalkyl ( eg, -CF 3 , CHF 2 ), -C 1 -C 6 haloalkoxy ( eg, -OCH 2 F, -OCF 3 ), -C 3 -C 9 cycloalkyl ( eg, cyclopropyl), 3-6 membered heterocyclyl ( eg, oxanyl, tetrahydrofuranyl), -C 1 -C6 haloalkoxy ( eg, -OCF3 , -OCHF2), -OMe, -C (=O)H, -C(=O)NHOH, and -C(=O) NH2 . 如請求項1至26中任一項之化合物，其中R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、-CHF2 、-OCHF2 、-OCF3 、環丙基、氧呾-3-基、四氫呋喃-3-基、-OMe、-C(=O)H、-C(=O)NHOH及-C(=O)NH2 。The compound of any one of claims 1 to 26, wherein R 2 is selected from -Cl, -Me, -Et, -i Pr, -CF 3 , -CHF 2 , -OCHF 2 , -OCF 3 , cyclopropyl , oxo-3-yl, tetrahydrofuran-3-yl, -OMe, -C(=O)H, -C(=O)NHOH and -C(=O)NH 2 . 如請求項1至26中任一項之化合物，其中R2 選自-C(=O)NH2 及-C(=O)H。The compound of any one of claims 1 to 26, wherein R 2 is selected from -C(=O)NH 2 and -C(=O)H. 如請求項1至26中任一項之化合物，其中R2 為-C(=O)NH2 。The compound of any one of claims 1 to 26, wherein R 2 is -C(=O)NH 2 . 如請求項1至26中任一項之化合物，其中R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、-CHF2 、-OCHF2 、-OCF3 、氧呾-3-基、四氫呋喃-3-基及環丙基。The compound of any one of claims 1 to 26, wherein R 2 is selected from -Cl, -Me, -Et, -i Pr, -CF 3 , -CHF 2 , -OCHF 2 , -OCF 3 , oxo and - 3-yl, tetrahydrofuran-3-yl and cyclopropyl. 如請求項1至35中任一項之化合物，其中R2 選自環丙基、-Me及-Et。The compound of any one of claims 1 to 35, wherein R 2 is selected from cyclopropyl, -Me and -Et. 如請求項1至11中任一項之化合物，其中R1 選自H、-OMe、-OEt、-OCF3 、-OCHF2 、-CHF2 、-Me、-Et、-OH及-NH2 ，且R2 選自-Cl、-Me、-Et、- i Pr、-CF3 、-CHF2 、-OCHF2 、-OCF3 、環丙基、-C(=O)NH2 及-C(=O)H，前提條件為當R2 為-Me時，R1 為NH2 。The compound of any one of claims 1 to 11, wherein R 1 is selected from H, -OMe, -OEt, -OCF 3 , -OCHF 2 , -CHF 2 , -Me, -Et, -OH and -NH 2 , and R 2 is selected from -Cl, -Me, -Et, -i Pr, -CF 3 , -CHF 2 , -OCHF 2 , -OCF 3 , cyclopropyl, -C(=O)NH 2 and -C (=O)H, with the proviso that when R 2 is -Me, R 1 is NH 2 . 如請求項1至11中任一項之化合物，其中R1 選自H、-CHF2 、-Me及-NH2 ，且R2 選自-Cl、-Me、-Et、-CF3 、-CHF2 、-OCHF2 及環丙基，前提條件為當R2 為-Me時，R1 為NH2 。The compound of any one of claims 1 to 11, wherein R 1 is selected from H, -CHF 2 , -Me and -NH 2 , and R 2 is selected from -Cl, -Me, -Et, -CF 3 , - CHF 2 , -OCHF 2 and cyclopropyl, provided that when R 2 is -Me, R 1 is NH 2 . 如請求項1至11中任一項之化合物，其中R1 選自-NH2 及-Me，且R2 選自環丙基、-Me及-Et。The compound of any one of claims 1 to 11, wherein R 1 is selected from -NH 2 and -Me, and R 2 is selected from cyclopropyl, -Me and -Et. 如請求項39之化合物，其中R1 為-NH2 ，且R2 選自環丙基、-Me或-Et。The compound of claim 39, wherein R 1 is -NH 2 and R 2 is selected from cyclopropyl, -Me or -Et. 如請求項1至37中任一項之化合物，其中R1 選自H、-OMe、 -OEt,-OCF3 、-OCHF2 、-Et及-OH，且R2 選自-C(=O)NH2 及-C(=O)H。The compound of any one of claims 1 to 37, wherein R 1 is selected from H, -OMe, -OEt, -OCF 3 , -OCHF 2 , -Et and -OH, and R 2 is selected from -C (=O ) NH2 and -C(=O)H. 如請求項41之化合物，其中R1 選自H及-OMe且R2 為-C(=O)NH2 。The compound of claim 41, wherein R 1 is selected from H and -OMe and R 2 is -C(=O)NH 2 . 如請求項1至42中任一項之化合物，其中R3 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa3 、-N(Ra3 )2 、-C(=O)Ra3 、-C(=O)ORa3 、-NRa3 C(=O)Ra3 、-NRa3 C(=O)ORa3 、-C(=O)N(Ra3 )2 及-OC(=O)N(Ra3 )2 。The compound of any one of claims 1 to 42, wherein R 3 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a3 , -N(R a3 ) 2 , -C(=O)R a3 , -C(=O) OR a3 , -NR a3 C(=O)R a3 , -NR a3 C(=O)OR a3 , -C(=O)N(R a3 ) 2 and -OC(=O)N(R a3 ) 2 . 如請求項1至43中任一項之化合物，其中R3 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基及-N(Ra3 )2 。The compound of any one of claims 1 to 43, wherein R 3 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl and -N(R a3 ) 2 . 如請求項1至44中任一項之化合物，其中Ra3 選自H及C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。The compound of any one of claims 1 to 44, wherein R a3 is selected from H and C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -tBu , -sec -Bu, -iso -Bu). 如請求項1至45中任一項之化合物，其中R3 選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)、-OH、-O-(C1 -C6 烷基)(例如， -OMe)、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。The compound of any one of claims 1 to 45, wherein R 3 is selected from -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr , -iPr , -nBu, -tBu, -sec -Bu, -iso -Bu), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe), -NH 2 , -NH-(C 1 -C 6 alkyl) ( For example, -NHMe) and -N-(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). 如請求項1至46中任一項之化合物，其中R3 選自H、-Me及-NH2 。The compound of any one of claims 1 to 46, wherein R 3 is selected from H, -Me and -NH 2 . 如請求項1至47中任一項之化合物，其中R3 選自H及-Me。The compound of any one of claims 1 to 47, wherein R3 is selected from H and -Me. 如請求項1至48中任一項之化合物，其中R3 為-Me。The compound of any one of claims 1 to 48, wherein R 3 is -Me. 如請求項1至49中任一項之化合物，其中R4 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、-ORa4 、-N(Ra4 )2 、-C(=O)Ra4 、-C(=O)ORa4 、-NRa4 C(=O)Ra4 、-NRa4 C(=O)ORa4 、-C(=O)N(Ra4 )2 及-OC(=O)N(Ra4 )2 。The compound of any one of claims 1 to 49, wherein R 4 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, -OR a4 , -N(R a4 ) 2 , -C(=O)R a4 , -C(=O) OR a4 , -NR a4 C(=O)R a4 , -NR a4 C(=O)OR a4 , -C(=O)N(R a4 ) 2 and -OC(=O)N(R a4 ) 2 . 如請求項1至50中任一項之化合物，其中R4 選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 鹵烷基及-N(Ra4 )2 。The compound of any one of claims 1 to 50, wherein R 4 is selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl and -N(R a4 ) 2 . 如請求項1至51中任一項之化合物，其中各Ra4 獨立地選自H及 -C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。The compound of any one of claims 1 to 51, wherein each R a4 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -t Bu, -sec -Bu, -iso -Bu). 如請求項1至52中任一項之化合物，其中R4 選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-nBu、- t Bu、-sec -Bu、-iso -Bu)、-OH、-O-(C1 -C6 烷基)(例如， -OMe)、-NH2 、-NH-(C1 -C6 烷基)(例如， -NHMe)及-N-(C1 -C6 烷基)2 (例如， NMe2 )。The compound of any one of claims 1 to 52, wherein R 4 is selected from -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu, -tBu, - sec -Bu, -iso -Bu), -OH, -O-(C 1 -C 6 alkyl) ( eg, -OMe), -NH 2 , -NH-(C 1 -C 6 alkyl) ( eg , -NHMe) and -N-(C 1 -C 6 alkyl) 2 ( eg, NMe 2 ). 如請求項1至53中任一項之化合物，其中R4 為H。The compound of any one of claims 1 to 53, wherein R4 is H. 如請求項1至54中任一項之化合物，其中各R6 獨立地選自-D、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代。The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from -D, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, - C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heterocyclyl Arylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C (=O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O) R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 , wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are considered Cases are substituted at any available position. 如請求項1至54中任一項之化合物，其中各R6 獨立地選自H、鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from H, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroaryl Alkylalkyl, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C( =O)R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N (R a6 ) 2 , wherein each of the alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl groups is in any Available positions are substituted by 0, 1, 2 or 3 instances of R 10 , wherein: 各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、 -S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、雜環基烷氧基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代；且其中：Each R 10 is independently selected from -D, =O, -CN, halo, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 - C9 cycloalkyl, 3-10 membered heterocyclyl, C6 - C10 membered aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heterocyclyl Arylalkyl, heterocyclylalkoxy, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O) R b10 , -NR b10 C(=O)OR b10 , -C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , - S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S (=O) 2 N(R b10 ) 2 , wherein each of R 10 is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl , heterocyclylalkoxy, arylalkyl, and heteroarylalkyl are optionally substituted at any available position; and wherein: 各Rb10 獨立地為H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；或經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。Each R b10 is independently H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 -C 9 cycloalkyl; or 3-10 membered heterocyclyl substituted with 0 or 1 instance of =0, -Me or a combination thereof. 如請求項1至54中任一項之化合物，其中各R6 獨立地選自鹵基、-CN、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基、環烷基烷基、-ORa6 、-N(Ra6 )2 、-C(=O)Ra6 、-C(=O)ORa6 、-NRa6 C(=O)Ra6 、-NRa6 C(=O)ORa6 、-C(=O)N(Ra6 )2 、-OC(=O)N(Ra6 )2 、-S(=O)Ra6 、-S(=O)2 Ra6 、-SRa6 、-S(=O)(=NRa6 )Ra6 、-NRa6 S(=O)2 Ra6 及-S(=O)2 N(Ra6 )2 ，其中各烷基、碳環基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 - C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroarylalkane group, arylalkyl, cycloalkylalkyl, -OR a6 , -N(R a6 ) 2 , -C(=O)R a6 , -C(=O)OR a6 , -NR a6 C(=O )R a6 , -NR a6 C(=O)OR a6 , -C(=O)N(R a6 ) 2 , -OC(=O)N(R a6 ) 2 , -S(=O)R a6 , -S(=O) 2 R a6 , -SR a6 , -S(=O)(=NR a6 )R a6 , -NR a6 S(=O) 2 R a6 and -S(=O) 2 N(R a6 ) 2 wherein each alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl is in any available position Substituted with 0, 1, 2 or 3 instances of R 10 , wherein: 各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、-ORb10 、 -N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、-S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、雜環基烷氧基、芳基烷基及雜芳基烷基視情況在任一可用位置經取代(例如， 經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)，且其中：Each R 10 is independently selected from -D, =O, -CN, halo, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 - C9 cycloalkyl, 3-10 membered heterocyclyl, C6 - C10 membered aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heterocyclyl Arylalkyl, heterocyclylalkoxy, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O) R b10 , -NR b10 C(=O)OR b10 , -C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , - S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S (=O) 2 N(R b10 ) 2 , wherein each of R 10 is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl , heterocyclylalkoxy, arylalkyl, and heteroarylalkyl are optionally substituted at any available position ( eg, with -Me, -Et, -iPr , cyclopropyl, oxo-3-yl , -OH , =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C ( = O)Me, -N(Me )2 , - CH2N ( CH3 ) 2 , -CH2N ( CH3 ) CH2CH3 , -N( iPr )(Et ) , -N( iPr )(Me), -N(Et) 2 , - 0, 1, 2, 3, 4, or 5 instances of N( CH3 )(Et), -NHC(=O)Me, or combinations thereof substituted), and wherein: 各Rb10 獨立地為H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；或經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。Each R b10 is independently H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 -C 9 cycloalkyl; or 3-10 membered heterocyclyl substituted with 0 or 1 instance of =0, -Me or a combination thereof. 如請求項1至57中任一項之化合物，其中各Ra6 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。The compound of any one of claims 1 to 57, wherein each R a6 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -t Bu, -sec -Bu, -iso -Bu). 如請求項1至54中任一項之化合物，其中各R6 獨立地選自H、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置視情況經取代。The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkane base, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, aryl Alkyl and cycloalkylalkyl groups, each of which is alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkane Radicals are optionally substituted at any available position. 如請求項1至54中任一項之化合物，其中各R6 獨立地選自-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置視情況經取代。The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are An available position is substituted as appropriate. 如請求項1至54中任一項之化合物，其中各R6 獨立地選自H、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基，其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkane base, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, aryl Alkyl and cycloalkylalkyl groups, each of which is alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkane group is substituted with 0, 1, 2 or 3 instances of R 10 at any available position, wherein: 各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、芳基烷基、雜芳基烷基、雜環基烷氧基、雜環基烷基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、 -S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)；且其中：Each R 10 is independently selected from -D, =O, -CN, halo, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10-membered heterocyclyl, C 6 -C 10 -membered aryl, 5-10-membered heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heteroaryl Cycloalkoxy, heterocyclylalkyl, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O) R b10 , -NR b10 C(=O)OR b10 , -C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , - S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S (=O) 2 N(R b10 ) 2 , wherein each of R 10 is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl , arylalkyl, and heteroarylalkyl are optionally substituted ( eg, with -Me, -Et, -iPr , cyclopropyl, oxo-3-yl, -OH, =O, -F, - OMe, -CH2CH2F, -CH2CHF2 , -CH2CH2CF3 , -C (=O)Me, -N ( Me )2 , -CH2N ( CH3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr)(Et), -N( i Pr)(Me), -N(Et) 2 , -N(CH 3 )(Et), -NHC (=0) 0, 1, 2, 3, 4, or 5 instances of Me or a combination thereof substituted); and wherein: 各Rb10 獨立地選自H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；及經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。Each R b10 is independently selected from H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 - C9cycloalkyl ; and 3-10 membered heterocyclyl substituted with 0 or 1 instance of =0, -Me, or a combination thereof. 如請求項1至54中任一項之化合物，其中各R6 獨立地選自-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C10 碳環基、3-10員雜環基、雜環基烷基、C6 -C10 芳基、5-10員雜芳基、雜芳基烷基、芳基烷基及環烷基烷基， 其中各烷基、環烷基、雜環基、環烷基烷基、雜環基烷基、芳基、雜芳基、芳基烷基及雜芳基烷基在任一可用位置經R10 之0、1、2或3個實例取代，其中：The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclyl alkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, heteroarylalkyl, arylalkyl and cycloalkylalkyl, wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are An available position is substituted with 0, 1, 2 or 3 instances of R 10 , wherein: 各R10 獨立地選自-D、=O、-CN、鹵基、-C1 -C6 烷基、-C1 -C6 雜烷基、-C1 -C6 鹵烷基、-C3 -C9 環烷基、3-10員雜環基、C6 -C10 芳基、5-10員雜芳基、環烷基烷基、芳基烷基、雜芳基烷基、雜環基烷基、雜環基烷氧基、-ORb10 、-N(Rb10 )2 、-C(=O)Rb10 、-C(=O)ORb10 、-NRb10 C(=O)Rb10 、-NRb10 C(=O)ORb10 、-C(=O)N(Rb10 )2 、-OC(=O)Rb10 、-OC(=O)N(Rb10 )2 、-S(=O)Rb10 、 -S(=O)2 Rb10 、-SRb10 、-S(=O)(=NRb10 )Rb10 、-NRb10 S(=O)2 Rb10 及-S(=O)2 N(Rb10 )2 ，其中R10 之各烷基、環烷基、雜烷基、雜環基、雜環基烷氧基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基視情況經取代(例如，經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代))；且Each R 10 is independently selected from -D, =O, -CN, halo, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl, -C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10-membered heterocyclyl, C 6 -C 10 -membered aryl, 5-10-membered heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heteroaryl Cycloalkyl, heterocyclylalkoxy, -OR b10 , -N(R b10 ) 2 , -C(=O)R b10 , -C(=O)OR b10 , -NR b10 C(=O) R b10 , -NR b10 C(=O)OR b10 , -C(=O)N(R b10 ) 2 , -OC(=O)R b10 , -OC(=O)N(R b10 ) 2 , - S(=O)R b10 , -S(=O) 2 R b10 , -SR b10 , -S(=O)(=NR b10 )R b10 , -NR b10 S(=O) 2 R b10 and -S (=O) 2 N(R b10 ) 2 , wherein each of R 10 is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, heterocyclylalkoxy, aryl, heteroaryl, cycloalkylalkane group, heterocyclylalkyl, arylalkyl, and heteroarylalkyl are optionally substituted (eg, with -Me, -Et, -iPr , cyclopropyl, oxo-3-yl, -OH, =O, -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C ( = O)Me, -N(Me )2 , -CH2N ( CH3 ) 2 , -CH2N ( CH3 ) CH2CH3 , -N( iPr )(Et ) , -N( iPr )(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=0)Me, or 0, 1, 2, 3, 4, or 5 instances of a combination thereof substituted)); and 各Rb10 獨立地選自H；-C1 -C6 烷基；-C1 -C6 鹵烷基；經=O之0或1個實例取代之-C1 -C6 雜烷基；C3 -C9 環烷基；及經=O、-Me或其組合之0或1個實例取代之3-10員雜環基。Each R b10 is independently selected from H; -C 1 -C 6 alkyl; -C 1 -C 6 haloalkyl; -C 1 -C 6 heteroalkyl substituted with 0 or 1 instance of =0; C 3 - C9cycloalkyl ; and 3-10 membered heterocyclyl substituted with 0 or 1 instance of =0, -Me, or a combination thereof. 如請求項1至54中任一項之化合物，其中各R6 獨立地選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- i Bu、sec -Bu、- t Bu)、-C3 -C10 單環或雙環碳環基(例如， 環丙基、環丁基、環戊基、環己基、環庚基、雙環[1.1.1]戊-基、4,5,6,7-四氫-1H-吲唑基、螺[3.3]庚基)、3-10員單環或雙環雜環基(例如， 氧呾基、氮雜環庚烷基、哌啶基、吡咯啶基、四氫呋喃基、四氫哌喃基、1,2-二氫吡啶基、嗎啉基)、C6 -C10 單環或雙環芳基(例如， 苯基、萘基、1,2,3,4- 四氫萘基、2,3-二氫-1H-茚基、1,2,3,4-四氫喹啉基、1,2-二氫喹啉基、1,2-二氫異喹啉基、1,2,3,4-四氫異喹啉基、色原烷基、吲哚啉基、異吲哚啉基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、2,3-二氫苯并呋喃基、苯并[d ][1,3]二氧雜環戊烯基、2,3-二氫-1H-苯并[d]咪唑基)、5-6員單環雜芳基(例如， 噻吩基、噻唑基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基)、8-10員雙環雜芳基(例如， 苯并[d]異噻唑基、吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b]噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、咪唑并[1,5-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基)，其中各烷基、碳環基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr, -i Pr, -i Bu, sec -Bu, -tBu ), -C3 - C10 monocyclic or bicyclic carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl -yl, 4,5,6,7-tetrahydro-1H-indazolyl, spiro[3.3]heptyl), 3-10 membered monocyclic or bicyclic heterocyclyl ( eg, oxanyl, azepanyl) alkyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2-dihydropyridyl, morpholinyl), C6 - C10 monocyclic or bicyclic aryl ( eg, phenyl , naphthyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2-dihydroquinoline Linyl, 1,2-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, chromogen alkyl, indolinyl, isoindolinyl, 3,4-bis Hydro-2H-benzo[b][1,4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[ d ][1,3]dioxolyl, 2,3 -Dihydro-1H-benzo[d]imidazolyl), 5-6 membered monocyclic heteroaryl ( eg, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl) , 8-10 membered bicyclic heteroaryl ( e.g., benzo[d]isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl, Quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl , benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1 ,2- a ]pyridyl, imidazo[1,5- a ]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl , 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridyl), wherein each alkyl, carbon Cyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10). 如請求項1至54中任一項之化合物，其中各R6 獨立地選自-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- i Bu、sec -Bu、- t Bu)、-C3 -C10 單環或雙環碳環基(例如， 環丙基、環丁基、環戊基、環己基、環庚基、雙環[1.1.1]戊-基、4,5,6,7-四氫-1H-吲唑基、螺[3.3]庚基)、3-10員單環或雙環雜環基(例如， 氧呾基、氮雜環庚烷基、哌啶基、吡咯啶基、四氫呋喃基、四氫哌喃基、1,2-二氫吡啶基、嗎啉基)、C6 -C10 單環或雙環芳基(例如， 苯基、萘基、1,2,3,4-四氫萘基、2,3-二氫-1H-茚基、1,2,3,4-四氫喹啉基、1,2-二氫喹啉基、1,2-二氫異喹啉基、1,2,3,4-四氫異喹啉基、色原烷基、吲哚啉基、異吲哚啉基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、2,3-二氫苯并呋喃基、苯并[d ][1,3]二氧雜環戊烯基、2,3-二氫-1H-苯并[d]咪唑基)、5-6員單環雜芳基(例如， 噻吩基、噻唑基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基)、8-10員雙環雜芳基(例如， 苯并[d]異噻唑基、吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b] 噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、咪唑并[1,5-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基)，其中各烷基、碳環基、雜環基、芳基及雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。The compound of any one of claims 1 to 54, wherein each R 6 is independently selected from -C 1 -C 6 alkyl ( eg, -Me, -Et, -Pr, -i Pr, -i Bu, sec -Bu, -tBu ), -C3 - C10 monocyclic or bicyclic carbocyclyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl -yl, 4,5,6,7-tetrahydro-1H-indazolyl, spiro[3.3]heptyl), 3-10 membered monocyclic or bicyclic heterocyclyl ( eg, oxanyl, azepanyl) alkyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2-dihydropyridyl, morpholinyl), C6 - C10 monocyclic or bicyclic aryl ( eg, phenyl , naphthyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2-dihydroquinoline Linyl, 1,2-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, chromogen alkyl, indolinyl, isoindolinyl, 3,4-bis Hydro-2H-benzo[b][1,4]oxazinyl, 2,3-dihydrobenzofuranyl, benzo[ d ][1,3]dioxolyl, 2,3 -Dihydro-1H-benzo[d]imidazolyl), 5-6 membered monocyclic heteroaryl ( eg, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl) , 8-10 membered bicyclic heteroaryl ( e.g., benzo[d]isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl, Quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, isoquinolinyl , benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1 ,2- a ]pyridyl, imidazo[1,5- a ]pyridyl, 1H-pyrazolo[4,3- b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl , 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridyl), wherein each alkyl, carbon Cyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted ( eg, substituted with 0 , 1, 2, or 3 instances of R10). 如請求項63之化合物，其中R6 為8-10員雙環雜芳基(例如吲哚基、苯并呋喃基、1H-吲唑基、2H-吲唑基、苯并[b]噻吩基、喹啉基、1,5-萘啶基、1,2-二氫-1,5-萘啶基、1,2,3,4-四氫-1,8-萘啶基、咪唑并[1,2-a]吡啶基、咪唑并[1,5-a]吡啶基、異喹啉基、苯并[d ]咪唑基、苯并[d ]噻唑基、苯并[d ]異噻唑基、苯并[d ]噁唑基、[1,2,4]三唑并[4,3-a ]吡啶基、咪唑并[1,2-a ]吡啶基、1H-吡唑并[4,3-b ]吡啶基)、1H-吡唑并[3,4-b]吡啶基、1H-噻吩并[2,3-c]吡唑基、1H-噻吩并[3,2-c]吡唑基、噻唑并[5,4-b]吡啶基、1,2,3,4-四氫-1,8-萘啶基)，其中雙環雜芳基視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。The compound of claim 63, wherein R 6 is 8-10 membered bicyclic heteroaryl (eg indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thienyl, Quinolinyl, 1,5-naphthyridinyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, imidazo[1 ,2-a]pyridyl, imidazo[1,5-a]pyridyl, isoquinolyl, benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, benzo[ d ]isothiazolyl, Benzo[ d ]oxazolyl, [1,2,4]triazolo[4,3- a ]pyridyl, imidazo[1,2- a ]pyridyl, 1H-pyrazolo[4,3 - b ]pyridyl), 1H-pyrazolo[3,4-b]pyridyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazole base, thiazolo[5,4-b]pyridyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), wherein bicyclic heteroaryl is optionally substituted ( eg, by R 10 0, 1, 2 or 3 instance substitutions). 如請求項1至54中任一項之化合物，其中各R6 獨立地選自H、-Me、- i Pr、- i Bu、sec -Bu、環丁基、環戊基、環己基、雙環[1.1.1]戊烷-1-基、螺[3.3]庚-2-基、4,5,6,7-四氫-1H-吲唑-6-基、哌啶-4-基、哌啶-3-基、吡咯啶-3-基、1,2-二氫吡啶-4-基、苯基、萘-2-基、1,2,3,4四氫喹啉-6-基、1,2,3,4-四氫萘-6-基、色原烷-6-基、1,5-萘啶-6-基、1,2,3,4-四氫-1,8-萘啶-6-基、2,3-二氫-1H-茚-5-基、吲哚啉-5-基、吲哚啉-4-基、2,3-二氫-1H-苯并[d]咪唑-5-基、2,3-二氫苯并呋喃-5-基、2,3-二氫苯并呋喃-6-基、苯并[d ][1,3]二氧雜環戊烯-5-基]、異吲哚啉-5-基、異吲哚啉-6-基、3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基、1,2-二氫喹啉-6-基、1,2-二氫異喹啉-7-基、噻吩-2-基、噻吩-3-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、吡唑-1-基、吡唑-5-基、吡唑-3-基、吡唑-4-基、 吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基、吲哚-4-基、吲哚-5-基、苯并呋喃-5-基、苯并呋喃-6-基、1H 吲唑-5-基、1H -吲唑-4-基、2H-吲唑-6-基、2H-吲唑-5-基、苯并[b ]噻吩-3-基、苯并[b ]噻吩-5-基、喹啉-6-基、喹啉-3-基、異喹啉-6-基、苯并[d ]咪唑并-5-基、1H-苯并[d]咪唑-4-基、苯并[d ]噻唑-5-基、苯并[d]噻唑-6-基、苯并[d]噻唑-4-基、苯并[d]異噻唑-5-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、[1,2,4]三唑并[4,3-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-6-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,5-a]吡啶-6-基、吡唑并[4,3-b ]吡啶-6-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-6-基、1H-噻吩并[2,3-c]吡唑-5-基、1H-噻吩并[3,2-c]吡唑-5-基、噻唑并[5,4-b]吡啶-6-基)，其各自視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。The compound of any one of claims 1 to 54, wherein each R is independently selected from H, -Me, -i Pr, -i Bu, sec -Bu, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1]Pentan-1-yl, spiro[3.3]hept-2-yl, 4,5,6,7-tetrahydro-1H-indazol-6-yl, piperidin-4-yl, piper Perid-3-yl, pyrrolidin-3-yl, 1,2-dihydropyridin-4-yl, phenyl, naphth-2-yl, 1,2,3,4 tetrahydroquinolin-6-yl, 1,2,3,4-Tetrahydronaphthalen-6-yl, Chromane-6-yl, 1,5-naphthyridin-6-yl, 1,2,3,4-tetrahydro-1,8- Naphthyridin-6-yl, 2,3-dihydro-1H-inden-5-yl, indolin-5-yl, indolin-4-yl, 2,3-dihydro-1H-benzo[ d]imidazol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[ d ][1,3]dioxane Penten-5-yl], isoindolin-5-yl, isoindolin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazine-7- base, 1,2-dihydroquinolin-6-yl, 1,2-dihydroisoquinolin-7-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4 -yl, thiazol-5-yl, pyrazol-1-yl, pyrazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridine -4-yl, pyrimidin-5-yl, indol-4-yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1 H indazol-5-yl, 1H -indazol-4-yl, 2H-indazol-6-yl, 2H-indazol-5-yl, benzo[ b ]thien-3-yl, benzo[ b ]thien-5-yl, Quinolin-6-yl, quinolin-3-yl, isoquinolin-6-yl, benzo[ d ]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[ d ]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-4-yl, benzo[d]isothiazol-5-yl, benzo[ d ]oxazol- 4-yl, benzo[ d ]oxazol-5-yl, [1,2,4]triazolo[4,3- a ]pyridin-6-yl, imidazo[1,2- a ]pyridine- 6-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,5-a]pyridin-6-yl, pyrazolo[4,3- b ]pyridin-6-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin- 5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c ]pyrazol-5-yl, thiazolo[5,4-b]pyridin-6-yl), each of which is optionally substituted ( eg, via 0, 1 , 2 of R or 3 instances instead). 如請求項1至54中任一項之化合物，其中各R6 獨立地選自-Me、- i Pr、- i Bu、sec -Bu、環丁基、環戊基、環己基、雙環[1.1.1]戊烷-1-基、螺[3.3]庚-2-基、4,5,6,7-四氫-1H-吲唑-6-基、哌啶-4-基、哌啶-3-基、吡咯啶-3-基、1,2-二氫吡啶-4-基、苯基、萘-2-基、1,2,3,4四氫喹啉-6-基、1,2,3,4-四氫萘-6-基、色原烷-6-基、1,5-萘啶-6-基、1,2,3,4-四氫-1,8-萘啶-6-基、2,3-二氫-1H-茚-5-基、吲哚啉-5-基、吲哚啉-4-基、2,3-二氫-1H-苯并[d]咪唑-5-基、2,3-二氫苯并呋喃-5-基、2,3-二氫苯并呋喃-6-基、苯并[d ][1,3]二氧雜環戊烯-5-基]、異吲哚啉-5-基、異吲哚啉-6-基、3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基、1,2-二氫喹啉-6-基、1,2-二氫異喹啉-7-基、噻吩-2-基、噻吩-3-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、吡唑-1-基、吡唑-5-基、吡唑-3-基、吡唑-4-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基、吲哚-4-基、吲哚-5-基、苯并呋喃-5-基、苯并呋喃-6-基、1H 吲唑-5-基、1H 吲唑-4-基、2H-吲唑-6-基、2H-吲唑-5-基、苯并[b ]噻吩-3-基、苯并[b ]噻吩-5-基、喹啉-6-基、喹啉-3-基、 異喹啉-6-基、苯并[d ]咪唑并-5-基、1H-苯并[d]咪唑-4-基、苯并[d ]噻唑-5-基、苯并[d]噻唑-6-基、苯并[d ]噻唑-4-基、苯并[d ]異噻唑-5-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、[1,2,4]三唑并[4,3-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-6-基、咪唑并[1,2-a ]吡啶-7-基、咪唑并[1,5-a]吡啶-6-基、吡唑并[4,3-b ]吡啶-6-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[3,4-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-5-基、1H-吡唑并[4,3-b]吡啶-6-基、1H-噻吩并[2,3-c]吡唑-5-基、1H-噻吩并[3,2-c]吡唑-5-基、噻唑并[5,4-b]吡啶-6-基)，其各自視情況經取代(例如， 經R10 之0、1、2或3個實例取代)。The compound of any one of claims 1 to 54, wherein each R is independently selected from -Me, -i Pr, -i Bu, sec -Bu, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1 .1]Pentan-1-yl, spiro[3.3]hept-2-yl, 4,5,6,7-tetrahydro-1H-indazol-6-yl, piperidin-4-yl, piperidine- 3-yl, pyrrolidin-3-yl, 1,2-dihydropyridin-4-yl, phenyl, naphth-2-yl, 1,2,3,4 tetrahydroquinolin-6-yl, 1, 2,3,4-Tetrahydronaphthalen-6-yl, Chromane-6-yl, 1,5-naphthyridin-6-yl, 1,2,3,4-tetrahydro-1,8-naphthyridine -6-yl, 2,3-dihydro-1H-inden-5-yl, indolin-5-yl, indolin-4-yl, 2,3-dihydro-1H-benzo[d] Imidazol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[ d ][1,3]dioxol -5-yl], isoindolin-5-yl, isoindolin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1,2-dihydroquinolin-6-yl, 1,2-dihydroisoquinolin-7-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl , thiazol-5-yl, pyrazol-1-yl, pyrazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4 -yl, pyrimidin-5-yl, indol-4-yl, indol-5-yl, benzofuran-5-yl, benzofuran-6-yl, 1 H indazol-5-yl, 1 H Indazol-4-yl, 2H-indazol-6-yl, 2H-indazol-5-yl, benzo[ b ]thiophen-3-yl, benzo[ b ]thien-5-yl, quinoline- 6-yl, quinolin-3-yl, isoquinolin-6-yl, benzo[ d ]imidazo-5-yl, 1H-benzo[d]imidazol-4-yl, benzo[ d ]thiazole -5-yl, benzo[d]thiazol-6-yl, benzo[ d ]thiazol-4-yl, benzo[ d ]isothiazol-5-yl, benzo[ d ]oxazol-4-yl , benzo[ d ]oxazol-5-yl, [1,2,4]triazolo[4,3- a ]pyridin-6-yl, imidazo[1,2- a ]pyridin-6-yl , imidazo[1,2- a ]pyridin-7-yl, imidazo[1,5-a]pyridin-6-yl, pyrazolo[4,3- b ]pyridin-6-yl, 1H-pyridin-6-yl Azolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl , 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-thieno[2,3-c]pyrazol-5-yl, 1H-thieno[3,2-c]pyrazole -5-yl, thiazolo[5,4-b]pyridin-6-yl), each of which is optionally substituted ( eg, 0 , 1 via R10) , 2 or 3 instances replaced). 如請求項1至67中任一項之化合物，其中R6 選自視情況經取代之苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-5-基及苯基(例如， 經R10 之0、1、2或3個實例取代)。The compound of any one of claims 1 to 67, wherein R is selected from optionally substituted phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl and Phenyl ( eg, substituted with 0 , 1, 2 or 3 instances of R10). 如請求項68之化合物，其中R6 選自經R10 之一個實例取代之苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基及嘧啶-5-基。The compound of claim 68, wherein R6 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin- 4 -yl and pyrimidin- 5 -yl substituted with an instance of R10. 如請求項68之化合物，其中R6 選自：The compound of claim 68, wherein R 6 is selected from:
Figure 110128222-A0202-13-0018-520
Figure 110128222-A0202-13-0018-520
 如請求項68之化合物，其中R6 為The compound of claim 68, wherein R 6 is
Figure 110128222-A0202-13-0018-521
Figure 110128222-A0202-13-0018-521
 如請求項1至67中任一項之化合物，其中R6 為視情況經取代之苯基(例如， 經R10 之0、1、2或3個實例取代)。The compound of any one of claims 1 to 67, wherein R6 is optionally substituted phenyl ( eg, substituted with 0 , 1, 2, or 3 instances of R10). 如請求項72之化合物，其中R6 為The compound of claim 72, wherein R 6 is
Figure 110128222-A0202-13-0018-522
Figure 110128222-A0202-13-0018-522
 如請求項1至67中任一項之化合物，其中R6 選自視情況經取代之雙環雜芳基(例如， 經R10 之0、1、2或3個實例取代)。The compound of any one of claims 1 to 67, wherein R 6 is selected from optionally substituted bicyclic heteroaryl ( eg, substituted with 0, 1, 2 or 3 instances of R 10 ). 如請求項74之化合物，其中R6 選自視情況經取代之1H -吲唑-5-基、2H -吲唑-5-基、苯并[d]異噻唑-5-基、苯并[d]噻唑-5-基、苯并[b]噻吩-5-基、苯并[d ]噁唑-4-基、苯并[d ]噁唑-5-基、喹啉-7-基、1H-噻吩并[2,3-c]吡唑-5-基、咪唑并[1,2-a]吡啶-7-基及咪唑并[1,5-a]吡啶-6-基(例如， 經R10 之0、1、2或3個實例取代)。The compound of claim 74, wherein R 6 is selected from optionally substituted 1 H -indazol-5-yl, 2 H -indazol-5-yl, benzo[d]isothiazol-5-yl, benzene zo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[ d ]oxazol-4-yl, benzo[ d ]oxazol-5-yl, quinolin-7- yl, 1H-thieno[2,3-c]pyrazol-5-yl, imidazo[1,2-a]pyridin-7-yl and imidazo[1,5-a]pyridin-6-yl ( For example, substituted with 0 , 1, 2 or 3 instances of R10). 如請求項75之化合物，其中R6 為
Figure 110128222-A0202-13-0019-523
、
Figure 110128222-A0202-13-0019-524
Figure 110128222-A0202-13-0019-531
 The compound of claim 75, wherein R 6 is
Figure 110128222-A0202-13-0019-523
,
Figure 110128222-A0202-13-0019-524
Figure 110128222-A0202-13-0019-531
 如請求項76之化合物，其中R6 為
Figure 110128222-A0202-13-0019-527
 The compound of claim 76, wherein R 6 is
Figure 110128222-A0202-13-0019-527
 如請求項1至77中任一項之化合物，其中各R10 獨立地選自-D、=O、鹵基(例如， F、Cl、Br)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、CH2 (CH3 )( i Pr))、-C1 -C6 雜烷基(例如， -CH(CH3 )(NMe2 )、-CH2 CH2 N(Me)(氧呾-3-基))、-CH2 CH(CH3 )(NMe2 )、-CH2 OH、-CH(OH)(CH3 )、 -C(OH)(CH3 )2 、-CH2 NH2 )、-C1 -C6 鹵烷基(例如， -CHF2 、-CH2 CF3 、-CF3 )、-C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)、3-10員雜環基(例如， 四氫呋喃基、四氫哌喃基、氧呾基、嗎啉基、吡咯啶基、哌啶基、哌啶-2-酮基、哌嗪基、哌嗪-2-酮基、吖呾基、十氫-1,6-萘啶基、2-氮雜螺[3.3]庚基、5-氧雜-2,8-二氮雜螺[3.5]壬基、8-氮雜雙環[3.2.1]辛基、2-氮雜雙環[2.2.2]辛基、3-氮雜雙環[3.2.0]庚基、3-氮雜雙環[3.1.1]庚基、3-氮雜雙環[3.1.0]己基、2-氮雜雙環[2.1.1]己基、1-氮雜雙環 [2.2.1]庚基、3-氮雜雙環[3.2.0]庚基、2,9-二氮雜螺[5.5]十一烷基、雙環[1.1.1]戊基、八氫環戊[c]吡咯基、十氫-1,6-萘啶基、八氫-1H-吡咯并[3,4-c]吡啶基、十氫-2,7-萘啶基、2,9-二氮雜螺[5.5]十一烷基)、5-10員雜芳基(例如， 吡啶基、咪唑并[1,2-a]吡啶基、咪唑基、吡唑基、噻唑基、噻吩基)、環烷基烷基(例如 -CH2 -環丙基)、雜環基烷基(例如， -CH2 -嗎啉基、-(CH2 )2 -吡咯啶基-(CH2 )2 -吡咯啶基-CH2 -咪唑基、-CH2 -吡唑基、-CH2 -1,2,4-三唑基、-CH2 -嗎啉基、-(CH2 )2 -嗎啉基)、雜環基烷氧基(例如，-O-(CH2 )2 -吡咯啶基、-O-CH2 -哌啶基、-O-CH2 -氧呾基、-O-CH2 -四氫呋喃基、-O-CH2 -四氫哌喃基)、雜芳基烷基(例如， -CH2 -三唑基、-CH2 -咪唑基、-CH2 -吡唑基)、-ORb10 (例如， -OH、-OMe、OEt、-O-四氫呋喃基、-O-四氫哌喃-4-基、-OCF3 、-OCHF2 )、-N(Rb10 )2 、(例如， -NH2 、-NHRb10 、-NHMe、-NMe2 、-NHCH2 CF3 、-NH-氧呾-3-基、-NH-(N-Me-2-側氧基吡咯啶-3-基)、-NRb10 C(=O)Rb10 (例如， -NHC(=O)Me)、-C(=O)N(Rb10 )2 、(例如， -C(=O)NH2 、C(=O)NHMe)、-OC(=O)Rb10 (例如， -OC(=O)Me)、-S(=O)Rb10 (例如， -SO2 Me)、-NRb10 S(=O)2 Rb10 (例如， NHSO2 Me)及-S(=O)2 N(Rb10 )2 (例如， SO2 NH2 、SO2 NHMe)，其中各烷基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基及雜芳基烷基視情況經取代(例如， 經-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合之0、1、2、3、4或5個實例取代)，且其中：The compound of any one of claims 1 to 77, wherein each R 10 is independently selected from -D, =O, halo ( eg, F, Cl, Br), -CN, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -sec -Bu, -tBu, CH2 ( CH3 )( iPr )), -C1 - C6heteroalkyl ( eg, - CH( CH3 )( NMe2 ), -CH2CH2N (Me)(oxo- 3 -yl)), -CH2CH( CH3 ) ( NMe2 ), -CH2OH , -CH( OH)( CH3 ) , -C (OH)( CH3 ) 2 , -CH2NH2 ) , -C1 - C6 haloalkyl ( eg, -CHF2, -CH2CF3 , -CF3 ), -C 3 -C 9 cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-10 membered heterocyclyl ( eg, tetrahydrofuranyl, tetrahydropyranyl, oxygen Alkyl, morpholinyl, pyrrolidinyl, piperidinyl, piperidin-2-one, piperazinyl, piperazin-2-one, acryl, decahydro-1,6-naphthyridinyl, 2-Azaspiro[3.3]heptyl, 5-oxa-2,8-diazaspiro[3.5]nonyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2 .2]Octyl, 3-azabicyclo[3.2.0]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[ 2.1.1] Hexyl, 1-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.0]heptyl, 2,9-diazaspiro[5.5]undecyl, bicyclo[ 1.1.1] Pentyl, octahydrocyclopenta[c]pyrrolyl, decahydro-1,6-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, decahydro-2, 7-naphthyridinyl, 2,9-diazaspiro[5.5]undecyl), 5-10 membered heteroaryl ( eg, pyridyl, imidazo[1,2-a]pyridyl, imidazolyl , pyrazolyl, thiazolyl, thienyl), cycloalkylalkyl ( eg -CH2 -cyclopropyl), heterocyclylalkyl ( eg, -CH2 -morpholinyl, -( CH2 ) 2 -pyrrolidinyl-( CH2 ) 2 -pyrrolidinyl- CH2 -imidazolyl, -CH2 -pyrazolyl, -CH2-1,2,4-triazolyl, -CH2 - morpholinyl , -( CH2 ) 2 -morpholinyl), heterocyclylalkoxy (eg, -O-( CH2 ) 2 -pyrrolidinyl, -O- CH2 -piperidinyl, -O- CH2 -Oxylanyl, -O- CH2 -tetrahydrofuranyl, -O- CH2 -tetrahydropyranyl), heteroarylalkyl ( eg, -CH2 -triazolyl, -CH2 -imidazolyl, -CH 2 - pyrazolyl), -OR b10 ( eg, -OH, -OMe, OEt, -O-tetrahydrofuranyl, -O-tetrahydropyran-4-yl, -OCF 3 , -OCHF 2 ), -N(R b10 ) 2 , ( eg, -NH 2 , -NHR b10 , -NHMe, -NMe 2 , -NHCH 2 CF 3 , -NH-oxon-3-yl, -NH-(N-Me-2-oxygen pyrrolidin-3-yl), -NR b10 C(=O)R b10 ( eg, -NHC(=O)Me), -C(=O)N(R b10 ) 2 , ( eg, -C( =O)NH 2 , C(=O)NHMe), -OC(=O)R b10 ( eg, -OC(=O)Me), -S(=O)R b10 ( eg, -SO 2 Me) , -NR b10 S(=O) 2 R b10 ( eg, NHSO 2 Me), and -S(=O) 2 N(R b10 ) 2 ( eg, SO 2 NH 2 , SO 2 NHMe), where each alkyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl are optionally substituted ( eg, with -Me, - Et, -iPr , cyclopropyl, oxo- 3 - yl, -OH , = O, -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C(=O)Me, -N(Me) 2 , -CH2N( CH3 ) 2 , -CH2N ( CH3 ) CH2CH3 , -N( iPr )(Et ) , -N 0, 1, 2, 3, 4, or 5 instance substitutions of ( i Pr)(Me), -N(Et) 2 , -N( CH3 )(Et), -NHC(=O)Me, or combinations thereof ), where: 各Rb10 獨立地選自H、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、-C1 -C6 鹵烷基(例如， -CF3 、-CHF2 、-CH2 CF3 )、經=O之0或1個實例 取代之-C1 -C6 雜烷基(例如， -CH2 CH2 NMe2 、-CH2 C(=O)NMe2 、-CH(CH3 )CH2 NMe2 、-CH(CH3 )C(=O)NMe2 )、C3 -C9 環烷基及經=O、-Me或其組合之0或1個實例取代之3-10員雜環基(例如四氫呋喃-3-基、四氫哌喃-4-基、氧呾-3-基、N-Me-2-側氧基吡咯啶-3-基、哌啶-4-基)。Each R b10 is independently selected from H, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -i Pr, -sec-Bu, -t Bu), -C 1 -C 6 halo Alkyl ( eg, -CF3 , -CHF2, -CH2CF3 ), -C1 - C6 heteroalkyl substituted with 0 or 1 instance of = 0 ( eg, -CH2CH2NMe2 , -CH 2 C(=O)NMe 2 , -CH(CH 3 )CH 2 NMe 2 , -CH(CH 3 )C(=O)NMe 2 ), C 3 -C 9 cycloalkyl and via =O 3-10 membered heterocyclyl (e.g. tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxo-3-yl, N-Me-2 - side oxypyrrolidin-3-yl, piperidin-4-yl). 如請求項1至78中任一項之化合物，其中各Rb10 獨立地選自H、-Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、-CF3 、-CHF2 、-CH2 CF3 、-CH2 CH2 NMe2 、-CH2 C(=O)NMe2 、-CH(CH3 )CH2 NMe2 、-CH(CH3 )C(=O)NMe2 )、四氫呋喃-3-基、四氫哌喃-4-基、氧呾-4-基、N-Me-2-側氧基吡咯啶-3-基及哌啶-4-基。The compound of any one of claims 1 to 78, wherein each R b10 is independently selected from H, -Me, -Et , -Pr, -iPr , -sec -Bu, -tBu, -CF3 , - CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 NMe 2 , -CH 2 C(=O)NMe 2 , -CH(CH 3 )CH 2 NMe 2 , -CH(CH 3 )C(=O) NMe 2 ), tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxypyran-4-yl, N-Me-2-oxypyrrolidin-3-yl and piperidin-4-yl. 如請求項1至75中任一項之化合物，其中各R10 獨立地選自由以下組成之群：-D、=O、-OH、-F、-Cl、-Br、-CN、-Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu、-OMe、-OEt、-CHF2 、-CH2 CF3 、-CF3 、-OCF3 、-OCHF2 、-CH2 OH、-CH(OH)(CH3 )、-CH2 OMe、-C(OH)(CH3 )2 、-CH2 NH2 、-CH(CH3 )(NMe2 )、-CH2 CH(CH3 )(NMe2 )、-CH2 (CH3 )( i Pr)、-NH2 、-NHMe、-NHCH2 CF3 、-NMe2 、環丙基、環丁基、環戊基、環己基、噻唑-2-基、噻唑-5-基、噻吩-2-基、四氫呋喃-3-基、四氫哌喃-4-基、氧呾-3-基、嗎啉-2-基、-CH2 -嗎啉-4-基、-(CH2 )2 -嗎啉-4-基、咪唑-2-基、1H-吡唑-5-基、1H-咪唑-4-基、咪唑并[1,2-a]吡啶-7-基、吡咯啶-1-基、吡咯啶-3-基、哌啶-4-基、哌啶-3-基、哌啶-2-酮-4-基、哌嗪-4-基、哌嗪-4-基、哌嗪-2-酮-5-基、吡啶-4-基、吡啶-3-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、1H-吡唑-5-基、吖呾-3-基、-(CH2 )2 -吡咯啶-1-基、-(CH2 )2 -吡咯啶-2-基、-CH2 -咪唑-1-基、-CH2 -吡唑-1-基、-CH2 -1,2,4-三唑-1-基、-CH2 -環丙基、-O(CH2 )2 NMe2 、-O-四氫呋喃-3-基、-O-四氫哌喃-4-基、-O-(N-Me-2-側氧基吡咯啶-3-基)、-O-(CH2 )2 -吡咯啶-2-基、-O-CH2 -哌啶-4-基、-O-CH2 -氧呾-3- 基、-NCH3 -CH2 -哌啶-4-基、-NH-氧呾-3-基、-NH-(N-Me-2-側氧基吡咯啶-3-基)、十氫-1,6-萘啶-6-基、2-氮雜螺[3.3]庚-6-基、5-氧雜-2,8-二氮雜螺[3.5]壬-8-基、8-氮雜雙環[3.2.1]辛-3-基、2-氮雜雙環[2.2.2]辛-4-基、3-氮雜雙環[3.2.0]庚-6-基、3-氮雜雙環[3.1.1]庚-1-基、3-氮雜雙環[3.1.0]己-6-基、1-氮雜雙環[2.2.1]庚-4-基、3-氮雜雙環[3.2.0]庚-6-基、2-氮雜雙環[2.1.1]己-4-基、2,9-二氮雜螺[5.5]十一烷-9-基、雙環[1.1.1]戊烷-2-基、八氫環戊[c]吡咯-5-基、十氫-1,6-萘啶-6-基、八氫-1H-吡咯并[3,4-c]吡啶-5-基、十氫-2,7-萘啶-2-基、2,9-二氮雜螺[5.5]十一烷-2-基、-NHC(=O)Me、-NHCH2 C(=O)NMe2 、-NHCH(CH3 )C(=O)NMe2 、-C(=O)NH2 、C(=O)NHMe、-OC(=O)Me、-SO2 Me、-NHSO2 Me,-SO2 NH2 and -SO2 NHMe，其中各-OMe、-OEt、-Me、-Et、-Pr、- i Pr、環丙基、環丁基、環戊基、環己基、四氫呋喃-3-基、氧呾-3-基、吡咯啶-1-基、吡咯啶-3-基、哌啶-4-基、哌啶-3-基、哌啶-2-酮-4-基、哌嗪-4-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、噻唑-2-基、噻吩-2-基、-CH2 -環丙基、-CH2 -嗎啉-4-基、-(CH2 )2 -嗎啉-4-基、-嗎啉-2-基、-(CH2 )2 -吡咯啶-1-基、-CH2 -1,2,4-三唑-1-基、-CH2 -咪唑-1-基、咪唑-2-基，-CH2 -吡唑-1-基、-OCH2 -哌啶-4-基、吖呾-3-基、2-氮雜螺[3.3]庚-6-基、2-甲基-5-氧雜-2,8-二氮雜螺[3.5]壬-8-基、8-氮雜雙環[3.2.1]辛-3-基及十氫-1,6-萘啶-6-基；且其中The compound of any one of claims 1 to 75, wherein each R 10 is independently selected from the group consisting of: -D, =O, -OH, -F, -Cl, -Br, -CN, -Me, -Et , -Pr, -iPr , -sec -Bu, -tBu, -OMe, -OEt , -CHF2 , -CH2CF3 , -CF3 , -OCF3 , -OCHF2 , -CH2 OH, -CH(OH)( CH3 ), -CH2OMe, -C(OH)( CH3 ) 2 , -CH2NH2 , -CH( CH3 ) ( NMe2 ) , -CH2CH ( CH3 )( NMe2 ), -CH2 ( CH3 )( iPr ), -NH2 , -NHMe , -NHCH2CF3 , -NMe2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, thiazol-2-yl, thiazol-5-yl, thiophen-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxypyran-3-yl, morpholin-2-yl, - CH 2 -morpholin-4-yl, -(CH 2 ) 2 -morpholin-4-yl, imidazol-2-yl, 1H-pyrazol-5-yl, 1H-imidazol-4-yl, imidazo[ 1,2-a]pyridin-7-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-on-4-yl , piperazin-4-yl, piperazin-4-yl, piperazin-2-one-5-yl, pyridin-4-yl, pyridin-3-yl, pyrazol-1-yl, pyrazol-3-yl base, pyrazol-4-yl, pyrazol-5-yl, 1H-pyrazol-5-yl, acridine-3-yl, -(CH 2 ) 2 -pyrrolidin-1-yl, -(CH 2 ) 2 -pyrrolidin-2-yl, -CH 2 -imidazol-1-yl, -CH 2 -pyrazol-1-yl, -CH 2 -1,2,4-triazol-1-yl, -CH 2 -Cyclopropyl, -O(CH 2 ) 2 NMe 2 , -O-tetrahydrofuran-3-yl, -O-tetrahydropyran-4-yl, -O-(N-Me-2-oxygen pyrrolidin-3-yl), -O-(CH 2 ) 2 -pyrrolidin-2-yl, -O-CH 2 -piperidin-4-yl, -O-CH 2 -oxygen-3-yl, -NCH 3 -CH 2 -piperidin-4-yl, -NH-oxygen-3-yl, -NH-(N-Me-2-oxypyrrolidin-3-yl), decahydro-1, 6-Naphthyridin-6-yl, 2-azaspiro[3.3]hept-6-yl, 5-oxa-2,8-diazaspiro[3.5]nonan-8-yl, 8-azabicyclo [3.2.1]Oct-3-yl, 2-azabicyclo[2.2.2]oct-4-yl, 3-azabicyclo[3.2.0]heptan-6-yl, 3-azabicyclo[3.1 .1]Hept-1-yl, 3-azabicyclo[3. 1.0] Hex-6-yl, 1-azabicyclo[2.2.1]hept-4-yl, 3-azabicyclo[3.2.0]heptan-6-yl, 2-azabicyclo[2.1.1] Hex-4-yl, 2,9-diazaspiro[5.5]undecan-9-yl, bicyclo[1.1.1]pentan-2-yl, octahydrocyclopenta[c]pyrrol-5-yl , decahydro-1,6-naphthyridin-6-yl, octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl, decahydro-2,7-naphthyridin-2-yl, 2 ,9-diazaspiro[5.5]undecan-2-yl, -NHC(=O)Me, -NHCH 2 C(=O)NMe 2 , -NHCH(CH 3 )C(=O)NMe 2 , -C (=O) NH2 , C(=O)NHMe, -OC(=O)Me, -SO2Me , -NHSO2Me , -SO2NH2 and -SO2NHMe , where each -OMe , -OEt, -Me, -Et , -Pr, -iPr, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, oxan-3-yl, pyrrolidine-1- base, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-on-4-yl, piperazin-4-yl, pyrazol-1-yl, pyrazole -3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thien-2-yl, -CH2 -cyclopropyl, -CH2 -morpholin-4-yl, -( CH2 ) 2 -morpholin-4-yl, -morpholin-2-yl, -( CH2 ) 2 -pyrrolidin-1-yl, -CH2-1,2,4 - triazole-1 -yl, -CH 2 -imidazol-1-yl, imidazol-2-yl, -CH 2 -pyrazol-1-yl, -OCH 2 -piperidin-4-yl, acridine-3-yl, 2- Azaspiro[3.3]hept-6-yl, 2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl, 8-azabicyclo[3.2.1]octane -3-yl and decahydro-1,6-naphthyridin-6-yl; and wherein 各R10 可獨立地經以下之0、1、2、3、4或5個實例取代：-Me、-Et、-i Pr、環丙基、氧呾-3-基、-OH、=O、-F、-OMe、-CH2 CH2 F、-CH2 CHF2 、-CH2 CH2 CF3 、-C(=O)Me、-N(Me)2 、-CH2 N(CH3 )2 、-CH2 N(CH3 )CH2 CH3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et)2 、-N(CH3 )(Et)、-NHC(=O)Me或其組合。Each R 10 may be independently substituted with 0, 1, 2, 3, 4 or 5 of the following instances: -Me, -Et, -iPr , cyclopropyl, oxo-3-yl, -OH, =O , -F, -OMe, -CH2CH2F , -CH2CHF2 , -CH2CH2CF3 , -C ( = O)Me, -N(Me )2 , -CH2N ( CH3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -N( i Pr)(Et), -N( i Pr)(Me), -N(Et) 2 , -N(CH 3 )( Et), -NHC(=O)Me, or a combination thereof. 如請求項1至67中任一項之化合物，其中R10 為視情況經取代之3-6員單環雜環基或視情況經取代之6-10員雙環雜環基。The compound of any one of claims 1 to 67, wherein R 10 is an optionally substituted 3-6 membered monocyclic heterocyclyl or an optionally substituted 6-10 membered bicyclic heterocyclyl. 如請求項80之化合物，其中R10 為-D、-Cl、-F、-Me、-CH2 -OH、The compound of claim 80, wherein R 10 is -D, -Cl, -F, -Me, -CH 2 -OH,
Figure 110128222-A0202-13-0023-528
Figure 110128222-A0202-13-0023-528
Figure 110128222-A0202-13-0024-529
Figure 110128222-A0202-13-0024-529
 如請求項1至82中任一項之化合物，其中各R7 獨立地選自H、鹵基(例如， F、Cl)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、-sec -Bu、- t Bu)、5員雜芳基(例如， 吡唑基)、-C1 -C6 鹵烷基(例如， -CF3 、-CHF2 、-CH2 CF3 )、-C1 -C6 羥基烷基(例如， -CH2 OH)、-C3 -C9 環烷基(例如， 環丙基、環丁基、環戊基、環己基)、-ORa7 (例如， -OH、-OMe、-OCHF2 )、-N(Ra7 )2 及-C(=O)N(Ra7 )2 (例如， -C(=O)NH2 、-C(=O)NHMe)。The compound of any one of claims 1 to 82, wherein each R 7 is independently selected from H, halo ( eg, F, Cl), -CN, -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -sec -Bu, -tBu), 5-membered heteroaryl ( eg, pyrazolyl), -C 1 -C 6 haloalkyl ( eg, -CF 3 , - CHF 2 , -CH 2 CF 3 ), -C 1 -C 6 hydroxyalkyl ( eg, -CH 2 OH), -C 3 -C 9 cycloalkyl ( eg, cyclopropyl, cyclobutyl, cyclopentane group, cyclohexyl), -OR a7 ( eg, -OH, -OMe, -OCHF 2 ), -N(R a7 ) 2 and -C(=O)N(R a7 ) 2 ( eg, -C(= O) NH2 , -C(=O)NHMe). 如請求項1至82中任一項之化合物，其中各Ra7 獨立地選自H及-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。The compound of any one of claims 1 to 82, wherein each R a7 is independently selected from H and -C 1 -C 6 alkyl ( eg, -Me, -Et , -Pr, -iPr , -nBu , -t Bu, -sec -Bu, -iso -Bu). 如請求項1至84中任一項之化合物，其中各R7 獨立地選自H及甲基。The compound of any one of claims 1 to 84, wherein each R 7 is independently selected from H and methyl. 如請求項1至84中任一項之化合物，其中各R7 為H。The compound of any one of claims 1 to 84, wherein each R7 is H. 如請求項1至84中任一項之化合物，其中各R7 為甲基。The compound of any one of claims 1 to 84, wherein each R 7 is methyl. 如請求項1至87中任一項之化合物，其中各R8 獨立地選自H、-D、鹵基(例如， -F、-Cl)、-CN、-C1 -C6 烷基(例如， -Me、-Et、-Pr、- i Pr、 -sec -Bu、- t Bu)、-C1 -C6 鹵烷氧基(例如， -OCF3 )、芳基烷基(例如， 苯甲基)、-C(=O)Ra8 (例如， -C(=O)Me、-C(=O)Et,-C(=O)Pr、-C(=O) i Pr)、-N(Ra8 )2 (例如， -NHMe、NH2 、NMe2 )、-NRa8 C(=O)Ra8 (例如， -NHC(=O)Me)、-CH2 C(=O)N(Ra8 )2 (例如， -CH2 C(=O)NH2 )及-ORa8 (例如， -OH、-OMe、-O i Pr)。The compound of any one of claims 1 to 87, wherein each R 8 is independently selected from H, -D, halo ( eg, -F, -Cl), -CN, -C 1 -C 6 alkyl ( For example, -Me, -Et , -Pr, -iPr , -sec -Bu, -tBu), -C1 - C6 haloalkoxy ( for example, -OCF3 ), arylalkyl ( for example, benzyl), -C(=O)R a8 ( for example, -C(=O)Me, -C(=O)Et, -C(=O)Pr, -C(=O) i Pr), -N(R a8 ) 2 ( eg, -NHMe, NH 2 , NMe 2 ), -NR a8 C(=O)R a8 ( eg, -NHC(=O)Me), -CH 2 C(=O) N(R a8 ) 2 ( eg, -CH 2 C(=O)NH 2 ) and -OR a8 ( eg, -OH, -OMe, -O i Pr). 如請求項1至88中任一項之化合物，其中各Ra8 獨立地選自H、-CF3 及-C1 -C6 烷基、(例如， -Me、-Et、-Pr、- i Pr、- n Bu、- t Bu、-sec -Bu、-iso -Bu)。The compound of any one of claims 1 to 88, wherein each R a8 is independently selected from H, -CF 3 and -C 1 -C 6 alkyl, ( eg, -Me, -Et, -Pr, -i Pr, -n Bu, -t Bu, -sec -Bu, -iso -Bu). 如請求項1至89中任一項之化合物，其中各R8 獨立地選自H、-D、-F、-Me,-Et、-sec -Bu、-CN、-OMe、-O i Pr、-OCF3 、苯甲基、-NHC(=O)Me、-NMe2 、-CH2 C(=O)NH2 、-C(=O) i Pr及-OH。The compound of any one of claims 1 to 89, wherein each R is independently selected from H, -D, -F, -Me, -Et , -sec-Bu, -CN, -OMe, -OiPr , -OCF3 , benzyl, -NHC(=O)Me, -NMe2, -CH2C (=O) NH2 , -C (=O) iPr and -OH. 如請求項1至89中任一項之化合物，其中各R8 獨立地選自H、-D、-F、-Me、-Et及-CN。The compound of any one of claims 1 to 89, wherein each R8 is independently selected from H, -D, -F, -Me, -Et and -CN. 如請求項1至89中任一項之化合物，其中各R8 獨立地選自H、-D、-F及-Me。The compound of any one of claims 1 to 89, wherein each R8 is independently selected from H, -D, -F and -Me. 如請求項1至92中任一項之化合物，其中n為0。 The compound of any one of claims 1 to 92, wherein n is 0. 如請求項1至92中任一項之化合物，其中n為1。 The compound of any one of claims 1 to 92, wherein n is 1. 如請求項1至92中任一項之化合物，其中n為2。 The compound of any one of claims 1 to 92, wherein n is 2. 如請求項1至92中任一項之化合物，其中n為3。 The compound of any one of claims 1 to 92, wherein n is 3. 12至92及95至96中任一項之化合物，其中表示為
Figure 110128222-A0202-13-0025-532
之部分選自：The compound of any one of 12 to 92 and 95 to 96, which is expressed as
Figure 110128222-A0202-13-0025-532
part from:
Figure 110128222-A0202-13-0026-533
Figure 110128222-A0202-13-0026-533
 如請求項97之化合物，其中表示為
Figure 110128222-A0202-13-0026-534
之部分選自：The compound of claim 97, which is expressed as
Figure 110128222-A0202-13-0026-534
part from:
Figure 110128222-A0202-13-0026-535
Figure 110128222-A0202-13-0026-535
Figure 110128222-A0202-13-0027-536
Figure 110128222-A0202-13-0027-536
 如請求項97至98中任一項之化合物，其中n為2。 The compound of any one of claims 97 to 98, wherein n is 2. 如請求項97至98中任一項之化合物，其中各R6 及R7 獨立地選自H及-CH3 。The compound of any one of claims 97 to 98, wherein each R 6 and R 7 is independently selected from H and -CH 3 . 如請求項97至98中任一項之化合物，其中R6 為H。The compound of any one of claims 97 to 98, wherein R 6 is H. 如請求項97至98中任一項之化合物，其中R6 為-CH3 。The compound of any one of claims 97 to 98, wherein R 6 is -CH 3 . 如請求項97至101中任一項之化合物，其中R7 為H。The compound of any one of claims 97 to 101, wherein R7 is H. 如請求項97至101中任一項之化合物，其中R7 為-CH3 。The compound of any one of claims 97 to 101, wherein R 7 is -CH 3 . 如請求項1至104中任一項之化合物，其中該化合物選自表1。 The compound of any one of claims 1 to 104, wherein the compound is selected from Table 1. 一種醫藥組成物，其包含如請求項1至105中任一項之化合物及醫藥學上可接受之載劑。 A pharmaceutical composition comprising the compound of any one of claims 1 to 105 and a pharmaceutically acceptable carrier. 如請求項106之醫藥組成物，其進一步包含第二治療劑。 The pharmaceutical composition of claim 106, further comprising a second therapeutic agent. 一種治療有需要之個體之MTAP缺乏及/或MTA累積疾病的方法，其藉由向該個體投與治療有效量之如請求項1至99中任一項之化合物 或如請求項100之醫藥學上可接受之組成物來進行。 A method of treating MTAP deficiency and/or MTA accumulation disease in an individual in need, by administering to the individual a therapeutically effective amount of the compound of any one of claims 1 to 99 Or as in the pharmaceutically acceptable composition of claim 100. 如請求項108之方法，其中該化合物或組成物與第二治療劑組合投與。 The method of claim 108, wherein the compound or composition is administered in combination with a second therapeutic agent. 一種治療有需要之個體之MTAP缺乏及/或MTA累積疾病的方法，其藉由向該個體投與治療有效量之如請求項107之醫藥學上可接受之組成物來進行。 A method of treating a disease of MTAP deficiency and/or MTA accumulation in an individual in need thereof by administering to the individual a therapeutically effective amount of a pharmaceutically acceptable composition of claim 107. 如請求項108至110中任一項之方法，其中該疾病為增殖性疾病。 The method of any one of claims 108 to 110, wherein the disease is a proliferative disease. 如請求項111之方法，其中該疾病為MTAP缺乏及/或MTA累積癌症。 The method of claim 111, wherein the disease is MTAP deficiency and/or MTA accumulating cancer. 如請求項112之方法，其中該癌症為神經膠質母細胞瘤、惡性周邊神經鞘瘤(MPNST)、食道癌(例如， 食道鱗狀細胞癌或食道腺癌)、膀胱癌(例如， 膀胱尿路上皮癌)、胰臟癌(例如， 胰臟腺癌)、間皮瘤、黑素瘤、非小細胞肺癌(NSCLC；例如 ，肺鱗狀或肺腺癌)、星細胞瘤、未分化多形性肉瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、白血病、頭頸癌、胃腺癌、黏液性纖維肉瘤、膽管癌、腦癌、胃癌、腎癌、乳癌、子宮內膜癌、尿路癌、肝癌、軟組織癌、胸膜或大腸癌或肉瘤。The method of claim 112, wherein the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer ( eg, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer ( eg, bladder urethra) skin cancer), pancreatic cancer ( eg, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; eg , lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic Sarcoma, Diffuse Large B-Cell Lymphoma (DLBCL), Leukemia, Head and Neck Cancer, Stomach Adenocarcinoma, Myxofibrosarcoma, Cholangiocarcinoma, Brain Cancer, Stomach Cancer, Kidney Cancer, Breast Cancer, Endometrial Cancer, Urinary Tract Cancer, Liver Cancer , soft tissue cancer, pleural or colorectal cancer or sarcoma. 一種治療有需要之個體之癌症的方法，其包含以下步驟： A method of treating cancer in an individual in need thereof, comprising the steps of: a)評定自該個體獲得之測試樣品中MTAP及/或MTA之水準，其中該MTA水準可直接(例如， 藉由ELISA或LC-MS/MS)或間接(例如， 藉由SDMA修飾之蛋白質ELISA或IHC或藉由RNA剪接)評定；a) Assessing the level of MTAP and/or MTA in a test sample obtained from the individual, wherein the MTA level can be directly ( eg, by ELISA or LC-MS/MS) or indirectly ( eg, by SDMA-modified protein ELISA) or IHC or by RNA splicing) assessment; b)將該測試樣品與參考物相比較，其中該測試樣品中與該參考物相比之MTAP缺乏及/或MTA累積表明該個體之該癌症將對以PRMT5抑制劑之治療性治療有反應；及 b) comparing the test sample to a reference, wherein MTAP deficiency and/or MTA accumulation in the test sample compared to the reference indicates that the cancer in the individual will respond to therapeutic treatment with a PRMT5 inhibitor; and c)向步驟b)中鑑別之該個體投與治療有效量之如請求項1至99中任一項之化合物或如請求項100或101之組成物。 c) administering to the individual identified in step b) a therapeutically effective amount of a compound as claimed in any one of claims 1 to 99 or a composition as claimed in claim 100 or 101.
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